cardiovascular-agents and Cardiovascular-Diseases

Cardiovascular diseases (CVDs) are the leading cause of mortality globally. Wald and Law proposed the idea of a "polypill"; a fixed dose combination therapy (FDC) in the form of a single pill to curb the CVD epidemic. Such a drug would include the combination of a broad spectrum of drugs including cholesterol lowering drugs, antihypertensive drugs, antiplatelet drugs, anticoagulation drugs, and antiarrhythmic drugs, which are frequently integrated to combat specific CVDs. This "polypill" holds the potential to pose several advantages like increased compliance, improved quality of life, risk factor control, psychological relief, and cost effectiveness along with minimal side effects. Several trials (like TIPS, UMPIRE, PolyIran, etc.) have tested different treatment strategies to test the hypothesis of Wald and Law. Unlike the past, physicians are now highly aware of this new strategy. The future of polypill in the management of CVD lies in a strategy where polypills are treated supplementary to the already existing preventive care, which includes lifestyle modifications and efforts to reduce tobacco use.

Topics: Antihypertensive Agents; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Humans; Platelet Aggregation Inhibitors; Quality of Life

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans

Advances in pharmacogenomics have paved the way for personalized medicine. The purpose of this review is to summarize the background, rationale, and evidence for pharmacogenomics in cardiovascular medicine.. Randomized clinical trials have supported the role of a genotype-guided approach for antiplatelet therapy in patients with coronary artery disease undergoing percutaneous coronary interventions. Additionally, there is increasing evidence supporting the association of certain genetic variants and risk of statin associated muscle symptoms. Furthermore, germline genetic variation is being used as a biomarker to target patients with specific therapy.. Pharmacogenomics has the potential to improve patient care by providing the right drug to the right patient and could guide the identification of novel drug therapies for cardiovascular disease.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Disease; Humans; Pharmacogenetics; Precision Medicine

Prevention and effective treatment of cardiovascular disease are progressive issues that grow in tandem with the average age of the world population. Over recent decades, the potential role of artificial intelligence in cardiovascular medicine has been increasingly recognized because of the incredible amount of real-world data (RWD) regarding patient health status and healthcare delivery that can be collated from a variety of sources wherein patient information is routinely collected, including patient registries, clinical case reports, reimbursement claims and billing reports, medical devices, and electronic health records. Like any other (health) data, RWD can be analysed in accordance with high-quality research methods, and its analysis can deliver valuable patient-centric insights complementing the information obtained from conventional clinical trials. Artificial intelligence application on RWD has the potential to detect a patient's health trajectory leading to personalized medicine and tailored treatment. This article reviews the benefits of artificial intelligence in cardiovascular prevention and management, focusing on diagnostic and therapeutic improvements without neglecting the limitations of this new scientific approach.

Topics: Artificial Intelligence; Cardiovascular Agents; Cardiovascular Diseases; Humans; Precision Medicine; Research Design

Cardiovascular disease is still the major cause of death worldwide. Beside the elevated blood pressure, a major modifiable risk factor is the elevated low-density lipoprotein (LDL) cholesterol. Although both risk factors are well manageable, therapeutic control remains poor with low adherence to medication being a major cause of insufficient treatment success. One solution to overcome this issue is the polypill concept, i.e. a combination of different drugs in one tablet. This not only increases adherence but also significantly improves patients' prognosis by reducing cardiovascular events.. This review focuses on current evidence published in randomized control trials in primary and secondary prevention. A major focus is on the recently published SECURE trial dealing with the polypill in secondary prevention.. Most trials dealing with the polypill concept focus on the control of risk factors such as blood pressure and LDL cholesterol while lacking a prognostic benefit in the form of a reduction in cardiovascular events. Recent trials such as the HOPE‑3, PolyIran and TIPS‑3 trials have shown a prognostic improvement for the polypill in primary prevention. In secondary prevention there has been a lack of prognostic benefit for the polypill to date. The recently published SECURE trial closed this gap by showing a significant reduction in major adverse cardiovascular events in post-infarct patients and also showing a reduction in cardiovascular death by 33%.. The concept of the polypill has evolved from a comfort method for patients aimed at facilitating adherence to an innovative therapeutic concept with a proven prognostic advantage compared to current treatment practice by reducing cardiovascular events and mortality. Therefore, it is time to implement the concept of the polypill in primary and secondary prevention to improve patients' prognosis and reduce the burden of cardiovascular disease worldwide.. HINTERGRUND: Herz-Kreislauf-Erkrankungen sind nach wie vor die häufigste Todesursache weltweit. Neben einem erhöhten Blutdruck ist ein weiterer modifizierbarer Risikofaktor ein erhöhtes Low-density-Lipoprotein-Cholesterin. Obwohl beides gut medikamentös kontrollierbar ist, bleibt die Kontrolle bisher mangelhaft. Eine wesentliche Ursache ist eine unzureichende Adhärenz zur Medikation. Eine Lösung hierfür ist das Konzept der „Polypill“, also die Kombination mehrerer Wirkstoffe in einer einzelnen Tablette. Hierdurch wird nicht nur die Therapieadhärenz verbessert, sondern auch eine Verringerung kardiovaskulärer Ereignisse und eine Verbesserung der Prognose der Patienten erreicht. ZIEL DER ÜBERSICHT: Diese Übersichtsarbeit fasst die aktuellen Evidenzen aus randomisierten klinischen Studien in der Primär- und Sekundärprävention zusammen. Ein wesentlicher Fokus liegt auf der aktuell publizierten SECURE-Studie, die die Wirksamkeit der „Polypill“ in der Sekundärprävention untersucht.. Viele Studien zur „Polypill“ beschäftigen sich mit der Kontrolle der Risikofaktoren und der Verbesserung der Therapieadhärenz, ohne jedoch einen prognostischen Vorteil zu adressieren. Neuere Studien wie HOPE‑3, PolyIran und TIPS‑3 konnten in der Primärprävention einen prognostischen Vorteil aufzeigen. In der Sekundärprävention war dies bis jetzt noch nicht geschehen. Diese Lücke wurde nun durch die SECURE-Studie geschlossen. Hier wurde bei Patienten nach Infarkt nicht nur eine signifikante Reduktion schwerwiegender kardiovaskulärer Ereignisse, sondern auch eine Reduktion kardiovaskulärer Todesfälle durch die „Polypill“ nachgewiesen.. Das Konzept der „Polypill“ hat sich von einer Komfortmaßnahme – einer Erleichterung der Medikamenteneinnahme für die Patienten – weiterentwickelt hin zu einem innovativen Therapiekonzept mit nachgewiesenem prognostischem Vorteil in Form einer Reduktion schwerwiegender Ereignisse und Todesfälle. Es ist an der Zeit, das Konzept der „Polypill“ breit einzusetzen, um die Bürde der Herz-Kreislauf-Erkrankungen weltweit zur verringern.

Topics: Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Humans; Secondary Prevention

Higher medication adherence reduces the risk of new cardiovascular events. However, there are individual and health system barriers that lead to lower adherence. The polypill has demonstrated benefits in cardiovascular morbidity and mortality mainly driven by an increase in adherence. We aim to evaluate the impact of the polypill on adherence to cardiovascular medication, its efficacy and safety in cardiovascular disease (CVD) prevention.. A systematic review following PRISMA guidelines was conducted. Databases were searched from January 2003 to December 2022. We included randomized, pragmatic, or real-world clinical trials and observational studies. The primary outcome was medication adherence, secondary outcomes were efficacy in cardiovascular disease in primary and secondary prevention and safety.. From the 490 publications screened, 13 met the inclusion criteria and were incorporated into a comparative table Of those included, 70% were randomized controlled trials (RCTs) and 53.8% focused on secondary prevention. Most of the studies received a high and moderate quality rating. Self-report, pill counting and, the Morisky scale were the most frequent methods to evaluate adherence (84.6%). Compared with standard medication, the polypill improved overall medication adherence by 13%, with percentages ranging from 7.6% to 34.9%. Moreover, a potential benefit was also observed in reducing Major Adverse Cardiovascular Events (MACE), particularly in secondary prevention studies, with hazard ratios ranged between 0.43 to 0.76. Compared to standard care, the profile of side effects was similar.. The polypill is an effective, safe, and practical strategy to improve adherence in people at risk of CVD. Although there is a demonstrated benefit in reducing MACE, predominantly in secondary prevention, there are still gaps in its efficacy in primary prevention and reducing total mortality. Therefore, the importance of obtaining long-term results of the polypill effect and how this strategy can be implemented in real practice.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Databases, Factual; Humans; Medication Adherence; Secondary Prevention

Cardiovascular diseases (CVD) are among the leading causes of death worldwide. Many lines of evidence suggest that the disturbances in circadian rhythm are responsible for the development of CVDs; however, circadian misalignment is not yet a treatable trait in clinical practice. The circadian rhythm is controlled by the central clock located in the suprachiasmatic nucleus and clock genes (molecular clock) located in all cells. Dyslipidaemia and vascular inflammation are two hallmarks of atherosclerosis and numerous experimental studies conclude that they are under direct influence by both central and molecular clocks. This review will summarise the results of experimental studies on lipid metabolism, vascular inflammation and circadian rhythm, and translate them into the pathophysiology of atherosclerosis and cardiovascular disease. We discuss the effect of time-respected administration of medications in cardiovascular medicine. We review the evidence on the effect of bright light and melatonin on cardiovascular health, lipid metabolism and vascular inflammation. Finally, we suggest an agenda for future research and recommend on clinical practice.

Topics: Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Circadian Rhythm; Dyslipidemias; Humans; Inflammation

Cardiovascular disease represents a source of major health problems worldwide, and although medical and technical advances have been achieved, they are still associated with high morbidity and mortality rates. Personalized medicine would benefit from novel tools to better predict individual prognosis and outcomes after intervention. Artificial intelligence (AI) has brought new insights to cardiovascular medicine, especially with the use of machine learning techniques that allow the identification of hidden patterns and complex associations in health data without any a priori assumptions. This review provides an overview on the use of artificial intelligence-based prediction models in vascular diseases, specifically focusing on aortic aneurysm, lower extremity arterial disease, and carotid stenosis. Potential benefits include the development of precision medicine in patients with vascular diseases. In addition, the main challenges that remain to be overcome to integrate artificial intelligence-based predictive models in clinical practice are discussed.

Topics: Artificial Intelligence; Cardiovascular Agents; Cardiovascular Diseases; Carotid Stenosis; Humans; Machine Learning

Topics: Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Concept Formation; Drug Combinations; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Medication Adherence; Treatment Outcome

Advances in pharmacogenomics have paved the way for personalized medicine. Cardiovascular diseases still represent the leading cause of mortality in the world. The aim of this review is to summarize the background, rationale, and evidence of pharmacogenomics in cardiovascular medicine, in particular, the use of antiplatelet drugs, anticoagulants, and drugs used for the treatment of dyslipidemia.. Randomized clinical trials have supported the role of a genotype-guided approach for antiplatelet therapy in patients with coronary heart disease undergoing percutaneous coronary interventions. Numerous studies demonstrate how the risk of ineffectiveness of new oral anticoagulants and vitamin K anticoagulants is linked to various genetic polymorphisms. Furthermore, there is growing evidence to support the association of some genetic variants and poor adherence to statin therapy, for example, due to the appearance of muscular symptoms. There is evidence for resistance to some drugs for the treatment of dyslipidemia, such as anti-PCSK9.. Pharmacogenomics has the potential to improve patient care by providing the right drug to the right patient and could guide the identification of new drug therapies for cardiovascular disease. This is very important in cardiovascular diseases, which have high morbidity and mortality. The improvement in therapy could be reflected in the reduction of healthcare costs and patient mortality.

Topics: Anticoagulants; Cardiovascular Agents; Cardiovascular Diseases; Dyslipidemias; Humans; Pharmacogenetics

This study aimed to investigate the association between cardiovascular drugs and depression/anxiety in patients with cardiovascular disease (CVD). This meta-analysis was registered in PROSPERO (International Prospective Register of Systematic Reviews; CRD42020197839) and conducted in accordance with the MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines. The PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP databases were systematically searched to identify all available studies on this topic. Random-effects multivariate meta-regression was performed to investigate the sources of study heterogeneity. Review Manager version 5.3 and Stata 12.0 were used for data analyses. This meta-analysis included 54 studies with a total number of 212,640 patients. Overall, in patients with CVD, aspirin (odds ratio [OR]:0.91, 95% confidence interval [CI]:0.86-0.96, P = 0.02) was associated with a lower risk of depression, while calcium channel blockers (CCB) (OR:1.21, 95%CI:1.05-1.38, P = 0.008), diuretics (OR:1.34, 95%CI:1.14-1.58, P = 0.0005), and nitrate esters (OR:1.32, 95%CI:1.08-1.61, P = 0.006) were associated with a higher risk of depression, additionally, statin (OR:0.79, 95%CI:0.71-0.88, P < 0.0001) was associated with a lower risk of anxiety, but diuretics (OR:1.39, 95%CI:1.26-1.52, P < 0.00001) was associated with a higher risk of anxiety. Subgroup analysis presented that, in patients with hypertension, β-blockers were associated with a higher risk of depression (OR:1.45, 95%CI:1.26-1.67, P < 0.00001); in patients with coronary artery disease (CAD), statin (OR:0.77, 95%CI:0.59-0.99, P = 0.04), and aspirin (OR:0.85, 95%CI:0.75-0.97, P = 0.02) were associated with a lower risk of depression, while CCB (OR:1.32, 95%CI:1.15-1.51, P < 0.0001) and diuretics (OR:1.36, 95%CI:1.12-1.64, P = 0.002) were associated with a higher risk of depression, additionally, diuretics was associated with a higher risk of anxiety (OR:1.41, 95%CI:1.28-1.55, P < 0.00001); in patients with heart failure, nitrate esters (OR:1.93, 95%CI:1.19-3.13, P = 0.007), and diuretics (OR:1.58, 95%CI: 1.02-2.43, P = 0.04) were associated with a higher risk of depression. The use of cardiovascular drugs should be considered when evaluating depression or anxiety in patients with CVD to improve the care and treatment of these patients.

Topics: Animals; Anxiety; Cardiovascular Agents; Cardiovascular Diseases; Depression; Humans

In the current paper, we review recently published studies that are helping us to understand how the treatment landscape for glucagon-like peptiide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors is moving forward. We have also included relevant articles related to cardiovascular disease prevention in the setting of obesity, atherogenic dyslipidaemia and chronic kidney disease.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

The notion that poikilotherms do not suffer from cardiovascular conditions is being increasingly challenged as diagnostic tools used in companion animal practice are applied to reptiles. However, the cause, diagnosis, and treatment of cardiac conditions in reptiles is difficult because of the scarcity of published literature. Auscultation, electrocardiography, radiography, and ultrasonography are helpful diagnostic techniques in herpetologic practice. Although the pharmacokinetics and pharmacodynamics of cardiovascular drugs are poorly understood in these animals, basic principles remain applicable; these include pharmacologic and nonpharmacologic interventions. Further research is needed to establish species-specific cardiac reference ranges and evidence-based treatment options.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Heart Diseases; Reptiles

Cardiovascular disease, including congestive heart failure, pericardial disease, and atherosclerosis, is becoming increasingly better recognized in companion birds. A wide range of medications is available to treat these conditions, including diuretics, vasodilators, positive and negative inotropes, antiarrhythmic agents, and pentoxifylline. This review systematically discusses each of these drug classes and their potential applications in avian species. Although treatment approaches remain largely empirical and extrapolated from small animal and human medicine, the management strategies presented here have the potential to both maintain quality of life and extend survival time for the avian cardiac patient.

Topics: Animals; Birds; Cardiovascular Agents; Cardiovascular Diseases; Heart Failure; Quality of Life

Awareness of racial/ethnic disparities represents a key challenge for healthcare systems that attempt to provide effective healthcare and to reduce existing inequalities in the use of and adherence to guideline-recommended cardiovascular drugs to improve clinical outcomes for cardiovascular disease (CVD). In this review, we describe important racial/ethnic differences between and within ethnic groups in the prevalence, risk factors, haemostatic factors, anti-inflammatory and endothelial markers, recurrence, and outcomes of CVD. We discuss important differences in the selection, doses, and response [efficacy and adverse drug reactions (ADRs)] in ethnically diverse patients treated with antithrombotics or lipid-lowering drugs. Differences in drug response are mainly related to racial/ethnic differences in the frequency of polymorphisms in genes encoding drug-metabolizing enzymes (DMEs) and drug transporters. These polymorphisms markedly influence the pharmacokinetics, dose requirements, and safety of warfarin, clopidogrel, and statins. This review aims to support a better understanding of the genetic differences between and among populations to identify patients who may experience an ADR or a lack of drug response, thus optimizing therapy and improving outcomes. The greater the understanding of the differences in the genetic variants of DMEs and transporters that determine the differences in the exposure, efficacy, and safety of cardiovascular drugs between races/ethnicities, the greater the probability that personalized medicine will become a reality.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clopidogrel; Coronary Artery Disease; Fibrinolytic Agents; Hemostatics; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imidazoles; Lipids; Organosilicon Compounds; Warfarin

In this article, authors report an inclusive discussion about the combinatorial approach for the treatment of cardiovascular diseases (CVDs) and for counteracting the cardiovascular risk factors. The mentioned strategy was demonstrated to be useful for improving the efficacy of pharmacological treatments and in CVDs showed superior efficacy with respect to the classical monotherapeutic approach.. According to this topic, authors analyzed the combinatorial treatments that are available on the market, highlighting clinical studies that demonstrated the efficacy of combinatorial drug strategies to cure CVDs and related risk factors. Furthermore, the review gives an outlook on the future perspective of this therapeutic option, highlighting novel drug targets and disease models that could help the future cardiovascular drug discovery.. The use of specifically designed and increasingly rational and effective drug combination therapies can therefore be considered the evolution of polypharmacy in cardiometabolic and CVDs. This approach can allow to intervene on multiple etiopathogenetic mechanisms of the disease or to act simultaneously on different pathologies/risk factors, using the combinations most suitable from a pharmacodynamic, pharmacokinetic, and toxicological perspective, thus finding the most appropriate therapeutic option.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Discovery; Humans; Risk Factors

Cardiovascular medications are vital for the secondary prevention of coronary arterial disease (CAD). However, the effect of cardiovascular medication may depend on the optimal adherence of the patients. This meta-analysis aims to determine the magnitude of adherence to vascular medications that influences the absolute and relative risks (RRs) of mortality in patients with CAD in real-world settings.. The Cochrane Library, PubMed, and EMBASE databases were searched through March 1, 2022. Prospective studies reporting association as RR and 95% confidence interval between cardiovascular medication adherence and any cardiovascular events and/or all-cause mortality in patients with CAD were included. A one-stage robust error meta-regression method was used to summarize the dose-specific relationships.. Evidence from the real word showed poor adherence to vascular medications contributes to a considerable proportion of all cardiovascular disease events and mortality in patients with CAD.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Disease; Humans; Prospective Studies

During the past few years, several innovative treatments for noncommunicable chronic disease have become available, including SGLT2i (sodium-glucose cotransporter-2 inhibitors), GLP-1a (glucagon-like-peptide 1 agonists), ARNI (angiotensin receptor-neprilysin inhibitors), and finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist. Each of these medications improves clinically relevant outcomes when added to existing therapies, and the indications for their use are rapidly expanding. Because existing drug regimens are already complex and costly, ensuring that society derives the maximal benefit from these new agents represents a major challenge. This Primer discusses how society can meet this challenge, which we address in terms of 5 principles: maximizing benefit, minimizing harm, optimizing uptake, increasing value for money, and ensuring equitable access. The Primer is most relevant for stakeholders in high-income countries, but the principles are broadly applicable to stakeholders in other settings, including low- and middle-income countries. We have focused the discussion on SGLT-2i, but the 5 principles herein could be used with reference to ARNI, finerenone, or any other health product.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Glucagon-Like Peptide-1 Receptor; Humans; Sodium-Glucose Transporter 2 Inhibitors

Lipidomics has shaped our knowledge of how lipids play a central role in cardiovascular diseases (CVD), whereas there is a lack of a summary of existing research findings. This study performed a bibliometric analysis of lipidomics research in cardiovascular medicine to reveal the core countries, institutions, key researchers, important references, major journals, research hotspots and frontiers in this field. From 2012 to 2021, a total of 761 articles were obtained from the Web of Science Core Collection database. There is a steady increase of publications yearly. The United States and China are on the top of the list regarding article output. The institutions with the most publications were the Baker Heart and Diabetes Institute, the Chinese Academy of Sciences and Harvard Medical School. Peter J Meikle was both the most published and most co-cited author. The major journal in this field is Journal of lipid research. Keyword co-occurrence analysis indicated that coronary heart disease, mass spectrometry, risk, fatty acid, and insulin resistance have become hot topics in this field and keyword burst detection suggests that metabolomics, activation, liver, low density lipoprotein are the frontiers of research in recent years. Collectively, lipidomics in CVD is still in its infancy with a steady increase yearly. More in-depth studies in this area are warranted in the future.

Topics: Bibliometrics; Cardiovascular Agents; Cardiovascular Diseases; Humans; Lipidomics; Metabolomics

Manifestations of cardiovascular diseases (CVDs) in a patient or a population differ based on inherent biological makeup, lifestyle, and exposure to environmental risk factors. These variables mean that therapeutic interventions may not provide the same benefit to every patient. In the context of CVDs, human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer an opportunity to model CVDs in a patient-specific manner. From a pharmacological perspective, iPSC-CM models can serve as go/no-go tests to evaluate drug safety. To develop personalized therapies for early diagnosis and treatment, human-relevant disease models are essential. Hence, to implement and leverage the utility of iPSC-CMs for large-scale treatment or drug discovery, it is critical to (i) carefully evaluate the relevant limitations of iPSC-CM differentiations, (ii) establish quality standards for defining the state of cell maturity, and (iii) employ techniques that allow scalability and throughput with minimal batch-to-batch variability. In this review, we briefly describe progress made with iPSC-CMs in disease modelling and pharmacological testing, as well as current iPSC-CM maturation techniques. Finally, we discuss current platforms for large-scale manufacturing of iPSC-CMs that will enable high-throughput drug screening applications.

Topics: Biomedical Research; Cardiology; Cardiotoxicity; Cardiovascular Agents; Cardiovascular Diseases; Cell Culture Techniques, Three Dimensional; Cell Differentiation; Cell Proliferation; Clinical Decision-Making; Drug Discovery; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Phenotype; Risk Assessment; Toxicity Tests

Mammalian models including non-human primates, pigs and rodents have been used extensively to study the mechanisms of cardiovascular disease. However, there is an increasing desire for alternative model systems that provide excellent scientific value while replacing or reducing the use of mammals. Here, we review the use of zebrafish, Danio rerio, to study cardiovascular development and disease. The anatomy and physiology of zebrafish and mammalian cardiovascular systems are compared, and we describe the use of zebrafish models in studying the mechanisms of cardiac (e.g. congenital heart defects, cardiomyopathy, conduction disorders and regeneration) and vascular (endothelial dysfunction and atherosclerosis, lipid metabolism, vascular ageing, neurovascular physiology and stroke) pathologies. We also review the use of zebrafish for studying pharmacological responses to cardiovascular drugs and describe several features of zebrafish that make them a compelling model for in vivo screening of compounds for the treatment cardiovascular disease. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.

Topics: Aging; Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Mammals; Stroke; Swine; Zebrafish

Sexual health has a fundamental role in overall health and well-being, and a healthy and dynamic sex life can make an important contribution to a good quality of life. Sexual dysfunction, and especially erectile dysfunction (ED) in men, is highly prevalent in patients with cardiovascular disease (CVD). CVD and ED have shared risk factors and pathophysiological links, such as endothelial dysfunction, inflammation and low plasma testosterone levels. ED has been shown to be an independent and early harbinger of future CVD events, providing an important window to initiate preventive measures. Therefore, screening and diagnosing ED is essential for the primary and secondary prevention of CVD because the assessment of ED offers an easy and low-cost prognostic tool that is an alternative to other investigational cardiovascular biomarkers. Moreover, ED is a major contributing factor to the discontinuation of, or poor adherence to, cardiovascular therapy. Cardiovascular drugs have divergent effects on erectile function, with diuretics and β-blockers having the worst profiles, and renin-angiotensin-aldosterone system inhibitors and nebivolol having the best profiles. Pharmacological treatment of ED has an equivocal effect on the risk of CVD, suggesting a complex interaction between ED and drugs for CVD. In this Review, we discuss how sexual function could be incorporated into the patient history taken by physicians treating individuals with CVD, not merely as part of the diagnostic work-up but as a means to pursue tangible and essential benefits in quality of life and cardiovascular outcomes.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Erectile Dysfunction; Humans; Male; Risk Factors

Prevention of cardiovascular events and regression of atherosclerotic changes are the primary aims of preventive cardiovascular medicine. Arterial thrombosis is caused by endothelial dysfunction, which disrupts vascular haemostasis. Glucagon-like peptide 1 (GLP-1) receptor agonists have been initially used as glucose lowering agents, but over time have been used for other indications due to their cardiorenal benefit, as well as their benefit in the regression of atherosclerosis process. The aim of this paper is to present the benefits of GLP-1 receptor agonists in the prevention of atherosclerotic changes, in the preservation of brain vascular function, and to show the possible role in the treatment of neurodegenerative diseases.

Topics: Atherosclerosis; Brain; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans

Stevia rebaudiana Bertoni is a native plant to Paraguay. The extracts have been used as a famous sweetening agent, and the bioactive components derived from stevia possess a broad spectrum of therapeutical potential for various illnesses. Among its medicinal benefits are anti-hypertensive, anti-tumorigenic, anti-diabetic, and anti-hyperlipidemia. Statins (3-hydro-3-methylglutaryl-coenzyme A reductase inhibitor) are a class of drugs used to treat atherosclerosis. Statins are explicitly targeting the HMG-CoA reductase, an enzyme in the rate-limiting step of cholesterol biosynthesis. Despite being widely used in regulating plasma cholesterol levels, the adverse effects of the drug are a significant concern among clinicians and patients. Hence, steviol glycosides derived from stevia have been proposed as an alternative in replacing statins. Diterpene glycosides from stevia, such as stevioside and rebaudioside A have been evaluated for their efficacy in alleviating cholesterol levels. These glycosides are a potential candidate in treating and preventing atherosclerosis provoked by circulating lipid retention in the sub-endothelial lining of the artery. The present review is an effort to integrate the pathogenesis of atherosclerosis, involvement of lipid droplets biogenesis and its associated proteins in atherogenesis, current approaches to treat atherosclerosis, and pharmacological potential of stevia in treating the disease.

Topics: Animals; Atherosclerosis; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Dyslipidemias; Heart Disease Risk Factors; Humans; Hypolipidemic Agents; Lipid Droplets; Lipids; Plant Extracts; Risk Assessment; Stevia; Treatment Outcome

Cardiovascular diseases are associated with an increased risk of depression, but it remains unclear whether treatment with cardiovascular agents decreases or increases this risk. The effects of drugs on individual usage are also often unknown. This review aimed to examine the correlation between depression and common cardiovascular drugs, develop more potent interventions for depression in cardiovascular patients, and further research on the bio-behavioural mechanisms linking cardiovascular drugs to depression.. The data in this review were obtained from articles included in PubMed, EMBASE, and Web of Science.. Clinical trials, observational studies, review literature, and guidelines about depression and cardiovascular drugs were selected for the article.. We systematically investigated whether the seven most used cardiovascular drugs were associated with altered risk of incident depression in this literature review. Statins have been proven to have antidepressant effects. Some studies believe angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARB) can exert an antidepressant influence by acting on the renin-angiotensin system, but further clinical trials are needed to confirm this. Beta-blockers have previously been associated with depression, but the current study found no significant association between beta blockers and the risk of depression. Aspirin may have antidepressant effects by suppressing the immune response, but its role as an antidepressant remains controversial. calcium channel blockers (CCBs) can regulate nerve signal transduction by adjusting calcium channels, but whether this effect is beneficial or harmful to depression remains unclear. Finally, some cases have reported that nitrates and diuretics are associated with depression, but the current clinical evidence is insufficient.. Statins have been proven to have antidepressant effect, and the antidepressant effects of ACEIs/ARB and aspirin are still controversial. CCBs are associated with depression, but it is unclear whether it is beneficial or harmful. No association has been found with β-blockers, diuretics, and nitrates.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Depression; Humans; Hypertension; Renin-Angiotensin System

Nitroxyl (HNO), the 1 electron-reduced and protonated form of nitric oxide (NO•), has emerged as a nitrogen oxide with a suite of vasoprotective properties and therapeutic advantages over its redox sibling. Although HNO has garnered much attention due to its cardioprotective actions in heart failure, its ability to modulate vascular function, without the limitations of tolerance development and NO• resistance, is desirable in the treatment of vascular disease. HNO serves as a potent vasodilator and antiaggregatory agent and has an ability to limit vascular inflammation and reactive oxygen species generation. In addition, its resistance to scavenging by reactive oxygen species and ability to target distinct vascular signaling pathways (Kv, KATP, and calcitonin gene-related peptide) contribute to its preserved efficacy in hypertension, diabetes, and hypercholesterolemia. In this review, the vasoprotective actions of HNO will be compared with those of NO•, and the therapeutic utility of HNO donors in the treatment of angina, acute cardiovascular emergencies, and chronic vascular disease are discussed.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Endothelial Cells; Endothelium, Vascular; Humans; Nitrogen Oxides; Platelet Aggregation Inhibitors; Signal Transduction; Vasodilator Agents

Bone marrow-derived hematopoietic stem/progenitor cells are vasculogenic and play an important role in endothelial health and vascular homeostasis by participating in postnatal vasculogenesis. Progenitor cells are mobilized from bone marrow niches in response to remote ischemic injury and migrate to the areas of damage and stimulate revascularization largely by paracrine activation of angiogenic functions in the peri-ischemic vasculature. This innate vasoprotective mechanism is impaired in certain chronic clinical conditions, which leads to the development of cardiovascular complications. Members of the renin-angiotensin system-angiotensin-converting enzymes (ACEs) ACE and ACE2, angiotensin II (Ang II), Ang-(1-7), and receptors AT1 and Mas-are expressed in vasculogenic progenitor cells derived from humans and rodents. Ang-(1-7), generated by ACE2, is known to produce cardiovascular protective effects by acting on Mas receptor and is considered as a counter-regulatory mechanism to the detrimental effects of Ang II. Evidence has now been accumulating in support of the activation of the ACE2/Ang-(1-7)/Mas receptor pathway by pharmacologic or molecular maneuvers, which stimulates mobilization of progenitor cells from bone marrow, migration to areas of vascular damage, and revascularization of ischemic areas in pathologic conditions. This minireview summarizes recent studies that have enhanced our understanding of the physiology and pharmacology of vasoprotective axis in bone marrow-derived progenitor cells in health and disease. SIGNIFICANCE STATEMENT: Hematopoietic stem progenitor cells (HSPCs) stimulate revascularization of ischemic areas. However, the reparative potential is diminished in certain chronic clinical conditions, leading to the development of cardiovascular diseases. ACE2 and Mas receptor are key members of the alternative axis of the renin-angiotensin system and are expressed in HSPCs. Accumulating evidence points to activation of ACE2 or Mas receptor as a promising approach for restoring the reparative potential, thereby preventing the development of ischemic vascular diseases.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Hematopoietic Stem Cells; Humans; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Signal Transduction; Stem Cells

Major depressive disorder (MDD) and anxiety disorders (AD) are both highly prevalent among individuals with arrhythmia, ischemic heart disease, heart failure, hypertension, and dyslipidemia. There should be increased support for MDD and AD diagnosis and treatment in individuals with cardiac diseases, because treatment rates have been low. However, cardiac-psychiatric drug interaction can make pharmacologic treatment challenging.. The objective of the present systematic review was to investigate cardiac-psychiatric drug interactions in three different widely used pharmacological databases (Micromedex, Up to Date, and ClinicalKey).. Among 4914 cardiac-psychiatric drug combinations, 293 significant interactions were found (6.0%). When a problematic interaction is detected, it may be easier to find an alternative cardiac medication (32.6% presented some interaction) than a psychiatric one (76.9%). Antiarrhythmics are the major class of concern. The most common problems produced by these interactions are related to cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest), increased exposure of cytochrome P450 2D6 (CYP2D6) substrates, or reduced renal clearance of organic cation transporter 2 (OCT2) substrates and include hypertensive crisis, increased risk of bleeding, myopathy, and/or rhabdomyolysis.. Unfortunately, there is considerable inconsistency among the databases searched, such that a clinician's discretion and clinical experience remain invaluable tools for the management of patients with comorbidities present in psychiatric and cardiac disorders. The possibility of an interaction should be considered. With a multidisciplinary approach, particularly involving a pharmacist, the prescriber should be alerted to the possibility of an interaction. MDD and AD pharmacologic treatment in cardiac patients could be implemented safely both by cardiologists and psychiatrists.. PROSPERO Systematic Review Registration Number: CRD42018100424.

Topics: Antipsychotic Agents; Cardiovascular Agents; Cardiovascular Diseases; Cytochrome P-450 CYP2D6; Databases, Pharmaceutical; Depressive Disorder, Major; Drug Interactions; Humans; Metabolic Clearance Rate; Organic Cation Transporter 2

The oral application of drugs is the most popular route through which the systemic effect can be achieved. Nevertheless, oral administration is limited by difficulties related to the physicochemical properties of the drug molecule, including low aqueous solubility, instability, low permeability, and rapid metabolism, all of which result in low and irregular oral bioavailability.. The enhancement of oral bioavailability of drug molecules with such properties could lead to extreme complications in drug preparations. Oral lipid-based nanoparticles seem to possess extensive advantages due to their ability to increase the solubility, simplifying intestinal absorption and decrease or eradicate the effect of food on the absorption of low soluble, lipophilic drugs and therefore improving the oral bioavailability.. The present review provides a summary of the general theory of lipid-based nanoparticles, their preparation methods, as well as their oral applications. Moreover, oral drug delivery challenges are discussed.. According to this review, the most frequent types of lipid-based nanoparticle, the solid lipid nanoparticles and nanostructured lipid carriers are potent oral carriers due to their ability to penetrate the oral drug adsorption barriers. Moreover, such lipid nanoparticles can be beneficial drug carriers against cardiovascular risk disorders as diabetes, hypertension, etc. Conclusion: In this review, the most current and promising studies involving Solid Lipid Nanoparticles and Nanostructured Lipid Carriers as oral drug carriers are reported aiming to assist researchers who focus their research on lipid-based nanoparticles.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Biological Availability; Cardiovascular Agents; Cardiovascular Diseases; Drug Carriers; Drug Delivery Systems; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Intestinal Absorption; Lipids; Nanoparticles; Permeability; Solubility

: Well known in past centuries as a herbal remedy for osteoarticular pain and commonly used in the treatment of gout and familial Mediterranean fever, colchicine has an emerging role in the setting of cardiovascular diseases. Its unique properties not only target the key mechanisms of recurrent inflammation underlying pericardial syndromes but also inflammation within atherosclerotic plaques, atrial fibrillation recurrence and adverse ventricular remodelling leading to heart failure.The effect of colchicine in the treatment of cardiovascular diseases along with essential pharmacology will be discussed, reviewing the most important and recent clinical studies. Colchicine is a valuable, well tolerated and inexpensive drug in the setting of cardiovascular diseases.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Colchicine; Drug Repositioning; Humans; Treatment Outcome

Chronic low-grade inflammation contributes to the development of several diseases, including cardiovascular disease. Adequate strategies to target inflammation in cardiovascular disease are in their infancy and remain an avenue of great interest. The purinergic receptor P2X7 is a ubiquitously expressed receptor that predominately mediates inflammation and cellular death. P2X7 is a ligand-gated cation channel that is activated in response to high concentrations of extracellular ATP, triggering the assembly and activation of the NLRP3 (nuclear oligomerization domain like receptor family pyrin domain containing 3) inflammasome and subsequent release of proinflammatory cytokines IL (interleukin)-1β and IL-18. Increased P2X7 activation and IL-1β and IL-18 concentrations have been implicated in the development of many cardiovascular conditions including hypertension, atherosclerosis, ischemia/reperfusion injury, and heart failure. P2X7 receptor KO (knockout) mice exhibit a significant attenuation of the inflammatory response, which corresponds with reduced disease severity. P2X7 antagonism blunts blood pressure elevation in hypertension and progression of atherosclerosis in animal models. IL-1β and IL-18 inhibition has shown efficacy in clinical trials reducing major adverse cardiac events, including myocardial infarction, and heart failure. With several P2X7 antagonists available with proven safety margins, P2X7 antagonism could represent an untapped potential for therapeutic intervention in cardiovascular disorders.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Interleukin-18; Interleukin-1beta; NLR Family, Pyrin Domain-Containing 3 Protein; Purinergic P2X Receptor Antagonists; Receptors, Purinergic P2X7; Signal Transduction

Caloric restriction mimetics (CRMs) are emerging as potential therapeutic agents for the treatment of cardiovascular diseases. CRMs include natural and synthetic compounds able to inhibit protein acetyltransferases, to interfere with acetyl coenzyme A biosynthesis, or to activate (de)acetyltransferase proteins. These modifications mimic the effects of caloric restriction, which is associated with the activation of autophagy. Previous evidence demonstrated the ability of CRMs to ameliorate cardiac function and reduce cardiac hypertrophy and maladaptive remodelling in animal models of ageing, mechanical overload, chronic myocardial ischaemia, and in genetic and metabolic cardiomyopathies. In addition, CRMs were found to reduce acute ischaemia-reperfusion injury. In many cases, these beneficial effects of CRMs appeared to be mediated by autophagy activation. In the present review, we discuss the relevant literature about the role of different CRMs in animal models of cardiac diseases, emphasizing the molecular mechanisms underlying the beneficial effects of these compounds and their potential future clinical application.

Topics: Acetyl Coenzyme A; Acetyltransferases; Animals; Autophagy; Biological Mimicry; Caloric Restriction; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Humans

The ability to generate multi-omics data coupled with deeply characterizing the clinical phenotype of individual patients promises to improve understanding of complex cardiovascular pathobiology. There remains an important disconnection between the magnitude and granularity of these data and our ability to improve phenotype-genotype correlations for complex cardiovascular diseases. This shortcoming may be due to limitations associated with traditional reductionist analytical methods, which tend to emphasize a single molecular event in the pathogenesis of diseases more aptly characterized by crosstalk between overlapping molecular pathways. Network medicine is a rapidly growing discipline that considers diseases as the consequences of perturbed interactions between multiple interconnected biological components. This powerful integrative approach has enabled a number of important discoveries in complex disease mechanisms. In this review, we introduce the basic concepts of network medicine and highlight specific examples by which this approach has accelerated cardiovascular research. We also review how network medicine is well-positioned to promote rational drug design for patients with cardiovascular diseases, with particular emphasis on advancing precision medicine.

Topics: Animals; Biomarkers; Biomedical Research; Cardiovascular Agents; Cardiovascular Diseases; Computational Biology; Drug Repositioning; Gene Expression Profiling; Gene Regulatory Networks; Genetic Association Studies; Humans; Precision Medicine; Predictive Value of Tests; Prognosis; Protein Interaction Maps; Proteome; Proteomics; Risk Assessment; Risk Factors; Signal Transduction; Systems Biology; Transcriptome

Atherosclerosis, the underlying cause of cardiovascular disease (CVD), is a worldwide cause of morbidity and mortality. Reducing ApoB-containing lipoproteins-chiefly, LDL (low-density lipoprotein)-has been the main strategy for reducing CVD risk. Although supported by large randomized clinical trials, the persistence of residual cardiovascular risk after effective LDL reduction has sparked an intense search for other novel CVD biomarkers and therapeutic targets. Recently, Lox-1 (lectin-type oxidized LDL receptor 1), an innate immune scavenger receptor, has emerged as a promising target for early diagnosis and cardiovascular risk prediction and is also being considered as a treatment target. Lox-1 was first described as a 50 kDa transmembrane protein in endothelial cells responsible for oxLDL (oxidized LDL) recognition, triggering downstream pathways that intensify atherosclerosis via endothelial dysfunction, oxLDL uptake, and apoptosis. Lox-1 is also expressed in platelets, where it enhances platelet activation, adhesion to endothelial cells, and ADP-mediated aggregation, thereby favoring thrombus formation. Lox-1 was also identified in cardiomyocytes, where it was implicated in the development of cardiac fibrosis and myocyte apoptosis, the main determinants of cardiac recovery following an ischemic insult. Together, these findings have revealed that Lox-1 is implicated in all the main steps of atherosclerosis and has encouraged the development of immunoassays for measurement of sLox-1 (serum levels of soluble Lox-1) to be used as a potential CVD biomarker. Finally, the recent development of synthetic Lox-1 inhibitors and neutralizing antibodies with promising results in animal models has made Lox-1 a target for drug development. In this review, we discuss the main findings regarding the role of Lox-1 in the development, diagnosis, and therapeutic strategies for CVD prevention and treatment.

Topics: Animals; Antibodies, Neutralizing; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Heart Disease Risk Factors; Humans; Predictive Value of Tests; Prognosis; Risk Assessment; Scavenger Receptors, Class E

Adropin is a nutritionally regulated peptide hormone, secreted primarily by the liver, which modulates metabolic homeostasis in a number of tissues. Growing evidence suggests that adropin is an important regulatory component in a number of cardiovascular pathologies, and may be central to the control of cardiac fuel metabolism and vascular function. In this mini-review, we examine the known facets of adropin biology, discuss open questions in the field, and speculate on the therapeutic potential of targeting adropin-related signaling pathways in cardiovascular diseases.

Topics: Animals; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Energy Metabolism; Humans; Intercellular Signaling Peptides and Proteins; Myocardium; Signal Transduction

Cardiovascular disease and cardiovascular disease-related disorders remain among the most common causes of maternal morbidity and mortality in the United States. Due to increased rates of obesity, delayed childbearing, and improvements in medical technology, greater numbers of women are entering pregnancy with preexisting medical comorbidities. Use of cardiovascular medications in pregnancy continues to increase, and medical management of cardiovascular conditions in pregnancy will become increasingly common. Obstetricians and cardiologists must familiarize themselves with the pharmacokinetics of the most commonly used cardiovascular medications in pregnancy and how these medications respond to the physiologic changes related to pregnancy, embryogenesis, and lactation.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Female; Heart Disease Risk Factors; Humans; Pregnancy; Pregnancy Complications, Cardiovascular; Risk Adjustment

Galectin-3 (gal-3), a member of the galectin family, is a glycoprotein with high affinity for β-galactoside. Gal-3 is a cytoplasmically synthesized protein that can shuttle between the cytoplasm and nucleus and can even be transported to the membrane and secreted into the extracellular environment. Cardio/cerebrovascular diseases generally refer to ischemic or hemorrhagic diseases occurring in the heart, brain and systemic tissues, which are characterized by high morbidity, high disability rates and high mortality rates. To date, considerable research has demonstrated that gal-3 expression is aberrantly increased and plays important roles in cardio/cerebrovascular diseases, such as acute ischemic stroke (AIS), myocardial fibrosis, acute coronary syndrome (ACS), and heart failure (HF). Hence, understanding the biological roles of gal-3 in these diseases may be essential for cardio/cerebrovascular disease treatment and diagnosis to improve patient quality of life. In this review, we summarize current research on the roles of gal-3 in human cardiovascular diseases and potential inhibitors of gal-3, which may provide new strategies for disease therapies.

Topics: Animals; Blood Proteins; Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Galectins; Humans; Molecular Targeted Therapy; Signal Transduction; Up-Regulation

Ivabradine is a unique agent that is distinct from beta-blockers and calcium channel blockers as it reduces heart rate without affecting myocardial contractility or vascular tone. Ivabradine is a use-dependent inhibitor targeting the sinoatrial node. It is approved for use in the United States as an adjunct therapy for heart rate reduction in patients with heart failure with reduced ejection fraction. In this scenario, ivabradine has demonstrated improved clinical outcomes due to reduction in heart failure readmissions. However, there has been conflicting evidence from prospective studies and randomized controlled trials for its use in stable ischemic heart disease regarding efficacy in symptom reduction and mortality benefit. Ivabradine may also play a role in the treatment of patients with inappropriate sinus tachycardia, who often cannot tolerate beta-blockers and/or calcium channel blockers. In this review, we highlight the evidence for the nuances of using ivabradine in heart failure, stable ischemic heart disease, and inappropriate sinus tachycardia to raise awareness for its vital role in the treatment of select populations.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Ivabradine; Myocardial Ischemia; Prospective Studies; Randomized Controlled Trials as Topic; Stroke Volume; Tachycardia, Sinus

The landmark discoveries of leptin and adiponectin firmly established adipose tissue as a sophisticated and highly active endocrine organ, opening a new era of investigating adipose-mediated tissue crosstalk. Both obesity-associated hyperleptinemia and hypoadiponectinemia are important biomarkers to predict cardiovascular outcomes, suggesting a crucial role for adiponectin and leptin in obesity-associated cardiovascular disorders. Normal physiological levels of adiponectin and leptin are indeed essential to maintain proper cardiovascular function. Insufficient adiponectin and leptin signaling results in cardiovascular dysfunction. However, a paradox of high levels of both leptin and adiponectin is emerging in the pathogenesis of cardiovascular disorders. Here, we (1) summarize the recent progress in the field of adiponectin and leptin and its association with cardiovascular disorders, (2) further discuss the underlying mechanisms for this new paradox of leptin and adiponectin action, and (3) explore the possible application of partial leptin reduction, in addition to increasing the adiponectin/leptin ratio as a means to prevent or reverse cardiovascular disorders.

Topics: Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Bariatric Surgery; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Leptin; Metabolism, Inborn Errors; Obesity; Signal Transduction

Cardiovascular diseases (CVDs) are one of the leading causes of the most considerable mortality globally, and it has been tried to find the molecular mechanisms and design new drugs that triggered the molecular target. Curcumin is the main ingredient of Curcuma longa (turmeric) that has been used in traditional medicine for treating several diseases for years. Numerous investigations have indicated the beneficial effect of Curcumin in modulating multiple signaling pathways involved in oxidative stress, inflammation, apoptosis, and proliferation. The cardiovascular protective effects of Curcumin against CVDs have been indicated in several studies. In the current review study, we provided novel information on Curcumin's protective effects against various CVDs and potential molecular signaling targets of Curcumin. Nonetheless, more studies should be performed to discover the exact molecular target of Curcumin against CVDs.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Curcumin; Humans; Molecular Targeted Therapy; Signal Transduction

Monoterpenes are one of the most studied plant's secondary metabolites, they are found abundantly in essential oils of aromatic plants. They also have a great range of pharmacological properties, such as antihypertensive, bradycardic, antiarrhythmic and hypotensive. In the face of the burden caused by cardiovascular disease (CVDs) worldwide, studies using monoterpenes to assess their cardiovascular effects have increased over the years.. This systematic review aimed to summarize the use of monoterpenes in animal models of any CVDs.. PubMed, SCOPUS, LILACS and Web of Science databases were used to search for articles that used monoterpenes, in any type of administration, to treat or prevent CVDs in animal models. The PRISMA guidelines were followed. Two independent researchers extracted main characteristics of studies, methods and outcomes. Data obtained were analyzed qualitatively and quantitatively.. At the ending of the search process, 33 articles were selected for the systematic review. Of these, 17 articles were included in the meta-analysis. A total of 16 different monoterpenes were found for the treatment of hypertension, myocardial infarction, pulmonary hypertension, cardiac hypertrophy and arrhythmia. The main actions include hypotension, bradycardia, vasodilatation, antiarrhythmic, and antioxidant and antiapoptotic properties. From our data, it can be suggested that monoterpenes may be a significant source for new drug development. However, there is still a need to apply these knowledge into clinical research and a long path to pursue before putting them in the market.. The variability of cardiovascular effects demonstrated by the monoterpenes highlighted them as a promising candidates for treatment or prevention of CVDs. Nevertheless, studies that investigate their biological sites of action needs to be further encouraged.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Humans; Hypertension; Monoterpenes; Myocardial Infarction; Oils, Volatile; Plants

Cardiovascular diseases (CVDs) are the leading cause of death globally. While the major focus of pharmacological and non-pharmacological interventions has been on targeting disease pathophysiology and limiting predisposing factors, our understanding of the cellular and molecular mechanisms underlying the pathogenesis of CVDs remains incomplete. One mechanism that has recently emerged is protein O-GlcNAcylation. This is a dynamic, site-specific reversible post-translational modification of serine and threonine residues on target proteins and is controlled by two enzymes: O-linked β-N-acetylglucosamine transferase (OGT) and O-linked β-N-acetylglucosaminidase (OGA). Protein O-GlcNAcylation alters the cellular functions of these target proteins which play vital roles in pathways that modulate vascular homeostasis and cardiac function. Through this review, we aim to give insights on the role of protein O-GlcNAcylation in cardiovascular diseases and identify potential therapeutic targets in this pathway for development of more effective medicines to improve patient outcomes.

Topics: Acetylglucosamine; Acetylglucosaminidase; Acylation; Animals; Antigens, Neoplasm; beta-N-Acetylhexosaminidases; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Enzyme Inhibitors; Glycosylation; Histone Acetyltransferases; Humans; Hyaluronoglucosaminidase; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational

Dietary flavonoids have shown potential in the prevention of noncommunicable diseases. The aim of the present study is to conduct a dose-response meta-analysis on the association between dietary intake of total, subclasses and individual flavonoids and risk of cardiovascular disease (CVD).. Electronic databases are searched. A total of 39 prospective cohort studies are included, comprising 1 501 645 individuals and a total of 33 637 cases of CVD, 23 664 of coronary heart disease (CHD), and 11 860 of stroke. Increasing dietary intake of total flavonoids is linearly associated with a lower risk of CVD. Among the main classes of flavonoids, increasing intake of anthocyanins and flavan-3-ols is inversely associated with risk of CVD, while flavonols and flavones with CHD. Only increasing flavanones showed a linear inverse association with stroke risk. Catechins showed a favorable effect toward all cardiovascular outcomes. Among individual compounds, intake of quercetin and kaempferol is linearly associated with lower risk of CHD and CVD, respectively. However, higher intake of all the aforementioned compounds is associated, with a various extent, with a lower risk of CVD when considering comparison of extreme categories of consumption.. The results of this study provide evidence of potential cardiovascular benefits of a flavonoid-rich diet.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diet; Dose-Response Relationship, Drug; Flavonoids; Humans; Risk Factors; Stroke

Hydrogen sulfide (H

Topics: Administration, Inhalation; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cell Movement; Humans; Hydrogen Sulfide; Neovascularization, Physiologic; Oxidative Stress

Drug development in cardiovascular disease is stagnating, with lack of efficacy and adverse effects being barriers to innovation. Human genetics can provide compelling evidence of causation through approaches such as Mendelian randomization, with genetic support for causation increasing the probability of a clinical trial succeeding. Mendelian randomization applied to quantitative traits can identify risk factors for disease that are both causal and amenable to therapeutic modification. However, important differences exist between genetic investigations of a biomarker (such as HDL cholesterol) and a drug target aimed at modifying the same biomarker of interest (such as cholesteryl ester transfer protein), with implications for the methodology, interpretation and application of Mendelian randomization to drug development. Differences include the comparative nature of the genetic architecture - that is, biomarkers are typically polygenic, whereas protein drug targets are influenced by either cis-acting or trans-acting genetic variants - and the potential for drug targets to show disease associations that might differ from those of the biomarker that they are intended to modify (target-mediated pleiotropy). In this Review, we compare and contrast the use of Mendelian randomization to evaluate potential drug targets versus quantitative traits. We explain how genetic epidemiological studies can be used to assess the aetiological roles of biomarkers in disease and to prioritize drug targets, including designing their evaluation in clinical trials.

Topics: Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Drug Development; Genomics; Humans

Creatine is an organic compound, consumed exogenously in the diet and synthesized endogenously via an intricate inter-organ process. Functioning in conjunction with creatine kinase, creatine has long been known for its pivotal role in cellular energy provision and energy shuttling. In addition to the abundance of evidence supporting the ergogenic benefits of creatine supplementation, recent evidence suggests a far broader application for creatine within various myopathies, neurodegenerative diseases, and other pathologies. Furthermore, creatine has been found to exhibit non-energy related properties, contributing as a possible direct and in-direct antioxidant and eliciting anti-inflammatory effects. In spite of the new clinical success of supplemental creatine, there is little scientific insight into the potential effects of creatine on cardiovascular disease (CVD), the leading cause of mortality. Taking into consideration the non-energy related actions of creatine, highlighted in this review, it can be speculated that creatine supplementation may serve as an adjuvant therapy for the management of vascular health in at-risk populations. This review, therefore, not only aims to summarize the current literature surrounding creatine and vascular health, but to also shed light onto the potential mechanisms in which creatine may be able to serve as a beneficial supplement capable of imparting vascular-protective properties and promoting vascular health.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Creatine; Dietary Supplements; Heart Disease Risk Factors; Humans

The prevalence of cardiovascular disease (CVD) in pregnancy, both diagnosed and previously unknown, is rising, and CVD is a leading cause of maternal morbidity and mortality. Historically, women of child-bearing potential have been underrepresented in research, leading to lasting knowledge gaps in the cardiovascular care of pregnant and lactating women. Despite these limitations, clinicians should be familiar with the safety of frequently used diagnostic and therapeutic interventions to adequately care for this at-risk population. This review, the fourth of a 5-part series, provides evidence-based recommendations regarding the use of common cardiovascular diagnostic tests and medications in pregnant and lactating women.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diagnostic Techniques, Cardiovascular; Female; Humans; Lactation; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy, High-Risk; Risk Adjustment

Cardiovascular diseases (CVDs) are considered as a major cause of death worldwide. Therefore, identifying and developing therapeutic strategies to treat and reduce the prevalence of CVDs is a major medical challenge. Several drugs used for the treatment of CVDs, such as captopril, emerged from natural products, namely snake venoms. These venoms are complex mixtures of bioactive molecules, which, among other physiological networks, target the cardiovascular system, leading to them being considered in the development and design of new drugs. In this review, we describe some snake venom molecules targeting the cardiovascular system such as phospholipase A2 (PLA2), natriuretic peptides (NPs), bradykinin-potentiating peptides (BPPs), cysteine-rich secretory proteins (CRISPs), disintegrins, fibrinolytic enzymes, and three-finger toxins (3FTXs). In addition, their molecular targets, and mechanisms of action-vasorelaxation, inhibition of platelet aggregation, cardioprotective activities-are discussed. The dissection of their biological effects at the molecular scale give insights for the development of future snake venom-derived drugs.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Models, Biological; Snake Venoms

Over the past decade, pharmacogenetic testing has emerged in clinical practice to guide selected cardiovascular therapies. The most common implementation in practice is CYP2C19 genotyping to predict clopidogrel response and assist in selecting antiplatelet therapy after percutaneous coronary intervention. Additional examples include genotyping to guide warfarin dosing and statin prescribing. Increasing evidence exists on outcomes with genotype-guided cardiovascular therapies from multiple randomized controlled trials and observational studies. Pharmacogenetic evidence is accumulating for additional cardiovascular medications. However, data for many of these medications are not yet sufficient to support the use of genotyping for drug prescribing. Ultimately, pharmacogenetics might provide a means to individualize drug regimens for complex diseases such as heart failure, in which the treatment armamentarium includes a growing list of medications shown to reduce morbidity and mortality. However, sophisticated analytical approaches are likely to be necessary to dissect the genetic underpinnings of responses to drug combinations. In this Review, we examine the evidence supporting pharmacogenetic testing in cardiovascular medicine, including that available from several clinical trials. In addition, we describe guidelines that support the use of cardiovascular pharmacogenetics, provide examples of clinical implementation of genotype-guided cardiovascular therapies and discuss opportunities for future growth of the field.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Pharmacogenetics

Globally, there has been little change in mortality rates from cardiovascular (CV) diseases or cancers over the past two decades (1997-2018). This is especially true for heart failure (HF) where 5-year mortality rates remain as high as 45-55%. In the same timeframe, the proportion of drug revenue, and regulatory drug approvals for cancer drugs, far out paces those for CV drugs. In 2018, while cancer drugs made 27% of Food and Drug Administration drug approvals, only 1% of drug approvals was for a CV drug, and over this entire 20 year span, only four drugs were approved for HF in the USA. Cardiovascular trialists need to reassess the design, execution, and purpose of CV clinical trials. In the area of oncology research, trials are much smaller, follow-up is shorter, and targeted therapies are common. Cardiovascular diseases and cancer are the two most common causes of death globally, and although they differ substantially, this review evaluates whether some elements of oncology research may be applicable in the CV arena. As one of the most underserved CV diseases, the review focuses on aspects of cancer research that may be applicable to HF research with the aim of streamlining the clinical trial process and decreasing the time and cost required to bring safe, effective, treatments to patients who need them. The paper is based on discussions among clinical trialists, industry representatives, regulatory authorities, and patients, which took place at the Cardiovascular Clinical Trialists Workshop in Washington, DC, on 8 December 2019 (https://www.globalcvctforum.com/2019 (14 September 2020)).

Topics: Cardiovascular Agents; Cardiovascular Diseases; Heart Failure; Humans; Treatment Outcome

The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1

Topics: Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; COVID-19; COVID-19 Drug Treatment; Drug Discovery; Endothelium, Vascular; Humans; Molecular Targeted Therapy; SARS-CoV-2

Endothelial dysfunction is a major contributing factor to diseases such as atherosclerosis, diabetes mellitus, obesity, hypertension, acute lung injury, preeclampsia, among others. Resveratrol (RSV) is a naturally occurring bioactive polyphenol found in grapes and red wine. According to experimental studies, RSV modulates several events involved in endothelial dysfunction such as impaired vasorelaxation, eNOS uncoupling, leukocyte adhesion, endothelial senescence, and endothelial mesenchymal transition. The endothelial protective effects of RSV are found to be mediated by numerous molecular targets (e.g. Silent Information Regulator 1 (SIRT1), 5' AMP-activated protein kinase (AMPK), endothelial nitric oxide synthase (eNOS), nuclear factor-erythroid-derived 2-related factor-2 (Nrf2), peroxisome proliferator-activated receptor (PPAR), Krüppel-like factor-2 (KLF2), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)). Herein, we present an updated review addressing pharmacological effects and molecular targets of RSV in maintaining endothelial function, and the potential of this phytochemical for endothelial dysfunction-associated disorders.

Topics: Angiogenesis Inhibitors; Animals; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Endothelial Cells; Endothelium, Vascular; Fibrinolytic Agents; Humans; Hypoglycemic Agents; Resveratrol; Signal Transduction

At present, the prevention and control of cardiovascular diseases (CAVDs) has made initial advancements, although the prevention and control of cerebrovascular diseases (CEVDs) has not yet achieved the desired progress. In this paper, we review the prevention and control of CEVDs and CAVDs, and analyze the differences in prevention effects, and the pathological and physiological structures pertaining to CEVDs and CAVDs. Combined with the different effects of low-dose aspirin in the primary prevention of CEVDs and CAVDs by meta-analysis, aspirin plays a more important role in the primary prevention of CAVDs than CEVDs. We recognize the misunderstandings and blind spots concerning prevention and control of CEVDs, which can be summarized as follows: (1) CEVDs and CAVDs can be controlled by the same methods and drugs; (2) considering the same pathological factors for cardiovascular diseases; (3) a lack of understanding of the particularity of CEVDs; (4) a focus on platelets and neglect of cerebrovascular protection. In summary, our research clarifies the differences in the prevention measures and drugs used for CEVDs and CAVDs. Of particular concern is the serious lack of preventive drugs for CEVDs in clinical use. An ideal drug for the prevention of CEVDs should have protective effects on the blood, the vascular endothelium, the blood-brain barrier (BBB), and other related factors. Our review aims to highlight several issues in the current prevention of CEVDs and CAVDs, and to provide an optimized plan for preventive drug discovery.

Topics: Animals; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Humans; Primary Prevention; Prognosis; Protective Factors; Risk Assessment; Risk Factors

Ferroptosis is a type of regulated cell death driven by iron dependent accumulation of cellular reactive oxygen species (ROS) when glutathione (GSH)-dependent lipid peroxidation repair systems are compromised. Nuclear receptor co-activator 4 (NCOA4)-mediated selective autophagy of ferritin, termed ferritinophagy, involves the regulation of ferroptosis. Emerging evidence has revealed that ferritinophagy and ferroptosis exert a significant role in the occurrence and development of cardiovascular disease. In the present review, we aimed to present a brief overview of ferritinophagy and ferroptosis focusing on the underlying mechanism and regulations involved. We summarize and discuss relevant research progress on the role of ferritinophagy and ferroptosis in cardiovascular diseases accompanied with potential applications of ferritinophagy and ferroptosis modulators in the treatment of ferroptosis-associated cardiovascular diseases.

Topics: Animals; Autophagy; Cardiovascular Agents; Cardiovascular Diseases; Ferritins; Ferroptosis; Humans; Lipid Peroxidation; Myocardium; Reactive Oxygen Species

Coronavirus disease 2019 (COVID-19), a mystified cryptic virus has challenged the mankind that has brought life to a standstill. Catastrophic loss of life, perplexed healthcare system and the downfall of global economy are some of the outcomes of this pandemic. Humans are raging a war with an unknown enemy. Infections, irrespective of age and gender, and more so in comorbidities are escalating at an alarming rate. Cardiovascular diseases, are the leading cause of death globally with an estimate of 31% of deaths worldwide out of which nearly 85% are due to heart attacks and stroke. Theoretically and practically, researchers have observed that persons with pre-existing cardiovascular conditions are comparatively more vulnerable to the COVID-19 infection. Moreover, they have studied the data between less severe and more severe cases, survivors and non survivors, intensive care unit (ICU) patients and non ICU patients, to analyse the relationship and the influence of COVID-19 on cardiovascular health of an individual, further the risk of susceptibility to submit to the virus. This review aims to provide a comprehensive particular on the possible effects, either direct or indirect, of COVID-19 on the cardiovascular heath of an individual.

Topics: Antiviral Agents; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Comorbidity; COVID-19; COVID-19 Drug Treatment; Host-Pathogen Interactions; Humans; Prognosis; Risk Assessment; Risk Factors; SARS-CoV-2

Endothelial-mesenchymal transition (EndMT) is widely involved in the occurrence and development of cardiovascular diseases. Although there is no direct evidence, it is very promising as an effective target for the treatment of these diseases. Endothelial cells need to respond to the complex cardiovascular environment through EndMT, but sustained stimuli will cause the imbalance of EndMT. Blocking the signal transduction promoting EndMT is an effective method to control the imbalance of EndMT. In particular, we also discussed the potential role of endothelial cell apoptosis and autophagy in regulating the imbalance of EndMT. In addition, promoting mesenchymal-endothelial transformation (MEndT) is also a method to control the imbalance of EndMT. However, targeting EndMT to treat cardiovascular disease still faces many challenges. By reviewing the research progress of EndMT, we have put forward some insights and translated them into challenges and opportunities for new treatment strategies for cardiovascular diseases.

Topics: Animals; Apoptosis; Autophagy; Cardiovascular Agents; Cardiovascular Diseases; Cell Plasticity; Endothelial Cells; Epithelial-Mesenchymal Transition; Humans; Phenotype; Signal Transduction

Fucoidan is a sulfated polysaccharide with various bioactivities. The application of fucoidan in cancer treatment, wound healing, and food industry has been extensively studied. However, the therapeutic value of fucoidan in cardiovascular diseases has been less explored. Increasing number of investigations in the past years have demonstrated the effects of fucoidan on cardiovascular system. In this review, we will focus on the bioactivities related to cardiovascular applications, for example, the modulation functions of fucoidan on coagulation system, inflammation, and vascular cells. Factors mediating those activities will be discussed in detail. Current therapeutic strategies and future opportunities and challenges will be provided to inspire and guide further research.

Topics: Animals; Blood Coagulation; Blood Platelets; Cardiovascular Agents; Cardiovascular Diseases; Endothelial Cells; Humans; Inflammation; Mice; Muscle, Smooth, Vascular; Polysaccharides; Rats; Selectins; Sulfates; Thrombin

Cardiovascular disease is the leading cause of death globally. While pharmacological advancements have improved the morbidity and mortality associated with cardiovascular disease, non-adherence to prescribed treatment remains a significant barrier to improved patient outcomes. A variety of strategies to improve medication adherence have been tested in clinical trials, and include the following categories: improving patient education, implementing medication reminders, testing cognitive behavioral interventions, reducing medication costs, utilizing healthcare team members, and streamlining medication dosing regimens. In this review, we describe specific trials within each of these categories and highlight the impact of each on medication adherence. We also examine ongoing trials and future lines of inquiry for improving medication adherence in patients with cardiovascular diseases.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Cognitive Behavioral Therapy; Comorbidity; Drug Costs; Humans; Medication Adherence; Patient Care Team; Patient Education as Topic; Polypharmacy; Practice Guidelines as Topic; Professional Role; Reminder Systems

The renin-angiotensin system is an important component of the cardiovascular system. Mounting evidence suggests that the metabolic products of angiotensin I and II - initially thought to be biologically inactive - have key roles in cardiovascular physiology and pathophysiology. This non-canonical axis of the renin-angiotensin system consists of angiotensin 1-7, angiotensin 1-9, angiotensin-converting enzyme 2, the type 2 angiotensin II receptor (AT

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Molecular Targeted Therapy; Proto-Oncogene Mas; Renin-Angiotensin System

Polypharmacy in older adults leads to increased risks of side effects and drug-drug interactions, affecting their health outcomes and quality of life. Deprescribing, the act of simplifying medication regimens, is challenging due to the lack of consensus guidelines.. To offer some guidance on managing medication regimens for older cardiovascular patients.. We reviewed the most recent pertinent guidelines and literature.. This review provides practical considerations for appropriate prescribing in the older population with cardiovascular disease in order to strike a balance between unnecessary or harmful medications and therapies with proven long-term benefits.. On-going dialogue between healthcare providers and patients allows close monitoring of medication effectiveness and prevention of side effects. Medication regimens require individualization, as patients' goals of care change with advancing age.

Topics: Age Factors; Aged; Aged, 80 and over; Aging; Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Health Knowledge, Attitudes, Practice; Humans; Inappropriate Prescribing; Medication Adherence; Polypharmacy; Risk Assessment; Risk Factors

Topics: Animals; Anti-HIV Agents; Cardiovascular Agents; Cardiovascular Diseases; Coronary Circulation; Coronary Vessels; Endothelium, Vascular; Heart Disease Risk Factors; HIV Infections; Humans; Inflammation Mediators; Microcirculation; Prognosis; Risk Assessment

Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for regenerative therapy, disease modeling, and drug discovery. iPSCs allow for the production of limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine. Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells. Despite significant advances, drug therapy and discovery for cardiovascular disease have lagged behind other fields such as oncology. We speculate that this paucity of drug discovery is due to a previous lack of efficient, reproducible, and translational model systems. Notably, existing drug discovery and testing platforms rely on animal studies and clinical trials, but investigations in animal models have inherent limitations due to interspecies differences. Moreover, clinical trials are inherently flawed by assuming that all individuals with a disease will respond identically to a therapy, ignoring the genetic and epigenomic variations that define our individuality. With ever-improving differentiation and phenotyping methods, patient-specific iPSC-derived cardiovascular cells allow unprecedented opportunities to discover new drug targets and screen compounds for cardiovascular disease. Imbued with the genetic information of an individual, iPSCs will vastly improve our ability to test drugs efficiently, as well as tailor and titrate drug therapy for each patient.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cell Lineage; Drug Development; Drug Evaluation, Preclinical; Humans; Induced Pluripotent Stem Cells; Precision Medicine; Randomized Controlled Trials as Topic

Cardiovascular diseases (CVD) and cancer are still the leading causes of death. There are many common etiologic factors, especially smoking and obesity. Therefore, it is not uncommon for CVD and cancer to coexist. Drug-drug interactions (DDIs) inevitably occur in this group of patients, where polypharmacy is increasing due to older age and multiple comorbidities. However, multidisciplinary studies, especially close collaboration of medical oncologists and cardiologists, who deals with the diagnosis and treatment of these diseases, awareness and preventive approaches to DDIs may reduce serious morbidity and mortality. In this review, information about the common treatments used in cardiology and oncology and possible DDIs are discussed.

Topics: Aged; Antineoplastic Agents; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Humans; Neoplasms

Cardiovascular disease (CVD), the main macro vascular complication of type 2 diabetes (T2D), increases the risk of death significantly in patients with T2D.. Most of the patients with T2D do not have obvious CVD symptoms. Due to the paucity of data, CVD screening in asymptomatic patients with T2D remains highly controversial.. This has driven a panel of experts to establish a novel consensus on how to approach patients with T2D at high CVD risk. The panel formulated a stepwise algorithm by which patients with T2D undergo initial risk stratification into low, intermediate and high risk using the ASCVD calculator. In patients with intermediate risk, coronary artery calcium measurement is used to further stratify those patients into new low and high-risk categories.. The panel recommends using standard diabetes care in low risk patients and using SGLT2 inhibitors and GLP1 agonists with cardio protective effect, on top of standard care, in high risk individuals.

Topics: Algorithms; Calcium; Cardiovascular Agents; Cardiovascular Diseases; Consensus; Coronary Vessels; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Mass Screening; Patient Selection; Protective Agents; Risk Assessment; Sodium-Glucose Transporter 2 Inhibitors; Tomography, X-Ray Computed

Hydrogen sulfide (H

Topics: Animals; Apoptosis; Autophagy; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Hydrogen Sulfide; Signal Transduction

Cardiovascular fibrosis refers to the scar tissue that develops in the injured heart and blood vessels from an aberrant wound healing response to organ injury or insult. Established fibrosis becomes a hallmark of chronic disease progression and a key contributor to tissue stiffness and dysfunction, which ultimately leads to heart failure. As wound healing and fibrotic responses to myocardial injury are multifactorial processes, current therapies that only target specific contributing factors to disease pathogenesis offer limited overall anti-fibrotic efficacy. As such, recent attention has turned to targeting the body's immune system, which orchestrates the wound healing response to tissue injury. This review focuses on the increasing body of work that has identified the NLRP3 inflammasome, a multiprotein oligomer complex responsible for activation of inflammatory responses via its production of IL-1β and IL-18, as an immune system-initiated facilitator of cardiovascular healing, but also an important contributor to tissue scarring following its persistent activation. The review summarises the factors that can elicit priming and activation of the inflammasome complex, how the activated inflammasome complex contributes to cardiovascular pathophysiology and fibrosis progression, and the molecular mechanisms involved from various cell culture and animal model studies that have utilised genetic deletion or pharmacological inhibition of specific components of the inflammasome. Finally, it outlines currently known and previously unrecognised cardiovascular receptors that may be pharmacologically targeted to ablate the contribution of the NLRP3 inflammasome to cardiovascular diseases characterised by fibrosis, by compounds that may be developed as effective adjunct therapies to current standard of care medication.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Fibrosis; Humans; NLR Family, Pyrin Domain-Containing 3 Protein; Treatment Outcome

The complex pathobiology underlying cardiovascular diseases (CVDs) has yet to be explained. Aberrant epigenetic changes may result from alterations in enzymatic activities, which are responsible for putting in and/or out the covalent groups, altering the epigenome and then modulating gene expression. The identification of novel individual epigenetic-sensitive trajectories at single cell level might provide additional opportunities to establish predictive, diagnostic and prognostic biomarkers as well as drug targets in CVDs. To date, most of studies investigated DNA methylation mechanism and miRNA regulation as epigenetics marks. During atherogenesis, big epigenetic changes in DNA methylation and different ncRNAs, such as miR-93, miR-340, miR-433, miR-765, CHROME, were identified into endothelial cells, smooth muscle cells, and macrophages. During man development, lipid metabolism, inflammation and homocysteine homeostasis, alter vascular transcriptional mechanism of fundamental genes such as ABCA1, SREBP2, NOS, HIF1. At histone level, increased HDAC9 was associated with matrix metalloproteinase 1 (MMP1) and MMP2 expression in pro-inflammatory macrophages of human carotid plaque other than to have a positive effect on toll like receptor signaling and innate immunity. HDAC9 deficiency promoted inflammation resolution and reverse cholesterol transport, which might block atherosclerosis progression and promote lesion regression. Here, we describe main human epigenetic mechanisms involved in atherosclerosis, coronary heart disease, ischemic stroke, peripheral artery disease; cardiomyopathy and heart failure. Different epigenetics mechanisms are activated, such as regulation by circular RNAs, as MICRA, and epitranscriptomics at RNA level. Moreover, in order to open new frontiers for precision medicine and personalized therapy, we offer a panoramic view on the most innovative bioinformatic tools designed to identify putative genes and molecular networks underlying CVDs in man.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Clinical Decision-Making; Epigenesis, Genetic; Epigenome; Humans; Precision Medicine; Signal Transduction

Coronary artery disease (CAD) and heart failure (HF) are major worldwide threat to health and well-being. Important progress in the treatment of CAD and HF have contributed to a decline in mortality around the world. A considerable number of epidemiological studies reported a strong independent association between elevated heart rate and major cardiovascular risk factors including atherosclerosis, ventricular arrhythmias, and left ventricular dysfunction. Ivabradine (IVA) is a pure heart rate-lowering agent with well-documented anti-anginal and anti-ischemic properties comparable to well-established anti-anginal agents, such as beta-blockers and calcium channel blockers. The heart rate reduction with IVA is beneficial in patients with CAD, chronic stable angina pectoris, and chronic HF, with an acceptable tolerance and safety profile. The pharmacodynamic and pharmacokinetic properties of this drug make it an important agent in the management of patients with CAD and HF. The aim of this short review is to explore recent results with IVA, a new medication that lowers heart rate by selectively inhibiting the

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Heart Rate; Humans; Ivabradine; Randomized Controlled Trials as Topic

Previous systematic reviews (2008; 2016) concluded similarity in outcomes between brand-name and generic drugs in cardiology, but they included ≥ 50% comparative bioavailability studies, not designed or powered to detect a difference in efficacy or safety between drug types. We aimed to summarise best-evidence regarding the effectiveness and safety of generic versus brand-name drugs used in cardiology.. For this systematic review of the literature, scientific databases (MEDLINE and EMBASE) were searched from January 1984 to October 2018. Original research reports comparing the clinical impact of brand-name versus generic cardiovascular drugs on humans treated in a real-life setting, were selected. Meta-analyses and subgroup analyses were performed. Heterogeneity (I. Among the 3148 screened abstracts, 72 met the inclusion criteria (n ≥ 1,000,000 patients, mean age 65 ± 10 years; 42% women). A total of 60% of studies showed no difference between drug types, while 26% concluded that the brand-name drug was more effective or safe, 13% were inconclusive and only 1% concluded that generics did better. The overall crude risk ratio of all-cause hospital visits for generic versus brand-name drug was 1.14 (95% confidence interval: 1.06-1.23; I. The crude risk of hospital visits was higher for patients exposed to generic compared to brand-name cardiovascular drugs. However, the evidence is insufficient and too heterogeneous to draw any firm conclusion regarding the effectiveness and safety of generic drugs in cardiology.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drugs, Generic; Humans; Patient Safety

The polypill, referring to a variety of combinations of low-cost cardiovascular and stroke preventive medications combined in a single tablet, has been evaluated as a population-based approach for cardiovascular disease prevention in several trials. This review summarizes the scope of the problem, main trial results, and their potential applicability to the US population.. Initial trials demonstrated the efficacy of the polypill approach. The most recent, the PolyIran study, showed the effectiveness of one form of a polypill for cardiovascular disease prevention, high medication adherence, and low adverse event rates. None of published polypill trials focused on stroke as the primary outcome and most were conducted in developing countries, limiting generalization to the US population. A US-based randomized trial with stroke as the primary outcome is needed to assess the usefulness of this approach for stroke prevention in the USA.

Topics: Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Humans; Medication Adherence; Stroke

Older people are increasingly susceptible to adverse drug reactions (ADRs) or therapeutic failure. This could be mediated by considerable polypharmacy, which increases the possibility of drug-drug and drug-gene interactions. Precision medicine, based on individual genetic variations, enables the screening of patients at risk for ADRs and the implementation of personalized treatment regimens. It combines genetic and genomic data with environmental and clinical factors in order to tailor prevention and disease-management strategies, including pharmacotherapy. The identification of genetic factors that influence drug absorption, distribution, metabolism, excretion, and action at the drug target level allows individualized therapy. Positive pharmacogenomic findings have been reported for the majority of cardiovascular drugs (CVD), suggesting that pre-emptive testing can improve efficacy and minimize the toxicity risk. Gene variants related to drug metabolism and transport variability or pharmacodynamics of major CVD have been translated into dosing recommendations. Pharmacogenetics consortia have issued guidelines for oral anticoagulants, antiplatelet agents, statins, and some beta-blockers. Since the majority of pharmacogenetics recommendations are based on the assessment of single drug-gene interactions, it is imperative to develop tools for the prediction of multiple drug-drug-gene interactions, which are common in the elderly with comorbidity. The availability of genomic testing has grown, but its clinical application is still insufficient.

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Precision Medicine

Patients with cardiovascular risk factors or established cardiovascular disease have an increased risk of developing coronavirus disease 19 and have a worse outcome when infected, but translating this notion into effective action is challenging. At present it is unclear whether cardiovascular therapies may reduce the likelihood of infection, or improve the survival of infected patients. Given the crucial importance of this issue for clinical cardiologists and all specialists dealing with coronavirus disease 19, we tried to recapitulate the current evidence and provide some practical recommendations.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cause of Death; Comorbidity; Coronavirus Infections; COVID-19; Europe; Female; Humans; Male; Pandemics; Pneumonia, Viral; Prevalence; Risk Assessment; Survival Analysis

The coronavirus disease-2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2. The link between cardiovascular disease and COVID-19 appears to be twofold. First, some reports of data indicate that certain groups of patients are more at risk of COVID-19. This includes patients with cardiovascular risk factors or pre-existing cardiovascular conditions and older patients. In addition, these patients incur disproportionately worse outcome. Second, SARS-CoV2 infection can be complicated by life-threatening cardiovascular acute diseases. Despite the rapid evolution of data on this pandemic, this review aims to highlight the cardiovascular considerations related to COVID-19 whether as comorbidities including concerns and uncertainty regarding the effect of renin-angiotensin-aldosterone system (RAAS) inhibitors on angiotensin conversion enzyme 2 or related to acute cardiovascular complications.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Coronavirus Infections; COVID-19; Humans; Pandemics; Pneumonia, Viral; Renin-Angiotensin System; Treatment Outcome

Background Sex differences in the management of cardiovascular disease have been reported in secondary care. We conducted a systematic review with meta-analysis of systematically investigated sex differences in cardiovascular medication prescription among patients at high risk or with established cardiovascular disease in primary care. Methods and Results PubMed and Embase were searched between 2000 and 2019 for observational studies reporting on the sex-specific prevalence of aspirin, statins, and antihypertensive medication prescription, including beta blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and diuretics, in primary care. Random effects meta-analysis was used to obtain pooled women-to-men prevalence ratios for each cardiovascular medication prescription. Metaregression models assessed the impact of age and year on the findings. A total of 43 studies were included, involving 2 264 600 participants (28% women) worldwide. Participants' mean age ranged from 51 to 76 years. The pooled prevalence of cardiovascular medication prescription for women was 41% for aspirin, 60% for statins, and 68% for any antihypertensive medications. Corresponding rates for men were 56%, 63%, and 69% respectively. The pooled women-to-men prevalence ratios were 0.81 (95% CI, 0.72-0.92) for aspirin, 0.90 (95% CI, 0.85-0.95) for statins, and 1.01 (95% CI, 0.95-1.08) for any antihypertensive medications. Women were less likely to be prescribed angiotensin-converting enzyme inhibitors (0.85; 95% CI, 0.81-0.89) but more likely with diuretics (1.27; 95% CI, 1.17-1.37). Mean age, mean age difference between the sexes, and year of study had no significant impact on findings. Conclusions Sex differences in the prescription of cardiovascular medication exist among patients at high risk or with established cardiovascular disease in primary care, with a lower prevalence of aspirin, statins, and angiotensin-converting enzyme inhibitors prescription in women and a lower prevalence of diuretics prescription in men.

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Drug Prescriptions; Drug Utilization; Female; Healthcare Disparities; Humans; Male; Middle Aged; Observational Studies as Topic; Practice Patterns, Physicians'; Primary Health Care; Risk Assessment; Risk Factors; Sex Factors

We thought to delve deeper into seven meta-analyses of major clinical trials focusing on Glucagon-Like Peptide-One Receptor Agonist (GLP-1 RA) cardioprotective effect.. We explored the role of GLP-1 RA in cardiovascular risk protection as the primary outcome in subjects with type 2 diabetes mellitus.. The current review has explored and critically appraised seven meta-analyses of placebo- controlled randomized clinical trials (RCT-s) involving GLP-1 RA used in diabetes that has exhibited major cardiovascular events as the primary outcome.. Based on the participants-intervention-comparison and outcomes (PICO), the total number of the participants in this review were (138750), the intervention was conducted with GLP-1 RA, the comparator was a placebo and the outcome was major cardiovascular events. The overall evidence for the cardioprotective effect of GLP-1 RA in diabetes was very clear in subjects with the cardiovascular risk of varying degrees. Most of the currently reviewed meta-analyses have not shown cardioprotection with GLP-1 RA in subjects with diabetes exhibiting high cardiovascular risk or medical history of cardiovascular diseases. Patient variability, in addition to potency parameters, will be the key to a successful member of the class. There will be avenues for selection of a candidate based on the suitability to patient preferences and characteristics.. The RCT-s for GLP-1 RA should characterize cardiovascular risk in subjects with diabetes such that disparities between established cardiovascular risk (high, moderate and low) or medical history of cardiovascular disease have been accounted for in subgroup analysis.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Protective Agents; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors

Vascular tissue consists of endothelial cells, vasoactive smooth muscle cells and perivascular nerves. The perivascular sensory neuropeptide CGRP has demonstrated potent vasodilatory effects in any arterial vasculature examined so far, and a local protective CGRP-circuit of sensory nerve terminal CGRP release and smooth muscle cell CGRP action is evident. The significant vasodilatory effect has shadowed multiple other effects of CGRP in the vascular tissue and we therefore thoroughly review vascular actions of CGRP on endothelial cells, vascular smooth muscle cells and perivascular nerve terminals. The actions beyond vasodilation includes neuronal re-uptake and neuromodulation, angiogenic, proliferative and antiproliferative, pro- and anti-inflammatory actions which vary depending on the target cell and anatomical location. In addition to the classical perivascular nerve-smooth muscle CGRP circuit, we review existing evidence for a shadowed endothelial autocrine pathway for CGRP. Finally, we discuss the impact of local and systemic actions of CGRP in vascular regulation and protection from hypertensive and ischemic heart conditions with special focus on therapeutic CGRP agonists and antagonists.

Topics: Animals; Arteries; Calcitonin Gene-Related Peptide; Cardiovascular Agents; Cardiovascular Diseases; Hormone Antagonists; Humans; Receptors, Calcitonin Gene-Related Peptide; Signal Transduction; Vasodilation

Inflammation is an obligatory marker of arterial disease, both stemming from the inflammatory activity of cholesterol itself and from well-established molecular mechanisms. Raised progenitor cell recruitment after major events and clonal hematopoiesis related mechanisms have provided an improved understanding of factors regulating inflammatory phenomena. Trials with inflammation antagonists have led to an extensive evaluation of biomarkers such as the high sensitivity C reactive protein (hsCRP), not exerting a causative role, but frequently indicative of the individual cardiovascular (CV) risk. Aim of this review is to provide indication on the anti-inflammatory profile of agents of general use in CV prevention, i.e. affecting lipids, blood pressure, diabetes as well nutraceuticals such as n-3 fatty acids. A crucial issue in the evaluation of the benefit of the anti-inflammatory activity is the frequent discordance between a beneficial activity on a major risk factor and associated changes of hsCRP, as in the case of statins vs PCSK9 antagonists. In hypertension, angiotensin converting enzyme inhibitors exert an optimal anti-inflammatory activity, vs the case of sartans. The remarkable preventive activity of SLGT-2 inhibitors in heart failure is not associated with a clear anti-inflammatory mechanism. Finally, icosapent ethyl has been shown to reduce the CV risk in hypertriglyceridemia, with a 27 % reduction of hsCRP. The inflammation-based approach to arterial disease has considerably gained from an improved understanding of the clinical diagnostic strategy and from a better knowledge on the mode of action of numerous agents, including nutraceuticals.

Topics: Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus; Dietary Supplements; Dyslipidemias; Gastrointestinal Microbiome; Heart Disease Risk Factors; Humans; Hypertension; Hypoglycemic Agents; Hypolipidemic Agents; Inflammation; Inflammation Mediators; Risk Assessment; Signal Transduction

Cardiovascular diseases are recognized to be a major cause of people morbidity and mortality. A host of stress signals contribute to the pathogenesis of cardiovascular disorders. Deficiency of hydrogen sulfide (H

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Hydrogen Sulfide; Nitric Oxide; Nitric Oxide Donors; Nitrogen Oxides

Cyclic guanosine 3',5'-monophosphate (cGMP) is the key second messenger molecule in nitric oxide signaling. Its rapid generation and fate, but also its role in mediating acute cellular functions has been extensively studied. In the past years, genetic studies suggested an important role for cGMP in affecting the risk of chronic cardiovascular diseases, for example, coronary artery disease and myocardial infarction. Here, we review the role of cGMP in atherosclerosis and other cardiovascular diseases and discuss recent genetic findings and identified mechanisms. Finally, we highlight open questions and promising research topics.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Cyclic GMP; Genetic Variation; Humans; Nitric Oxide; Phenotype; Second Messenger Systems

Sestrin2 is a cysteine sulfinyl reductase that plays crucial roles in regulation of antioxidant actions. Sestrin2 provides cytoprotection against multiple stress conditions, including hypoxia, endoplasmic reticulum (ER) stress and oxidative stress. Recent research reveals that upregulation of Sestrin2 is induced by various transcription factors such as p53 and activator protein 1 (AP-1), which further promotes AMP-activated protein kinase (AMPK) activation and inhibits mammalian target of rapamycin protein kinase (mTOR) signaling. Sestrin2 triggers autophagy activity to reduce cellular reactive oxygen species (ROS) levels by promoting nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) activation and Kelch-like ECH-associated protein 1 (Keap1) degradation, which plays a pivotal role in homeostasis of metabolic regulation. Under hypoxia and ER stress conditions, elevated Sestrin2 expression maintains cellular homeostasis through regulation of antioxidant genes. Sestrin2 is responsible for diminishing cellular ROS accumulation through autophagy via AMPK activation, which displays cardioprotection effect in cardiovascular diseases. In this review, we summarize the recent understanding of molecular structure, biological roles and biochemical functions of Sestrin2, and discuss the roles and mechanisms of Sestrin2 in autophagy, hypoxia and ER stress. Understanding the precise functions and exact mechanism of Sestrin2 in cellular homeostasis will provide the evidence for future experimental research and aid in the development of novel therapeutic strategies for cardiovascular diseases.

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Cell Hypoxia; Humans; Molecular Targeted Therapy; NF-E2-Related Factor 2; Nuclear Proteins; Oxidative Stress; Signal Transduction; TOR Serine-Threonine Kinases

SLE is increasingly recognized as an important risk factor for cardiovascular disease. Premature CAD and several other cardiac manifestations are resulting in significant morbidity and premature death among young and older adults. There is a considerable unmet need for developing specific guidelines toward the primary and secondary prevention of cardiovascular disease in SLE patients.. The authors describe the prevalence of various cardiovascular manifestations, associated with traditional and lupus-specific risk factors. They summarize the evidence behind various nonpharmacological and pharmacological options such as cardiac medications, antimalarials, anti-inflammatory, and immunosuppressant medications.. There is considerable literature claiming that the traditional Framingham score used to calculate the risk in the general population would not clearly predict the 10-year risk among SLE patients as they do not include lupus-specific risk factors such as accelerated inflammation, immunometabolic changes, thrombosis, vasospasm, vasculitis, and endothelial dysfunction into account. Identifying potential risk factors among SLE patients and treating hyperlipidemia regardless of their risk scores may be the first step in reducing mortality. Blocking lupus-specific inflammatory pathways by targeting validated biomarkers of pathogenesis has great future potential and more studies are needed on their cardiovascular benefits.

Topics: Aged; Anti-Inflammatory Agents; Antimalarials; Cardiovascular Agents; Cardiovascular Diseases; Humans; Immunosuppressive Agents; Inflammation; Lupus Erythematosus, Systemic; Prevalence; Risk Factors

As transcriptional co-activators, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) can regulate cell proliferation, migration, differentiation, and apoptosis by interacting with the transcription factors [e.g., transcriptional enhancer associate domain (TEAD) family members]. Polarity and junctional proteins, mechanical stress, and G protein-coupled receptors (GPCRs) are Hippo pathway-dependent upstream regulatory pathways of YAP and TAZ activity. In addition, posttranslational modifications (such as phosphorylation, O-GlcNAcylation, acetylation, methylation, geranylgeranylation, and palmitoylation) also participate in the regulation of YAP and TAZ activity. YAP and TAZ have recently been implicated in the pathological process of vascular and heart diseases. The activation of YAP and TAZ promotes atherosclerosis, angiogenesis, restenosis, pulmonary hypertension, myocardial hypertrophy, and myocardial fibrosis, whereas the inhibition of YAP and TAZ is involved in aortic aneurysms, aortic dissection, myocardial ischemia-reperfusion injury, and myocardial infarction. Thus, both YAP and TAZ may be potential targets for treating cardiovascular diseases. In this review, we discuss the latest findings regarding YAP and TAZ and the potential drugs that target these compounds to treat cardiovascular diseases. This review lays the foundation for a future direction of cardiovascular disease research.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Intracellular Signaling Peptides and Proteins; Molecular Targeted Therapy; Protein Conformation; Protein Processing, Post-Translational; Signal Transduction; Structure-Activity Relationship; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; YAP-Signaling Proteins

Thrombosis initiated by abnormal platelet aggregation is a pivotal pathological event that precedes most cases of cardiovascular diseases (CVD). Recently, growing evidence indicates that platelet could be a potential target for CVD prevention. However, as the conventional antithrombotic management strategy, applications of current antiplatelet agents are somewhat limited by their various side effects, such as bleeding risk and drug resistance. Hence, efforts have been made to search for agents as complementary therapies. Ginsenoside, the principal active component extracted from Panax ginseng, has gained much attention for its regulations on multiple crucial events of platelet aggregation. From structural characteristics to clinical applications, this review anatomized the intrinsic structure-function relationship of antiplatelet potency of ginsenosides, and the involved signal pathways were specifically summarized. Additionally, the emphasis was placed on clinical studies that investigate the antithrombotic efficacy of ginsenosides in the treatment of CVD. Further, a broad overview of approaches for improving the bioavailability of ginsenosides was concluded. Limitations and prospects of current studies were also discussed. This study may provide some new insights into the systematic understanding of ginsenosides in CVD treatment and lay a foundation for future research.

Topics: Animals; Biological Availability; Blood Platelets; Cardiovascular Agents; Cardiovascular Diseases; Ginsenosides; Humans; Molecular Structure; Muscle, Smooth, Vascular; Neointima; Platelet Aggregation; Platelet Aggregation Inhibitors; Signal Transduction; Structure-Activity Relationship; Vascular Remodeling

Coronavirus disease 2019 (COVID-19) is declared as a pandemic that has spread worldwide, affecting 205 countries. The disease affected 1, 40, 43, 176 individuals and caused 5, 97, 583 deaths around the globe. The organism responsible for the cause of disease is Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). SARS-CoV-2 enters into the cell via receptors present on the cell surface named angiotensin-converting enzyme 2 (ACE2) receptor. Notwithstanding ACE2 receptors acts as a gateway for infection, and most of the cardiovascular patients are treated with the ACE inhibitors. Thus, the role of ACE inhibitors or angiotensin receptor blockers may play a critical role in the severity or outcome of disease. Also, the effect of ACE inhibitors varies with the polymorphism in ACE2 receptors present in the individuals. Hence, it is the need of the hour to investigate the mechanisms which could better aid in the treatment of COVID-19-infected cardiovascular disease (CVD) patients.

Topics: Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Betacoronavirus; Cardiovascular Agents; Cardiovascular Diseases; Coronavirus Infections; COVID-19; Host Microbial Interactions; Humans; Pandemics; Patient Safety; Peptidyl-Dipeptidase A; Pharmacogenomic Variants; Pneumonia, Viral; Polymorphism, Genetic; Prognosis; Risk Assessment; Risk Factors; SARS-CoV-2; Virus Internalization

Epigenetic processing takes centre stage in cardiometabolic diseases (obesity, metabolic syndrome, type 2 diabetes, hypertension), where it participates in adiposity, inflammation, endothelial dysfunction, vascular insulin resistance and atherosclerosis. Epigenetic modifications, defined as heritable changes in gene expression that do not entail mutation in the DNA sequence, are mainly induced by environmental stimuli (stress, pollution, cigarette smoking) and are gaining considerable interest due to their causal role in cardiovascular disease, and their amenability to pharmacological intervention. Importantly, epigenetic modifications acquired during life can be transmitted to the offspring and exert their biological effects across multiple generations. Indeed, such transgenerational transmission of epigenetic signals may contribute to anticipating cardiovascular and metabolic disease phenotypes already in children and young adults. A deeper understanding of environmental factors and their effects on the epigenetic machinery and transcriptional programs is warranted to develop effective mechanism-based therapeutic strategies. The clinical application of epigenetic drugs-also known as "epi-drugs"-is currently exploding in the field of cardiovascular disease. The present review describes the main epigenetic networks underlying cardiometabolic alterations and sheds light on specific points of intervention for pharmacological reprogramming in this setting.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Epigenesis, Genetic; Gene-Environment Interaction; Humans; Metabolic Syndrome; Risk Factors; Signal Transduction

The COVID-19 pandemic is an unprecedented healthcare emergency causing mortality and illness across the world. Although primarily affecting the lungs, the SARS-CoV-2 virus also affects the cardiovascular system. In addition to cardiac effects, e.g. myocarditis, arrhythmias, and myocardial damage, the vasculature is affected in COVID-19, both directly by the SARS-CoV-2 virus, and indirectly as a result of a systemic inflammatory cytokine storm. This includes the role of the vascular endothelium in the recruitment of inflammatory leucocytes where they contribute to tissue damage and cytokine release, which are key drivers of acute respiratory distress syndrome (ARDS), in disseminated intravascular coagulation, and cardiovascular complications in COVID-19. There is also evidence linking endothelial cells (ECs) to SARS-CoV-2 infection including: (i) the expression and function of its receptor angiotensin-converting enzyme 2 (ACE2) in the vasculature; (ii) the prevalence of a Kawasaki disease-like syndrome (vasculitis) in COVID-19; and (iii) evidence of EC infection with SARS-CoV-2 in patients with fatal COVID-19. Here, the Working Group on Atherosclerosis and Vascular Biology together with the Council of Basic Cardiovascular Science of the European Society of Cardiology provide a Position Statement on the importance of the endothelium in the underlying pathophysiology behind the clinical presentation in COVID-19 and identify key questions for future research to address. We propose that endothelial biomarkers and tests of function (e.g. flow-mediated dilatation) should be evaluated for their usefulness in the risk stratification of COVID-19 patients. A better understanding of the effects of SARS-CoV-2 on endothelial biology in both the micro- and macrovasculature is required, and endothelial function testing should be considered in the follow-up of convalescent COVID-19 patients for early detection of long-term cardiovascular complications.

Topics: Angiotensin-Converting Enzyme 2; Cardiovascular Agents; Cardiovascular Diseases; COVID-19; COVID-19 Drug Treatment; Cytokines; Endothelium, Vascular; Host-Pathogen Interactions; Humans; Inflammation Mediators; Prognosis; Risk Assessment; Risk Factors; SARS-CoV-2; Virus Internalization

Hypertension and cardiovascular diseases (CVD) are very common conditions and account for significant medical disability and death worldwide. Therefore, their successful management is very critical for the prevention of the significant cardiovascular and socioeconomic consequences arising from their poor management.. These new chemical entities have different mechanisms of action and in preliminary studies have been successful in the treatment of hypertension, CVD, heart failure, stroke, and type 2 diabetes mellitus. These drugs can be used either alone or in combination with other antihypertensive and cardiovascular drugs. Hopefully, these new classes of cardiovascular drugs would be effective for the treatment of hypertension and CVD and decrease their socioeconomic consequences.

Topics: Animals; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Development; Drug Discovery; Humans; Hypertension

Cardiovascular disease is a major cause of morbidity and mortality worldwide. Innovative new treatment options for this cardiovascular pandemic are urgently needed. Activation of purinergic receptors (PRs) is critically involved in the development and progression of cardiovascular disease including atherosclerosis, ischemic heart disease, hypertension, and diabetes. PRs have been targeted for the treatment of several cardiovascular diseases in a clinical setting. The P2Y

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Development; Drug Discovery; Humans; Molecular Targeted Therapy; Purinergic Agonists; Purinergic Antagonists; Receptors, Purinergic; Signal Transduction

: Pharmacological treatment recommended by guidelines for very high-risk patients with established cardiovascular disease (CVD) includes lipid-lowering drugs, antihypertensive agents and antiplatelet therapy. Depending on the associated comorbidities, this baseline regimen has to be complemented with other drugs. Therefore, the number of pills to be taken is usually high and adherence to these multiple pill therapeutic regimens and long-term persistence on treatment is low, being the main factor for insufficient control of cardiovascular risk factors. The CNIC (Centro Nacional de Investigaciones Cardiovasculares, Ministerio de Ciencia e Innovación, España) polypill is the only polypill containing low-dose aspirin approved by the EMA and marketed in Europe, and has demonstrated to improve adherence. For this reason, guidelines recommend its use for secondary prevention of CVD, and also for primary prevention of cardiovascular events in patients with multiple cardiovascular risk factors and advanced atherosclerotic process at high risk of thrombosis and low risk of bleeding. This article pretends to simplify the steps that clinicians may follow to switch from any baseline regimen to the polypill with the use of several algorithms and tables showing the equivalent effective daily doses of different angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and statins to facilitate switching, as well as the steps to be followed depending of the initial levels of BP and LDL-cholesterol values to achieve BP and lipid control with the association to the polypill of other BP-lowering or lipid-lowering drugs whenever needed.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Humans; Hypertension; Practice Guidelines as Topic; Primary Prevention; Secondary Prevention

The incidence and prevalence of type 2 diabetes mellitus are increasing in the United States and worldwide. The individual-level risk of atherosclerotic cardiovascular disease events in primary prevention populations with type 2 diabetes mellitus is highly heterogeneous. Accurate risk stratification in this group is paramount to optimize the use of preventive therapies. Herein, we review the use of the coronary artery calcium score as a decision aid in individuals with type 2 diabetes mellitus without clinical atherosclerotic cardiovascular disease to guide the use of preventive pharmacotherapies, such as aspirin, lipid-lowering mediations, and cardiometabolic agents. The magnitude of expected risk reduction for each of these therapies must be weighed against its cost and potential adverse events. Coronary artery calcium has the potential to improve risk stratification in select individuals beyond clinical and laboratory risk factors, thus providing a more granular assessment of the expected net benefit with each therapy. In patients with diabetes mellitus and stable chest pain, coronary computed tomography angiography increases the sensitivity for coronary artery disease diagnoses compared with functional studies because of the detection of nonobstructive atherosclerosis. Most importantly, this anatomic approach may improve cardiovascular outcomes by increasing the use of evidence-based preventive therapies informed by plaque burden. We therefore provide an updated discussion of the pivotal role of coronary computed tomography angiography in the workup of stable chest pain in patients with diabetes mellitus in the context of recent landmark trials, such as PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), SCOT-HEART trial (Scottish Computed Tomography of the Heart), and ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches). Finally, we also outline the current role of coronary computed tomography angiography in acute chest pain presentations.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clinical Decision-Making; Computed Tomography Angiography; Coronary Angiography; Diabetes Mellitus, Type 2; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Patient-Centered Care; Predictive Value of Tests; Primary Prevention; Prognosis; Risk Assessment

Alzheimer's disease (AD) is a complex, progressive, neurodegenerative disorder. As with other common chronic diseases, multiple risk factors contribute to the onset and progression of AD. Many researchers have evaluated the epidemiologic and pathophysiological association between AD, cardiovascular diseases (CVDs), and cerebrovascular diseases (CBVDs), including commonly reported risk factors such as diabetes, hypertension, and dyslipidemia. Relevant therapies of CVDs/CBVDs for the attenuation of AD have also been empirically investigated. Considering the challenges of new drug development, in terms of cost and time, multifactorial approaches such as therapeutic repositioning of CVD/CBVD medication should be explored to delay the onset and progression of AD. Thus, in this review, we discuss our current understanding of the association between cardiovascular risk factors and AD, as revealed by clinical and non-clinical studies, as well as the therapeutic implications of CVD/CBVD medication that may attenuate AD. Furthermore, we discuss future directions by evaluating ongoing trials in the field.

Topics: Alzheimer Disease; Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Clinical Trials as Topic; Diabetes Mellitus; Disease Progression; Drug Repositioning; Dyslipidemias; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Neuroprotective Agents

The obesity pandemic now affects hundreds of millions of people worldwide. As obesity rates continue to increase, emergency physicians are called on with increasing frequency to resuscitate obese patients. This article discusses important anatomic, physiologic, and practical challenges imposed by obesity on resuscitative care. Impacts on hemodynamic monitoring, airway and ventilator management, and pharmacologic therapy are discussed. Finally, several important clinical scenarios (trauma, cardiac arrest, and sepsis), in which alterations to standard treatments may benefit obese patients, are highlighted.

Topics: Airway Management; Analgesics; Anti-Bacterial Agents; Body Composition; Cardiovascular Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Emergency Service, Hospital; Heart Arrest; Humans; Hypnotics and Sedatives; Lung Volume Measurements; Obesity; Oxygen Consumption; Pharmacokinetics; Positive-Pressure Respiration; Resuscitation; Sepsis; Wounds and Injuries

The gut microbiome and intestinal dysfunction have emerged as potential contributors to the development of cardiovascular disease (CVD). Alterations in gut microbiome are well documented in hypertension, atherosclerosis, and heart failure and have been investigated as a therapeutic target. However, a perhaps underappreciated but related role for intestinal barrier function has become evident. Increased intestinal permeability is observed in patients and mouse models of CVD. This increased intestinal permeability can enhance systemic inflammation, alter gut immune function, and has been demonstrated as predictive of adverse cardiovascular outcomes. The goal of this review is to examine the evidence supporting a role for intestinal barrier function in cardiovascular disease and its prospect as a novel therapeutic target. We outline key studies that have investigated intestinal permeability in hypertension, coronary artery disease, atherosclerosis, heart failure, and myocardial infarction. We highlight the central mechanisms involved in the breakdown of barrier function and look at emerging evidence for restored barrier function as a contributor to promising treatment strategies such as short chain fatty acid, probiotic, and renin angiotensin system-targeted therapeutics. Recent studies of more selective targeting of the intestinal barrier to improve disease outcomes are also examined. We suggest that although current data supporting a contribution of intestinal permeability to CVD pathogenesis are largely associative, it appears to be a promising avenue for further investigation. Additional studies of the mechanisms of barrier restoration in CVD and testing of intestinal barrier-targeted compounds will be required to confirm their potential as a new class of CVD therapeutic.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Gastrointestinal Agents; Gastrointestinal Microbiome; Humans; Intestinal Absorption; Intestines; Permeability

Cardiovascular disease (CVD) is the most wide-spread disorder all over the world. The personalized and precision diagnosis, treatment and prevention of CVD is still a challenge. With the developing of metagenome sequencing technologies and the paradigm shifting to data-driven discovery in life science, the computer aided microbiota biomarker discovery for CVD is becoming reality. We here summarize the data resources, knowledgebases and computational models available for CVD microbiota biomarker discovery, and review the present status of the findings about the microbiota patterns associated with the therapeutic effects on CVD. The future challenges and opportunities of the translational informatics on the personalized drug usages in CVD diagnosis, prognosis and treatment are also discussed.

Topics: Animals; Bacteria; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Dysbiosis; Host-Pathogen Interactions; Humans; Metagenome; Metagenomics; Precision Medicine; Predictive Value of Tests; Risk Assessment; Risk Factors

The review highlights selected studies related to cardiovascular disease (CVD) prevention that were presented at the 2020 European Society of Cardiology (ESC) Congress-The Digital Experience.. The studies reviewed include clinical trials on novel RNA interference-based lipid-lowering therapies AKCEA-APOCIII-L

Topics: Benzhydryl Compounds; Betacoronavirus; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Congresses as Topic; Coronavirus Infections; COVID-19; Eicosapentaenoic Acid; Europe; Glucosides; Humans; Lipid Regulating Agents; Oligonucleotides; Pandemics; Pneumonia, Viral; SARS-CoV-2; Societies, Medical; Telecommunications

The contribution of natural products (NPs) to cardiovascular medicine has been extensively documented, and many have been used for centuries. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Over the past 40 years, approximately 50% of newly developed cardiovascular drugs were based on NPs, suggesting that NPs provide essential skeletal structures for the discovery of novel medicines. After a period of lower productivity since the 1990s, NPs have recently regained scientific and commercial attention, leveraging the wealth of knowledge provided by multi-omics, combinatorial biosynthesis, synthetic biology, integrative pharmacology, analytical and computational technologies. In addition, as a crucial part of complementary and alternative medicine, Traditional Chinese Medicine has increasingly drawn attention as an important source of NPs for cardiovascular drug discovery. Given their structural diversity and biological activity NPs are one of the most valuable sources of drugs and drug leads. In this review, we briefly described the characteristics and classification of NPs in CVDs. Then, we provide an up to date summary on the therapeutic potential and the underlying mechanisms of action of NPs in CVDs, and the current view and future prospect of developing safer and more effective cardiovascular drugs based on NPs.

Topics: Animals; Biological Products; Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Drugs, Chinese Herbal; Humans; Legislation, Drug; Medicine, Chinese Traditional; Patents as Topic

Chronic heart failure is one of the most common medical conditions, affecting more than 23 million people worldwide. Despite established guideline-based, multidrug pharmacotherapy, chronic heart failure is still the cause of frequent hospitalisation, and about 50% die within five years of diagnosis.. To assess the effectiveness and safety of ivabradine in individuals with chronic heart failure.. We searched CENTRAL, MEDLINE, Embase, and CPCI-S Web of Science in March 2020. We also searched ClinicalTrials.gov and the WHO ICTRP. We checked reference lists of included studies. We did not apply any time or language restrictions.. We included randomised controlled trials in which adult participants diagnosed with chronic heart failure were randomly assigned to receive either ivabradine or placebo/usual care/no treatment. We distinguished between type of heart failure (heart failure with a reduced ejection fraction or heart failure with a preserved ejection fraction) as well as between duration of ivabradine treatment (short term (< 6 months) or long term (≥ 6 months)).. Two review authors independently assessed trials for inclusion, extracted data, and checked data for accuracy. We calculated risk ratios (RR) using a random-effects model. We completed a comprehensive 'Risk of bias' assessment for all studies. We contacted authors for missing data. Our primary endpoints were: mortality from cardiovascular causes; quality of life; time to first hospitalisation for heart failure during follow-up; and number of days spent in hospital due to heart failure during follow-up. Our secondary endpoints were: rate of serious adverse events; exercise capacity; and economic costs (narrative report). We assessed the certainty of the evidence applying the GRADE methodology.. We included 19 studies (76 reports) involving a total of 19,628 participants (mean age 60.76 years, 69% male). However, few studies contributed data to meta-analyses due to inconsistency in trial design (type of heart failure) and outcome reporting and measurement. In general, risk of bias varied from low to high across the included studies, with insufficient detail provided to inform judgement in several cases. We were able to perform two meta-analyses focusing on participants with heart failure with a reduced ejection fraction (HFrEF) and long-term ivabradine treatment. There was evidence of no difference between ivabradine and placebo/usual care/no treatment for mortality from cardiovascular causes (RR 0.99, 95% confidence interval (CI) 0.88 to 1.11; 3 studies; 17,676 participants; I. We found evidence of no difference in cardiovascular mortality and serious adverse events between long-term treatment with ivabradine and placebo/usual care/no treatment in participants with heart failure with HFrEF. Nevertheless, due to indirectness (male predominance), the certainty of the available evidence is rated as moderate.

Topics: Bias; Cardiovascular Agents; Cardiovascular Diseases; Chemotherapy, Adjuvant; Chronic Disease; Exercise Tolerance; Female; Heart Failure; Humans; Ivabradine; Male; Middle Aged; Placebos; Randomized Controlled Trials as Topic; Stroke Volume

Lysine acetylation is a conserved, reversible, post-translational protein modification regulated by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs; also known as histone deacetylases (HDACs)) that is involved in many cellular signalling pathways and diseases. Studies in animal models have revealed a regulatory role of reversible lysine acetylation in hypertension, vascular diseases, arrhythmia, heart failure and angiogenesis. Evidence from these studies indicates a therapeutic role of KDAC inhibitors (also known as HDAC inhibitors) in cardiovascular diseases. In this Review, we describe the diverse roles of KATs and KDACs in both the normal and the diseased heart. Among KDACs, class II and class III HDACs seem to have a protective role against both cardiac damage and vessel injury, whereas class I HDACs protect against vessel injury but have deleterious effects on the heart. These observations have important implications for the clinical utility of HDAC inhibitors as therapeutic agents for cardiovascular diseases. In addition, we summarize the latest data on nonacetylation acylations in the context of cardiovascular disease.

Topics: Acetylation; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Lysine; Lysine Acetyltransferases; Molecular Targeted Therapy; Protein Processing, Post-Translational; Signal Transduction

microRNAs (miRNAs) are an evolutionarily conserved class of small single-stranded noncoding RNAs. The aberrant expression of specific miRNAs has been implicated in the development and progression of diverse cardiovascular diseases. For many decades, miRNA therapeutics has flourished, taking advantage of the fact that miRNAs can modulate gene expression and control cellular phenotypes at the posttranscriptional level. Genetic replacement or knockdown of target miRNAs by chemical molecules, referred to as miRNA mimics or inhibitors, has been used to reverse their abnormal expression as well as their adverse biological effects in vitro and in vivo in an effort to fully implement the therapeutic potential of miRNA-targeting treatment. However, the limitations of the chemical structure and delivery systems are hindering progress towards clinical translation. Here, we focus on the regulatory mechanisms and therapeutic trials of several representative miRNAs in the context of specific cardiovascular diseases; from this basic perspective, we evaluate chemical modifications and delivery vectors of miRNA-based chemical molecules and consider the underlying challenges of miRNA therapeutics as well as the clinical perspectives on their applications.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; MicroRNAs; Small Molecule Libraries

Urotensin II (UII) is a vasoactive peptide that interacts with a specific receptor called the UT receptor. UII has been implicated in cardiovascular regulation, with promising therapeutic applications based on UT receptor antagonism. The endogenous ligands of the UT receptor: UII and urotensin-related peptide (URP), differentially bind and activate this receptor. Also, the receptor localization is not restricted to the plasma membrane, possibly inducing different physiological responses that could support its inconsistent, but potent, vasoactive activity. These properties could explain the disappointing outcomes in clinical studies, in contrast to the positive preclinical results regarding heart failure, pulmonary hypertension, atherosclerosis and diabetes mellitus. These aspects should be considered in future investigations to a better comprehension of the role of UII as a potential therapeutic target.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Drug Discovery; Humans; Ligands; Receptors, G-Protein-Coupled; Signal Transduction; Tissue Distribution; Urotensins

Urocortin-2 (Ucn-2) is a peptide of the corticotrophin releasing factor-related family with several effects within the cardiovascular system. A variety of molecular mechanisms has been proposed to underlie some of these effects, although others remain mostly hypothetical. Growing interest in the cardiovascular properties of this peptide promoted several pre-clinical studies in the settings of heart failure and ischemia, as well as some experiments in the fields of systemic and pulmonary arterial hypertension. Most of these studies report promising results, with Ucn-2 showing therapeutic potential in these settings, and few clinical trials to date are trying to translate this potential to human cardiovascular disease. Ucn-2 also appears to have potential as a biomarker of diagnostic/prognostic relevance in cardiovascular disease, this being a recent field in the study of this peptide needing further corroboration. Regarding the increasing amount of evidence in Ucn-2 investigation, this work aims to make an updated review on its cardiovascular effects and molecular mechanisms of action and therapeutic potential, and to identify some research barriers and gaps in the study of this cardioprotective peptide.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Corticotropin-Releasing Hormone; Hemodynamics; Humans; Treatment Outcome; Urocortins; Ventricular Function

People with diabetes are at a higher risk of atherosclerotic cardiovascular disease (ASCVD) compared with those without diabetes. Though aspirin has been shown to have an overall net clinical benefit when used for secondary prevention of ASCVD in people with and without diabetes, the evidence for primary prevention, especially in those with diabetes, remains inconsistent. In this article, we review the latest studies examining the risks and benefits of aspirin use for primary prevention of ASCVD in adults with diabetes, discuss key aspects in assessing the risk-benefit ratio of aspirin use for primary prevention of ASCVD, and summarize current guidelines from professional societies on aspirin use for primary prevention in adults with diabetes.. In the general population, past studies have shown no difference in the beneficial effect of aspirin for primary cardiovascular disease prevention by diabetes status. However, several randomized controlled studies and meta-analyses in adults with diabetes have shown lack of net clinical benefit of aspirin use for primary prevention of ASCVD. The recent ASCEND trial documented cardiovascular benefit of aspirin for primary prevention in adults with diabetes but suggested that the increased risk of bleeding may outweigh the cardiovascular benefit. The decision to initiate aspirin for primary prevention of ASCVD must be considered carefully on an individual basis to balance the cardiovascular benefit and bleeding risk in all patients, especially those with diabetes. A multifactorial approach that focuses on managing ASCVD risk factors such as hypertension, dyslipidemia, dysglycemia, and smoking is recommended in all patients. More research is needed to identify subgroups of people with diabetes who are more likely to benefit from aspirin use for primary prevention of ASCVD and develop better antithrombotic strategies that shift the risk-benefit balance toward an overall net clinical benefit.

Topics: Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Complications; Humans; Primary Prevention; Risk Assessment

Cardiovascular drug research and development (R&D) has been in active state and continuously attracts attention from the pharmaceutical industry. However, only one individual drug can eventually reach the market from about the 10,000 compounds tested. It would be useful to learn from these failures when developing better strategies for the future. Discontinued drugs were identified from a search performed by Thomson Reuters Integrity. Additional information was sought through PubMed, ClinicalTrials.gov, and pharmaceutical companies search. Twelve compounds discontinued for cardiovascular disease treatment after reaching Phase I-III clinical trials from 2016 to 2018 are detailed in this manuscript, and the reasons for these failures are reported. Of these, six candidates (MDCO-216, TRV027, ubenimex, sodium nitrite, losmapimod, and bococizumab) were dropped for lack of clinical efficacy, the other six for strategic or unspecified reasons. In total, three candidates were discontinued in Phase I trials, six in Phase II, and three in Phase III. It was reported that the success rate of drug R&D utilizing selection biomarkers is higher. Four candidate developments (OPC-108459, ONO-4232, GSK-2798745, and TAK-536TCH) were run without biomarkers, which could be used as surrogate endpoints in the 12 cardiovascular drugs discontinued from 2016 to 2018. This review will be useful for those involved in the field of drug discovery and development, and for those interested in the treatment of cardiovascular disease.

Topics: Animals; Biomarkers, Pharmacological; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Drug Development; Humans; Treatment Outcome

Patients with cancer survivors are at increased risk of cardiovascular disease(CVD). Cardio-oncology has developed as a new discipline with the advances in cancer treatment. There are many new challenges for the clinician and a new frontier for research and investigation. There is an urgent need for further study on the prevention of cardiovascular toxicity. Imperatorin (IMP) is a natural form of coumarin and extract from several plants with diver's pharmacokinetic effects, including antioxidant and anti-inflammatory properties. This review focus on the molecular mechanisms and pharmacological effects of Imperatorin maybe provide potential cancer and cardiovascular protection that targets IMP. Further studies are required to elucidate the entire spectrum of cytotoxic activities of these compounds to validate and expand their preclinical and clinical applications and to clarify the potential role of IMP.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Furocoumarins; Humans; Inflammation Mediators; Neoplasms; Oxidative Stress; Signal Transduction

Life expectancy in patients with all stages of chronic kidney disease (CKD) falls far short of that in the general population. Cardiovascular disease is the leading cause of mortality in pediatric patients with CKD. In contrast to the intimal atherosclerotic lesions that characterize cardiovascular disease in the general population, vascular endothelial dysfunction, medial arterial calcification, and cardiac dysfunction contribute to cardiovascular pathological conditions in CKD. The pathogenesis of these lesions, the origins of which can be identified in the absence of traditional cardiovascular risk factors, is incompletely understood. CKD-mediated vascular calcification in CKD is characterized by a transition of vascular smooth muscle cells to an osteoblast-like phenotype and altered bone and mineral metabolism are strongly linked to progressive cardiovascular disease in this population. Renal osteodystrophy therapies, including phosphate binders, vitamin D analogs, and calcimimetics, have an impact on the progression of cardiovascular disease. However, cardiovascular disease has its origins before the development of secondary hyperparathyroidism, and optimal therapeutic regimens that minimize cardiac dysfunction, vascular calcification, and early mortality remain to be defined.

Topics: Age Factors; Arteries; Bone and Bones; Calcimimetic Agents; Cardiovascular Agents; Cardiovascular Diseases; Chelating Agents; Child; Chronic Kidney Disease-Mineral and Bone Disorder; Disease Progression; Endothelium, Vascular; Humans; Kidney Transplantation; Minerals; Renal Insufficiency, Chronic; Tunica Media; Vascular Calcification; Vitamin D

Nonadherence to cardiovascular medicines occurs in 60% of subjects with chronic cardiovascular disease and leads to poor outcomes. In an attempt to improve adherence and cardiovascular outcomes, interventions are often used. Interventions may involve a pharmacist, but it is not always clear whether these are effective.. The primary objective of this review is to determine whether interventions by pharmacists, alone, discussing adherence to medicines, improve adherence to medicines for cardiovascular disease. Subsequently, the review links the characteristics of the individual studies with effectiveness or lack of effect. The second objective of this review is to consider whether any improvement in adherence with interventions by pharmacist is associated with better clinical outcomes.. A literature search of PubMed and CINAHL for 'pharmacist', 'medicine' with 'adherence' or 'compliance' or 'persistence' was undertaken. To be included in this review, papers had to be of a pharmacist working alone and in person in an intervention of subjects with hypertension, hyperlipidemia (prior to or after a coronary artery event) or heart failure. The paper had to be published in a peer review journal, with a measure of adherence to medicines. The effectiveness of the intervention had to be evaluated after ≥6 months.. Only 3 out of 8 interventions by pharmacists in hypertension, and 5 out of 12 interventions in subjects with hyperlipidemia led to improved adherence to medicines. In contrast, all 6 interventions by a pharmacist in subjects with heart failure were successful in improving adherence. One characteristic of successful interventions by pharmacists to improve adherence to cardiovascular medicines is that they must be more than brief/single interventions. A second characteristic is that the intervention should not involve subjects who are already highly adherent, as it is unlikely adherence can be improved in this population. Only 2 of 3 successful interventions in hypertension were associated with small reductions in blood pressure, and only one intervention in hyperlipidemia was shown to decrease LDL-cholesterol to a small extent. In subjects with heart failure, 5 of the 6 successful studies of the successful interventions by pharmacists to increase adherence also showed improved clinical outcomes.. When planning an intervention to improve adherence to medicines and cardiovascular outcomes in subjects with hypertension or hyperlipidemic, by a pharmacist alone, or as part of a multi-faceted interventions, it is essential to use an intervention that has been shown to be effective, as most interventions are not effective at improving adherence or only improve adherence and clinical outcomes to a small extent. In heart failure, there is well documented evidence of interventions by pharmacists that do improve clinical outcomes, which should be adopted widely.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Health Communication; Humans; Medication Adherence; Pharmacists; Professional Role

Thrombotic disorders are characterized by an increase in the probability of the formation of unnecessary thrombi that might be due to the activation of the coagulation cascade or the circulating platelets. Platelets or thrombocytes play an essential role in hemostasis but abnormal platelet function leads to the development of a number of cardiovascular complications, including thrombotic disorders. Under pathological conditions, platelets are associated with the development of different thrombotic disorders, including atherosclerosis, arterial thrombosis and stroke, deep venous thrombosis and pulmonary embolism; therefore, platelets are the target of a number of anti-thrombotic strategies. Flavonoids, a large group of polyphenols ubiquitously expressed in fruits and vegetables that have attracted considerable attention because of their benefits in human health, including the reduction of the risk of cardiovascular disease. Flavonoids have been reported to reduce platelet activity by attenuating agonist-induced GPIIb/IIIa receptor activation, mobilization of intracellular free Ca2+, granule exocytosis, as well as activation of different signaling molecules such as mitogen- activated protein kinases or phospholipases. This review summarizes the current studies concerning the modulation of platelet activation by flavonoids, giving especial attention to those events associated to thrombotic disorders.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Flavonoids; Humans; Platelet Activation; Thrombosis

Soluble guanylyl cyclase (sGC) is an effector enzyme of nitric oxide (NO). Recent work has unravelled how levels of this enzyme are controlled, and highlighted a role in vascular disease. We provide a timely summary of available knowledge on transcriptional regulation of sGC, including influences from the NOTCH signalling pathway and genetic variants. It is speculated that hypertension-induced repression of sGC starts a vicious circle that can be initiated by periods of stress, diet or genetic factors, and a key tenet is that reduction in sGC further raises blood pressure. The idea that dysregulation of sGC contributes to syndromes caused by defective NOTCH signalling is advanced, and we discuss drug repositioning for vascular disease prevention. The advantage of targeting sGC expression rather than activity is also considered. It is argued that transcriptional inputs on sGC arise from interactions with other cells, the extracellular matrix and microRNAs (miRNAs), and concluded that the promise of sGC as a target for prevention of cardiovascular disease has increased in recent time.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Gene Expression Regulation; Guanylate Cyclase; Humans; Receptors, Notch

Chronic Obstructive Pulmonary Disease (COPD) and Cardiovascular Diseases (CV) Often Coexist. COPD and CVD are complex diseases characterized by a strict interaction between environment and genetic. The mechanisms linking these two diseases are complex, multifactorial and not entirely understood, influencing the therapeutic approach. COPD is characterized by several comorbidities, it hypothesized the treatment of cardiovascular co-morbidities that may reduce morbidity and mortality. Flavonoids are an important class of plant low molecular weight Secondary Metabolites (SMs). Convincing data from laboratory, epidemiological, and human clinical studies point the important effects on CVD risk prevention.. This review aims to provide up-to-date information on the ability of Flavonoids to reduce the CVD risk.. Current studies support the potential of Flavonoids to prevent the risk of CVD. Well-designed clinical studies are suggested to evaluate advantages and limits of Flavonoids for managing CVD comorbidity in COPD.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Flavonoids; Humans; Pulmonary Disease, Chronic Obstructive

Use of cardiovascular medication has increased over time, especially for primary and secondary prevention, with polypharmacy common.. Review of published systematic reviews of the factors and outcomes associated with adherence to cardiovascular medication using MEDLINE, Embase, CINAHL and PsycINFO databases. Quality was assessed using the AMSTAR tool.. Of 789 systematic reviews identified, 45 met the inclusion criteria and passed the quality assessment; 34 focused on factors associated with adherence, and 11 on outcomes. High heterogeneity, both between and within reviews, precluded meta-analysis and so a pooled estimate of adherence levels could not be derived. Adherence was associated with disease factors, therapy factors, healthcare factors, patient factors and social factors, though with some inconsistencies. In total, 91% of reviews addressing outcomes reported that low adherence was associated with poorer clinical and economic endpoints.. Factors from across five key domains relate to non-adherence to cardiovascular medications, and may contribute to poorer clinical outcomes. Interventions to improve adherence should be developed to address modifiable factors and targeted at those at highest risk of non-adherence. Adherence research is highly heterogeneous to-date and efforts to standardize this should be implemented to improve comparability.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Female; Humans; Male; Medication Adherence; Polypharmacy; Socioeconomic Factors; Treatment Outcome

Telepharmacy is devised to provide pharmacy operations and patient care at a distance and to expand access to healthcare, enhance patients' safety and improve patient outcomes. A variety of technologies, models of care and interventions are used to develop and provide telepharmacy services, serving diversified populations with different pathological conditions, including cardiovascular diseases. Unfortunately, very few randomized controlled studies have evaluated the clinical efficacy of the implementation of telepharmacy services in the management of various cardiovascular conditions, with the strongest evidence being limited to telemonitoring studies in the areas of hypertension and diabetes. Although the clinical efficacy of telepharmacy, and its cost effectiveness, are far from being fully proved, the inclusion of telepharmacy services in healthcare models may offer the unique opportunity to increase access to screening and improve care of cardiovascular conditions.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Community Pharmacy Services; Delivery of Health Care, Integrated; Humans; Patient Care Team; Pharmacists; Professional Role; Telemedicine

Prescription of cardiovascular drugs is aimed at preventing and treating morbid conditions affecting the cardiovascular system. However, apart from their primary therapeutic target, some of the ordinary drugs used in cardiology daily practice also have additional pharmacological actions. Among these ancillary actions, those primarily affecting global and cardiac metabolism deserve special attention. In fact, apart from primary cardiac metabolic diseases, most cardiovascular diseases are heavily influenced by the patient's metabolic status and adaptation to the disease itself. In this context, drugs affecting global and cardiovascular metabolism besides their recognized main mechanism of action may be of special interest, for both potential beneficial and deleterious effects, especially in the long-term period. In all cases, these effects should be well understood and known by all physicians managing patients with cardiovascular morbidities. The aim of this article is to describe the direct metabolic actions of some of the principal cardiovascular drugs.

Topics: Animals; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Energy Metabolism; Humans; Risk Factors; Treatment Outcome

Most cardiovascular diseases are caused by modifiable risk factors yet prevalence continues to increase and heart disease remains the leading cause of death in the United States. Screening, identifying and appropriately managing high risk patients are strategies to shift the paradigm from treatment to prevention. Pharmacists are an underutilized population health resource despite robust evidence to support their roles as interdisciplinary team members and direct patient care providers in both inpatient and outpatient settings. This article aims to highlight the multifaceted function and impact of clinical pharmacists on cardiovascular risk reduction and disease management.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Disease Management; Humans; Patient Care Team; Pharmacists; Risk Reduction Behavior; United States

A large body of evidence indicates that mitochondrial dysfunction has a major role in the pathogenesis of multiple cardiovascular disorders. Over the past 2 decades, extraordinary efforts have been focused on the development of agents that specifically target mitochondria for the treatment of cardiovascular disease. Despite such an intensive wave of investigation, no drugs specifically conceived to modulate mitochondrial functions are currently available for the clinical management of cardiovascular disease. In this Review, we discuss the therapeutic potential of targeting mitochondria in patients with cardiovascular disease, examine the obstacles that have restrained the development of mitochondria-targeting agents thus far, and identify strategies that might empower the full clinical potential of this approach.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Mitochondria, Heart; Molecular Targeted Therapy

Type 2 diabetes mellitus and cardiovascular diseases (CVD) have become the main cause of morbidity and death worldwide. In addition, current anti-diabetic and cardiovascular therapy is based on conventional drugs that have limited effectiveness and adverse side effects. In this regard, the role of medicinal herbs as a complementary or an alternative medicine is of great interest. Urtica dioica L. (Urticaceae), which is the focus of this review, has been widely used in traditional medicine to treat a variety of ailments, including, diabetes, hypertension and prostate cancer. The aim of this article is to review current knowledge related to the anti-diabetic and cardiovascular properties of U. dioica, with particular emphasis on the bioactive compounds, the plant parts used, and the action mechanism behind lowering blood glucose level and reducing risk of CVD. We also discuss the chemical composition and toxicological properties of the plant. From this review, it was suggested that the anti-diabetic and the cardiovascular effects of U. dioica are attributed to different classes of compounds, such as polyphenols, triterpens, sterols, flavonoids, and lectin which reduce the blood glucose level and the risk of CVD by their antihypertensive, antioxidant and anti-inflammatory properties and/or by interfering with different cellular signalization pathways, including increase of NO, inhibition of α-amylase and α-glycosidase, modulation of GLUT4 and protection of pancreatic β-cells, among others. The identification of the plant constituents and the understanding of their exact action mechanisms are necessary to prove the efficacy of the plant and develop it as pharmacological drug.

Topics: Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Phytochemicals; Phytotherapy; Urtica dioica

Direct-acting antivirals (DAAs) are known victims (substrate) and perpetrators (cause) of drug-drug interactions (DDIs). These DAAs are used for the treatment of hepatitis C virus (HCV) infections and are highly effective drugs. Drugs used for cardiovascular risk management are frequently used by HCV-infected patients, whom also are treated with DAAs. Therefore, the aim of this review was to describe DDIs between cardiovascular drugs (CVDs) and DAAs. An extensive literature search was performed containing search terms for the marketed DAAs and CVDs (β-blocking agents, ACE inhibitors, angiotensin II antagonists, renin inhibitors, diuretics, calcium channel blockers, statins/ezetimibe, fibrates, platelet aggregation inhibitors, vitamin K antagonists, heparins, direct Xa inhibitors, nitrates, amiodarone, and digoxin). In particular, the drug labels from the European Medicines Agency and the US Food and Drug Administration were used. A main finding of this review is that CVDs are mostly victims of DDIs with DAAs. Therefore, when possible, monitoring of pharmacodynamics is recommended when coadministering these drugs with DAAs. Nevertheless, it is sometimes better to discontinue a drug on a temporary basis (statins, ezetimide). The DAAs are victims of DDIs in combination with bisoprolol, carvedilol, labetalol, verapamil, and gemfibrozil. Despite there are many DDIs predicted in this review, most of these DDIs can be managed by monitoring the efficacy and toxicity of the victim drug or by switching to another CVD/DAA.

Topics: Antiviral Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Drug Therapy, Combination; Hepatitis C; Humans; Risk

Saffron as a natural product has long been used to impede and treat different disorders including cardiovascular disease (CVDs). Stigma is the most principal part of saffron. Various compounds such as carotenoids and flavonoids are the essential components of saffron stigma. The health benefits of saffron have been shown in previous studies; however, there is a lack of comprehensive data on the mechanistic aspects of its cardiovascular-health properties. This current comprehensive review focuses on the medicinal applications of saffron, and then the new findings regarding its cardiovascular-health effects and various cellular and molecular mechanisms of action will be debated.. The literature search of MEDLINE, Embase, PubMed, Google Scholar and Cochrane Library was performed for all comparative studies since 2000-2018 with the limitations of the English language.. The results provided new evidence about antioxidant, anti-inflammatory, anti- atherogenic, anti- apoptotic, anti- hypertensive, and hypolipidemic effects of saffron. Pharmacological effects of saffron are due to a number of ingredients contained within this spice, including safranal, crocetin and crocins.. Our study concludes that saffron with wide range of usefulness in medicine may be the potent candidate in the process of new drug production for the treatment of CVDs.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Crocus; Humans; Plant Preparations

The endothelium is a thin innermost layer of flat cells which release various mediators including endothelin-1 (ET-1), prostanoids, von Willebrand factor (vWF) and endothelium-derived relaxing factor (EDRF; nitric oxide) to regulate vascular tone. Endothelial nitric oxide synthase (eNOS) is a key enzyme that generates nitric oxide (NO). NO maintains vascular homeostasis and cardiac functions by influencing major vascular protective properties such as anti-platelet, anti-proliferative, anti-migratory, antioxidant and anti-inflammatory action in vessels. Abnormal endothelial production and release of NO lead to vascular endothelial dysfunction (VED) and further leads to pathogenesis in myocardial and other tissues. Numerous pharmacological agents such as angiotensin-converting enzyme inhibitors, statins, calcium channel blockers, ET-1 receptor antagonists, insulin sensitizers, antioxidants and supplements like tetrahydrobiopterin, arginine and folate have been implicated in the treatment of VED, but their therapeutic potency was restricted due to some unavoidable adverse effects. The new era with advances in nanotechnology and its ability to target a specific disease, nano-medicine explored an innovative gateway for advanced therapy for VED. The present commentary reveals the various available, pipeline nano-medicine, their interaction with endothelium and in other associated pathological conditions and their delivery strategies for target-specific treatment of VED.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Carriers; Drug Compounding; Endothelium, Vascular; Humans; Nanomedicine; Nanoparticles; Signal Transduction; Technology, Pharmaceutical

The burden of cardiovascular diseases (CVD) is increasing, particularly in low-middle-income countries such as most of Latin America. This region presents specific socioeconomic characteristics, generating a high incidence of CVD despite efforts to control the problem. A consensus statement has been developed by Inter-American Society of Cardiology with the aim of answering some important questions related to CVD in this region and the role of the polypill in cardiovascular (CV) prevention as an intervention to address these issues. A multidisciplinary team composed of Latin American experts in the prevention of CVD was convened by the Inter-American Society of Cardiology and participated in the process and the formulation of statements. To characterize the prevailing situation in Latin American countries, we describe the most significant CV risk factors in the region. The barriers that impair the use of CV essential medications are also reviewed. The role of therapeutic adherence in CV prevention and how the polypill emerges as an effective strategy for optimizing adherence, accessibility, and affordability in the treatment of CVDs are discussed in detail. Clinical scenarios in which the polypill could represent an effective intervention in primary and secondary CV prevention are described. This initiative is expected to help professionals involved in the management of CVD and public health policymakers develop optimal strategies for the management of CVDs.

Topics: Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Consensus; Humans; Latin America; Medication Adherence; Public Health; Risk Factors; Secondary Prevention; Societies, Medical; United States

Endothelial cells (ECs) are the innermost layer of blood vessels that play important roles in homeostasis and vascular function. However, recent evidence suggests that the onset of inflammation and the production of reactive oxygen species impair the function of ECs and are a main factor in the development of cardiovascular disease (CVD). In this study, we investigated the effects of inflammatory markers, oxidative stress, and treatment on ECs in CVD patients. This review article is based on the material obtained from PubMed up to 2018. The key search terms used were "Cardiovascular Disease," "Endothelial Cell Dysfunction," "Inflammation," "Treatment," and "Oxidative Stress." The generation of reactive oxygen species (ROS) as well as reduced nitric oxide (NO) production by ECs impairs the function of blood vessels. Therefore, treatment of CVD patients leads to the expression of transcription factors activating anti-oxidant mechanisms and NO production. In contrast, NO production by inflammatory agents can cause ECs repair due to differentiation of endothelial progenitor cells (EPCs). Therefore, identifying the molecular pathways leading to the differentiation of EPCs through mediation of factors induced by inflammatory factors can be effective in regenerative medicine for ECs repair.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Cytokines; Endothelium, Vascular; Gene Expression Regulation; Humans; Inflammation Mediators; MicroRNAs; Oxidative Stress; Reactive Oxygen Species; Signal Transduction

Cardiovascular Disease (CVD) is the major cause of death worldwide, especially in Western society. Flavonoids are a large group of polyphenolic compounds widely distributed in plants, present in a considerable amount in fruit and vegetable. Several epidemiological studies found an inverse association between flavonoids intake and mortality by CVD. The antioxidant effect of flavonoids was considered the main mechanism of action of flavonoids and other polyphenols. In recent years, the role of modulation of signaling pathways by direct interaction of flavonoids with multiple protein targets, namely kinases, has been increasingly recognized and involved in their cardiovascular protective effect. There are strong evidence, in in vitro and animal experimental models, that some flavonoids induce vasodilator effects, improve endothelial dysfunction and insulin resistance, exert platelet antiaggregant and atheroprotective effects, and reduce blood pressure. Despite interacting with multiple targets, flavonoids are surprisingly safe. This article reviews the recent evidence about cardiovascular effects that support a beneficial role of flavonoids on CVD and the potential molecular targets involved.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Flavonoids; Humans

Terpenes are a class of secondary metabolites that can be found in a variety of animal and plants species. They are considered the most structurally diversified and abundant of all natural compounds. Several studies have shown the application of terpenes, such as carvacrol, linalool, and limonene in many pharmaceutical and medicinal fields, including cardiovascular disorders, the leading cause of death worldwide.. In this review, the authors outlined patents from the last 10 years relating to the therapeutic application of terpenes for the treatment and/or prevention of cardiovascular diseases found in different databases, emphasizing the possibility of these compounds becoming new drugs that may help to decrease the burden of these disorders.. There has been a growing awareness over recent years of the therapeutic use of terpenes and their derivatives as new pharmaceutical products. Patents involving the use of terpenes have been especially important in the technological development of new strategies for the treatment of cardiovascular diseases by bringing new scientific knowledge into the pharmaceutical industry. Therefore, the development of biotechnologies using natural products should be encouraged in order to increase the variety of drugs available for the treatment of cardiovascular diseases.

Topics: Animals; Biological Products; Biotechnology; Cardiovascular Agents; Cardiovascular Diseases; Drug Development; Humans; Patents as Topic; Terpenes

Patients with cardiovascular disease (CVD) frequently have erectile dysfunction (ED) because the two conditions have similar risk factors and potential mechanisms. The therapeutic effect of CVD is strongly dependent upon long-term management of the condition. Patients with CVD tend to have poor medication compliance, and the coexistence of ED often discourages patients with CVD from continuing their long-term CVD management, thus worsening CVD treatment compliance. The two major reasons for poor compliance are that (i) the adverse effects of cardiovascular medications on erectile function drive people to reduce the prescribed dosage or even stop taking the medications to obtain satisfactory sexual arousal and (ii) a worsening mental state due to ED reduces medication compliance. The regular administration of phosphodiesterase-5 inhibitors (PDE5is) guarantees that the prescribed medication dosages are easy to comply with and that they improve the mental status of patients by enhancing their erectile function, resulting in improved long-term management of CVD through medication compliance. PDE5is themselves also play a role in reducing cardiovascular events and improving the prognosis. We recommend prescribing PDE5is for ED and suggest that PDE5i administration is a promising strategy to improve the long-term management of patients with both ED and CVD.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Erectile Dysfunction; Health Status; Humans; Male; Medication Adherence; Penile Erection; Phosphodiesterase 5 Inhibitors; Quality of Life; Time Factors; Treatment Outcome

Bromodomain and extra-terminal (BET) inhibitors, acting via epigenetic mechanisms, have been developed recently as potential new treatments for cancer, including prostate cancer, and inflammatory conditions. Some BET inhibitors, such as RVX-208, also raise high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 levels. A recent meta-analysis of three small trials (n = 798) found that RVX-208 protected against major adverse cardiovascular events (MACE), raising the question as to whether this protective effect was an artefact, a chance finding, or mediated by HDL-C, anti-inflammatory pathways, or other factors. Notably, the effect of RVX-208 on MACE was largely driven by revascularizations, but fewer interventions in the treatment arm could have arisen accidently from favorable effects of RVX-208 on HDL-C and C-reactive protein influencing decisions about patient care. A larger (n = 2400) trial of RVX-208, BETonMACE (NCT02586155), with a more restricted definition of MACE, excluding hospitalizations, will shortly provide clarity. A successful BETonMACE trial would raise the question as to whether RVX-208 operates via lipids, inflammation, or other means, because several previous HDL-C modulators and anti-inflammatories have not provided effective means of treating cardiovascular disease and reducing overall mortality. Re-conceptualizing cardiovascular disease within the well-established evolutionary biology theory that growth and specifically reproduction trade-off against longevity might provide a more comprehensive explanation. Drivers of the gonadotropic axis, particularly androgens, suppress both HDL-C and the immune system while promoting ischemic heart disease and stroke. As such, any effects of RVX-208 on cardiovascular disease might be the result of reducing androgens, of which higher HDL-C and reduced inflammation are biomarkers. Notably, several other effective treatments for cardiovascular disease, such as statins and spironolactone, are known anti-androgens. Results of the BETonMACE trial, and corresponding insight about the mechanism of BET inhibitors in cardiovascular disease, are eagerly awaited.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Epigenesis, Genetic; Humans; Proteins; Quinazolinones

Thirty years ago, a novel axis of the renin-angiotensin system (RAS) was unveiled by the discovery of angiotensin-(1-7) [ANG-(1-7)] generation in vivo. Later, angiotensin-converting enzyme 2 (ACE2) was shown to be the main mediator of this reaction, and Mas was found to be the receptor for the heptapeptide. The functional analysis of this novel axis of the RAS that followed its discovery revealed numerous protective actions in particular for cardiovascular diseases. In parallel, similar protective actions were also described for one of the two receptors of ANG II, the ANG II type 2 receptor (AT

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Congresses as Topic; Humans; Oligopeptides; Peptide Fragments; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction

Type 2 diabetes mellitus is a major risk factor for cardiovascular disease. However, compiled data suggest that type 2 diabetes affects the risk of cardiovascular disease differentially according to sex. In recent years, large meta-analyses have confirmed that women with type 2 diabetes have a higher relative risk of incident coronary heart disease, fatal coronary heart disease, and stroke compared with their male counterparts. The reasons for these disparities are not completely elucidated. A greater burden of cardiometabolic risk in women was proposed as a partial explanation. Indeed, several studies suggest that women experience a larger deterioration in major cardiovascular risk factors and put on more weight than do men during their transition from normoglycemia to overt type 2 diabetes. This excess weight is associated with higher levels of biomarkers of endothelial dysfunction, inflammation, and procoagulant state. Moreover, sex differences in the prescription and use of some cardiovascular drugs may compound an "existing" disparity. We searched PubMed for articles published in English and French, by using the following terms: ("cardiovascular diseases") AND ("diabetes mellitus") AND ("sex disparity" OR "sex differences" OR "sex related differences" OR "sex-related differences" OR "sex disparities"). In this article, we review the available literature on the sex aspects of primary and secondary prevention of cardiovascular disease in people with type 2 diabetes, in the predisposition to cardiovascular disease in those people, and in the control of diabetes and associated cardiovascular risk factors.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Global Health; Healthy Lifestyle; Humans; Incidence; Primary Prevention; Risk Factors; Secondary Prevention; Sex Factors

The past 20 years have seen remarkable advances in the treatment of HIV such that most people diagnosed with HIV today can live long, healthy lives by taking antiretrovirals which are usually life-long. Advancements in antiretroviral therapy include the availability of well tolerated, single tablet regimens that are associated with a lower risk of drug-drug interactions. Despite this, many people living with HIV infection might be taking antiretroviral agents that are associated with significant drug-drug interactions. Because HIV infection itself is associated with cardiovascular complications and this population is living longer, concomitant use of antiretrovirals and medications to treat cardiovascular-related diseases is often required. For this reason, it is imperative that clinicians are aware of the potential for clinically significant drug-drug interactions between antiretroviral agents and cardiac medications as well as the useful HIV drug interaction resources that might provide guidance. Available data on significant interactions are summarized and suggested guidance regarding management is discussed.

Topics: Anti-HIV Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; HIV Infections; Humans; Medication Therapy Management

Inflammation participates in the pathogenesis of both cancer and cardiovascular disease. This review examines the mechanistic commonalities between these two scourges of humanity through the lens of inflammation biology. Inflammatory pathways contribute to the initiation, the progression, and the complication of both malignant tumours and atherosclerotic plaques. Modulation of inflammatory pathways have proven transformative in the treatment of cancers and have crossed the threshold of clinical reality as treatments to reduce the risk of cardiovascular events. The finding that clonal haematopoiesis drives both leukaemia and cardiovascular events provides yet another link between these two seemingly disparate diseases. The nascent specialty of cardio-oncology has initially focused on the cardiovascular complications of cancer therapies. The recognition of a more profound pathophysiologic connection between cancer and cardiovascular diseases should expand the concept of cardio-oncology. Embracing the mechanistic connection and transcending traditional barriers between disciplines offers immense opportunities for speeding innovative research that can address the growing burden of both cancer and cardiovascular disease.

Topics: Age Factors; Aging; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Cytokines; Humans; Inflammation; Inflammation Mediators; Medical Oncology; Neoplasms; Prognosis; Risk Assessment; Risk Factors; Signal Transduction; Translational Research, Biomedical

Our understanding of the complexity of cardiovascular disease pathophysiology remains very incomplete and has hampered cardiovascular drug development over recent decades. The prevalence of cardiovascular diseases and their increasing global burden call for novel strategies to address disease biology and drug discovery. Areas covered: This review describes the recent history of cardiovascular drug discovery using in vivo phenotype-based screening in zebrafish. The rationale for the use of this model is highlighted and the initial efforts in the fields of disease modeling and high-throughput screening are illustrated. Finally, the advantages and limitations of in vivo zebrafish screening are discussed, highlighting newer approaches, such as genome editing technologies, to accelerate our understanding of disease biology and the development of precise disease models. Expert opinion: Full understanding and faithful modeling of specific cardiovascular disease is a rate-limiting step for cardiovascular drug discovery. The resurgence of in vivo phenotype screening together with the advancement of systems biology approaches allows for the identification of lead compounds which show efficacy on integrative disease biology in the absence of validated targets. This strategy bypasses current gaps in knowledge of disease biology and paves the way for successful drug discovery and downstream molecular target identification.

Topics: Animals; Cardiomyopathies; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Drug Discovery; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Humans; Systems Biology; Zebrafish

Numerous studies have investigated use of acetylsalicylic acid (ASA) for prevention of cardiovascular deaths. The vast majority of the work in this area has focused on secondary prevention. However, underuse of ASA still remains a major issue. Fewer studies have investigated the impact of ASA on primary prevention of cardiovascular death. A meta-analysis of individual participant data from six randomized studies, published in 2009, showed decrease in serious vascular events but at the cost of causing increased bleeding and hemorrhagic stroke. Recent studies have raised a number of key questions regarding the benefits and risks of using ASA for primary prevention.

Topics: Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Hemorrhage; Humans; Primary Prevention; Prognosis; Protective Factors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors

Cardiovascular disease is a major contributor to global morbidity and mortality and is the common end point of many chronic diseases. The endothelins comprise three structurally similar peptides of 21 amino acids in length. Endothelin 1 (ET-1) and ET-2 activate two G protein-coupled receptors - endothelin receptor type A (ET

Topics: Angiogenesis Inhibitors; Animals; Biological Products; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Endothelins; Humans

With an increasing global burden of coronary artery disease (CAD), early detection and timely management of risk factors are crucial to reduce morbidity and mortality in such patients. Diabetes mellitus (DM) is considered an independent risk factor for the development of CAD. Metformin, an anti-diabetic drug, has been shown in pre-clinical and clinical studies, to lower the cardiovascular events in the DM patients. Growing evidence suggests that metformin has a protective effect on coronary artery beyond its hypoglycemic effects. Given its global availability, route of administration and cost, metformin provides an alternate/additional therapeutic option for primary and secondary prevention of CAD in DM and non-diabetics alike. Future prospective cohort-based studies and randomized clinical trials are needed to identify 'at-risk' population who may potentially benefit from metformin.

Topics: Animals; Biomarkers; Blood Glucose; Cardiovascular Agents; Cardiovascular Diseases; Clinical Decision-Making; Diabetes Mellitus; Humans; Hypoglycemic Agents; Metformin; Risk Factors; Treatment Outcome

New-onset atrial fibrillation (NOAF) is common and associated with increased morbidity and mortality. However, its clinical importance and management in critically ill patients are not well described. The aim of this scoping review is to assess the epidemiology and management strategies of NOAF during critical illness.. The review was conducted in accordance with the PRISMA extension for scoping reviews. We searched PubMed, EMBASE and the Cochrane Library for studies assessing the incidence, outcome and management strategies of NOAF in adult critically ill patients. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.. A total of 99 studies were included, of which 79 were observational and 20 were interventional. The incidence of NOAF varied from 1.7% to 43.9% with considerable inter-population variation (very low quality of evidence). Commonly identified risk factors for NOAF included higher age, cardiovascular comorbidities and sepsis. The occurrence of NOAF was associated with adverse outcomes, including stroke, prolonged length of stay and mortality (very low quality of evidence). We found limited data on the optimal management strategy with no evidence for firm benefit or harm for any intervention (very low/low quality of evidence).. The definition and incidence of NOAF in critically ill patients varied considerably and many risk factors were identified. NOAF seemed to be associated with adverse outcomes, but data were very limited and current management strategies are not evidence-based.

Topics: Age Factors; Atrial Fibrillation; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Critical Illness; Electrocardiography; Hematologic Tests; Hospitalization; Humans; Incidence; Length of Stay; Risk Factors; Sepsis; Severity of Illness Index; Sex Factors; Stroke

Cardiovascular disease is the leading cause of death worldwide. Despite overwhelming socioeconomic impact and mounting clinical needs, our understanding of the underlying pathophysiology remains incomplete. Multiple forms of cardiovascular disease involve an acute or chronic disturbance in cardiac myocytes, which may lead to potent activation of the Unfolded Protein Response (UPR), a cellular adaptive reaction to accommodate protein-folding stress. Accumulation of unfolded or misfolded proteins in the Endoplasmic Reticulum (ER) elicits three signaling branches of the UPR, which otherwise remain quiescent. This ER stress response then transiently suppresses global protein translation, augments production of protein-folding chaperones, and enhances ER-associated protein degradation, with an aim to restore cellular homeostasis. Ample evidence has established that the UPR is strongly induced in heart disease. Recently, the mechanisms of action and multiple pharmacological means to favorably modulate the UPR are emerging to curb the initiation and progression of cardiovascular disease. Here, we review the current understanding of the UPR in cardiovascular disease and discuss existing therapeutic explorations and future directions.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Humans; Unfolded Protein Response

The clinical benefit of aspirin for the primary prevention of cardiovascular disease (CVD) in diabetes remains uncertain. To evaluate the efficacy and safety of aspirin for the primary prevention of cardiovascular outcomes and all-cause mortality events in people with diabetes, we conducted an updated meta-analysis of published randomised controlled trials (RCTs) and a pooled analysis of individual participant data (IPD) from three trials.. Randomised controlled trials of aspirin compared with placebo (or no treatment) in participants with diabetes with no known CVD were identified from MEDLINE, Embase, Cochrane Library, and manual search of bibliographies to January 2019. Relative risks with 95% confidence intervals were used as the summary measures of associations.. We included 12 RCTs based on 34,227 participants with a median treatment duration of 5.0 years. Comparing aspirin use with no aspirin, there was a significant reduction in risk of major adverse cardiovascular events (MACE)0.89 (0.83-0.95), with a number needed to treat (NNT)of 95 (95% CI 61 to 208) to prevent one MACE over 5 years average follow-up. Evidence was lacking of heterogeneity and publication bias among contributing trials for MACE. Aspirin use had no effect on other endpoints including all-cause mortality; however, there was a significant reduction in stroke for aspirin dosage ≤ 100 mg/day 0.75 (0.59-0.95). There were no significant effects of aspirin use on major bleeding and other bleeding events, though some of the estimates were imprecise. Pooled IPD from the three trials (2306 participants) showed no significant evidence of an effect of aspirin on any of the outcomes evaluated; however, aspirin reduced the risk of MACE in non-smokers 0.70 (0.51-0.96) with a NNT of 33 (95% CI 20 to 246) to prevent one MACE.. Aspirin has potential benefits in cardiovascular primary prevention in diabetes. The use of low dose aspirin may need to be individualised and based on each individual's baseline CVD and bleeding risk. Systematic review registration PROSPERO: CRD42019122326.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus; Female; Hemorrhage; Humans; Male; Middle Aged; Primary Prevention; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Treatment Outcome; Young Adult

Vascular aging is a major risk factor and driver of agerelated cardiovascular diseases (CVD). Atherosclerosis, hypertension, and other CVD lead to vascular dysfunction that involves multiple pathological processes such as oxidative stress, endothelial dysfunction, inflammation, and autophagy. Epigenetics refers to genetic changes that occur when the DNA remains unchanged that include DNA methylation, histone modification, and non-coding RNA. It has been reported that epigenetics plays an effective regulatory role in CVD and affects cardiovascular repair function. Presently, drugs targeting epigenetics have applications in malignant tumors and inflammation. Therefore, exploration of epigenetic mechanisms in vascular aging will allow us to understand the pathogenesis of diseases related to vascular aging. This review focuses on the pathological changes in vascular aging and analyzes the relationship between vascular aging and epigenetics. Additionally, this review focuses on the pathogenesis of vascular aging related diseases from a new perspective in order to develop epigenetic-based treatment strategies for patients with age-related cardiovascular diseases.

Topics: Age Factors; Aging; Animals; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Chromatin Assembly and Disassembly; DNA Methylation; Epigenesis, Genetic; Hemodynamics; Humans; MicroRNAs; Signal Transduction; Vascular Remodeling

The kidney and cardiovascular system are closely related to each other during the modulation of the cardiovascular homeostasis. However, the search for new alternatives for the treatment and diagnosis of cardiovascular diseases does not take into account this relationship, so their evaluation results and the advantages offered by their global and integrative analysis are wasted. For example, a variety of receptors that are overexpressed in both pathologies is large enough to allow expansion in the search for new molecular targets and ligands. Nanotechnology offers pharmacological targeting strategies to kidney, heart, and blood vessels for overcoming one of the essential restrictions of traditional cardiovascular therapies the ones related to their unspecific pharmacodynamics distribution in these critical organs.. Drug or contrast agent nano-targeting for treatment or diagnosis of atherosclerosis, thrombosis, renal cancer or fibrosis, glomerulonephritis, among other renal, cardiac and blood vessels pathologies would allow an increase in their efficacy and a reduction of their side effects. Such effects are possible because, through pharmacological targeting, the drug is mainly found at the desired site. Review Purpose: In this mini-review, active, passive, and physical targeting strategies of several nanocarriers that have been assessed and proposed for the treatment and diagnosis of different cardiovascular diseases, are being addressed.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Early Diagnosis; Gene Expression Regulation; Gene Regulatory Networks; Humans; Kidney Diseases; Ligands; Nanoparticles; Renal Agents

The role of aspirin as a means of primary prevention remains controversial.. We have conducted a meta-analysis of all randomized controlled trials (RCTs) to evaluate the role of aspirin in primary prevention.. Literature search was performed via PubMed, Embase, and the Cochrane Library for all related RCTs. All-cause mortality was the primary endpoint. Secondary endpoints included major adverse cardiovascular events (MACE), myocardial infarction (MI), cardiovascular mortality, cerebrovascular events, and bleeding events. We used a random effects model to report the risk ratios (RRs) with 95% confidence intervals (CIs).. Our analysis included 17 RCTs (164,862 patients; 83,309 received aspirin and 81,744 received placebo). Our study did not demonstrate any significant reduction in all-cause mortality for patients treated with aspirin when compared with placebo (RR 0.97; 95% CI 0.93-1.01; P = 0.13). Sensitivity analysis performed by excluding healthy elderly (≥ 65) showed significant reductions in all-cause mortality in the aspirin-treated patients (RR 0.94; 95% CI 0.90-0.99; P = 0.01). There were no significant differences between both groups regarding cardiovascular mortality and cerebrovascular events (P > 0.05). However, aspirin-treated patients significantly reduced MACE and MI events (RR 0.89; 95% CI 0.85-0.93; P < 0.001 and RR 0.88; 95% CI 0.78-0.98; P = 0.02, respectively), respectively. However, aspirin was associated with a significantly higher incidence of bleeding, including major bleeding and intracranial bleeding (P < 0.001).. Aspirin use in primary prevention has resulted in a lower incidence of MACE and MI without significantly effecting cerebrovascular events. However, aspirin was associated with a higher bleeding risk. Use of aspirin as a means of primary prevention should be thoroughly discussed with patients and pursued based on the risk of cardiovascular disease while also considering bleeding risk.

Topics: Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Clinical Decision-Making; Hemorrhage; Humans; Incidence; Primary Prevention; Protective Factors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Treatment Outcome

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Drug Development; Drug Discovery; Gastrointestinal Microbiome; Humans; Metabolic Diseases

This review will serve to highlight the clinical rationale used in the selection of sodium-glucose cotransporter 2 inhibitors (SGLT2-i) or glucagon-like peptide 1 receptor agonists (GLP1-ra).. SGLT2-i and GLP1-ra are the first anti-hyperglycemics to demonstrate significant cardiovascular benefit in multiple cardiovascular outcomes trials (CVOTs), with benefits that are consistent across class of medication. Diabetes is a major risk factor for morbidity and mortality from cardiovascular disease. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) and glucagon-like peptide 1 receptor agonists (GLP1-ra) are the first anti-hyperglycemics to demonstrate significant cardiovascular benefit. Given the unique side effect and benefit profiles, appropriate consideration of these agents with a focus on cardiovascular risk reduction requires an individualized approach.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Patient Selection; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

The multifactorial origin of cardiovascular diseases has led to polypharmacy in primary and secondary prophylaxis with evidence-based medications, such as statins, antihypertensive drugs and platelet aggregation inhibitors. The number of prescribed drugs correlates inversely to adherence and can lead to treatment failure. Fixed-dose combination drugs (polypills) could increase the medication adherence of patients, reduce risks and prevent cardiovascular events.. This review is based on publications that were retrieved from Medline (via PubMed) and The Cochrane Library. The clinical database ClinicalTrials.gov. was also considered.. In the studies on primary prevention conducted to date, fixed-dose combinations showed a superior control of risk factors, e.g. hypertension and low-density lipoprotein (LDL) cholesterol compared to placebo and at least non-inferiority compared to usual care. In secondary prevention, the effect of the polypill is mostly on the reduction of blood pressure and LDL cholesterol in non-adherent patients; however, evidence that fixed-drug combinations reduce cardiovascular morbidity and mortality compared to standard therapy is lacking.. The polypill can be considered as an alternative to polypharmacy after a risk-benefit assessment, especially in non-adherent patients. Ongoing studies are investigating the effect of the polypill on cardiovascular events. Current polypills are limited by the lack of sufficient dosages of the individual components to avoid overtreatment and undertreatment at the individual treatment level.

Topics: Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Risk Factors; Tablets

Shortly after the discovery of the role of hydrogen sulfide (H. There remains a need to better understand the underlying mechanisms for some of the observed effects of H. The proof-of-concept clinical studies reviewed herein pave the way for examination, in a clinical setting, of several other potential applications of H

Topics: Animals; Arthritis; Captopril; Cardiovascular Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Humans; Hydrogen Sulfide; Naproxen

Sexual dysfunction affects millions of people with an increasing prevalence, worldwide. The pathophysiology of the disease shares several similarities with cardiovascular disease (CVD), including atherosclerosis, endothelial dysfunction, structural vascular damage and subclinical inflammation. Erectile dysfunction (ED) and female sexual dysfunction are common among patients with CVD and risk factors such as hypertension, diabetes, obesity and metabolic syndrome. Given the common pathogenesis of the diseases, ED is an independent prognostic factor of future ED events. Patients with overt ED or risk factors are usually treated with several drugs for the management of these conditions. Several of these drugs have been evaluated for their effect on sexual activity.. Among the antihypertensive drugs, diuretics and beta-blockers seem to exert a detrimental impact on sexual function, with nebivolol being the only beta-blocker with favorable properties through an increase in nitric oxide bioavailability. In contrast, renin-angiotensin system inhibitors and calcium-channel blockers have a neutral effect on sexual activity. Hypoglycemic drugs have been less evaluated in the ED setting, with metformin, pioglitazone and liraglutide presenting favorable results. Statins on the other hand have not provided consistent results with observational studies suggesting a detrimental role in sexual activity and a few randomized studies indicating a neutral or even beneficial effect on erectile function.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Drug Interactions; Erectile Dysfunction; Female; Humans; Male; Penile Erection; Phosphodiesterase Inhibitors; Polypharmacy; Prevalence; Risk Factors; Sexual Behavior; Treatment Outcome

There is significant evidence that internal pools of G protein-coupled receptors (GPCRs) exist and may be affected by both endogenous signaling molecules and hydrophobic pharmaceutical ligands, once assumed to only affect cell surface versions of these receptors. Here, we discuss evidence that the biology of nuclear GPCRs in particular is complex, rich, and highly interactive with GPCR signaling from the cell surface. Caging existing GPCR ligands may be an excellent means of further stratifying the phenotypic effects of known pharmacophores such as β-adrenergic, angiotensin II, and type B endothelin receptor ligands in the cardiovascular system. We describe some synthetic strategies we have used to design ligands to go from in cellulo to in vivo experiments. We also consider how surface and intracellular GPCR signaling might be integrated and ways to dissect this. If they could be selectively targeted, nuclear GPCRs and their associated nucleoligands would represent a completely novel area for exploration by Pharma.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Cell Nucleus; Drug Design; Drug Repositioning; Humans; Ligands; Molecular Structure; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; Signal Transduction; Structure-Activity Relationship

The compound epigallocatechin-3-gallate (EGCG), the major polyphenolic compound present in green tea [Camellia sinensis (Theaceae], has shown numerous cardiovascular health promoting activity through modulating various pathways. However, molecular understanding of the cardiovascular protective role of EGCG has not been reported.. This review aims to compile the preclinical and clinical studies that had been done on EGCG to investigate its protective effect on cardiovascular and metabolic diseases in order to provide a systematic guidance for future research.. Research papers related to EGCG were obtained from the major scientific databases, for example, Science direct, PubMed, NCBI, Springer and Google scholar, from 1995 to 2017.. EGCG was found to exhibit a wide range of therapeutic properties including anti-atherosclerosis, anti-cardiac hypertrophy, anti-myocardial infarction, anti-diabetes, anti-inflammatory and antioxidant. These therapeutic effects are mainly associated with the inhibition of LDL cholesterol (anti-atherosclerosis), inhibition of NF-κB (anti-cardiac hypertrophy), inhibition of MPO activity (anti-myocardial infarction), reduction in plasma glucose and glycated haemoglobin level (anti-diabetes), reduction of inflammatory markers (anti-inflammatory) and the inhibition of ROS generation (antioxidant).. EGCG shows different biological activities and in this review, a compilation of how this bioactive molecule plays its role in treating cardiovascular and metabolic diseases was discussed.

Topics: Animals; Anti-Inflammatory Agents; Camellia sinensis; Cardiovascular Agents; Cardiovascular Diseases; Catechin; Humans; Metabolic Diseases; Tea

Exercise and pharmacologic therapies to prevent and treat cardiovascular disease have advanced largely through independent efforts. Understanding of first-line drug therapies, findings from preclinical animal studies, and the need for research initiatives related to complementary cardioprotective exercise-pharma interventions are reviewed from the premise that contemporary cardioprotective therapies must include adjunctive exercise and lifestyle interventions in addition to pharmacologic agents.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Combined Modality Therapy; Exercise Therapy; Humans; Life Style; Secondary Prevention

Numerous studies have indicated that marine natural products are one of the most important sources of the lead compounds in drug discovery for their unique structures, various bioactivities and less side effects. In this review, the marine natural products with cardiovascular pharmacological effects reported after 2000 will be presented. Their structural types, relevant biological activities, origin of isolation and information of strain species will be discussed in detail. Finally, by describing our studies as an example, we also discuss the chances and challenges for translating marine-derived compounds into preclinical or clinical trials.

Topics: Alkaloids; Animals; Aquatic Organisms; Biological Products; Cardiovascular Agents; Cardiovascular Diseases; Drug Discovery; Humans; Ketones; Peptides; Phenols; Steroids; Terpenes

We recently found that thymidine phosphorylase (TYMP), also known as platelet-derived endothelial cell growth factor, plays an important role in platelet activation in vitro and thrombosis in vivo by participating in multiple signaling pathways. Platelets are a major source of TYMP. Since platelet-mediated clot formation is a key event in several fatal diseases, such as myocardial infarction, stroke and pulmonary embolism, understanding TYMP in depth may lead to uncovering novel mechanisms in the development of cardiovascular diseases. Targeting TYMP may become a novel therapeutic for cardiovascular disorders. In this review article, we summarize the discovery of TYMP and the potential molecular mechanisms of TYMP involved in the development of various diseases, especially cardiovascular diseases. We also offer insights regarding future studies exploring the role of TYMP in the development of cardiovascular disease as well as in therapy.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Discovery; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Humans; Molecular Targeted Therapy; Protein Conformation; Structure-Activity Relationship; Thymidine Phosphorylase

Cardiovascular medications are effective in prevention of cardiovascular diseases (CVD); however, medication non-adherence contributes to morbidity and mortality.. This systematic review and meta-analysis aims to summarise the evidence regarding the relationship between characteristics of drug therapy (pharmacotherapy) and medication non-adherence in the CVD population.. Systematic searches in PubMed, LILACS, Academic Search and CINAHL databases for observational studies that enrolled adults with CVD were performed, from January 1960 to December 2015. The meta-analysis tested the association between characteristics of pharmacotherapy and self-reported medication non-adherence outcome, using a random effects model. To investigate heterogeneity, we performed subgroup analysis and sensitivity analysis.. Twenty-four cross-sectional studies and 7 cohort studies were included in this review. Based on 31 studies including 27 441 participants, we performed meta-analyses for all the characteristics of drug therapy that at least 2 studies evaluated, with a total of fourteen meta-analyses. The pooled results showed that studies which evaluate whether participants have insurance or another program that assists with medication costs, but not full coverage (OR = 0.63; 95% CI: 0.53-0.74; P < .001; I. The results of this review suggest that access to insurance or another program that assists with medication costs was a protection factor for non-adherence. On the other hand, a high frequency of dosing was a risk factor for non-adherence. Therefore, these characteristics of pharmacotherapy must be considered to improve medication adherence among CVD patients.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Chronic Disease; Drug Administration Schedule; Drug Costs; Global Health; Humans; Medication Adherence; Models, Statistical; Observational Studies as Topic

Child-appropriate drug formulations are mandatory for an efficient and safe drug therapy in children. Since the implementation of supportive legislations development of novel drug formulations has significantly been enforced despite the fact that children are a heterogeneous group of patients with varying needs according to age, maturation and disease.. In this review, recent advances and current strategies are evaluated how to overcome the specific hurdles in pediatric drug development. For cardiovascular diseases as an example, EMA's decisions on pediatric investigation plans (PIPs) have been evaluated. New developments with innovative platform technologies such as mini-tablets and orodispersible preparations have been identified indicating a clear shift from liquid preparations to small-sized solid (multiparticulate) or orodispersible dosage forms. Reasons for this shift of paradigm are discussed.. Innovative platform technologies for solid drug dosage forms such as mini-tablets, orodispersible tablets or film preparations will continue to conquer the pharmaceutical market. Still, there are some major issues to be resolved, e.g. how to ensure quality of the new dosage forms and dose accuracy in flexible dosing, but the governmental incentives will continue to accelerate development of pediatric medicines and will bridge the still existing gaps in the near future.

Topics: Administration, Oral; Cardiovascular Agents; Cardiovascular Diseases; Chemistry, Pharmaceutical; Child; Drug and Narcotic Control; Drug Development; European Union; Humans

Topics: Arteriosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Female; Humans; Lipoprotein(a); Male; Middle Aged; Oligonucleotides, Antisense; Risk Factors

Nicotinamide adenine dinucleotide (NAD

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Dietary Supplements; Energy Metabolism; Humans; Myocytes, Cardiac; NAD; Oxidation-Reduction; Signal Transduction

Cardiovascular disease remains a significant global health burden, and development of cardiovascular drugs in the current regulatory environment often demands large and expensive cardiovascular outcome trials. Thus, the use of quantitative pharmacometric approaches which can help enable early Go/No Go decision making, ensure appropriate dose selection, and increase the likelihood of successful clinical trials, have become increasingly important to help reduce the risk of failed cardiovascular outcomes studies. In addition, cardiovascular safety is an important consideration for many drug development programs, whether or not the drug is designed to treat cardiovascular disease; modeling and simulation approaches also have utility in assessing risk in this area. Herein, examples of modeling and simulation applied at various stages of drug development, spanning from the discovery stage through late-stage clinical development, for cardiovascular programs are presented. Examples of how modeling approaches have been utilized in early development programs across various therapeutic areas to help inform strategies to mitigate the risk of cardiovascular-related adverse events, such as QTc prolongation and changes in blood pressure, are also presented. These examples demonstrate how more informed drug development decisions can be enabled by modeling and simulation approaches in the cardiovascular area.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Development; Drug Discovery; Humans; Risk Assessment

Mitochondrial aldehyde dehydrogenase (ALDH-2) plays a major role in the ethanol detoxification pathway by removing acetaldehyde. Therefore, ALDH-2 inhibitors such as disulfiram represent the first therapeutic targeting of ALDH-2 for alcoholism therapy. Areas covered: Recently, ALDH-2 was identified as an essential bioactivating enzyme of the anti-ischemic organic nitrate nitroglycerin, bringing ALDH-2 again into the focus of clinical interest. Mechanistic studies on the nitroglycerin bioactivation process revealed that during bioconversion of nitroglycerin and in the presence of reactive oxygen and nitrogen species the active site thiols of ALDH-2 are oxidized and the enzyme activity is lost. Thus, ALDH-2 activity represents a useful marker for cardiovascular oxidative stress, a concept, which has been meanwhile supported by a number of animal disease models. Mechanistic studies on the protective role of ALDH-2 in different disease processes identified the detoxification of 4-hydroxynonenal by ALDH-2 as a fundamental process of cardiovascular, cerebral and antioxidant protection. Expert opinion: The most recent therapeutic exploitation of ALDH-2 includes activators of the enzyme such as Alda-1 but also cell-based therapies (ALDH-bright cells) that deserve further clinical characterization in the future.

Topics: Aldehyde Dehydrogenase, Mitochondrial; Animals; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Drug Design; Humans; Molecular Targeted Therapy; Oxidative Stress

The preventive effects of olive oil against different diseases have been attributed to its high phenolic compound content. The objective of this study was to examine available scientific evidence on the beneficial effects against chronic diseases of olive oil phenolic compounds.. This article examines recently published data on olive oil phenolic compounds and their potential benefits in the prevention of cardiovascular disease, cancer, neurodegenerative disease, and osteoporosis.. The antioxidant, anti-proliferative, pro-apoptotic, and anti-inflammatory activities of olive oil phenolic compounds have preventive effects against heart disease and cancer. These compounds also exert neuroprotective and neuromodulator effects against neurodegenerative disease, inhibiting the development of amyloid plaques. Finally, they are known to protect against osteoporosis, favoring bone regeneration.. Dietary intake of olive oil can be recommended by healthcare professionals as an important source of phenolic compounds that play a role in the prevention of chronic disease and the consequent improvement in quality of life.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Bone Density Conservation Agents; Cardiovascular Agents; Cardiovascular Diseases; Diet, Healthy; Humans; Neoplasms; Neurodegenerative Diseases; Neuroprotective Agents; Olive Oil; Osteoporosis; Phenols; Protective Factors; Risk Factors

The aim of this study is to examine the cardioprotective properties of Glucagon-like peptide-1 receptor agonist, a class of antihyperglycemic therapy, via meta-analysis of four recently published cardiovascular outcomes trials.. Meta-analysis was performed pooling data from the ELIXA, LEADER, SUSTAIN-6 and EXSCEL trials. A random effects model was used to generate risk ratio with 95% confidence interval for cardiovascular and safety outcomes.. A total of 33,457 patients were included in the meta-analysis. Based on the study, GLP-1R agonists significantly reduced all-cause mortality (RR 0.89; 95% CI 0.82 to 0.96) and cardiovascular mortality (RR 0.88; 95% CI 0.80 to 0.97) when compared to placebo. When long-acting agents were analyzed alone, reduction in major adverse cardiac events (RR 0.88; 95% CI 0.81 to 0.97) and non-fatal strokes (RR 0.87; 95% CI 0.76 to 0.99) also showed significance.. Overall, GLP-1R agonists appear to have cardioprotective properties likely via modification of metabolic parameters such as glycemic control, weight loss, and improvement in blood pressure. Additional studies are warranted to compare cardiovascular outcomes among the different agents.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Randomized Controlled Trials as Topic; Risk Factors; Signal Transduction; Treatment Outcome

Many cardiovascular diseases present renin-angiotensin-aldosterone system (RAAS) hyperactivity as an important pathophysiological mechanism to be target in the therapeutic approaches. Moreover, arterial stiffness is currently considered as a new independent risk factor for cardiovascular disease in different clinical conditions, including hypertension and chronic kidney disease. In fact, excessive stimulation of angiotensin type 1 (AT1) receptors, as well as mineralocorticoid receptors, results in cellular growth, oxidative stress and vascular inflammation, which may lead to arterial stiffness and accelerate the process of vascular aging. In the last decades, a vasoprotective axis of the RAAS has been discovered, and now it is well established that new components with antioxidant and anti-inflammatory properties play important roles promoting vasodilation, natriuresis and reducing collagen deposition, thus attenuating arterial stiffness and improving endothelial function. In this review, we will focus on these pathophysiological mechanisms and the relevance of RAAS inhibition by different strategies to increase arterial compliance and to decelerate vascular aging.

Topics: Age Factors; Aging; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Humans; Inflammation Mediators; Mineralocorticoid Receptor Antagonists; Oxidative Stress; Renin-Angiotensin System; Risk Factors; Signal Transduction; Sodium Chloride, Dietary; Treatment Outcome; Vascular Remodeling; Vascular Stiffness

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Perioperative Care; Surgical Procedures, Operative

Nonadherence to medications is common in cardiovascular diseases because of their long duration, the patient age and the complexity of therapy. Its prevalence depends on the population, the types of drugs and the disease under study. Adherence decreases from the initial prescription and it is usually under 80%, a value defined as satisfactory. Adverse outcomes of nonadherence consist of an increase in ambulatory visits and hospitalization and death rates. The causes of nonadherence are multiple and depend on the patient, the type of medication, the healthcare professional, and the health system. Methods adopted to reduce nonadherence include sanitary education, direct patient-doctor-pharmacist interactions and the use of electronic devices of alert. "Deprescribing", a mechanism proposed to reduce unnecessary or redundant medications, may improve the situation of long-term drug use in patients with cardiovascular disease, thus increasing adherence. Recommendations from the guidelines are sometimes confounding and the role of polypill therapy is still controversial.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Deprescriptions; Hospitalization; Humans; Medication Adherence; Patient Education as Topic; Practice Guidelines as Topic; Professional-Patient Relations

The World Health Organization suggests that the cardiovascular diseases (CVDs) are the major cause of mortality and account for two-thirds of the deaths all over the world. These diseases kill about 17 million people every year and 3 in every 10 deaths are due to these diseases. The past decade has seen considerable improvements in diagnosis as well as treatment of various heart diseases. Various new therapeutic targets are being identified through in-depth knowledge of the disease mechanisms which has favored the testing of new strategies leading to newer treatment options. Opioid peptides and G-protein-coupled opioid receptors (ORs) have been previously studied widely in terms of central nervous system actions in mitigating the pain and drug abuse. The OR agonism or antagonism induces cytoprotective states in the myocardium, rendering these receptors as an attractive target for protection of heart from the fatal heart diseases. The opioids can provide an extended window of protection of the heart from various diseases. Although the mechanisms may not be fully understood, they seem to play a crucial role in various CVDs such as hypertension, hyperlipidemia, ischemic heart disease myocardial ischemia, and congestive heart failure. Since these compounds are already being used in acute and chronic pain, soon these compounds might be approved for use as cardioprotective agents. The following review focuses on the new information acquired on the role of the ORs in various CVDs.

Topics: Analgesics, Opioid; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Narcotic Antagonists; Receptors, Opioid; Signal Transduction; Treatment Outcome

Pharmacogenetics is an emerging area of medicine, and more work is needed to fully integrate it into a clinical setting for the benefit of patients. Genetic markers can influence the action of many drugs, including those that prevent and treat cardiovascular conditions. Genotyping is not yet commonplace, but guidelines are being put in place to help practitioners determine the effect a genetic marker may have on certain drugs. With advancements in genetic technology and falling costs, genotyping could be available to all patients via a simple saliva test. This would be a cost-effective way for practitioners to determine the most effective treatment for individuals, reducing "trial and error," adverse effects, and rehospitalization rates and increasing patient compliance. Cardiovascular diseases are the leading causes of death worldwide, so using the most effective medication to treat or prevent them is of utmost importance in reducing incidence and mortality.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cost-Benefit Analysis; Genetic Markers; Humans; Pharmacogenetics

Topics: Biomarkers; Blood Glucose; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Kidney; Protective Factors; Renal Agents; Risk Factors; Treatment Outcome

CypA (cyclophilin A) is a ubiquitous and highly conserved protein with peptidyl prolyl isomerase activity. Because of its highly abundant level in the cytoplasm, most studies have focused on the roles of CypA as an intracellular protein. However, emerging evidence suggests an important role for extracellular CypA in the pathogenesis of several diseases through receptor (CD147 or other)-mediated autocrine and paracrine signaling pathways. In this review, we will discuss the shared and unique pathological roles of extracellular and intracellular CypA in human cardiovascular diseases. In addition, the evolving role of post-translational modifications of CypA in the pathogenesis of disease is discussed. Finally, recent studies with drugs specific for extracellular CypA show its importance in disease pathogenesis in several animal models and make extracellular CypA a new therapeutic target.

Topics: Animals; Autocrine Communication; Basigin; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Cyclophilin A; Enzyme Inhibitors; Humans; Paracrine Communication; Protein Processing, Post-Translational; Signal Transduction

Multi-target and combinatorial therapies have been focused for the past several decades. These approaches achieved considerable therapeutic efficacy by modulating the activities of the targets in complex diseases such as HIV-1 infection, cancer and diabetes disease. Most of the diseases cannot be treated efficiently in terms of single gene target, because it involves the cessation of the coordinated function of distinct gene groups. Most of the cellular components work efficiently by interacting with other cellular components and all these interactions together represent interactome. This interconnectivity shows that a defect in a single gene may not be restricted to the gene product itself, but may spread along the network. So, drug development must be based on the network-based perspective of disease mechanisms. Many systematic diseases like neurodegenerative disorders, cancer and cardiovascular cannot be treated efficiently by the single gene target strategy because these diseases involve the complex biological machinery. In clinical trials, many mono-therapies have been found to be less effective. In mono-therapies, the long term treatment, for the systematic diseases make the diseases able to acquired resistance because of the disease nature of the natural evolution of feedback loop and pathway redundancy. Multi-target drugs might be more efficient. Multi-target therapeutics might be less vulnerable because of the inability of the biological system to resist multiple actions. In this study, we will overview the recent advances in the development of methodologies for the identification of drug target interaction and its application in the poly-pharmacology profile of the drug.

Topics: Antineoplastic Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Evaluation, Preclinical; Gene Regulatory Networks; Humans; Molecular Targeted Therapy; Neoplasms; Neurodegenerative Diseases; Neuroprotective Agents; Polypharmacology

This review summarizes recent progress in understanding the role of p53-upregulated mediator of apoptosis (PUMA) in molecular pathways with respect to its potential therapeutic applications. Particular emphasis is given to the PUMA´s role in ionizing radiation-induced signalling as radiotoxicity of normal tissue is mediated mostly via apoptosis. PUMA and its p53-dependent and p53- independent induction are described and potential use as a new target for the development of radioprotective agents is suggested. Further implications, including targeting PUMA to prevent and treat cardiovascular and neurodegenerative diseases, are also discussed together with an overview of other therapeutic applications. Finally, basic chemical structures for the development of novel PUMA modulators such as pifithrine derivatives, kinase inhibitors or modulators of Bcl-2 protein family are described.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Cardiovascular Agents; Cardiovascular Diseases; DNA Damage; Humans; Molecular Targeted Therapy; Neoplasms; Neurodegenerative Diseases; Neuroprotective Agents; Protein Binding; Proto-Oncogene Proteins; Radiation Injuries; Radiation Tolerance; Radiation-Protective Agents; Signal Transduction; Tumor Suppressor Protein p53

Inflammation participates in the initiation and progression of atherosclerotic cardiovascular disease, and it is a critical inciting factor leading to acute ischemic events. Evidence has shown that certain anti-inflammatory medications used to treat non-atherosclerotic inflammatory diseases reduce cardiovascular events. This article reviews evidence that commonly used anti-inflammatory therapies (colchicine, allopurinol, methotrexate), reduce cardiovascular events. We discuss potential mechanisms of action, efficacy, and safety of these therapies and propose a clinical trials design to investigate their efficacy.

Topics: Allopurinol; Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cardiovascular Diseases; Colchicine; Humans; Methotrexate; Treatment Outcome

Heat shock proteins (HSPs) are an important family of protective proteins. They are involved actively in an array of cellular processes, including protective effects on the cardiovascular system in response to various stimuli. Increasing evidence shows that pharmacologic interventions that induce expression of HSPs may be a novel approach for the treatment of cardiovascular diseases. However, agents that induce expression of HSPs used previously are toxic or have harmful side effects, which limit their clinical application. Geranylgeranylacetone (GGA) is not only a widely used antiulcer agent in Asia, but also a nontoxic inducer of HSPs expression. It increases the expression of HSPs rapidly in the presence of ischemia, anoxia, oxidative stress, and toxicants, thereby having significant protective effects. The cardioprotective effects of GGA have been corroborated by experiments in vivo and in vitro. Importantly, several derivatives of GGA have been synthesized that have improved pharmaco-chemical and HSPs-boosting properties. In this review, the current knowledge and potential cardioprotective mechanisms of GGA are summarized comprehensively. We discuss the protective effects of GGA in cardiovascular diseases and myocardial injury induced by physical or chemical injury. Currently available information suggests that GGA could be employed as a novel pharmacologic intervention against cardiovascular disease.

Topics: Animals; Anti-Arrhythmia Agents; Apoptosis; Arrhythmias, Cardiac; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Diterpenes; Endothelium, Vascular; Heat-Shock Proteins; Humans; Insulin Resistance; Myocardium; Oxidative Stress; Treatment Outcome

As average life expectancy continues to rise in the developed world, age-associated pathologies are increasing in prevalence. The hallmarks of cardiac ageing include cardiomyocyte loss, fibrosis and hypertrophy, all of which contribute to an increased incidence of cardiac disease. At the molecular level, cellular ageing is characterized by increased ROS production, mitochondrial dysfunction and the accumulation of damaged proteins and organelles. Cardiomyocytes and other senescent cell types rely upon autophagy, a lysosome-mediated degradation pathway, to remove potentially toxic protein aggregates and damaged organelles from the cellular milieu. However, increasing lines of evidence point to an age-associated decrease in cardiomyocyte autophagy, with predictably negative consequences for cardiac function and health. Conversely, stimulation of autophagy has been shown to improve cellular health and cardiac function and to increase lifespan in numerous model organisms. Clearly, autophagy represents a critical pathway for cellular vitality, as well as a promising therapeutic target for the treatment of age-related cardiac pathologies. In this review, we will discuss the mechanism of autophagy and its regulation in the cell, the role of autophagy in the ageing heart, and how the autophagy pathway might be targeted to improve cardiac health.

Topics: Age Factors; Aging; Animals; Autophagy; Autophagy-Related Proteins; Cardiovascular Agents; Cardiovascular Diseases; Humans; Longevity; Mitochondria, Heart; Mitophagy; Myocytes, Cardiac; Risk Factors; Risk Reduction Behavior; Signal Transduction

Cysteine protease cathepsins have traditionally been considered as lysosome-restricted proteases that mediate proteolysis of unwanted proteins. However, studies from the past decade demonstrate that these proteases are localized not only in acidic compartments (endosomes and lysosomes), where they participate in intracellular protein degradation, but also in the extracellular milieu, plasma membrane, cytosol, nucleus, and nuclear membrane, where they mediate extracellular matrix protein degradation, cell signalling, and protein processing and trafficking through the plasma and nuclear membranes and between intracellular organelles. Studies in experimental disease models and on cathepsin-selective inhibitors, as well as plasma and tissue biomarker data from animal models and humans, have verified the participation of cysteinyl cathepsins in the pathogenesis of many cardiovascular diseases, including atherosclerosis, myocardial infarction, cardiac hypertrophy, cardiomyopathy, abdominal aortic aneurysms, and hypertension. Clinical trials of cathepsin inhibitors in chronic inflammatory diseases suggest the utility of these inhibitors for the treatment of cardiovascular diseases and associated complications. Moreover, development of cell transfer technologies that enable ex vivo cell treatment with cathepsin inhibitors might limit the unwanted systemic effects of cathepsin inhibition and provide new avenues for targeting cysteinyl cathepsins. In this Review, we summarize the available evidence implicating cysteinyl cathepsins in the pathogenesis of cardiovascular diseases, discuss their potential as biomarkers of disease progression, and explore the potential of cathepsin inhibitors for the treatment of cardiovascular diseases.

Topics: Animals; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Cathepsins; Cysteine Proteases; Cysteine Proteinase Inhibitors; Humans; Molecular Targeted Therapy; Signal Transduction

Precision medicine is an integrative approach to cardiovascular disease prevention and treatment that considers an individual's genetics, lifestyle, and exposures as determinants of their cardiovascular health and disease phenotypes. This focus overcomes the limitations of reductionism in medicine, which presumes that all patients with the same signs of disease share a common pathophenotype and, therefore, should be treated similarly. Precision medicine incorporates standard clinical and health record data with advanced panomics (ie, transcriptomics, epigenomics, proteomics, metabolomics, and microbiomics) for deep phenotyping. These phenotypic data can then be analyzed within the framework of molecular interaction (interactome) networks to uncover previously unrecognized disease phenotypes and relationships between diseases, and to select pharmacotherapeutics or identify potential protein-drug or drug-drug interactions. In this review, we discuss the current spectrum of cardiovascular health and disease, population averages and the response of extreme phenotypes to interventions, and population-based versus high-risk treatment strategies as a pretext to understanding a precision medicine approach to cardiovascular disease prevention and therapeutic interventions. We also consider the search for resilience and Mendelian disease genes and argue against the theory of a single causal gene/gene product as a mediator of the cardiovascular disease phenotype, as well as an Erlichian magic bullet to solve cardiovascular disease. Finally, we detail the importance of deep phenotyping and interactome networks and the use of this information for rational polypharmacy. These topics highlight the urgent need for precise phenotyping to advance precision medicine as a strategy to improve cardiovascular health and prevent disease.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Computational Biology; Demography; Drug Discovery; Forecasting; Gene-Environment Interaction; Genetic Association Studies; Genetic Diseases, Inborn; Genetic Variation; Humans; Mutation; Pharmacogenetics; Phenotype; Precision Medicine

The advent of biologic therapy has enhanced our ability to augment disease in an increasingly targeted manner. The use of biologics in cardiovascular disease (CVD) has steadily increased over the past several decades. Much of the early data on biologics and CVD were derived from their use in rheumatologic populations. Atherosclerosis, myocardial infarction, and heart failure have been closely linked to the inflammatory response. Accordingly, cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 have been targeted. Noninflammatory mediators, such as proprotein convertase subtilisin kexin type 9 (PCSK9), have been selected for therapeutic intervention as well. Furthermore, RNA interference (RNAi) therapy has emerged and may serve as another targeted therapeutic mechanism. Herein, we will review the history, obstacles, and advances in using biologic therapy for CVD.

Topics: Animals; Anti-Inflammatory Agents; Biological Products; Cardiotoxicity; Cardiovascular Agents; Cardiovascular Diseases; Cytokines; Humans; Inflammation Mediators; Liposomes; Proprotein Convertase 9; RNA, Small Interfering; RNAi Therapeutics; Signal Transduction; Treatment Outcome

This review discusses common mental health disorders and their associations with cardiovascular disease risks. Commonly found mental health disorders include depression, anxiety, and personality types. The link between depression and cardiovascular disease mortality has been established. Depression is also common in patients with heart failure. In addition to discussing psychological disorders, a review of psychotropic drugs is also included. Drugs are described for therapy for depression and anxiety, as well as associations with cardiovascular drug-drug interactions. Drug-drug interactions are more common and potentially dangerous in elderly patients, in whom the conditions often coexist. The most common drug-drug interactions involve the P450 system of enzymes.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Humans; Mental Disorders; Psychopharmacology; Psychotropic Drugs; Risk Factors

Considerable interindividual variability in response to cardiovascular pharmacotherapy exists with drug responses varying from being efficacious to inadequate to induce severe adverse events. Fueled by advancements and multidisciplinary collaboration across disciplines such as genetics, bioinformatics, and basic research, the vision of personalized medicine, rather than a one-size-fits-all approach, may be within reach. Pharmacogenetics offers the potential to optimize the benefit-risk profile of drugs by tailoring diagnostic and treatment strategies according to the individual patient. To date, a multitude of studies has tried to delineate the effects of gene-drug interactions for drugs commonly used to treat cardiovascular-related disease. The focus of this review is on how genetic variability may modify drug responsiveness and patient outcomes following therapy with commonly used cardiovascular drugs including clopidogrel, warfarin, statins, and β-blockers. Also included are examples of how genetic studies can be used to guide drug discovery and examples of how genetic information may be deployed in clinical decision making.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Long QT Syndrome; Pharmacogenetics; Precision Medicine

Apelin is a vasoactive peptide and is an endogenous ligand for APJ receptors, which are widely expressed in blood vessels, heart, and cardiovascular regulatory regions of the brain. A growing body of evidence now demonstrates a regulatory role for the apelin/APJ receptor system in cardiovascular physiology and pathophysiology, thus making it a potential target for cardiovascular drug discovery and development. Indeed, ongoing studies are investigating the potential benefits of apelin and apelin-mimetics for disorders such as heart failure and pulmonary arterial hypertension. Apelin causes relaxation of isolated arteries, and systemic administration of apelin typically results in a reduction in systolic and diastolic blood pressure and an increase in blood flow. Nonetheless, vasopressor responses and contraction of vascular smooth muscle in response to apelin have also been observed under certain conditions. The goal of the current review is to summarize major findings regarding the apelin/APJ receptor system in blood vessels, with an emphasis on regulation of vascular tone, and to identify areas of investigation that may provide guidance for the development of novel therapeutic agents that target this system.

Topics: Animals; Apelin; Apelin Receptors; Cardiovascular Agents; Cardiovascular Diseases; Drug Development; Drug Discovery; Heart Failure; Humans; Hypertension, Pulmonary; Ligands; Muscle, Smooth, Vascular

Flavonoids are integral components of various vegetation and in foods; consequently, they represent an inevitable part of the diet. Historical and epidemiological proof recommend that diet plans consisting of flavonoids such as quercetin have positive health benefits, especially on the heart. Flavonoids have been proven to be active against hypertension, inflammation, diabetes and vascular diseases. Quercetin exhibits significant heart related benefits as inhibition of LDL oxidation, endothelium-independent vasodilator effects, reduction of adhesion molecules and other inflammatory markers, the protective effect on nitric oxide and endothelial function under conditions of oxidative stress, prevention of neuronal oxidative and inflammatory damage and platelet antiaggregant effects. Searching for experimental evidence to validate the cardioprotective effects of quercetin, we review here the recent detailed in vivo studies. Quercetin and its derivatives lead to an enhancement in heart features, indicating the prospective for quercetin to be used therapeutically in the treatment of cardiac diseases. Several evidence-based studies suggest mechanisms to observe cardiovascular diseases such as aging effects, hypertension, angiotensin-converting enzyme activity and endothelial-dependent and independent functions. Different animal models including human are also used to elucidate the in vivo role of quercetin in cardiovascular diseases. The role of quercetin and its derivatives may go beyond their existence in food and has potential as a lead molecule in drug development programs.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Molecular Structure; Quercetin

Poly(ADP-ribosyl)ation is an immediate cellular repair response to DNA damage and is catalyzed primarily by poly(ADP-ribose)polymerase-1 (PARP1), which is the most abundant of the 18 different PARP isoforms and accounts for more than 90% of the catalytic activity of PARP in the cell nucleus. Upon detection of a DNA strand break, PARP1 binds to the DNA, cleaves nicotinamide adenine dinucleotide between nicotinamide and ribose and then modifies the DNA nuclear acceptor proteins by formation of a bond between the protein and the ADP-ribose residue. This generates ribosyl-ribosyl linkages that act as a signal for other DNA-repairing enzymes and DNA base repair. Extensive DNA breakage in cells results in excessive activation of PARP with resultant depletion of the cellular stores of nicotinamide adenine dinucleotide (NAD+) which slows the rate of glycolysis, mitochondrial electron transport, and ultimately ATP formation in these cells. This paper focuses on PARP in DNA repair in atherosclerosis, acute myocardial infarction/reperfusion injury, and congestive heart failure and the role of PARP inhibitors in combating the effects of excessive PARP activation in these diseases. Free oxygen radicals and nitrogen radicals in arteries contribute to disruption of the vascular endothelial glycocalyx, which increase the permeability of the endothelium to inflammatory cells and also low-density lipoproteins and the accumulation of lipid in the vascular intima. Mild inflammation and DNA damage within vascular cells promote PARP1 activation and DNA repair. Moderate DNA damage induces caspase-dependent PARP cleavage and vascular cell apoptosis. Severe DNA damage due to vascular inflammation causes excessive activation of PARP1. This causes endothelial cell depletion of NAD+ and ATP, downregulation of atheroprotective SIRT1, necrotic cell death, and ultimately atherosclerotic plaque disruption. Inhibition of PARP decreases vascular endothelial cell adhesion P-selectin and ICAM-1 molecules, inflammatory cells, pro-death caspase-3, and c-Jun N-terminal kinase (JNK) activation and upregulates prosurvival extracellular signal-regulated kinases and AKT, which decrease vascular cell apoptosis and necrosis and limit atherosclerosis and plaque disruption. In myocardial infarction with coronary occlusion then reperfusion, which occurs with coronary angioplasty or thrombolytic therapy, reperfusion injury occurs in as many as 31% of patients and is caused by inflammatory cells, free ox

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Disease Models, Animal; DNA Damage; DNA Repair; Energy Metabolism; Humans; Myocytes, Cardiac; Oxidative Stress; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Signal Transduction

Over the past few decades, lot of evidences have shown atherosclerosis as a chronic progressive disease with an exquisite inflammatory feature. More recently, the role of innate immune response in the onset and progression of coronary artery disease (CAD) and an adaptive immunity imbalance, mostly involving T cell sub-sets, have been documented. Therefore, like in many other inflammatory and autoimmune disorders, an altered innate-adaptive immunity crosstalk could represent the key of the inflammatory burden leading to atherosclerotic plaque formation and progression and to the breakdown of plaque stability. In this review, we will address the role of inflammasome in innate immunity and in the imbalance of adaptive immunity. We will discuss how this altered immune crosstalk is related to CAD onset and progression. We will also discuss how unravelling the key molecular mechanisms is of paramount importance in the development of therapeutic tools to delay the chronic progression and prevent the acute destabilization of atherosclerotic plaque.

Topics: Adaptive Immunity; Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Immunity, Innate; Immunologic Factors; Immunotherapy; Inflammasomes; Inflammation Mediators; Signal Transduction; T-Lymphocytes

Topics: Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Cholesterol, LDL; Deprescriptions; General Practice; Humans

Rudolph Virchow (1821-1902) recognized inflammation in histological preparations of coronary arteries and proposed that inflammation plays a causal role in atherosclerosis. Despite this seminal observation, the main focus of research and drug development programs has been cholesterol alone, and inflammation received less attention over time. However, during the past several decades extensive observations supported the importance of inflammation in the development and destabilization of atherosclerosis. Studies in patients affected by rheumatological diseases suggested an interaction between chronic inflammation and atherosclerotic cardiovascular disease. Randomized clinical studies with lipid lowering agents suggested that part of the beneficial effect may have been related to reduction in inflammation. More recently, a few studies were designed to directly address the role of anti-inflammatory treatments in reducing risk of atherosclerotic heart disease beyond traditional risk factors. In this article, we review the pathophysiologic contribution of inflammation to atherosclerosis, biomarkers of inflammation and the evidence collected in observational studies regarding the role of chronic inflammation in the development of atherosclerotic heart disease. Finally, we discuss the most recent randomized clinical trials of anti-inflammatory agents directed at stemming atherosclerotic cardiovascular disease.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Humans; Inflammation; Inflammation Mediators; Signal Transduction

Cardiovascular diseases (CVDs) are the primary causes of death worldwide. Among the numerous signaling molecules involved in CVDs, transcriptional factors directly influence gene expression and play a critical role in regulating cell function and the development of diseases. Activating transcription factor (ATF) 3 is an adaptive-response gene in the ATF/cAMP responsive element-binding (CREB) protein family of transcription factors that acts as either a repressor or an activator of transcription via the formation of homodimers or heterodimers with other ATF/CREB members. A appropriate ATF3 expression is important for the normal physiology of cells, and dysfunction of ATF3 is associated with various pathophysiological responses such as inflammation, apoptosis, oxidative stress and endoplasmic reticulum stress, and diseases, including CVDs. This review focuses on the role of ATF3 in cardiac hypertrophy, heart failure, atherosclerosis, ischemic heart diseases, hypertension and diabetes mellitus to provide a novel therapeutic target for CVDs.

Topics: Activating Transcription Factor 3; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Gene Expression Regulation; Humans; Molecular Targeted Therapy; Signal Transduction; Transcription, Genetic

Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) frequently occur together and their coexistence is associated with worse outcomes than either condition alone. Pathophysiological links between COPD and CVD include lung hyperinflation, systemic inflammation and COPD exacerbations. COPD treatments may produce beneficial cardiovascular (CV) effects, such as long-acting bronchodilators, which are associated with improvements in arterial stiffness, pulmonary vasoconstriction, and cardiac function. However, data are limited regarding whether these translate into benefits in CV outcomes. Some studies have suggested that treatment with long-acting β

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Comorbidity; Female; Humans; Lung; Male; Middle Aged; Prognosis; Pulmonary Disease, Chronic Obstructive; Respiratory System Agents; Risk Factors

Endothelial nitric oxide synthase (NOS3) is a key enzyme responsible for nitric oxide (NO) generation in the vascular endothelium. Endothelial dysfunction is characterized by reduced NO production, and is a hallmark of cardiovascular diseases. Drugs with cardiovascular action may activate NOS3 and result in NO release and vasodilation. Moreover, genetic variations affect NOS3 expression and activity, and may partially explain the variability in the responses to cardiovascular drugs. We reviewed NO signaling and genetic effects on NO formation, and the effects of NOS3 polymorphisms, haplotypes and gene-gene interactions within NO signaling pathways on the responses to cardiovascular drugs. We discuss the role of rare NOS3 variants and further gene-gene interactions analysis for the development of novel therapies for cardiovascular diseases.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Haplotypes; Humans; Nitric Oxide; Nitric Oxide Synthase Type III; Pharmacogenetics; Polymorphism, Genetic; Signal Transduction

Inflammation is an important innate immune response to infection or tissue damage. Inflammasomes are involved in the onset and development of inflammation. The NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome is the best-characterized inflammasome. Recent evidence has indicated the importance of the NLRP3 inflammasome in the pathophysiology of cardiovascular disorders. To further understand the roles of the NLRP3 inflammasome in the cardiovascular system, we provide a comprehensive overview and discuss the remaining questions. First, a summary of NLRP3 inflammasome in the cardiovascular system is introduced. Then, the associations between NLRP3 inflammasome and cardiovascular disorders are presented. Finally, we discuss existing problems and potential directions with this issue. The information compiled here summarizes recent progress, thus potentially aiding in the understanding of the NLRP3 inflammasome in cardiovascular disorders, designing experimental and clinical research about the NLRP3 inflammasome, and promoting therapeutics for cardiovascular disorders.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cardiovascular Diseases; Humans; Immunity, Innate; Inflammasomes; Molecular Targeted Therapy; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction

Previous decades have seen significant progress in the biological understanding of cardiovascular disease, as well as major advances in computational and information technologies. However, anticipated improvements in outcomes, quality, and cost of cardiovascular medicine at the individual and population levels from these advances have lagged expectations. Further, trends showing widening gaps in the pace of technological development and its successful uptake and application in practice suggests that substantial systemic changes are needed. Recent declines in key U.S. health outcomes have added further urgency to seek scalable approaches that deliver the right treatment to the right patient and to develop information-driven policies that improve health. The clinical care and research enterprises are currently in the midst of assimilating changes entrained by a "fourth industrial revolution" marked by the convergence of biology, physical sciences, and information science. These changes, if managed appropriately, can simultaneously enable cost-effective personalized medical care as well as more effective and targeted population health interventions. In this paper derived from a lecture in honor of cardiologist Paul Dudley White, the author explores how White's prescient insights into prevention and treatment continue to resonate today as we seek to assimilate ubiquitous computing, sophisticated sensor technologies, and bidirectional digital communication into the practice of cardiology. How the ongoing acceleration in basic science and information technologies can be wedded to the principles articulated by White as we pursue scalable approaches to personalized medicine is also examined.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Delivery of Health Care, Integrated; Electronic Health Records; Forecasting; Humans; Mortality; Precision Medicine; Review Literature as Topic; United States

Increased heart rate (HR) is associated with deleterious effects on several disease conditions. Chronic heart failure (CHF) is one of the cardiovascular diseases with recurrent hospitalization burden and an ongoing drain on health-care expenditure. Despite advancement in medicine, management of CHF remains a challenge to health-care providers. Ivabradine selectively and specifically inhibits the pacemaker I(f) ionic current which reduces the cardiac pacemaker activity. The main effect of ivabradine therapy is the substantial lowering of HR. It does not influence intracardiac conduction, contractility, or ventricular repolarization. As shown in numerous clinical studies, ivabradine improves clinical outcomes and quality of life and reduces the risk of death from heart failure (HF) or other cardiovascular causes. Recently updated HF guidelines recommend ivabradine as a class II indication for reduction of HF hospitalizations. Based on the principle of benefits of reduced HR, the ivabradine in patients with ischemic heart disease, sepsis, and multiple organ dysfunction syndrome has also been studied. It can also be a useful agent for HR reduction in patients with contraindications to use beta-blockers or those who cannot tolerate them. In this review, we provide an overview of efficacy and safety of ivabradine and its combination with currently recommended pharmacological therapy in different conditions.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cause of Death; Global Health; Humans; Ivabradine; Survival Rate

More than four decades passed since sigma receptors were first mentioned. Since then, existence of at least two receptor subtypes and their tissue distributions have been proposed. Nowadays, it is clear, that sigma receptors are unique ubiquitous proteins with pluripotent function, which can interact with so many different classes of proteins. As the endoplasmic resident proteins, they work as molecular chaperones - accompany various proteins during their folding, ensure trafficking of the maturated proteins between cellular organelles and regulate their functions. In the heart, sigma receptor type 1 is more dominant. Cardiac sigma 1 receptors regulate response to endoplasmic reticulum stress, modulates calcium signaling in cardiomyocyte and can affect function of voltage-gated ion channels. They contributed in pathophysiology of cardiac hypertrophy, heart failure and many other cardiovascular disorders. Therefore, sigma receptors are potential novel targets for specific treatment of cardiovascular diseases.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Myocardium; Myocytes, Cardiac; Receptors, sigma; Sigma-1 Receptor

Although sex-specific differences in cardiovascular medicine are well known, the exact influences of sex on the effect of cardiovascular drugs remain unclear. Women and men differ in body composition and physiology (hormonal influences during the menstrual cycle, menopause, and pregnancy) and they present differences in drug pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics, so that is not rare that they may respond differently to cardiovascular drugs. Furthermore, women are also less often treated with evidence-based drugs thereby preventing optimization of therapeutics for women of all ages, experience more relevant adverse drug reactions than men, and remain underrepresented in most clinical trials. Thus, current guidelines for prevention, diagnosis, and medical treatment for cardiovascular diseases are based on trials conducted predominantly in middle-aged men. A better understanding of these sex-related differences is fundamental to improve the safety and efficacy of cardiovascular drugs and for developing proper individualized cardiovascular therapeutic strategies both in men and women. This review briefly summarizes gender differences in the pharmacokinetics and pharmacodynamics of cardiovascular drugs and provides recommendations to close the gaps in our understanding of sex-specific differences in drug efficacy and safety.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Global Health; Humans; Morbidity; Sex Factors; Survival Rate

Hypertension is a leading cause of morbidity and mortality worldwide. A major pathophysiological factor contributing to hypertension is reduced nitric oxide (NO) bioavailability. Strategies to address this pathophysiological mechanism could offer significant advantages. Areas covered: In this review we aimed at examining a variety of drugs (statins, beta-adrenergic receptor blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin II type-1 receptor blockers) used to treat hypertension and other cardiovascular diseases, particularly with respect to their potential of increasing NO bioavailability and activity in the cardiovascular system. There is now evidence supporting the notion that many cardiovascular drugs activate NO signaling or enhance NO bioavailability as a contributing mechanism to their beneficial cardiovascular effects. Moreover, other drugs may attenuate NO inactivation by superoxide and other reactive oxygen species by exerting antioxidant effects. More recently, the NO oxidation products nitrite and nitrate have been acknowledged as sources of NO after recycling back to NO. Activation of the nitrate-nitrite-NO pathway is an alternate pathway that may generate NO from both anions and exert antihypertensive effects. Expert opinion: In this review, we provide an overview of the possible mechanisms by which these drugs enhance NO bioavailability and help in the therapy of hypertension.

Topics: Animals; Antihypertensive Agents; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Humans; Hypertension; Nitric Oxide; Reactive Oxygen Species

In this review we discuss the sex/estrogen-specific modulation of cardiovascular function and responses to current therapeutics. We discuss how anatomical differences such as a smaller kidney size, and lower glomerular filtration rate in females, reduce the clearance and increase the toxicity of some drugs in females. Other important sex differences include the dampening effect of estrogen on central sympathetic and renin angiotensin systems. Further, we discuss how a shift in myocardial redox status leads to paradoxical transformation of estrogen into a pro-inflammatory hormone. Finally, the review, along with cited recent publications, identify some areas that need further investigation to advance our understanding of the sex differences in cardiovascular disease outcomes to help develop female specific interventions for these anomalies.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Estrogens; Humans; Sex Characteristics

Topics: Cardiovascular Agents; Cardiovascular Diseases; Health Care Surveys; Humans; Patient Compliance

Chronic diseases are the primary cause of mortality worldwide, accounting for 67% of deaths. One of the major challenges in developing new treatments is the lack of understanding of the exact underlying biological and molecular mechanisms. Chronic cardiovascular diseases are the single most common cause of death worldwide, and sudden deaths due to cardiac arrhythmias account for approximately 50% of all such cases. Traditional genetic screening for genes involved in cardiac disorders is labourious and frequently fails to detect the mutation that explains or causes the disorder. However, when mutations are identified, human induced pluripotent stem cells (hiPSCs) derived from affected patients make it possible to address fundamental research questions directly relevant to human health. As such, hiPSC technology has recently been used to model human diseases and patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs) thus offer a unique opportunity to investigate potential disease-causing genetic variants in their natural environment. The purpose of this review is to present the current state of knowledge regarding hiPSC-CMs, including their potential, limitations, and challenges and to discuss future prospects.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cell Culture Techniques; Cell Differentiation; Genetic Predisposition to Disease; Humans; Induced Pluripotent Stem Cells; Mutation; Myocytes, Cardiac; Phenotype

Colchicine is one of the oldest known drugs that remains part of the current pharmacopeia. Recent studies have examined the efficacy of colchicine in cardiology with promising results. We conducted a search of electronic databases for studies on colchicine in cardiovascular medicine published through October 2016. As the utilization of colchicine in the management of cardiac conditions grows, it is paramount that internists and cardiologists are familiarized with its benefits and risks. We present a comprehensive review of the role of colchicine in the management of cardiovascular diseases with a strong emphasis on side effects and potential drug interactions.

Topics: Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Colchicine; Drug Interactions; Humans

Prevalence of cardiovascular (CV) disease is increasing worldwide. One of the most important risk factors for CV disease is hypertension that is very often related to obesity and metabolic syndrome. The search for key mechanisms, linking high blood pressure (BP), glucose and lipid dysmetabolism together with higher CV risk and mortality, is attracting increasing attention. Cardiac natriuretic peptides (NPs), including ANP and BNP, may play a crucial role in maintaining CV homeostasis and cardiac health, given their impact not only on BP regulation, but also on glucose and lipid metabolism. The summa of all metabolic activities of cardiac NPs, together with their CV and sodium balance effects, may be very important in decreasing the overall CV risk. Therefore, in the next future, cardiac NPs system, with its two receptors and a neutralizing enzyme, might represent one of the main targets to treat these multiple related conditions and to reduce hypertension and metabolic-related CV risk.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Humans; Hypertension; Natriuretic Peptide, Brain; Prognosis; Receptors, Atrial Natriuretic Factor; Risk Assessment; Risk Factors; Signal Transduction

There is a large misalignment between unmet need and both private and public investment activity in cardiovascular disease. In this paper, we quantify the magnitude of the gap, analyze a range of potential root causes in two main categories (issues of feasibility and valuation), and propose steps toward solutions to close the gap.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Discovery; Health Services Needs and Demand; Humans; Reimbursement, Incentive

In the 15 years following the release of the first complete human genome sequences, our understanding of rare and common genetic variation as determinants of cardiovascular disease susceptibility, prognosis, and therapeutic response has grown exponentially. As such, the use of genomics to enhance the care of patients with cardiovascular diseases has garnered increased attention from clinicians, researchers, and regulatory agencies eager to realize the promise of precision genomic medicine. However, owing to a large burden of "complex" common diseases, emphasis on evidence-based practice, and a degree of unfamiliarity/discomfort with the language of genomic medicine, the development and implementation of genomics-guided approaches designed to further individualize the clinical management of a variety of cardiovascular disorders remains a challenge. In this review, we detail a practical approach to genetic testing initiation and interpretation as well as review the current state of cardiovascular genetic and pharmacogenomic testing in the context of relevant society and regulatory agency recommendations/guidelines.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Genetic Predisposition to Disease; Genetic Testing; Genome-Wide Association Study; Genomics; Humans; Pharmacogenetics; Precision Medicine; Prognosis

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are two common, heterogeneous, long-term illnesses which cause significant morbidity and mortality. Although they both present with breathlessness, they are treated differently. Treatment of COPD focuses mainly on relieving short-term breathlessness, whilst treatment of HF has focused on long term morbidity and mortality. Areas covered: In this review, we aim to highlight the diagnostic challenges in distinguishing COPD from HF. We also explore the implications of their overlap, and the use of biomarkers and treatments for HF in patients with COPD to improve long-term outcomes. Expert commentary: Cardiovascular morbidity and mortality amongst patients with COPD is substantial. Approaches which identify patients with COPD at highest cardiovascular risk may therefore be helpful. A trial targeting those patients with COPD and raised natriuretic peptide levels might be the way to test whether cardiovascular medication has anything to offer the respiratory patient.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Heart Failure; Humans; Natriuretic Peptides; Pulmonary Disease, Chronic Obstructive; Risk Factors

Formerly, hyperuricemia was mainly restricted to the rich population, but now-a-days it is a condition affecting wide parts of western civilization. Although only a minority of our population develops clinically relevant symptomatic hyperuricemia, there is growing evidence that elevated serum uric acid levels might be associated with elevated cardiovascular risk and cardiovascular disease progression. But it is not clear whether uric acid is just a biomarker or exerts detrimental effects itself. The xanthine oxidoreductase (XOR) is an essential enzyme for the generation of uric acid. A typical pharmacological therapy to reduce the uric acid amounts is inhibition of XOR. There is good evidence that inhibition of uric acid reduces cardiovascular events in patients. The question arises if XOR inhibition might be an attractive target to reduce cardiovascular events in patients with high or even normal uric acid levels.. This review summarizes the available publications on the relationship between XOR and cardiovascular co-morbidities.. The association of elevated serum uric acid level with oxidative damage in the vessel wall, inflammatory and proliferative vascular changes, hypertension and impaired kidney function are depicted. In addition, the therapeutics currently approved for the treatments of hyperuricemia are outlined and an overview regarding novel, currently researched XOR inhibitors is provided.. Observational and small prospective studies already have given hints for positive cardiovascular effects of XOR inhibition. However, larger prospective studies investigating cardiovascular outcomes are awaited to validate the potential beneficial effect of XOR inhibition for reduction of the cardiovascular burden.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Enzyme Inhibitors; Humans; Hyperuricemia; Risk Factors; Xanthine Oxidase

Polypill and its role in cardiovascular disease (CVD) prevention has been extensively discussed and debated since the inception of the concept in 2003. This article reviews the subsequent accumulated research in this area.. Several short and intermediate to long-term studies with different brands of polypills have analysed the impact of polypill in phase II and III trials. The strengths of polypill that have emerged include better adherence, equivalent or better risk factor control and quality of life among polypill users as compared to usual care. The lurking limitations include difficulty with dose adjustment to targets, fear of mass medicalisation and low acceptability among physicians. The current literature supports polypill use in reducing blood pressure and cholesterol levels for CVD prevention with improvement in adherence to medication. However, the long-term outcome of polypill on CVD events and mortality are unavailable and are currently being studied in clinical trials.

Topics: Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Medication Adherence; Platelet Aggregation Inhibitors; Primary Prevention; Quality of Life; Risk Factors; Treatment Outcome

The burden of cardiovascular and metabolic diseases worldwide is staggering. The emergence of systems approaches in biology promises new therapies, faster and cheaper diagnostics, and personalized medicine. However, a profound understanding of pathogenic mechanisms at the cellular and molecular levels remains a fundamental requirement for discovery and therapeutics. Animal models of human disease are cornerstones of drug discovery as they allow identification of novel pharmacological targets by linking gene function with pathogenesis. The zebrafish model has been used for decades to study development and pathophysiology. More than ever, the specific strengths of the zebrafish model make it a prime partner in an age of discovery transformed by big-data approaches to genomics and disease. Zebrafish share a largely conserved physiology and anatomy with mammals. They allow a wide range of genetic manipulations, including the latest genome engineering approaches. They can be bred and studied with remarkable speed, enabling a range of large-scale phenotypic screens. Finally, zebrafish demonstrate an impressive regenerative capacity scientists hope to unlock in humans. Here, we provide a comprehensive guide on applications of zebrafish to investigate cardiovascular and metabolic diseases. We delineate advantages and limitations of zebrafish models of human disease and summarize their most significant contributions to understanding disease progression to date.

Topics: Animals; Animals, Genetically Modified; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Drug Discovery; Genetic Predisposition to Disease; Humans; Metabolic Diseases; Phenotype; Species Specificity; Zebrafish

To systematically review current evidence regarding the minimum acceptable risk reduction of a cardiovascular event that patients feel would justify daily intake of a preventive medication.. We used the Web of Science to track the forward and backward citations of a set of five key articles until 15 November 2016. Studies were eligible if they quantitatively assessed the minimum acceptable benefit-in absolute values-of a cardiovascular disease preventive medication among a sample of the general population and required participants to choose if they would consider taking the medication.. Of 341 studies screened, we included 22, involving a total of 17 751 participants: 6 studied prolongation of life (POL), 12 studied absolute risk reduction (ARR) and 14 studied number needed to treat (NNT) as measures of risk reduction communicated to the patients. In studies framed using POL, 39%-54% (average: 48%) of participants would consider taking a medication if it prolonged life by <8 months and 56%-73% (average: 64%) if it prolonged life by ≥8 months. In studies framed using ARR, 42%-72% (average: 54%) of participants would consider taking a medication that reduces their 5-year cardiovascular disease (CVD) risk by <3% and 50%-89% (average: 77%) would consider taking a medication that reduces their 5-year CVD risk by ≥3%. In studies framed using 5-year NNT, 31%-81% (average: 60%) of participants would consider taking a medication with an NNT of >30 and 46%-87% (average: 71%) with an NNT of ≤30.. Many patients require a substantial risk reduction before they consider taking a daily medication worthwhile, even when the medication is described as being side effect free and costless.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Health Behavior; Humans; Medication Adherence; Patient Preference

Cardiovascular disease remains a leading cause of morbidity and mortality worldwide. The development of therapeutic agents for the treatment of cardiovascular diseases has always been a priority because of the huge potential market for these drugs. These medications should be part of the anesthesiologist's armamentarium because the typical surgical patient is older and has more comorbidities than in the past. This article reviews commonly used cardiovascular medications that are important in managing patients with unstable hemodynamics.

Topics: Anesthesia; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Heart Rate; Hemodynamics; Humans

Mitochondria are the prime source of ATP in cardiomyocytes. Impairment of mitochondrial metabolism results in damage to existing proteins and DNA. Such deleterious effects are part and parcel of the aging process, reducing the ability of cardiomyocytes to counter stress, such as myocardial infarction and consequent reperfusion. In such conditions, mitochondria in the heart of aged individuals exhibit decreased oxidative phosphorylation, decreased ATP production, and increased net reactive oxygen species production; all of these effects are independent of the decrease in number of mitochondria that occurs in these situations. Rather than being associated with the mitochondrial population in toto, these defects are almost exclusively confined to those organelles positioned between myofibrils (interfibrillar mitochondria). It is in complex III and IV where these dysfunctional aspects are manifested. In an apparent effort to correct mitochondrial metabolic defects, affected organelles are to some extent eliminated by mitophagy; at the same time, new, unaffected organelles are generated by fission of mitochondria. Because these cardiac health issues are localized to specific mitochondria, these organelles offer potential targets for therapeutic approaches that could favorably affect the aging process in heart.

Topics: Age Factors; Aging; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cellular Senescence; Energy Intake; Energy Metabolism; Humans; Mitochondria, Heart; Mitochondrial Dynamics; Myocytes, Cardiac; Risk Reduction Behavior

Polypharmacy is now a frequent aspect and reality of current medicine practice, driven by managing multiple comorbidities, especially in older adults. However and unfortunately, polypharmacy can expose patients to adverse drug reactions, and drug-drug or drug-disease interactions. On the other hand, clinicians are often hesitant to add new drugs to complex regimens even when recommended by evidence-based medicine and guidelines. In addition, there is frequently a failure to assess which medications might not be beneficial and may therefore be stopped.. Cardiovascular disease prevalence is increasing despite the efforts to prevent this with pandemics of obesity and diabetes as leading causes. The healthcare system is facing an increasing number of cardiovascular diseases in older patients with multiple comorbidities. New cardiovascular guidelines encourage multiple drug use to control these conditions and improve mortality and morbidity. However, use of multiple drugs can lead to inappropriate drug interactions and increased adverse outcomes. On the other hand, the so-called polypill has been proposed as a means to decrease the burden of multiple medications as well as increase cardiovascular disease prevention.. This review discusses multiple issues of polypharmacy and its challenges, with a focus on cardiovascular diseases.

Topics: Age Factors; Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Polypharmacy

Cerebrovascular and cardiovascular diseases are caused by impairment of the brain and/or heart circulation. Insufficient blood flow results in decreased oxygen delivery (ischemia), which affects mitochondrial functioning and consequently leads to insufficient ATP production. The predominant mitochondrial outer membrane protein, the voltage dependent anion selective channel (VDAC), is considered to be crucial for mitochondrial functioning. In human mitochondria, as in other vertebrates, three isoforms of VDAC (VDAC1-VDAC3) are present, and they likely play different roles.. In this review, we summarize the available data concerning VDAC involvement in cardiovascular and cerebrovascular diseases with regard to VDAC isoforms and discuss the use of possible VDAC-related intervention targets as well as known VDAC-interacting and cytoprotection- conferring molecules in the treatment of cerebrovascular and cardiovascular diseases.. The suitable references on disorders defined as cerebrovascular and cardiovascular diseases as well as VDAC contribution to these conditions were searched using PubMed and ClinicalTrials.gov databases. The review is based on the 138 carefully selected articles.. Mitochondrial dysfunction triggered by changes in VDAC properties undoubtedly contributes to cell death and related diseases, including cerebrovascular and cardiovascular diseases. Thus, beside diagnostic application, modulation of VDAC activity, including its isoforms, is thus of great importance for the development of efficient therapeutic interventions. Moreover, identification of VDAC-interacting molecules that protect against mitochondrial dysfunction and cell death seems to be of great importance.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cell Death; Cerebrovascular Disorders; Drug Delivery Systems; Humans; Mitochondria; Nervous System Diseases; Protein Isoforms; Voltage-Dependent Anion Channels

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cardiovascular Diseases; Chemokine CCL2; Humans; Ligands; Monocytes; Phenotype; Receptors, CCR2; Signal Transduction

While the use of aspirin in the secondary prevention of cardiovascular (CVD) is well established, aspirin in primary prevention is not systematically recommended because the absolute CV event reduction is similar to the absolute excess in major bleedings. Recently, emerging evidence suggests the possibility that the assumption of aspirin, may also be effective in the prevention of cancer. By adding to the CV prevention benefits the potential beneficial effect of aspirin in reducing the incidence of mortality and cancer could tip the balance between risks and benefits of aspirin therapy in the primary prevention in favour of the latter and broaden the indication for treatment with in populations at average risk. While prospective and randomized study are currently investigating the effect of aspirin in prevention of both cancer and CVD, clinical efforts at the individual level to promote the use of aspirin in global (or total) primary prevention could be already based on a balanced evaluation of the benefit/risk ratio.

Topics: Aspirin; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Hemorrhage; Humans; Patient Selection; Primary Prevention; Risk Assessment; Risk Factors; Treatment Outcome

Health inequalities are differences in health status or the distribution of health determinants between distinct populations or groups. These have important impacts on the accessibility and effectiveness of cardiovascular disease preventive measures. This article discusses the most relevant issues on this topic.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Ethnicity; Female; Health Behavior; Health Knowledge, Attitudes, Practice; Health Status Disparities; Healthcare Disparities; Humans; Male; Risk Factors; Risk Reduction Behavior; Secondary Prevention; Sex Factors; Socioeconomic Factors

Cardiovascular disease (CVD) and cancer are leading causes of mortality and morbidity worldwide. Strategies to improve their treatment and prevention are global priorities and major focus of World Health Organization's joint prevention programs. Emerging evidence suggests that modifiable risk factors including diet, sedentary lifestyle, obesity and tobacco use are central to the pathogenesis of both diseases and are reflected in common genetic, cellular, and signaling mechanisms. Understanding this important biological overlap is critical and may help identify novel therapeutic and preventative strategies for both disorders. In this review, we will discuss the shared genetic and molecular factors central to CVD and cancer and how the strategies commonly used for the prevention of atherosclerotic vascular disease can be applied to cancer prevention.

Topics: Animals; Anticarcinogenic Agents; Biomarkers, Tumor; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Risk Factors; Signal Transduction

In the latter part of the 20th century, drug development in cardiovascular diseases (CVDs) was a paragon of "modern" therapeutics, bringing about a substantial number of effective, well-tolerated agents targeting some of the most prevalent diseases of the Western world. These drugs were often examples of rational drug development targeting specific pathophysiologic pathways previously elucidated through basic research (e.g., targeting of the renin-angiotensin system or the cholesterol synthesis pathway). The widespread adoption of these ground-breaking medications in practice and into medical guidelines undoubtedly played a role in the fall of morbidity and mortality from CVD in the United States in recent decades. For instance, the combined, age-adjusted rates of death due to heart disease and CVD fell in the United States from an aggregate of 329.6 per 100,000 in 1999 to 203.5 in 2014. Although lifestyle trends (e.g., decreased smoking prevalence) contributed to this decline, the impact of safe and effective medications for common CVD conditions cannot be dismissed. Yet, despite the drop in CVD morbidity and mortality, CVDs remain a leading cause of morbidity and mortality in the United States and, therefore, a large area of unmet medical need.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Discovery; General Practice; Humans; Research; United States; United States Food and Drug Administration

Cardiovascular disease accounts for nearly one in three deaths globally, but few novel therapies have reached patients and clinicians in recent years. This translational report reviews trends in the development and approval of cardiovascular drugs and evaluates recent innovation in the field of cardiovascular disease therapeutics. New policies are needed to better support the development of safe and effective therapies with the greatest potential to improve patient health outcomes.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Discovery; Humans; Translational Research, Biomedical

The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease.. The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe.. We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development.. The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Drug Discovery; Drug Evaluation, Preclinical; Drug Industry; Humans

Cardiovascular disease is still the leading cause of death worldwide. There are many environmental and genetic factors that play a role in the development of cardiovascular disease. The treatment of cardiovascular disease is beginning to move in the direction of personalized medicine by using biomarkers from the patient's genome to design more effective treatment plans. Pharmacogenomics have already uncovered many links between genetic variation and response of many different drugs. Areas covered: This article will focus on the main polymorphisms that impact the risk of adverse effects and response efficacy of statins, clopidogrel, aspirin, β-blockers, warfarin dalcetrapib and vitamin E. The genes discussed include SLCO1B1, ABCB1, CYP3A4, CYP3A5, CYP2C19, PTGS1, PTGS2, ADRB1, ADCY9, CYP2C19, PON1, CES1, PEAR1, GPIIIa, CYP2D6, CKORC1, CYP2C9 and Hp. Expert opinion: Although there are some convincing results that have already been incorporated in the labelling treatment guidelines, most gene-drug relationships have been inconsistent. A better understanding of the relationships between genetic factors and drug response will provide more opportunities for personalized diagnosis and treatment of cardiovascular disease.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Genetic Variation; Humans; Pharmacogenetics; Polymorphism, Genetic; Precision Medicine

Aliskiren was shown to increase adverse events in patients with diabetes and concomitant renin-angiotensin blockade. We aim to investigate the efficacy and safety of aliskiren in patients with diabetes and increased cardiovascular risk or established cardiovascular disease.. MEDLINE and Embase were searched for prospective studies comparing addition of aliskiren to standard medical therapy in patients with diabetes and cardiovascular disease, or ⩾1 additional cardiovascular risk factor (hypertension, abnormal lipid profile, microalbuminuria/proteinuria, chronic kidney disease). Relative risk for efficacy (all-cause mortality, combined cardiovascular mortality and hospitalisation) and safety (hyperkalaemia, hypotension, renal impairment) outcomes was calculated.. Of 2151 studies identified in the search, seven studies enrolling 13,395 patients were included. Aliskiren had no effect on all-cause mortality (relative risk: 1.05, 95% confidence interval: 0.90 to 1.24, p = 0.53), or combined cardiovascular mortality or heart failure hospitalisation (relative risk: 1.07, 95% confidence interval: 0.81 to 1.40, p = 0.64). Patients receiving aliskiren had a greater risk of developing hyperkalaemia (relative risk: 1.32, 95% confidence interval: 1.14 to 1.53, p = 0.0003) and renal impairment (relative risk: 1.15, 95% confidence interval: 1.02 to 1.30, p = 0.03), but not hypotension.. Patients with diabetes and cardiovascular disease or cardiovascular risk do not benefit from the addition of aliskiren to standard medical therapy. Detrimental safety profile in pooled analysis supports current warnings.

Topics: Amides; Cardiovascular Agents; Cardiovascular Diseases; Chi-Square Distribution; Diabetes Mellitus; Fumarates; Humans; Odds Ratio; Renin-Angiotensin System; Risk Assessment; Risk Factors; Treatment Outcome

Personalized management of cardiovascular disorders (CVD), also referred to as personalized or precision cardiology in accordance with general principles of personalized medicine, is selection of the best treatment for an individual patient. It involves the integration of various "omics" technologies such as genomics and proteomics as well as other new technologies such as nanobiotechnology. Molecular diagnostics and biomarkers are important for linking diagnosis with therapy and monitoring therapy. Because CVD involve perturbations of large complex biological networks, a systems biology approach to CVD risk stratification may be used for improving risk-estimating algorithms, and modeling of personalized benefit of treatment may be helpful for guiding the choice of intervention. Bioinformatics tools are helpful in analyzing and integrating large amounts of data from various sources. Personalized therapy is considered during drug development, including methods of targeted drug delivery and clinical trials. Individualized recommendations consider multiple factors - genetic as well as epigenetic - for patients' risk of heart disease. Examples of personalized treatment are those of chronic myocardial ischemia, heart failure, and hypertension. Similar approaches can be used for the management of atrial fibrillation and hypercholesterolemia, as well as the use of anticoagulants. Personalized management includes pharmacotherapy, surgery, lifestyle modifications, and combinations thereof. Further progress in understanding the pathomechanism of complex cardiovascular diseases and identification of causative factors at the individual patient level will provide opportunities for the development of personalized cardiology. Application of principles of personalized medicine will improve the care of the patients with CVD.

Topics: Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Cell- and Tissue-Based Therapy; Computational Biology; Genetic Predisposition to Disease; Genomics; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Life Style; Lipids; Myocardial Ischemia; Nanotechnology; Pharmacogenomic Testing; Polymorphism, Single Nucleotide; Precision Medicine; Systems Biology

Circulatory failure in preterm and term newborn infants is commonly treated with inotropes or vasoactive medications. In this structured literature review, the available data on pharmacodynamic effects of the inotropes adrenaline, dobutamine, dopamine, levosimendan, milrinone, noradrenaline, and the vasoactive drugs vasopressin and hydrocortisone are presented.. Structured searches were conducted to identify relevant articles according to pre-defined inclusion criteria which were human clinical trials published after 2000.. Out of 101 identified eligible studies only 22 studies met the criteria for evidence based practice guidelines level I to IV. The most prevalent pharmacodynamic effects were increase in blood pressure and/or heart rate, which were also the most frequently studied circulatory parameters.. This review demonstrates the need for further systematic studies on all reviewed drugs with incorporation of novel non-invasive biomarkers in this vulnerable patient group, for more timely and appropriate treatment for clinical efficacy.

Topics: Blood Pressure; Cardiotonic Agents; Cardiovascular Agents; Cardiovascular Diseases; Child Development; Data Analysis; Heart Rate; Humans; Infant, Newborn

Cardiovascular diseases are a leading cause of death in developed and developing countries and decrease the quality of life, which has enormous social and economic consequences for the population. Recent studies on essential oils have attracted attention and encouraged continued research of this group of natural products because of their effects on the cardiovascular system. The pharmacological data indicate a therapeutic potential for essential oils for use in the treatment of cardiovascular diseases. Therefore, this review reports the current studies of essential oils chemical constituents with cardiovascular activity, including a description of their mechanisms of action.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Hypertension; Oils, Volatile

The clinical use of ivabradine has and continues to evolve along channels that are predicated on its mechanism of action. It selectively inhibits the funny current (I

Topics: Benzazepines; Cardiovascular Agents; Cardiovascular Diseases; Cyclic Nucleotide-Gated Cation Channels; Heart Rate; Humans; Ivabradine

It has long been a controversial hotspot whether resting heart rate (RHR) is a risk factor or a marker for death. Ivabradine, a specific inhibitor of the If current in the sinoatrial node, is a pure RHR lowering agent. The study was aimed to investigate whether ivabradine would reduce more RHR, cardiovascular disease (CVD) mortality, and all-cause mortality than those placebo or beta-blockers.. The authors performed a meta-analysis of 8 randomized controlled clinical studies (with 40,357 participants), and 3 studies of those which were ivabradine versus placebo (36,069 participants) and other 5 studies ivabradine versus beta-blockers (4288 participants) were available. The authors compared the association of the RHR reduction with death from CVD causes (2674 in 40,285 participants) and the rate of all-cause death (3143 deaths in 38,037 participants), and assessed improvement in death rates with the use of ivabradine.. The change of RHR from baseline to endpoint was 8 to 16 beats/min (bpm) in ivabradine group, 1 to 8 bpm in placebo group, and 4 to 24 bpm in beta-blockers group. In ivabradine versus placebo, the reduced risks of CVD mortality and all-cause morbidity were not significantly (risk ratio [RR] 1.02; 95% confidence interval [CI] 0.91-1.14, P = .737; RR: 1.00, 95% CI: 0.92-1.09, P = .992, respectively). CVD and all-cause morbidity were similar for ivabradine versus beta-blockers (RR: 1.04; 95% CI: 0.80-1.37, P = .752; RR: 1.17, 95% CI: 0.53-2.60, P = .697, respectively).. Ivabradine had a neutral effect on mortality, suggesting that a pure RHR lowering agent did not reduce CVD mortality, all-cause mortality and improve the lifespan.

Topics: Adrenergic beta-Antagonists; Aged; Benzazepines; Cardiovascular Agents; Cardiovascular Diseases; Cause of Death; Female; Heart Rate; Humans; Ivabradine; Male; Middle Aged; Odds Ratio; Randomized Controlled Trials as Topic; Rest; Risk Factors; Treatment Outcome

Epidemiologic studies have previously suggested that premenopausal females have reduced incidence of cardiovascular disease (CVD) when compared to age-matched males, and the incidence and severity of CVD increases postmenopause. The lower incidence of cardiovascular disease in women during reproductive age is attributed at least in part to estrogen (E2). E2 binds to the traditional E2 receptors (ERs), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ), as well as the more recently identified G-protein-coupled ER (GPR30), and can exert both genomic and non-genomic actions. This review summarizes the protective role of E2 and its receptors in the cardiovascular system and discusses its underlying mechanisms with an emphasis on oxidative stress, fibrosis, angiogenesis, and vascular function. This review also presents the sexual dimorphic role of ERs in modulating E2 action in cardiovascular disease. The controversies surrounding the clinical use of exogenous E2 as a therapeutic agent for cardiovascular disease in women due to the possible risks of thrombotic events, cancers, and arrhythmia are also discussed. Endogenous local E2 biosynthesis from the conversion of testosterone to E2 via aromatase enzyme offers a novel therapeutic paradigm. Targeting specific ERs in the cardiovascular system may result in novel and possibly safer therapeutic options for cardiovascular protection.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Estrogens; Humans; Receptors, Estrogen

Bile acids (BA), for decades considered only to have fat-emulsifying functions in the gut lumen, have recently emerged as novel cardio-metabolic modulators. They have real endocrine effects, acting via multiple intracellular receptors in various organs and tissues. BA affect energy homeostasis through the modulation of glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor (FXR), as well as the cytoplasmic membrane G protein-coupled BA receptor TGR5 in a variety of tissues; although numerous other intracellular targets of BA are also in play.The roles of BA in the pathogenesis of diabetes, obesity, metabolic syndrome, and cardiovascular diseases are seriously being considered, and BA and their derivatives seem to represent novel potential therapeutics to treat these diseases of civilization.

Topics: Animals; Anti-Obesity Agents; Bile Acids and Salts; Cardiovascular Agents; Cardiovascular Diseases; Drug Discovery; Gastrointestinal Microbiome; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Intestinal Mucosa; Intestines; Lipid Metabolism; Metabolic Diseases; Probiotics; Signal Transduction

Avoiding medications in which the risks outweigh the benefits in the elderly patient is a challenge for physicians, and different criteria to identify inappropriate prescription (IP) exist to aid prescribers. Definition of IP indicators in the Italian geriatric population affected by cardiovascular disease and chronic comorbidities could be extremely useful for prescribers and could offer advantages from a public health perspective. The purpose of the present study was to identify IP indicators by means of a systematic literature review coupled with consensus criteria. A systematic search of PubMed, EMBASE, and CENTRAL databases was conducted, with the search structured around four themes and combining each with the Boolean operator "and". The first regarded "prescriptions", the second "adverse events", the third "cardiovascular conditions", and the last was planned to identify studies on "older people". Two investigators independently reviewed titles, abstracts, full texts, and selected articles addressing IP in the elderly affected by cardiovascular condition using the following inclusion criteria: studies on people aged ≥65 years; studies on patients with no restriction on age but with data on subjects aged ≥65 years; and observational effectiveness studies. The database searches produced 5,742 citations. After removing duplicates, titles and abstracts of 3,880 records were reviewed, and 374 full texts were retrieved that met inclusion criteria. Thus, 49 studies reporting 32 potential IP indicators were included in the study. IP indicators regarded mainly drug-drug interactions, cardio- and cerebrovascular risk, bleeding risk, and gastrointestinal risk; among them, only 19 included at least one study that showed significant results, triggering a potential warning for a specific drug or class of drugs in a specific context. This systematic review demonstrates that both cardiovascular and non-cardiovascular drugs increase the risk of adverse drug reactions in older adults with cardiovascular diseases.

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Drug Interactions; Hemorrhage; Humans; Inappropriate Prescribing; Stroke

The use of nitroglycerin in the treatment of angina pectoris began not long after its original synthesis in 1847. Since then, the discovery of nitric oxide as a biological effector and better understanding of its roles in vasodilation, cell permeability, platelet function, inflammation, and other vascular processes have advanced our knowledge of the hemodynamic (mostly mediated through vasodilation of capacitance and conductance arteries) and nonhemodynamic effects of organic nitrate therapy, via both nitric oxide-dependent and -independent mechanisms. Nitrates are rapidly absorbed from mucous membranes, the gastrointestinal tract, and the skin; thus, nitroglycerin is available in a number of preparations for delivery via several routes: oral tablets, sublingual tablets, buccal tablets, sublingual spray, transdermal ointment, and transdermal patch, as well as intravenous formulations. Organic nitrates are commonly used in the treatment of cardiovascular disease, but clinical data limit their use mostly to the treatment of angina. They are also used in the treatment of subsets of patients with heart failure and pulmonary hypertension. One major limitation of the use of nitrates is the development of tolerance. Although several agents have been studied for use in the prevention of nitrate tolerance, none are currently recommended owing to a paucity of supportive clinical data. Only 1 method of preventing nitrate tolerance remains widely accepted: the use of a dosing strategy that provides an interval of no or low nitrate exposure during each 24-h period. Nitric oxide's important role in several cardiovascular disease mechanisms continues to drive research toward finding novel ways to affect both endogenous and exogenous sources of this key molecular mediator.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Administration Routes; Humans; Nitrogen Oxides; Nitroglycerin

Observational studies have suggested a possible protective role of vitamin D on the cardiovascular system. The available evidence does not support either cardiovascular benefits or harms of vitamin D supplementation. This chapter provides an overview and discussion of the current knowledge of vitamin D effects from a cardiovascular health perspective. It focuses on vitamin D in relation to cardiovascular disease, i.e. ischemic heart disease, and stroke; the traditional cardiovascular risk factors hypertension, abnormal blood lipids, obesity; and the emerging risk factors hyperparathyroidism, microalbuminuria, chronic obstructive pulmonary diseases, and non-alcoholic fatty liver disease. Meta-analyses of observational studies have largely found vitamin D levels to be inversely associated with cardiovascular risk and disease. However, Mendelian randomization studies and randomized, controlled trials (RCTs) have not been able to consistently replicate the observational findings. Several RCTs are ongoing, and the results from these are needed to clarify whether vitamin D deficiency is a causal and reversible factor to prevent cardiovascular disease.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Dietary Supplements; Humans; Prognosis; Risk Factors; Vitamin D; Vitamin D Deficiency

This white paper provides a summary of the presentations and discussions from a think tank on "Enabling Social Listening for Cardiac Safety Monitoring" trials that was cosponsored by the Drug Information Association and the Cardiac Safety Research Consortium, and held at the White Oak headquarters of the US Food and Drug Administration on June 3, 2016. The meeting's goals were to explore current methods of collecting and evaluating social listening data and to consider their applicability to cardiac safety surveillance. Social listening is defined as the act of monitoring public postings on the Internet. It has several theoretical advantages for drug and device safety. First, these include the ability to detect adverse events that are "missed" by traditional sources and the ability to detect adverse events sooner than would be allowed by traditional sources, both by affording near-real-time access to data from culturally and geographically diverse sources. Social listening can also potentially introduce a novel patient voice into the conversation about drug safety, which could uniquely augment understanding of real-world medication use obtained from more traditional methodologies. Finally, it can allow for access to information about drug misuse and diversion. To date, the latter 2 of these have been realized. Although regulators from the Food and Drug Administration and the United Kingdom's Medicines and Healthcare Products Regulatory Agency participated in the think tank along with representatives from industry, academia, and patient groups, this article should not be construed to constitute regulatory guidance.

Topics: Biomedical Research; Cardiovascular Agents; Cardiovascular Diseases; Drug Monitoring; Endpoint Determination; Heart; Humans

Hypertensive urgencies and emergencies are common situations in clinical practice. Hypertensive urgencies are characterized by acute elevation of blood pressure without target organ damage. Hypertensive emergencies are life-threatening situations characterized by acute elevation of blood pressure and target organ damage. The aims of blood pressure control, antihypertensive drugs to use and route of administration will depend on the presence or absence of target organ damage and individual patient characteristics. The correct diagnosis and treatment of these situations are essential for patient prognosis. © 2017 SEHLELHA. Published by Elsevier España, S.L.U. All rights reserved.

Topics: Acute Disease; Ambulatory Care; Antihypertensive Agents; Aortic Dissection; Cardiovascular Agents; Cardiovascular Diseases; Catecholamines; Emergencies; Hospitalization; Humans; Hypertension, Malignant; Hypertensive Encephalopathy; Stress, Psychological

MicroRNAs (miRNAs) are small conserved noncoding RNAs which function as posttranscriptional regulators of gene expression. Studies over the last 20 years have revealed the essential functions of miRNAs in regulating cardiovascular biology (such as cardiovascular cell differentiation, growth, proliferation and apoptosis) and crucial roles in controlling cardiovascular disease (CVD), indicating the potential of these small molecules as therapeutic targets and/or agents for CVD. Moreover, miRNAs in the circulation or other body fluids are stable and readily detectable, and more importantly often disease-associated, which makes them promising novel biomarkers for diagnosis and prognosis of CVDs. Furthermore, emerging evidence uncovered miRNAs as new targets and/or regulators of cardiovascular medications given the ability of miRNAs to interact with some cardiovascular drugs, which opens up new opportunities for the research and development of novel CVD drugs. Herein, we summarize current knowledge regarding the potential applications of miRNAs in the therapy of CVD, including myocardial ischemia, cardiac hypertrophy/heart failure, interstitial fibrosis, arrhythmia, diabetes and hypertension and discuss the therapeutic potential and challenge of miRNAs in drug discovery.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Gene Expression Regulation; Humans; MicroRNAs; Molecular Targeted Therapy

Identifying appropriate molecular targets is a critical step in drug development. Despite many advantages, the traditional tools of observational epidemiology and cellular or animal models of disease can be misleading in identifying causal pathways likely to lead to successful therapeutics. Here, we review some favorable aspects of human genetics studies that have the potential to accelerate drug target discovery. These include using genetic studies to identify pathways relevant to human disease, leveraging human genetics to discern causal relationships between biomarkers and disease, and studying genetic variation in humans to predict the potential efficacy and safety of inhibitory compounds aimed at molecular targets. We present some examples taken from studies of plasma lipids and coronary artery disease to highlight how human genetics can accelerate therapeutics development.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Discovery; Genetic Predisposition to Disease; Genomics; Humans; Molecular Targeted Therapy; Pharmacogenetics; Phenotype; Risk Factors; Signal Transduction

Cardiovascular disease remains the most common cause of death in persons with diabetes regardless of age. Increasing age combined with diabetes exert a synergistic effect on the vascular system increasing the atherosclerosis burden in older people with diabetes. Due to their high baseline risk, they stand to benefit most from interventions to reduce cardiovascular risk. Older people with diabetes are functionally heterogeneous and their management is challenging. Fit and independent individuals are likely to benefit from tight targets while a relaxed approach putting quality of life at the heart of management plans is more appropriate in the frail and dependent individuals with limited life expectancy.

Topics: Aging; Blood Glucose; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus; Diet; Exercise; Glycated Hemoglobin; Health Behavior; Humans; Hypoglycemic Agents; Life Style; Lipids; Physical Fitness; Quality of Life; Risk Factors; Risk Reduction Behavior

Excess visceral adipose tissue is associated with increased risk of high blood pressure, lipid disorders, type 2 diabetes, and cardiovascular disease. Adipose tissue is an endocrine organ with multiple humoral and metabolic roles in regulating whole-body physiology. However, perivascular adipose tissue (PVAT) also plays a functional role in regulating the contractile state of the underlying smooth muscle cell layer. Work during the past decade has shown that this adipose-vascular coupling is achieved by production of numerous substances released from PVAT. Animal disease models have been instrumental in identifying biological and pathophysiological functions of this regulation. These studies have produced strong evidence that alterations in the paracrine control of PVAT in the regulation of arterial tone contribute to vascular dysfunction in obesity, hypertension, and cardiometabolic disease. Perivascular relaxing factors, or perhaps their putative targets, might represent exciting new targets for the prevention and treatment of cardiovascular and metabolic diseases.

Topics: Adipokines; Adipose Tissue; Animals; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Hypertension; Hypoglycemic Agents; Muscle, Smooth, Vascular; Obesity

The availability of effective drugs targeting the major risk factors of cardiovascular disease (CVD) has reduced morbidity and mortality. Cumulative relative risk of CVD events can be reduced by 75 % with a combination of aspirin, a β-adrenoceptor antagonist (β-blocker), an HMG-CoA reductase inhibitor (statin), and an angiotensin-converting enzyme inhibitor. The principal pharmacodynamics of these drugs cannot explain the entirety of their cardioprotective action, as other drugs with similar pharmacologic targets have not been associated with favorable clinical effects. This raises the possibility that the cardioprotective drugs have a unique pleiotropic activity that contributes to their clinical efficacy. Recent data suggest that reducing cellular stress such as oxidative, inflammatory, and endoplasmic reticulum stress, might be a common denominator of the drugs with proven efficacy in reducing CVD risk. In this communication, the evidence in favor of this hypothesis is discussed, and ongoing trials with therapeutic agents targeting cellular stresses are reviewed.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Oxidative Stress; Stress, Physiological

Background Despite a wide range of medications being available for the prevention of cardiovascular events such as stroke, myocardial infarction and mortality in both a primary and secondary setting, patient adherence to complex therapy regimens involving different drug classes remains low worldwide. Combining antiplatelet, antihypertensive, lipid-lowering and potentially further drugs into one 'polypill' has the potential to increase adherence, thereby reducing risk factors to a greater extent and for a longer duration. The World Health Organization has recently highlighted increased adherence as a key development need for reducing cardiovascular disease. Methods Recent clinical trial data regarding adherence, reductions in cardiovascular risk and outcomes, safety and tolerability and the cost-effectiveness of the polypill approach are summarised and reviewed. In addition, ongoing trials and the questions they intend to answer are considered. References were retrieved from a PubMed literature search (date range 1990-2016) using the terms 'polypill', 'cardiovascular events' and 'adherence', and selected based on relevance. The website www.clinicaltrials.gov was also consulted for the identification of ongoing trials. Conclusions To date, the polypill approach has been conclusively shown to increase adherence relative to usual care in all patients, with those in a primary care setting or with poor baseline adherence potentially standing to benefit most. Concomitant risk factor reductions have also been suggested. However, whether this translates into a reduction in cardiovascular events and generates good cost-effectiveness in a given healthcare environment is currently under further investigation.

Topics: Administration, Oral; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Cost Savings; Cost-Benefit Analysis; Drug Combinations; Drug Costs; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Medication Adherence; Platelet Aggregation Inhibitors; Preventive Health Services; Protective Factors; Risk Assessment; Risk Factors; Tablets

Cardiovascular diseases are the leading cause of global deaths. The current paradigm in medicine seeks novel approaches for the treatment of progressive or end-stage diseases. The organ transplantation option is limited in availability, and unfortunately, a significant number of patients are lost while waiting for donor organs. Animal studies have shown that upon myocardial infarction, it is possible to stop adverse remodeling in its tracks and reverse with tissue engineering methods. Regaining the myocardium function and avoiding further deterioration towards heart failure can benefit millions of people with a significantly lesser burden on healthcare systems worldwide. The advent of induced pluripotent stem cells brings the unique advantage of testing candidate drug molecules on organ-on-chip systems, which mimics human heart in vitro. Biomimetic three-dimensional constructs that contain disease-specific or normal cardiomyocytes derived from human induced pluripotent stem cells are a useful tool for screening drug molecules and studying dosage, mode of action and cardio-toxicity. Tissue engineering approach aims to develop the treatments for heart valve deficiency, ischemic heart disease and a wide range of vascular diseases. Translational research seeks to improve the patient's quality of life, progressing towards developing cures, rather than treatments. To this end, researchers are working on tissue engineered heart valves, blood vessels, cardiac patches, and injectable biomaterials, hence developing new ways for engineering bio-artificial organs or tissue parts that the body will adopt as its own. In this review, we summarize translational methods for cardiovascular tissue engineering and present useful tables on pre-clinical and clinical applications.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Myocytes, Cardiac; Regeneration; Tissue Engineering; Tissue Scaffolds; Translational Research, Biomedical

In 1964, Robert A. O'Reilly's research group identified members of a family who required remarkably high warfarin doses (up to 145 mg/day, 20 times the average dose) to achieve appropriate anticoagulation. Since this time, pharmacogenetics has become a mainstay of cardiovascular science, and genetic variants have been implicated in several fundamental classes of medications used in cardiovascular medicine.. In this review, we discuss genetic variants that affect drug response to 3 classes of cardiovascular drugs: statins, platelet P2Y12 inhibitors, and anticoagulants. These genetic variations have pharmacodynamic and pharmacokinetic effects and have been shown to explain differences in drug response such as lipid lowering, prevention of cardiovascular disease, and prevention of stroke, as well as incidence of adverse events such as musculoskeletal side effects and bleeding. Several groups have begun to implement pharmacogenetics testing as part of routine clinical care with the goal of improving health outcomes. Such strategies identify both patients at increased risk of adverse outcomes and alternative strategies to mitigate this risk as well as patients with "normal" genotypes, who, armed with this information, may have increased confidence and adherence to prescribed medications. While much is known about the genetic variants that underlie these effects, translation of this knowledge into clinical practice has been hampered by difficulty in implementing cost-effective, point-of-care tools to improve physician decision-making as well as a lack of data, as of yet, demonstrating the efficacy of using genetic information to improve health.. Many genetic variants that affect individual responses to drugs used in cardiovascular disease prevention and treatment have been described. Further study of these variants is needed before successful implementation into clinical practice.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Genetic Variation; Humans; Pharmacogenetics

Cardiovascular disease (CVD) is the leading cause of global mortality and is expected to reach 23 million deaths by 2030. Eighty percent of CVD deaths occur in low-income and middle-income countries (LMICs). Although CVD prevention and treatment guidelines are available, translating these into practice is hampered in LMICs by inadequate health care systems that limit access to lifesaving medications. In this review article, we describe the deficiencies in the current LMIC supply chains that limit access to effective CVD medicines, and discuss existing solutions that are translatable to similar settings so as to address these deficiencies.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Developing Countries; Health Services Accessibility; Humans; Patient-Centered Care; Poverty; Socioeconomic Factors

The prevalence of diabetes mellitus (DM) is steadily rising in the U.S., both in the general population and among those with cardiovascular disease (CVD). Understanding how to treat a patient with both conditions is becoming increasingly important. With multiple therapeutic options for CVD management, some medications will invariably impact glycemia in this group of patients. The concept of "DM-friendly" management of CVD is based on a treatment approach of selecting medications that do not impair glycemic control and provide equivalent cardioprotective effects. This article reviews the glycemic effects of various classes of medications commonly used to treat CVD.. Data sources were all PubMed- and Google Scholar-referenced articles in English-language peer-reviewed journals from 1980 through April 2016. Studies selected could include observational studies or prospective clinical trials. Prospective clinical trials included in this review focused on investigating the association of the medication of interest with glycemic outcomes. Meta-analyses and systematic reviews were also included.. The data on glycemic effects were lacking for many of the medication classes and individual medications examined. However, in our review, certain beta-blockers and renin angiotensin aldosterone system inhibitors, and select calcium channel blockers were consistently shown to have favorable glycometabolic profiles when compared with other commonly used cardiovascular therapies.. Several commonly prescribed medications for the treatment of CVD, such as certain beta-blockers and renin angiotensin aldosterone system inhibiting agents, are associated with favorable glycometabolic effects. As clinicians are more often faced with the challenge of treating patients with DM and concomitant CVD, consideration of how common cardiovascular medications may affect glycemia should be incorporated into the clinical decision making process.. A1C = hemoglobin A1C ACE = angiotensin-converting enzyme ARB = angiotensin II receptor blocker CCB = calcium channel blocker CI = confidence interval CVD = cardiovascular disease DM = diabetes mellitus MI = myocardial infarction RR = relative risk.

Topics: Blood Glucose; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus; Humans

Osteoporosis and cardiovascular diseases are epidemiologically associated. Calcification phenomena of atherosclerotic plaque involve cytokines and growth factors also involved in bone remodeling. Drugs given for either of these two conditions could act on these mechanisms. Can osteoporosis drugs have an influence on the occurrence of cardiovascular events? Conversely, can the treatment of hypertension alter the course of osteoporosis? It is possible that administration of high doses of calcium (1g/day) in patients who already have important dietary intake can increase the risk of myocardial infarction. Epidemiological studies show links between low serum vitamin D levels and cardiovascular disease but interventional studies show that vitamin D administration in moderately deficient subjects vitamin D does not prevent the occurrence of cardiovascular events. Cohort studies show a beneficial effect of beta-blockers and thiazides administered to hypertensive patients: they reduce by 20% risk of fracture of the proximal femur. Should we focus on these anti-hypertensive treatments for our patients with osteoporosis?

Topics: Adrenergic beta-Antagonists; Antihypertensive Agents; Bone Density Conservation Agents; Calcium; Calcium, Dietary; Cardiovascular Agents; Cardiovascular Diseases; Denosumab; Diphosphonates; Drug Interactions; Humans; Hypercalcemia; Hypertension; Myocardial Infarction; Osteoporosis; Sodium Chloride Symporter Inhibitors; Teriparatide; Vitamin D; Vitamin D Deficiency

Pharmacological prophylaxis has been proven to reduce the risk of cardiovascular events in individuals with atherosclerotic occlusive arterial disease. However, the role of prophylaxis in individuals with abdominal aortic aneurysm (AAA) remains unclear. Several studies have shown that despite successful repair, those people with AAA have a poorer rate of survival than healthy controls. People with AAA have an increased prevalence of coronary heart disease and risk of cardiovascular events. Despite this association, little is known about the effectiveness of pharmacological prophylaxis in reducing cardiovascular risk in people with AAA. This is an update of a Cochrane review first published in 2014.. To determine the long-term effectiveness of antiplatelet, antihypertensive or lipid-lowering medication in reducing mortality and cardiovascular events in people with abdominal aortic aneurysm (AAA).. For this update the Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register (14 April 2016). In addition, the CIS searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 3) and trials registries (14 April 2016) and We also searched the reference lists of relevant articles.. Randomised controlled trials in which people with AAA were randomly allocated to one prophylactic treatment versus another, a different regimen of the same treatment, a placebo, or no treatment were eligible for inclusion in this review. Primary outcomes included all-cause mortality and cardiovascular mortality.. Two review authors independently selected studies for inclusion, and completed quality assessment and data extraction. We resolved any disagreements by discussion. Only one study met the inclusion criteria of the review, therefore we were unable to perform meta-analysis.. No new studies met the inclusion criteria for this update. We included one randomised controlled trial in the review. A subgroup of 227 participants with AAA received either metoprolol (N = 111) or placebo (N = 116). There was no clear evidence that metoprolol reduced all-cause mortality (odds ratio (OR) 0.17, 95% confidence interval (CI) 0.02 to 1.41), cardiovascular death (OR 0.20, 95% CI 0.02 to 1.76), AAA-related death (OR 1.05, 95% CI 0.06 to 16.92) or increased nonfatal cardiovascular events (OR 1.44, 95% CI 0.58 to 3.57) 30 days postoperatively. Furthermore, at six months postoperatively, estimated effects were compatible with benefit and harm for all-cause mortality (OR 0.71, 95% CI 0.26 to 1.95), cardiovascular death (OR 0.73, 95% CI 0.23 to 2.39) and nonfatal cardiovascular events (OR 1.41, 95% CI 0.59 to 3.35). Adverse drug effects were reported for the whole study population and were not available for the subgroup of participants with AAA. We considered the study to be at a generally low risk of bias. We downgraded the quality of the evidence for all outcomes to low. We downgraded the quality of evidence for imprecision as only one study with a small number of participants was available, the number of events was small and the result was consistent with benefit and harm.. Due to the limited number of included trials, there is insufficient evidence to draw any conclusions about the effectiveness of cardiovascular prophylaxis in reducing mortality and cardiovascular events in people with AAA. Further good-quality randomised controlled trials that examine many types of prophylaxis with long-term follow-up are required before firm conclusions can be made.

Topics: Antihypertensive Agents; Aortic Aneurysm, Abdominal; Cardiovascular Agents; Cardiovascular Diseases; Cause of Death; Humans; Metoprolol; Randomized Controlled Trials as Topic; Risk Factors

Elderly and women have been often under-represented in randomised clinical trials (RCTs) testing the effect of treatments on cardiovascular diseases (CVDs) even though these diseases highly affect both of them.. Taking into account these issues, the aim of this review is to critically analyse the topic of under-representation of elderly and women in cardiovascular RCTs.. Compared to their younger counterparts, elderly have a higher incidence of disease-related morbidities, take more medicines and account for more adverse drug related events. Similarly, women present several differences in CVD pathophysiology, clinical manifestations and outcomes in comparison to their male counterparts. For these reasons, the results of RCTs obtained in younger men cannot be simply translated in elderly and women. Unfortunately, although international guidelines have been published to increase the enrolment of elderly and women, their recruitment is still insufficient. Thus, the inclusion of these subgroups in cardiovascular RCTs is a key aspect to acquire evidence-based knowledge in the understanding and management of CVDs in elderly and women.

Topics: Age Factors; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Female; Global Health; Humans; Incidence; Male; Morbidity; Patient Participation; Sex Factors; Survival Rate

Even if cardiovascular disease (CVD) drugs are supported by high level proofs, the results of CVD treatment present great disparities: there are still patients dying with supposed optimal treatment, patients facing adverse events and CVD remains the primary cause of death in the world. Pharmacogenomics is the basis of personalisation of the treatment able to allow higher medication success rates. In this review, we will present detailed examples of CVD drugs to highlight the complexity of this challenging field and we will discuss novel concepts that should be considered for a fastest integration of pharmacogenomics in clinical practice of CVD. Areas Covered: The complexity of pharmacogenetics and pharmacogenomics of CVD drugs are presented though examples of medications such as statins, with a focus on their effectiveness and adverse effects. Expert Opinion: The application of personalised medicine in the CVD medical practice requires the study of human genome with regard to drugs pharmacokinetics, pharmacodynamics, interactions and tolerance profile. The existing state -of-the-art of CVD drugs gives hopes for a future revolution in the drug development that will maximise cardiovascular patients benefit while decreasing their risks for adverse effects. Article Highlights Box: • Coronary heart disease (CHD) remains the first cause of death worldwide. • Cardiovascular treatment has a significant percentage of insufficient efficacy, poor tolerance and compliance. • Predicting the response to therapy while diminishing the side effects is the basis of personalised medicine; pharmacogenomics is leading towards this direction. • The response to CVD therapy and side effects are in the heart of CVD pharmacogenomics and significant progress has been noted. • The application of pharmacogenomics in the CVD medical practice is facing many methodological, technical, ethical, behavioral and financial issues, while cost-effectiveness is the main prerequisite. • The consideration of gene × gene × environment interactions and the inclusion of "omics" data in pharmacogenomic studies of CVD drugs will facilitate the generation of reliable results and will promote tailored treatments and new strategies of drug research and development.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cost-Benefit Analysis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pharmacogenetics; Practice Patterns, Physicians'; Precision Medicine

The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. In addition to its well-established role in maintaining vascular homeostasis, the endothelium has been increasingly recognized as a key player in modulating healthy adipose tissue expansion in response to excess calories by providing adipocyte precursors and driving angiogenesis. When this increased storage need is unmet, excessive deposition of fat occurs at ectopic locations, including perivascular adipose tissue (PVAT). PVAT is in intimate contact with the vessel wall, hence affecting vascular function and structure. In lean individuals, PVAT exerts anticontractile and anti-inflammatory activities to protect the vasculature. In obesity, instead, these beneficial properties are lost and PVAT releases inflammatory mediators, promotes oxidative stress, and contributes to vascular dysfunction. The underlying mechanisms elicited by these outside-in signals include resistance to the vasodilator actions of insulin and activation of endothelin (ET)-1-mediated vasoconstriction. A number of adipokines and gut hormones, which are important modulators of food intake, energy balance, glucose and lipid metabolism, insulin sensitivity, and inflammation, have also positive vascular actions. This feature makes them promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant benefits. There is, therefore, real hope that unleashing the power of fat- and gut-derived substances might provide effective dual-action therapies for obesity and its complications.

Topics: Adipokines; Adipose Tissue; Adiposity; Animals; Anti-Obesity Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Endothelium, Vascular; Gastrointestinal Hormones; Humans; Insulin Resistance; Molecular Targeted Therapy; Obesity; Paracrine Communication; Signal Transduction; Vascular Remodeling

Medication non-adherence is common among renal dialysis patients. High degrees of non-adherence in randomized controlled trials (RCTs) can lead to failure to detect a true treatment effect. Cardio-protective pharmacological interventions have shown no consistent benefit in RCTs involving dialysis patients. Whether non-adherence contributes to this lack of efficacy is unknown. We aimed to investigate how medication adherence and drug discontinuation were assessed, reported and addressed in RCTs, evaluating cardiovascular or mortality outcomes in dialysis patients.. Electronic database searches were performed in MEDLINE, EMBASE & Cochrane CENTRAL for RCTs published between 2005-2015, evaluating self-administered medications, in adult dialysis patients, which reported clinical cardiovascular or mortality endpoints, as primary or secondary outcomes. Study characteristics, outcomes, methods of measuring and reporting adherence, and data on study drug discontinuation were analyzed.. Of the 642 RCTs in dialysis patients, 22 trials (12 placebo controlled), which included 19,322 patients, were eligible. The trialed pharmacological interventions included anti-hypertensives, phosphate binders, lipid-lowering therapy, cardio-vascular medications, homocysteine lowering therapy, fish oil and calcimimetics. Medication adherence was reported in five trials with a mean of 81% (range: 65-92%) in the intervention arm and 84.5% (range: 82-87%) in the control arm. All the trials that reported adherence yielded negative study outcomes for the intervention. Study-drug discontinuation was reported in 21 trials (mean 33.2%; 95% CI, 22.0 to 44.5, in intervention and 28.8%; 95% CI, 16.8 to 40.8, in control). Trials with more than 20% study drug discontinuation, more often yielded negative study outcomes (p = 0.018). Non-adherence was included as a contributor to drug discontinuation in some studies, but the causes of discontinuation were not reported consistently between studies, and non-adherence was listed under different categories, thereby potentiating the misclassification of adherence.. Reporting of medication adherence and study-drug discontinuation in RCTs investigating cardiovascular or mortality endpoints in dialysis patients are inconsistent, making it difficult to compare studies and evaluate their impact on outcomes. Recommendations for consistent reporting of non-adherence and causes of drug discontinuation in RCTs will therefore help to assess their impact on clinical outcomes.

Topics: Antihypertensive Agents; Calcimimetic Agents; Cardiovascular Agents; Cardiovascular Diseases; Fish Oils; Humans; Hypolipidemic Agents; Kidney Failure, Chronic; Medication Adherence; Mortality; Randomized Controlled Trials as Topic; Renal Dialysis; Treatment Outcome

Cardiovascular disease (CVD) is a major cause of disability and premature death. Despite European guidelines advocating the use of medical therapies in CVD, many patients still do not achieve the guideline-recommended treatment, which highlights the need for change and innovations in this field. This requirement has been widely recognised by the national ministries of health, several European cardiology societies, and the European Parliament, who support the initiation of strategies to improve and promote cardiovascular health.. One of the key risk factors to recurrent cardiovascular events is the lack of adherence to medication and this has been added to the agenda of the European Commission. With the intention to improve treatment adherence in CVD, polypills have been investigated and numerous studies demonstrate that they significantly improve medication adherence, which contributes to the improvement of health outcomes. In Europe, the first cardiovascular polypill, developed by a public-private partnership (CNIC-Ferrer), recently became available for general prescription as a therapy for CVD prevention. This polypill significantly improves adherence, preventing fatal and non-fatal cardiovascular events, and appears to be a cost-effective strategy to improve sustainability of the health care systems in CVD.. Given the importance of urgent and simple solutions to restraining the pandemic nature of CVD, the polypill approach should therefore be considered by physicians and public health systems as an available and innovative option to improve cardiovascular health.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Therapy, Combination; Europe; Humans; Medication Adherence

Cardiovascular diseases are a major cause of disability and they are currently responsible for a significant number of deaths in a large percentage of the world population. A large number of therapeutic options have been developed for the management of cardiovascular diseases. However, they are insufficient to stop or significantly reduce the progression of these diseases, and may produce unpleasant side effects. In this situation, the need arises to continue exploring new technologies and strategies in order to overcome the disadvantages and limitations of conventional therapeutic options. Thus, treatment of cardiovascular diseases has become one of the major focuses of scientific and technological development in recent times. More specifically, there have been important advances in the area of nanotechnology and the controlled release of drugs, destined to circumvent many limitations of conventional therapies for the treatment of diseases such as hyperlipidemia, hypertension, myocardial infarction, stroke and thrombosis.

Topics: Animals; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Delayed-Action Preparations; Diffusion of Innovation; Drug Carriers; Drug Compounding; Humans; Nanomedicine; Nanoparticles; Technology, Pharmaceutical

The treatment of dyslipidemia with lifestyle interventions and statin-based therapy has been an important defense against atherosclerotic cardiovascular disease and its complications. It has been well documented for more than 2 decades that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) reduce the risk of events. The evolution of drug development and randomized clinical trials in cardiovascular medicine has resulted in the conclusion that lower cholesterol concentrations result in greater benefit. However, how aggressive one should be in lowering cholesterol levels and to what level has not been definitively established. In this brief review I aim to defend the hypothesis that lower is better on the basis of the evidence to date. This will include indirect evidence from randomized clinical trials with statins and novel lipid-modifying drugs. In addition, there is a wealth of epidemiology and Mendelian randomization genetic data to support this. Also, on-treatment low-density lipoprotein cholesterol concentrations show a robust relationship with cardiovascular disease events. Finally, most national guidelines groups around the world continue to advocate for a treat to target philosophy. As such, the prevailing philosophy is that lowering low-density lipoprotein cholesterol to very low levels is our best preventative strategy particularly for those at the highest risk. We eagerly await the results of ongoing clinical trials that will more firmly establish if this concept will ultimately be proven correct.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cholesterol, LDL; Humans

Polypills have been approved in more than 30 countries, but worldwide experience with and availability of polypills remain limited, unlike fixed-dose combinations in other diseases such as HIV, tuberculosis, and malaria. In this Series review, we aim to propose a guide for the use of polypills in future research and clinical activities and to synthesise contemporary evidence supporting the use of polypills for prevention of atherosclerosis. Polypill uses can be categorised by population and indication, both of which influence the balance between benefits and risks. Populations include secondary prevention, high-risk primary prevention based on formal risk assessment, and primary prevention based on single risk factor measurement, such as age, also known as mass treatment. For each population, potential indications are initiation, step-up of current drug therapy, and straight substitution of individual drug components. We summarise efficacy and safety results from 13 polypill trials (9059 participants) done in 32 countries. Polypills improve adherence, are generally well tolerated, and reduce risk factor levels, although heterogeneity limits the certainty of the effect on risk factors. Trials published to date have not been designed to detect differences in clinical outcomes, and thus no significant differences between polypill and comparator groups have been reported. Polypill therapy could be one of the most scalable strategies to reduce the risk of premature mortality from atherosclerosis by 25% by 2025 by improving medication adherence and access, but further trial data and clinical experience will be useful to determine how polypills can best be implemented to achieve this goal.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diffusion of Innovation; Drug Combinations; Drug Substitution; Evidence-Based Medicine; Humans; Primary Prevention; Randomized Controlled Trials as Topic; Risk Assessment; Treatment Outcome

Regulatory approvals for cardiovascular polypills are increasing rapidly across more than 30 countries. The evidence clearly shows polypills improve adherence and cardiovascular disease risk factors for patients with indications for use of polypill components-ie, those with established cardiovascular disease or at high risk. However, the implementation of polypills into clinical practice has many challenges. The clinical trials literature provides insights into the clinical impact of a polypill strategy, including cost-effectiveness, safety of use, substantial improvement in adherence, and better risk factor control than usual care. Despite the clear need for such a strategy and the available clinical data backing up the use of the polypill in different patient populations, challenges to widespread implementation, such as an absence of government reimbursement and poor physician uptake (identified from on the ground experience in countries following commercial rollout), have greatly obstructed real-world implementation. Obtaining the full public health benefit of polypills will require education, advocacy, endorsement, and implementation by key global agencies such as WHO and national clinical bodies, as well as endorsement from governments.

Topics: Attitude of Health Personnel; Cardiovascular Agents; Cardiovascular Diseases; Drug Approval; Drug Combinations; Drug Compounding; Drugs, Essential; Forecasting; Humans; Life Style; Patient Acceptance of Health Care; Practice Patterns, Physicians'; Primary Prevention; Public Health; Randomized Controlled Trials as Topic; Reimbursement Mechanisms; Secondary Prevention

Cardiovascular disease is the disease that affects the cardiovascular system, vascular diseases of the brain and kidney, and peripheral arterial disease. Despite of all advances in pharmacological and clinical treatment, heart failure is a leading cause of morbidness and mortality worldwide. Many new therapeutic advance strategies, including cell transplantation, gene delivery or therapy, and cytokines or other small molecules, have been research to treat heart failure. The main aim of this review article is to focus on nano carriers advancement and addressing the problems associated with old and modern therapeutics such as nonspecific effects and poor stability.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Dendrimers; DNA; Drug Delivery Systems; Genetic Therapy; Humans; Liposomes; Micelles; Microbubbles; Nanomedicine; Nanoparticles; Pulsatile Flow; Tablets; Ultrasonic Therapy

Current clinical cardiovascular practice requires a clinician to have a strong foundation in multiple aspects of pharmacology. Modern cardiovascular regimens are complex, and optimal management, application of evolving guidelines, and adoption of new therapies build off a more basic understanding of pharmacokinetics and pharmacodynamics. In addition, it is likely time to add a third pillar into this discussion, the expanding field of pharmacogenomics referring to the genetic influences on drug response. This field has increasing applications in medicine and clearly holds significant promise for cardiovascular disease management. Awareness of pharmacogenomic advances and the fundamentals of pharmacokinetics and pharmacodynamics can help the clinician more easily deliver great care. Here we attempt to briefly summarize and simplify key concepts of pharmacokinetics, pharmacodynamics, and pharmacogenomics relevant to the cardiovascular disease practitioner.

Topics: Biotransformation; Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Genotype; Humans; Pharmacogenetics; Phenotype; Risk Factors

PDE5 inhibitors (PDE5i) are widely known as treatment for erectile dysfunction (ED). This favorable action has emerged as a "side effect" from pioneering studies when PDE5i have been originally proposed as treatment for coronary artery disease (CAD). PDE5i showed marginal benefits for CAD treatment; although disappointing for that indication, they improved systemic and pulmonary vasodilation and ameliorated general endothelial function. Therefore, PDE5i have been approved and licensed also for pulmonary artery hypertension (PAH), besides ED. Nowadays, fine-tuned biomolecular mechanisms of PDE5i are well recognized to be beneficial onto myocardial contractility and geometry, to reduce tissue fibrosis, hypertrophy and apoptosis. PDE5i consistently exert benefits on heart failure, infarct, cardiomyopathy. The concept that PDE5i likely blunt Th1-driven inflammatory processes, which shift the homeostatic balance from health to disease, has emerged; PDE5i seem to decrease the release of active biomolecules from cells to tissues interested by inflammation. In this view, following clinical and basic research progresses, PDE5i can be undoubtedly "re-allocated" for cardiac indications and, hopefully, they could be approved as therapeutic tools to treat and prevent heart disease. This review aims to summarize PDE5i different clinical applications, from past to present and future, focusing on their potential power as treatment for cardiac diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelium, Vascular; Evidence-Based Medicine; Heart; Humans; Hypertension, Pulmonary; Myocardium; Phosphodiesterase 5 Inhibitors; Vasodilator Agents

Phosphodiesterase 5 inhibitors (PDE5i) were developed while investigating novel treatments for coronary artery disease, but their andrological side effects shifted their indication toward the management of erectile dysfunction. Although PDE5i are now also indicated for pulmonary arterial hypertension and there are mounting preclinical and clinical evidences about their potentially beneficial cardiac effects, their use remains controversial and the involved mechanisms remain unclear.. This review aimed to analyze the effects of PDE5i administration in various animal and humans models of cardiovascular diseases.. Animal studies have shown that PDE5i have protective effects in several models of cardiac disease. In humans, some studies showed that PDE5i improves microvascular and endothelial dysfunction and exerts positive effects in different samples of cardiovascular (CV) impairment. In contrast, other studies found no benefit (and no harm) in heart failure with preserved ejection fraction. The discrepancies in these findings are likely related to the fact that the mechanisms targeted by PDE5i in human disease are still poorly understood and the target population not yet identified. The mechanisms of actions herein reviewed suggest that hypertrophy, microvascular impairment, and inflammation, should be variably present for PDE5i to work. All these conditions frequently coexist in diabetes. A gender responsiveness has also been recently proposed.. Continuous PDE5 inhibition may exert cardioprotective effects, improving endothelial function and counteracting cardiac remodeling in some but not all conditions. A better patient selection could help to clarify the controversies on PDE5i use for CV disorders.

Topics: Animals; Cardiotonic Agents; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Heart; Heart Diseases; Humans; Microvessels; Myocardium; Phosphodiesterase 5 Inhibitors; Reproducibility of Results

Randomised controlled trials (RCTs) in humans revealed contradictory results regarding the effect of vitamin C supplementation on blood lipids. We aimed to conduct a systematic review and meta-analysis of RCTs investigating the effect of vitamin C supplementation on total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides and to determine whether the effects are modified by the participants' or intervention characteristics.. Four databases (PubMed, Embase, Scopus and Cochrane Library) were searched from inception until August 2014 for RCTs supplementing adult participants with vitamin C for ≥ 2 weeks and reporting changes in blood lipids.. Overall, vitamin C supplementation did not change blood lipids concentration significantly. However, supplementation reduced total cholesterol in younger participants (≤52 years age) (-0.26 mmol/L, 95% CI: -0.45, -0.07) and LDL-C in healthy participants (-0.32 mmol/L, 95% CI: -0.57, -0.07). In diabetics, vitamin C supplementation reduced triglycerides significantly (-0.15 mmol/L, 95% CI: -0.30, -0.002) and increased HDL-C significantly (0.06 mmol/L, 95% CI: 0.02, 0.11). Meta-regression analyses showed the changes in total cholesterol (β: -0.24, CI: -0.36, -0.11) and in triglycerides (β: -0.17, CI: -0.30, -0.05) following vitamin C supplementation were greater in those with higher concentrations of these lipids at baseline. Greater increase in HDL-C was observed in participants with lower baseline plasma concentrations of vitamin C (β: -0.002, CI: -0.003, -0.0001).. Overall, vitamin C supplementation had no significant effect on lipid profile. However, subgroup and sensitivity analyses showed significant reductions in blood lipids following supplementation in sub-populations with dyslipidaemia or low vitamin C status at baseline. PROSPERO Database registration: CRD42014013487, http://www.crd.york.ac.uk/prospero/.

Topics: Antioxidants; Ascorbic Acid; Ascorbic Acid Deficiency; Cardiovascular Agents; Cardiovascular Diseases; Dyslipidemias; Humans; Hyperlipidemias; Hypolipidemic Agents; Oxidative Stress; Randomized Controlled Trials as Topic; Reproducibility of Results; Risk

There are several challenging statistical problems identified in the regulatory review of large cardiovascular (CV) clinical outcome trials and central nervous system (CNS) trials. The problems can be common or distinct due to disease characteristics and the differences in trial design elements such as endpoints, trial duration, and trial size. In schizophrenia trials, heavy missing data is a big problem. In Alzheimer trials, the endpoints for assessing symptoms and the endpoints for assessing disease progression are essentially the same; it is difficult to construct a good trial design to evaluate a test drug for its ability to slow the disease progression. In CV trials, reliance on a composite endpoint with low event rate makes the trial size so large that it is infeasible to study multiple doses necessary to find the right dose for study patients. These are just a few typical problems. In the past decade, adaptive designs were increasingly used in these disease areas and some challenges occur with respect to that use. Based on our review experiences, group sequential designs (GSDs) have borne many successful stories in CV trials and are also increasingly used for developing treatments targeting CNS diseases. There is also a growing trend of using more advanced unblinded adaptive designs for producing efficacy evidence. Many statistical challenges with these kinds of adaptive designs have been identified through our experiences with the review of regulatory applications and are shared in this article.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Central Nervous System Agents; Central Nervous System Diseases; Clinical Trials as Topic; Humans; Research Design; Treatment Outcome

The peptide hormone relaxin has traditionally been linked to the maternal adaptation of the cardiovascular system during the first trimester of pregnancy. By promoting nitric oxide formation through different molecular signaling events, relaxin has been proposed as a pleiotropic and cardioprotective hormone in the setting of many cardiovascular diseases. In fact, preclinical studies were able to demonstrate that relaxin promotes vasodilatation and angiogenesis, ameliorates ischemia/reperfusion injury, and regulates extracellular matrix turnover and remodeling. In the RELAX-AHF phase 3 clinical trial, serelaxin (recombinant human relaxin) was shown to be safe, and it exerted survival benefits in patients with acute heart failure. RELAX-AHF-2 is currently ongoing, and it aims to address a larger population and evaluate harder clinical outcomes. Besides heart failure, acute myocardial infarction, peripheral arterial disease, and stable coronary disease could be target diseases for treatment with serelaxin in future clinical trials.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Recombinant Proteins; Relaxin; Signal Transduction; Treatment Outcome

Breast cancer treatments have evolved over the past decades, although several widely used treatments have adverse cardiac effects. Radiotherapy generally improves the survival of women with breast cancer, although its deleterious cardiovascular effects pose competing risks of morbidity and/or mortality. In the past, radiation-associated cardiovascular disease was a phenomenon considered to take more than a decade to manifest, but newer research suggests that this latency is much shorter. Knowledge of coronary anatomy relative to the distribution of the delivered radiation dose has improved over time, and as a result, techniques have enabled this risk to be decreased. Studies continue to be performed to better understand, prevent and mitigate against radiation-associated cardiovascular disease. Treatments such as anthracyclines, which are a mainstay of chemotherapy for breast cancer, and newer targeted agents such as trastuzumab both have established risks of cardiotoxicity, which can limit their effectiveness and result in increased morbidity and/or mortality. Interest in whether β-blockers, statins and/or angiotensin-converting enzyme (ACE)-inhibitors might have therapeutic and/or preventative effects in these patients is currently increasing. This Review summarizes the incidence, risks and effects of treatment-induced cardiovascular disease in patients with breast cancer and describes strategies that might be used to minimize this risk.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cardiovascular Agents; Cardiovascular Diseases; Female; Humans; Incidence; Primary Prevention; Radiation Injuries; Radiotherapy; Risk Assessment; Risk Factors; Treatment Outcome

This meta-analysis aimed to compare the efficacy and adverse events, either serious or mild/moderate, of all generic versus brand-name cardiovascular medicines. We searched randomized trials in MEDLINE, Scopus, EMBASE, Cochrane Controlled Clinical Trial Register, and ClinicalTrials.gov (last update December 1, 2014). Attempts were made to contact the investigators of all potentially eligible trials. Two investigators independently extracted and analyzed soft (including systolic blood pressure, LDL cholesterol, and others) and hard efficacy outcomes (including major cardiovascular adverse events and death), minor/moderate and serious adverse events. We included 74 randomized trials; 53 reported ≥1 efficacy outcome (overall sample 3051), 32 measured mild/moderate adverse events (n = 2407), and 51 evaluated serious adverse events (n = 2892). We included trials assessing ACE inhibitors (n = 12), anticoagulants (n = 5), antiplatelet agents (n = 17), beta-blockers (n = 11), calcium channel blockers (n = 7); diuretics (n = 13); statins (n = 6); and others (n = 3). For both soft and hard efficacy outcomes, 100 % of the trials showed non-significant differences between generic and brand-name drugs. The aggregate effect size was 0.01 (95 % CI -0.05; 0.08) for soft outcomes; -0.06 (-0.71; 0.59) for hard outcomes. All but two trials showed non-significant differences in mild/moderate adverse events, and aggregate effect size was 0.07 (-0.06; 0.20). Comparable results were observed for each drug class and in each stratified meta-analysis. Overall, 8 serious possibly drug-related adverse events were reported: 5/2074 subjects on generics; 3/2076 subjects on brand-name drugs (OR 1.69; 95 % CI 0.40-7.20). This meta-analysis strengthens the evidence for clinical equivalence between brand-name and generic cardiovascular drugs. Physicians could be reassured about prescribing generic cardiovascular drugs, and health care organization about endorsing their wider use.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug-Related Side Effects and Adverse Reactions; Drugs, Generic; Humans; Randomized Controlled Trials as Topic; Therapeutic Equivalency

Despite being used for a long time as food and beverage by Brazilian people who live on the Amazon bay, only in the beginning of this century, açaí berries have been the object of scientific research. Açaí berries are rich in polyphenols that probably explains its versatile pharmacological actions and huge consumption, not only in Brazil but also in Europe and United States. In this review, not all but some pharmacological aspects of açaí berries are analyzed. Chemical and pharmacological differences between extracts obtained from the skin and seed of açaí are considered. Polyphenols from the seed of açaí increase endothelial nitric oxide production leading to endothelium-dependent relaxation, reduce reactive oxygen species and regulate key targets associated with lipid metabolism in different conditions such as hypertension, renal failure, and metabolic syndrome. We review the novel mechanisms of actions of açaí on different targets which could trigger the health benefits of açaí such as antioxidant, vasodilator, antihypertensive, cardioprotector, renal protector, antidyslipidemic, antiobesity, and antidiabetic effects in cardiovascular and metabolic disturbances.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Euterpe; Fruit; Humans; Metabolic Diseases; Phytochemicals; Phytotherapy; Plant Extracts; Plants, Medicinal

Clinical care for patients with rare diseases may be complicated by comorbidities. Administration of medications to treat comorbidities may elicit potentially harmful drug-drug interactions (DDIs). Genetic background may also influence DDI occurrence. We investigated the range of comorbid conditions in patients with Gaucher disease type I (GD1), the pharmacotherapies prescribed and the potential for DDI with enzyme replacement and substrate reduction therapies and additional medications, specifically cytochrome P450 (CYP) metabolizing medications.. A literature review examined comorbid conditions and pharmacotherapies reported in GD1. Analysis of two national databases reported real-world prescription practices in patients with GD1 (Germany, N=87; US, N=374). Prescribed drugs were assessed for known interactions with isoenzymes from the hepatic CYP enzyme family.. The literature reported GD1 symptomatology and comorbid conditions in broad agreement with the known clinical picture. German patients received 86 different medications whereas US patients received 329 different medications. An average of 3.2 medications (Germany) and 7 medications (US) per patient were prescribed. Moderate/strong inhibitors of CYP isoenzymes were prescribed to 20% and 57% of patients in the US and Germany, respectively.. This study describes the extensive number of comorbid conditions and drugs prescribed to patients with GD1, and the importance of determining CYP isoenzyme interaction to reduce DDI risk.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Drug Interactions; Enzyme Replacement Therapy; Gaucher Disease; Glucosylceramidase; Humans

Investment in cardiovascular drug development is on the decline as large cardiovascular outcomes trials require considerable investments in time, efforts and financial resources. Pharmacogenomics has the potential to help revive the cardiovascular drug development pipeline by providing new and better drug targets at an earlier stage and by enabling more efficient outcomes trials. This article will review some of the recent developments highlighting the value of pharmacogenomics for drug development. We discuss how genetic biomarkers can enable the conduct of more efficient clinical outcomes trials by enriching patient populations for good responders to the medication. In addition, we assess past drug development programs which support the added value of selecting drug targets that have established genetic evidence supporting the targeted mechanism of disease. Finally, we discuss how pharmacogenomics can provide valuable evidence linking a drug target to clinically relevant outcomes, enabling novel drug discovery and drug repositioning opportunities.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Drug Discovery; Genetic Markers; Humans; Pharmacogenetics

Hemodynamic disturbance in the sick neonate is common, highly diverse in underlying pathophysiology and dynamic. Dysregulated systemic and cerebral blood flow is hypothesized to have a negative impact on neurodevelopmental outcome and survival. An understanding of the physiology of the normal neonate, disease pathophysiology, and the properties of vasoactive medications may improve the quality of care and lead to an improvement in survival free from disability. In this review we present a modern approach to cardiovascular therapy in the sick neonate based on a more thoughtful approach to clinical assessment and actual pathophysiology. Targeted neonatal echocardiography offers a more detailed insight into disease processes and offers longitudinal assessment, particularly response to therapeutic intervention. The pathophysiology of common neonatal conditions and the properties of cardiovascular agents are described. In addition, we outline separate treatment algorithms for various hemodynamic disturbances that are tailored to clinical features, disease characteristics and echocardiographic findings.

Topics: Algorithms; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Critical Illness; Echocardiography; Hemodynamics; Humans; Infant, Newborn; Infant, Newborn, Diseases; Symptom Assessment; Treatment Outcome

Genetic factors identified from genome-wide association studies have been used to understand causative variants for complex diseases. Studies conducted on large populations of individuals from many geographical regions have provided insights into genetic pathways involved in the causal pathway for atherosclerotic cardiovascular disease. A single genetic trait may ineffectively evaluate the pathway of interest, and it may not account for other complementary genetic pathways that may be activated at various stages of the disease process or evidence-based therapies that alter the molecular and cellular milieu.

Topics: Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Genome-Wide Association Study; Humans; Mendelian Randomization Analysis; Risk Factors

Animal venoms are a mixture of bioactive compounds produced as weapons and used primarily to immobilize and kill preys. As a result of the high potency and specificity for various physiological targets, many toxins from animal venoms have emerged as possible drugs for the medication of diverse disorders, including cardiovascular diseases. Captopril, which inhibits the angiotensin-converting enzyme (ACE), was the first successful venom-based drug and a notable example of rational drug design. Since captopril was developed, many studies have discovered novel bradykinin-potentiating peptides (BPPs) with actions on the cardiovascular system. Natriuretic peptides (NPs) have also been found in animal venoms and used as template to design new drugs with applications in cardiovascular diseases. Among the anti-arrhythmic peptides, GsMTx-4 was discovered to be a toxin that selectively inhibits the stretch-activated cation channels (SACs), which are involved in atrial fibrillation. The present review describes the main components isolated from animal venoms that act on the cardiovascular system and presents a brief summary of venomous animals and their venom apparatuses.

Topics: Amino Acid Sequence; Animals; Bradykinin; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Drug Discovery; Humans; Molecular Sequence Data; Peptides; Renin-Angiotensin System; Venoms

Reactive oxygen species (ROS) and oxidative stress have long been linked to aging and diseases prominent in the elderly such as hypertension, atherosclerosis, diabetes and atrial fibrillation (AF). NADPH oxidases (Nox) are a major source of ROS in the vasculature and are key players in mediating redox signalling under physiological and pathophysiological conditions. In this review, we focus on the Nox-mediated ROS signalling pathways involved in the regulation of 'longevity genes' and recapitulate their role in age-associated vascular changes and in the development of age-related cardiovascular diseases (CVDs). This review is predicated on burgeoning knowledge that Nox-derived ROS propagate tightly regulated yet varied signalling pathways, which, at the cellular level, may lead to diminished repair, the aging process and predisposition to CVDs. In addition, we briefly describe emerging Nox therapies and their potential in improving the health of the elderly population.

Topics: Aging; Cardiovascular Agents; Cardiovascular Diseases; Humans; Molecular Targeted Therapy; NADPH Oxidases; Oxidation-Reduction; Oxidative Stress; Signal Transduction

Endoplasmic reticulum is a principal organelle responsible for folding, post-translational modifications and transport of secretory, luminal and membrane proteins, thus palys an important rale in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is a condition that is accelerated by accumulation of unfolded/misfolded proteins after endoplasmic reticulum environment disturbance, triggered by a variety of physiological and pathological factors, such as nutrient deprivation, altered glycosylation, calcium depletion, oxidative stress, DNA damage and energy disturbance, etc. ERS may initiate the unfolded protein response (UPR) to restore cellular homeostasis or lead to apoptosis. Numerous studies have clarified the link between ERS and cardiovascular diseases. This review focuses on ERS-associated molecular mechanisms that participate in physiological and pathophysiological processes of heart and blood vessels. In addition, a number of drugs that regulate ERS was introduced, which may be used to treat cardiovascular diseases. This review may open new avenues for studying the pathogenesis of cardiovascular diseases and discovering novel drugs targeting ERS.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Endoplasmic Reticulum Stress; Humans; Molecular Chaperones; Unfolded Protein Response

The macrocycles representing a unique chemical structure bridging conventional small molecules and large biomolecules, have attracted more and more attention in drug discovery over the past decade, and tremendous progress has been made toward the macrocyclization synthesis and structure diversification recently. Because of their favored size, flexibility and complexity, macrocycles can engage previously undruggable targets through numerous and spatially distributed binding interactions, and offer many privileged features including high potency, prominent selectivity, as well as favorable pharmacokinetics properties, and unique intellectual property(IP) space, and even safety profiles, etc. Currently around 70 macrocyclic molecules have been approved for clinical therapy, over 76 macrocycles are being evaluated in clinical trials from phase I to phase III. It is believed that the macrocycles will play more and more important role in the future, and provide very distinctive and promising opportunities for drug discovery along with the development of synthetic methodology, phenotypical screening, and computational studies.

Topics: Anti-Infective Agents; Antineoplastic Agents, Phytogenic; Cardiovascular Agents; Cardiovascular Diseases; Drug Discovery; Humans; Immune System Diseases; Macrocyclic Compounds; Neoplasms

Epicardial fat is the visceral fat depot of the heart. Given its rapid metabolism, organ fat specificity and simple objective measurability, epicardial fat can serve as target for pharmaceutical agents targeting the adipose tissue. Epicardial fat has shown to significantly respond to thiazolidinediones, glucagon like peptide 1 receptor agonists, dipeptidyl peptidase-4 inhibitors and statins. Epicardial fat may represent a measurable risk factor and modifiable therapeutic target. Targeted pharmaceutical interventions may allow the epicardial fat to resume its physiological role. A drug-induced browning effect on epicardial fat suggests the development of pharmacological strategies to increase energy consumption. The potential of modulating the epicardial fat transcriptome with targeted pharmacological agents can open new avenues in the pharmacotherapy of cardio-metabolic diseases.

Topics: Adipose Tissue; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Fats; Humans; Pericardium; Risk Factors

Meldonium (mildronate; 3-(2,2,2-trimethylhydrazinium)propionate; THP; MET-88) is a clinically used cardioprotective drug, which mechanism of action is based on the regulation of energy metabolism pathways through l-carnitine lowering effect. l-Carnitine biosynthesis enzyme γ-butyrobetaine hydroxylase and carnitine/organic cation transporter type 2 (OCTN2) are the main known drug targets of meldonium, and through inhibition of these activities meldonium induces adaptive changes in the cellular energy homeostasis. Since l-carnitine is involved in the metabolism of fatty acids, the decline in its levels stimulates glucose metabolism and decreases concentrations of l-carnitine related metabolites, such as long-chain acylcarnitines and trimethylamine-N-oxide. Here, we briefly reviewed the pharmacological effects and mechanisms of meldonium in treatment of heart failure, myocardial infarction, arrhythmia, atherosclerosis and diabetes.

Topics: Animals; Biomarkers; Cardiotonic Agents; Cardiovascular Agents; Cardiovascular Diseases; Humans; Methylhydrazines; Myocardium

In contrast to earlier long-chain (LC) omega-3 (i.e. EPA and DHA) investigations, some recent studies have not demonstrated significant effects of EPA and DHA on cardiovascular disease (CVD) outcomes. The neutral findings may have been due to experimental design issues, such as: maintenance on aggressive cardiovascular drug treatment overshadowing the benefits of LC omega-3s, high background LC omega-3 intake, too few subjects in the study, treatment duration too short, insufficient LC omega-3 dosage, increase in omega-6 fatty acid intake during the study, failure to assess the LC omega-3 status of the subjects prior to and during treatment and lack of clarity concerning which mechanisms were expected to produce benefits. At the 11th ISSFAL Congress, a workshop was held on conducting LC omega-3 clinical trials with cardiovascular outcomes, with the goal of gaining a better understanding concerning aspects of experimental design that should be considered when planning clinical studies related to EPA and DHA and potential cardiovascular benefits.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Data Interpretation, Statistical; Dietary Supplements; Fatty Acids, Omega-3; Humans; Randomized Controlled Trials as Topic; Sample Size; Treatment Outcome

Cardiovascular diseases are the leading cause of death affecting 17.3 million people across the globe and are estimated to affect 23.3 million people by year 2030. In recent years, about 7.3 million people died due to coronary heart disease, 9.4 million deaths due to high blood pressure and 6.2 million due to stroke, where obesity and atherosclerotic progression remain the chief pathological factors. The search for newer and better cardiovascular agents is the foremost need to manage cardiac patient population across the world. Several natural and (semi) synthetic chalcones deserve the credit of being potential candidates to inhibit various cardiovascular, hematological and anti-obesity targets like angiotensin converting enzyme (ACE), cholesteryl ester transfer protein (CETP), diacylglycerol acyltransferase (DGAT), acyl-coenzyme A: cholesterol acyltransferase (ACAT), pancreatic lipase (PL), lipoprotein lipase (LPL), calcium (Ca(2+))/potassium (K(+)) channel, COX-1, TXA2 and TXB2. In this review, a comprehensive study of chalcones, their therapeutic targets, structure activity relationships (SARs), mechanisms of actions (MOAs) have been discussed. Chemically diverse chalcone scaffolds, their derivatives including structural manipulation of both aryl rings, replacement with heteroaryl scaffold(s) and hybridization through conjugation with other pharmacologically active scaffold have been highlighted. Chalcones which showed promising activity and have a well-defined MOAs, SARs must be considered as prototype for the design and development of potential anti-hypertensive, anti-anginal, anti-arrhythmic and cardioprotective agents. With the knowledge of these molecular targets, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective chalcone derivatives as potential cardiovascular agents.

Topics: Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Chalcones; Humans; Structure-Activity Relationship

The CXC chemokines, CXCL4, -9, -10, -11, CXCL4L1, and the CC chemokine CCL21, activate CXC chemokine receptor 3 (CXCR3), a cell-surface G protein-coupled receptor expressed mainly by Th1 cells, cytotoxic T (Tc) cells and NK cells that have a key role in immunity and inflammation. However, CXCR3 is also expressed by vascular smooth muscle and endothelial cells, and appears to be important in controlling physiological vascular function. In the last decade, evidence from pre-clinical and clinical studies has revealed the participation of CXCR3 and its ligands in multiple cardiovascular diseases (CVDs) of different aetiologies including atherosclerosis, hypertension, cardiac hypertrophy and heart failure, as well as in heart transplant rejection and transplant coronary artery disease (CAD). CXCR3 ligands have also proven to be valid biomarkers for the development of heart failure and left ventricular dysfunction, suggesting an underlining pathophysiological relation between levels of these chemokines and the development of adverse cardiac remodelling. The observation that several of the above-mentioned chemokines exert biological actions independent of CXCR3 provides both opportunities and challenges for developing effective drug strategies. In this review, we provide evidence to support our contention that CXCR3 and its ligands actively participate in the development and progression of CVDs, and may additionally have utility as diagnostic and prognostic biomarkers.

Topics: Animals; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Chemokines, CXC; Drug Design; Humans; Ligands; Molecular Targeted Therapy; Predictive Value of Tests; Prognosis; Receptors, CXCR3; Signal Transduction

The aim of this study was to investigate whether polypill-based care for the prevention of cardiovascular disease (CVD) is associated with a change in lifestyle risk factors when compared with usual care, among patients with CVD or high calculated cardiovascular risk.. We conducted an individual participant data meta-analysis of three trials including patients from Australia, England, India, Ireland, the Netherlands and New Zealand that compared a strategy using a polypill containing aspirin, statin and antihypertensive therapy with usual care in patients with a prior CVD event or who were at high risk of their first event. Analyses investigated any differential effect on anthropometric measures and self-reported lifestyle behaviours.. Among 3140 patients (75% male, mean age 62 years and 76% with a prior CVD event) there was no difference in lifestyle risk factors in those randomised to polypill-based care compared with usual care over a median of 15 months, either across all participants combined, or in a range of subgroups. Furthermore, narrow confidence intervals (CIs) excluded any major effect; for example differences between the groups in body mass index was -0.1 (95% CI -0.2 to 0.1) kg/m(2), in weekly duration of moderate intensity physical activity was -2 (-26 to 23) minutes and the proportion of smokers was 16% vs 17% (RR 0.98, 0.84 to 1.15) at the end of trial.. This analysis allays concern that polypill-based care may lead to neglect of lifestyle risk factors, at least among high-risk patients. Maximally effective preventive approaches should address lifestyle factors alongside pharmaceutical interventions, as recommended by major international guidelines.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Global Health; Humans; Life Style; Morbidity; Primary Prevention; Risk Factors

To review the current understanding of hemodialysis-mediated clearance of commonly used cardiovascular medications.. Although cardiovascular drug dialyzability is poorly understood, many drug classes appear to include agents with substantially different degrees of dialyzability. Recent data suggest that more readily dialyzable beta-blockers associate with higher short-term mortality in patients initiating these drugs when on hemodialysis. Although this relationship was not observed in a later study with angiotensin-converting enzyme inhibitors of varying dialyzability, studies of this kind are currently limited by pharmacokinetic data that are either incomplete or no longer applicable to modern hemodialysis procedures.. There are substantial deficits in our understanding of cardiovascular medication dialyzability, which relates in large part to advances in the process of hemodialysis that have rendered older studies of dialyzability irrelevant. The importance of cardiovascular disease in patients receiving hemodialysis demands a better understanding of the effect hemodialysis exerts on cardiovascular drug pharmacokinetics.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Cardiovascular Diseases; Humans; Kidney Failure, Chronic; Renal Dialysis; Treatment Outcome

Excellent reviews on central N-methyl-D-aspartate receptor (NMDAR) signaling and function in cardiovascular regulating neuronal pools have been reported. However, much less attention has been given to NMDAR function in peripheral tissues, particularly the heart and vasculature, although a very recent review discusses such function in the kidney. In this short review, we discuss the NMDAR expression and complexity of its function in cardiovascular tissues. In conscious (contrary to anesthetized) rats, activation of the peripheral NMDAR triggers cardiovascular oxidative stress through the PI3K-ERK1/2-NO signaling pathway, which ultimately leads to elevation in blood pressure. Evidence also implicates Ca release, in the peripheral NMDAR-mediated pressor response. Despite evidence of circulating potent ligands (eg, D-aspartate and L-aspartate, L-homocysteic acid, and quinolinic acid) and also their coagonist (eg, glycine or D-serine), the physiological role of peripheral cardiovascular NMDAR remains elusive. Nonetheless, the cardiovascular relevance of the peripheral NMDAR might become apparent when its signaling is altered by drugs, such as alcohol, which interact with the NMDAR or its downstream signaling mechanisms.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Drug Discovery; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Humans; Protein Conformation; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Structure-Activity Relationship

The development and progression of cardiovascular disease (CVD) and renal disorders are very closely related. In patients with chronic kidney disease (CKD), therapies proven to protect the cardiovascular and renal systems simultaneously are generally used only at low doses or not at all. In particular, patients with CKD who receive angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, or mineralocorticoid-receptor antagonists (MRAs) often do not experience complete blockade of the renin-angiotensin-aldosterone system, primarily owing to the risk of hyperkalaemia. In this Review, we provide an overview of the available treatments required for adequate cardiorenal protection in patients with CKD. Drugs such as β-blockers that interfere with renin secretion will be discussed, in addition to agents that can prevent hyperkalaemia, such as potassium binders and nonsteroidal MRAs. Furthermore, the current literature on the role of statins, in addition to new compounds and dosing recommendations for the treatment of patients with CKD will also be reviewed. Further studies with these new compounds and doses are needed to ascertain whether these approaches can improve the long-term cardiovascular and renal prognosis in patients with CKD.

Topics: Cardio-Renal Syndrome; Cardiovascular Agents; Cardiovascular Diseases; Humans; Renal Agents; Renal Insufficiency, Chronic; Renin-Angiotensin System; Risk Factors; Treatment Outcome

In the last decades, many factors thought to be associated with the atherosclerotic process and cardiovascular events have been studied, and some of these have been shown to correlate with clinical outcome, such as arterial stiffness, endothelial dysfunction and immunoinflammatory markers. Arterial stiffness is an important surrogate marker that describes the capability of an artery to expand and contract in response to pressure changes. It can be assessed with different techniques, such as the evaluation of PWV and AIx. It is related to central systolic pressure and it is an independent predictor of cardiovascular morbidity and mortality in hypertensive patients, type 2 diabetes, end-stage renal disease and in elderly populations. The endothelium has emerged as the key regulator of vascular homeostasis, in fact, it has not merely a barrier function but also acts as an active signal transducer for circulating influences that modify the vessel wall phenotype. When its function is lost, it predisposes the vasculature to vasoconstriction, leukocyte adherence, platelet activation, thrombosis and atherosclerosis. Non-invasive methods were developed to evaluate endothelial function, such as the assesment of FMD, L-FMC and RHI. Moreover in the last years, a large number of studies have clarified the role of inflammation and the underlying cellular and molecular mechanisms that contribute to atherogenesis. For clinical purposes, the most promising inflammatory biomarker appears to be CRP and a variety of population-based studies have showed that baseline CRP levels predict future cardiovascular events. Each of the markers listed above has its importance from the pathophysiological and clinical point of view, and those can also be good therapeutic targets. However, it must be stressed that assessments of these vascular markers are not mutually exclusive, but rather complementary and those can offer different views of the same pathology. The purpose of this review is to analyze the role of arterial stiffness, endothelial dysfunction and immunoinflammatory markers as surrogate endpoint, assessing the correlations between these markers and evaluating the therapeutic perspectives that these offer.

Topics: Animals; Arteries; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Humans; Inflammation

Metabolic syndrome is defined by a constellation of complex coexisting cardiometabolic risk factors such as hyperglycemia, dyslipidemia, inflammation, abdominal obesity, coagulopathies, and hypertension that raise the risk of diabetes mellitus and cardiovascular disease. Recently, there has been an increasing interest in the use of herbs and natural compounds in prevention and treatment of diseases and a large number of published articles have focused on this issue. Rosmarinus officinalis L. or rosemary (Lamiaceae) is a rich source of phenolic phytochemicals having significant anti-oxidant, anti-inflammatory, hypoglycemic, hypolipidemic, hypotensive, anti-atherosclerotic, anti-thrombotic, hepatoprotective, and hypocholesterolemic effects. The purpose of this review is to highlight the interesting pharmacological effects of rosemary, and its active compounds, and the related mechanisms in the management of metabolic syndrome that are documented in in vitro and in vivo studies.

Topics: Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Antioxidants; Biomarkers; Blood Glucose; Cardiovascular Agents; Cardiovascular Diseases; Gluconeogenesis; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Inflammation Mediators; Lipids; Metabolic Syndrome; Oxidative Stress; Phytotherapy; Plant Extracts; Plants, Medicinal; Risk Factors; Rosmarinus; Weight Gain

Shortages of cardiovascular drugs have become increasingly common, representing an ongoing public health crisis. Given few therapeutic alternatives to many of the drugs in short supply, these shortages also pose a major challenge for cardiovascular care professionals. Although changes in the regulatory environment have led to some improvements in recent years, problems involving manufacturing processes remain the most common underlying cause. Because of the complex nature of drug shortages, sustainable solutions to prevent and mitigate them will require collaboration between regulatory agencies, drug manufacturers, and other key stakeholder groups. In this report, we describe the scope of the cardiovascular drug shortage crisis in the United States, including its underlying causes and the efforts currently being made to address it. Furthermore, we provide specific recommendations for how cardiovascular care professionals can be involved in efforts to limit the impact of drug shortages on patient care as well as policy changes aimed at preventing and mitigating them.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Health Services Accessibility; Health Services Needs and Demand; Humans; Quality Improvement; United States

Histone deacetylases (HDACs) play integral roles in many cardiovascular biological processes ranging from transcriptional and translational regulation to protein stabilization and localization. There are 18 known HDACs categorized into 4 classes that can differ on the basis of substrate targets, subcellular localization, and regulatory binding partners. HDACs are classically known for their ability to remove acetyl groups from histone and nonhistone proteins that have lysine residues. However, despite their nomenclature and classical functions, discoveries from many research groups over the past decade have suggested that nondeacetylase roles exist for class IIa HDACs. This is not surprising given that class IIa HDACs have, for example, relatively poor deacetylase capabilities and are often shuttled in and out of nuclei upon specific pathological and nonpathological cardiac events. This review aims to consolidate and elucidate putative nondeacetylase roles for class IIa HDACs and, where possible, highlight studies that provide evidence for their noncanonical roles, especially in the context of cardiovascular maladies. There has been great interest recently in exploring the pharmacological regulators of HDACs for use in therapeutic interventions for treating cardiovascular diseases and inflammation. Thus it is of interest to earnestly consider nonenzymatic and or nondeacetylase roles of HDACs that might be key in potentiating or abrogating pathologies. These noncanonical HDAC functions may possibly yield new mechanisms and targets for drug discovery.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Protein Conformation; Signal Transduction; Structure-Activity Relationship

Cardiovascular diseases (CVD) represent the highest burden of disease globally. Medicines are a critical intervention used to prevent and treat CVD. This review describes access to medication for CVD from a health system perspective and strategies that have been used to promote access, including providing medicines at lower cost, improving medication supply, ensuring medicine quality, promoting appropriate use, and managing intellectual property issues. Using key evidence in published and gray literature and systematic reviews, we summarize advances in access to cardiovascular medicines using the 5 health system dimensions of access: availability, affordability, accessibility, acceptability, and quality of medicines. There are multiple barriers to access of CVD medicines, particularly in low- and middle-income countries. Low availability of CVD medicines has been reported in public and private healthcare facilities. When patients lack insurance and pay out of pocket to purchase medicines, medicines can be unaffordable. Accessibility and acceptability are low for medicines used in secondary prevention; increasing use is positively related to country income. Fixed-dose combinations have shown a positive effect on adherence and intermediate outcome measures such as blood pressure and cholesterol. We have a new opportunity to improve access to CVD medicines by using strategies such as efficient procurement of low-cost, quality-assured generic medicines, development of fixed-dose combination medicines, and promotion of adherence through insurance schemes that waive copayment for long-term medications. Monitoring progress at all levels, institutional, regional, national, and international, is vital to identifying gaps in access and implementing adequate policies.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Developing Countries; Health Services Accessibility; Humans; Poverty

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Drug Discovery; Forecasting; Humans; Molecular Targeted Therapy; Precision Medicine; Treatment Outcome

Acute inflammation is a host-protective response that is mounted in response to tissue injury and infection. Initiated and perpetuated by exogenous and endogenous mediators, acute inflammation must be resolved for tissue repair to proceed and for homeostasis to be restored. Resolution of inflammation is an actively regulated process governed by an array of mediators as diverse as those that initiate inflammation. Among these, resolvins have emerged as a genus of evolutionarily conserved proresolving mediators that act on specific cellular receptors to regulate leukocyte trafficking and blunt production of inflammatory mediators, while also promoting clearance of dead cells and tissue repair. Given that chronic unresolved inflammation is emerging as a central causative factor in the development of cardiovascular diseases, an understanding of the endogenous processes that govern normal resolution of acute inflammation is critical for determining why sterile maladaptive cardiovascular inflammation perpetuates. Here, we provide an overview of the process of resolution with a focus on the enzymatic biosynthesis and receptor-dependent actions of resolvins and related proresolving mediators in immunity, thrombosis, and vascular biology. We discuss how nutritional and current therapeutic approaches modulate resolution and propose that harnessing resolution concepts could potentially lead to the development of new approaches for treating chronic cardiovascular inflammation in a manner that is not host disruptive.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cardiovascular Diseases; Docosahexaenoic Acids; Humans; Lipid Metabolism; Thrombosis

Cardiovascular disease (CVD) is still the leading cause of death worldwide. The overall growth of this epidemic during the last decade is largely because of the increasing incidence of CVD in low and middle-income countries, where inadequate health policies, poor availability, and lack of affordable medications, as well as poor patient adherence to treatment all limit the efficacy of cardiovascular prevention strategies. Complementary to a promotion of healthy lifestyles, a fixed dose combination or a 'polypill,' containing two or more drugs addressed at controlling various risk factors, might reduce costs and improve patient accessibility and adherence to treatment. As of now, several clinical trials have shown that combination pills are well tolerated and decrease risk factors for CVD, with a projected improvement of end points by as much as 60-70% by reducing blood pressure and low-density lipoprotein cholesterol. However, uncertainty remains about changes of hard end points, long-term adherence, cost-effectiveness and the 'medicalization' of asymptomatic individuals who account for a large percentage of the world population. Because cardiovascular risk increases significantly for patients aged more than 50 years, it has been proposed to use a polypill to treat specifically all such patients. However, approach to be neither practical nor cost-effective, because it involves a large number of patients at low risk. Some investigators have suggested to incorporate the Coronary Artery Calcium Score with the Framingham Risk Score to identify a suitable target population of patients benefitting most from the polypill. Trials in progress will shed light on several issues currently debated and unresolved.

Topics: Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Cost-Benefit Analysis; Drug Combinations; Humans; Lipoproteins, LDL; Medication Adherence; Primary Prevention; Randomized Controlled Trials as Topic; Risk Factors; Secondary Prevention

Angiotensin II (Ang II) is well-considered to be the principal effector of the renin-angiotensin system (RAS), which binds with strong affinity to the angiotensin II type 1 (AT1R) and type 2 (AT2R) receptor subtype. However, activation of both receptors is likely to stimulate different signalling mechanisms/pathways and produce distinct biological responses. The haemodynamic and non-haemodynamic effects of Ang II, including its ability to regulate blood pressure, maintain water-electrolyte balance and promote vasoconstriction and cellular growth are well-documented to be mediated primarily by the AT1R. However, its biological and functional effects mediated through the AT2R subtype are still poorly understood. Recent studies have emphasized that activation of the AT2R regulates tissue and organ development and provides in certain context a potential counter-regulatory mechanism against AT1R-mediated actions. Thus, this review will focus on providing insights into the biological role of the AT2R, in particular its actions within the renal and cardiovascular system.

Topics: Angiotensin II; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Kidney; Kidney Diseases; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Signal Transduction

Aging, cancer, and chronic disease have remained at the forefront of basic biological research for decades. Within this context, significant attention has been paid to the role of telomerase, the enzyme responsible for lengthening telomeres, the nucleotide sequences located at the end of chromosomes found in the nucleus. Alterations in telomere length and telomerase activity are a common denominator to the underlying pathology of these diseases. While nuclear-specific, telomere-lengthening effects of telomerase impact cellular/organismal aging and cancer development, non-canonical, extra-nuclear, and non-telomere-lengthening contributions of telomerase have only recently been described and their exact physiological implications are ill defined. Although the mechanism remains unclear, recent reports reveal that the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), regulates levels of mitochondrial-derived reactive oxygen species (mtROS), independent of its established role in the nucleus. Telomerase inhibition has been the target of chemotherapy (directed or indirectly) for over a decade now, yet no telomerase inhibitor is FDA approved and few are currently in late-stage clinical trials, possibly due to underappreciation of the distinct extra-nuclear functions of telomerase. Moreover, evaluation of telomerase-specific therapies is largely limited to the context of chemotherapy, despite reports of the beneficial effects of telomerase activation in the cardiovascular system in relation to such processes as endothelial dysfunction and myocardial infarction. Thus, there is a need for better understanding of telomerase-focused cell and organism physiology, as well as development of telomerase-specific therapies in relation to cancer and extension of these therapies to cardiovascular pathologies. This review will detail findings related to telomerase and evaluate its potential to serve as a therapeutic target.

Topics: Animals; Antineoplastic Agents; Cardiovascular Agents; Cardiovascular Diseases; Enzyme Activation; Enzyme Activators; Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Neoplasms; Signal Transduction; Telomerase; Telomere Homeostasis; Telomere Shortening

Ivabradine is a unique medication recently approved in the USA for the treatment of select heart failure patients. It was first approved for use in several countries around the world over a decade ago as an anti-anginal agent, with subsequent approval for use in heart failure patients. Since ivabradine has selective activity blocking the I f currents in the sinus node, it can reduce heart rate without appreciable effects on blood pressure. Given this heart-rate-specific effect, it has been investigated in many off-label indications as an alternative to traditional heart-rate-reducing medications such as beta blockers and calcium channel blockers. We conducted searches of PubMed and Google Scholar for ivabradine, heart failure, HFrEF, HFpEF, angina, coronary artery disease, inappropriate sinus tachycardia, postural orthostatic hypotension, coronary computed tomography angiography and atrial fibrillation. We reviewed and included studies, case reports, and case series published between 1980 and June 2016 if they provided information relevant to the practicing clinician. In many cases, larger clinical trials are needed to solidify the benefit of ivabradine, although studies indicate benefit in most therapeutic areas explored to date. The purpose of this paper is to review the current labeled and off-label uses of ivabradine, with a focus on clinical trial data.

Topics: Adrenergic beta-Antagonists; Benzazepines; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Heart Rate; Humans; Ivabradine; Off-Label Use

About 10,000 compounds will be tested for an individual drug to eventually reach the market. It might be helpful recapitulating previous failures and identifying the main factors of the disappointments.. In this review, the author(s) detailed the 7 cardiovascular compounds discontinued after reaching animal studies or Phase I-III clinical trials during 2015. Meanwhile, the reasons for these discontinuations were reported. Among these drugs, most discontinuations (6 drugs) were attributed to lack of efficacy. In general, failures due to lack of efficacy and safety demonstrate the need for the development of more predictive animal models. However, recent related studies showed that the absence of toxicity in animals provided little or virtually no evidential weight that adverse drug reactions would also be absent in humans. In this case, microdosing and collaborating more closely with biotech companies may be the better choices to improve the success ratio.. Future researches may benefit from the seven developments and investigators conducting similar studies may learn from these failures.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Drugs, Investigational; Humans; Treatment Failure

Suboptimal adherence to medications taken chronically for secondary prevention of cardiovascular disease (CVD, e.g., aspirin) continues to burden the healthcare system despite the well-established benefits of prevention. We conducted a literature search to examine patient adherence to medications for secondary prevention of CVD-as evaluated by prescription refill data, electronic medication monitors, pill counts, and physiologic markers-to better identify an unmet need for measures to improve patient adherence to these therapies.. English-language articles were obtained from the PubMed database using the following key words or combinations thereof "adherence," "compliance," "secondary prevention," and "cardiovascular disease." Publications that provided adherence data only for primary prevention, lacked data on medication adherence (e.g., focus on guideline adherence), emphasized quality-of-care outcomes, or focused on outcomes of acute interventions were excluded.. Multiple patient-, disease-, and treatment-related factors may contribute to poor adherence to treatment regimens, and therefore, a multifactorial approach will likely be needed to improve compliance with prescribed treatments for CVD. Although no magic bullet exists to assure full adherence, adherence programs coupled with patient counseling and education (inclusive of over-the-counter therapies), along with treatments that are less complex or avoid bothersome adverse effects, are more likely to be associated with successful outcomes.. Given the burden of CVD to the community and the healthcare system, nonadherence to CVD-preventative medications such as aspirin remains a substantial area of unmet need and represents a key opportunity for the development of quality-of-care enhancement programs to improve health outcomes in this patient population.

Topics: Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Humans; Medication Adherence; Recurrence; Risk Factors; Secondary Prevention; Treatment Outcome

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; United States; United States Food and Drug Administration

Cardiovascular disease (CVD) mortality in the UK is declining; however, CVD burden comes not only from deaths, but also from those living with the disease. This review uses national datasets with multiple years of data to present secular trends in mortality, morbidity, and treatment for all CVD and specific subtypes within the UK. We produced all-ages and premature age-standardised mortality rates by gender, standardised to the 2013 European Standard Population, using data from the national statistics agencies of the UK. We obtained data on hospital admissions from the National Health Service records, using the main diagnosis. Prevalence data come from the Quality and Outcome Framework and national surveys. Total CVD mortality declined by 68% between 1980 and 2013 in the UK. Similar decreases were seen for coronary heart disease and stroke. Coronary heart disease prevalence has remained constant at around 3% in England and 4% in Scotland, Wales, and Northern Ireland. Hospital admissions for all CVD increased by over 46 000 between 2010/2011 and 2013/2014, with more than 36 500 of these increased admissions for men. Hospital admission trends vary by country and CVD condition. CVD prescriptions and operations have increased over the last decade. CVD mortality has declined notably for both men and women while hospital admissions have increased. CVD prevalence shows little evidence of change. This review highlights that improvements in the burden of CVD have not occurred equally between the four constituent countries of the UK, or between men and women.

Topics: Adolescent; Adult; Age Distribution; Age of Onset; Aged; Cardiac Surgical Procedures; Cardiovascular Agents; Cardiovascular Diseases; Coronary Disease; Female; Health Status Disparities; Healthcare Disparities; Hospitalization; Humans; Male; Middle Aged; Practice Patterns, Physicians'; Prevalence; Risk Factors; Sex Distribution; Stroke; Time Factors; United Kingdom; Young Adult

Chemokines are critical components in pathology. The roles of chemokine CC motif ligand 4 (CCL4) and its receptor are associated with diabetes mellitus (DM) and atherosclerosis cardiovascular diseases. However, due to the complexity of these diseases, the specific effects of CCL4 remain unclear, although recent reports have suggested that multiple pathways are related to CCL4. In this review, we provide an overview of the role and potential mechanisms of CCL4 and one of its major receptors, fifth CC chemokine receptor (CCR5), in DM and cardiovascular diseases. CCL4-related mechanisms, including CCL4 and CCR5, might provide potential therapeutic targets in DM and/or atherosclerosis cardiovascular diseases.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Chemokine CCL4; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Ligands; Receptors, CCR5; Signal Transduction

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drugs, Investigational; Humans; Species Specificity; Translational Research, Biomedical

microRNAs (miRNA) are small non-coding RNAs (sRNA) that post-transcriptionally regulate gene (mRNA) expression and are implicated in many biological processes and diseases. Many miRNAs have been reported to be altered in cardiovascular disease (CVD); both cellular and extracellular miRNA levels are affected by hypercholesterolemia and atherosclerosis. We and other groups have reported that lipoproteins transport miRNAs in circulation and these lipoprotein signatures are significantly altered in hypercholesterolemia and coronary artery disease (CAD). Extracellular miRNAs are a new class of potential biomarkers for CVD; however, they may also be new drug targets as high-density lipoproteins (HDL) transfer functional miRNAs to recipient cells in an endocrine-like form of intercellular communication that likely suppresses vascular inflammation. Recently, RNA-based drugs have emerged as the next frontier in drug therapy, and there are many miRNA inhibitors and mimics in clinical development. Here, we discuss specific miRNA drug targets and how their manipulation may impact CVD. We also address the potential for manipulating HDL-miRNA levels to treat CVD and the use of HDL as a delivery vehicle for RNA and chemical drugs. Finally, we outline the current and future challenges for HDL and miRNA-based therapeutics for the prevention and treatment of CVD.

Topics: Animals; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Drug Design; Humans; Lipoproteins, HDL; MicroRNAs

Cardiovascular diseases (CVD) remain the leading cause of death worldwide with an estimated 17.5 million deaths per year. Since its initial conception over a decade ago, the use of cardiovascular polypills has gained increasing momentum as a strategy to lower risk factor levels and prevent CVD. Several new data have emerged including the recent publication of the first outcomes trial using polypills. Areas covered: In this review, the authors summarize the current literature on the safety, efficacy, and cost-effectiveness of polypills for primary and secondary prevention of CVD, describe the current controversies in this field, and identify important areas for future research. The authors searched PubMed, CENTRAL, and ClinicalTrials.gov from inception till 25 June 2016 using the search term 'polypill.' Expert opinion: Cardiovascular polypills containing aspirin, statin, and one or more anti-hypertensive medications, along with lifestyle interventions, represent an attractive, safe, and cost-effective strategy for primary and secondary prevention of CVD. Future research efforts should focus on identifying patients who will benefit the most from the use of polypills, marketing several polypills with different components and doses, and developing novel regulatory strategies for making polypills more readily available in all countries worldwide.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cost-Benefit Analysis; Drug Combinations; Humans; Primary Prevention; Risk Factors; Secondary Prevention

Angina pectoris is a common presenting symptom of underlying coronary artery disease or reduced coronary flow reserve. Patients with angina have impaired quality of life; and need to be treated optimally with antianginal drugs to control symptoms and improve exercise performance. A wide range of antianginal medications are approved for the treatment of angina, and often more than one class of antianginal drugs are used to adequately control the symptoms. This expert opinion highlights the likely cardiac adverse effects of available antianginal drugs, and how to minimize these in individual patients and especially during combination treatment. Areas covered: All approved antianginal drugs, including the older and newly approved medications with different mechanism of action to the older drugs as well as some of the unapproved herbal medications. The safety profiles and potential cardiac side effects of these medications when used as monotherapy or as combination therapy are discussed and highlighted. Expert opinion: Because of the different cardiac safety profiles and possible side effects, we recommend selection of initial drug or adjustment of therapy based on the resting heart rate; blood pressure, hemodynamic status; and resting left ventricular function, concomitant medications and any associated comorbidities.

Topics: Angina Pectoris; Animals; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Drug Therapy, Combination; Heart Rate; Humans; Plant Preparations; Quality of Life; Ventricular Function, Left

Topics: Benzazepines; Cardiovascular Agents; Cardiovascular Diseases; Drug Utilization; Humans; Ivabradine; Off-Label Use

Cardiovascular disease has become the leading cause of death and constitutes a serious public health issue in China. Faced with the burgeoning epidemic of cardiovascular disease and the huge burden and economic losses it causes, the Chinese government has attached the utmost importance to cardiovascular research, increasing funding to support basic and clinical studies, integrating resources and recruiting outstanding talent from overseas. The continued and growing support from the government has yielded substantial changes in terms of new discoveries, scientific publications and drug research and development within the last decade. In spite of the advances in cardiovascular research, China still faces significant challenges ahead in encouraging innovation, developing the prevention-oriented health policies and strengthening international collaboration.

Topics: Biomedical Research; Cardiovascular Agents; Cardiovascular Diseases; China; Drug Discovery; Humans

Vascular-derived hydrogen peroxide (H2O2) serves as an important signaling molecule in the cardiovascular system and contributes to vascular homeostasis. H2O2 is a second messenger, transducing the oxidative signal into biological responses through posttranslational protein modification. The balance between oxidant and antioxidant systems regulates intracellular redox status, and their imbalance causes oxidative or reductive stress, leading to cellular damage in cardiovascular systems. Excessive H2O2 deteriorates vascular functions and promotes vascular disease through multiple pathways. The RhoA/Rho-kinase pathway plays an important role in various fundamental cellular functions, including production of excessive reactive oxygen species, leading to the development of cardiovascular diseases. Rho-kinase (ROCK1 and ROCK2) belongs to the family of serine/threonine kinases and is an important downstream effector of the small GTP-binding protein RhoA. Rho-kinase plays a crucial role in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, stroke, and heart failure. Thus, Rho-kinase inhibitors may be useful for the treatment of cardiovascular diseases in humans. In this review, we will briefly discuss the roles of vascular-derived H2O2 and review the recent progress in the translational research on the therapeutic importance of the Rho-kinase pathway in cardiovascular medicine.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Cyclophilin A; Humans; Hydrogen Peroxide; Inflammation Mediators; Oxidation-Reduction; Oxidative Stress; Protein Kinase Inhibitors; rho-Associated Kinases; Signal Transduction

Topics: Adult; Anti-Retroviral Agents; Antipsychotic Agents; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Drug Interactions; HIV Infections; Humans; Mental Disorders

The erythropoietin-producing hepatocellular carcinoma (Eph) receptor tyrosine kinase family plays important roles in developmental processes, adult tissue homeostasis, and various diseases. Interaction with Eph receptor-interacting protein (ephrin) ligands on the surface of neighboring cells triggers Eph receptor kinase-dependent signaling. The ephrins can also transmit signals, leading to bidirectional cell contact-dependent communication. Moreover, Eph receptors and ephrins can function independently of each other through interplay with other signaling systems. Given their involvement in many pathological conditions ranging from neurological disorders to cancer and viral infections, Eph receptors and ephrins are increasingly recognized as attractive therapeutic targets, and various strategies are being explored to modulate their expression and function. Eph receptor/ephrin upregulation in cancer cells, the angiogenic vasculature, and injured or diseased tissues also offer opportunities for Eph/ephrin-based targeted drug delivery and imaging. Thus, despite the challenges presented by the complex biology of the Eph receptor/ephrin system, exciting possibilities exist for therapies exploiting these molecules.

Topics: Animals; Antineoplastic Agents; Antiviral Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Ephrins; Humans; Ligands; Molecular Targeted Therapy; Neoplasms; Nervous System Diseases; Receptors, Eph Family; Signal Transduction; Virus Diseases

The APJ is a class A, rhodopsin-like G protein-coupled receptor (GPCR) with high sequence similarity to the angiotensin receptor AT1. APJ has been shown to be widely expressed in humans tissues, including the central nervous system, cardiovascular system, adipocytes and others. APJ plays an important role in the occurrence and development of cardiovascular and metabolic diseases including atherosclerosis (AS), coronary heart disease (CAD), heart failure(HF), pulmonary arterial hypertension (PAH), myocardial hypertrophy and atrial fibrillation, especially hypertension. Previous researchers found that apelin/APJ could induce vasodilation and then reduce blood pressure. Despite APJ is closely associated with many diseases, there are no drugs that can activate or inhibit APJ directly. In the current review, we have summarized recently reported peptides, small molecule agonists and antagonists targeting APJ. Given the role of apelin/APJ in hypertension and other cardiovascular diseases, we believe that the peptides and compounds based on APJ will be developed for treatment of these diseases.

Topics: Apelin Receptors; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Humans; Hypertension; Molecular Structure; Molecular Targeted Therapy; Mutation; Receptors, G-Protein-Coupled; Signal Transduction; Small Molecule Libraries; Structure-Activity Relationship

Resting heart rate is central to cardiac output and is influenced by changes occurring in numerous diseases. It predicts longevity and cardiovascular diseases, and current evidence suggests that it is also an important marker of outcome in cardiovascular disease, including heart failure. Beta-blockers improve outcomes in heart failure; however, they have effects outside reducing heart rate. Ivabradine has demonstrated efficacy in reducing rehospitalizations and mortality in heart failure and in improving exercise tolerance and reducing angina attacks in patients with coronary artery disease, whereas selective heart rate reduction may also prove to be beneficial in therapeutic areas outside those in which ivabradine has already demonstrated clinical efficacy. This review provides an update on the associations between heart rate and cardiovascular outcomes in various conditions, the experimental effects of heart rate reduction with ivabradine, and the potential new indications in cardiovascular disease.

Topics: Benzazepines; Cardiovascular Agents; Cardiovascular Diseases; Heart Rate; Humans; Ivabradine; Rest; Risk Factors; Treatment Outcome

Cardiovascular disease is the leading cause of death worldwide. Despite advancements in diagnosis and treatment of cardiovascular disease, the incidence of cardiovascular disease is still rising. Therefore, new lines of medications are needed to treat the growing population of patients with cardiovascular disease. Although the majority of the existing pharmacotherapies for cardiovascular disease are synthesized molecules, natural compounds, such as resveratrol, are also being tested. Resveratrol is a non-flavonoid polyphenolic compound, which has several biological effects. Preclinical studies have provided convincing evidence that resveratrol has beneficial effects in animal models of hypertension, atherosclerosis, stroke, ischemic heart disease, arrhythmia, chemotherapy-induced cardiotoxicity, diabetic cardiomyopathy, and heart failure. Although not fully delineated, some of the beneficial cardiovascular effects of resveratrol are mediated through activation of silent information regulator 1 (SIRT1), AMP-activated protein kinase (AMPK), and endogenous anti-oxidant enzymes. In addition to these pathways, the anti-inflammatory, anti-platelet, insulin-sensitizing, and lipid-lowering properties of resveratrol contribute to its beneficial cardiovascular effects. Despite the promise of resveratrol as a treatment for numerous cardiovascular diseases, the clinical studies for resveratrol are still limited. In addition, several conflicting results from trials have been reported, which demonstrates the challenges that face the translation of the exciting preclinical findings to humans. Herein, we will review much of the preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular disease and provide information about the physiological and molecular signaling mechanisms involved. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

Topics: Animals; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Heart Rate; Humans; Resveratrol; Stilbenes; Vasodilation

Epidemiological studies support a strong association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. Experimental evidence from different angles supports the view that low HDL is unlikely an innocent bystander in the development of heart failure. HDL exerts direct cardioprotective effects, which are mediated via its interactions with the myocardium and more specifically with cardiomyocytes. HDL may improve cardiac function in several ways. Firstly, HDL may protect the heart against ischaemia/reperfusion injury resulting in a reduction of infarct size and thus in myocardial salvage. Secondly, HDL can improve cardiac function in the absence of ischaemic heart disease as illustrated by beneficial effects conferred by these lipoproteins in diabetic cardiomyopathy. Thirdly, HDL may improve cardiac function by reducing infarct expansion and by attenuating ventricular remodelling post-myocardial infarction. These different mechanisms are substantiated by in vitro, ex vivo, and in vivo intervention studies that applied treatment with native HDL, treatment with reconstituted HDL, or human apo A-I gene transfer. The effect of human apo A-I gene transfer on infarct expansion and ventricular remodelling post-myocardial infarction illustrates the beneficial effects of HDL on tissue repair. The role of HDL in tissue repair is further underpinned by the potent effects of these lipoproteins on endothelial progenitor cell number, function, and incorporation, which may in particular be relevant under conditions of high endothelial cell turnover. Furthermore, topical HDL therapy enhances cutaneous wound healing in different models. In conclusion, the development of HDL-targeted interventions in these strategically chosen therapeutic areas is supported by a strong clinical rationale and significant preclinical data.

Topics: Administration, Topical; Animals; Apolipoprotein A-I; Cardiovascular Agents; Cardiovascular Diseases; CD36 Antigens; Diabetic Cardiomyopathies; Endothelial Cells; Genetic Therapy; Humans; Lipoproteins, HDL; Myocardial Reperfusion Injury; Myocytes, Cardiac; Regeneration; Skin; Stem Cells; Treatment Outcome; Wound Healing

Optimising secondary prevention of cardiovascular disease has the greatest potential to reduce recurrent events, yet despite major guidelines there are ongoing treatment gaps. FFSAABC (Fish oils, Fibrates, Statins, Aspirin, Angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, Beta blockers and Clopidogrel) is one mnemonic previously adopted to assist clinicians in remembering medications for use in secondary prevention. The aim of this narrative review is to examine the current evidence base for medications recommended for patients with established cardiovascular disease and the current applicability of this, or a revised mnemonic for their use.. Randomised controlled trials and systematic reviews were sought examining Fish oils, Fibrates, Statins, Aspirin, Angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, Beta blockers or Clopidogrel vs placebo in secondary prevention. The emerging evidence base for other contemporary therapies including the P2Y12 inhibitors (ticagrelor and prasugrel) and aldosterone antagonists was also reviewed.. Definitive evidence supports the use of statins, aspirin, angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, and P2Y12 antagonists (clopidogrel, ticagrelor or prasugrel) for the secondary prevention of cardiovascular disease. Aldosterone antagonists have strong evidence in the presence of systolic heart failure. There is a weaker evidence base for the routine use of omega-3 fatty acid supplementation although this therapy carries minimal harms. Fenofibrate reduces cardiovascular events in dyslipidaemic patients, with additional benefits in patients with diabetes.. Mnemonic upgrading from a Fairly Fast SAAB Convertible to a Fairly Fast SA(2)A(2)B (Fish oils, Fibrate, Statin, Antiplatelets (Aspirin+Other), ACE/ARB, Aldosterone Antagonist, Beta-blocker) may help to ensure patients receive best practice evidence-based pharmacotherapies for the secondary prevention of cardiovascular disease.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Randomized Controlled Trials as Topic

Intravenous lipid emulsion (ILE) and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) are being used together or in close succession in the management of circulatory failure secondary to cardiotoxic drug poisoning. There have been reports of mechanical problems, including fat emulsion agglutination, clogging, increased blood clot formation and even cracking of parts of the machine, in patients concurrently receiving VA-ECMO and ILE as part of parenteral nutrition.. To ascertain the adverse effects associated with the combined use of ILE and ECMO in the poisoned patient.. PubMed and OVID (1966 to 9 June 2014) and EMBASE (1947 to 9 June 2014) were searched to identify publications relating to studies and/or case reports where ILE had been used at the same time when VA-ECMO was used - 7 were identified. In addition, the abstracts published between 2006 and 2013 inclusive of those from the North American Congress of Clinical Toxicology and the congresses of the European Association of Poisons Centres and Clinical Toxicologists were searched to identify additional cases and 2 were found. Finally all cases posted on lipidrescue.org were reviewed to determine if they related to the use of ILE with VA-ECMO and no new cases were identified. In vitro study. An in vitro study involving the continuous infusion of 20% ILE at 3 mL/h for 24 h demonstrated layering (separation of intact fat emulsion from blood) and agglutination (clumping resulting in little or no flow of fat emulsion through the circuit) in all circuits within 30 min of starting the fat emulsion infusion.. An observational study based in 42 centres that regularly used 'fat emulsion' during VA-ECMO treatment reported cracking of stopcocks (the valve which restricts flow in the VA-ECMO tubing) (n = 10, 23.8%); fat emulsion agglutination (n = 11, 26.2%); clogging and associated malfunction of the membrane oxygenator (n = 2, 4.8%); and increased blood clot formation in the circuits (n = 2, 4.8%). In a prospective observational study of 9 neonates on VA-ECMO receiving intravenous nutrition, layering and agglutination were seen in four sets of VA-ECMO tubing and blood clots were found in seven circuits. Nine case reports were identified where ILE was used with VA-ECMO for the management of circulatory failure/instability secondary to cardiotoxic drug poisoning. In two of these case reports, the authors specifically stated that ILE did not cause any mechanical complications with the VA-ECMO; the other seven reports made no comment as to whether there were any complications or not.. There is in vitro and clinical evidence that the combined use of ILE and extracorporeal membrane oxygenation may be associated with fat deposition in the VA-ECMO circuits and increased blood clot formation. Clinicians managing poisoned patients with both of these novel treatment modalities should be aware of these potential complications.

Topics: Adolescent; Adult; Cardiovascular Agents; Cardiovascular Diseases; Combined Modality Therapy; Equipment Design; Equipment Failure; Extracorporeal Membrane Oxygenation; Fat Emulsions, Intravenous; Female; Humans; Infant; Male; Middle Aged; Poisoning; Risk Factors; Shock; Treatment Outcome; Young Adult

Cardiovascular disease is the leading cause of death worldwide. As such, there is great interest in identifying novel mechanisms that govern the cardiovascular response to disease-related stress. First described in failing hearts, autophagy within the cardiovascular system has been widely characterized in cardiomyocytes, cardiac fibroblasts, endothelial cells, vascular smooth muscle cells, and macrophages. In all cases, a window of optimal autophagic activity appears to be critical to the maintenance of cardiovascular homeostasis and function; excessive or insufficient levels of autophagic flux can each contribute to heart disease pathogenesis. In this Review, we discuss the potential for targeting autophagy therapeutically and our vision for where this exciting biology may lead in the future.

Topics: Animals; Autophagy; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Endothelium, Vascular; Humans; Muscle, Smooth, Vascular; Myocardium

Chronic obstructive pulmonary disease (COPD) is frequently accompanied by multimorbidities in affected patients. Even though the majority of these comorbidities are also related to advanced age and cigarette smoke, also COPD itself has significant impact on insurgence, or worsening of these conditions. As a consequence, COPD is regarded as a complex disease with pulmonary and extra-pulmonary involvement. According to current guidelines for the management of COPD patients, the comprehensive treatment of this condition should target respiratory symptoms as well as comorbidities. Cardiovascular disease is one of the most frequent comorbidities in COPD patients and there are several strategies for reducing the risk of cardiovascular disease in COPD patients. These include smoking cessation, pharmacologic prevention of cardiovascular disease, and the treatment of COPD. Beta-blockers for the prevention of cardiovascular disease have been traditionally limited in COPD patients, albeit current evidence supporting their efficacy and safety in these patients. With regard to COPD medications, corticosteroids are generally not recommended, except for exacerbations, while long-acting beta2-agonists have demonstrated an acceptable profile of cardiovascular safety. Long-acting anticholinergic bronchodilators, in particular tiotropium in the mist inhaler formulation, have been associated with an increased risk of major cardiovascular events and mortality. Data on this issue remain, however, controversial. Glycopyrronium, a recently introduced anticholinergic, demonstrated. a rapid and sustained relief of respiratory symptoms with a favorable safety profile and no increase in cardiovascular risk, in monotherapy and in combination with a long-acting beta2-agonist in a comprehensive trial program indicating a valid option for COPD patients with CV comorbidities.

Topics: Bronchodilator Agents; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Humans; Life Style; Patient Selection; Prognosis; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Risk Factors; Risk Reduction Behavior; Smoking; Smoking Cessation

Mineralocorticoid receptor (MR) antagonism is a well-established treatment modality for patients with hypertension, heart failure, and left ventricular systolic dysfunction (LVSD) post-myocardial infarction (MI). There are emerging data showing potential benefits of MR antagonists in other cardiovascular conditions. Studies have shown association between MR activation and the development of myocardial fibrosis, coronary artery disease, metabolic syndrome, and cerebrovascular diseases. This review examines the preclinical and clinical data of MR antagonists for novel indications including heart failure with preserved ejection fraction (HFPEF), pulmonary arterial hypertension (PAH), arrhythmia, sudden cardiac death, valvular heart disease, metabolic syndrome, renal disease, and stroke. MR antagonists are not licensed for these conditions yet; however, emerging data suggest that indication for MR antagonists are likely to broaden; further studies are warranted.

Topics: Animals; Arrhythmias, Cardiac; Cardiovascular Agents; Cardiovascular Diseases; Death, Sudden, Cardiac; Disease Progression; Heart Failure; Humans; Hypertension, Pulmonary; Mineralocorticoid Receptor Antagonists; Models, Biological; Off-Label Use; Receptors, Mineralocorticoid; Severity of Illness Index

Non-adherence to cardiovascular medications is a problem worldwide, even in Australia, which has a socialized medical system, Medicare.. The aim of this systematic review was to evaluate the burden of non-adherence to cardiovascular medications and factors thereof in Australia.. Pubmed, Embase, CINAHL, PsycInfo, Cochrane Library databases were searched.. Articles were included if they were in English, peer-reviewed and provided empirical data on adherence to cardiovascular medication for an Australian cohort.. A meta-analysis of prevalence of medication non-adherence using the double arcsine square root transformed proportion was undertaken. Studies were pooled in homogenous prevalence groups and factors that differed across groups were ascertained.. Five studies, including eight datasets and 76,867 subjects were analyzed. Three more or less homogenous prevalence categories were discernable: low [19 %, 95 % confidence interval (CI) 15-24], moderate (26 %, 95 % CI 23-29) and high (43 %, 95 % CI 43-44; this was a single study) prevalence of non-adherence. There were minimal clear patterns across groups in relation to typical factors of non-adherence (patient, condition, healthcare system or socioeconomic factors). Measurements used for non-adherence were similar for six of the eight included datasets, suggesting this did not affect prevalence of non-adherence or inclusion in a prevalence group.. Non-adherence to cardiovascular medications is a serious problem in the aging Australian setting with an overall prevalence of between 14 and 43 %. The lack of patterns in the typical factors of non-adherence suggests that another factor, such as patients' beliefs about their conditions and medications, may be playing a stronger role in their non-adherence than clinical or sociodemographic factors. This is an area for further research.

Topics: Aged; Australia; Cardiovascular Agents; Cardiovascular Diseases; Databases, Factual; Humans; Medication Adherence

Peptidyl-prolyl cis-trans-isomerases are a highly conserved family of immunophilins. The three peptidyl-prolyl cis-trans-isomerase subfamilies are cyclophilins, FK-506-binding proteins, and parvulins. Peptidyl-prolyl cis-trans-isomerases are expressed in multiple human tissues and regulate different cellular functions, e.g. calcium handling, protein folding, and gene expression. Moreover, these subfamilies have been shown to be consistently involved in several cardiac and vascular diseases including heart failure, arrhythmias, vascular stenosis, endothelial dysfunction, atherosclerosis, and hypertension. This review provides a concise description of the peptidyl-prolyl cis-trans-isomerases and presents an incisive selection of studies focused on their relationship with cardiovascular diseases.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Cyclophilins; Enzyme Inhibitors; Humans; Molecular Targeted Therapy; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Signal Transduction; Tacrolimus Binding Proteins

Progress in human genetic and genomic research has led to the identification of genetic variants associated with specific cardiovascular diseases (CVDs), but the pathogenic mechanisms remain unclear. Recent studies have analyzed the involvement of epigenetic mechanisms such as DNA methylation and histone modifications in the development and progression of CVD. Preliminary work has investigated the correlations between DNA methylation, histone modifications, and RNA-based mechanisms with CVDs including atherosclerosis, heart failure (HF), myocardial infarction (MI), and cardiac hypertrophy. Remarkably, both in utero programming and postnatal hypercholesterolemia may affect the epigenetic signature in the human cardiovascular system, thereby providing novel early epigenetic-related pharmacological insights. Interestingly, some dietary compounds, including polyphenols, cocoa, and folic acid, can modulate DNA methylation status, whereas statins may promote epigenetic-based control in CVD prevention through histone modifications. We review recent findings on the epigenetic control of cardiovascular system and new challenges for therapeutic strategies in CVDs.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; DNA Methylation; Epigenesis, Genetic; Histones; Humans; MicroRNAs

The role of chemokines and their receptors in controlling several physiological and pathological processes has only become evident in the last couple of years. From a sole function of chemo-attraction, our view on chemokine receptor activation has switched to the regulation of pleiotropic signaling pathways influencing numerous molecular and cellular processes. The large number of chemokines and receptors and hence possible combinations of chemokine-chemokine receptor interactions, as well as the expression profiles of chemokines and chemokine receptors within particular cell types, has contributed to the complexity of chemokine receptor signaling as we see it today. The chemokine CCL2 and its main chemokine receptor CCR2 have been implicated in the pathogenesis of several different disease processes, including vascular permeability and attraction of immune cells during metastasis, a number of different neurological disorders, autoimmune disease, obesity, and atherosclerosis. Here we review recent findings on the role of the CCL2-CCR2 axis in the regulation of these diseases. We believe that research has only gained a first glimpse of what chemokines can control and what the underlying mechanisms are. There is certainly more to be found that will - with high certainty - have strong implications for clinical applications in the near future.

Topics: Animals; Antineoplastic Agents; Autocrine Communication; Autoimmune Diseases; Cardiovascular Agents; Cardiovascular Diseases; Central Nervous System; Chemokine CCL2; Drug Design; Humans; Immunosuppressive Agents; Metabolic Syndrome; Molecular Targeted Therapy; Neoplasms; Nervous System Diseases; Receptors, CCR2; Signal Transduction; Tumor Microenvironment

The stability of mRNA has emerged as a key step in the regulation of eukaryotic gene expression and function. RNA stabilizing proteins (RSPs) contain several RNA recognition motifs, and selectively bind to adenylate-uridylate-rich elements in the 3' untranslated region of several mRNAs leading to altered processing, stability, and translation. These post-transcriptional gene regulations play a critical role in cellular homeostasis; therefore act as molecular switch between 'normal cell' and 'disease state.' Many mRNA binding proteins have been discovered to date, which either stabilize (HuR/HuA, HuB, HuC, HuD) or destabilize (AUF1, tristetraprolin, KSRP) the target transcripts. Although the function of RSPs has been widely studied in cancer biology, its role in cardiovascular pathologies is only beginning to evolve. The current review provides an overall understanding of the potential role of RSPs, specifically HuR-mediated mRNA stability in myocardial infarction, hypertension and hypertrophy. Also, the effect of RSPs on various cellular processes including inflammation, fibrosis, angiogenesis, cell-death, and proliferation and its relevance to cardiovascular pathophysiological processes is presented. We also discuss the potential clinical implications of RSPs as therapeutic targets in cardiovascular diseases.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cell Death; Cell Proliferation; ELAV-Like Protein 1; Gene Expression Regulation; Humans; Molecular Targeted Therapy; Neovascularization, Pathologic; RNA Stability; RNA, Messenger; Sensitivity and Specificity

Systematic reviews of animal studies have revealed serious limitations in internal and external validity strongly affecting the reliability of this research. In addition inter-species differences are likely to further limit the predictive value of animal research for the efficacy and tolerability of new drugs in humans. Important changes in the research process are needed to allow efficient translation of preclinical discoveries to the clinic, including improvements in the laboratory and publication practices involving animal research and early incorporation of human proof-of-concept studies to optimize the interpretation of animal data for its predictive value for humans and the design of clinical trials.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Species Specificity; Translational Research, Biomedical

This White Paper provides a summary of presentations and discussions at a Cardiovascular Safety Outcome Trials Think Tank cosponsored by the Cardiac Safety Research Consortium, the US Food and Drug Administration, and the American College of Cardiology, held at American College of Cardiology's Heart House, Washington, DC, on February 19, 2014. Studies to assess cardiovascular (CV) risk of a new drug are sometimes requested by regulators to resolve ambiguous safety signals seen during its development or among other members of its class. Think Tank participants thought that important considerations in undertaking such studies were as follows: (1) plausibility-how likely it is that a possible signal indicating risk is real, based on strength of evidence, and/or whether a plausible mechanism of action for potential CV harm has been identified; (2) relevance-what relative and absolute CV risk would need to be excluded to determine that the drug had an acceptable benefit-to-risk balance for its use in the intended patient population; and (3) how plausibility and relevance influence the timing and approach to further safety assessment.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Congresses as Topic; Drug Approval; Humans; United States; United States Food and Drug Administration

Pharmacogenomics (PGx) is the science that examines how an individual's genetic make-up affects the safety and efficacy of therapeutic drugs. PGx of response to cardiovascular (CV) medications is of the most successfully translated branches of PGx into the clinical workout. However, the clinical implementation of PGx of CV drugs is yet far beyond the growth of our understanding of the role of genetics in drug therapy. A considerable amount of efforts have been devoted by the regulatory agents like the food and drug administration (FDA) as well as the expert-based networks such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) to overcome the existing barriers. This has been done, at least in part, for some of the most widely prescribed CV drugs, including clopidogrel, warfarin and simvastatin for which the PGx knowledge have been satisfactorily robust to provoke the CPIC to issue the guidelines for these drugs and the FDA to update the drugs' labeling, both strongly recommended the use of genotype-guided dosing for these medications, provided that the genetic data are available. For other drugs, however, studies have produced contradictory results and further large and well-designed clinical trials are required to expand and confirm the clinical utility of their PGx data. This review paper presents the current state of knowledge in the field of PGx of CV medications and describes the facilities assisting to the translation of PGx data into the clinical practice. Afterward, the existing body of PGx literature of the most-commonly used CV medications is comprehensively discussed.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Genetic Association Studies; Genome-Wide Association Study; Humans; Pharmacogenetics

Abdominal aortic aneurysm refers to abdominal aortic dilation of 3.0 cm or greater. The main risk factors are age older than 65 years, male sex, and smoking history. Other risk factors include a family history of abdominal aortic aneurysm, coronary artery disease, hypertension, peripheral artery disease, and previous myocardial infarction. Diagnosis may be made by physical examination, an incidental finding on imaging, or ultrasonography. The U.S. Preventive Services Task Force released updated recommendations for abdominal aortic aneurysm screening in 2014. Men 65 to 75 years of age with a history of smoking should undergo one-time screening with ultrasonography based on evidence that screening will improve abdominal aortic aneurysm-related mortality in this population. Men in this age group without a history of smoking may benefit if they have other risk factors (e.g., family history of abdominal aortic aneurysm, other vascular aneurysms, coronary artery disease). There is inconclusive evidence to recommend screening for abdominal aortic aneurysm in women 65 to 75 years of age with a smoking history. Women without a smoking history should not undergo screening because the harms likely outweigh the benefits. Persons who have a stable abdominal aortic aneurysm should undergo regular surveillance or operative intervention depending on aneurysm size. Surgical intervention by open or endovascular repair is the primary option and is typically reserved for aneurysms 5.5 cm in diameter or greater. There are limited options for medical treatment beyond risk factor modification. Ruptured abdominal aortic aneurysm is a medical emergency presenting with hypotension, shooting abdominal or back pain, and a pulsatile abdominal mass. It is associated with high prehospitalization mortality. Emergent surgical intervention is indicated for a rupture but has a high operative mortality rate.

Topics: Age Distribution; Aged; Aged, 80 and over; Aneurysm, Ruptured; Aortic Aneurysm, Abdominal; Cardiovascular Agents; Cardiovascular Diseases; Diagnostic Imaging; Female; Humans; Male; Mass Screening; Obesity; Practice Guidelines as Topic; Risk Factors; Sex Distribution; Smoking; Vascular Surgical Procedures

Although cardiovascular mortality has been decreasing in industrialized countries, there continues to be a substantial residual risk; thus, novel therapeutic agents and new targets of therapy have been sought. One highly plausible therapeutic target is high-density lipoprotein (HDL). HDL is a key player in reverse cholesterol transport and possesses a slew of other cardioprotective properties; however, recent trials with agents known to increase HDL levels have generally not shown any reduction in cardiovascular events. Further analysis of these trials suggest that fibrates have consistently reduced some cardiovascular outcomes, at least in the subgroup of patients with high serum triglycerides and low HDL cholesterol (HDLc) levels. Since fibrates, unlike niacin or cholesterol ester transfer protein inhibitors, increase HDLc level mostly through the stimulation of apolipoprotein A-I production, it is suggested that the quality and functionality of HDL are enhanced when de novo synthesis rather than inhibition of turnover is the mechanism of increasing HDL level. In this communication, the evidence for and against the cardioprotective properties of HDL is reviewed and the contemporary clinical trials are discussed.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cholesterol, HDL; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Lipoproteins, HDL; Niacin; Randomized Controlled Trials as Topic; Triglycerides

Aging is associated with a progressive loss of function in all organs. Under normal conditions the physiologic compensation for age-related deficits is sufficient, but during times of stress the limitations of this reserve become evident. Explanations for this reduction in reserve include the changes in the microcirculation that occur during the normal aging process. The microcirculation is defined as the blood flow through arterioles, capillaries and venules, which are the smallest vessels in the vasculature and are embedded within organs and tissues. Optimal strategies to maintain the microvasculature following surgery and other stressors must use multifactorial approaches. Using skin as the model organ, we will review the anatomical and functional changes in the microcirculation with aging, and some of the available clinical strategies to potentially mitigate the effect of these changes on important clinical outcomes.

Topics: Age Factors; Aging; Animals; Cardiovascular Agents; Cardiovascular Diseases; Hemodynamics; Humans; Life Style; Microcirculation; Microvessels; Regional Blood Flow; Risk Factors; Risk Reduction Behavior; Skin

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Female; Humans; Male; Patient Selection; Risk Factors; Sex Characteristics

Herbal products have been used as conventional medicines for thousands of years, particularly in Eastern countries. Thousands of clinical and experimental investigations have focused on the effects and mechanisms-of-action of herbal medicine in the treatment of cardiovascular diseases (CVDs). Considering the history of clinical practice and the great potentials of herb medicine and/or its ingredients, a review on this topic would be helpful. This article discusses possible effects of herbal remedies in the prevention and treatment of CVDs. Crucially, we also summarize some underlying pharmacological mechanisms for herb products in cardiovascular regulations, which might provide interesting information for further understanding the effects of herbal medicines, and boost the prospect of new herbal products against CVDs.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Humans; Medicine, Traditional; Phytotherapy; Plant Preparations; Plants, Medicinal

Modulation of the low affinity adenosine receptor subtype, the A2b adenosine receptor (A2bAR), has gained interest as a therapeutic target in various pathologic areas associated with cardiovascular disease. The actions of the A2bAR are diverse and at times conflicting depending on cell and tissue type and the timing of activation or inhibition of the receptor. The A2bAR is a promising and exciting pharmacologic target, however, a thorough understanding of A2bAR action is necessary to reach the therapeutic potential of this receptor. This review will focus on the role of the A2bAR in various cardiovascular and metabolic pathologies in which the receptor is currently being studied. We will illustrate the complexities of A2bAR signaling and highlight areas of research with potential for therapeutic development.

Topics: Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Metabolic Diseases; Molecular Targeted Therapy; Receptor, Adenosine A2B; Signal Transduction

Topics: Biomedical Research; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Humans; Pharmacogenetics

Rho-kinase (ROCKs) is an important downstream effector of the small GTP-binding protein Ras homolog gene family member A. There are 2 isoforms of ROCK, ROCK1 and ROCK2, and they have different functions in several vascular components. The Ras homolog gene family member A/ROCK pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation, and apoptosis, whereas its excessive activity is involved in the pathogenesis of cardiovascular diseases. For the past 20 years, a series of translational research studies have demonstrated the important roles of ROCK in the pathogenesis of cardiovascular diseases. At the molecular and cellular levels, ROCK upregulates several molecules related to inflammation, thrombosis, and fibrosis. In animal experiments, ROCK plays an important role in the pathogenesis of vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, and heart failure. Finally, at the human level, ROCK is substantially involved in the pathogenesis of coronary vasospasm, angina pectoris, hypertension, pulmonary hypertension, and heart failure. Furthermore, ROCK activity in circulating leukocytes is a useful biomarker for the assessment of disease severity and therapeutic responses in vasospastic angina, heart failure, and pulmonary hypertension. In addition to fasudil, many other ROCK inhibitors are currently under development for various indications. Thus, the ROCK pathway is an important novel therapeutic target in cardiovascular medicine.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Endothelium, Vascular; Humans; Molecular Targeted Therapy; Muscle, Smooth, Vascular; Protein Kinase Inhibitors; rho-Associated Kinases; Signal Transduction; Translational Research, Biomedical

Cardiovascular diseases, which lead to cardiovascular events including death, progress with many deleterious pathophysiological sequels. If a cause-and-effect relationship follows a one-to-one relation, we can focus on a cause to treat an effect, but such a relation cannot be applied in cardiovascular diseases. To identify novel drugs in the cardiovascular field, we generally adopt two different strategies: induction and deduction. In the cardiovascular field, it is difficult to use deduction because cardiovascular diseases are caused by many factors, leading us to use induction. In this method, we consider all clinical data, such as medical records or genetic data, and identify a few candidates. Recent computational and mathematical advances enable us to use data-mining methods to uncover hidden relationships between many parameters and clinical outcomes. However, because these candidates are not identified as promoting or inhibiting factors, or as causal or consequent factors of cardiovascular diseases, we need to test them in basic research, and bring them back to the clinical field to test their efficacy in clinical trials. With such a "back-and-forth loop" between clinical observation and basic research, data-mining methods may provide novel strategies leading to new tools for clinicians, basic findings for researchers, and better outcomes for patients.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Data Mining; Drug Discovery; Human Genome Project; Humans; Medical Records; Translational Research, Biomedical

There is a general sense that most outcomes trials in patients receiving dialysis failed to yield statistically significant benefits, in contrast to many cardiovascular (CV) trials in the general population. It is unknown whether methodologic reasons caused this discrepancy. We performed a systematic MEDLINE search for randomized trials with mortality end points of the 42 compounds most commonly used for CV indications. In total, 115 trials were selected for review. We further reviewed 9 mortality end point trials in patients receiving dialysis. The CV trials in populations not receiving dialysis enrolled from 66 to 33,357 participants with an average of 4,910; 59% of the trials showed statistically significant results. The average hazard ratio (HR) was 0.77, ranging from 0.10 to 1.65; 10 drugs had ≥5 published trials each. In the population receiving dialysis, most drugs were studied in single trials; the average number of patients was 1,500 with a range of 127 to 3,883. The average HR was 0.77 and ranged from 0.06 to 1.30. Only 22% of the trials showed statistically significant results. The limitations listed in the general population and dialysis studies were similar. In conclusion, no apparent methodologic issues were detected (other than sample size) that could justify the lower frequency of randomized trials with statistically significant results in patients receiving dialysis. The most obvious difference was the paucity of trials with each drug in the dialysis cohorts; this lowers the chances of at least 1 trial being successful.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Kidney Failure, Chronic; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Renal Dialysis; Research Design

Insulin-like growth factor-1, angiotensin-(1-7) and angiotensin-(1-9) have been proposed to be important mediators in cardioprotection. A large body of evidence indicates that insulin like growth factor-1 has pleotropic actions in the heart (i.e., contractility, metabolism, hypertrophy, autophagy, senescence and cell death) and, conversely, its deficiency is associated with impaired cardiac function. Recently, we reported that insulin like growth factor-1 receptor is also located in plasma membrane invaginations with perinuclear localization, highlighting the role of nuclear Ca(2+) signaling in the heart. In parallel, angiotensin-(1-7) and angiotensin (1-9) acting through Mas receptor and angiotensin type 2 receptor have emerged as a novel anti-hypertensive molecules promoting vasodilatation and preventing heart hypertrophy. In this review we discuss the scientific evidence available regarding insulin-like growth factor-1, angiotensin-(1-7) and angiotensin-(1-9) in cardioprotection and its potential application as novel therapeutic targets for treating cardiac diseases.

Topics: Angiotensin I; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cardiovascular System; Humans; Insulin-Like Growth Factor I; Models, Cardiovascular; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 2; Receptor, IGF Type 1; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction

Cardiovascular disease is the leading cause of morbidity and mortality worldwide, thereby putting a large burden on our healthcare costs. Using both human genetic approaches, as well as forward and reverse genetic strategies in animal models, significant progress has been made to unravel the genetic and molecular etiology of human cardiovascular disease that is crucial to define novel therapeutic targets. In this context, the zebrafish has emerged as an important in vivo vertebrate animal system to study and to model human cardiovascular diseases as well as for in vivo cardiovascular drug discovery.. This review describes the rationale for using the in vivo model system zebrafish in whole-organism-based drug discovery strategies. It also highlights recent developments in the fields of drug target identification, disease modeling, and automation of high-throughput small compound screening.. Novel genome-editing techniques such as the clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) and transcription activator-like effector nuclease (TALEN) technologies allow highly efficient and reliable disease modeling in the in vivo system zebrafish. The ambition of developing personalized therapeutic options will clearly be fostered by the establishment of animal disease models that accurately simulate the patient's situation and the use of these disease models in 'next-generation' high-throughput small compound screens to define treatment options tailored to individual needs. To define suitable targets for therapeutic modulation, systems biology approaches that study complex biological systems as an integrated whole will pave the way to successful in vivo disease modeling and future drug discovery.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Drug Discovery; High-Throughput Screening Assays; Humans; Molecular Targeted Therapy; Systems Biology; Zebrafish

Potassium (K(+)) channels, with their diversity, often tissue-defined distribution, and critical role in controlling cellular excitability, have long held promise of being important drug targets for the treatment of dysrhythmias in the heart and abnormal neuronal activity within the brain. With the exception of drugs that target one particular class, ATP-sensitive K(+) (KATP) channels, very few selective K(+) channel activators or inhibitors are currently licensed for clinical use in cardiovascular and neurological disease. Here we review what a range of human genetic disorders have told us about the role of specific K(+) channel subunits, explore the potential of activators and inhibitors of specific channel populations as a therapeutic strategy, and discuss possible reasons for the difficulty in designing clinically relevant K(+) channel modulators.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Myocardium; Nervous System Diseases; Neurons; Potassium Channel Blockers; Potassium Channels

Endothelial dysfunction has prognostic, diagnostic and therapeutic significance in cardiovascular disease, but the endothelial phenotype is still not measured routinely to stratify the cardiovascular risk and tailor therapy. Flow-mediated dilation (FMD), the gold-standard technique for the functional assessment of endothelial function that is increasingly used in clinical settings measures the nitric oxide (NO)-dependent function only. However, the endothelial dysfunction involves a plethora of pathophysiologically important biochemical changes beyond alterations in the NO bioavailability. Still, in many diseases, some plasma protein biomarkers reflecting the pro-thrombotic and the pro-inflammatory endothelial phenotypes have poor selectivity, specificity, and a weak predictive value if they are used alone. Therefore, a multi biomarker strategy seems to be a reasonable and promising alternative. Here, we propose a multi-biomarker strategy to diagnose the endothelial dysfunction and to monitor the efficacy of an endothelium-targeted therapy. This strategy is based on the panel of endothelial biomarkers, reflecting various aspects and mechanisms of dysfunctional endothelium. The potential of an advanced analytical platform like the ultra-high performance liquid chromatography (UHPLC) coupled to mass spectrometry-based multiple reaction monitoring for simultaneous quantification of multiple endothelial biomakers is also discussed.

Topics: Animals; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Humans; Risk Factors; Vasodilation

The combination of aspirin and the thienopyridine clopidogrel is a cornerstone in the prevention of atherothrombotic events. These two agents act in concert to ameliorate the prothrombotic processes stimulated by plaque rupture and vessel injury complicating cardiovascular disease. Guidelines recommend the use of clopidogrel in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention, and the drug remains the most utilized P2Y12 receptor inhibitor despite the fact that newer antiplatelet agents are now available. In recent years, numerous studies have shown inconsistency in the efficacy of clopidogrel to prevent atherothrombotic events. Studies of platelet function testing have shown variability in the response to clopidogrel. One of the major reason for this phenomenon lies in the interaction between clopidogrel and other drugs that may affect clopidogrel absorption, metabolism, and ultimately its antiplatelet action. Importantly, these drug-drug interactions have prognostic implications, since patients with high on-treatment platelet reactivity associated with reduced clopidogrel metabolism have an increased risk of ischemia. Previous systematic reviews have focused on drug-drug interactions between clopidogrel and specific pharmacologic classes, such as proton pump inhibitors, calcium channel blockers, and statins. However, more recent pieces of scientific evidence show that clopidogrel may also interact with newer drugs that are now available for the treatment of cardiovascular patients. Accordingly, the aim of this review is to highlight and discuss recent data on drug-drug interactions between clopidogrel and third-generation proton pump inhibitors, pantoprazole and lansoprazole, statins, pitavastatin, and antianginal drug, ranolazine.

Topics: Animals; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Clopidogrel; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Platelet Function Tests; Proton Pump Inhibitors; Ticlopidine

Little is known about the benefits and risks of the long-term use of cardiovascular drugs. Evidence from randomized clinical trials (RCTs) rarely goes beyond a few years of follow-up, but patients are often given continuous treatment with multiple drugs well into old age. We focus on 4 commonly used cardiovascular drug classes: aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitors given to patients after myocardial infarction. However, the issues raised apply more broadly to all long-term medications across cardiovascular diseases and the whole of medicine. The evidence and limitations of RCTs are addressed, as well as current practice in pre-licensing trials, the increasing problems of polypharmacy (especially in the elderly), the lack of trial evidence for withdrawal of drugs, the role of regulatory authorities and other stakeholders in this challenging situation, and the potential educational solutions for the medical profession. We conclude with a set of recommendations on how to improve the situation of long-term drug use.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Biomedical Research; Cardiovascular Agents; Cardiovascular Diseases; Drug Administration Schedule; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myocardial Infarction; Patient Care; Randomized Controlled Trials as Topic

Lectin-like oxidized low-density lipoprotein receptor-1 (SR-E1, LOX-1, OLR1) was first discovered as a vascular receptor for modified lipoprotein particles nearly 20 years ago. Since then, in vitro and in vivo studies have demonstrated an association between LOX-1, a soluble form (sLOX-1) and a number of diseases including atherosclerosis, arthritis, hypertension and pre-eclampsia. However, converting such discoveries into tools and drugs for routine clinical use is dependent on translational preclinical and clinical studies but such studies have only begun to emerge in the past decade. In this review, we identify the key clinical applications and corresponding criteria that need to be addressed for the effective use of LOX-1-related probes and molecules for patient benefit in different disease states.

Topics: Animals; Antibodies; Antibody Specificity; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Epitopes; Humans; Immunologic Techniques; Molecular Targeted Therapy; Predictive Value of Tests; Scavenger Receptors, Class E; Signal Transduction; Translational Research, Biomedical

The second messenger cyclic adenosine monophosphate (cAMP) can bind and activate protein kinase A (PKA). The cAMP/PKA system is ubiquitous and involved in a wide array of biological processes and therefore requires tight spatial and temporal regulation. Important components of the safeguard system are the A-kinase anchoring proteins (AKAPs), a heterogeneous family of scaffolding proteins defined by its ability to directly bind PKA. AKAPs tether PKA to specific subcellular compartments, and they bind further interaction partners to create local signalling hubs. The recent discovery of new AKAPs and advances in the field that shed light on the relevance of these hubs for human disease highlight unique opportunities for pharmacological modulation. This review exemplifies how interference with signalling, particularly cAMP signalling, at such hubs can reshape signalling responses and discusses how this could lead to novel pharmacological concepts for the treatment of disease with an unmet medical need such as cardiovascular disease and cancer.

Topics: A Kinase Anchor Proteins; Amino Acid Sequence; Animals; Antineoplastic Agents; Cardiovascular Agents; Cardiovascular Diseases; Conserved Sequence; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Humans; Molecular Sequence Data; Molecular Targeted Therapy; Neoplasms; Protein Interaction Maps; Second Messenger Systems

Adherence to medication is generally defined as the extent to which people take medications as prescribed by their healthcare providers. It can be assessed in many ways (e.g., by self-reporting, pill counting, direct observation, electronic monitoring, or by pharmacy records). This overview reports effects of prompting mechanisms on adherence to cardiovascular medications, however adherence has been measured.. We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of prompting mechanisms to improve adherence to long-term medication for cardiovascular disease in adults? We searched Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).. At this update, searching of electronic databases retrieved 174 studies. After deduplication and removal of conference abstracts, 80 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 45 studies and the further review of 35 full publications. Of the 35 full articles evaluated, one RCT was added at this update. We performed a GRADE evaluation of seven PICO combinations.. In this systematic overview, we categorised the efficacy for seven comparisons based on information relating to the effectiveness and safety of prompting mechanisms, alone and in combination with reminder packaging or patient education.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Packaging; Humans; Medication Adherence; Patient Education as Topic; Reminder Systems

Hypertension is one of the major risk factor able to promote development and progression of several cardiovascular diseases, including left ventricular hypertrophy and dysfunction, myocardial infarction, stroke, and congestive heart failure. Also, it is one of the major driven of high cardiovascular risk profile in patients with metabolic complications, including obesity, metabolic syndrome and diabetes, as well as in those with renal disease. Thus, effective control of hypertension is a key factor for any preventing strategy aimed at reducing the burden of hypertension-related cardiovascular diseases in the clinical practice. Among various regulatory and contra-regulatory systems involved in the pathogenesis of cardiovascular and renal diseases, renin-angiotensin system (RAS) plays a major role. However, despite the identification of renin and the availability of various assays for measuring its plasma activity, the specific pathophysiological role of RAS has not yet fully characterized. In the last years, however, several notions on the RAS have been improved by the results of large, randomized clinical trials, performed in different clinical settings and in different populations treated with RAS inhibiting drugs, including angiotensin converting enzyme (ACE) inhibitors and antagonists of the AT1 receptor for angiotensin II (ARBs). These findings suggest that the RAS should be considered to have a central role in the pathogenesis of different cardiovascular diseases, for both therapeutic and preventive purposes, without having to measure its level of activation in each patient. The present document will discuss the most critical issues of the pathogenesis of different cardiovascular diseases with a specific focus on RAS blocking agents, including ACE inhibitors and ARBs, in the light of the most recent evidence supporting the use of these drugs in the clinical management of hypertension and hypertension-related cardiovascular diseases.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Arterial Pressure; Cardiovascular Agents; Cardiovascular Diseases; Humans; Kidney; Renin-Angiotensin System; Treatment Outcome; Ventricular Function, Left

The sympathetic nervous exerts a key role in cardiovascular homeostasis control by regulating cardiac output, systemic vascular resistance, heart rate and blood pressure.. Data collected during the past 30 years have unequivocally shown that in a considerable number of cardiovascular as well as noncardiovascular disease there is a marked activation of the sympathetic nervous system which exerts in the long-term period unfavourable haemodynamic, metabolic, cardiovascular and renal effects.. This paper will review the current knowledge on the alterations in sympathetic function described in cardiovascular disease, with particular focus on hypertension, heart failure and myocardial infarction.. The consequences of the phoenomenon will be discussed together with its therapeutic implications. This will be done by examining the impact of nonpharmacological as well as pharmacological interventions on sympathetic cardiovascular drive. The effects of new invasive approaches, such as carotid baroreceptor stimulation as well as renal nerves ablation, will be also briefly discussed.

Topics: Autonomic Nervous System Diseases; Cardiovascular Agents; Cardiovascular Diseases; Electric Stimulation Therapy; Heart Failure; Humans; Hypertension; Myocardial Infarction; Pressoreceptors; Sympathectomy

This paper contains discussion of application of methods of assessment of vascular stiffness in clinical practice, comparison of such parameters as pulse wave velocity, ankle-brachial and cardio-ankle vascular index (CAVI), as well as analysis of advantages of cardio-ankle CAVI for diagnosis, evaluation of effectiveness of treatment, and prognosis in various cardiovascular diseases.

Topics: Blood Flow Velocity; Blood Pressure Determination; Cardiovascular Agents; Cardiovascular Diseases; Humans; Prognosis; Pulse Wave Analysis; Vascular Stiffness

Cardiovascular diseases are the major cause of non-communicable illness in both developing and developed nations, representing 30% of global deaths. New therapeutic approaches are desperately needed. Nanomedicine represents one such approach, and involves using molecular entities on the scale of 10-150 nanometers, for purposes of diagnosing, treating, and preventing disease. This review provides a basic overview of nanotechnology, then reviews specific applications of nanotechnology to cardiovascular diseases. Most research has focused on diagnosing and treating atherosclerosis using nanoparticles (NPs). However, researchers are beginning to study NPs for use in acute coronary syndromes, revascularization procedures, and heart failure. Antimicrobial NPs directed at biofilms likely have applicability to identifying and treating endocarditis. Despite the large disease burden of cardiovascular diseases, there are fewer researchers and less funding being applied to this research. Additional investment in NP therapies would pay great dividends once these therapies come of age.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Nanomedicine; Nanoparticles; Nanotechnology; Particle Size

Medicinal chemistry has been transformed by major technological and conceptual innovations over the last three decades: structural biology and bioinformatics, structure and property based molecular design, the concepts of multidimensional optimization (MDO), in silico and experimental high-throughput molecular property analysis. The novel technologies advanced gradually and in synergy with biology and Roche has been at the forefront. Applications in drug discovery programs towards new medicines in cardiovascular and metabolic diseases are highlighted to show impact and advancement: the early discovery of endothelin antagonists for endothelial dysfunction (Bosentan), 11-beta hydroxysteroid dehydrogenase (11β-HSD1) inhibitors for dysregulated cellular glucocorticoid tonus (type 2 diabetes and metabolic syndrome) and non-covalent hormone sensitive lipase (HSL) inhibitors to study the scope of direct inhibition of lipolysis in the conceptual frame of lipotoxicity and type 2 diabetes.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Chemistry, Pharmaceutical; Drug Delivery Systems; Drug Design; Humans; Metabolic Diseases

During the last decade, there has been a tremendous effort to develop different cardiovascular polypills in response to the upsurge in global cardiovascular disease worldwide. The pharmacological development of such a strategy has proven to be extremely complex from a formulation standpoint. Not all drugs are suitable for use in a polypill because of potential drug incompatibilities between them. Candidate agents must be safe, well tolerated, effective, guideline recommended and physiochemically compatible with the other components of the pill. The Fuster-CNIC-Ferrer cardiovascular (CV) polypill has been found to be the first-in-class polypill to be approved and commercialized in Europe and Latinamerican Countries. In this article, we review the pharmacological properties of its three components, including the clinical evidence supporting their use in patients with established cardiovascular disease, their pharmacokinetic properties, adverse effects, drug interactions and contraindications.

Topics: Aspirin; Atorvastatin; Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Humans; Ramipril; Secondary Prevention

Cardiovascular risk modification in terms of comprehensive medical therapy (antithrombotic therapy, lipid-lowering therapy, antihypertensive medication) and lifestyle modification (healthy diet, regular exercise, weight loss, smoking cessation) is the cornerstone of secondary prevention. It is now clear that even in those undergoing PCI or bypass surgery, appropriate lifestyle modification and aggressive medical therapy are paramount for optimizing long-term outcomes. However, what has emerged from studies that examined the role of medical therapy in the context of coronary heart disease is that only ∼50% of the patients in these studies are achieving target treatment goals for blood pressure, lipid and glycemic control. Non-adherence is thought to be a very large contributor to this problem; across all health-care categories, non-adherence is estimated to account for $290 billion of annual health-care expenditure in the United States and €1.25 billion in European Union, with poor adherence to CVD medication accounting for 9% of all European CVD events. Socioeconomic factors may have a role in patients' discontinuing their medications, and a major initiative to combat this problem is the increasing focus on the polypill. The idea of combining numerous medications into a single tablet to reduce CV risk was first proposed more than a decade ago. This combined formulation not only significantly enhances patient convenience and adherence but also drives savings for the healthcare systems. Several randomized clinical trials have consistently demonstrated the effects of polypills on CV risk factors and adherence, and major trials are underway to study the effect on hard clinical outcomes.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cost of Illness; Drug Combinations; Humans; Medication Adherence; Secondary Prevention

Cardiovascular disease (CVD), including ischaemic heart disease (IHD) and heart failure (HF), and chronic obstructive pulmonary disease (COPD) are often concomitant because they share both risk factors (smoke) and pathological pathways (systemic inflammation). Cardiovascular disease and COPD association is increasing overtime. Several registries clearly showed a negative impact on the clinical outcome of the concomitant presence of CVD and COPD. Patients with CVD and COPD present an increased risk for myocardial infarction, HF, and hospital admission for acute exacerbation of COPD, with a negative impact on prognosis. To reduce the effect of this negative association, it is of paramount importance the pharmacological treatment with both cardiovascular and respiratory drugs, according to current guidelines. Nevertheless, several registries and studies showed that evidence-based drugs (both cardiovascular and respiratory) are often under administered in this subset of patients. In this overview, we summarize the available data regarding the use of cardiovascular drugs (antiplatelet agents, angiotensin converting enzyme inhibitors, β-blockers, and statins) in COPD patients, with or without concomitant IHD. Furthermore, we report advantages and disadvantages of respiratory drugs (β2 agonists, anti-cholinergics, and corticosteroids) administration in COPD patients with CVD.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Pulmonary Disease, Chronic Obstructive; Registries

Whether systemic treatments for psoriasis or psoriatic arthritis affect cardiovascular comorbidities is a clinically significant question.. To examine the effects of biologic agents and other Disease-Modifying Antirheumatic Drugs (DMARDs) used to treat psoriasis and psoriatic arthritis on cardiovascular risk factors and adverse cardiovascular outcomes.. MEDLINE (1980-October 2012), Web of Science, the EULAR abstract database, and the AAD annual meeting abstract archive were searched for studies evaluating biologic and other DMARD therapy for psoriasis and psoriatic arthritis that reported cardiovascular events as primary outcomes.. From 20 studies that met the search criteria for the review, 81,469 patients with psoriasis and/or psoriatic arthritis were included in the data synthesis of the current literature. While the data on the cardioprotective effect of methotrexate exist in patients with rheumatoid arthritis, its effect on the psoriasis and psoriatic arthritis populations with regards to cardiovascular outcomes are inconclusive at this time. The association of hypertension with long-term cyclosporine use prompts discontinuation of cyclosporine in selected patients. The use of TNF inhibitors may be associated with reduced risk of adverse cardiovascular events in preliminary epidemiologic studies; however, large randomized controlled trials and epidemiologic studies with well-characterized populations will be necessary to elucidate their exact effects. The short-term data regarding the safety of IL-12/23 inhibitors showed that, to date, there are no increased cardiovascular events compared to the general population.. To date, epidemiologic data is insufficient to reach definitive conclusions with regards to the effects of biologics and other DMARDs on cardiovascular outcomes in psoriasis and psoriatic arthritis patients. Adequately powered, long-term, controlled studies are necessary to determine the cardioprotective effects of TNF inhibitors observed in preliminary studies on psoriasis and psoriatic arthritis populations.

Topics: Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Psoriatic; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Humans; Psoriasis; Recombinant Fusion Proteins; Risk Factors

Epidemiologic data support the association of psoriasis and psoriatic arthritis with adverse cardiovascular outcomes. Shared pathogenesis in endothelial dysfunction may underlie psoriasis and atherosclerosis. Tumor necrosis factor (TNF) inhibitors may modulate endothelial dysfunction seen in patients with psoriasis and psoriatic arthritis.. To perform a systematic review that investigated endothelial function in psoriasis and psoriatic arthritis and the effect of TNF inhibitors on endothelial function in psoriasis and psoriatic arthritis.. MEDLINE (1980-October 2012), Web of Science, the EULAR abstract database, and the AAD annual meeting abstract archive were searched for cross-sectional or longitudinal studies that 1) examined endothelial function in patients with psoriasis or psoriatic arthritis, or 2) investigated the effect of TNF inhibitor therapy on endothelial function.. Twenty articles and four abstracts with 2261 patients evaluated endothelial function in psoriasis and psoriatic arthritis, which was measured by pulse wave velocity, flow-mediated dilation, nitroglycerine-induced vasodilation, carotid intima-media thickness, peripheral arterial tonometry, or aortic stiffness parameters. The majority of the data suggests that patients with psoriasis and psoriatic arthritis have significantly increased arterial stiffness, impaired endothelial-dependent vasodilation, increased carotid intima-media thickness, and decreased aortic elasticity compared to the general population. Two out of three studies showed that TNF inhibitors improved endothelial function in psoriasis and psoriatic arthritis.. Measurements of endothelial function were not standardized across studies.. The preponderance of literature suggests that endothelial function is significantly impaired in patients with psoriasis and psoriatic arthritis compared to the general population. Preliminary evidence suggests that TNF inhibitors may improve endothelial function in the psoriasis and psoriatic arthritis populations.

Topics: Adalimumab; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Psoriatic; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Etanercept; Evidence-Based Medicine; Humans; Immunoglobulin G; Infliximab; Psoriasis; Receptors, Tumor Necrosis Factor; Risk Factors; Systemic Vasculitis; Tumor Necrosis Factor-alpha

In recent years, the scientific community has gained significant insight into the complex interaction between inflammation and the cardiovascular system in patients with rheumatoid arthritis (RA), which leads to increased cardiovascular (CV) morbidity and mortality in these patients. Our common understanding of this association is that persistent inflammation contributes to the development of premature atherosclerosis. Consequently, the question arises whether control of inflammation with antirheumatic treatment will be able to improve CV outcome. While there are a lot of data that demonstrate improvement of numerous CV surrogate markers in patients treated with virtually all antirheumatic drug classes, there is much less information about the possible translation of these beneficial effects into improved CV outcome. In summary, the published evidence suggests that tumor necrosis factor (TNF) alpha inhibitors may improve CV outcome. The same is true for methotrexate (MTX). However, it is not clear whether MTX works via suppression of inflammation or through drug specific mechanisms. For other traditional disease-modifying antirheumatic drugs and biologic therapies, there are no convincing data for improved CV outcome. Only a few drugs (glucocorticoids and NSAIDs) have been associated with increased CV risk. Treating RA aggressively, as recommended by current guidelines, is likely to have a beneficial effect on CV outcomes.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Arthritis, Rheumatoid; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Molecular Targeted Therapy; Rheumatoid Vasculitis; Treatment Outcome

There are numerous national and international guidelines on the use of aspirin for the primary prevention of cardiovascular disease. Given the uncertainties about aspirin in primary prevention, our aim was to compare the recommendations and the reported evidence in guidelines for the treatment with aspirin of subjects free of cardiovascular disease with or without diabetes.. Guidelines were retrieved through Medline and other electronic databases and through a web-based search for guideline development organizations. The content of the recommendations and the underlying evidence were analysed with qualitative and bibliometric methods. In addition, we searched for recent studies to assess whether they underscore the current recommendations. We included 12 guidelines: six European, three North American, and one each from New Zealand, Australia, and the World Health Organization. Recommendations differ with regard to outcome (morbidity, mortality), time span (years of risk), cut-off percentage between high and low risk, and the dose of aspirin. Most guidelines are not in line with recent evidence, which show that aspirin is of uncertain net value as the reduction in absolute risk for occlusive CV events needs to be weighed against an increase in the risk of major bleeds.. We found conflicting recommendations in various guidelines about the use of aspirin for the primary prevention of cardiovascular events, which reflect differences in selection of the evidence and in the timing of publication. According to recent evidence, in general, the use of aspirin seems no longer justifiable in primary prevention in patients with or without diabetes.

Topics: Aspirin; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus; Evidence-Based Medicine; Hemorrhage; Humans; Patient Selection; Practice Guidelines as Topic; Primary Prevention; Risk Assessment; Risk Factors; Treatment Outcome

Many experimental and clinical studies have demonstrated that elevated leptin concentration in patients with obesity/metabolic syndrome contributes to the pathogenesis of cardiovascular disorders including arterial hypertension, atherosclerosis, restenosis after coronary angioplasty and myocardial hypertrophy. Receptor tyrosine kinases belonging to the ErbB family, especially ErbB1 (epidermal growth factor receptor) and ErbB2 are abundantly expressed in the blood vessels and the heart. EGFR is activated not only by its multiple peptide ligands but also by many other factors including angiotensin II, endothelin-1, norepinephrine, thrombin and prorenin; the phenomenon referred to as "transactivation". Augmented EGFR signaling contributes to abnormalities of vascular tone and renal sodium handling as well as vascular remodeling and myocardial hypertrophy through various intracellular mechanisms, in particular extracellular signal-regulated kinases (ERK) and phosphoinositide 3-kinase (PI3K). Recent experimental studies indicate that chronically elevated leptin transactivates the EGFR through the mechanisms requiring reactive oxygen species and cytosolic tyrosine kinase, c-Src. In addition, hyperleptinemia increases ErbB2 activity in the arterial wall. Stimulation of EGFR and ErbB2 downstream signaling pathways such as ERK and PI3K in the vascular wall and the kidney may contribute to the increase in vascular tone, enhanced tubular sodium reabsorption as well as vascular and renal lesions in hyperleptinemic obese subjects.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; ErbB Receptors; Humans; Leptin; Receptor, ErbB-2; Receptor, ErbB-3; Receptor, ErbB-4; Signal Transduction; Transcriptional Activation; Up-Regulation

Cardiovascular diseases are the leading causes of death in men and women in industrialized countries. While the effects of biological sex on cardiovascular pathophysiology have long been known, the sex-specific mechanisms mediating these processes have been further elucidated over recent years. This review aims at analysing the sex-based differences in cardiac structure and function in adult mammals, and the sex-based differences in the main molecular mechanisms involved in the response of the heart to pathological situations. It emerged from this review that the sex-based difference is a variable that should be dealt with, not only in basic science or clinical research, but also with regards to therapeutic approaches.

Topics: Aging; Animals; Cardiovascular Agents; Cardiovascular Diseases; Female; Heart; Humans; Male; Models, Biological; Myocardium; Neurotransmitter Agents; Sex Characteristics

Pharmacological response depends on multiple factors and one of them is sex-gender. Data on the specific effects of sex-gender on pharmacokinetics, as well as the safety and efficacy of numerous medications, are beginning to emerge. Nevertheless, the recruitment of women for clinical research is inadequate, especially during the first phases. In general, pharmacokinetic differences between males and females are more numerous and consistent than disparities in pharmacodynamics. However, sex-gender pharmacodynamic differences are now increasingly being identified at the molecular level. It is now even becoming apparent that sex-gender influences pharmacogenomics and pharmacogenetics. Sex-related differences have been reported for several parameters, and it is consistently shown that women have a worse safety profile, with drug adverse reactions being more frequent and severe in women than in men. Overall, the pharmacological status of women is less well studied than that of men and deserves much more attention. The design of clinical and preclinical studies should have a sex-gender-based approach with the aim of tailoring therapies to an individual's needs and concerns.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Evidence-Based Medicine; Female; Humans; Male; Pharmacogenetics; Precision Medicine; Research Design; Sex Characteristics; Vascular Resistance

The beta isoform of Neuregulin-1 (NRG-1β), along with its receptors (ErbB2-4), is required for cardiac development. NRG-1β, as well as the ErbB2 and ErbB4 receptors, is also essential for maintenance of adult heart function. These observations have led to its evaluation as a therapeutic for heart failure. Animal studies and ongoing clinical trials have demonstrated beneficial effects of two forms of recombinant NRG-1β on cardiac function. In addition to the possible role for recombinant NRG-1βs as heart failure therapies, endogenous NRG-1β/ErbB signaling appears to play a role in restoring cardiac function after injury. The potential mechanisms by which NRG-1β may act as both a therapy and a mediator of reverse remodeling remain incompletely understood. In addition to direct effects on cardiac myocytes NRG-1β acts on the vasculature, interstitium, cardiac fibroblasts, and hematopoietic and immune cells, which, collectively, may contribute to NRG-1β's role in maintaining cardiac structure and function, as well as mediating reverse remodeling.

Topics: Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; ErbB Receptors; Heart Failure; Humans; Neuregulin-1; Recombinant Proteins; Signal Transduction; Ventricular Remodeling

We aim to demonstrate the effect of placebo adherence on reducing CV mortality.. Good adherence, whether to drug or placebo treatment, is associated with lower CV mortality. However, current evidence for the positive effect of placebo adherence on reducing CV mortality is relatively weak.. We conducted a fixed-effect meta-analysis of eight randomized clinical trials to evaluate the effect of placebo adherence on reducing CV mortality. We made a comparison between good placebo adherence and poor drug adherence.. Compared with poor adherence to drug treatment, good adherence to placebo treatment was associated with lower CV mortality (OR = 0.68, 95% CI 0.60-0.77).. Good adherence to placebo has a positive effect on reducing CV mortality. The effect of adherence on reducing CV mortality may be independent of the drug effect.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Chi-Square Distribution; Humans; Medication Adherence; Odds Ratio; Placebo Effect; Placebos; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

Combination pills containing aspirin, multiple blood pressure (BP) lowering drugs, and a statin have demonstrated safety, substantial risk factor reductions, and improved medication adherence in the prevention of cardiovascular disease (CVD). The individual medications in combination pills are already recommended for use together in secondary CVD prevention. Therefore, current information on their pharmacokinetics, impact on the risk factors, and tolerability should be sufficient to persuade regulators and clinicians to use fixed-dose combination pills in high-risk individuals, such as in secondary prevention. Long-term use of these medicines, in a polypill or otherwise, is expected to reduce CVD risk by at least 50-60% in such groups. This risk reduction needs confirmation in prospective randomized trials for populations for whom concomitant use of the medications is not currently recommended (e.g. primary prevention). Given their additive benefits, the combined estimated relative risk reduction (RRR) in CVD from both lifestyle modification and a combination pill is expected to be 70-80%. The first of several barriers to the widespread use of combination therapy in CVD prevention is physician reluctance to use combination pills. This reluctance may originate from the belief that lifestyle modification should take precedence, and that medications should be introduced one drug at a time, instead of regarding combination pills and lifestyle modification as complementary and additive. Second, widespread availability of combination pills is also impeded by the reluctance of large pharmaceutical companies to invest in development of novel co-formulations of generic (or 'mature') drugs. A business model based on 'mass approaches' to drug production, packaging, marketing, and distribution could make the combination pill available at an affordable price, while at the same time providing a viable profit for the manufacturers. A third barrier is regulatory approval for novel multidrug combination pills, as there are few precedents for the approval of combination products with four or more components for CVD. Acceptance of combination therapy in other settings suggests that with concerted efforts by academics, international health agencies, research funding bodies, governments, regulators, and pharmaceutical manufacturers, combination pills for prevention of CVD in those with disease or at high risk (e.g. those with multiple risk factors) can be made available world

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Approval; Drug Combinations; Drug Costs; Evidence-Based Medicine; Humans; Primary Prevention; Randomized Controlled Trials as Topic; Risk Reduction Behavior; Secondary Prevention

Dipeptidyl-peptidase-IV (DPP-IV) inhibitors are a new class of oral hypoglycaemic agents recently approved for the management of type 2 diabetes mellitus. Early data suggested that they had a positive impact on the cardiovascular system: treatment appeared to result in improvements in cardiac performance, blood pressure and lipid levels. However, recent clinical findings bring this into question. Our understanding of the physiological actions of these agents is complicated by the fact that DPP-IV has a wide range of substrates in addition to glucagon-like peptide 1. Indeed, DPP-IV inhibition alters concentrations of a wide variety of cytokines and neuropeptides. A deeper understanding of the physiological effects of these drugs as well as their true impact on cardiovascular risk is needed before consideration can be given to extending their use beyond the treatment of diabetes.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Signal Transduction; Treatment Outcome

During 2013, a meta-analysis provided evidence that cystatin C improves estimated glomerular filtration rate in cardiovascular risk categorization in chronic kidney disease (CKD). Another study showed that low diastolic blood pressure (DBP) is harmful in patients with CKD, challenging the paradigm of treating elevated systolic blood pressure regardless of DBP. Overall, mortality rates in CKD have decreased but further improvement is required.

Topics: Animals; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Disease Progression; Glomerular Filtration Rate; Humans; Incidence; Prevalence; Prognosis; Renal Insufficiency, Chronic; Risk Factors; Survival Rate

Patients with Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) have a significantly increased risk of cardiovascular disease (CVD). The reason for this is unclear but may be due, at least in part, to the failure of endothelial repair mechanisms. Over the last 15 years there has been much interest in the mechanisms of endothelial renewal and its potential as a therapy for CVD. In the circulation there are two distinct populations of cells; myeloid angiogenic cells (MACs) which augment repair by the paracrine secretion of angiogenic factors, and outgrowth endothelial cells (OECs) which are true endothelial progenitor cells (EPCs) and promote vasculogenesis by differentiating into mature endothelium. There are marked abnormalities in the number and function of these cells in patients with RA and SLE. Inflammatory cytokines including interferon-alpha (IFNα) and tumour-necrosis factor alpha (TNFα) both impair MAC and OEC function ex vivo and may therefore contribute to the CVD risk in these patients. Whilst administration of mononuclear cells, MACs and other progenitors has improved cardiovascular outcomes in the acute setting, this is not a viable option in chronic disease. The pharmacological manipulation of MAC/OEC function in vivo however has the potential to significantly improve endothelial repair and thus reduce CVD in this high risk population.

Topics: Angiogenic Proteins; Animals; Arthritis, Rheumatoid; Cardiovascular Agents; Cardiovascular Diseases; Endothelial Cells; Humans; Immunosuppressive Agents; Inflammation Mediators; Lupus Erythematosus, Systemic; Regeneration; Stem Cell Transplantation; Stem Cells

Pharmacological prophylaxis has been proven to reduce the risk of cardiovascular events in patients with atherosclerotic occlusive arterial disease. However, the role of prophylaxis in patients with abdominal aortic aneurysm (AAA) remains unclear. Several studies have shown that despite successful repair, those with AAA have a poorer rate of survival than healthy controls. People with AAA have an increased prevalence of coronary heart disease and risk of cardiovascular events. Despite this association, little is known about the effectiveness of pharmacological prophylaxis in reducing cardiovascular risk in people with AAA.. To determine the long-term effectiveness of antiplatelet, antihypertensive or lipid-lowering medication in reducing mortality and cardiovascular events in people with abdominal aortic aneurysm (AAA).. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2013) and CENTRAL (2013, Issue 3). Reference lists of relevant articles were also checked.. Randomised controlled trials in which people with AAA were randomly allocated to one prophylactic treatment versus another, a different regimen of the same treatment, a placebo, or no treatment were eligible for inclusion in this review. Primary outcomes included all-cause mortality and cardiovascular mortality.. Selection of the studies, quality assessment and data extraction were completed independently by two review authors. Any disagreements were resolved by discussion. Only one study was included in the review, therefore meta-analysis could not be performed.. One randomised controlled study was included in the review. A subgroup of 227 patients with AAA received either metoprolol (N = 111) or placebo (N = 116). There was no clear evidence that metoprolol reduced all-cause mortality (odds ratio (OR) 0.17, 95% confidence interval (CI) 0.02 to 1.41), cardiovascular death (OR 0.20, 95% CI 0.02 to 1.76), AAA-related death (OR 1.05, 95% CI 0.06 to 16.92) or increased nonfatal cardiovascular events (OR 1.44, 95% CI 0.58 to 3.57) 30 days postoperatively. Furthermore, at six months postoperatively, estimated effects were compatible with benefit and harm for all-cause mortality (OR 0.71, 95% CI 0.26 to 1.95), cardiovascular death (OR 0.73, 95% CI 0.23 to 2.39) and nonfatal cardiovascular events (OR 1.41, 95% CI 0.59 to 3.35). Adverse drug effects were reported for the whole study population and were not available for the subgroup of participants with AAA. The study was deemed to be at a generally low risk of bias.. Due to the limited number of trials, there is insufficient evidence to draw any conclusions about the effectiveness of cardiovascular prophylaxis in reducing mortality and cardiovascular events in people with AAA. Further good-quality randomised controlled trials examining many types of prophylaxis with long-term follow-up are required before firm conclusions can be made.

Topics: Antihypertensive Agents; Aortic Aneurysm, Abdominal; Cardiovascular Agents; Cardiovascular Diseases; Cause of Death; Humans; Metoprolol; Randomized Controlled Trials as Topic; Risk Factors

Although primarily a lung disease, chronic obstructive pulmonary disease (COPD) is now recognized to have extrapulmonary effects on distal organs, the so-called systemic effects and comorbidities of COPD. Skeletal muscle dysfunction, nutritional abnormalities including weight loss, cardiovascular complications, metabolic complications, and osteoporosis, among others, are all well-recognized associations in COPD. These extrapulmonary effects add to the burden of mortality and morbidity in COPD and therefore should be actively looked for, assessed, and treated.

Topics: Anemia; Cardiovascular Agents; Cardiovascular Diseases; Humans; Lung Neoplasms; Muscular Atrophy; Osteoporosis; Pulmonary Disease, Chronic Obstructive

Three innovative pharmaceuticals which might play an important role in the field of cardiology in the near future were recently tested in large clinical studies. Serelaxin, a vasoactive hormone peptide that is produced during pregnancy, reduces vessel resistance, increases cardiac output, and improves renal function. Lately, it was demonstrated that serelaxin significantly reduces congestion symptoms in patients with acute heart failure. As a secondary endpoint the mortality at day 180 was reduced. Therefore, serelaxin seems to be a promising new drug for the treatment of acute heart failure which might have a prognostic impact. Edoxaban is a selective factor Xa inhibitor, which inhibits thrombin production and thrombus formation. Two recently published studies reported that edoxaban is at least as effective as the vitamin K antagonist warfarin in prevention and treatment of venous thromboembolism and in the prevention of stroke and systemic embolism due to nonvalvular atrial fibrillation. Compared to warfarin, edoxaban significantly exhibited less frequent severe bleeding complications. Edoxaban will probably soon be the fourth new oral anticoagulant available for patients. The serine protease proprotein convertase subtilisin/kexin 9 (PCSK9) reduces the ability of the liver to bind low-density lipoprotein cholesterol (LDL-C) and to remove it from the circulation. Recently, a monoclonal antibody for PCSK9 was developed which induces a LDL-C plasma level reduction up to 73 % and also decreases lipoprotein(a) and apolipoprotein B. PCSK9 inhibition is a promising new mechanism for LDL-C reduction and the corresponding drug will be presumably approved soon by the regulatory authorities.

Topics: Antibodies, Monoclonal; Atrial Fibrillation; Cardiovascular Agents; Cardiovascular Diseases; Cholesterol, LDL; Clinical Trials, Phase III as Topic; Cyclophosphamide; Drug Approval; Drugs, Investigational; Female; Heart Failure; Humans; Hypercholesterolemia; Pregnancy; Proprotein Convertase 9; Proprotein Convertases; Recombinant Proteins; Relaxin; Serine Endopeptidases; Stroke; Venous Thromboembolism

The prevalence of type 2 diabetes is increasing worldwide, and diabetes is a strong adverse prognostic factor among patients with cardiovascular (CV) disease. Four classes of drugs that are commonly used for CV risk reduction, statins, niacin, thiazide diuretics, and ß-blockers, have been shown to increase the risk of new-onset diabetes (NOD) by 9% to 43% in meta-analyses or large-scale clinical trials. Clinical predictors for drug-related NOD appear to be similar to the predictors that have been described for NOD unrelated to drugs: fasting blood glucose >100 mg/dL and features of the metabolic syndrome such as body mass index >30 kg/m(2), serum triglycerides >150 mg/dL, and elevated blood pressure, among others. The mechanisms whereby these drugs increase the risk of NOD are incompletely understood, although different hypotheses have been suggested. Lifestyle intervention consisting of diet and exercise has been shown in multiple studies to reduce the risk of NOD by approximately 50%, with persistent benefit during long-term follow-up. In patients at high risk for NOD, niacin should be avoided, and for hypertension, an angiotensin-converting enzyme inhibitor or even a ß1-selective blocker might be a better choice than a standard ß-blocker. For thiazide diuretics and particularly statins, benefit in terms of CV event reduction outweighs the risk of NOD.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Global Health; Humans; Prevalence; Risk Factors

Stroke is a disease with significant morbidity, mortality, and economic and social impacts. It is a complex entity whose pathogenesis involves multiple environmental and genetic factors, with the latter having a role in up to 50% of strokes. The objective of the review is to analyze the available methods for the genetic diagnosis including linkage studies of variation in copy number, gene - candidate approximations, or whole genome (GWAS) and polymorphisms associated with its pathogenesis. We describe several single nucleotide polymorphisms (SNPs) associated with stroke in association studies and GWAS such as SNPs of angiotensin, the aldosterone system, paraoxonases, nitric oxide, coagulation, and fibrinolysis system, among others. We also analyze the role of certain polymorphisms in the phenotype of the carotid plaque, intracranial aneurysms and lobar hemorrhages. Pharmacogenomic aspects in which SNPs affect the response and safety regarding the use of different drugs are also described. Several SNPs that significantly contribute to the risk of stroke are also described. The advent of techniques like GWAS has contributed to the understanding of genetics and pharmacogenomics of stroke.

Topics: Biotransformation; Cardiovascular Agents; Cardiovascular Diseases; Gene Dosage; Genetic Linkage; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Molecular Diagnostic Techniques; Pharmacogenetics; Polymorphism, Single Nucleotide; Stroke

The obstructive sleep apnoea syndrome (OSAS) had become a major public health concern in modern society due to its high prevalence but, above all, to its associated morbidity, especially cardiovascular.. Untreated OSAS is associated with an increased incidence of fatal (myocardial infarction and stroke) (odds ratio: 2.87) and non-fatal cardiovascular events (myocardial infarction, stroke, coronary artery bypass surgery and coronary angiography) (odds ratio: 3.17). Moreover, the prevalence of hypertension in patients with OSAS is high, between 35 and 80%. The pathophysiological mechanisms leading to these complications are mainly due to intermittent hypoxia secondary to repeated episodes of apnoea/hypopnoea during sleep. These mechanisms include sympathetic hyperactivation, impairment of vasomotor reactivity, vascular inflammation, oxidative stress and metabolic disorders. In patients with OSAS, the impact of continuous positive pressure is proven in terms of prevention of cardiovascular events although blood pressure reduction is limited. Obviously these effects are proportional to observance.. OSAS does increase the cardiovascular risk, independently of other risk factors. Although the impact of treatment is relatively low in decreasing blood pressure, it seems essentially effective in preventing cardiovascular morbidity. Therefore, OSAS screening, and the association of specific treatments in cardio-metabolic patients and OSAS patients respectively, should be included in clinical strategies.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Comorbidity; Continuous Positive Airway Pressure; Endothelium, Vascular; Glucose Intolerance; Humans; Hypertension; Hypoxia; Metabolic Syndrome; Nitric Oxide; Obesity; Oxidative Stress; Prevalence; Sleep Apnea, Obstructive; Sympathetic Nervous System; Vasculitis

The renin-angiotensin system (RAS) has pivotal roles in the regulation of normal physiology and the pathogenesis of cardiovascular disease. Angiotensin-converting enzyme (ACE) 2, and its product angiotensin 1-7, are thought to have counteracting effects against the adverse actions of other, better known and understood, members of the RAS. The physiological and pathological importance of ACE2 and angiotensin 1-7 in the cardiovascular system are not completely understood, but numerous experimental studies have indicated that these components have protective effects in the heart and blood vessels. Here, we provide an overview on the basic properties of ACE2 and angiotensin 1-7 and a summary of the evidence from experimental and clinical studies of various pathological conditions, such as hypertension, atherosclerosis, myocardial remodelling, heart failure, ischaemic stroke, and diabetes mellitus. ACE2-mediated catabolism of angiotensin II is likely to have a major role in cardiovascular protection, whereas the relevant functions and signalling mechanisms of actions induced by angiotensin 1-7 have not been conclusively determined. The ACE2-angiotensin 1-7 pathway, however, might provide a useful therapeutic target for the treatment of cardiovascular disease, especially in patients with overactive RAS.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Humans; Peptide Fragments; Peptidyl-Dipeptidase A

Ischemic heart disease and stroke are the leading causes of death worldwide. What was once thought to be an endemic disease of high income countries has become a global epidemic, as low and middle income countries have adopted Western lifestyles, to the point that noncommunicable diseases are now the main cause of death in these regions, above and beyond communicable diseases, malnutrition, and injury. As a result, a large proportion of individuals at high 10-year risk of a cardiovascular event live in low- and middle-income countries, and the most of all cardiovascular events occur in developing countries. A large amount of evidence supports the use of pharmacological treatment for the prevention of cardiovascular death in this population, including antiplatelet drugs, β-blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors, however, the efficacy of cardiovascular event prevention is hampered by several problems, including inadequate prescription of medication, poor adherence to treatment, limited availability of medications, and unaffordable cost of treatment. Here we examine the use of fixed-dose combination therapy, and how this therapy could improve adherence to treatment, reduce the cost, and improve treatment affordability in low-income countries.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cause of Death; Clinical Trials as Topic; Drug Combinations; Global Health; Humans; Risk Factors; Socioeconomic Factors; Survival Rate

In 2012, the United Nations estimated that globally, 34 million people were living with human immunodeficiency virus (HIV) infection at the end of 2011. About 6.5% of AIDS-related mortality is attributable to cardiovascular disease. HIV related cardiovascular disease is diverse. In this review we explore the different disease states associated with HIV such as cardiomyopathy, coronary artery disease, dyslipidemia, electrocardiographic abnormalities, prolonged QT interval and sudden death. The pathophysiology of these numerous diseases is complex and multifactorial. Current management of these patients is challenging due to multiple drug-drug interactions and side effects. However, the approach to prevention is quite familiar, taking on the same rules that apply for any patient to minimize cardiovascular disease risk. The challenges are many, therefore for HIV patients who present after a cardiovascular event, or for prevention of cardiovascular disease, the concept of a heart team is essential, where cardiovascular specialists and the HIV care team work side by side to ensure safety of medications (avoid drug interactions) and to institute a goal directed prevention plan of care.

Topics: Anti-Retroviral Agents; Cardiovascular Agents; Cardiovascular Diseases; Chronic Disease; Drug Interactions; HIV Infections; Humans

Cardiovascular diseases (CVD) continue to represent the major cause of death, morbidity and healthcare expenditure worldwide. Current medical therapy fails to effectively halt disease progression and to reduce adverse clinical outcomes, reflecting incomplete understanding of pathomechanisms as well as the need to expand current pharmacotherapeutic strategies. Hypertension and heart failure, the most important CVD entities, are associated with imbalance in neurohormonal systems activity such as the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system and the endothelin system. Blockade of the RAAS constitutes the most successful pharmacotherapeutic concept in hypertension and heart failure to date. The RAAS-opposing natriuretic peptide system constitutes the body's own BP-lowering system, and mediates a multitude of beneficial actions within cardiovascular tissues. The metallopeptidase neprilysin (NEP) hydrolyzes natriuretic peptides. Conceptually, NEP inhibition would increase salutary natriuretic peptide actions in CVD. However, stand-alone NEP inhibitors (NEPi) lacked efficacy beyond standard pharmacotherapy. Combined blockers of NEP and the endothelin system demonstrated efficacy in preclinical studies but have not been evaluated in clinical trials. A decade ago, omapatrilat and other dual-acting NEPi-ACEi (vasopeptidase-inhibitors) were promising agents for hypertension and heart failure. Despite greater efficacy, development of vasopeptidase-inhibitors was halted due to significant off-target effects in some cohorts, most notably increased frequency of angioedema in hypertensive subjects. Novel angiotensin-receptor-neprilysin-inhibitors (ARNi) seek to fully exploit clinical efficacy of combined RAAS-blockade and NEPi-mediated natriuretic peptide augmentation, and hopefully do so with improved clinical safety. We herein review current knowledge of NEPi as stand-alone and combined pharmacotherapeutic agents in hypertension and heart failure.

Topics: Animals; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Drug Therapy, Combination; Heart Failure; Humans; Hypertension; Neprilysin; Renin-Angiotensin System

Cardiovascular diseases (CVDs) remain the major cause of morbidity and mortality globally. Despite the large number of cardiovascular drugs available for pharmacological therapies, factors limiting the efficient oral use are identified, including low water solubility, pre-systemic metabolism, food intake effects and short half-life. Numerous in vivo proof-of-concepts studies are presented to highlight the viability of lipid-based delivery to optimize the oral delivery of cardiovascular drugs. In particular, the key performance enhancement roles of oral lipid-based drug delivery systems (LBDDSs) are identified, which include i) improving the oral bioavailability, ii) sustaining/controlling drug release, iii) improving drug stability, iv) reducing food intake effect, v) targeting to injured sites, and vi) potential for combination therapy. Mechanisms involved in achieving these features, range of applicability, and limits of available systems are detailed. Future research and development efforts to address these issues are discussed, which is of significant value in directing future research work in fostering translation of lipid-based formulations into clinical applications to reduce the prevalence of CVDs.

Topics: Administration, Oral; Biological Availability; Cardiovascular Agents; Cardiovascular Diseases; Delayed-Action Preparations; Drug Carriers; Drug Delivery Systems; Drug Stability; Emulsions; Food-Drug Interactions; Humans; Lipids; Nanoparticles; Solutions; Suspensions

Rural residents face numerous barriers to healthcare access and studies suggest poorer health outcomes for rural patients. Therefore we undertook a systematic review to determine if cardiovascular medication utilization and adherence patterns differ for rural versus urban patients.. A comprehensive search of major electronic datasets was undertaken for controlled clinical trials and observational studies comparing utilization or adherence to cardiovascular medications in rural versus urban adults with cardiovascular disease or diabetes. Two reviewers independently identified citations, extracted data, and evaluated quality using the STROBE checklist. Risk estimates were abstracted and pooled where appropriate using random effects models. Methods and reporting were in accordance with MOOSE guidelines.. Fifty-one studies were included of fair to good quality (median STROBE score 17.5). Although pooled unadjusted analyses suggested that patients in rural areas were less likely to receive evidence-based cardiovascular medications (23 studies, OR 0.88, 95% CI 0.79, 0.98), pooled data from 21 studies adjusted for potential confounders indicated no rural-urban differences (adjusted OR 1.02, 95% CI 0.91, 1.13). The high heterogeneity observed (I(2) = 97%) was partially explained by treatment setting (hospital, ambulatory care, or community-based sample), age, and disease. Adherence did not differ between urban versus rural patients (3 studies, OR 0.94, 95% CI 0.39, 2.27, I(2) = 91%).. We found no consistent differences in rates of cardiovascular medication utilization or adherence among adults with cardiovascular disease or diabetes living in rural versus urban settings. Higher quality evidence is needed to determine if differences truly exist between urban and rural patients in the use of, and adherence to, evidence-based medications.

Topics: Adult; Aged; Aged, 80 and over; Australia; Canada; Cardiovascular Agents; Cardiovascular Diseases; Databases, Factual; Diabetes Mellitus, Type 2; Europe; Female; Humans; Middle Aged; Patient Compliance; Risk Factors; Rural Population; United States; Urban Population

Fibrinogen is cleaved by thrombin to fibrin, which provides the blood clot with its essential structural backbone. As an acute phase protein, the plasma levels of fibrinogen are increased in response to inflammatory conditions. In addition to fibrinogen levels, fibrin clot structure is altered by a number of factors. These include thrombin levels, treatment with common cardiovascular medications, such as aspirin, anticoagulants, statins and fibrates, as well as metabolic disease states such as diabetes mellitus and hyperhomocysteinaemia. In vitro studies of fibrin clot structure can provide information regarding fibre density, clot porosity, the mechanical strength of fibres and fibrinolysis. A change in fibrin clot structure, to a denser clot with smaller pores which is more resistant to lysis, is strongly associated with cardiovascular disease. This pathological change is present in patients with arterial as well as venous diseases, and is also found in a moderate form in relatives of patients with cardiovascular disease. Pharmacological therapies, aimed at both the treatment and prophylaxis of cardiovascular disease, appear to result in positive changes to the fibrin clot structure. As such, therapies aimed at 'normalising' fibrin clot structure may be of benefit in the prevention and treatment of cardiovascular disease.

Topics: Arterial Occlusive Diseases; Blood Coagulation; Cardiovascular Agents; Cardiovascular Diseases; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Humans; Porosity; Venous Thrombosis

Trimetazidine is a cytoprotective drug whose cardiovascular effectiveness, especially in patients with stable ischemic heart disease, has been the source of much controversy in recent years; some have gone so far as to treat the medication as a 'placebo drug' whose new side effects, such as Parkinsonian symptoms, outweigh its benefits. This article is an attempt to present the recent key studies, including meta-analyses, on the use of trimetazidine in chronic heart failure, also in patients with diabetes mellitus and arrhythmia, as well as in peripheral artery disease. This paper also includes the most recent European Society of Cardiology guidelines, including those of 2013, on the use of trimetazidine in cardiovascular disease.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Heart Failure; Humans; Peripheral Arterial Disease; Trimetazidine

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Administration Schedule; Drug Combinations; Humans; Precision Medicine; Randomized Controlled Trials as Topic; Secondary Prevention

The glycocalyx is a jelly layer covering the endothelium constituted by glycosaminoglycans (GAGs), proteoglycans and adsorbed plasma proteins. This structure take part in several physiological and pathological vascular events. The glycocalyx acts as mechanosensor to shear stress and participates to regulation of vascular tone, permeability, coagulation and complement activation. Moreover it regulates the interaction and activation of blood cells with endothelial cells. The presence of a thick, normal glycocalyx is required for physiological vascular functions, whereas these functions are impaired by its damage by noxious agents. Indeed, glycocalyx alterations are involved in the pathogenesis of atherosclerosis, ischemia-reperfusion and diabetic vascular complications. GAGs such as sulodexide are promising agents to control endothelial dysfunction. They act at multiple levels: they promote glycocalyx reconstitution, control glycocalyx degrading enzymes, exert anti-inflammatory effects and have anti-apoptotic and anti-senescence effects on endothelial cells. Clinical studies support the evidence that glycosaminoglycans are useful to restore a normal endothelial function.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Glycocalyx; Glycosaminoglycans; Humans; Proteoglycans; Signal Transduction

Treatment of vascular diseases should be based on established pathophysiological concepts, and this also applies to chronic venous disease (CVD). On the basis of the latest research in this field, this paper summarizes the most advanced pathophysiological knowledge regarding the hemodynamics of the large veins and of the microcirculation, the endothelial function and inflammation, and the use of sulodexide in the treatment of CVD. The emerging theories on the pathophysiology of CVD consider inflammation, endothelial glycocalyx dysfunction, and the consequent changes in the extracellular matrix to play key roles in the development of CVD, and support a renewed interest in the research and application of sulodexide. As part of active approach to the treatment of CVD including edema and trophic venous alterations, sulodexide could help to alleviate progressive signs and symptoms of disease in any clinical CEAP class of CVD, from C1 to C6.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Glycosaminoglycans; Hemodynamics; Humans; Microcirculation; Treatment Outcome; Veins

Administration of drugs and other therapeutic agents has been the central strategy of contemporary medicine for cardiovascular disease. The use of a drug delivery system (DDS) is always demanded to enhance the efficacy and safety of therapeutic agents, and improve the signal-to-noise ratio of imaging agents. Nano-scale materials modify in vivo drug kinetics, depending on (patho)physiological mechanisms such as vascular permeability and incorporation by the mononuclear phagocyte system, which constitute 'passive-targeting' properties of nano-DDS. By contrast, an 'active-targeting' strategy employs a specific targeting structure on nano-DDS, which binds to the target molecule that is specific for a certain disease process, such as tumor specific antigens and the induction of adhesion molecules. In this review, we summarize recent studies that applied nano-DDS for the diagnosis and treatment of cardiovascular disease, especially focusing on atherosclerosis and myocardial ischemia-reperfusion (IR) injury. Pathophysiological changes in atherosclerosis and myocardial IR injury are successfully targeted by nano-DDS and preclinical studies in animals showed positive effects of nano-DDS enhancing efficacy and reducing adverse effects. The development of nano-DDS in clinical medicine is keenly being awaited.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Equipment Design; Humans; Nanoparticles

Cardiovascular disease (CVD) remains still the leading cause of death in the United States, and it is estimated to be the leading cause of death in the developing countries by 2020. In addition, the modifiable cardiovascular risk factors (CVRFs), hypertension, hypercholesterolemia, diabetes, and obesity, have increased significantly and by 2020 will account for 80% of all CVD deaths worldwide. Because the CVD and stroke risk increases significantly for subjects aged >50 years, it has been proposed to treat these subjects with a polypill containing 4 to 5 drugs, which is known to reduce the CVRFs for all subjects aged ≥55 years with an estimated reduction of CVD and stroke by 80%. However, this proposal is neither practical nor cost-effective, because it will involve a large number of subjects. Some investigators suggest to incorporate the coronary artery calcium score (CACS) with the Framingham Risk Score (FRS) to reduce the number of subjects who will benefit from the polypill. They have shown that patients with a CACS = 0 at age 50 years will derive no benefit from the polypill regardless of existing CVRFs, whereas those with a CACS of >100 will derive the best benefit. This strategy will reduce the number of qualified subjects for treatment with the polypill by 60%. Greater benefits will be derived with the combination of CACS and FRS. Additionally, other issues will have to be considered before approval of a polypill, and these issues will be discussed in this concise review. In conclusion, a polypill treatment strategy may be effective in the prevention of CVD and stroke, but, to be cost-effective, it may be reasonable to target patients with a high CACS and FRS.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Global Health; Humans; Incidence; Primary Prevention; Risk Factors; Stroke; Survival Rate

Cancer most commonly arises in the elderly who are often burdened with comorbidities. Medications used for treating these comorbidities may alter cancer prognosis. Understanding the impact of these medications on cancer is important in order to make effective evidence-based decisions about managing comorbidities while improving cancer outcomes.. The evidence on diabetes, statins, antihypertensive and anti-inflammatory medications and their association with cancer recurrence and cancer-specific mortality are reviewed. The strengths and limitations of the existing literature, the current state of the field and future directions are discussed.. Metformin and aspirin were associated with a reduced risk of cancer recurrence and cancer-specific mortality. The evidence for statins and antihypertensive medications on cancer survival was inconsistent. There were few studies to suggest that any of the medication classes of interest were associated with negative effects on cancer survival. Methodological shortcomings within observational studies, such as confounding, distinguishing between use of medications pre-cancer versus post-cancer diagnosis/treatment, misclassification of exposures/outcomes, informative censoring and competing risks, must be considered. New observational studies addressing these limitations are essential. Some clinical trials are underway to further investigate the beneficial effects of these drugs and completed trials have confirmed results demonstrated in observational studies.

Topics: Aged; Anti-Inflammatory Agents; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Neoplasm Recurrence, Local; Neoplasms; Prognosis; Survival

The review analyzes the possible effect of cardiac drugs on the course of osteoporosis (OP). The fact that atherosclerosis and OP share the mechanisms of development, among which the enhanced activity of the sympathetic part of the autonomic nervous system and endothelial dysfunction are most important, is beyond question now. In this connection, beta-adrenoblockers, nebivolol in particular, attract attention. Nebivolol is known to be a selective beta1-adrenoblocker that has an additional vasodilator property, by stimulating the synthesis of nitric oxide. This may serve to increase bone mineral density and slow down the progression of OP. At the same time, most investigations in this area are retrospective therefore final conclusions call for randomized prospective studies that will be able to evaluate more objectively the effect of cardiac drugs on the prevention of OP or its progression delay.

Topics: Benzopyrans; Bone Density; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Ethanolamines; Humans; Nebivolol; Nitric Oxide; Osteoporosis; Retrospective Studies; Vasodilator Agents; Vasomotor System

L-carnitine supplementation has been associated with a significant reduction in all-cause mortality, ventricular arrhythmia, and angina in the setting of acute myocardial infarction (MI). However, on account of strict homeostatic regulation of plasma L-carnitine concentrations, higher doses of L-carnitine supplementation may not provide additional therapeutic benefits. This study aims to evaluate the effects of various oral maintenance dosages of L-carnitine on all-cause mortality and cardiovascular morbidities in the setting of acute MI.. After a systematic review of several major electronic databases (PubMed, EMBASE, and the Cochrane Library) up to November 2013, a meta-analysis of five controlled trials (n = 3108) was conducted to determine the effects of L-carnitine on all-cause mortality and cardiovascular morbidities in the setting of acute MI.. The interaction test yielded no significant differences between the effects of the four daily oral maintenance dosages of L-carnitine (i.e., 2 g, 3 g, 4 g, and 6 g) on all-cause mortality (risk ratio [RR] = 0.77, 95% CI [0.57-1.03], P = 0.08) with a statistically insignificant trend favoring the 3 g dose (RR = 0.48) over the lower 2 g dose (RR = 0.62), which was favored over the higher 4 g and 6 g doses (RR = 0.78, 0.78). There was no significant differences between the effects of the daily oral maintenance dosages of 2 g and 6 g on heart failure (RR = 0.53, 95% CI [0.25-1.13], P = 0.10), unstable angina (RR = 0.90, 95% CI [0.51-1.58], P = 0.71), or myocardial reinfarction (RR = 0.74, 95% CI [0.30-1.80], P = 0.50).. There appears to be no significant marginal benefit in terms of all-cause mortality, heart failure, unstable angina, or myocardial reinfarction in the setting of acute MI for oral L-carnitine maintenance doses of greater or less than 3 g per day.

Topics: Administration, Oral; Cardiovascular Agents; Cardiovascular Diseases; Carnitine; Chi-Square Distribution; Drug Administration Schedule; Drug Dosage Calculations; Humans; Odds Ratio; Recurrence; Risk Factors; Secondary Prevention; Treatment Outcome

Phosphodiesterase-5 (PDE5) inhibitors have been approved by the US Food and Drug Administration for the treatment of erectile dysfunction and more recently for pulmonary arterial hypertension (World Health Organization functional class I). PDE5 inhibitors can induce vasodilation; in addition, through a complex pathway involving nitric oxide, cyclic guanosine monophosphate, and protein kinase G, it can reduce apoptosis and suppress cell proliferation. The presence of PDE5 inhibitors in various tissues and systemic vasculature make them potential targets in a variety of cardiovascular diseases. In many in vitro and in vivo studies, PDE5 inhibitors have been shown to have positive effects in systolic and diastolic congestive heart failure, ischemic heart disease, doxorubicin cardiomyopathy, and pulmonary arterial hypertension. They also improved vasoconstriction in Raynaud phenomenon, peripheral artery disease, and hypoxic brain conditions. This article reviews the therapeutic potentials of PDE5 inhibitors in different cardiovascular diseases.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Phosphodiesterase 5 Inhibitors; Signal Transduction; Treatment Outcome

Multiple, potentially practice-changing cardiology trials have been presented or published over the past year. In this paper, we summarize and place in clinical context, new data regarding management of acute coronary syndrome and ST-elevation myocardial infarction (copeptin assessment, otamixaban, cangrelor, prasugrel, sodium nitrite, inclacumab, ranolazine, preventive coronary intervention of non-culprit lesions, immediate thrombolytic therapy versus transfer for primary intervention), new coronary intervention data (thrombectomy, radial access, pressure wire fractional flow reserve, antiplatelet therapy duration and gene-guidance, permanent and biodegradable polymers, coronary bifurcation and strategies), and coronary artery bypass data (off pump vs. on pump). Latest trials in trans-aortic valve implantation, heart failure (eplerenone, aliskiren, spironolactone, sildenafil, dopamine, nesiritide, omecamtiv mecarbil, the algisyl left ventricular augmentation device, and echo-guided cardiac resynchronization), atrial fibrillation (edoxaban, dabigatran, and ablation), cardiac arrest (hypothermia, LUCAS™ mechanical chest compression), and cardiovascular prevention (vitamins, renal denervation for resistant hypertension, renal artery stenting, saxagliptin, alogliptin, and gastric banding) are also discussed.

Topics: Acute Coronary Syndrome; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Surgical Procedures; Humans; Myocardial Infarction; Stents; Thrombolytic Therapy

The prevention of cardiovascular disease (CVD) by using a polypill has gained increasing momentum as a strategy to contain progression of the disease. Since its initial conception just over a decade ago, only a handful of trials have been completed assessing the efficacy and safety of this innovative concept. The results of these trials have supported the viability of the polypill in CVD prevention and management, albeit with a few caveats, essentially related to the lack of evidence on the effect of the polypill to effectively reduce cardiovascular events. The polypill has the potential to control the global health epidemic of CVD by effectively reaching underdeveloped regions of the world, simplifying healthcare delivery, improving cost-effectiveness, increasing medication adherence, and supporting a comprehensive prescription of evidence-based cardioprotective drugs. Major trials underway will provide definitive evidence on the efficacy of the polypill in reducing cardiovascular events in a cost-effective manner. The results of these studies will determine whether a polypill strategy can quell the burgeoning public health challenge of CVD and will potentially provide the evidence to implement an effective, simple, and innovative solution to restrain the global CVD pandemic.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Humans; Randomized Controlled Trials as Topic; Secondary Prevention

Genetic manipulation of the kallikrein-kinin system (KKS) in mice, with either gain or loss of function, and study of human genetic variability in KKS components which has been well documented at the phenotypic and genomic level, have allowed recognizing the physiological role of KKS in health and in disease. This role has been especially documented in the cardiovascular system and the kidney. Kinins are produced at slow rate in most organs in resting condition and/or inactivated quickly. Yet the KKS is involved in arterial function and in renal tubular function. In several pathological situations, kinin production increases, kinin receptor synthesis is upregulated, and kinins play an important role, whether beneficial or detrimental, in disease outcome. In the setting of ischemic, diabetic or hemodynamic aggression, kinin release by tissue kallikrein protects against organ damage, through B2 and/or B1 bradykinin receptor activation, depending on organ and disease. This has been well documented for the ischemic or diabetic heart, kidney and skeletal muscle, where KKS activity reduces oxidative stress, limits necrosis or fibrosis and promotes angiogenesis. On the other hand, in some pathological situations where plasma prekallikrein is inappropriately activated, excess kinin release in local or systemic circulation is detrimental, through oedema or hypotension. Putative therapeutic application of these clinical and experimental findings through current pharmacological development is discussed in the chapter.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Genetic Predisposition to Disease; Genetic Variation; Humans; Kallikreins; Kidney Diseases; Kinins; Phenotype; Renal Agents; Signal Transduction

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; ErbB Receptors; Humans; Neoplasms; Receptor, ErbB-2

Endothelins are endothelial peptides, the properties of which have been investigated for over 25 years. They play a special role in the pathophysiology of many diseases of the cardiovascular system. Endothelin-1, which is the most explored one, is a potent vasoconstrictor. It increases renal water and sodium excretion, augments cell growth and proliferation and has proinflammatory activity, by intensifying the production of reactive oxygen and nitrogen species (ROS and RNS). ET-1 takes part in the progression of such diseases as hypertension, atherosclerosis, heart and renal failure. The physio- and pathological effects of endothelins are mediated through ETA and ETB receptors. Blocking these receptors, in particular the ETA receptor, can prevent negative effects of endothelins. Long-term efforts to create drugs which act like that have brought relevant results. Endothelin receptor antagonists (ERA) are a new class of medicines, which are indicated in the treatment of pulmonary arterial hypertension. There are also optimistic results of trials with ERA administered in other disorders. On the basis of these data we may conclude that there will be more indications for this group of drugs. This review discusses properties and new research directions of ERA registered in pharmacotherapy.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Endothelin Receptor Antagonists; Humans; Hypertension

The aim of the present meta-analysis of cohort studies was to focus on monounsaturated fat (MUFA) and cardiovascular disease, cardiovascular mortality as well as all-cause mortality, and to distinguish between the different dietary sources of MUFA.. Literature search was performed using the electronic databases PUBMED, and EMBASE until June 2nd, 2014. Study specific risk ratios and hazard ratios were pooled using a inverse variance random effect model.. Thirty-two cohort studies (42 reports) including 841,211 subjects met the objectives and were included. The comparison of the top versus bottom third of the distribution of a combination of MUFA (of both plant and animal origin), olive oil, oleic acid, and MUFA:SFA ratio in each study resulted in a significant risk reduction for: all-cause mortality (RR: 0.89, 95% CI 0.83, 0.96, p = 0.001; I2 = 64%), cardiovascular mortality (RR: 0.88, 95% CI 0.80, 0.96, p = 0.004; I2 = 50%), cardiovascular events (RR: 0.91, 95% CI 0.86, 0.96, p = 0.001; I2 = 58%), and stroke (RR: 0.83, 95% CI 0.71, 0.97, p = 0.02; I2 = 70%). Following subgroup analyses, significant associations could only be found between higher intakes of olive oil and reduced risk of all-cause mortality, cardiovascular events, and stroke, respectively. The MUFA subgroup analyses did not reveal any significant risk reduction.. The results indicate an overall risk reduction of all-cause mortality (11%), cardiovascular mortality (12%), cardiovascular events (9%), and stroke (17%) when comparing the top versus bottom third of MUFA, olive oil, oleic acid, and MUFA:SFA ratio. MUFA of mixed animal and vegetable sources per se did not yield any significant effects on these outcome parameters. However, only olive oil seems to be associated with reduced risk. Further research is necessary to evaluate specific sources of MUFA (i.e. plant vs. animal) and cardiovascular risk.

Topics: Administration, Oral; Cardiovascular Agents; Cardiovascular Diseases; Diet, Mediterranean; Fatty Acids, Monounsaturated; Health Status; Humans; Olive Oil; Plant Oils; Risk Factors

A number of epidemiological/observational studies, as well as large-scale randomized intervention studies, have been conducted to provide evidence for the efficacy of ω-3 fatty acids against atherosclerotic diseases. Currently, ω-3 fatty acids are commercially available in many parts of the world containing the same active ingredients as Lotriga(®) (ω-3-acid ethyl esters 90 [O3AE highly concentrated ω-3 fatty acid ethyl esters, consisting of eicosapentaenoic acid-ethyl ester and docosahexaenoic acid-ethyl ester [EPA-E/DHA-E]). A recent head-to-head comparative study of O3AEE90 versus EPA-E demonstrated that O3AEE90 4g/day led to a significantly greater reduction in triglycerides (TG) than EPA-E 1.8g/day and that O3AEE90 2g/day produced comparable effects on TG to those with EPA-E 1.8g/day. While both agents were shown to be useful in lowering TG, the hallmark feature of O3AEE90, that is, the presence of the DHA-E component versus its absence in EPA-E, needs to be further examined for its clinical implications.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Humans; Hypertriglyceridemia; Platelet Aggregation Inhibitors

Topics: Cardiovascular Agents; Cardiovascular Diseases; Genetic Testing; Humans; Pharmacogenetics

microRNAs (miRNAs) are a class of conserved, short, non-coding RNAs that have important and potent capacities to regulate gene expression at the posttranscriptional level. In the past several years, the aberrant expressions of miRNAs in the cardiovascular system have been widely reported, and the crucial roles of some special miRNAs in heart development and pathophysiology of various cardiovascular diseases have been gradually recognized. Recently, it was discovered that miRNAs are presented in peripheral circulation abundantly and stably. This has raised the possibility of using circulating miRNAs as biomarkers for diseases. Furthermore, some studies demonstrated that circulating miRNAs may serve as novel extracellular communicators of cell-cell communication. These discoveries not only reveal the functions of circulating miRNAs in cardiovascular system but also inform the development of miRNAs therapeutic strategies. In this review, we discuss the potential roles of circulating miRNAs in a variety of cardiovascular diseases from biomarkers to therapeutic targets to clearly understand the roles of circulating miRNAs in cardiovascular system.

Topics: Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Humans; MicroRNAs

Cardiovascular disease (CVD) remains the leading cause of death worldwide, despite the significant advances in medicine. Autophagy, a process of self-cannibalization employed by mammalian cells for the recycling of cellular contents, is altered not only in a number of CVDs, but in other diseases, as well. Many FDA-approved drugs are known to induce autophagy-mediated side effects in the cardiovascular system. In some cases, such drug-induced autophagy could be harnessed and used for treating CVD, greatly reducing the duration and cost of CVD treatments. However, because the induction of autophagy in cardiovascular targets can be both adaptive and maladaptive under specific settings, the challenge is to determine whether the changes stimulated by drug-induced autophagy are, in fact, beneficial. In this review, we surveyed a number of CVDs in which autophagy is known to occur, and we also address the role of FDA-approved drugs for which autophagy-mediated side effects occur within the cardiovascular system. The therapeutic potential of using small molecule modulators of autophagy in the management of CVD progression is discussed.

Topics: Animals; Autophagy; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Myocardium

Cardiovascular disease represents the main cause of death worldwide. Novel therapies to reduce elevated blood pressure and treat resistant hypertension, to consequently reduce the associated cardiovascular risk factors, are still required. Among the different strategies commonly used in medicinal chemistry to develop new molecules, the synthesis of multitarget/hybrid compounds combining two or more pharmacophore groups targeting simultaneously selected factors involved in cardiovascular diseases, has gained increasing interest. This review will focus on the most recent literature on multifunctional cardiovascular drugs, paying particular attention on hybrid compounds bearing natural scaffolds, considering that compounds derived from medicinal extracts are generally appealing for the medicinal chemist as they often bear the so-called "privileged structures". Moreover, taking into account many excellent reviews dealing with multitarget cardiovascular drugs published in the last few years, mainly devoted to RAAS inhibition and/or NO donors hybrid drugs, herein the most significant results obtained and the benefits and limitations of these approaches will be highlighted.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Drug Design; Humans; Hypertension; Molecular Targeted Therapy; Renin-Angiotensin System

Functional integrity of the vascular endothelium is of fundamental importance for normal vascular function. A key factor regulating endothelial function is the bioavailability of nitric oxide (NO). Recently, the enzyme arginase has emerged as an important regulator of NO production by competing for l-arginine, which is a substrate for both arginase and NO synthase. Increased activity of arginase may reduce the availability of l-arginine for NO synthase, thus reducing NO production, increasing formation of reactive oxygen species, and leading ultimately to endothelial dysfunction. Increased activity and expression of arginase have been demonstrated in several pathological cardiovascular conditions, including hypertension, pulmonary arterial hypertension, atherosclerosis, myocardial ischaemia, congestive heart failure, and vascular dysfunction in diabetes mellitus. Experimental studies have demonstrated that inhibition of arginase under these conditions increases NO bioavailability, reduces oxidative stress, improves vascular function, and protects against ischaemia-reperfusion injury. Initial clinical interventional studies are also promising. The purpose of this review is to discuss the role of arginase in cardiovascular pathologies, its contribution to the development of several cardiovascular disease states and the feasibility of using arginase inhibition as a therapeutic strategy.

Topics: Animals; Arginase; Arginine; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Enzyme Inhibitors; Humans; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress

The burden of cardiovascular disease is high in patients with chronic kidney disease or end-stage renal disease. The presence of kidney dysfunction affects the cardiovascular system in multiple ways, including accelerated progression of atherosclerosis and valvular disease, the exacerbation of congestive heart failure, and the development of pericardial disease. This comorbidity results not only from the concordance of shared risk factors, but also from other issues specific to this population, such as systemic inflammation and vascular calcification. Furthermore, both the sensitivity and specificity of noninvasive testing modalities, and the efficacy of several pharmacotherapeutic strategies, are diminished in this population. The exclusion of patients with severe kidney disease from many clinical trials of cardiac interventions raises various therapeutic uncertainties, and kidney disease itself is likely to alter the underlying cardiovascular physiology. In this Review, we discuss aspects of the epidemiology, pathophysiology, and diagnosis of cardiovascular disease in patients with kidney disease, and propose specific, evidence-based recommendations for pharmacological and surgical treatment.

Topics: Cardiac Surgical Procedures; Cardiovascular Agents; Cardiovascular Diseases; Humans; Kidney Failure, Chronic; Kidney Transplantation; Percutaneous Coronary Intervention; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors; Treatment Outcome

The critical role of mitochondria in cardiomyocyte survival and death has become an exciting field of research in cardiac biology. Indeed, it is accepted that mitochondrial dysfunction plays a crucial role in the pathogenesis of multiple cardiac diseases. Besides the obvious relevance of mitochondria in energy production, calcium homeostasis, and reactive oxygen species (ROS) production, new processes like mitochondrial fusion/fission, phosphorylation and nitrosylation modifications in mitochondrial proteins have been suggested to form part of a cast of key players in cardiac disease. This review describes currently studied drugs and compounds that target mitochondria in the scenario of cardiovascular diseases.

Topics: Animals; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Cell Death; Drug Design; Humans; Ion Transport; Membrane Transport Modulators; Mitochondria, Heart; Mitochondrial Dynamics; Mitochondrial Proteins; Mitochondrial Turnover; Myocytes, Cardiac; Oxidative Stress; Phosphorylation; Protein Processing, Post-Translational; Reactive Oxygen Species

This review discusses the latest developments in G protein coupled receptor (GPCR) signalling related to the transactivation of cell surface protein kinase receptors and the therapeutic implications.. Multiple GPCRs have been known to transactivate protein tyrosine kinase receptors for almost two decades. More recently it has been discovered that GPCRs can also transactivate protein serine/threonine kinase receptors such as that for transforming growth factor (TGF)-β. Using the model of proteoglycan synthesis and glycosaminoglycan elongation in human vascular smooth muscle cells which is a component of an in vitro model of atherosclerosis, the dual tyrosine and serine/threonine kinase receptor transactivation pathways appear to account for all of the response to the agonists, endothelin and thrombin.. The broadening of the paradigm of GPCR receptor transactivation explains the broad range of activities of these receptors and also the efficacy of GPCR antagonists in cardiovascular therapeutics. Deciphering the mechanisms of transactivation with the aim of identifying a common therapeutic target remains the next challenge.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Endothelin Receptor Antagonists; Endothelins; Humans; Molecular Targeted Therapy; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Receptor-Interacting Protein Serine-Threonine Kinases; Receptors, Cell Surface; Receptors, Endothelin; Receptors, Thrombin; Signal Transduction; Thrombin

The endothelium has a central role in the regulation of blood flow through continuous modulation of vascular tone. This is primarily accomplished by balanced release of endothelial relaxing and contractile factors. The healthy endothelial cells are essential for maintenance of vascular homeostasis involving antioxidant, anti-inflammatory, pro-fibrinolytic, anti-adhesive, or anticoagulant effects. Oppositely, endothelial dysfunction is primarily characterized by impaired regulation of vascular tone as a result of reduced endothelial nitric oxide (NO) synthase activity, lack of cofactors for NO synthesis, attenuated NO release, or increased NO degradation. So far, the pharmacological approach in improving/reversal of endothelial dysfunction was shown to be beneficial in clinical trials that have investigated actions of different cardiovascular drugs. The aim of this paper was to summarize some of the latest clinical findings related to therapeutic possibilities for improving endothelial dysfunction in different pathological conditions. In the majority of presented clinical investigations, the assessment of improvement or reversal of endothelial dysfunction was performed through the flow-mediated dilatation measurement, and in some of those endothelial progenitor cells' count was used for the same purpose. Still, given the fast and continuous development of this field, the evidence acquisition included the MEDLINE data base screening and the selection of articles published between 2010 and 2012.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Glucose Tolerance Test; Humans; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Obesity; Polycystic Ovary Syndrome; Renal Dialysis; Risk Factors; Signal Transduction; Stem Cells; Vascular Diseases

Future innovative therapies targeting cardiovascular disease (CVD) have the potential to improve health outcomes and to contain rising healthcare costs. Unsustainable increases in the size, cost and duration of clinical trial programs necessary for regulatory approval, however, threaten the entire innovation enterprise. Rising costs for clinical trials are due in large part to increasing demands for hard cardiovascular clinical endpoints as measures of therapeutic efficacy. The development and validation of predictive and surrogate biomarkers, as laboratory or other objective measures predictive or reflective of clinical endpoints, are an important part of the solution to this challenge. This review will discuss insights applicable to CVD derived from the use of predictive biomarkers in oncologic drug development, the evolving role of high density lipoprotein (HDL) in CVD drug development and the impact biomarkers and surrogates have on the continued investment from multiple societal sources critical for innovative CVD drug discovery and development.

Topics: Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Cholesterol, HDL; Clinical Trials as Topic; Drug Approval; Drug Discovery; Humans; Neoplasms

Topics: Angiotensin Receptor Antagonists; Biological Availability; Cardiovascular Agents; Cardiovascular Diseases; Humans; Protective Agents; Renin-Angiotensin System; Treatment Outcome

Permeability glycoprotein (P-gp) mediates the export of drugs from cells located in the small intestine, blood-brain barrier, hepatocytes, and kidney proximal tubule, serving a protective function for the body against foreign substances. Intestinal absorption, biliary excretion, and urinary excretion of P-gp substrates can therefore be altered by either the inhibition or induction of P-gp. A wide spectrum of drugs, such as anticancer agents and steroids, are known P-gp substrates and/or inhibitors, and many cardiovascular drugs have recently been observed to have clinically relevant interactions as well. We review the interactions among commonly prescribed cardiovascular drugs that are P-gp substrates and observe interactions involving P-gp that may be relevant to clinical practice. Cardiovascular drugs with narrow therapeutic indexes (e.g., antiarrhythmic agents, anticoagulant agents) have demonstrated large increases in concentrations when coadministered with potent P-gp inhibitors, thus increasing the risk for drug toxicity. Therefore, dose adjustment or use of alternative agents should be considered when strong P-gp-mediated drug-drug interactions are present. Finally, interactions between novel drugs and known P-gp inhibitors are now being systematically evaluated during drug development, and recommended guidelines for the administration of P-gp substrate drugs will be expanded.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cardiovascular Agents; Cardiovascular Diseases; Humans; Protein Structure, Tertiary; Protein Transport

Sphingosine-1-phosphate (S1P) regulates important functions in cardiac and vascular homeostasis. It has been implied to play causal roles in the pathogenesis of many cardiovascular disorders such as coronary artery disease, atherosclerosis, myocardial infarction, and heart failure. The majority of S1P in plasma is associated with high-density lipoproteins (HDL), and their S1P content has been shown to be responsible, at least in part, for several of the beneficial effects of HDL on cardiovascular risk. The attractiveness of S1P-based drugs for potential cardiovascular applications is increasing in the wake of the clinical approval of FTY720, but answers to important questions on the effects of S1P in cardiovascular biology and medicine must still be found. This chapter focuses on the current understanding of the role of S1P and its receptors in cardiovascular physiology, pathology, and disease.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Drug Design; Hemodynamics; Humans; Lipoproteins, HDL; Lysophospholipids; Signal Transduction; Sphingosine

Cardiovascular disease is a leading cause of death worldwide. Many pharmacologic therapies are available that aim to reduce the risk of cardiovascular disease but there is significant inter-individual variation in drug response, including both efficacy and toxicity. Pharmacogenetics aims to personalize medication choice and dosage to ensure that maximum clinical benefit is achieved whilst side effects are minimized. Over the past decade, our knowledge of pharmacogenetics in cardiovascular therapies has increased significantly. The anticoagulant warfarin represents the most advanced application of pharmacogenetics in cardiovascular medicine. Prospective randomized clinical trials are currently underway utilizing dosing algorithms that incorporate genetic polymorphisms in cytochrome P450 (CYP)2C9 and vitamin k epoxide reductase (VKORC1) to determine warfarin dosages. Polymorphisms in CYP2C9 and VKORC1 account for approximately 40 % of the variance in warfarin dose. There is currently significant controversy with regards to pharmacogenetic testing in anti-platelet therapy. Inhibition of platelet aggregation by aspirin in vitro has been associated with polymorphisms in the cyclo-oxygenase (COX)-1 gene. However, COX-1 polymorphisms did not affect clinical outcomes in patients prescribed aspirin therapy. Similarly, CYP2C19 polymorphisms have been associated with clopidogrel resistance in vitro, and have shown an association with stent thrombosis, but not with other cardiovascular outcomes in a consistent manner. Response to statins has been associated with polymorphisms in the cholesterol ester transfer protein (CETP), apolipoprotein E (APOE), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, calmin (CLMN) and apolipoprotein-CI (APOC1) genes. Although these genes contribute to the variation in lipid levels during statin therapy, their effects on cardiovascular outcomes requires further investigation. Polymorphisms in the solute carrier organic anion transporter 1B1 (SLCO1B1) gene is associated with increased statin exposure and simvastatin-induced myopathy. Angiotensin-converting enzyme (ACE) inhibitors and β-adrenoceptor antagonists (β-blockers) are medications that are important in the management of hypertension and heart failure. Insertion and deletion polymorphisms in the ACE gene are associated with elevated and reduced serum levels of ACE, respectively. No significant association was reported between the polymorphism and blood pressure reduction

Topics: Animals; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Cardiovascular Agents; Cardiovascular Diseases; Cytochrome P-450 CYP2C9; Disease Management; Humans; Pharmacogenetics; Warfarin

Erectile dysfunction is common in the patient with cardiovascular disease. It is an important component of the quality of life and it also confers an independent risk for future cardiovascular events. The usual 3-year time period between the onset of erectile dysfunction symptoms and a cardiovascular event offers an opportunity for risk mitigation. Thus, sexual function should be incorporated into cardiovascular disease risk assessment for all men. A comprehensive approach to cardiovascular risk reduction (comprising of both lifestyle changes and pharmacological treatment) improves overall vascular health, including sexual function. Proper sexual counselling improves the quality of life and increases adherence to medication. This review explores the critical connection between erectile dysfunction and cardiovascular disease and evaluates how this relationship may influence clinical practice. Algorithms for the management of patient with erectile dysfunction according to the risk for sexual activity and future cardiovascular events are proposed.

Topics: Adult; Aged; Algorithms; Cardiovascular Agents; Cardiovascular Diseases; Diagnosis, Differential; Drug Interactions; Erectile Dysfunction; Exercise; Heart Failure; Humans; Hypertension; Impotence, Vasculogenic; Life Style; Male; Medical History Taking; Middle Aged; Phosphodiesterase 5 Inhibitors; Referral and Consultation; Risk Assessment; Risk Factors; Sex Counseling; Sexual Behavior; Sexual Dysfunctions, Psychological; Testosterone

Liver transplantation is the standard of care for acute and chronic end-stage liver disease. Advances in medical therapy and surgical techniques have transformed the long-term survival of liver-transplant (LT) recipients. The prevalence of post-transplant cardiovascular complications has been rising with increased life expectancy after liver transplantation. Currently, deaths related to cardiovascular complications are one of the main causes of long-term mortality in LT recipients, as cardiovascular disease is the reason of 19-42% of non-liver-related mortality after transplant. On the other hand, metabolic syndrome is common among LT recipients before and after transplantation. In fact, their components (abdominal obesity, diabetes mellitus, hypertension and dyslipidemia) are often exacerbated by transplant-specific factors, such as immunosuppression, inappropriate diet, smoking and a sedentary lifestyle, and add a significant risk of developing atherosclerosis. These aspects are discussed in this article.

Topics: Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Humans; Liver Transplantation; Metabolic Syndrome; Risk Assessment; Risk Factors; Risk Reduction Behavior; Survivors; Time Factors; Treatment Outcome

The past decade has seen tremendous advances in our understanding of the genetic factors influencing response to a variety of drugs, including those targeted at treatment of cardiovascular diseases. In the case of clopidogrel, warfarin, and statins, the literature has become sufficiently strong that guidelines are now available describing the use of genetic information to guide treatment with these therapies, and some health centers are using this information in the care of their patients. There are many challenges in moving from research data to translation to practice; we discuss some of these barriers and the approaches some health systems are taking to overcome them. The body of literature that has led to the clinical implementation of CYP2C19 genotyping for clopidogrel, VKORC1, CYP2C9; and CYP4F2 for warfarin; and SLCO1B1 for statins is comprehensively described. We also provide clarity for other genes that have been extensively studied relative to these drugs, but for which the data are conflicting. Finally, we comment briefly on pharmacogenetics of other cardiovascular drugs and highlight β-blockers as the drug class with strong data that has not yet seen clinical implementation. It is anticipated that genetic information will increasingly be available on patients, and it is important to identify those examples where the evidence is sufficiently robust and predictive to use genetic information to guide clinical decisions. The review herein provides several examples of the accumulation of evidence and eventual clinical translation in cardiovascular pharmacogenetics.

Topics: Animals; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Biotransformation; Cardiovascular Agents; Cardiovascular Diseases; Clopidogrel; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; Genotype; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver-Specific Organic Anion Transporter 1; Mixed Function Oxygenases; Organic Anion Transporters; Patient Selection; Pharmacogenetics; Phenotype; Platelet Aggregation Inhibitors; Precision Medicine; Risk Assessment; Risk Factors; Ticlopidine; Vitamin K Epoxide Reductases; Warfarin

Variability in drug responsiveness is a sine qua non of modern therapeutics, and the contribution of genomic variation is increasingly recognized. Investigating the genomic basis for variable responses to cardiovascular therapies has been a model for pharmacogenomics in general and has established critical pathways and specific loci modulating therapeutic responses to commonly used drugs such as clopidogrel, warfarin, and statins. In addition, genomic approaches have defined mechanisms and genetic variants underlying important toxicities with these and other drugs. These findings have not only resulted in changes to the product labels but also have led to development of initial clinical guidelines that consider how to facilitate incorporating genetic information to the bedside. This review summarizes the state of knowledge in cardiovascular pharmacogenomics and considers how variants described to date might be deployed in clinical decision making.

Topics: Adrenergic beta-Antagonists; Cardiovascular Agents; Cardiovascular Diseases; Clopidogrel; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Polymorphism, Genetic; Practice Guidelines as Topic; Ticlopidine; Warfarin

Dipeptidyl peptidase 4 (DPP-4) is a serine protease enzyme expressed widely in many tissues, including the cardiovascular system. The incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from the small intestine into the vasculature during a meal, and these incretins have a potential to release insulin from pancreatic beta cells of islets of Langerhans, affording a glucose-lowering action. However, both incretins are hurriedly degraded by the DPP-4. Inhibitors of DPP-4, therefore, enhance the bioavailability of GLP-1 and GIP, and thus have been approved for better glycemic management in patients afflicted with type 2 diabetes mellitus (T2DM). Five different DPP-4 inhibitors, often called as 'gliptins', namely sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin have been approved hitherto for clinical use. These drugs are used along with diet and exercise to lower blood sugar in diabetic subjects. T2DM is intricately related with an increased risk of cardiovascular disease. Growing body of evidence suggests that gliptins, in addition to their persuasive anti-diabetic action, have a beneficial pleiotropic action on the heart and vessels. In view of the fact of cardiovascular disease susceptibility of patients afflicted with T2DM, gliptins might offer additional therapeutic benefits in treating diabetic cardiovascular complications. Exploring further the cardiovascular pleiotropic potentials of gliptins might open a panorama in impeccably employing these agents for the dual management of T2DM and T2DM-associated perilous cardiovascular complications. This review will shed lights on the newly identified beneficial pleiotropic actions of gliptins on the cardiovascular system.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents

Cardiovascular diseases are responsible for a significant proportion of global mortality and morbidity. Modifiable risk factors like hypertension, hyperlipidemia, physical inactivity, unhealthy diet, tobacco use, obesity and inflammatory states contribute to an increased risk of cardiovascular diseases. The mortality risk increases with increase in number of risk factors. So, simultaneous modification of multiple risk factors is expected to reduce mortality due to these disorders more than the reduction of any individual risk factor. Based on the same rationale, the polypill strategy is based on utilizing a once-daily fixed-dose combination pill to reduce multiple cardiovascular risk factors simultaneously. Two cardiovascular epidemiologists, Wald and Law, proposed the strategy in a patent application in 2000. The idea of combining multiple medications to improve efficacy of treatment has been effectively applied in the treatment of many cancers, HIV/AIDS, tuberculosis and malaria. However, such combination strategy has not been tested in preventing a chronic disease. Thus, this idea has generated a lot of interest as well as controversy. In this article, we will review the pharmacokinetics, clinical trials, advantages and limitations of the polypill strategy.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Drug Combinations; Humans; Patents as Topic; Primary Prevention; Risk Factors

The appropriate cooperation of patients is very important during therapy. The term of compliance used earlier for the definition of patient´s cooperation refers to a sub- or over-ordination of the relationship betwees physicians and patients. Nowadays the term of adherence is used, which suggests a higher level of patient cooperation because it assumes an active contribution of the patient. The adherence of patients to cardiocascular medical therapy in developed countries is just 50%, and this indicates that half of the patients do not take the prescribed medication. Because of the lack of medication, morbidity and mortality are increasing. There can be many reasons for the lack of patient cooperation, which should be taken account during medical treatment. Improving patient adherence can decrease the risk for complications and progression of the disease, which can improve health condition and reduce health care and social costs.. A megfelelő beteg-együttműködés alapvető fontosságú minden terápia során. A beteg-együttműködés kifejezésére korábban a compliance meghatározás szolgált, amely azonban az orvos–beteg kapcsolat alá- és fölérendeltségét jelentette. Jelenleg az adherencia kifejezést használjuk, amely a beteg-együttműködés magasabb fokát jelenti, mivel feltételezi a beteg aktív közreműködését is. A betegek cardiovascularis terápia iránti adherenciája a fejlett országokban is csak mintegy 50%, ami azt jelenti, hogy a betegek fele nem szedi a számára felírt készítményeket. A gyógyszeres kezelés hiánya miatt e betegeknél növekszik a morbiditás és a mortalitás. A beteg-együttműködés hiányának számos oka lehet, és a betegek kezelése során ezekre is figyelemmel kell lennünk. Az adherencia javításával csökkenthető a szövődmények kialakulásának és a betegségprogresszió előrehaladásának a kockázata, amelyek összességében javítják az egészségi állapotot, és nem mellékesen csökkennek a betegre fordított egészségbiztosítási és társadalmi költségek is. Orv. Hetil., 2013, 154, 883–888.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cost of Illness; Disease Progression; Health Care Costs; Humans; Medication Adherence; Patient Compliance; Patient Education as Topic; Physician's Role; Self Administration; Time Factors

Authors analyze actual situation in treatment of cardiovascular diseases in older patients. Different groups of recommended drugs are discussed separately; possible risks for elderly patients are stressed. Angiotensin converting enzyme inhibitors-this group is widely used in older patients because of their hypotensive effect, positive influence on cardiac failure, and positive modulation of endothelial dysfunction. The risk of hyperkalemia must be considered. Antiaggregants and anticoagulants are proved as potent prophylactic treatment, but the associated risk of gastrointestinal bleeding must be weighed very carefully. Bradycardia related to β-blockers, especially in combination with other medications lowering the heart rate must be taken into account. Otherwise, this group brings the highest profit in cardiovascular diseases as for morbidity and mortality. Attention is paid to calcium channel blockers, statins, diuretics, nitrates, and digoxin. A table listing the possible side effects and clinical symptoms of overdose by medications most frequently used in the elderly concludes the article.

Topics: Aged; Aged, 80 and over; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Female; Humans; Incidence; Male; Middle Aged; Risk Factors

The aim of this study was to determine the extent to which adherence to individual vascular medications, assessed by different methods, influences the absolute and relative risks (RRs) of cardiovascular disease (CVD) and all-cause mortality.. We performed a systematic review and meta-analysis of prospective epidemiological studies (cohort, nested case-control, or clinical trial) identified through electronic searches using MEDLINE, Web of Science, EMBASE, and Cochrane databases, involving adult populations (≥ 18 years old) and reporting risk estimates of cardiovascular medication adherence with any CVD (defined as any fatal or non-fatal coronary heart disease, stroke or sudden cardiac death) and/or all-cause mortality (defined as mortality from any cause) outcomes. Relative risks were combined using random-effects models. Forty-four unique prospective studies comprising 1 978 919 non-overlapping participants, with 135 627 CVD events and 94 126 cases of all-cause mortality. Overall, 60% (95% CI: 52-68%) of included participants had good adherence (adherence ≥ 80%) to cardiovascular medications. The RRs (95% CI) of development of CVD in those with good vs. poor (<80%) adherence were 0.85 (0.81-0.89) and 0.81 (0.76-0.86) for statins and antihypertensive medications, respectively. Corresponding RRs of all-cause mortality were 0.55 (0.46-0.67) and 0.71 (0.64-0.78) for good adherence to statins and antihypertensive agents. These associations remained consistent across subgroups representing different study characteristics. Estimated absolute risk differences for any CVD associated with poor medication adherence were 13 cases for any vascular medication, 9 cases for statins and 13 cases for antihypertensive agents, per 100 000 individuals per year.. A substantial proportion of people do not adhere adequately to cardiovascular medications, and the prevalence of suboptimal adherence is similar across all individual CVD medications. Absolute and relative risk assessments demonstrate that a considerable proportion of all CVD events (~9% in Europe) could be attributed to poor adherence to vascular medications alone, and that the level of optimal adherence confers a significant inverse association with subsequent adverse outcomes. Measures to enhance adherence to help maximize the potentials of effective cardiac therapies in the clinical setting are urgently required.

Topics: Adult; Aged; Cardiovascular Agents; Cardiovascular Diseases; Cause of Death; Epidemiologic Methods; Humans; Medication Adherence; Middle Aged; Young Adult

A pathway-based genome-wide association analysis has recently identified Rac1 as one of the biologically important gene in coronary heart diseases. The role of the small GTPase Rac1 in cardiac hypertrophy and atherosclerosis has also been documented in clinical studies with the HMG-CoA reductase inhibitors and in in vitro and in vivo settings using transgenic and knockout mice. Thus, Rac1 has emerged as a new pharmacological target for the treatment of cardiovascular diseases. The activation state of Rac1 depends on the release of guanosine diphosphate and the binding of guanosine triphosphate. This cycling is regulated by the guanine nucleotide exchange factors, as activators, and by the GTPase-activating proteins. Three categories of selective Rac1 inhibitors have been developed affecting different steps of this pathway: antagonists of Rac1-guanine nucleotide exchange factor interaction, allosteric inhibitors of nucleotide binding to Rac1, and antagonists of Rac1-mediated NADPH oxidase activity. These chemical compounds have shown to selectively inhibit Rac1 activation in cultured cell lines without affecting the homologous proteins RhoA and Cdc42. Moreover, pioneer studies have been conducted with Rac1 inhibitors in in vivo experimental models of cardiovascular diseases with encouraging results. The present review summarizes the current knowledge of the role of Rac1 in cardiovascular diseases and the pharmacological approaches that have been developed to selectively inhibit its function.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Genome-Wide Association Study; Humans; Mice; Mice, Knockout; Mice, Transgenic; Molecular Targeted Therapy; rac1 GTP-Binding Protein

The implications of reactive oxygen species in cardiovascular disease have been known for some decades. Rationally, therapeutic antioxidant strategies combating oxidative stress have been developed, but the results of clinical trials have not been as good as expected. Therefore, to move forward in the design of new therapeutic strategies for cardiovascular disease based on prevention of production of reactive oxygen species, steps must be taken on two fronts, ie, comprehension of reduction-oxidation signaling pathways and the pathophysiologic roles of reactive oxygen species, and development of new, less toxic, and more selective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors, to clarify both the role of each NADPH oxidase isoform and their utility in clinical practice. In this review, we analyze the value of NADPH oxidase as a therapeutic target for cardiovascular disease and the old and new pharmacologic agents or strategies to prevent NADPH oxidase activity. Some inhibitors and different direct or indirect approaches are available. Regarding direct NADPH oxidase inhibition, the specificity of NADPH oxidase is the focus of current investigations, whereas the chemical structure-activity relationship studies of known inhibitors have provided pharmacophore models with which to search for new molecules. From a general point of view, small-molecule inhibitors are preferred because of their hydrosolubility and oral bioavailability. However, other possibilities are not closed, with peptide inhibitors or monoclonal antibodies against NADPH oxidase isoforms continuing to be under investigation as well as the ongoing search for naturally occurring compounds. Likewise, some different approaches include inhibition of assembly of the NADPH oxidase complex, subcellular translocation, post-transductional modifications, calcium entry/release, electron transfer, and genetic expression. High-throughput screens for any of these activities could provide new inhibitors. All this knowledge and the research presently underway will likely result in development of new drugs for inhibition of NADPH oxidase and application of therapeutic approaches based on their action, for the treatment of cardiovascular disease in the next few years.

Topics: Animals; Antioxidants; Biomedical Research; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Enzyme Inhibitors; Humans; Isoenzymes; Models, Molecular; Molecular Targeted Therapy; NADPH Oxidases; Oxidative Stress; Reactive Oxygen Species; Signal Transduction

The continued high rate of cardiovascular morbidity and mortality has attracted wide concern and great attention of pharmaceutical industry. In order to reduce the attrition of cardiovascular drug R&D, it might be helpful recapitulating previous failures and identifying the potential factors to success. This perspective mainly analyses the 30 cardiovascular drugs dropped from clinical development in 2012. Reasons causing the termination of the cardiovascular drugs in the past 5 years are also tabulated and analysed. The analysis shows that the attrition is highest in Phase II trials and financial and strategic factors and lack of clinical efficacy are the principal reasons for these disappointments. To solve the four problems (The 'better than the Beatles' problem, the 'cautious regulator' problem, the 'throw money at it' tendency and the 'basic researchbrute force' bias) is recommended as the main measure to increase the number and quality of approvable products.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Drug Discovery; Drugs, Investigational; Humans

'Oxidative stress' is a term defining states of elevated reactive oxygen species (ROS) levels. Normally, ROS control several physiological processes, such as host defence, biosynthesis of hormones, fertilization and cellular signalling. However, oxidative stress has been involved in different pathologies, including metabolic syndrome and numerous cardiovascular diseases. A major source of ROS involved in both metabolic syndrome and cardiovascular pathophysiology is the NADPH oxidase (NOX) family of enzymes. NOX is a multi-component enzyme complex that consists of membrane-bound cytochrome b-558, which is a heterodimer of gp91phox and p22phox, cytosolic regulatory subunits p47phox and p67phox, and the small GTP-binding protein Rac1. Rac1 plays many important biological functions in cells, but perhaps the most unique function of Rac1 is its ability to bind and activate the NOX complex. Furthermore, Rac1 has been reported to be a key regulator of oxidative stress through its co-regulatory effects on both nitric oxide (NO) synthase and NOX. Therefore, the main goal of this review is to give a brief outline about the important role of the Rac1-NOX axis in the pathophysiology of both metabolic syndrome and cardiovascular disease.

Topics: Animals; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Enzyme Inhibitors; Humans; Metabolic Syndrome; NADPH Oxidases; Oxidative Stress; rac GTP-Binding Proteins; rac1 GTP-Binding Protein; Signal Transduction

Residual risk, the ongoing appreciable risk of major cardiovascular events (MCVE) in statin-treated patients who have achieved evidence-based lipid goals, remains a concern among cardiologists. Factors that contribute to this continuing risk are atherogenic non-low-density lipoprotein (LDL) particles and atherogenic processes unrelated to LDL cholesterol, including other risk factors, the inherent properties of statin drugs, and patient characteristics, ie, genetics and behaviors. In addition, providers, health care systems, the community, public policies, and the environment play a role. Major statin studies suggest an average 28% reduction in LDL cholesterol and a 31% reduction in relative risk, leaving a residual risk of about 69%. Incomplete reductions in risk, and failure to improve conditions that create risk, may result in ongoing progression of atherosclerosis, with new and recurring lesions in original and distant culprit sites, remodeling, arrhythmias, rehospitalizations, invasive procedures, and terminal disability. As a result, identification of additional agents to reduce residual risk, particularly administered together with statin drugs, has been an ongoing quest. The current model of atherosclerosis involves many steps during which disease may progress independently of guideline-defined elevations in LDL cholesterol. Differences in genetic responsiveness to statin therapy, differences in ability of the endothelium to regenerate and repair, and differences in susceptibility to nonlipid risk factors, such as tobacco smoking, hypertension, and molecular changes associated with obesity and diabetes, may all create residual risk. A large number of inflammatory and metabolic processes may also provide eventual therapeutic targets to lower residual risk. Classically, epidemiologic and other evidence suggested that raising high-density lipoprotein (HDL) cholesterol would be cardioprotective. When LDL cholesterol is aggressively lowered to targets, low HDL cholesterol levels are still inversely related to MCVE. The efflux capacity, or ability to relocate cholesterol out of macrophages, is believed to be a major antiatherogenic mechanism responsible for reduction in MCVE mediated in part by healthy HDL. HDL cholesterol is a complex molecule with antioxidative, anti-inflammatory, anti-thrombotic, antiplatelet, and vasodilatory properties, among which is protection of LDL from oxidation. HDL-associated paraoxonase-1 has a major effect on endothelial f

Topics: Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Dyslipidemias; Evidence-Based Medicine; Guideline Adherence; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Lipids; Medication Adherence; Practice Guidelines as Topic; Practice Patterns, Physicians'; Predictive Value of Tests; Preventive Health Services; Risk Assessment; Risk Factors; Treatment Outcome

To avoid perioperative cardiac complications and deterioration of renal function in chronic kidney disease (CKD), anesthesiologists are required to manage respiration and circulation properly. Three mechanisms are considered to worsen renal function during inappropriate mechanical ventilation; first, hypercapnia or hypoxemia, second, unstable systemic hemodynamic, and third, systemic inflammatory mediators derived from pulmonary biotrauma. Many circulatory problems are present in CKD patients, for example, hypertension, cardiac hypertrophy, cardiomyopathy, ischemic heart disease, arterial sclerotic valve disease, salt and water retention etc. Blood pressure in CKD patients should be controlled properly before surgery. Renal blood flow and renal perfusion pressure should be maintained by aggressive fluid therapy to avoid perioperative acute kidney injury (AKI) on CKD, while cardiac congestion should also be avoided. Perioerative renal protective effects of human atrial natriuretic peptide (hANP) on CKD still needs further investigation. Appropriate hemodynamic monitoring, including direct arterial pressure, left ventricular preload, intravascular volume and cardiac output could be helpful for anesthesiologists to manage CKD patients safely. In the area of CKD and anesthesia, there is lack of evidence in respiratory and circulatory strategies. Prospective studies in these aspects are required in the future.

Topics: Acute Kidney Injury; Atrial Natriuretic Factor; Cardiovascular Agents; Cardiovascular Diseases; Fluid Therapy; Hemodynamics; Humans; Monitoring, Intraoperative; Perioperative Care; Positive-Pressure Respiration; Postoperative Complications; Renal Insufficiency, Chronic; Respiration, Artificial

For the past 40 years, beta-blockers have been widely used in cardiovascular medicine, reducing morbidity as well as mortality. Beta-blockers are currently used in a number of cardiovascular conditions such as systolic heart failure, postmyocardial infarction, and in prevention and treatment of arrhythmias. They are not recommended as the first line antihypertensive therapy, particularly in the elderly, unless there are specific indications. Despite the benefits of beta-blockers, tolerability concerns in patients with co-morbidities have limited their use. Some of these problems were overcome with the discovery of cardioselective beta-blockers. The third generation beta-blockers have additional properties of vasodilatation and advantages in terms of minimizing the adverse effects of beta-blockers. Some of the advantages include improvement of insulin resistance, decrease in cholesterol as well as alleviation of erectile dysfunction. Acute treatment with beta-blockers modifies local muscular metabolic properties and impairs endurance exercise capacity whereas the influence of chronic is debated controversially.

Topics: Adrenergic beta-Antagonists; Animals; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Exercise Tolerance; Humans; Muscle, Skeletal; Recovery of Function; Risk Assessment; Treatment Outcome

Black Cumin (Nigella sativa), which belongs to the botanical family of Ranunculaceae, commonly grows in Eastern Europe, the Middle East, and Western Asia. Its ripe fruit contains tiny black seeds, known as "Al-Habba Al-Sauda" and "Al-Habba Al-Barakah" in Arabic and black seed or black cumin in English. Seeds of Nigella sativa are frequently used in folk medicine in the Middle East and some Asian countries for the promotion of good health and the treatment of many ailments. However, data for the cardiovascular benefits of black cumin are not well-established. We reviewed the literature from 1960 to March 2012 by using the following key words: "Nigella sativa," "black seeds," and "thymoquinone." Herein, we discussed the most relevant articles to find out the role of Nigella sativa in the cardiovascular diseases spectrum especially when there is a paucity of information and need of further studies in human to establish the utility of Nigella sativa in cardiovascular system protection.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Nigella sativa; Plant Extracts

Data from large epidemiological studies suggest that elevated heart rate is independently associated with cardiovascular and all-cause mortality in patients with hypertension and in those with established cardiovascular disease. Clinical trial findings also suggest that the favorable effects of beta-blockers and other heart rate-lowering agents in patients with acute myocardial infarction and congestive heart failure may be, at least in part, due to their heart rate-lowering effects. Contemporary clinical outcome prediction models such as the Global Registry of Acute Coronary Events (GRACE) score include admission heart rate as an independent risk factor.. This article critically reviews the key epidemiology concerning heart rate and cardiovascular risk, potential mechanisms through which an elevated resting heart rate may be disadvantageous and evaluates clinical trial outcomes associated with pharmacological reduction in resting heart rate.. Prospective randomised data from patients with significant coronary heart disease or heart failure suggest that intervention to reduce heart rate in those with a resting heart rate >70 bpm may reduce cardiovascular risk. Given the established observational data and randomised trial evidence, it now appears appropriate to include reduction of elevated resting heart rate by lifestyle +/- pharmacological therapy as part of a secondary prevention strategy in patients with cardiovascular disease.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Heart Rate; Humans; Risk Assessment; Risk Factors; Treatment Outcome

The scientific literature clearly establishes the occurrence of cardiovascular (CV) accidents and myocardial ischemic episodes is unevenly distributed during the 24 h. Such temporal patterns result from corresponding temporal variation in pathophysiologic mechanisms and cyclic environmental triggers that elicit the onset of clinical events. Moreover, both the pharmacokinetics and pharmacodynamics of many, though not all, CV medications have been shown to be influenced by the circadian time of their administration, even though further studies are necessary to better clarify the mechanisms of such influence on different drug classes, drug molecules, and pharmaceutical preparations. Twenty-four-hour rhythmic organization of CV functions is such that defense mechanisms against acute events are incapable of providing the same degree of protection during the day and night. Instead, temporal gates of excessive susceptibility exist, particularly in the morning and to a lesser extent evening (in diurnally active persons), to aggressive mechanisms through which overt clinical manifestations may be triggered. When peak levels of critical physiologic variables, such as blood pressure (BP), heart rate (HR), rate pressure product (systolic BP × HR, surrogate measure of myocardial oxygen demand), sympathetic activation, and plasma levels of endogenous vasoconstricting substances, are aligned together at the same circadian time, the risk of acute events becomes significantly elevated such that even relatively minor and usually harmless physical and mental stress and environmental phenomena can precipitate dramatic life-threatening clinical manifestations. Hence, the delivery of CV medications needs to be synchronized in time, i.e., circadian time, in proportion to need as determined by established temporal patterns in risk of CV events, and in a manner that averts or minimizes undesired side effects.

Topics: Aortic Aneurysm; Arrhythmias, Cardiac; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cardiovascular Agents; Cardiovascular Diseases; Circadian Rhythm; Heart Rate; Humans; Myocardial Ischemia; Myocardium; Stroke; Takotsubo Cardiomyopathy; Time Factors

Responses to drug therapy vary from benefit to no effect to adverse effects which can be serious or occasionally fatal. Increasing evidence supports the idea that genetic variants can play a major role in this spectrum of responses. Well-studied examples in cardiovascular therapeutics include predictors of steady-state warfarin dosage, predictors of reduced efficacy among patients receiving clopidogrel for drug eluting stents, and predictors of some serious adverse drug effects. This review summarizes contemporary approaches to identifying and validating genetic predictors of variability in response to drug treatment. Approaches to incorporating this new knowledge into clinical care, and the barriers to this concept, are addressed.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Pharmacogenetics

The counter-regulatory axis of the renin-angiotensin system (RAS) is a novel therapeutic target in cardiovascular disease. Pathophysiological effects mediated via angiotensin II (Ang II) are well established in regulation of blood pressure, cardiac and vascular remodeling, and renal sodium handling, which lead to disorders such as hypertension and associated end-organ damage, atherosclerosis and heart failure. The counter-regulatory axis of the RAS is centered on the angiotensin-converting enzyme 2/angiotensin-1-7 (Ang-[1-7])/Mas receptor axis and has been shown to inhibit many detrimental phenotypes in cardiovascular disease. More recently, an alternative peptide, angiotensin-(1-9) (Ang-[1-9]), has been reported as a potential new member of this axis. This review will discuss the cardiovascular regulatory roles of Ang-(1-7) and Ang-(1-9) in the counter-regulatory axis of the RAS, and the potential for new therapeutic approaches in cardiovascular disease.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Humans; Peptide Fragments; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Ventricular Remodeling

Piper has been used for long timelike condiment and food, but also in traditional medicine around of the world. This work resumes the available and up to date work done on members of the Piperaceae family and their uses for therapeutic purposes.. Information on Piper genus was gathered via internet using scientific databases such as Scirus, Google Scholar, CAB-abstracts, MedlinePlus, Pubmed, SciFinder, Scopus and Web of Science.. The largeleafed perennial plant Piper is used for its spicy aromatic scent and flavor. It has an important presence in the cuisine of different cultures. Another quality of these plants is their known medicinal properties. It has been used as emollient, antirheumatic, diuretic, stimulant, abortifacient, anti-inflammatory, antibacterial, antifungal and antidermatophytic. A survey of the literature shows that the genus Piper is mainly known for its alkaloids with cytotoxic, chemopreventive, antimetastatic and antitumor properties in several types of cancer. Studies of its alkaloids highlight the existence of various potential leads to develop new anti-cancer agents. Modern pharmacology studies have demonstrated that its crude extracts and active compounds possess wide pharmacological activities, especially asantioxidant, anti-depressive, hepatoprotective, antimicrobial, anti-obesity, neuropharmacological, to treat cognitive disorders, anti-hyperlipidemic, anti-feedant, cardioactive, immuno-enhancing, and anti-inflamatory. All this evidence supporting its traditional uses.. This review summarizes the up-to-date and comprehensive information concerning the botany, traditional use, phytochemistry and pharmacology of Piper together with its toxicology, and discusses the possible trend and scope for further research on Piper in the future.

Topics: Alkaloids; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-Obesity Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Central Nervous System Agents; Cognition Disorders; Humans; Neoplasms; Obesity; Piper; Plant Extracts; Platelet Aggregation Inhibitors

Despite the efficacy of statin therapy, patients treated with these agents face substantial residual risk that is associated with achieved levels of LDL cholesterol (LDL-C). These observations suggest a potential benefit of additional strategies to promote further LDL-C reduction. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an attractive target in this regard. Abrogation of PCSK9 function prevents PCSK9-mediated catabolism of LDL receptors, increases cell surface LDL receptor density, and promotes clearance of LDL and other atherogenic lipoproteins from the circulation. Thus far, the most advanced approaches to block PCSK9 action are monoclonal antibodies and anti-sense oligonucleotides. Among statin-treated patients, these agents may produce additional LDL-C lowering exceeding 50 %. In rare genetic experiments of nature, individuals with dominant negative or dual loss of function mutations of PCSK9 appear to have no adverse health effects resulting from lifelong, very low levels of LDL-C. In short-term trials, PCSK9 antibodies have been generally well-tolerated. However, evidence to support long-term safety and efficacy of PCSK9 therapy to reduce cardiovascular risk awaits the results of large cardiovascular outcome trials.

Topics: Anticholesteremic Agents; Cardiovascular Agents; Cardiovascular Diseases; Cholesterol, LDL; Humans; Proprotein Convertase 9; Proprotein Convertases; Serine Endopeptidases; Serine Proteinase Inhibitors

The unexpected discovery that somatic cells can be reprogrammed to a pluripotent state yielding induced pluripotent stem cells has made it possible to produce cardiovascular cells exhibiting inherited traits and disorders. Use of these cells in high throughput analyses should broaden our insight into fundamental disease mechanisms and provide many benefits for patients, including new therapeutics and individually tailored therapies. Here we review recent progress in generating induced pluripotent stem cell-based models of cardiovascular disease and their multiple applications in drug development.

Topics: Animals; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Drug Discovery; Gene Expression Regulation; Genetic Predisposition to Disease; Genomics; High-Throughput Screening Assays; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Phenotype; Risk Assessment; Toxicity Tests

The rationale of the present review is to analize the activity of Rosmarinus officinalis in the the cardiovascular system. A MEDLINE database search (from January 1970 to December 2011) using only rosmarinic acid as searched term.. The references search revealed 509 references about rosmarinic acid in 40 years (the first reference is from 1970). There is a powerful prevalence of antioxidant and cancer studies. Other diseases are few cited, as inflammation, brain (Alzheimer and Parkinson disease) and, memory; allergy; diabetes; atherosclerosis, and; hypertension. It is necessary to consider the complete absence of studies on coronary artery disease, myocardial ischemia, heart failure or ischemia/reperfusion injury.. Rosmarinic acid is underestimated as an experimental cardiovascular drug and deserves more attention.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cinnamates; Depsides; Humans; Rosmarinic Acid

Neuregulin-1 (NRG-1)/ErbB signaling has an indispensable role in cardiac development and in the maintenance of the structural and functional integrity of the human adult heart in health and disease. Several animal studies have now demonstrated the therapeutic effects of NRG-1 during acute cardiac injury and during chronic heart failure, with improvements in cardiac performance and animal survival. Phase I and II clinical trials for chronic heart failure in humans are now in progress.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; ErbB Receptors; Humans; Neuregulin-1; Receptor, ErbB-2; Receptor, ErbB-4; Recombinant Proteins; Signal Transduction

Potassium (K(+) ) channels are important in cardiovascular disease both as drug targets and as a cause of underlying pathology. Voltage-dependent K(+) (K(V) ) channels are inhibited by the class III antiarrhythmic agents. Certain vasodilators work by opening K(+) channels in vascular smooth muscle cells (VSMCs), and K(+) channel activation may also be a route to improving endothelial function. The two-pore domain K(+) (K(2P) ) channels form a group of 15 known channels with an expanding list of functions in the cardiovascular system. One of these K(2P) channels, TREK-1, is the focus of this review. TREK-1 channel activity is tightly regulated by intracellular and extracellular pH, membrane stretch, polyunsaturated fatty acids (PUFAs), temperature, and receptor-coupled second messenger systems. TREK-1 channels are also activated by volatile anesthetics and some neuroprotectant agents, and they are inhibited by selective serotonin reuptake inhibitors (SSRIs) as well as amide local anesthetics. Some of the clinical cardiovascular effects and side effects of these drugs may be through their actions on TREK-1 channels. It has recently been suggested that TREK-1 channels have a role in mechano-electrical coupling in the heart. They also seem important in the vascular responses to PUFAs, and this may underlie some of the beneficial cardiovascular effects of the essential dietary fatty acids. Development of selective TREK-1 openers and inhibitors may provide promising routes for intervention in cardiovascular diseases.

Topics: Animals; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Heart; Humans; Ion Channel Gating; Myocardium; Permeability; Potassium Channels, Tandem Pore Domain

Tanshinone IIA (TS), a pharmacologically active component isolated from the rhizome of the Chinese herb Salvia miltiorrhiza Bunge (Danshen), has been clinically used in Asian countries for the prevention and treatment of coronary heart disease. Recently, the pharmacological properties of TS in the cardiovascular system have attracted great interest. Emerging experimental studies and clinical trials have demonstrated that TS prevents atherogenesis as well as cardiac injury and hypertrophy. In atherosclerosis, TS acts by inhibiting LDL oxidation, monocyte adhesion to endothelium, smooth muscle cell migration and proliferation, macrophage cholesterol accumulation, proinflammatory cytokine expression and platelet aggregation. TS has some activity and potential to stabilize atherosclerotic plaques. The cardioprotective effects of TS are mainly related to its anti-oxidant and anti-inflammatory actions. In this review, we focus on the protective effects and the mechanism of action of TS in the cardiovascular system, and provide a novel perspective on clinical use of TS.

Topics: Abietanes; Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Treatment Outcome

Pharmacogenetics is the search for heritable genetic polymorphisms that influence responses to drug therapy. The most important application of pharmacogenetics is to guide choosing agents with the greatest potential of efficacy and smallest risk of adverse drug reactions. Many studies focusing on drug-gene interactions have been published in recent years, some of which led to adaptation of FDA recommendations, indicating that we are on the verge of the clinical application of genetic information in drug therapy. This systematic review provides a comprehensive overview of the current knowledge on pharmacogenetics of all major drug classes currently used in the treatment of cardiovascular diseases.

Topics: Adrenergic alpha-Antagonists; Anticoagulants; Apolipoproteins E; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Drug Resistance; Forecasting; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Kinesins; Muscular Diseases; Peptidyl-Dipeptidase A; Pharmacogenetics; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polymorphism, Genetic; Purinergic P2Y Receptor Antagonists; Renin-Angiotensin System; Risk Factors

Prevention and treatment of atherosclerosis is still a clinical challenge in the cardiovascular medicine. The classical belief that atherosclerotic lesion development solely depends on lipid deposition has been replaced by the current concept that activation of immune and inflammatory responses plays a central role in plaque initiation and progression. In this review we summarize studies on human and genetically modified animals describing a finite number of cellular and molecular mechanisms that underlie immunoinflammation in atherosclerotic plaques. We focus on the pro- and antiinflammatory mediators activated during atherogenesis and the intracellular signaling pathways regulating these events. Besides the advances on established pharmacological agents, we propose potential strategies for reduction/stabilization of atherosclerotic plaques based on the clinical data in inflammatory-associated pathologies and on the encouraging studies in experimental models of atherosclerosis. We emphasize the potential of such novel inhibitors comprising receptor antagonists, neutralizing antibodies, kinase inhibitors, peptide-based technologies, and chemicals as emerging antiinflammatory strategies for the treatment of atherosclerotic disease complications.

Topics: Adaptive Immunity; Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Cytokines; Humans; Immunity, Innate; Inflammation; Inflammation Mediators; Signal Transduction

Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates and require the cofactors reduced nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R-)5,6,7,8-tetrahydrobiopterin (BH(4)). All NOS bind calmodulin and contain haem. Neuronal NOS (nNOS, NOS I) is constitutively expressed in central and peripheral neurons and some other cell types. Its functions include synaptic plasticity in the central nervous system (CNS), central regulation of blood pressure, smooth muscle relaxation, and vasodilatation via peripheral nitrergic nerves. Nitrergic nerves are of particular importance in the relaxation of corpus cavernosum and penile erection. Phosphodiesterase 5 inhibitors (sildenafil, vardenafil, and tadalafil) require at least a residual nNOS activity for their action. Inducible NOS (NOS II) can be expressed in many cell types in response to lipopolysaccharide, cytokines, or other agents. Inducible NOS generates large amounts of NO that have cytostatic effects on parasitic target cells. Inducible NOS contributes to the pathophysiology of inflammatory diseases and septic shock. Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins.

Topics: Animals; Arginine; Biopterins; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Genetic Therapy; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Isoenzymes; Mice; Neovascularization, Physiologic; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III

Focal adhesions (FA) are important mediators of endothelial cytoskeletal interactions with the extracellular matrix (ECM) via transmembrane receptors, integrins and integrin-associated intracellular proteins. This communication is essential for a variety of cell processes including EC barrier regulation and is mediated by the non-receptor protein tyrosine kinase, focal adhesion kinase (FAK). As FA mediate the basic response of EC to a variety of stimuli and FAK is essential to these responses, the idea of targeting EC FAK as a therapeutic strategy for an assortment of diseases is highly promising. In particular, inhibition of FAK could prove beneficial in a variety of cancers via effects on EC proliferation and angiogenesis, in acute lung injury (ALI) via the attenuation of lung vascular permeability, and in rheumatoid arthritis via reductions in synovial angiogenesis. In addition, there are potential therapeutic benefits of FAK inhibition in cardiovascular disease and diabetic nephropathy as well. Several drugs that target EC FAK are now in existence and include agents currently under investigation in preclinical models as well as drugs that are readily available such as the sphingolipid analog FTY720 and statins. As the role of EC FAK in the pathogenesis of a variety of diseases continues to be explored and new insights are revealed, drug targeting of FAK will continue to be an important area of investigation and may ultimately lead to highly novel and effective strategies to treat these diseases.

Topics: Acute Lung Injury; Angiogenesis Inhibitors; Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Cardiovascular Agents; Cardiovascular Diseases; Diabetic Nephropathies; Endothelial Cells; Focal Adhesion Protein-Tyrosine Kinases; Humans; Neoplasms; Neovascularization, Pathologic; Protein Kinase Inhibitors; Respiratory System Agents; Signal Transduction

Atherosclerotic cardiovascular diseases remain the leading cause of morbidity and mortality in both developed and developing countries. Adequate treatment of vascular risk factors, such as low-density lipoprotein cholesterol and systolic blood pressure are known to reduce the future risk of cardiovascular disease in these patients. However currently, large treatment gaps exist among high-risk individuals, in whom the guidelines recommend concomitant treatment with aspirin, statin, and blood-pressure lowering agents. Combining aspirin, cholesterol, and blood-pressure lowering agents into a single pill called the cardiovascular polypill has been proposed as complementary care in the prevention of cardiovascular diseases in both intermediate- and high-risk patient populations. It is now a decade since the first recommendations to develop and trial cardiovascular polypills. The major scientific debate has been about the appropriate initial target population. This review article focuses on the potential role of fixed-dose combination therapy in different patient populations, outlines the pros and cons of combination therapy, and emphasizes the rationale for trialing their use. Current and planned future cardiovascular polypill trials are summarized and the pre-requisites for implementation of the polypill strategy in both primary and secondary prevention are described. The recent development of combination pills containing off-patent medications holds promise for highly affordable and effective treatment and evidence is emerging on the use of this strategy in high-risk populations.

Topics: Administration, Oral; Antihypertensive Agents; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; History, 20th Century; History, 21st Century; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Polypharmacy; Practice Guidelines as Topic; Primary Prevention; Risk Assessment; Risk Factors; Secondary Prevention; Tablets; Treatment Outcome

Xanthine oxidase inhibition (XOI) reduces oxidative stress in the vasculature. Moreover it reduces uric acid levels, a risk factor for the development of cardiovascular disease. As such, XOI holds a potentially dual mechanism for the treatment of cardiovascular disease.. Through systematic review, we sought to clarify the extent of available evidence that has evaluated the effect of XOI upon clinical or surrogate markers of cardiovascular disease and function in humans.. A systematic search strategy was used to interrogate the Ovid Medline (1950-June Week 4 2010) and Embase (1980-2010 Week 25) databases, to identify relevant studies. Meta-analysis was planned for frequently studied endpoints.. Thirty-eight publications (reporting 40 studies) were identified. There was heterogeneity between studies in all aspects of study design, including the outcome measures of interest. Prospective assessment of surrogate markers predominated. Combined meta-analysis was feasible for three outcome parameters, with favorable modifications in each following xanthine oxidase inhibition: brachial artery flow mediated dilatation (five studies: XOI n = 75, control n = 69) increased by 2.50% (95% CI, 0.15-4.84); forearm blood flow responses to acetylcholine infusion (five studies: XOI n = 74, control n = 74) increased by 68.80 (95% CI, 18.70-118.90; percent change relative to noninfused control arm); circulating markers of oxidative stress (malondialdehyde, six studies: XOI n = 78, control n = 68) reduced by 0.56 nmol/mL (95% CI, 0.26-0.87).. XOI improves endothelial function and circulating markers of oxidative stress in patients with, or at risk of, cardiovascular disease. Large prospective studies examining definitive end points are lacking but now appear indicated.

Topics: Antioxidants; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Enzyme Inhibitors; Exercise Tolerance; Hemodynamics; Humans; Inflammation Mediators; Myocardial Contraction; Oxidative Stress; Ventricular Function, Left; Xanthine Oxidase

Human genetic variation in the form of single nucleotide polymorphisms as well as more complex structural variations such as insertions, deletions and copy number variants, is partially responsible for the clinical variation seen in response to pharmacotherapeutic drugs. This affects the likelihood of experiencing adverse drug reactions and also of achieving therapeutic success. In this paper, we review key studies in cardiovascular pharmacogenetics that reveal genetic variations underlying the outcomes of drug treatment in cardiovascular disease. Examples of genetic associations with drug efficacy and toxicity are described, including the roles of genetic variability in pharmacokinetics (e.g. drug metabolizing enzymes) and pharmacodynamics (e.g. drug targets). These findings have functional implications that could lead to the development of genetic tests aimed at minimizing drug toxicity and optimizing drug efficacy in cardiovascular medicine.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Polymorphism, Genetic

There is increasing evidence that endothelin receptor blockade and, in particular, ET(A) receptor blockade not only confers protection against proteinuric renal disease in diabetes but also confers vasculoprotection.. Recent clinical trials using ET(A) receptor blockade in treating proteinuria and chronic kidney disease as well as atherosclerosis show great promise; however, adverse effects are still problematic.. Endothelin receptor blockade is associated with a significant attenuation of proteinuria and these effects are mediated in part via inhibition of inflammatory and oxidative stress related pathways as well profibrotic pathways. The addition of ET(A) receptor blockade to currently established therapies such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may result in additional or synergistic renoprotection and vasculoprotection in hypertension and, in particular, in the context of diabetes.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Chronic Disease; Diabetic Nephropathies; Endothelin Receptor Antagonists; Endothelins; Humans; Hypertension; Kidney; Kidney Diseases; Proteinuria; Receptors, Endothelin; Signal Transduction

Data supporting an association between high levels of serum urate and cardiovascular disease have continued to emerge. Basic science data, small clinical trials, and epidemiologic studies have provided support for the idea of a true causal effect. In this paper, we present evidence about the association between hyperuricemia and selected cardiovascular diseases. Although data generated so far compellingly support pharmacologic urate-lowering therapy in selected cases with high cardiovascular risk, further evidence is necessary before widely advocating this approach to prevent cardiovascular outcomes putatively associated with hyperuricemia.

Topics: Animals; Antihypertensive Agents; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Humans; Hyperuricemia; Risk Factors; Treatment Outcome

Muscarinic receptor activation plays an essential role in parasympathetic regulation of cardiovascular function. The primary effect of parasympathetic stimulation is to decrease cardiac output by inhibiting heart rate. However, pharmacologically, muscarinic agonists are actually capable of producing both inhibitory and stimulatory effects on the heart as well as vasculature. This reflects the fact that muscarinic receptors are expressed throughout the cardiovascular system, even though they are not always involved in mediating parasympathetic responses. In the heart, in addition to regulating heart rate by altering the electrical activity of the sinoatrial node, activation of M₂ receptors can affect conduction of electrical impulses through the atrioventricular node. These same receptors can also regulate the electrical and mechanical activity of the atria and ventricles. In the vasculature, activation of M₃ and M₅ receptors in epithelial cells can cause vasorelaxation, while activation of M₁ or M₃ receptors in vascular smooth muscle cells can cause vasoconstriction in the absence of endothelium. This review focuses on our current understanding of the signaling mechanisms involved in mediating these responses.

Topics: Acetylcholine; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Muscarinic Agonists; Muscarinic Antagonists; Parasympathetic Nervous System; Receptors, Muscarinic; Signal Transduction

Over the past several decades, liposomes have been used in a variety of applications, from delivery vehicles to cell membrane models. In terms of pharmaceutical use, they can offer control over the release of active agents encapsulated into their lipid bilayer or aqueous core, while providing protection from degradation in the body. In addition, liposomes are versatile carriers, because targeting moieties can be conjugated on the surface to enhance delivery efficiency. It is for these reasons that liposomes have been applied as carriers for a multitude of drugs and genetic material, and as contrast agents, aimed to treat and diagnose cardiovascular diseases.. This review details advancements in liposome technology used in the field of cardiovascular medicine. In particular, the application of liposomes to cardiovascular disease treatment and diagnosis, with a focus on delivering drugs, genetic material and improving cardiovascular imaging, will be explored. Advances in targeting liposomes to the vasculature will also be detailed.. Liposomes may provide the means to deliver drugs and other pharmaceutical agents for cardiovascular applications; however, there is still a vast amount of research and clinical trials that must be performed before a formulation is brought to market. Advancements in targeting abilities within the body, as well as the introduction of theranostic liposomes, capable of both delivering treating and imaging cardiac diseases, may be expected in the future of this burgeoning field.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Contrast Media; Delayed-Action Preparations; Drug Carriers; Gene Transfer Techniques; Humans; Liposomes

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenol phytoalexin present in a variety of plant species and has been implicated to explain the health benefits of red wine. A wide range of health beneficial effects have been demonstrated for resveratrol in animal studies. In this review, we summarize the cardiovascular effects of resveratrol with emphasis on the molecular targets of the compound. In this regard, resveratrol stimulates endothelial production of nitric oxide, reduces oxidative stress, inhibits vascular inflammation and prevents platelet aggregation. In animal models of cardiovascular disease, resveratrol protects the heart from ischemia-reperfusion injury, reduces blood pressure and cardiac hypertrophy in hypertensive animals, and slows the progression of atherosclerosis. A number of direct and indirect target molecules mediating the aforementioned cardiovascular effects of resveratrol have been identified. These include, among others, the estrogen receptor α, the adenosine receptors, the cyclooxygenase 1, the histone/protein deacetylase sirtuin 1, the AMP-activated protein kinase, the Akt kinase, the nuclear factor-E2-related factor-2, and NF-κB. Molecular mechanisms involved in the signal cascades are discussed.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Molecular Targeted Therapy; Nitric Oxide; Resveratrol; Stilbenes

Cardiovascular diseases (CVDs) are a large burden on the healthcare system. Medicines are the primary treatment for these diseases; however, adherence to therapy is low. To optimise treatment and health outcomes for patients, it is important that adherence to cardiovascular medicines is maintained at an optimal level. Therefore, identifying effective interventions to improve adherence and persistence to cardiovascular therapy is of great significance.. This paper presents a review of the literature on interventions used in the community setting which aim to improve adherence to cardiovascular medicines in patients with hypertension, dyslipidaemia, congestive heart failure or ischaemic heart disease.. Several databases (Medline, EMBASE, PsychINFO, IPA, CINAHL, Pubmed, Cochrane) were searched for studies which were published from 1979-2009, evaluated interventions intended to improve adherence to cardiovascular medicines in the community setting, had at least one measure of adherence, and consisted of an intervention and comparison/control group.. Among 36 eligible studies (consisting of 7 informational, 15 behavioural, 1 social, and 13 combined strategy interventions), 17 (1 informational, 10 behavioural, and 6 combined) reported a significant improvement in adherence and/or persistence. Behavioural interventions were the most successful. Twenty-one studies (4 informational, 9 behavioural, and 8 combined) also demonstrated improvements in clinical outcomes, though, effects were frequently variable, contradictory and not related to changes in adherence.. Several types of interventions are effective in improving adherence and/or persistence within the CVD area and in the community setting. Behavioural interventions have shown the greatest success (compared to other types of interventions); and adding informational strategies has not resulted in further improvements in adherence. Improving adherence and persistence to cardiovascular medicines is a dynamic process that is influenced by many factors, and one which requires long term multiple interventions to promote medicine taking in patients.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Community Pharmacy Services; Counseling; Health Knowledge, Attitudes, Practice; Humans; Medication Adherence; Motivation; Organizational Objectives; Patient Education as Topic; Professional-Patient Relations; Program Development; Social Behavior

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diagnostic Techniques, Cardiovascular; Disease Progression; Electrocardiography; Global Health; Humans; Incidence; Muscular Dystrophies; Prognosis

Adenosine receptor stimulation has negative inotropic and dromotropic actions, reduces cardiac ischemia-reperfusion injury and remodeling, and prevents cardiac arrhythmias. In the vasculature, adenosine modulates vascular tone, reduces infiltration of inflammatory cells and generation of foam cells, and may prevent the development of atherosclerosis as a result. Modulation of insulin sensitivity may further add to the anti-atherosclerotic properties of adenosine signaling. In the kidney, adenosine plays an important role in tubuloglomerular feedback and modulates tubular sodium reabsorption. The challenge is to take advantage of the beneficial actions of adenosine signaling while preventing its potential adverse effects, such as salt retention and sympathoexcitation. Drugs that interfere with adenosine formation and elimination or drugs that allosterically enhance specific adenosine receptors seem to be most promising to meet this challenge.

Topics: Adenosine; Animals; Arrhythmias, Cardiac; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Humans; Insulin; Kidney; Receptors, Purinergic P1; Reperfusion Injury; Signal Transduction

Uncaria species (Gouteng in Chinese) have been used as a plant medicine to treat ailments of cardiovascular and central nervous systems. As the main alkaloid constituent of Uncaria species, isorhynchophylline has drawn extensive attention toward antihypertensive and neuroprotective activities in recent years. Isorhynchophylline mainly acts on cardiovascular and central nervous systems diseases including hypertension, brachycardia, arrhythmia, and sedation, vascular dementia, and amnesia. Isorhynchophylline also has effects on anticoagulation, inhibition vascular smooth muscle cell apoptosis and proliferation, anti-multidrug resistant of lung cells, anti-endotoxemic, and antispasmodic. The active mechanisms are related to modulation on calcium ion channel, protection neural and neuroglial cells against β-amyloid(25-35)-induced neurotoxicity and via inducing autophagy. As a candidate drug of several cardiovascular and central nervous systems diseases, isorhynchophylline will attract scientists to pursue the potential related pharmacological effects and its mechanism with new technologies. But relatively few clinical application of isorhynchophylline has been conducted on its pharmacological activities. It requires more in vivo validations and further investigations of antihypertensive and neuroprotective mechanisms of isorhynchophylline.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Central Nervous System Diseases; Humans; Indole Alkaloids; Neuroprotective Agents; Oxindoles; Phytotherapy; Plant Extracts; Uncaria

The asymmetric methylarginines inhibit nitric oxide synthesis in vivo by competing with L-arginine at the active site of nitric oxide synthase. High circulating levels of asymmetric dimethylarginine predict adverse outcomes, specifically vascular events but there is now increasing experimental and epidemiological evidence that these molecules, and the enzymes that regulate this pathway, play a mechanistic role in cardiovascular diseases. Recent data have provided insight into the impact of altered levels of these amino acids in both humans and rodents, however these reports also suggest a simplistic approach based on measuring, and modulating circulating asymmetric dimethylarginine alone is inadequate. This review outlines the basic biochemistry and physiology of endogenous methylarginines, examines both the experimental and observational evidence for a role in disease pathogenesis, and examines the potential for therapeutic regulation of these molecules.

Topics: Amidohydrolases; Animals; Arginine; Binding Sites; Binding, Competitive; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Catalytic Domain; Enzyme Inhibitors; Humans; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine

With the rising global incidence of cardiovascular disease, the challenge for the pharmaceutical industry is to identify novel biomarkers that will allow not only for the development of the next generation of cardiometabolic therapeutics, but also to serve as a sensitive mechanism to monitor and predict drug efficacy and potential toxicity. The advent of an 'omics' (systems biological) approach has vast implications for future disease treatment and prevention. Lipidomics is the latest addition to the 'omics' family and is rapidly gaining attention due to the technological improvements in mass spectrometry, allowing for the characterization of large number of lipids (and their respective subclasses) in a short amount of time with relatively minimal preparation.. The authors discuss the various techniques involved in plasma lipidomics as well as outline the role that lipidomics will play in phenotyping disease processes and corresponding therapeutic strategies. The article was formed through comprehensive Medline search of relevant publications in this area.. Despite the wealth of data that will emerge regarding the various lipid-molecular interactions and the functions of lipids within cells, a major challenge will be the parallel emergence of novel bioinformatics platforms in order to integrate this enormous data set with information generated from the emerging fields of genomics and proteomic analysis. Despite these challenges, lipidomics is likely to result in the reclassification of diseases from a molecular perspective and play a key role the eventuation of personalized medicine.

Topics: Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Computational Biology; Drug Design; Drug Discovery; Drug Industry; Humans; Lipids; Mass Spectrometry

Topics: Animals; Anti-Obesity Agents; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus; Humans; Hypoglycemic Agents; Obesity

Taxanes are cytotoxic drugs that stabilize cellular microtubules and are among the most active of the antineoplastic agents being widely used in the treatment of cancer patients. Furthermore, taxanes comprise a valuable tool in interventional cardiology. Following treatment with taxanes, in many patients, the risk of cardiovascular complications has recently been noted. This review examines the cardiac toxicity of treatment with taxanes and their use in cardiology and analyzes issues in clinical practice.

Topics: Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Cardiovascular Agents; Cardiovascular Diseases; Drug Synergism; Humans; Risk Assessment; Risk Factors; Taxoids; Tubulin Modulators

The renin-angiotensin-aldosterone system (RAAS) has evolved in humans as one of the main physiological networks by which blood pressure and blood flow to vital organs is maintained. The RAAS has evolved to circumvent life-threatening events such as hemorrhage and starvation. Although short-term activation of this system had been well suited to counteract such catastrophes of early man, excessive chronic activation of the RAAS plays a fundamental role in the development and progression of cardiovascular disease in modern man. The RAAS is an intricate network comprising a number of major organ systems (heart, kidney, and vasculature) and signaling pathways. The main protagonists are renin, angiotensinogen (Ang), angiotensin I (Ang I), angiotensin II (Ang II), and aldosterone (Aldo). The study and delineation of each of these substances has allowed modern medicine to create targets by which cardiovascular disease can be treated. The main modulators that have been synthesized in this respect are angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor blockers (MRBs), and direct renin inhibitors (DRIs). Over the past few decades, each of these substances has proven efficacious to varying degrees amongst a number of clinical settings. Additionally, there exists data for and against the use of these agents in combination. The use of these agents in combination poses a larger question conceptually: can excessive pharmacological inhibition of the RAAS lead to patient harm? This perspective will examine the concept of a neurohormonal inhibition ceiling in pertinent experimental and clinical trials.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Neurotransmitter Agents; Renin-Angiotensin System

In recent years, ACE Inhibitors (ACEIs) and Angiotensin II receptor antagonists (also known as AT1 receptor antagonists (AT1-RAs), angiotensin receptor blockers (ARBs), or Sartans), have become the drugs of choice for the treatment of hypertension, heart and renal failure, coronary artery diseases, myocardial infarction and diabetes. By suppressing angiotensin and potentiating bradykinin effects, ACEIs and ARBs activate hemodynamic, metabolic and cellular mechanisms that not only reduce high blood pressure, but also protect the endothelium, the heart, the kidney and the brain, namely the target organs which are at risk in cardiovascular diseases. Major therapeutic benefits of these drugs are the reduction of cardiovascular events and the amelioration of the quality of life and of the patient survival. Results from large clinical trials have established that ACEIs and ARBs are efficient and safe drugs, suitable for the chronic treatments of cardiovascular diseases. Side effects are rare and easily manageable in most cases. The following is a brief review of the basic actions and mechanisms by which two opposing systems, the renin-angiotensin (RAS) and the kallikrein-kinin (KKS), interact in the regulation of cardiovascular and fluid homeostasis to keep the balance in healthy life and correct the imbalance in pathological conditions. Here we discuss how and why imbalances created by overactive RAS are best corrected by treatments with ACEI or AT1-RAs.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular Agents; Cardiovascular Diseases; Homeostasis; Humans; Kallikrein-Kinin System; Kallikreins; Kinins; Practice Guidelines as Topic; Receptors, Bradykinin; Renin-Angiotensin System; Signal Transduction

Diabetes mellitus currently affects more than 170 million individuals worldwide and is expected to afflict another 200 million individuals in the next 30 years. Complications of diabetes as a result of oxidant stress affect multiple systems throughout the body, but involvement of the cardiovascular system may be one of the most severe in light of the impact upon cardiac and vascular function that can result in rapid morbidity and mortality for individuals. Given these concerns, the signaling pathways of the mammalian target of rapamycin (mTOR) offer exciting prospects for the development of novel therapies for the cardiovascular complications of diabetes. In the cardiovascular and metabolic systems, mTOR and its multi-protein complexes of TORC1 and TORC2 regulate insulin release and signaling, endothelial cell survival and growth, cardiomyocyte proliferation, resistance to β-cell injury, and cell longevity. Yet, mTOR can, at times, alter insulin signaling and lead to insulin resistance in the cardiovascular system during diabetes mellitus. It is therefore vital to understand the complex relationship mTOR and its downstream pathways hold during metabolic disease in order to develop novel strategies for the complications of diabetes mellitus in the cardiovascular system.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Diabetes Complications; Diabetes Mellitus; Humans; Signal Transduction; TOR Serine-Threonine Kinases

Cardiovascular disease (CVD) risk assessment tools such as the Framingham Risk Functions, often called Framingham Risk Scores, are common in the evaluation of the CVD risk among individuals in the general population. These functions are multivariate risk algorithms that combine data on CVD risk factors, such as sex, age, systolic blood pressure, total cholesterol level, high-density lipoprotein cholesterol level, smoking behavior, and diabetes status, to produce an estimate (or risk) of developing CVD or a component of it (such as coronary heart disease, stroke, peripheral vascular disease, and heart failure) over a fixed period (eg, the next 10 years). These estimates of CVD risk are often major inputs in recommending drug treatments, such as agents to reduce cholesterol level. The Framingham Risk Functions are valid in diverse populations, at times requiring a calibration adjustment for proper applicability. With the realization that individuals with human immunodeficiency virus (HIV) infection often have elevated CVD risk factors, the evaluation of CVD risk for these individuals becomes a serious concern. Researchers have recently developed new CVD risk functions specifically for HIV-infected patients and have also examined the extension of existing Framingham Risk Functions to the HIV-infected population. This article first reviews briefly the Framingham Study and risk functions, covering their objectives, their components, evaluation of their performance, and transportability and validity on non-Framingham populations. It then reviews the development of CVD risk functions for HIV-infected individuals and comments on the usefulness of extending the Framingham risk equation to the HIV-infected population and the need to develop more-specific risk prediction equations uniquely tailored to this population.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Global Health; HIV Infections; Humans; Risk Factors; Time Factors; United States

Cardiovascular disease remains the commonest health problem in developed countries, and residual risk after implementing all current therapies is still high. The use of marine omega-3 fatty acids (DHA and EPA) has been recommended to reduce cardiovascular risk by multiple mechanisms.. To update the current evidence on the influence of omega-3 on the rate of cardiovascular events.. We used the MEDLINE and EMBASE databases to identify clinical trials and randomized controlled trials of omega-3 fatty acids (with quantified quantities) either in capsules or in dietary intake, compared to placebo or usual diet, equal to or longer than 6 months, and written in English. The primary outcome was a cardiovascular event of any kind and secondary outcomes were all-cause mortality, cardiac death and coronary events. We used RevMan 5·1 (Mantel-Haenszel method). Heterogeneity was assessed by the I2 and Chi2 tests. We included 21 of the 452 pre-selected studies.. We found an overall decrease of risk of suffering a cardiovascular event of any kind of 10 % (OR 0·90; [0·85-0·96], p = 0·001), a 9 % decrease of risk of cardiac death (OR 0·91; [0·83-0·99]; p = 0·03), a decrease of coronary events (fatal and non-fatal) of 18 % (OR 0·82; [0·75-0·90]; p < 1 × 10⁻⁴), and a trend to lower total mortality (5 % reduction of risk; OR 0·95; [0·89-1·02]; p = 0·15. Most of the studies analyzed included persons with high cardiovascular risk.. marine omega-3 fatty acids are effective in preventing cardiovascular events, cardiac death and coronary events, especially in persons with high cardiovascular risk.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Coronary Disease; Diet; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans

The following are highlights from the new series, Circulation: Cardiovascular Quality and Outcomes Topic Review. This series will summarize the most important manuscripts, as selected by the Editor, that have published in the Circulation portfolio. The objective of this new series is to provide our readership with a timely, comprehensive selection of important papers that are relevant to the quality and outcomes and general cardiology audience. The studies included in this article represent the most significant research in the area of cardiovascular disease in the elderly.

Topics: Age Factors; Aged; Aged, 80 and over; Cardiac Catheterization; Cardiac Surgical Procedures; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Female; Health Services Research; Humans; Male; Outcome and Process Assessment, Health Care; Predictive Value of Tests; Risk Assessment; Risk Factors; Treatment Outcome

Cardiovascular complications are the leading cause of death and morbidity in patients with diabetes; accounting for around 7 out of 10 of all causes of death in this population. Returning patients to normoglycaemia alone has been shown to have little effect on cardiovascular end points, therefore new therapies and strategies are required in order to reduce the incidence and improve outcomes of cardiovascular disease in diabetic individuals. The metabolic enzyme AMP-activated protein kinase (AMPK) has emerged in recent years as an attractive potential therapeutic target for diabetic vascular disease, and studies have shown improved endothelial and smooth muscle cell function following AMPK activation. Additionally, improved lipid profiles, reduced hypertrophic cardiomyocyte growth and protection from cardiac ischaemia-reperfusion injury have also been observed as beneficial outcomes of AMPK therapy. In this review we will discuss in detail the potential downstream targets of AMPK activation in the cardiovascular system. We will also provide an overview of long-known and newly discovered direct and indirect AMPK activators, as well as novel synthesised AMPK-activating compounds, which will highlight the potential for further exploiting AMPK in a therapeutic context for cardiovascular disease in diabetes.

Topics: AMP-Activated Protein Kinases; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Delivery Systems; Enzyme Activation; Humans; Hypoglycemic Agents; Up-Regulation

To review the relationship between health literacy and adherence to cardiovascular/diabetes medication.. We searched EMBASE (1974-February 2012) and MEDLINE (1948-February 2012). Search terms included health literacy, numeracy, health education and related terms, health literacy measurement tools, and medication adherence.. English-language articles of all study designs were considered. Articles were included if they had a measurement of health literacy and medication adherence and if participants were older adults taking drugs for cardiovascular illness or diabetes mellitus.. A total of 1310 citations were reviewed, including 9 articles that reported on 7 research studies. Most studies were retrospective, and all were based in the US. Because there was considerable diversity in measurements, participant characteristics, and outcome measures, we conducted a narrative synthesis rather than a meta-analysis. In assessing study validity, we looked at participant selection, method of measuring health literacy and medication adherence, missing data or losses, and adjustment for confounders. Of the 7 included studies, only 1 found a demonstrable association between health literacy and refill adherence. One clinical trial failed to show significant improvements in medication adherence after an intervention to improve health literacy.. The current evidence does not show a definite association between health literacy and medication adherence in older adults with cardiovascular disease or diabetes mellitus. In the absence of a definite link, efforts to develop interventions to improve health literacy would not necessarily improve adherence to cardiovascular medications. There is an urgent need for robust studies outside of the US, with wider, generalized recruitment of participants.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Health Literacy; Humans; Hypoglycemic Agents; Medication Adherence; Self Administration

Underuse is defined as the absence of initiation of an effective treatment in subjects with a condition for which one or several drug classes have demonstrated their efficacy. Indeed, "effective treatment" actually means favourable benefit/risk ratio. To propose a detailed and functional definition of underuse for frail elderly we should discuss, beforehand, the better way to assess benefit/risk ratio of drugs in this population. Our work is based on a literature review in the field of inappropriate prescription and therapeutic optimization. We can foresee the hard way to accurately define underuse for frail geriatric patients because of the difficulties encountered to demonstrate drug efficacy, drug effectiveness, or even more drug risk in this specific population. Potential benefit of underused medications in this population are poorly evaluated before and even after market authorization. Premarketing clinical trials and pharmacovigilance also yield only relatively restricted information on safety of use. Underuse is a non optimal prescription modality and presumes a judgment on prescription act. This can lead to recommendations or quality indicators. It should therefore be scientifically valid and closely fit with a loss of health or loss of quality of life with a satisfying proof level. But the literature generally adopts an unsophisticated point of view. Medication introduction on the basis of a debatable definition of underuse could lead to an accumulation of useless drugs with potential adverse effects which is overuse.

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Frail Elderly; France; Humans; Inappropriate Prescribing; Quality Indicators, Health Care; Risk Assessment; Treatment Outcome; Utilization Review

We reviewed this subject in 2009, pointing out that, to the process of atherothrombosis, glycocalyx dysfunction and damage must be added to the previous known causitive factors. Glycocalyx dysfunction is possibly the very first step in the process of atherothrombosis, being a protective layer between the endothelial cells and the blood. We emphasise the unique feature of glycocalyx mediated vasodilatation in that it is initiated purely by mechanical changes, i.e., changes in vascular wall shear stress, allowing conduit arteries to adjust diameter to demanded blood flow rate. The predeliction of atheroma to sites of low shear stress, the inhibition of the shear response by lumenal hyperglycaemia, and the fact that the response is mediated by nitric oxide (NO), an anti-atheromatous agent has led to the hypothesis that impairment of this pathway is pro-atherogenic. In the microcirculation it has been shown that the glycocalyx must be added to the factors involved in the Starling hypothesis of tissue fluid generation and exchange. As a consequence glycoalyx dysfunction in hyperglycaemia has been postulated to cause oedema and microalbinuria. We suggested that perhaps the arterial glycocalyx will become the most important for future early prevention of people at risk of cardiovascular disease. The advances in this subject since 2009 are the subject of the present review. What has struck us when searching the literature is that research into the glycocalyx has increased very much and now comes from many disciplines; e.g., diabetes, hypertension, bioengineering, physiology, critical care, cardiology, shock. This update is by no means exhaustive, but hopes, again, to bring to the attention of the pharmaceutical industry, the need for grants in the appropriate experimental models.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Endothelial Cells; Glycocalyx; Humans

Combination therapy, specifically with aspirin, cholesterol and blood pressure-lowering drugs, substantially reduces the risk of coronary heart disease, but the full preventive effect is only realized if treatment continues indefinitely. Our objective was to provide a summary estimate of adherence to drugs that prevent coronary heart disease, according to drug class and use in people who have had a myocardial infarction (secondary prevention) and people who have not (primary prevention).. A meta-analysis of data on 376,162 patients from 20 studies assessing adherence using prescription refill frequency for the following 7 drug classes was performed: aspirin, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium-channel blockers, thiazides, and statins. Meta-regression was used to examine the effects of age, payment, and treatment duration.. The summary estimate for adherence across all studies was 57% (95% confidence interval [CI], 50-64) after a median of 24 months. There were statistically significant differences in adherence between primary and secondary prevention: 50% (CI, 45-56) and 66% (CI, 56-75), respectively (P=.012). Adherence was lower for thiazides (42%) than for angiotensin receptor blockers (61%) in primary prevention (P=.02). There were no other statistically significant differences between any of the drug classes in primary or secondary prevention studies. Adherence decreased by 0.15% points/month (P=.07) and was unrelated to age or whether patients paid for their pills.. Adherence to preventive treatment is poor and little related to class of drug, suggesting that side effects are not the main cause. General, rather than class-specific, measures at improving adherence are needed.

Topics: Adrenergic beta-Antagonists; Age Factors; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anticholesteremic Agents; Antihypertensive Agents; Aspirin; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Drug Administration Schedule; Drug Costs; Drug Prescriptions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Medication Adherence; Myocardial Infarction; Platelet Aggregation Inhibitors; Primary Prevention; Secondary Prevention; Self Administration; Sodium Chloride Symporter Inhibitors; Time Factors

The transient receptor potential channel (TRP) family comprises at least 28 genes in the human genome. These channels are widely expressed in many different tissues, including those of the cardiovascular system. The transient receptor potential channel melastatin 4 (TRPM4) is a Ca(2+)-activated non-specific cationic channel, which is impermeable to Ca(2+). TRPM4 is expressed in many cells of the cardiovascular system, such as cardiac cells of the conduction pathway and arterial and venous smooth muscle cells. This review article summarizes the recently described roles of TRPM4 in normal physiology and in various disease states. Genetic variants in the human gene TRPM4 have been linked to several cardiac conduction disorders. TRPM4 has also been proposed to play a crucial role in secondary hemorrhage following spinal cord injuries. Spontaneously hypertensive rats with cardiac hypertrophy were shown to over-express the cardiac TRPM4 channel. Recent studies suggest that TRPM4 plays an important role in cardiovascular physiology and disease, even if most of the molecular and cellular mechanisms have yet to be elucidated. We conclude this review article with a brief overview of the compounds that have been shown to either inhibit or activate TRPM4 under experimental conditions. Based on recent findings, the TRPM4 channel can be proposed as a future target for the pharmacological treatment of cardiovascular disorders, such as hypertension and cardiac arrhythmias.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Gene Expression Regulation; Genetic Variation; Humans; TRPM Cation Channels

Several cardiovascular drugs may induce or worsen orthostatic hypotension especially in patients treated for hypertension, coronary artery disease and heart failure. Orthostatic hypotension is more frequent in polymedicated elderly patients with co-morbidities (prevalence 23%). In hypertensive elderly patients, the combination of three antihypertensive agents including a beta-blocker induces more frequently orthostatic hypotension. Supplementation in water and especially salt is generally not recommended in case of hypertension and heart failure. Education of patient to preventive counter-pressure maneuvers and muscle training of the lower limbs must be part of treatment. Midodrine causes supine hypertension in almost 25% of patients precluding to take this medication at the end of the afternoon. In severe heart failure, midodrine seems to be helpful to optimize drug treatment in patients suffering from hypotension.

Topics: Age Factors; Aged; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Contraindications; Drinking Water; Drug Therapy, Combination; Heart Failure; Humans; Hypotension, Orthostatic; Iatrogenic Disease; Midodrine; Patient Education as Topic; Polypharmacy; Vasoconstrictor Agents

Resveratrol (3,5,4'-trans-trihydroxystilbene) is a naturally occurring phytoalexin that is found in medicinal plants, grape skin, peanuts and red wine. Resveratrol exhibits a remarkable range of biological activities, including anticancer activity, antitubulin activity, anti-cardiovascular disease activity, etc. Several other natural products are structurally similar to resveratrol and also present in food. In addition, a series of resveratrol derivatives have been synthesized by the addition of defined functional groups to increase the potency or enhance the activity of specific properties of resveratrol. These resveratrol derivatives might provide promising functions as cardiovascular disease chemopreventive agents. In this review, we will attempt to summarize the main developments of resveratrol derivatives in cardiovascular disease and the main developments have occurred in derivatives of resveratrol's structure-activity relationship and cardiovascular disease over the last couple of decades.

Topics: AMP-Activated Protein Kinases; Apoptosis; Cardiovascular Agents; Cardiovascular Diseases; Humans; Hydroxamic Acids; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Resveratrol; Sirtuin 1; Stilbenes

Liposome-based pharmaceuticals used within the cardiovascular system are reviewed in this article. The delivery of diagnostic and therapeutic agents by plain liposomes and liposomes with surface-attached targeting antibodies or polyethylene glycol to prolong their circulation time and accumulation at vascular injuries, ischemic zones or sites of thrombi are also discussed. An overview of the advantages and disadvantages of liposome-mediated in vitro, ex vivo and in vivo targeting is presented, including discussion of the targeting of liposomes to pathological sites on the blood vessel wall and a description of liposomes that can be internalized by endothelial cells. Diagnostic liposomes used to target myocardial infarction and the relative importance of liposome size, targetability of immunoliposomes and prolonged circulation time on the efficiency of sealing hypoxia-induced plasma membrane damage to cardiocytes are discussed as a promising approach for therapy. The progress in the use of targeted liposomal plasmids for the transfection of hypoxic cardiomyocytes and myocardium is presented. Stent-mediated liposomal-based drug delivery is also reviewed briefly.

Topics: Animals; Antibodies; Biological Transport; Cardiovascular Agents; Cardiovascular Diseases; Chemistry, Pharmaceutical; Drug Compounding; Drug Stability; Humans; Lipids; Liposomes; Molecular Imaging; Polyethylene Glycols; Technology, Pharmaceutical

Reactive oxygen species (ROS) are implicated as injurious and as signaling agents in human maladies including inflammation, hyperoxia, ischemia-reperfusion and acute lung injury. ROS produced by the endothelium play an important role in vascular pathology. They quench, for example, nitric oxide, and mediate pro-inflammatory signaling. Antioxidant interventions targeted for the vascular endothelium may help to control these mechanisms. Animal studies have demonstrated superiority of targeting ROS-quenching enzymes catalase and superoxide dismutase to endothelial cells over nontargeted formulations. A diverse arsenal of targeted antioxidant formulations devised in the last decade shows promising results for specific quenching of endothelial ROS. In addition to alleviation of toxic effects of excessive ROS, these targeted interventions suppress pro-inflammatory mechanisms, including endothelial cytokine activation and barrier disruption. These interventions may prove useful in experimental biomedicine and, perhaps, in translational medicine.

Topics: Animals; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Chemistry, Pharmaceutical; Drug Carriers; Drug Design; Endothelium, Vascular; Humans; Oxidative Stress; Reactive Oxygen Species; Signal Transduction

Current acetylsalicylic acid (ASA) dosing algorithms for the prevention of secondary thrombotic events in acute coronary syndrome (ACS) patients are inconsistent and lack sufficient data support.. We performed a systematic review of the literature for studies that assessed clinical outcomes in patients with ACS following coronary stent insertion (SI) or medical treatment (MT). Acetylsalicylic acid dosing was stratified into low- (<160 mg) and high- (≥ 160 mg) dose categories. Outcomes were assessed at 1, 6, and 12 months and included major bleeding, myocardial infarction, and all-cause death. A random-effects meta-analysis was used to estimate the value of the mean for each outcome variable.. Of 12,472 publications identified, 136 studies with 289,330 patients were analyzed. In the 1-month SI analysis, proportions of patients (95% CI) in the low- and high-dose ASA categories experiencing major bleeding were 2.1% (1.5-2.6) and 1.9% (0.0-3.8); proportions with myocardial infarction were 2.1% (1.3-2.8) and 1.8% (0.9-2.6); and proportions of all-cause death were 2.8% (2.2-3.4) and 2.4% (1.3-3.5), respectively. Results were similar in the MT analysis, except that major bleeding rates for low and high doses were 1.7% (1.3-2.2) and 4.0% (2.2-5.8), respectively. Regression analyses suggested that the proportion of patients reporting each of the outcomes evaluated were not significantly different between the low- and high-dose categories, with the exception of the 1-month major bleeding following MT.. Our results suggest no improved clinical outcomes associated with higher ASA maintenance doses in ACS patients receiving SI or MT. In the MT analysis, there was more major bleeding in the first month after an ACS event with high-dose ASA.

Topics: Acute Coronary Syndrome; Aged; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Bypass; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Hemorrhage; Humans; Male; Middle Aged; Prosthesis Implantation; Stents

Topics: Animals; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Contrast Media; Humans; Immunoconjugates; Liposomes; Predictive Value of Tests; Treatment Outcome

The clinical utility and ultimately guideline recommendations for aldosterone receptor-blocking agents in cardiovascular disorders is clearly mentioned by a number of major clinical outcome trials. This article reviews the pharmacology, clinical efficacy and safety of the two currently available receptor blocking agents: spironolactone and eplerenone. The potential utility of eplerenone and other mineralocorticoid receptor agents beyond current clinical indications will also be examined.

Topics: Aldosterone; Animals; Cardiovascular Agents; Cardiovascular Diseases; Eplerenone; Humans; Hydrocortisone; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Spironolactone

This paper provides an update on the mechanisms of vascular impairment associated with insulin resistance and the pathogenesis of diabetic nephropathy and peripheral artery disease (PAD). It also considers the optimal treatment strategies for systemic vascular protection in light of recent findings. This area is of major clinical importance given the ongoing global epidemic of type 2 diabetes and the pivotal role played by insulin resistance in the mechanism of vascular impairment that manifests as macroangiopathy and microangiopathy. Timely diagnosis and intervention is critical in patients with systemic arteriosclerotic disease. Therefore, treatment strategies are aimed not only at targeting the presenting pathology, but also at reducing the risk of cardiovascular events. These efforts can help reduce the risk of both cardiovascular events and mortality. Treatment for PAD includes pharmacotherapy, endovascular treatment, and vascular reconstruction, along with exercise therapy. Because PAD can cause ischemia in the lower extremities, typical drug approaches include use of vasodilators and antiplatelet agents. Beraprost sodium and cilostazol are common choices in Japan, and their risks and benefits are discussed. Of note, beraprost has several therapeutic properties, including vascular endothelial protection, and antiplatelet and anti-inflammatory effects, in addition to vasodilatory activity. In patients with PAD, these activities improve the pathological process in the lower extremities and reduce the incidence of systemic vascular events. Recent preclinical findings indicate that beraprost improves not only ischemic extremities through its vasodilatory properties, but also reduces the insulin resistance which affects vascular endothelium. In this way, beraprost may contribute to an overall systemic vascular protective action. The use of agents, such as beraprost, which are capable of improving insulin resistance and resulting vascular endothelial function at an earlier disease stage, may ultimately contribute to increasing the life expectancy of patients with PAD.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endovascular Procedures; Exercise Therapy; Humans; Hypoglycemic Agents; Insulin Resistance; Peripheral Arterial Disease; Treatment Outcome

Melatonin synchronizes circadian rhythms with light/dark period and it was demonstrated to correct chronodisruption. Several melatonin receptor agonists with improved pharmacokinetics or increased receptor affinity are being developed, three of them are already in clinical use. However, the actions of melatonin extend beyond chronobiology to cardiovascular and metabolic systems as well. Given the high prevalence of cardiovascular disease and their common occurrence with chronodisruption, it is of utmost importance to classify the cardiometabolic effects of the newly approved and putative melatoninergic drugs.. In the present review, the available (although very sparse) data on such effects, in particular by the approved (circadin, ramelteon, agomelatine) or clinically advanced (tasimelteon, piromelatine = Neu-P11, TIK-301) compounds are summarized. The authors have searched for an association with blood pressure, vascular reactivity, ischemia, myocardial and vascular remodeling and metabolic syndrome.. The data suggest that cardiovascular effects of melatonin are at least partly mediated via MT(1)/MT(2) receptors and associated with its chronobiotic action. Therefore, despite the sparse direct evidence, it is believed that these effects will be shared by melatonin analogs as well. With the expected approval of novel melatoninergic compounds, it is suggested that the investigation of their cardiovascular effects should no longer be neglected.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Circadian Rhythm; Drug Design; Humans; Melatonin; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2

The decision whether to treat individuals not previously known to have cardiovascular disease is based on a new risk table in which Dutch research data on morbidity have been incorporated. An explanation of the roles of additional risk factors ignored in the cardiovascular risk function, such as a sedentary lifestyle and a high BMI, is provided. A method for estimating the cardiovascular risk in patients with diabetes mellitus and rheumatoid arthritis has been developed. New recommendations concerning the measurement of blood pressure at home and in the ambulatory setting have been formulated. The recommendations for the choice of antihypertensive drugs have been revised. The recommendations on handling therapy-resistant hypertension are provided. Recommendations for choosing statins based on a current cost-effectiveness analysis are provided.

Topics: Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Humans; Hypertension; Hypolipidemic Agents; Netherlands; Practice Guidelines as Topic; Risk Assessment; Risk Management

Pharmacological inhibitions of the renin-angiotensin-aldosterone system (RAAS) are crowned with one of the greatest success in the current field of cardiovascular medicine. In addition to the systemic effects including elevation of blood pressure and retention of sodium and water, sustained and excessive RAAS activation has direct and deleterious effects on a wide variety of tissues. Recent studies have deciphered the regulatory mechanisms underlying tissue RAAS activation at cellular and molecular levels, and suggested pathogenic roles of RAAS activation in hitherto unanticipated disorders such as muscular dystrophy, osteoporosis, cancer, and aging itself. Novel drugs targeting RAAS are under research and development in search for further efficacy, specificity, and even multifunctionality. This review will discuss the current progress and future perspective of RAAS research.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Cardiovascular Diseases; Humans; Hypertension; Renin; Renin-Angiotensin System

This review considers issues dealing with the role of nitric oxide and endothelial function/dysfunction in providing a number of physiological and pathophysiological processes and various body systems functioning. It also covers in details the possible ways of pharmacological management of endothelial dysfunction (ED) using drugs of different pharmacological groups (classes). Diverse pharmacological effects which have various degree of intensity and presented at various stages of ED pathogenesis are discussed. The value and urgency of search and development of agents with endothelial protection potential are studied in available experimental and clinical works on the considerable role of endothelial system in cardiovascular diseases and lack of specific means for prevention and treatment of endothelial dysfunction. Integrated morphological-functional approach to assessment of ED and endothelial protection of substances was developed and implemented in experimental practice in Cardiovascular Agents Laboratory of the Volgograd State Medical University Research Institute of Pharmacology. Various ED models were tested and most valid ones were selected. Endothelial protection of new compounds such as Salifen and Flavicin are considered and compared with cardiovascular drugs, antioxidants with metabolic effects, GABA derivatives. These drugs are assumed to belong to a new class of drugs--endothelial protection drugs.

Topics: Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Endothelium, Vascular; Flavonoids; GABA Agents; Humans; Medication Therapy Management; Metabolism; Nitric Oxide; Protective Agents

Biomarkers have proven to be critical tools in both cardiovascular clinical practice and clinical research. In clinical practice, biomarkers are used to identify patients at risk for disease, stratify disease severity, guide intervention decisions and monitor patient response to therapy. Biomarkers are also used extensively to improve the design of cardiovascular clinical trials, identify 'at-risk' populations, allow for preliminary screening for response, identify appropriate dose ranges, study subgroup differences and identify early safety concerns. The purpose of this paper is to describe current key cardiovascular biomarker initiatives and to outline some of the important considerations in applying these biomarkers in a clinical trial setting, utilizing the examples of HDL cholesterol, HDL-targeted therapies and imaging tools used to assess HDL-targeted therapies as a case study.

Topics: Biomarkers; Biomedical Research; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Coronary Angiography; Device Approval; Drug Approval; Drugs, Investigational; Humans; United States; United States Food and Drug Administration

Intracranial artery stenosis (ICAS) is a narrowing of an intracranial artery, which is a common etiology for ischemic stroke. In this commentary, we review key aspects of the discrimination between non-stroke controls and ischemic stroke patients on the background of phospholipid ω3-fatty acid (DHA, EPA) composition. The discussion is embedded in the presentation of general effects of long-chain ω3 polyunsaturated fatty acids (PUFAs) in cardio-cerebro-vascular diseases (CCVDs) and Alzheimer dementia (AD).. ICAS is a common stroke subtype and has emerged as a major factor in recurrent stroke and vascular mortality. DHA and EPA are important fatty acids to distinguish between NCAS (no cerebral arteriosclerotic stenosis) and ICAS in stroke. The risk of ICAS is inversely correlated with the DHA content in phospholipids. Furthermore, a mechanistic explanation has been proposed for the beneficial effects of PUFAs in CCVDs and AD.. Whereas the beneficial effects of EPA/DHA for cardiovascular diseases and stroke seem to be beyond question, preventive effects in patients with very mild cognitive dysfunction and beginning Alzheimer's disease undoubtedly need confirmation by larger clinical trials. A collaborative international basic science approach is warranted considering cautiously designed studies in order to avoid ethical problems.

Topics: Alzheimer Disease; Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Constriction, Pathologic; Dementia, Vascular; Diet; Dietary Supplements; Fatty Acids, Omega-3; Humans; Intracranial Arterial Diseases; Nutrition Policy; Stroke

In recent years, prominent roles for microRNAs (miRNAs) have been uncovered in several cardiovascular disorders. The ability to therapeutically manipulate miRNA expression and function through systemic or local delivery of miRNA inhibitors, referred to as antimiRs, has triggered enthusiasm for miRNAs as novel therapeutic targets. Here, we focus on the pharmacokinetic and pharmacodynamic properties of current antimiR designs and their relevance to cardiovascular indications, and evaluate the opportunities and obstacles associated with this new therapeutic modality.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Gene Expression Regulation; Humans; MicroRNAs

Early trials evaluating the effect of omega 3 fatty acids (ω-3 FA) reported benefits for mortality and cardiovascular events but recent larger studies trials have variable findings. We assessed the effects of ω-3 FA on cardiovascular and other important clinical outcomes.. We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for all randomized studies using dietary supplements, dietary interventions, or both. The primary outcome was a composite of cardiovascular events (mostly myocardial infarction, stroke, and cardiovascular death). Secondary outcomes were arrhythmia, cerebrovascular events, hemorrhagic stroke, ischemic stroke, coronary revascularization, heart failure, total mortality, nonvascular mortality, and end-stage kidney disease. Twenty studies including 63030 participants were included. There was no overall effect of ω-3 FA on composite cardiovascular events (relative risk [RR]=0.96; 95% confidence interval [CI], 0.90-1.03; P=0.24) or on total mortality (RR=0.95; 95% CI, 0.86-1.04; P=0.28). ω-3 FA did protect against vascular death (RR=0.86; 95% CI, 0.75-0.99; P=0.03) but not coronary events (RR=0.86; 95% CI, 0.67-1.11; P=0.24). There was no effect on arrhythmia (RR=0.99; 95% CI, 0.85-1.16; P=0.92) or cerebrovascular events (RR=1.03; 95% CI, 0.92-1.16; P=0.59). Adverse events were more common in the treatment group than the placebo group (RR=1.18, 95% CI, 1.02-1.37; P=0.03), predominantly because of an excess of gastrointestinal side effects.. ω-3 FA may protect against vascular disease, but the evidence is not clear-cut, and any benefits are almost certainly not as great as previously believed.

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Dietary Supplements; Evidence-Based Medicine; Fatty Acids, Omega-3; Female; Humans; Male; Middle Aged; Odds Ratio; Treatment Outcome

The environment in which the field of cardiology finds itself has been rapidly changing. This supplement, an expansion of a report created for the Board of Trustees, is intended to provide a timely snapshot of the socio-economic, political, and scientific aspects of this environment as it applies to practice both in the United States and internationally. This publication should assist healthcare professionals looking for the most recent statistics on cardiovascular disease and the risk factors that contribute to it, drug and device trends affecting the industry, and how the practice of cardiology is changing in the United States.

Topics: Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Surgical Procedures; Health Policy; Humans; Prevalence; Risk Factors; Societies, Medical; United States; Workforce

Patients with diabetes and prediabetes are at high risk for micro- and macrovascular complications. A multifactorial management strategy improves their prognosis considerably. Of concern is that these patients often fall between two specialties: cardiovascular medicine and diabetology. Practice guidelines for this patient category have been issued in collaboration between the European Society of Cardiology and the European Association for the Study of Diabetes to ascertain management according to the best available evidence. This article discusses why and for whom such guidelines are important.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Evidence-Based Medicine; Humans; Hypoglycemic Agents; Practice Guidelines as Topic; Prediabetic State; Risk Reduction Behavior

All coronary patients should be advised and have the opportunity to access a comprehensive cardiovascular prevention and rehabilitation programme, addressing all aspects of lifestyle - smoking cessation, healthy eating and being physically active - together with more effective management of blood pressure, lipids and glucose. To achieve the clinical benefits of a multidisciplinary and multifactorial prevention programme we need to integrate professional lifestyle interventions with effective risk factor management, and evidence based drug therapies, appropriately adapted to the medical, cultural, and economic setting of a country. The challenge is to engage and motivate cardiologists, physicians and health professionals to routinely practice high quality preventive cardiology in hospital and community, and a health care system which invests in prevention.

Topics: Attitude of Health Personnel; Cardiovascular Agents; Cardiovascular Diseases; Clinical Competence; Combined Modality Therapy; Guideline Adherence; Health Knowledge, Attitudes, Practice; Humans; Motivation; Practice Guidelines as Topic; Primary Prevention; Risk Assessment; Risk Factors; Risk Reduction Behavior; Secondary Prevention; Treatment Outcome

Increasing life expectancy in industrialized societies has resulted in a huge population of older adults with cardiovascular disease. Despite advances in device therapy and surgery, the mainstay of treatment for these disorders remains pharmacological. Hypertension affects two-thirds of older adults and remains a potent risk factor for coronary artery disease, chronic heart failure, atrial fibrillation, and stroke in this age group. Numerous trials have demonstrated reduction in these adverse outcomes with antihypertensive drugs. After acute myocardial infarction, β-adrenergic blockers reduce mortality regardless of patient age. Statins and antiplatelet drugs have proven beneficial in both primary and, especially, secondary prevention of coronary events in older adults. In elders with chronic heart failure, loop diuretics must be used cautiously, owing to their higher potential for adverse effects, whereas angiotensin-converting-enzyme inhibitors and β-blockers reduce symptoms and prolong survival. The high risk of stroke in elderly patients with atrial fibrillation is markedly reduced with warfarin, although bleeding risk is increased. The high prevalence of polypharmacy among older adults with cardiovascular disease, coupled with age-associated physiological changes and comorbidities, provides major challenges in adherence and avoidance of drug-related adverse events.

Topics: Age Factors; Aged; Aging; Cardiovascular Agents; Cardiovascular Diseases; Evidence-Based Medicine; Female; Humans; Male; Middle Aged; Patient Selection; Risk Assessment; Treatment Outcome

Nowadays, the great saphenous vein is the vascular conduit that is most frequently employed in coronary and peripheral revascularization surgery. It is known that saphenous vein bypass grafts have shorter patency than arterial ones, partly because the wall of the normal saphenous vein has different structural and functional characteristics. The features of this vein can be affected by the large distention pressures it is submitted to during its preparation and insertion into the arterial system. Indeed, a vein graft is subjected to considerable changes in hemodynamic forces upon implantation into the arterial circulation, since it is transplanted from a non-pulsatile, low-pressure, low-flow environment with minimal shear stress to a highpressure system with pulsatile flow, where it undergoes cyclic strain and elevated shear. These changes can be responsible for functional and morphological alterations in the vessel wall, culminating in intima hyperproliferation and atherosclerotic degeneration, which contribute to early graft thrombosis. This review has followed a predetermined strategy for updating information on the human saphenous vein (HSV). Besides presenting the aspects relative to the basic pharmacology, this text also includes surgical aspects concerning HSV harvesting, the possible effects of the major groups of cardiovascular drugs on the HSV, and finally the interference of major cardiovascular diseases in the vascular reactivity of the HSV.

Topics: Animals; Blood Vessel Prosthesis Implantation; Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Bypass; Humans; Saphenous Vein; Tissue and Organ Harvesting

Hypertension is one of the cardiovascular diseases that might cause cardiovascular remodeling and endothelial dysfunction besides high blood pressure. Angiotensin II (Ang II) receptors are implicated in hypertension. Genetic and epigenetic manipulations of the Ang II receptors play a crucial part in the programming of cardiovascular diseases, and certain variants of the Ang II type 1 and Ang II type 2 receptors are constitutively predisposed to higher cardiovascular risk and hypertension. In this review, we focus on the expression, mode of action of Ang II receptors, and their role in programming the cardiovascular diseases in utero. In addition, we discuss possible therapeutic interventions of Ang II stimulation. Collectively, this information might lead us to new drug designs against cardiovascular diseases.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Discovery; Female; Humans; Pregnancy; Receptors, Angiotensin

Microparticles (MPs) derived from platelets, monocytes, endothelial cells, red blood cells, and granulocytes may be detected in low concentrations in normal plasma and at increased levels in atherothrombotic cardiovascular diseases. The elucidation of the cellular mechanisms underlying the generation of circulating MPs is crucial for improving our understanding of their pathophysiological role in health and disease. The flopping of phosphatidylserine (PS) to the outer leaflet of the plasma membrane is the key event that will ultimately lead to the shedding of procoagulant MPs from activated or apoptotic cells. Research over the last few years has revealed important roles for calcium-, mitochondrial-, and caspase-dependent mechanisms leading to PS exposure. The study of Scott cells has unraveled different molecular mechanisms that may contribute to fine-tuning of PS exposure and MP release in response to a variety of specific stimuli. The pharmacological modulation of MP release may have a substantial therapeutic impact in the management of atherothrombotic vascular disorders. Because PS exposure is a key feature in pathological processes different from hemostasis and thrombosis, the most important obstacle in the field of MP-modulating drugs seems to be carefully targeting MP release to relevant cell types at an optimal level, so as to achieve a beneficial action and limit possible adverse effects.

Topics: Animals; Apoptosis; Blood Coagulation; Blood Platelets; Calcium Channels; Cardiovascular Agents; Cardiovascular Diseases; Cell-Derived Microparticles; Cytoskeleton; Humans; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Phospholipids; Signal Transduction

Americans are under assault by a fierce epidemic of obesity, diabetes, and cardiovascular disease, of their own doing. Lowered death rates from heart disease and reduced rates of smoking are seriously threatened by the inexorable rise in overweight and obesity. Latest data indicate that 32% of children are overweight or obese, and fewer than 17% exercise sufficiently. Over 68% of adults are overweight, 35% are obese, nearly 40% fulfill criteria for the metabolic syndrome, 8-13% have diabetes, 34% have hypertension, 36% have prehypertension, 29% have prediabetes, 15% of the population with either diabetes, hypertension, or dyslipidemia are undiagnosed, 59% engage in no vigorous activity, and fewer than 5% of the US population qualifies for the American Heart Association (AHA) definition of ideal cardiovascular health. Health, nutrition, and exercise illiteracy is prevalent, while misinformation and unrealistic expectations are the norm. Half of American adults have at least one cardiovascular risk factor. Up to 65% do not have their conventional risk biomarkers under control. Of those patients with multiple risk factors, fewer than 10% have all of them adequately controlled. Even when patients are treated according to evidence-based protocols, about 70% of cardiac events remain unaddressed. Undertreatment is also common. Poor patient adherence, probably well below 50%, adds further difficulty in reducing cardiovascular risk. Available data indicate that only a modest fraction of the total cardiovascular risk burden in the population is actually now being eliminated. A fresh view of these issues, a change in current philosophy, leading to new and different, multimechanistic methods of prevention may be needed. Adherence to published guidelines will improve substantially outcomes in both primary and secondary prevention. Primordial prevention, which does not allow risk values to appear in a population, affords more complete protection than subsequent partial reversal of elevated risk factors or biomarkers. Current evidence supports recent calls for massive educational programs supporting primordial prevention, individual responsibility and pride in achieving population-wide ideal cardiovascular health through lifestyle modification. Environmental and social changes will be necessary, along with major supportive adjustments in the food industry and the assistance of the media. Cooperation is critical to the success of such an initiative.

Topics: Adolescent; Adult; Aged; Cardiovascular Agents; Cardiovascular Diseases; Child; Evidence-Based Medicine; Guideline Adherence; Health Behavior; Health Knowledge, Attitudes, Practice; Humans; Middle Aged; Patient Education as Topic; Practice Guidelines as Topic; Preventive Health Services; Preventive Medicine; Risk Assessment; Risk Factors; Risk Reduction Behavior; Young Adult

Few drugs have been labeled for pediatric cardiovascular indications, and many children with cardiac disease are prescribed drugs off-label. Recent initiatives have narrowed this gap, and as a result, there are an increasing number of cardiology trials in the pediatric population. Many studies, however, have either failed to show a dose response in children or have not shown efficacy in children when they have established efficacy in adults. Clinical trials are challenging in children; many factors such as lack of development of a liquid formulation, failure to fully incorporate pharmacokinetic information into trial design, poor dose selection, the lack of clinical equipoise, and the use of difficult surrogate and composite primary endpoints have led to the difficulties and failures observed in several pediatric cardiovascular trials. These lessons learned may help to inform future pediatric clinical trial development.

Topics: Age Factors; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Child; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans

IGF-1 (insulin-like growth factor-1) plays a unique role in the cell protection of multiple systems, where its fine-tuned signal transduction helps to preserve tissues from hypoxia, ischaemia and oxidative stress, thus mediating functional homoeostatic adjustments. In contrast, its deprivation results in apoptosis and dysfunction. Many prospective epidemiological surveys have associated low IGF-1 levels with late mortality, MI (myocardial infarction), HF (heart failure) and diabetes. Interventional studies suggest that IGF-1 has anti-atherogenic actions, owing to its multifaceted impact on cardiovascular risk factors and diseases. The metabolic ability of IGF-1 in coupling vasodilation with improved function plays a key role in these actions. The endothelial-protective, anti-platelet and anti-thrombotic activities of IGF-1 exert critical effects in preventing both vascular damage and mechanisms that lead to unstable coronary plaques and syndromes. The pro-survival and anti-inflammatory short-term properties of IGF-1 appear to reduce infarct size and improve LV (left ventricular) remodelling after MI. An immune-modulatory ability, which is able to suppress 'friendly fire' and autoreactivity, is a proposed important additional mechanism explaining the anti-thrombotic and anti-remodelling activities of IGF-1. The concern of cancer risk raised by long-term therapy with IGF-1, however, deserves further study. In the present review, we discuss the large body of published evidence and review data on rhIGF-1 (recombinant human IGF-1) administration in cardiovascular disease and diabetes, with a focus on dosage and safety issues. Perhaps the time has come for the regenerative properties of IGF-1 to be assessed as a new pharmacological tool in cardiovascular medicine.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus; Humans; Insulin-Like Growth Factor I; Mice; Recombinant Proteins; Thrombosis

published data indicate that heart rate is an independent strong predictor of cardiovascular and all-cause mortality in men and women of all ages, with and without cardiovascular disease, including atherosclerosis, ventricular arrhythmias, and left ventricular dysfunction. Ivabradine is a pure heart-rate-lowering agent with well-documented antianginal and anti-ischemic properties comparable to well-established anti-anginal agents.. this short review explores recent results with ivabradine, a new medication that lowers heart rate by selectively inhibiting the I (f) current. This review also describes future potential applications.. measurement of heart rate represents an important component of the assessment of patients with coronary artery disease and chronic heart failure, and should be viewed in the same light as other risk factors, because a high heart rate has direct detrimental effects not only on myocardial ischemia but also on the progression of atherosclerosis, ventricular arrhythmias and left ventricular function. Ivabradine has anti-ischemic and antianginal efficacy equivalent to that of β-blockers and calcium channel antagonists in the treatment of chronic stable angina pectoris. Recently ivabradine has been shown to improve cardiac outcomes in stable coronary artery disease and left ventricular systolic dysfunction in patients who have heart rates of ≥ 70 bpm and in patients with stable angina.

Topics: Angina Pectoris; Animals; Benzazepines; Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Disease; Female; Heart Rate; Humans; Ivabradine; Male; Risk Factors; Ventricular Dysfunction, Left

Erectile dysfunction is a major problem with an increasing prevalence in cardiovascular high-risk patients due to its association with cardiovascular risk factors. Drugs used for evidence-based treatment of cardiovascular diseases have been reported to decrease erectile function, but possible mechanisms are poorly characterised.. MEDLINE, EMBASE and Cochrane Registry search were performed including manuscripts until January 2010. Searching terms are: 'erectile dysfunction or impotence' in combination with 'ACE-inhibitors', 'angiotensin', 'beta-blockers', 'calcium antagonist' and 'diuretics'. Animal studies, letters, reviews, case-reports and manuscripts other than English language and trials dealing with combination treatment are excluded.. Analysis of literature revealed five epidemiological trials evaluating the effect of different cardiovascular drugs on erectile function. There were eight trials evaluating the effect of beta-blockers, five trials evaluating the effect of ace-inhibitors or angiotensin-receptor-blockers and one trial evaluating the effect of diuretics on erectile function. Results of these trials demonstrate that only thiazide diuretics and beta-blockers except nebivolol may adversely influence erectile function. ACE-inhibitors, angiotensin-receptor-blockers and calcium-channel-blockers are reported to have no relevant or even a positive effect on erectile function.. Inappropriate patients' concerns about adverse effects of cardiovascular drugs on erectile function might limit the use of important medications in cardiovascular high-risk patients. Knowledge about the effects of drug-treatments on erectile function and about the major role of the endothelium in penile function might improve patients' adherence to evidence based treatment of cardiovascular diseases.

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diuretics; Erectile Dysfunction; Humans; Male; Medication Adherence; Patient Education as Topic

There has been considerable interest in the elevated risk of cardiovascular disease associated with serious mental illness. Although the contemporary literature has paid much attention to major depression and schizophrenia, focus on the risk of cardiovascular mortality for patients with bipolar disorder has been more limited, despite some interest in the historical literature.. We reviewed the historical and contemporary literature related to cardiovascular morbidity and mortality in bipolar disorder.. In studies that specifically assess cardiovascular mortality, bipolar disorder has been associated with a near doubling of risk when compared with general population estimates. This may be explained by the elevated burden of cardiovascular risk factors found in this population. These findings predate modern treatments for bipolar disorder, which may further influence cardiovascular risk.. Given the substantial risk of cardiovascular disease, rigorous assessment of cardiovascular risk is warranted for patients with bipolar disorder. Modifiable risk factors should be treated when identified. Further research is warranted to study mechanisms by which this elevated risk for cardiovascular disease are mediated and to identify systems for effective delivery of integrated medical and psychiatric care for individuals with bipolar disorder.

Topics: Behavior Control; Bipolar Disorder; Cardiovascular Agents; Cardiovascular Diseases; Cause of Death; Comorbidity; Early Diagnosis; Humans; Life Style; Psychotherapy; Psychotropic Drugs; Risk Assessment

For decades, oxidative stress has been discussed as a key mechanism of endothelial dysfunction and cardiovascular disease. However, attempts to validate and exploit this hypothesis clinically by supplementing antioxidants have failed. Nevertheless, this does not disprove the oxidative stress hypothesis. As a certain degree of reactive oxygen species (ROS) formation appears to be physiological and beneficial. To reduce oxidative stress therapeutically, two alternative approaches are being developed. One is the repair of key signalling components that are compromised by oxidative stress. These include uncoupled endothelial nitric oxide (NO) synthase and oxidized/heme-free NO receptor soluble guanylate cyclase. A second approach is to identify and effectively inhibit the relevant source(s) of ROS in a given disease condition. A highly likely target in this context is the family of NADPH oxidases. Animal models, including NOX knockout mice and new pharmacological inhibitors of NADPH oxidases have opened up a new era of oxidative stress research and have paved the way for new cardiovascular therapies.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; NADPH Oxidases; Oxidative Stress

Cardiovascular disease in children is common and results in significant morbidity and mortality. The sickest children with cardiovascular disease may require support with extracorporeal membrane oxygenation (ECMO), which provides life-saving assistance for children with refractory cardiorespiratory failure. Many classes of cardiovascular drugs are used in children, but very few of these agents have been well studied in children. The knowledge gap is even more pronounced in children supported by ECMO. Pharmacokinetic (PK) data collected to date (primarily from antibiotics and sedatives) suggest that the ECMO circuit has the potential to significantly alter the PK of drugs including changes in clearance and volume of distribution. Of all cardiovascular drugs administered to children supported by ECMO, only 11 have been partially studied and reported in the medical literature. Esmolol, amiodarone, nesiritide, bumetanide, sildenafil, and prostaglandin E1 seem to require dosing modifications in children supported by ECMO, whereas it seems that hydralazine, nicardipine, furosemide, epinephrine, and dopamine can be dosed similarly to children not supported by ECMO. However, trials evaluating the PK of these drugs in patients supported by ECMO are extremely limited (ie, case reports), and therefore, definitive dosing recommendations are not plausible. Research efforts should focus on evaluating the PK of drugs in patients on ECMO to avoid therapeutic failures or unnecessary toxicities.

Topics: Adolescent; Cardiovascular Agents; Cardiovascular Diseases; Child; Child, Preschool; Combined Modality Therapy; Critical Illness; Diuretics; Drug Administration Schedule; Drug Therapy, Combination; Extracorporeal Membrane Oxygenation; Humans; Infant; Infant, Newborn; Treatment Outcome

Individual response to medication is highly variable. For many drugs, a substantial proportion of patients show suboptimal response at standard doses, whereas others experience adverse drug reactions (ADRs). Pharmacogenomics aims to identify genetic factors underlying this variability in drug response, providing solutions to improve drug efficacy and safety. We review recent advances in pharmacogenomics of cardiovascular drugs and cardiovascular ADRs, including warfarin, clopidogrel, β-blockers, renin-angiotensin-aldosterone system inhibitors, drug-induced long QT syndrome, and anthracycline-induced cardiotoxicity. We particularly focus on the applicability of pharmacogenomic findings to pediatric patients in whom developmental changes in body size and organ function may affect drug pharmacokinetics and pharmacodynamics. Solid evidence supports the importance of gene variants in CYP2C9 and VKORC1 for warfarin dosing and in CYP2C19 for clopidogrel response in adult patients. For the other cardiovascular drugs or cardiovascular ADRs, further studies are needed to replicate or clarify genetic associations before considering uptake of pharmacogenetic testing in clinical practice. With the exception of warfarin and anthracycline-induced cardiotoxicity, there is lack of pharmacogenomic studies on cardiovascular drug response or ADRs aimed specifically at children or adolescents. The first pediatric warfarin pharmacogenomic study indeed indicates differences from adults, pointing out the importance and need for pediatric-focused pharmacogenomic studies.

Topics: Adolescent; Adult; Aryl Hydrocarbon Hydroxylases; Cardiotoxins; Cardiovascular Agents; Cardiovascular Diseases; Child; Clinical Trials as Topic; Cytochrome P-450 CYP2C9; Dose-Response Relationship, Drug; Female; Humans; Male; Mixed Function Oxygenases; Vitamin K Epoxide Reductases

The pharmacogenetics is one of the most promising fields of medicine. The conclusion of the Genome Project allowed this field to start discovering complex factors modulating the response to drugs, and new technologies are close a great expansion of the area. The cardiovascular diseases are currently among the major causes of hospitalizations and death, and have been the target of a large part of genetic studies of complex diseases. Parallel to the susceptibility to disease markers identification, it is necessary to investigate how different genetic profiles can change the responses to the currently used drugs. The biological system that controls the endothelial production of the nitric oxide has been one of the greatest targets in the pharmacological responses to the drugs used in the cardiovascular diseases therapy. This review aims at approaching the current knowledge on interaction among the genetic variations of eNOS and the pharmacological responses to the drugs used in the cardiovascular system.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Nitric Oxide; Nitric Oxide Synthase Type III; Pharmacogenetics; Polymorphism, Genetic

The renin–angiotensin–aldosterone system (RAAS) plays a pivotal role in regulating blood pressure, volume, and electrolytes. The final product of RAAS cascade is angiotensin II, which exerts diverse biological activities via binding to one of three known receptor types, with different binding consequences. Despite the success with conventional strategies to limit angiotensin II production and action, these agents promote a reflex rise in plasma renin activity, which is thought to be associated with an increased incidence of cardiovascular events. Several renin inhibitors have been synthesized in order to counteract deleterious consequences of renin activity and RAAS activation; aliskiren is the first of these new non-peptide direct renin inhibitors to be approved for the treatment of hypertension. The paper reviews pharmacokinetics of aliskiren and its role in hypertension, with particular regard to those studies that compared clinical efficacy of aliskiren in comparison and in addition to other antihypertensive drug strategies.

Topics: Amides; Cardiovascular Agents; Cardiovascular Diseases; Fumarates; Humans; Renin; Renin-Angiotensin System

Topics: American Heart Association; Cardiac Surgical Procedures; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Humans; United States

Aspirin has been recommended for the prevention of major adverse cardiovascular events (MACE, composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) in diabetic patients without previous cardiovascular disease. However, recent meta-analyses have prompted re-evaluation of this practice. The study objective was to evaluate the relative and absolute benefits and harms of aspirin for the prevention of incident MACE in patients with diabetes.. We performed a systematic review and meta-analysis on seven studies (N=11,618) reporting on the use of aspirin for the primary prevention of MACE in patients with diabetes. Two reviewers conducted a systematic search of electronic databases (MEDLINE, EMBASE, the Cochrane Library, and BIOSIS) and hand searched bibliographies and clinical trial registries. Reviewers extracted data in duplicate, evaluated the quality of the trials, and calculated pooled estimates.. A total of 11,618 participants were included in the analysis. The overall risk ratio (RR) for MACE was 0.91 (95% confidence intervals, CI, 0.82-1.00) with little heterogeneity among trials (I2 0.0%). Secondary outcomes of interest included myocardial infarction (RR, 0.85; 95% CI, 0.66-1.10), stroke (RR, 0.84; 95% CI, 0.64-1.11), cardiovascular death (RR, 0.95; 95% CI, 0.71-1.27), and all-cause mortality (RR, 0.95; 95% CI, 0.85-1.06). There were higher rates of hemorrhagic and gastrointestinal events. In absolute terms, these relative risks indicate that for every 10,000 diabetic patients treated with aspirin, 109 MACE may be prevented at the expense of 19 major bleeding events (with the caveat that the relative risk for the latter is not statistically significant).. The studies reviewed suggest that aspirin reduces the risk of MACE in patients with diabetes without cardiovascular disease, while also causing a trend toward higher rates of bleeding and gastrointestinal complications. These findings and our absolute benefit and risk calculations suggest that those with diabetes but without cardiovascular disease lie somewhere between primary and secondary prevention patients on the spectrum of benefit and risk. This underscores the importance of considering individual risk in clinical decision making regarding aspirin in those with diabetes.

Topics: Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Complications; Evidence-Based Medicine; Female; Gastrointestinal Diseases; Hemorrhage; Humans; Incidence; Male; Patient Selection; Primary Prevention; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Patients are considered to be at high risk of cardiovascular events if they have diabetes, chronic kidney disease, stroke, established coronary artery disease, or a coronary artery disease equivalent. Blood pressure-lowering therapy has been shown to reduce cardiovascular events in these patients significantly. Identification of high-risk patients by global risk evaluation is recommended for every hypertensive patient. Treatment of hypertension in high-risk patients with an angiotensin-converting enzyme inhibitor or an angiotensin receptor antagonist, with or without addition of a dihydropyridine calcium channel antagonist, is a reasonable approach based on current clinical trials.

Topics: Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Hypertension; Patient Selection; Risk Assessment; Risk Factors; Treatment Outcome

To compare the strengths and limitations of cardiovascular risk scores available for clinicians in assessing the global (absolute) risk of cardiovascular disease.. Review of cardiovascular risk scores.. Medline (1966 to May 2009) using a mixture of MeSH terms and free text for the keywords 'cardiovascular', 'risk prediction' and 'cohort studies'.. A study was eligible if it fulfilled the following criteria: (1) it was a cohort study of adults in the general population with no prior history of cardiovascular disease and not restricted by a disease condition; (2) the primary objective was the development of a cardiovascular risk score/equation that predicted an individual's absolute cardiovascular risk in 5-10 years; (3) the score could be used by a clinician to calculate the risk for an individual patient.. 21 risk scores from 18 papers were identified from 3536 papers. Cohort size ranged from 4372 participants (SHS) to 1591209 records (QRISK2). More than half of the cardiovascular risk scores (11) were from studies with recruitment starting after 1980. Definitions and methods for measuring risk predictors and outcomes varied widely between scores. Fourteen cardiovascular risk scores reported data on prior treatment, but this was mainly limited to antihypertensive treatment. Only two studies reported prior use of lipid-lowering agents. None reported on prior use of platelet inhibitors or data on treatment drop-ins.. The use of risk-factor-modifying drugs-for example, statins-and disease-modifying medication-for example, platelet inhibitors-was not accounted for. In addition, none of the risk scores addressed the effect of treatment drop-ins-that is, treatment started during the study period. Ideally, a risk score should be derived from a population free from treatment. The lack of accounting for treatment effect and the wide variation in study characteristics, predictors and outcomes causes difficulties in the use of cardiovascular risk scores for clinical treatment decision.

Topics: Adult; Aged; Cardiovascular Agents; Cardiovascular Diseases; Cohort Studies; Female; Humans; Male; Middle Aged; Risk Assessment; Risk Factors; Treatment Outcome

Acetyl-L-carnitine (ALC) and propionyl-L-carnitine (PLC) are two naturally occurring carnitine derivates formed by carnitine acetyltransferase. The beneficial cardiovascular effects of ALC and PLC have been extensively evaluated in animals and humans during the last 20 years. For instance, many clinical trials have suggested ALC and PLC as potential strategies in the management of peripheral arterial disease, heart and cerebral ischemia, and congestive heart failure. As a result, several experts have already aimed to revise the clinical evidence supporting the therapeutic use of ALC and PLC. On the basis of their conclusions, our aim was a critical review of the effectiveness of ALC and PLC in the treatment of cardiovascular diseases. Type 2 diabetes mellitus is an independent risk factor for the development of cardiovascular disease. Therefore we also describe recent studies that have addressed the emerging use of ALC and PLC amelioration of the insulin resistant state and its related morbidities.

Topics: Acetylcarnitine; Animals; Cardiovascular Agents; Cardiovascular Diseases; Carnitine; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Humans; Hypoglycemic Agents; Insulin Resistance; Treatment Outcome

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Genetic Variation; Humans; Pharmacogenetics; Treatment Outcome

Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP450) products of arachidonic acid and EETs are endogenous lipid mediators synthesized by the vascular endothelium which perform important biological functions, including vasodilation, anti-inflammation, antimigratory, and cellular signaling regulations. However, EETs are rapidly degraded by soluble epoxide hydrolase (sEH) to the corresponding diols: dihydroxyeicosatrienoic acids (DHETs), which have little active in causing vasorelaxation. A number of studies have supported that the inhibition of sEH (sEHIs) had cardiovascular protective effects in hypertension, cardiac hypertrophy, atherosclerosis, ischemia-reperfusion injury, and ischemic stroke. Moreover, sEHIs could slow the progression of inflammation, protect end-organ damage and prevent ischemic events, also, attenuate endothelial dysfunction, suggesting that the pharmacological blockade of sEH might provide a broad and novel avenue for the treatment of many cardiovascular diseases.

Topics: Animals; Brain Ischemia; Cardiomegaly; Cardiovascular Agents; Cardiovascular Diseases; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Hypertension; Polymorphism, Genetic; Reperfusion Injury; Risk; Stroke

On May 13, 2010, a resolution passed at the United Nations for a high-level meeting with heads of state on noncommunicable chronic diseases (NCDs), catapulting NCDs atop the political and health agendas. This meeting on NCDs, slated for September 2011, provides the rare political moment to commit to scaling up international, regional, and national efforts to prevent and treat NCDs, giving the issue the priority it deserves. An analogous high-profile meeting transpired in 2001 on human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), effectively serving as the nucleating event for a vigorous global and political movement towards universal prevention and treatment. As was the case at the HIV/AIDS meeting, a key priority area in the new NCD movement remains ensuring universal access to reliable, affordable essential medicines to prevent and treat NCDs. The upcoming meeting, therefore, provides the perfect opportunity to capitalize on the increased political and social awareness of NCDs and to apply the lessons learned from the HIV/antiretroviral experience in order to improve access to essential medicines for NCDs. Social mobilization and political advocacy, used in tandem with technical solutions, is an important lesson from the HIV experience, and will likely be important to ensure access to essential medicines for NCDs, including cardiovascular disease. Here, we use cardiovascular disease as a specific case study to examine the issue, outlining early solutions while drawing parallels and analogies to the HIV experience.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Developed Countries; Developing Countries; Global Health; Health Services Accessibility; Humans; United Nations

Cardiovascular disease is the number one cause of death globally. Design of cardiovascular drugs based on new paradigms is therefore a prominent goal of medicinal chemistry. Designed multiple ligands, targeting two or more proteins involved in pathogenesis of disease have become a viable concept in drug discovery. Although adjustment of the activities ratio at the different targets is a demanding and challenging task, modulation of two or more targets involved in a cardiovascular disease may be more successful for therapeutic application than treatment directed against each target alone, because of improved pharmacodynamic and pharmacokinetic properties of designed multitarget drugs. The article reviews the applications of multitarget approach to cardiovascular drug design, covering angiotensin-converting enzyme/neutral endopeptidase inhibitors, neutrale endopeptidase/endothelin-converting enzyme inhibitors, angiotensin-converting enzyme/neutral endopeptidase/endothelin-converting enzyme inhibitors, dual angiotensin/endothelin receptor and angiotensin1/angotensin2 receptor antagonists and angiotensin receptor antagonist/neutral endopeptidase inhibitors.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Aspartic Acid Endopeptidases; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Endothelin-Converting Enzymes; Endothelins; Enzyme Inhibitors; Humans; Metalloendopeptidases; Natriuretic Peptides; Neprilysin; Protease Inhibitors; Renin-Angiotensin System

Preoperative cardiovascular management is an essential component of overall perioperative cardiovascular care. It involves preoperative detection and management of cardiovascular disease and prediction of both short- and long-term cardiovascular risk. It thereby not only affects anaesthetic perioperative management (e.g. choice of anaesthetic drug and method, type of monitoring, and postoperative care) but also surgical decision-making (e.g. postponement, modification, and cancellation of surgical procedure). The ultimate goal of preoperative cardiovascular management is to improve overall patient outcome. This requires individualized management. Although preoperative cardiac management has improved during the past decades, we are not yet in the situation where we can accurately predict individual perioperative risk. The individual stress response and the individual interactions between pharmacological intervention and intra- and postoperative risk factors are highly variable. More importantly, preoperative cardiac management is only one aspect of overall perioperative care. There are numerous intra- and postoperative factors which have been shown to affect overall outcome. However, not all of them can reliably be predicted or modified in a way to positively affect overall outcome. Recognition of such factors and aggressive attempts at appropriate intervention may reduce overall risk more than preoperative management in isolation. Without defining and subsequently targeting intra- and postoperative risk factors, the benefit of preoperative cardiac management will be limited.

Topics: Algorithms; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Exercise Test; Humans; Myocardial Revascularization; Postoperative Complications; Preoperative Care; Risk Assessment

The pathogenesis of many cardiovascular diseases is associated with reduced nitric oxide (NO) bioavailability and/or increased endothelial NO synthase (eNOS)-dependent superoxide formation. These findings support that restoring and conserving adequate NO signaling in the heart and blood vessels is a promising therapeutic intervention. In particular, modulating eNOS, e.g., through increasing the bioavailability of its substrate and cofactors, enhancing its transcription, and interfering with other modulators of eNOS pathway, such as netrin-1, has a high potential for effective treatments of cardiovascular diseases. This review provides an overview of the possibilities for modulating eNOS and how this may be translated to the clinic in addition to describing the genetic models used to study eNOS modulation.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Humans; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Protein Processing, Post-Translational; Signal Transduction

Rho-kinase (ROCKs) belongs to the family of serine/threonine kinases and is an important downstream effector of the small GTP-binding protein RhoA. There are two isoforms of Rho-kinase, ROCK1 and ROCK2, and they have different functions with ROCK1 for circulating inflammatory cells and ROCK2 for vascular smooth muscle cells. It has been demonstrated that the RhoA/Rho-kinase pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation, and apoptosis, leading to the development of cardiovascular disease. The important role of Rho-kinase in vivo has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia-reperfusion injury, hypertension, pulmonary hypertension, stroke, and heart failure. Furthermore, the beneficial effects of fasudil, a selective Rho-kinase inhibitor, have been demonstrated for the treatment of several cardiovascular diseases in humans. Thus the Rho-kinase pathway is an important new therapeutic target in cardiovascular medicine.

Topics: Animals; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Humans; Inflammation Mediators; Molecular Targeted Therapy; Myocardium; Oxidative Stress; Protein Kinase Inhibitors; rho-Associated Kinases; Signal Transduction

Cardiovascular disease is the leading determinant of mortality and morbidity in women. Functional foods are attracting interest as potential regulators of the susceptibility to disease. Supported by epidemiological evidence, chocolate has emerged as a possible modulator of cardiovascular risk. Chocolate, or cocoa as the natural source, contains flavanols, a subclass of flavonoids. The latter years have witnessed an increasing number of experimental and clinical studies that suggest a protective effect of chocolate against atherogenesis. Oxidative stress, inflammation, and endothelial function define three biological mechanisms that have shown sensitivity to chocolate. Moreover, the consumption of chocolate has been involved in the protective modulation of blood pressure, the lipid profile, the activation of platelets, and the sensitivity to insulin. Dark chocolate seems more protective than milk or white chocolate. Despite this array of benefits, there is a lack of well designed clinical studies demonstrating cardiovascular benefit of chocolate. The high caloric content of chocolate, particularly of some less pure forms, imposes caution before recommending uncontrolled consumption.

Topics: Animals; Cacao; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Flavonols; Functional Food; Humans; Inflammation; Insulin; Lipids; Phytotherapy; Plant Preparations; Platelet Activation

Signaling by nitric oxide (NO) determines several cardiovascular functions including blood pressure regulation, cardiac and smooth muscle hypertrophy, and platelet function. NO stimulates the synthesis of cGMP by soluble guanylyl cyclases and thereby activates cGMP-dependent protein kinases (PKGs), mediating most of the cGMP functions. Hence, an elucidation of the PKG signaling cascade is essential for the understanding of the (patho)physiological aspects of NO. Several PKG signaling pathways were identified, meanwhile regulating the intracellular calcium concentration, mediating calcium desensitization or cytoskeletal rearrangement. During the last decade it emerged that the inositol trisphosphate receptor-associated cGMP-kinase substrate (IRAG), an endoplasmic reticulum-anchored 125-kDa membrane protein, is a main signal transducer of PKG activity in the cardiovascular system. IRAG interacts specifically in a trimeric complex with the PKG1β isoform and the inositol 1,4,5-trisphosphate receptor I and, upon phosphorylation, reduces the intracellular calcium release from the intracellular stores. IRAG motifs for phosphorylation and for targeting to PKG1β and 1,4,5-trisphosphate receptor I were identified by several approaches. The (patho)physiological functions for the regulation of smooth muscle contractility and the inhibition of platelet activation were perceived. In this review, the IRAG recognition, targeting, and function are summarized compared with PKG and several PKG substrates in the cardiovascular system.

Topics: Amino Acid Sequence; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Humans; Inositol 1,4,5-Trisphosphate Receptors; Membrane Proteins; Molecular Sequence Data; Molecular Targeted Therapy; Nitric Oxide; Phosphoproteins; Phosphorylation; Protein Kinase Inhibitors; Signal Transduction

The unique clinical circumstances that are typically encountered by cardiology providers when caring for patients undergoing treatment for cancer require an in-depth understanding of the recommended treatments for the diagnosis and management of heart failure and ischemic heart disease. It is also recognized that there is not a broadly described clinical research basis from which to provide guidance when specific clinical decision making is required. Thus, it is imperative that cardiology and oncology closely collaborate when difficult patient decisions arise. Engaging each discipline together with active patient involvement in clinical care will undoubtedly provide optimal care for our patients.

Topics: Aged; Antineoplastic Agents; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Comprehensive Health Care; Drug Interactions; Evidence-Based Medicine; Female; Humans; Interdisciplinary Communication; Male; Medical Oncology; Middle Aged; Monitoring, Physiologic; Neoplasms; Patient Selection; Risk Assessment

To identify cardiovascular health services with a high level of evidence to suggest that they deliver favorable value.. Evidence synthesis using the Cost-Effectiveness Analysis Registry.. We queried the registry to identify published cost-effectiveness analyses of cardiovascular health services in the United States. In addition to searching the registry, we performed supplementary searches of published literature for cost-effectiveness studies of cardiovascular interventions that were endorsed by guidelines of national medical and scientific societies. We defined favorable value as an incremental cost-effectiveness ratio of $100,000 or less per quality-adjusted life-year.. Our initial review of cardiovascular health services in the United States revealed 174 separate peer-reviewed studies. Of those, 157 studies did not meet our inclusion criteria, leaving 17 studies for further evaluation that covered the following services with potentially high value: statins to prevent myocardial infarction (for primary and secondary prevention), screening for and treatment of high blood pressure (diuretics or beta-blockers and angiotensin-converting enzyme inhibitors in the case of diabetes) to prevent myocardial infarction and stroke, warfarin sodium and low-molecular-weight heparin to prevent pulmonary emboli, implantable cardiac defibrillators for patients at high risk of sudden death, antiplatelet drugs (aspirin and clopidogrel bisulfate) to prevent future myocardial infarction, beta-blockers for patients who have had myocardial infarction, warfarin to prevent future stroke in persons with nonvalvular atrial fibrillation, and percutaneous procedures to relieve claudication symptoms.. We describe a new way of synthesizing cost-effectiveness evidence for use by consumers, payers, and other decision makers.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cost-Benefit Analysis; Evidence-Based Medicine; Health Services; Humans; Quality-Adjusted Life Years; Registries; United States

The endothelium lies in a strategic anatomical position between the circulating blood and the vascular smooth-muscle cells. It is a source of vasodilators such as nitric oxide, prostacyclin, and hyperpolarizing factor as well as heparin-like substances and other molecules with antiproliferative properties. These effects of endothelial cells may explain why platelets and monocytes usually do not adhere at the blood vessel wall. However, under pathological conditions, endothelial dysfunction occurs and significantly contributes to the increase of platelet- -vessel wall interaction, vasoconstriction, pro-inflammation, and proliferation. Under these conditions, endothelium-dependent vasodilation is reduced, and endothelium-dependent constrictor responses are augmented. Upon vessel wall injury, the platelets rapidly adhere to the exposed sub-endothelial matrix, which is mediated by several cellular receptors present on platelets or endothelial cells and various adhesive proteins. Subsequent platelet activation results in the recruitment of additional platelets and the generation of platelet aggregates, so forming a stable platelet plug. Therapeutic strategies aimed at improving or preserving endothelial function therefore may be promising in terms of preventing and treating coronary artery disease. Diagnostic modalities for assessing endothelial function should allow for the early detection of vascular endothelial dysfunction before the manifestation of serious adverse vascular disorders.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Genetic Therapy; Humans; Treatment Outcome

Cardiovascular disease and cancer are 2 of the leading causes of death globally. Certain cardiovascular medications have been linked to an increased risk for cancer. Although individual reviews of specific classes of cardiovascular medications have been published previously, a more complete review of several classes has not been performed. The aim of this review is to evaluate the associations of various cardiovascular agents with the risk for developing cancer and provide guidance for clinicians. A comprehensive search of published research was conducted using MEDLINE from 1994 to 2011. Three trials demonstrated an increased risk for cancer using angiotensin II receptor blockers. Additionally, risk for cancer was shown in a number of trials that included the use of angiotensin II receptor blockers in combination with angiotensin-converting enzyme inhibitors. Five trials suggested that diuretics increased the risk for specific cancers, especially in women and those who had been using diuretics for >4 years. Statins and ezetimibe, in contrast, did not show this increased risk. Prasugrel was shown to be associated with an increased risk for cancer in 1 study. It appears that the use of certain cardiovascular medications is associated with an increased risk for cancer. In conclusion, clinicians need to balance the risks and benefits of the use of these agents and provide the appropriate therapy on an individual basis.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Global Health; Humans; Incidence; Neoplasms; Risk Factors

Activation of the renin-angiotensin system plays a major role in cardiovascular morbidity and mortality. Recently, angiotensin II receptor blockers (ARBs) have been the subject of a number of large clinical cardiovascular outcome trials, indicating beneficial effects of ARBs with more than 384,000 patient-years of data in different cardiovascular diseases along the cardiovascular continuum, from patients with risk factors, through high cardiovascular risk, to patients with heart failure. This article reviews the implications of these trials for the optimal management of cardiovascular risk.

Topics: Angiotensin II Type 1 Receptor Blockers; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Disease Progression; Evidence-Based Medicine; Humans; Renin-Angiotensin System; Treatment Outcome

Despite encouraging advances in our knowledge of the prevention and treatment of atherothrombosis, cardiovascular (CV) disease remains the leading cause of death worldwide. The impressive growth of this epidemic during the last decade is due largely to the increasing incidence of CV diseases in low- and middle-income countries (LMICs). The uncontrolled rise in the incidence of risk factors (obesity, hypertension, tobacco, high cholesterol, diabetes) in these countries accounts largely for the increasing incidence of CV diseases. Lifestyle modification and pharmacologic treatment have been very effective in improving the risk profile in those individuals at high risk. In Western countries the impact of all these preventive and therapeutic interventions has been a substantial decline in CV mortality; however, the scenario is quite different in LMICs. Several problems limit the efficacy of secondary prevention strategies: inadequate health policies, poor availability, and lack of affordable medication in LMICs, as well as poor patient adherence to treatment. It has been suggested that along with the promotion of healthy lifestyles, a fixed-dose combination or polypill containing 2 or more drugs addressed to control different risk factors would improve accessibility to treatment, cost, and patient adherence to treatment. This review analyzes the potential role of the polypill strategy in primary and secondary CV prevention.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cost-Benefit Analysis; Developing Countries; Drug Combinations; Drug Costs; Global Health; Health Knowledge, Attitudes, Practice; Health Services Accessibility; Humans; Medication Adherence; Preventive Health Services; Risk Assessment; Risk Factors

There are numerous drug-drug interactions (DDIs) related to cardiovascular medications and many of these are mediated via the cytochrome P450 (CYP) system. Some of these may lead to serious adverse events and it is, therefore, essential that clinicians are aware of the important interactions that occur.. An extensive literature search was performed to analyze the CYP-mediated cardiovascular DDIs that lead to a loss of efficacy or potential toxicity. Cardiovascular drugs may be victims or act as perpetrators of DDIs. The paper analyzes CYP-mediated drug interactions concerning anticoagulants, antiplatelet agents, antiarrhythmics, β-blockers, calcium antagonists, antihypertensive medications, lipid-lowering drugs and oral antidiabetic agents.. Cardiovascular DDIs involving the CYP system are numerous. Additionally, the spectrum of drugs prescribed is constantly changing, particularly with cardiovascular diseases and it is not necessarily the case that drugs that had shown safety earlier will always show safety. Clinicians are encouraged to develop their knowledge of CYP-mediated DDIs so that they can choose safe drug combination regimens, adjust drug dosages appropriately and conduct therapeutic drug monitoring for drugs with narrow therapeutic indices.

Topics: Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Anticoagulants; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Monitoring; Humans; Hypolipidemic Agents; Platelet Aggregation Inhibitors

Medications are a cornerstone of the prevention and management of cardiovascular disease. Long-term medication adherence has been the subject of increasing attention in the developed world but has received little attention in resource-limited settings, where the burden of disease is particularly high and growing rapidly. To evaluate prevalence and predictors of non-adherence to cardiovascular medications in this context, we systematically reviewed the peer-reviewed literature.. We performed an electronic search of Ovid Medline, Embase and International Pharmaceutical Abstracts from 1966 to August 2010 for studies that measured adherence to cardiovascular medications in the developing world. A DerSimonian-Laird random effects method was used to pool the adherence estimates across studies. Between-study heterogeneity was estimated with an I(2) statistic and studies were stratified by disease group and the method by which adherence was assessed. Predictors of non-adherence were also examined.. Our search identified 2,353 abstracts, of which 76 studies met our inclusion criteria. Overall adherence was 57.5% (95% confidence interval [CI] 52.3% to 62.7%; I(2) 0.98) and was consistent across study subgroups. Studies that assessed adherence with pill counts reported higher levels of adherence (62.1%, 95% CI 49.7% to 73.8%; I(2) 0.83) than those using self-report (54.6%, 95% CI 47.7% to 61.5%; I(2) 0.93). Adherence did not vary by geographic region, urban vs. rural settings, or the complexity of a patient's medication regimen. The most common predictors of poor adherence included poor knowledge, negative perceptions about medication, side effects and high medication costs.. Our study indicates that adherence to cardiovascular medication in resource-limited countries is sub-optimal and appears very similar to that observed in resource-rich countries. Efforts to improve adherence in resource-limited settings should be a priority given the burden of heart disease in this context, the central role of medications in their management, and the clinical and economic consequences of non-adherence.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Developing Countries; Health Resources; Humans; Medication Adherence

Poor adherence to efficacious cardiovascular-related medications has led to considerable morbidity, mortality, and avoidable health care costs. This article provides results of a recent think-tank meeting in which various stakeholder groups representing key experts from consumers, community health providers, the academic community, decision-making government officials (Food and Drug Administration, National Institutes of Health, etc), and industry scientists met to evaluate the current status of medication adherence and provide recommendations for improving outcomes. Below, we review the magnitude of the problem of medication adherence, prevalence, impact, and cost. We then summarize proven effective approaches and conclude with a discussion of recommendations to address this growing and significant public health issue of medication nonadherence.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Community Health Services; Community Pharmacy Services; Drug Costs; Fees, Pharmaceutical; Humans; Medication Adherence; Morbidity; Survival Rate; United States

The therapeutic areas of infectious diseases and oncology have benefited from abundant scaffold diversity in natural products, able to interact with many specific targets within the cell and indeed for many years have been source or inspiration for the majority of FDA approved drugs. The present review describes natural products (NPs), semi-synthetic NPs and NP-derived compounds that have undergone clinical evaluation or registration from 2005 to 2010 by disease area i.e. infectious (bacterial, fungal, parasitic and viral), immunological, cardiovascular, neurological, inflammatory and related diseases and oncology.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Biological Products; Cardiovascular Agents; Cardiovascular Diseases; Communicable Diseases; Drug Discovery; Humans; Inflammation; Metabolic Diseases; Neoplasms; Nervous System Diseases; Plant Extracts; Plants, Medicinal

The field of stem cell research was revolutionized with the advent of induced pluripotent stem cells. By reprogramming somatic cells to pluripotent stem cells, most ethical concerns associated with the use of embryonic stem cells are overcome, such that many hopes from the stem cell field now seem a step closer to reality. Several methods and cell sources have been described to create induced pluripotent stem cells and we discuss their characteristics in terms of feasibility and efficiency. From these cells, cardiac progenitors and cardiomyocytes can be derived by several protocols and most recent advances as well as remaining limitations are being discussed. However, in the short time period this technology has been around, evidence emerges that induced pluripotent stem cells may be more prone to genetic defects and maintain an epigenetic memory and thus may not be entirely the same as embryonic stem cells. Despite the lack of a complete fundamental understanding of stem cell biology, and even more of ways how to coax them into defined cell types, the technology is quickly adopted by industry. This paper gives an overview of the current applications of induced pluripotent stem cells in cardiovascular drug development and highlights active areas of research towards functional repair of the damaged heart. Adult stem cells have already been taken to clinical trials and we discuss these results in light of potential and hurdles to be taken to move induced pluripotent stem cells to the clinic.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cell Differentiation; Drug Discovery; Epigenesis, Genetic; Heart; Humans; Induced Pluripotent Stem Cells; Models, Biological; Myocytes, Cardiac; Regeneration; Stem Cell Transplantation

Patients vary in their responses to drug therapy, and some of that variability is genetically determined. This review outlines general approaches used to identify genetic variation that influences drug response. Examples from specific therapeutic areas are presented, such as cholesterol management, arrhythmias, heart failure, hypertension, warfarin anticoagulation, and antiplatelet agents. A brief view of potential pathways to implementation is presented.

Topics: Biological Transport; Biotransformation; Cardiovascular Agents; Cardiovascular Diseases; Drug Dosage Calculations; Genetic Variation; Humans; Patient Selection; Pharmacogenetics; Precision Medicine; Risk Assessment; Treatment Outcome

Over the last few years, the implication of the (pro)renin receptor [(P)RR] in the pathogenesis of end-organ damage has been shown through many different studies. The (P)RR plays a dual role when stimulated by renin or prorenin as it enhances both cell surface production of angiotensin and stimulates angiotensin-independent intracellular signaling cascades. Since Ichihara's group demonstrated activation of prorenin when it was bound to antibodies targeted against a specific region in the renin prosegment, they designed a complementary decapeptide to this region called the handle region to use as a potential (P)RR blocker (PRRB). The effects of systemic administration of the PRRB on the development and progression of different renal, cardiac and ocular pathologies have been observed and have thus proposed the blocker as a potential new treatment for these afflictions. Conversely, the specificity of the PRRB has been questioned as conflicting results have been reported in the literature. A recent study has described a new high affinity binding site for renin and prorenin to the (P)RR called the hinge region. Hence, although there is great promise in the (P)RR potential as a therapeutic target, still much research is required to better identify adequate blockers.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Humans; Prorenin Receptor; Receptors, Cell Surface; Renin; Signal Transduction; Vacuolar Proton-Translocating ATPases

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a calcium-independent phospholipase A2 that circulates in plasma in association with lipoprotein particles, whereas in atherosclerotic plaques it is co-localized with macrophages. Lp-PLA2 generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a role in the development of atherosclerotic lesions and formation of a necrotic core, leading to more vulnerable plaques. Epidemiologic studies demonstrate that increased circulating levels of Lp-PLA2 predict an increased risk of myocardial infarction, stroke and cardiovascular mortality. Furthermore, histologic examination of diseased human coronary arteries reveals intense presence of the enzyme in atherosclerotic plaques that are prone to rupture. These considerations suggest Lp-PLA2 as a promising therapeutic target in cardiovascular disease. Plasma levels of Lp-PLA2 are increased in various types of hyperlipidemias, while hypolipidemic drugs reduce plasma Lp-PLA2 activity and mass along with the improvement of plasma lipid profile. A selective inhibitor of Lp-PLA2 activity, darapladib, has been developed and studies in animal models and humans have shown that it effectively and safely reduces Lp-PLA2 activity in plasma and in atherosclerotic plaques. Furthermore, in animal models darapladib decreases plaque area and necrotic core area whereas in humans it prevents the expansion of necrotic core volume. Whether the results obtained from the use of darapladib in studies in vitro, as well as in preclinical and clinical studies would translate into benefits on cardiovascular event outcomes, awaits to be proved in 2 ongoing phase 3 trials.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Atherosclerosis; Benzaldehydes; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Oximes; Risk

Heart rate is a major determinant of cardiac output, myocardial oxygen consumption and coronary blood flow under physiological and pathological conditions. Experimental and clinical data have demonstrated that heart rate reduction is the main mechanism for reducing ischemia, improving left ventricular function, decreasing the risk of plaque rupture and post myocardial infarction mortality. Nowadays betablockers are the best class of drugs that can lower heart rate in patients with cardiovascular diseases, but sometimes their use is limited by some contraindications. Ivabradine is a new drug that reduces the firing rate of pacemaker cells in the sinoatrial node through a different mechanism with respect to betablockers. The purpose of this review is to investigate the main trials that support Ivabradine adoption in clinical practice.

Topics: Adrenergic beta-Antagonists; Angina Pectoris; Benzazepines; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Cyclic Nucleotide-Gated Cation Channels; Heart Failure; Heart Rate; Humans; Ivabradine; Myocardial Ischemia; Prognosis; Sinoatrial Node

Relaxin (RLX), formerly known for its effects on reproduction and pregnancy, has been later shown to be a pleiotropic hormone, capable of also targeting numerous non-reproductive organs of the cardiovascular, nervous, respiratory, tegumental, excretory and digestive systems. Most of these effects have been studied in animal models, but there is compelling evidence that RLX also acts in humans. In more recent years, human luteal-type (H2) RLX synthesised by recombinant DNA technology has been investigated in clinical trials, mostly oriented to assess its therapeutic potential in cardiovascular disease. This indication was based on the accumulating pre-clinical evidence that RLX possesses prominent biological effects on systemic and coronary blood vessels, cardiomyocyte growth and differentiation, and cardiac/vascular connective tissue remodelling. This mini-review was intended as an update of our previous article that appeared in this journal in 2009, as the last 2 years have been characterised by fundamental achievements on the clinical profile of RLX. Eventually, after many years of inconclusive studies, RLX appears to be about to reach a recognised dignity as a cardiovascular drug.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cell Differentiation; Clinical Trials as Topic; DNA, Recombinant; Humans; Myocytes, Cardiac; Relaxin

Pharmacological outcomes depend on many factors, with many of them being sexually dimorphic. Thus, physiological gender/sex (GENS) differences can influence pharmacokinetics, pharmacodynamics and, thus, bioavailability and resulting in efficacy of treatment, meaning GENS differences should be an important consideration in therapeutics. In particular, drug response can change according to different hormonal environments. Therefore, GENS-specific differences have a particular clinical relevance in terms of drug delivery, especially for those substances with a narrow therapeutic margin. Since adverse effects are more frequent among women, safety is a key issue. Overall, the status of women, from a pharmacological point of view, is often different and less studied than that of men and deserves particular attention. Further studies focused on women's responses to drugs are necessary in order to make optimal pharmacotherapeutic decisions.

Topics: Biological Availability; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Female; Humans; Male; Sex Factors; Treatment Outcome

Albeit great efforts in reducing the burden of cardiovascular diseases (CVD), their prevalence continues to grow worldwide. Among the causes for this rising burden, the upcoming pandemic of obesity and diabetes further enhances the estimates of CV mortality and healthcare costs over the next decades. Nevertheless, advances in CVD treatment has increased life-expectancy, and future perspectives announce a growing aging population, with increasing comorbid conditions predisposing to CVD. Despite the emphasis on primary prevention, CV risk factors are still poorly controlled and a further need for CV drugs is upcoming. In chronic CVD such as hypertension, ischemic heart disease (IHD) and heart failure, the progressive use of multiple drugs is common and is recommended by international guidelines. However, the chronic use of five or more medications, defined as polypharmacy, has shown to be neither always efficacious nor safe. Polypharmacy is associated with an increased morbidity and costs. The use of multiple medications often leads to inappropriate drug use, underprescription, low adherence and side effects. In order to overcome these issues, a fixed-dose combination pill ('polypill') for the prevention of CVD has been recently proposed. A hypothetical meta-analysis estimated for this strategy a reduction of IHD and stroke by 88 and 80% respectively in people aged 55 or over. Such polypill can be cost effective and increase patient adherence. However, large randomized trials are required to define its impact on clinical outcomes. This review will focus on challenges of polypharmacy in CV medicine, illustrating potential options to face this emerging crisis.

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Cost-Benefit Analysis; Drug Costs; Humans; Middle Aged; Polypharmacy; Practice Guidelines as Topic; Primary Prevention; Risk Factors

Subnormal plasma levels of high-density lipoprotein cholesterol (HDL-C) constitute a major cardiovascular risk factor; raising low HDL-C levels may therefore reduce the residual cardiovascular risk that frequently presents in dyslipidaemic subjects despite statin therapy. Cholesteryl ester transfer protein (CETP), a key modulator not only of the intravascular metabolism of HDL and apolipoprotein (apo) A-I but also of triglyceride (TG)-rich particles and low-density lipoprotein (LDL), mediates the transfer of cholesteryl esters from HDL to pro-atherogenic apoB-lipoproteins, with heterotransfer of TG mainly from very low-density lipoprotein to HDL. Cholesteryl ester transfer protein activity is elevated in the dyslipidaemias of metabolic disease involving insulin resistance and moderate to marked hypertriglyceridaemia, and is intimately associated with premature atherosclerosis and high cardiovascular risk. Cholesteryl ester transfer protein inhibition therefore presents a preferential target for elevation of HDL-C and reduction in atherosclerosis. This review appraises recent evidence for a central role of CETP in the action of current lipid-modulating agents with HDL-raising potential, i.e. statins, fibrates, and niacin, and compares their mechanisms of action with those of pharmacological agents under development which directly inhibit CETP. New CETP inhibitors, such as dalcetrapib and anacetrapib, are targeted to normalize HDL/apoA-I levels and anti-atherogenic activities of HDL particles. Further studies of these CETP inhibitors, in particular in long-term, large-scale outcome trials, will provide essential information on their safety and efficacy in reducing residual cardiovascular risk.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Fibric Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Niacin

Due to the increase in average life expectancy and the higher incidence of cardiovascular disease with advancing age, more elderly patients present for cardiac surgery nowadays. Advances in pre- and postoperative care mean that more elderly patients can be operated on safely and with a satisfactory outcome. Currently, coronary artery bypass surgery, aortic and mitral valve surgery and surgery of the ascending aorta are performed in elderly patients.. In this review, we summarize the outcome of elderly patients undergoing various cardiac surgical procedures and give future perspectives for the treatment of elderly patients with cardiac surgery.. A PubMed search for the period from 1980 to February 2009 was conducted with the following key words: 'elderly patient', 'cardiac surgery', 'CABG aortic surgery', 'mitral valve surgery' and 'endocarditis'. Additional information concerning population demographics was obtained from the World Health Organization homepage.. More and more cardiac surgical procedures are offered to elderly patients. The short- and long-term survival rates of elderly patients are comparable to those of younger patients. Nevertheless, the risk for these patients is only acceptable in the absence of comorbidities. In particular, renal dysfunction, cerebrovascular disease and a poor clinical state are associated with a worse outcome in elderly patients.. The data available show that most cardiac surgical procedures can be performed in elderly patients with a satisfactory outcome. Careful patient selection, flawless surgery, meticulous hemostasis, perfect anesthesia and myoacardial protection are basic requirements for the success of cardiac surgery in elderly patients.

Topics: Age Factors; Aged; Aged, 80 and over; Cardiac Surgical Procedures; Cardiovascular Agents; Cardiovascular Diseases; Female; Hematologic Agents; Humans; Male; Middle Aged; Survival Rate; Treatment Outcome

Since patients with peripheral arterial occlusive disease (PAOD) are at high-risk for cardiovascular morbidity and mortality, preventive measures aimed to reduce cardiovascular adverse events are advocated in the current guidelines. We conducted a systematic review to assess the implementation of secondary prevention (SP) measures in PAOD patients.. PubMed, Cochrane Library, EMBASE and Web of Science databases were searched to perform a systematic review of the literature from 1999 till June 2008 on SP for PAOD patients. Assessment of study quality was done following the Cochrane Library review system. The record outcomes were antiplatelet agents, heart rate lowering agents, blood pressure lowering agents, lipid lowering agents, glucose lowering agents, smoking cessation and walking exercise.. From a total of 2137 identified studies, 83 observational studies met the inclusion criteria, of which 24 were included in the systematic review comprising 34 157 patients. These patients suffered from coronary artery disease (n=3516, 41%), myocardial infraction (n=2647, 38%), angina pectoris (n=1790, 31%), congestive heart failure (n=2052, 14%), diabetes mellitus (n=10 690, 31%),hypertension (n=20 823, 73%) and hyperlipidaemia (n=15 067, 64%). Contrary to what the guidelines prescribe, antiplatelet agents, heart rate lowering agents, blood pressure lowering agents and lipid lowering agents were prescribed in 63%, 34%, 46% and 45% of the patients, respectively. Glucose lowering agents were prescribed in 81% and smoking cessation in 39% of the patients.. The majority of patients suffering from PAOD do not receive the entire approach of SP measures as suggested by the current guidelines. To our knowledge, the cause of this undertreatment is multifactorial: patient, physician or health-care-related.

Topics: Aged; Arterial Occlusive Diseases; Cardiovascular Agents; Cardiovascular Diseases; Evidence-Based Medicine; Exercise; Female; Guideline Adherence; Humans; Male; Middle Aged; Peripheral Vascular Diseases; Practice Guidelines as Topic; Risk Assessment; Risk Factors; Risk Reduction Behavior; Secondary Prevention; Smoking Cessation; Walking

Preoperative evaluation and perioperative management of cardiac disease in patients undergoing vascular surgery (VS) is important for patients and vascular surgeons. Recent evidence has emerged that has allowed us to develop contemporary paradigms for evaluating and managing coronary artery disease in VS patients perioperatively.. The utility of stress testing, the role of preoperative coronary revascularization, the optimal use of beta-blockers and statins, and the role of antiplatelet therapy in VS patients were reviewed in the literature.. The revised Lee cardiac risk index, based on the number of risk factors (high-risk surgery, ischemic heart disease, congestive heart failure, cerebrovascular disease, insulin-dependent diabetes mellitus, renal failure, hypertension, and age >75) quantitates cardiac risk. Stress testing is not predictive of myocardial ischemia/infarction (MI) or death and is only recommended in patients with unstable angina or an active arrhythmia. Stress testing for patients with 0 to 2 risk factors delays VS up to 3 weeks. In high-risk patients (>or=3 risk factors), it helps to identify patients who may develop myocardial ischemia and would benefit from a 30-day period to optimize medical therapy before VS. Stress testing and coronary catheterization do not predict which coronary artery to revascularize to prevent MI or death. Revascularization does not decrease MI or death rates at 1 month or 6 years. Although beta-blocker treatment decreases cardiac risk with VS, timing and dosage (titration) influence outcomes, improper usage may increase stroke and death rate, and not all VS patients should be taking these drugs. Patients with >or=1 risk factor should be considered to begin a low dose beta-blocker 1 month before VS. Preoperative statin use sharply decreases MI, stroke, and death perioperatively and long-term postoperatively.. Routine stress testing should not be performed before VS. The Lee index should be used to stratify risk in patients undergoing VS. Patients with >or=3 risk factors or active cardiac conditions should undergo stress testing, if VS can be delayed. All VS patients, except those with 0 risk factors, should be considered for a beta-blocker (bisoprolol, 2.5-5 mg/d started 1 month before VS, titrated to a pulse <70 beats/min and a systolic blood pressure >or=120 mm Hg). Intermediate risk factors may not require aggressive heart rate control but simply maintenance on a low-dose beta-blocker. Statins should be started (ideally 30 days) before all VS using long-acting formulations such as fluvastatin (80 mg/d) for patients unable to take oral medication.

Topics: Adrenergic beta-Antagonists; Algorithms; American Heart Association; Cardiovascular Agents; Cardiovascular Diseases; Clinical Protocols; Coronary Artery Disease; Exercise Test; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myocardial Revascularization; Patient Selection; Perioperative Care; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Predictive Value of Tests; Preoperative Care; Risk Assessment; Risk Factors; United States; Vascular Surgical Procedures

The role of vascular endothelium in cardiovascular disorders is well recognized. Mature endothelial cells contribute to the repair of endothelial injury, but they only have a limited capacity to do so. This has led to growing interest and further investigation into circulating endothelial progenitor cells (EPCs) and their role in vascular healing, repair, and postnatal neovascularization. The current perception of vascular health is that of a balance between ongoing injury and resultant vascular repair, mediated at least in part by circulating EPCs. Circulating EPCs play an important role in accelerating endothelialization at areas of vascular damage, and EPC enumeration is a viable strategy for assessing reparative capacity. Recent studies have shown that EPCs are affected both in number and function by several cardiovascular risk factors as well as various cardiovascular disease states, such as hypertension, hypercholesterolemia, and coronary artery disease. The present review summarizes the most relevant studies on the effects of cardiovascular drugs on vascular function and EPCs, focusing on their mechanisms of action.

Topics: Angiogenesis Inducing Agents; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cell Differentiation; Cell Proliferation; Endothelial Cells; Humans; Neovascularization, Physiologic; Regeneration; Stem Cells

Inflammation drives the formation, progression, and rupture of atherosclerotic plaques. Experimental studies have demonstrated that an inflammatory subset of monocytes/macrophages preferentially accumulate in atherosclerotic plaque and produce proinflammatory cytokines. T lymphocytes can contribute to inflammatory processes that promote thrombosis by stimulating production of collagen-degrading proteinases and the potent procoagulant tissue factor. Recent data link obesity, inflammation, and modifiers of atherosclerotic events, a nexus of growing clinical concern given the worldwide increase in the prevalence of obesity. Modulators of inflammation derived from visceral adipose tissue evoke production of acute phase reactants in the liver, implicated in thrombogenesis and clot stability. Additionally, C-reactive protein levels rise with increasing levels of visceral adipose tissue. Adipose tissue in obese mice contains increased numbers of macrophages and T lymphocytes, increased T lymphocyte activation, and increased interferon-gamma (IFN-gamma) expression. IFN-gamma deficiency in mice reduces production of inflammatory cytokines and inflammatory cell accumulation in adipose tissue. Another series of in vitro and in vivo mouse experiments affirmed that adiponectin, an adipocytokine, the plasma levels of which drop with obesity, acts as an endogenous antiinflammatory modulator of both innate and adaptive immunity in atherogenesis. Thus, accumulating experimental evidence supports a key role for inflammation as a link between risk factors for atherosclerosis and the biology that underlies the complications of this disease. The recent JUPITER trial supports the clinical utility of an assessment of inflammatory status in guiding intervention to limit cardiovascular events. Inflammation is thus moving from a theoretical concept to a tool that provides practical clinical utility in risk assessment and targeting of therapy.

Topics: Adaptive Immunity; Adiponectin; Adipose Tissue; Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunity, Innate; Inflammation; Inflammation Mediators; Monocytes; Obesity; Risk Factors; Signal Transduction; Thrombosis; Translational Research, Biomedical

More than 15 million people in the U.S. consume herbal remedies or high-dose vitamins. The number of visits to providers of complementary and alternative medicine exceeds those to primary care physicians, for annual out-of-pocket costs of $30 billion. Use of herbal products forms the bulk of treatments, particularly by elderly people who also consume multiple prescription medications for comorbid conditions, which increases the risk of adverse herb-drug-disease interactions. Despite the paucity of scientific evidence supporting the safety or efficacy of herbal products, their widespread promotion in the popular media and the unsubstantiated health care claims about their efficacy drive consumer demand. In this review, we highlight commonly used herbs and their interactions with cardiovascular drugs. We also discuss health-related issues of herbal products and suggest ways to improve their safety to better protect the public from untoward effects.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Herb-Drug Interactions; Humans; Phytotherapy; Plants, Medicinal; Treatment Outcome

In the western world, cardiovascular disease is the leading cause of death for both sexes. These diseases show substantial differences between the sexes with respect to epidemiology, biology and clinical aspects. In recent years, more attention has been directed towards sex differences in pharmacological effects. Although both sexes are included in most pharmacological trials, the proportion of women is often too low to enable sex-specific analyses.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anticholesteremic Agents; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Female; Fibrinolytic Agents; Humans; Male; Sex Characteristics; Sex Factors; Treatment Outcome

Alternative medications as a term call up many different meanings, significance, and perceptions to various medical practitioners. Some are good; others are bad. A wide range of alternative medications with relevance or connection to cardiovascular (CV) disease have been considered. While many are worthless, others have definite benefit, and at least one, chelation therapy, is associated with definite harm, significant risk, no benefit, and enrichment of the practitioners who prescribe it. The issues concerning alternative therapies will likely never be studied with randomized clinical trials due to the lack of a profit motive on the part of pharmaceutical companies--only rarely do other institutions, such as the National Institutes of Health, support medicinal studies. Basic knowledge of alternative therapies is essential for the CV specialist and other practicing physicians and other practitioners, since at least a few of their patients will take these medications regardless of medical advice. The result is that a number of these alternative medications will then interact with conventional CV medications, many times unfavorably.

Topics: Attitude of Health Personnel; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Complementary Therapies; Drug Interactions; Health Knowledge, Attitudes, Practice; Humans; Practice Patterns, Physicians'; Risk Assessment

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA-reductase) inhibitors, otherwise known as statins, are currently the medical treatment of choice for hypercholesterolemia. Hypercholesterolemia is a known risk factor for cardiovascular disease, and statin therapy has led to a significant reduction in morbidity and mortality from adverse cardiac events, stroke, and peripheral arterial disease. In addition to achieving a therapeutic decrease in serum cholesterol levels, statin therapy appears to promote other effects that are independent of changes in serum cholesterol. These ''pleiotropic'' effects include attenuation of vascular inflammation, improved endothelial cell function, stabilization of atherosclerotic plaque, decreased vascular smooth muscle cell migration and proliferation, and inhibition of platelet aggregation. This article is part I of a 2-part review, and it focuses on the pleiotropic effects of statins at the cellular level.

Topics: Atherosclerosis; Biomarkers; Blood Platelets; Cardiovascular Agents; Cardiovascular Diseases; Cholesterol; Disease Progression; Endothelial Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Inflammation; Muscle, Smooth, Vascular; Treatment Outcome

At least 1 in 7 cardiology patients now reports nonadherence to prescribed medications, potentially leading to negative outcomes across a broad range of cardiovascular diseases. This nonadherence can begin as early as the time of prescription or any time thereafter and occurs for a variety of reasons, including communication difficulties, polypharmacy, and a variety of objective and perceived side-effects. Among elderly, low-income, and disabled patients, drug costs represent a growing source of medication nonadherence and can be markedly reduced through the use of drug assistance programs and low-cost generic medications without sacrificing evidence-based therapy. Depression also contributes strongly to nonadherence and is widely prevalent in cardiovascular populations. Improvements in depression are mirrored by improvements in adherence. A systematic screening to identify the presence of nonadherence and many of its causes can be accomplished with minimal impact on visit length. In conclusion, once specific concerns are recognized, options frequently exist to help patients and providers address many of the most common difficulties.

Topics: Age Factors; Cardiovascular Agents; Cardiovascular Diseases; Depressive Disorder; Drug Prescriptions; Evidence-Based Medicine; Female; Humans; Male; Needs Assessment; Patient Compliance; Patient Education as Topic; Risk Assessment; Socioeconomic Factors; United States

Medications for the prevention and treatment of cardiovascular disease save lives but adherence is often inadequate. The optimal role for physicians in improving adherence remains unclear.. Using existing evidence, we set the goal of evaluating the physician's role in improving medication adherence.. We conducted systematic searches of English-language peer-reviewed publications in MEDLINE and EMBASE from 1966 through 12/31/2008.. We selected randomized controlled trials of interventions to improve adherence to medications used for preventing or treating cardiovascular disease or diabetes.. Articles were classified as either (1) physician "active"-a physician participated in designing or implementing the intervention; (2) physician "passive"-physicians treating intervention group patients received patient adherence information while physicians treating controls did not; or (3) physicians noninvolved. We also identified studies in which healthcare professionals helped deliver the intervention. We did a meta-analysis of the studies involving healthcare professionals to determine aggregate Cohen's D effect sizes (ES).. We identified 6,550 articles; 168 were reviewed in full, 82 met inclusion criteria. The majority of all studies (88.9%) showed improved adherence. Physician noninvolved studies were more likely (35.0% of studies) to show a medium or large effect on adherence compared to physician-involved studies (31.3%). Among interventions requiring a healthcare professional, physician-noninvolved interventions were more effective (ES 0.47; 95% CI 0.38-0.56) than physician-involved interventions (ES 0.25; 95% CI 0.21-0.29; p < 0.001). Among physician-involved interventions, physician-passive interventions were marginally more effective (ES 0.29; 95% CI 0.22-0.36) than physician-active interventions (ES 0.23; 95% CI 0.17-0.28; p = 0.2).. Adherence interventions utilizing non-physician healthcare professionals are effective in improving cardiovascular medication adherence, but further study is needed to identify the optimal role for physicians.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Health Personnel; Humans; Medication Adherence; Physician's Role; Randomized Controlled Trials as Topic

Therapies that aim to modify cardiac substrate utilisation are designed to increase metabolic efficiency. Although the main energy supply for the heart is generally provided by the oxidation of fatty acids, the heart is a metabolic omnivore and able to consume glucose as well as lactate and amino acids in varying proportions. A shift from fatty acid oxidation to glucose oxidation leads to lower oxygen consumption per unit of ATP produced. This concept of reduced oxygen utilisation underlies the use of metabolic modulating agents to treat chronic stable angina. Furthermore, the model of an energy-starved heart now forms the basis for our understanding of both ischaemic and non-ischaemic heart failure. Potential alterations in substrate utilisation and thus myocardial efficiency underlie the use of metabolic agents in heart failure. This is achieved by either promoting glucose or reducing the utilisation of fatty acids. Such a shift results in a relatively greater production of ATP per unit of oxygen consumed. With an ongoing demand for treatment options in ischaemic heart disease and a growing epidemic of heart failure, new treatment modalities beyond contemporary therapy need consideration.

Topics: Adenosine Triphosphate; Blood Glucose; Cardiovascular Agents; Cardiovascular Diseases; Fatty Acids; Humans; Mitochondria, Heart; Myocardium; Oxidation-Reduction; Oxygen Consumption

Edible mushrooms are a valuable source of nutrients and bioactive compounds in addition to a growing appeal for humans by their flavors and culinary features. Recently, they have become increasingly attractive as functional foods for their potential beneficial effects on human health. Hence, food industry is especially interested in cultivated and wild edible mushrooms. Cardiovascular diseases are one of the most prevalent causes of morbidity and mortality in the Western world. Several investigations have shown the influence of mushrooms intake on some metabolic markers (total, LDL, HDL cholesterol, fasting triacylglycerol, homocysteine, blood pressure, homeostatic function and oxidative and inflammatory damage), which potentially may reduce the risk of suffering cardiovascular diseases. Relevant nutritional aspects of mushrooms include a high fiber supply, a low fat content with low trans isomers of unsaturated fatty acids and a low concentration of sodium as well as the occurrence of components such as eritadenine, phenolic compounds, sterols (such as ergosterol), chitosan, triterpenes, etc., which are considered as important responsible agents for some hitherto healthy properties. The aims of this review are to report putative positive effects of mushrooms consumption on cardiovascular diseases risk markers and to identify some putative bioactive compounds involved in these effects.

Topics: Agaricales; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Functional Food; Humans; Nutritive Value; Phytotherapy

Cardiovascular disease is a major co-morbidity in chronic obstructive pulmonary disease (COPD) patients and is a predictor of all-cause mortality. This paper reviews the study design and data analyses of observational studies of cardiovascular drug effects in patients with COPD and evaluates the potential for bias on the validity of their findings. Three recent observational studies of statin use in the setting of COPD show surprisingly high efficacy results which, by their magnitude, demand closer analysis. Such analysis reveals that immortal time and immeasurable time biases likely accounted for dramatic findings of reduced mortality with aggressive treatment for cardiovascular disease. After removing these sources of bias, the effects are mitigated or may disappear entirely. Investigation of methods and results in the statin studies reviewed in this article reveals significant bias that has skewed the results of these early studies. Correcting these methodological flaws with proper statistical analysis may attenuate or even eliminate these apparent benefits.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Pulmonary Disease, Chronic Obstructive

Vitamin D has been known to medical science for almost a century. Yet, it is only in the last 15 years that we have realized that the biological effects of vitamin D extend far beyond the control of calcium metabolism. Recent observational evidence suggests strong links between low vitamin D levels and a range of cardiovascular conditions, including stroke, myocardial infarction, hypertension, and diabetes. Interventional studies are beginning to explore whether vitamin D supplementation can modify vascular health and prevent cardiovascular disease. This article reviews the physiology and function of vitamin D, examines the current observational and intervention data in cardiovascular disease, and discusses future research and current practice recommendations.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Dietary Supplements; Evidence-Based Medicine; Humans; Practice Guidelines as Topic; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

Atherosclerosis disease and its extent in childhood correlate positively with established risk factors, namely obesity, hypercholesterolemia, diabetes mellitus, and hypertension. The safety and efficacy of some dietary interventions to modulate risk factors in childhood are documented by an increasing body of evidence. The present review analyzes nutritional and nutraceutical current strategies addressed to modify some risk factors of atherosclerosis in childhood. In particular, studies concerning nutrients such as fibers, omega-3-fatty acids, vitamin D, antioxidants, and calcium have been evaluated. An overall analysis suggests that some nutraceuticals might represent an attractive tool to lower the development of atherosclerotic-related cardiovascular complication in children. Nevertheless, at this moment, due to the methodological weakness that characterizes the majority of the analyzed studies, nutrients or supplements should not be considered as a therapeutic tool potentially usable for clinical purpose in children at risk for cardiovascular disease.

Topics: Adolescent; Age Factors; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Child; Diet; Dietary Supplements; Evidence-Based Medicine; Humans; Nutritional Status; Risk Assessment; Risk Factors; Treatment Outcome

An "unhealthy" diet is considered as a main cause of increased atherosclerotic cardiovascular disease in the industrialized countries. There is a substantial interest in the potential cardiovascular protective effects of "nutraceuticals," that is food-derived substances that exert beneficial health effects. The correct understanding of cardiovascular effects of these compounds will have important implications for cardiovascular prevention strategies. Endothelial dysfunction is thought to play an important role in development and progression of atherosclerosis, and the characterization of the endothelial effects of several nutraceuticals may provide important insights into their potential role in cardiovascular prevention. At the same time, the analysis of the endothelial effects of nutraceuticals may also provide valuable insights into mechanisms of why certain nutraceuticals may not be effective in cardiovascular prevention, and it may aid in the identification of food-derived substances that may have detrimental cardiovascular effects. These findings further support the notion that nutraceuticals do need support from large clinical outcome trials with respect to their efficacy and safety profile for cardiovascular prevention, before their widespread use can be recommended. In fact, the term nutraceutical was coined to encourage an extensive and profound research activity in this field, and numerous large-scale clinical outcome trials to examine the effects of nutraceuticals on cardiovascular events have now been performed or are still ongoing. Whereas it is possible that single nutraceuticals may be effective in cardiovascular prevention, this field of research provides also valuable insights into which food components may be particularly important for cardiovascular prevention, to further advice the composition of a particularly healthy diet. The present review summarizes recent studies on the endothelial effects of several nutraceuticals, that have been intensely studied.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Diet; Dietary Supplements; Endothelium, Vascular; Evidence-Based Medicine; Functional Food; Humans; Treatment Outcome

Despite declining rates of cardiovascular disease (CVD) mortality in developed countries, lower socioeconomic groups continue to experience a greater burden of the disease. There are now many evidence-based treatments and prevention strategies for the management of CVD and it is essential that their impact on the more disadvantaged group is understood if socioeconomic inequalities in CVD are to be reduced.. To determine whether key interventions for CVD prevention and treatment are effective among lower socioeconomic groups, to describe barriers to their effectiveness and the potential or actual impact of these interventions on the socioeconomic gradient in CVD.. Interventions were selected from four stages of the CVD continuum. These included smoking reduction strategies, absolute risk assessment, cardiac rehabilitation, secondary prevention medications, and heart failure self-management programmes. Electronic searches were conducted using terms for each intervention combined with terms for socioeconomic status (SES).. Only limited evidence was found for the effectiveness of the selected interventions among lower SES groups and there was little exploration of socioeconomic-related barriers to their uptake. Some broad themes and key messages were identified. In the majority of findings examined, it was clear that the underlying material, social and environmental factors associated with disadvantage are a significant barrier to the effectiveness of interventions.. Opportunities to reduce socioeconomic inequalities occur at all stages of the CVD continuum. Despite this, current treatment and prevention strategies may be contributing to the widening socioeconomic-CVD gradient. Further research into the impact of best-practice interventions for CVD upon lower SES groups is required.

Topics: Benchmarking; Cardiovascular Agents; Cardiovascular Diseases; Evidence-Based Medicine; Health Services Accessibility; Health Services Research; Healthcare Disparities; Humans; Preventive Health Services; Risk Assessment; Risk Factors; Secondary Prevention; Self Care; Smoking Cessation; Socioeconomic Factors; Treatment Outcome

The Rho/rho-kinase (ROCK) pathway has an important role in the pathogenesis of several cardiovascular diseases. The activation of ROCK is involved in the regulation of vascular tone, endothelial dysfunction, inflammation and remodeling. The inhibition of ROCK has a beneficial effect in a variety of cardiovascular disorders. Evidence from animal models and from clinical use of ROCK inhibitors, such as Y-27632, fasudil and statins (i.e. pleiotropic effects), supports the hypothesis that ROCK is a potential therapeutic target. This review provides a current understanding of the role of ROCK pathway in the regulation of vascular function and the use of ROCK inhibitors in the treatment of cardiovascular disorders.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Disease Models, Animal; Drug Delivery Systems; Drug Design; Enzyme Inhibitors; Humans; rho-Associated Kinases

Our understanding of signaling pathways and cues vital for cardiac regeneration is being refined by laboratories worldwide. As various mechanisms enabling cardiac regeneration are becoming elucidated, delivery vehicles suited for these potential therapeutics must also be developed. This review focuses on advances in two technologies, novel degradable microspheres for controlled release systems and self-assembling peptide nanofibers for cell and factor delivery. Polyketals, a new class of resorbable polymers, are well suited for treating inflammatory diseases due to biocompatible degradation products. Polyketals have been used to deliver small molecule inhibitors and antioxidant proteins to rat models of myocardial infarction with notable improvements in cardiac function. Self-assembling peptide nanofibers are a class of hydrogels that are well-defined scaffolds made up of 99% water and amenable to incorporation of a variety of bioactive cues. Work done by our laboratory and others have demonstrated functional improvements using these hydrogels as both a drug delivery vehicle for proteins as well as a defined microenvironment for transplanted cells. Combining non-inflammatory polymer microspheres for sustained release of drugs with self-assembling nanofibers yields multifunctional scaffolds that may soon drive the body's healing response following myocardial infarction towards cardiac regeneration.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cell Transplantation; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Humans; Hydrogels; Microspheres; Nanofibers; Peptides; Polymers; Regeneration; Tissue Scaffolds; Translational Research, Biomedical

Many behavioral and physiological processes, including locomotor activity, blood pressure, body temperature, sleep (fasting)/wake (feeding) cycles, and metabolic regulation display diurnal rhythms. The biological clock ensures proper metabolic alignment of energy substrate availability and processing. Studies in animals and humans highlight a strong link between circadian disorders and altered metabolic responses and cardiovascular events. Shift work, for instance, increases the risk to develop metabolic abnormalities resembling the metabolic syndrome. Nuclear receptors have long been known as metabolic regulators. Several of them (ie, Rev-erbalpha, RORalpha, and peroxisome proliferation-activated receptors) are subjected to circadian variations and are integral components of molecular clock machinery. In turn, these nuclear receptors regulate downstream target genes in a circadian manner, acting to properly gate metabolic events to the appropriate circadian time window.

Topics: Adipose Tissue; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Circadian Rhythm; Energy Metabolism; Humans; Receptors, Cytoplasmic and Nuclear; Risk Factors; Signal Transduction

The second messengers, cAMP and cGMP, regulate a number of physiological processes in the myocardium, from acute contraction/relaxation to chronic gene expression and cardiac structural remodeling. Emerging evidence suggests that multiple spatiotemporally distinct pools of cyclic nucleotides can discriminate specific cellular functions from a given cyclic nucleotide-mediated signal. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing intracellular cyclic AMP and/or cyclic GMP, control the amplitude, duration, and compartmentation of cyclic nucleotide signaling. To date, more than 60 different isoforms have been described and grouped into 11 broad families (PDE1-PDE11) based on differences in their structure, kinetic and regulatory properties, as well as sensitivity to chemical inhibitors. In the heart, PDE isozymes from at least six families have been investigated. Studies using selective PDE inhibitors and/or genetically manipulated animals have demonstrated that individual PDE isozymes play distinct roles in the heart by regulating unique cyclic nucleotide signaling microdomains. Alterations of PDE activity and/or expression have also been observed in various cardiac disease models, which may contribute to disease progression. Several family-selective PDE inhibitors have been used clinically or pre-clinically for the treatment of cardiac or vascular-related diseases. In this review, we will highlight both recent advances and discrepancies relevant to cardiovascular PDE expression, pathophysiological function, and regulation. In particular, we will emphasize how these properties influence current and future development of PDE inhibitors for the treatment of pathological cardiac remodeling and dysfunction.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Isoenzymes; Molecular Targeted Therapy; Myocardium; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Second Messenger Systems; Translational Research, Biomedical

Flavonoids are a class of naturally occurring polyphenols abundant in edibles and beverages of plant origin. Epidemiological studies consistently associate high flavonoid intake with a reduced risk for the development of cardiovascular diseases. So far these beneficial effects have been mainly attributed to nonspecific antioxidant and antiinflammatory properties. However, there is an increasing body of evidence that flavonoids specifically target molecular structures including cardiovascular ion channels. Playing a pivotal role in the regulation of vascular tone and cardiac electric activity, ion channels represent a major target for the induction of antihypertensive and cardioprotective effects. Thus, pharmacological properties of flavonoids on cardiovascular ion channels, ion currents and tissue preparations are being increasingly addressed in experimental studies. Whereas it has become clear that cardiovascular ion channels represent an important molecular target of flavonoids, the published data have not yet been systematically reviewed.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Dietary Supplements; Flavonoids; Humans; Ion Channels; Ion Transport; Membrane Potentials

Cardiovascular disease is the leading cause of death worldwide, showing a dramatically growing prevalence. It is still associated with a poor clinical prognosis, indicating insufficient long-term treatment success of currently available therapeutic strategies. Investigations of the pathomechanisms underlying cardiovascular disorders uncovered the Ca(2+) binding protein S100A1 as a critical regulator of both cardiac performance and vascular biology. In cardiomyocytes, S100A1 was found to interact with both the sarcoplasmic reticulum ATPase (SERCA2a) and the ryanodine receptor 2 (RyR2), resulting in substantially improved Ca(2+) handling and contractile performance. Additionally, S100A1 has been described to target the cardiac sarcomere and mitochondria, leading to reduced pre-contractile passive tension as well as enhanced oxidative energy generation. In endothelial cells, molecular analyses revealed a stimulatory effect of S100A1 on endothelial NO production by increasing endothelial nitric oxide synthase activity. Emphasizing the pathophysiological relevance of S100A1, myocardial infarction in S100A1 knockout mice resulted in accelerated transition towards heart failure and excessive mortality in comparison with wild-type controls. Mice lacking S100A1 furthermore displayed significantly elevated blood pressure values with abrogated responsiveness to bradykinin. On the other hand, numerous studies in small and large animal heart failure models showed that S100A1 overexpression results in reversed maladaptive myocardial remodeling, long-term rescue of contractile performance, and superior survival in response to myocardial infarction, indicating the potential of S100A1-based therapeutic interventions. In summary, elaborate basic and translational research established S100A1 as a multifaceted therapeutic target in cardiovascular disease, providing a promising novel therapeutic strategy to future cardiologists.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Endothelial Cells; Genetic Therapy; Humans; Models, Molecular; Molecular Targeted Therapy; Myocytes, Cardiac; Protein Conformation; S100 Proteins; Signal Transduction; Translational Research, Biomedical

Transient receptor potential channels are a large superfamily of non-selective and non-voltage-gated ion channels that convey signaling information linked to a broad range of sensory inputs. In the cardiovascular system, the canonical transient receptor potential (TRPC) family has been particularly found to play a role in vascular and cardiac disease, responding to neurohormonal and mechanical load stimulation. TRPC1, TRPC3, and TRPC6 are often upregulated in models of cardiovascular disease, and their inhibition ameliorates the associated pathophysiology. Studies in gene deletion models and overexpression models of wild-type and dominant-negative proteins supports a direct role of these channels, which likely act together as heterotetramers to influence signaling. Recent evidence has further revealed the importance of protein kinase G phosphorylation as a mechanism to suppress TRPC6 channel current and dependent signaling in vascular and cardiac myocytes. This suggests a novel mechanism underlying benefits of drugs such as sildenafil, a phosphodiesterase type 5 inhibitor, nitrates, and atrial natriuretic peptides. This review describes new evidence supporting a pathophysiologic role of these three TRPC channels, and the potential utility of inhibition strategies to treat cardiovascular disease.

Topics: Animals; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Humans; Molecular Targeted Therapy; Myocardium; Signal Transduction; Translational Research, Biomedical; TRPC Cation Channels

Arterial aging can be attributed to two different pathophysiological changes--increase in arterial stiffness and disturbed wave reflections. The capacity of the aorta to absorb the force exerted by the left ventricular ejection and dampen pulsatile flow becomes diminished with advancing age, owing to the progressive hardening of the arterial wall. These changes contribute to increase blood pressure, mainly systolic blood pressure and pulse pressure, which can trigger cardiovascular events. Understanding the pulsatile arterial hemodynamics that elevate cardiovascular risk has led to the use of pharmacological therapies, which prevent arterial stiffness and reduce wave reflections, and improve cardiovascular morbidity and mortality. Antifibrotic agents, such as those that block the renin-angiotensin-aldosterone pathway, are often given in association with diuretics, calcium-channel blockers, or both, but not with standard beta-blockers. Consistent reductions in cardiovascular outcomes obtained using these agents can be predicted through noninvasive measurements of central systolic blood pressure and pulse pressure.

Topics: Adult; Age Factors; Aged; Aging; Arteries; Cardiovascular Agents; Cardiovascular Diseases; Female; Hemodynamics; Humans; Male; Middle Aged

The commonest medical conditions following menopause are osteoporosis and atherosclerotic disease. This review considers the safety of pharmacotherapy of osteoporosis in cardiology patients. Drugs used for osteoporosis treatment may have adverse effects on the cardiovascular system. This article has detailed analysed of current drug classes, such as the bisphosphonates and strontium ranelate, as well as reviewed of the controversy surrounding hormone replacement therapy (HRT) and the selective estrogen receptor modulators (SERMs). Additionally, we discuss the adverse effects on the heart of calcium and drugs influencing calcium metabolism such as vitamin D, parathormone and calcitonin. We look at the interference between osteoporosis treatment and the drugs used for atherosclerosis. Moreover, the side effects on bones of cardiology drugs are analysed. Lastly, the possible advantages of selected drugs used for cardiovascular diseases in terms of osteoporosis prevention are evaluated.

Topics: Age Factors; Bone and Bones; Bone Density Conservation Agents; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Drug Interactions; Female; Humans; Male; Osteoporosis; Osteoporosis, Postmenopausal; Risk Assessment; Sex Factors

Cardiovascular and cerebrovascular diseases share many pathophysiological traits, often impact one another and share several risk factors, though not always to the same magnitude. Therefore, it is not surprising that many classes of cardiovascular drugs have demonstrated effectiveness in the primary prevention, acute treatment and secondary prevention of stroke. Important advances have been made since 2007 in the use of antiplatelets, anticoagulants, antihypertensives, antiarrhythmics and statins for the treatment of stroke. This review summarizes selected clinical trials of cardiovascular drugs completed from 2007 to 2010 that generated important evidence supporting the efficacy of these drugs in stroke treatment. Ongoing trials and preclinical research of promising agents and treatment strategies are also discussed.

Topics: Anti-Arrhythmia Agents; Anticoagulants; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Clinical Trials as Topic; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Platelet Aggregation Inhibitors; Risk Factors

One of the primary impediments to successful drug R&D is the frequent failure of successfully translating positive results obtained in animal models to human disease. To a large degree, this discrepancy is secondary to the substantial biological differences between species. Non-human primate models have the advantage of significant physiological, metabolic, biochemical and genetic similarity to humans. Despite this advantage, there has been a relative paucity of non-human primate models used in the study of disease states that currently underlie the most common causes of morbidity and mortality, such as chronic myocardial ischemia leading to heart failure. This review describes a primate model of heart failure that closely mimics the cardiomyopathic process observed in humans. The primary advantage of this non-human primate model is that, unlike existing heart failure models, it allows for continuous study during progressive stages of heart failure, including myocardial ischemia, progressive left ventricular remodeling and end-stage congestive heart failure. In addition to this model of heart failure, other non-human primate models for cardiovascular drug R&D are also reviewed.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Chlorocebus aethiops; Disease Models, Animal; Haplorhini; Heart Failure; Macaca fascicularis; Models, Animal; Primates

This review focuses on new insights provided by gene-modified animals into the cardiovascular pharmacology of serotonin. During their development, mice mutant for tryptophan hydroxylase 1 and lacking peripheral serotonin, or mutant for 5-HT(2B) receptors, display cardiac defects and dilated cardiomyopathy. The 5-HT(4) receptor is important for the maturation of cardiac conduction. In fact, transgenic approaches have revealed that adult cardiac status is strongly influenced by maternal serotonin. Serotonin has long been known to be a vasoconstrictor in adult physiology. Analysis of animals knocked-out for the serotonin transporter suggested a role in blood pressure control and revealed an effect of 5-HT(2B) receptor antagonists in hypertension. In the lung vasculature, mice lacking the 5-HT(2B) receptor gene that are exposed to chronic hypoxia are resistant to pulmonary hypertension, while 5-HT(1B) receptor and serotonin transporter mutant animals show partial resistance. In platelets, mutant mice revealed that serotonin transporter regulates not only the mechanisms by which serotonin is packaged and secreted but also platelet aggregation. Studies looking at adult cardiac remodeling showed that mice lacking the 5-HT(2B) receptor gene were protected from cardiac hypertrophy. Their fibroblasts were unable to secrete cytokines. Crossing these animals with mice overexpressing the receptor in cardiomyocytes revealed the contribution of cardiac fibroblasts and 5-HT(2B) receptors to cardiac hypertrophy. In mice lacking the monoamine oxidase-A gene, the role of serotonin degradation in cardiac hypertrophy was confirmed. Works with gene-modified animals has contributed strongly to the re-evaluation of the influence of serotonin on cardiovascular regulation, though several unknowns remain to be investigated.

Topics: Animals; Animals, Genetically Modified; Blood Platelets; Cardiovascular Abnormalities; Cardiovascular Agents; Cardiovascular Diseases; Heart; Hemostasis; Mice; Mice, Knockout; Rats; Rats, Mutant Strains; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Serotonin

Cardiovascular disease constitutes a major and increasing health burden in developed countries. Although treatments have progressed, the development of novel treatments for patients with cardiovascular diseases remains a major research goal. The endoplasmic reticulum (ER) is the cellular organelle in which protein folding, calcium homeostasis, and lipid biosynthesis occur. Stimuli such as oxidative stress, ischemic insult, disturbances in calcium homeostasis, and enhanced expression of normal and/or folding-defective proteins lead to the accumulation of unfolded proteins, a condition referred to as ER stress. ER stress triggers the unfolded protein response (UPR) to maintain ER homeostasis. The UPR involves a group of signal transduction pathways that ameliorate the accumulation of unfolded protein by increasing ER-resident chaperones, inhibiting protein translation and accelerating the degradation of unfolded proteins. The UPR is initially an adaptive response but, if unresolved, can lead to apoptotic cell death. Thus, the ER is now recognized as an important organelle in deciding cell life and death. There is compelling evidence that the adaptive and proapoptotic pathways of UPR play fundamental roles in the development and progression of cardiovascular diseases, including heart failure, ischemic heart diseases, and atherosclerosis. Thus, therapeutic interventions that target molecules of the UPR component and reduce ER stress will be promising strategies to treat cardiovascular diseases. In this review, we summarize the recent progress in understanding UPR signaling in cardiovascular disease and its related therapeutic potential. Future studies may clarify the most promising molecules to be investigated as targets for cardiovascular diseases.

Topics: Animals; Apoptosis; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Endoplasmic Reticulum; Humans; Oxidative Stress; Unfolded Protein Response

Cardiovascular diseases are a leading cause of hospitalizations and death in the United States and elsewhere in the world. Developing new therapeutic agents for cardiovascular diseases has always been the priority for the pharmaceutical industry because of the huge potential market for these drugs. Some of these newer drugs are frequently used in the practice of cardiovascular anesthesiology. This article reviews the recent advances in cardiovascular medications related to the practice of cardiac anesthesia.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Diastole; Heart Failure; Humans; Hydrazones; Muscle Contraction; Myofibrils; Natriuretic Peptide, Brain; Nicardipine; Pyridazines; Pyridines; Sarcomeres; Simendan; Urea

In November 2009 the first European guidelines were presented regarding preoperative risk assessment and perioperative management in non-cardiac surgery. They were designed by the European Society of Cardiology (ESC) and endorsed by the European Society of Anesthesiology.In a standardized manner, patient-specific clinical variables, their exercise capacity and surgery-specific risk factors are summarized to a recommendation concerning medication and preoperative cardiac evaluation. These guidelines are straightforward and feasible for cardiologists as well as specialists in internal medicine and general practicioners. Nevertheless, some points still lack evidence.

Topics: Activities of Daily Living; Age Factors; Angina Pectoris; Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Coronary Angiography; Diabetes Mellitus, Type 1; Electrocardiography; Europe; Evidence-Based Medicine; Exercise Test; Health Status Indicators; Heart Failure; Humans; Metabolic Equivalent; Practice Guidelines as Topic; Preoperative Care; Renal Insufficiency

The list of potential cardiovascular biomarkers has expanded dramatically in recent years; however, the number of regulatory agency-approved diagnostic tests that guide treatment has been relatively unchanged compared with this growth in the discovery of putative biomarkers. Surrogate biochemical endpoints such as LDL and HDL are included in the current guidelines of various regulatory agencies for the management of cardiovascular diseases, as a result of many years of research. Inclusion of tests for these markers, as well as any future tests, in treatment guidelines requires data obtained from large-scale clinical trials comparing these endpoints with 'hard' clinical endpoints, such as morbidity and mortality. Consequently, current guidelines are limited to conventional in vitro tests and incorporate few novel tests for guiding or modifying treatment. Despite the failure to include newer in vitro tests in cardiovascular treatment and prevention paradigms, ongoing biomarker discovery and assay optimization has provided many improvements in drug discovery and development, and has afforded opportunities for the optimized medical treatment of patients with cardiovascular disease.

Topics: Biomarkers; C-Reactive Protein; Cardiovascular Agents; Cardiovascular Diseases; Drug Discovery; Humans; Natriuretic Peptide, Brain; Troponin I

The pharmaceutical development of a cardiovascular polypill presents several unique challenges. The selection of the type and number of active drugs to be incorporated requires important consideration of clinical, pharmaceutical and commercial issues, and the final decision with regard to the polypill's components depends on how these issues are prioritized. Once the drug combination has been chosen, developers must determine which pharmaceutical formulation should be used. The most appropriate method of drug delivery can vary markedly and depends on the characteristics of the drugs to be combined. Finally, careful consideration of how to gather the type of information required by regulatory agencies before a particular polypill can be approved for use in the general population is crucial. Although the association of multiple, active ingredients in a single dosage form would represent a major step forward in the prevention of cardiovascular conditions, a careful evaluation of all the above-mentioned variables and a well thought-out development plan is mandatory to maximize the chances of success.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Chemistry, Pharmaceutical; Drug Administration Schedule; Drug Approval; Drug Combinations; Drug Compounding; Drug Costs; Drug Industry; Humans; Intellectual Property; Treatment Outcome

Ischemic heart disease and stroke are the leading causes of death worldwide. A large proportion of individuals at high 10-year risk of a cardiovascular event live in low-income and middle-income countries, and the large majority of all cardiovascular events occur in developing countries. A large amount of evidence supports the use of pharmacological treatment for the prevention of cardiovascular death in this population, including antiplatelet drugs, beta blockers, lipid-lowering agents and angiotensin-converting-enzyme inhibitors. However, the efficacy of cardiovascular prevention is hampered by several problems, including inadequate prescription of medication, poor adherence to treatment, limited availability of medications and unaffordable cost of treatment. Here we examine the use of fixed-dose combination therapy (a 'polypill'), and how this therapy could improve adherence to treatment, reduce the cost and improve treatment affordability in low-income countries.

Topics: Adrenergic beta-Antagonists; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Developing Countries; Drug Combinations; Drug Costs; Health Services Accessibility; Humans; Hypolipidemic Agents; Medication Adherence; Patient Selection; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Practice Patterns, Physicians'; Secondary Prevention; Treatment Outcome

Aldosterone is an adrenal hormone that regulates sodium, fluid, and potassium balance. Jerome Conn first described the syndrome of autonomous and excessive aldosterone secretion or "primary aldosteronism." Contrary to the historical belief, recent studies indicate that primary aldosteronism is a common cause of hypertension with a prevalence of 5-10% among general hypertensive patients. Various animal models have demonstrated that aldosterone in association with a high salt diet results in target-organ inflammation and fibrosis. Similarly, cross-sectional and observational human studies have demonstrated the association of aldosterone with development and severity of hypertension, congestive heart failure, coronary artery disease, chronic kidney disease, and metabolic syndrome. Several interventional studies have also demonstrated the beneficial effects of mineralocorticoid receptor antagonists in these disease processes, particularly hypertension, heart failure, and post myocardial infarction, further supporting the role of aldosterone in their pathogenesis. We review the role of aldosterone in these various cardiovascular disease processes along with potential mechanisms and treatment.

Topics: Adrenalectomy; Aldosterone; Animals; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Heart Failure; Humans; Hyperaldosteronism; Hypertension; Kidney Diseases; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Treatment Outcome

The large conduit arteries of the thorax and abdomen are elastic while those in the arms and legs are muscular. Alterations in wall properties of elastic arteries occur over time and are usually permanent in nature; acute changes can, however, occur is response to a change in transmural pressure. Chronic alterations in properties of muscular arteries are minimal but changes (e.g vasoconstriction, vasodilation or tone) do occur in response to smooth muscle cell (SMC) stimulation. In general an increase in arterial stiffness (and wave reflection) increases systolic blood pressure (BP) and is detrimental while a decrease is beneficial. The augmentation in systolic BP increases left ventricular (LV) mass, wasted energy, tension-time index (TTI) and myocardial oxygen demand while the fall in diastolic BP decreases coronary artery perfusion causing a mismatch in ventricular/vascular coupling and an imbalance in the myocardial oxygen supply/demand ratio. Cardiovascular hormones such as renin, angiotensin, aldosterone, parathormone, sympathomimetic amines and endothelin induce vasoconstriction and increase arterial stiffness while insulin, thyroxine, testosterone, atrial natriuretic peptide (ANP), estrogen and nitric oxide (NO) have the opposite effect. The undesirable effects can be reversed with selected blocking agents. Vasodilator drugs have little direct active effect on large elastic arteries and unaugmented BP but can markedly reduce wave reflection amplitude and duration and augmentation index by decreasing stiffness of the muscular arteries and reducing transmission velocity of the reflected wave from the periphery to the heart. This decrease in amplitude and increase in travel time (or delay) of the reflected wave causes a generalized decrease in systolic BP, arterial wall stress, wasted LV energy and TTI.

Topics: Animals; Arteries; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Muscle, Smooth, Vascular; Vasodilator Agents

The incidence of peripheral arterial disease (PAD) is on the increase and is associated with a major health concern in current practical care. The most common disease process underlying PAD is atherosclerosis. Atherosclerosis is a complex generalized disease affecting several arterial beds, including the peripheral and coronary circulation. Especially in patients with PAD, high incidences of coronary artery disease (CAD) have been observed, which may be asymptomatic or symptomatic. The prognosis of patients with PAD is related to the presence and extent of underlying CAD. In patients with PAD undergoing major vascular surgery, cardiac complications are the major cause of perioperative morbidity and mortality and indicate a high-risk for adverse long-term cardiac outcome. In order to improve outcome for PAD patients, assessment and aggressive therapy of atherosclerotic risk factors and usage of cardio-protective medications is recommended. Unfortunately, substantial differences in risk factor management and treatment and long-term outcome have been reported between PAD and CAD patients.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Disease; Humans; Peripheral Vascular Diseases; Predictive Value of Tests; Risk Assessment; Risk Factors; Risk Reduction Behavior; Treatment Outcome; Vascular Surgical Procedures

The pharmacotherapy of complex pathological states at the cardiovascular level often requires different and complementary pharmacodynamic properties. This is frequently achieved through the administration of "cocktails", composed by several drugs possessing different mechanisms of action. In the last years, a revision of the "one-compound-one-target" paradigm led to a wide development of new classes of molecules, possessing more pharmacological targets. Among them, this innovative strategy produced interesting hybrid drugs, with a dual mechanism of action: a) a fundamental and well-established pharmacodynamic profile and b) the release of nitric oxide (NO), playing a pivotal role in the modulation of the function of cardiovascular system, where it induces vasorelaxing and antiplatelet responses. These new pharmacodynamic hybrids present the advantage of adding to a main mechanism of action (for example, cyclooxygenase inhibition, beta-antagonism or ACE-inhibition) also a slow release of NO, useful either to reduce the adverse side effects and/or to improve the effectiveness of the drug. This review presents the chemical features of many examples of NO-releasing hybrids of cardiovascular drugs and explains the pharmacological improvements conferred by the addition of such NO-donor properties.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Nitric Oxide; Nitric Oxide Donors; Platelet Aggregation Inhibitors; Structure-Activity Relationship; Vasodilation

Curcumin (diferuloylmethane) is a polyphenol responsible for the yellow color of the curry spice turmeric. It has been used in a variety of diseases in traditional medicine. Modern scientific research has demonstrated its anti-inflammatory, anti-oxidant, anti-carcinogenic, anti-thrombotic, and cardiovascular protective effects. In this review, we focused mainly on the effects of curcumin on the cardiovascular system. The antioxidant effects of curcumin have been shown to attenuate adriamycin-induced cardiotoxicity and may prevent diabetic cardiovascular complications. The anti-thrombotic, anti-proliferative, and anti-inflammatory effects of curcumin and the effect of curcumin in decreasing the serum cholesterol level may protect against the pathological changes occurring with atherosclerosis. The p300-HAT inhibitory effects of curcumin have been demonstrated to ameliorate the development of cardiac hypertrophy and heart failure in animal models. The inflammatory effects of curcumin may have the possibility of preventing atrial arrhythmias and the possible effect of curcumin for correcting the Ca(2+) homeostasis may play a role in the prevention of some ventricular arrhythmias. The preclinical studies from animal to clinical data in human are discussed.

Topics: Anti-Inflammatory Agents; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Curcumin; Fibrinolytic Agents; Humans

The use of confocal microscopy has shown that the nucleus plays an important role in excitation-contraction and excitation-secretion coupling of several excitable and nonexcitable cardiovascular cells. It has shown that the nuclear membranes, like the sarcolemmal membrane, possess ionic transporters as well as G protein-coupled receptors (GPCRs), which play a major role in modulating both cytosolic and nuclear ionic homeostasis and nuclear signalling. During spontaneous contraction of heart cells, the increase in cytosolic Ca2+ was immediately followed by a transient increase in nuclear Ca2+. The nuclear Ca2+ rise during excitation-contraction and excitation-secretion coupling was both dependent and independent of changes in cytosolic Ca2+. Nuclear membrane GPCRs, such as those of angiotensin II, neuropeptide Y, and ET-1, were functional and contributed to modulation of nuclear ionic homeostasis via direct and (or) indirect modulation of nuclear membrane ionic transporters such as channels, pumps, and exchangers. The signalling of nuclear membrane GPCRs may also contribute to modulation of gene expression, which may regulate proliferation and remodelling of cells and, indeed, life and death. Direct or indirect targeting of nuclear membrane ionic transporters and GPCRs may constitute a new target for drug action.

Topics: Active Transport, Cell Nucleus; Animals; Calcium Signaling; Cardiovascular Agents; Cardiovascular Diseases; Humans; Ion Transport; Membrane Transport Modulators; Membrane Transport Proteins; Nuclear Envelope; Receptors, G-Protein-Coupled; Sodium

Recently, results of several cardiovascular clinical trials conducted in Japan were published. Most of them were designed as prospective randomized open-label blinded end-point (PROBE)-type trials, in which patients were randomly allocated to different regimens and both the patients and doctors are aware of the regimen being administered. Although the PROBE design enables performing trials resembling real-world practices, entails low costs and renders patient recruitment easier, it presents several conditions that have to be satisfied to acquire accurate results, due to its open-label nature. Principally, the so-called hard end points, which are judged by objective criteria, should be used as primary end points in order to prevent biases. In this article, a general description of various designs of clinical studies is provided, followed by a description of the PROBE design, and the precautions to be taken while conducting PROBE-designed trials by comparing trials conducted in Japan and the West.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Case-Control Studies; Cohort Studies; Double-Blind Method; Endpoint Determination; Epidemiologic Methods; Humans; Placebos; Prospective Studies; Randomized Controlled Trials as Topic; Research Design; Retrospective Studies

Radiopharmaceuticals can provide unique information for drug development also in cardiovascular applications. Radiopharmaceuticals offer possibility to study noninvasively cardiac perfusion, oxygen consumption, oxidative and substrate metabolism, myocardial efficiency of work, neural actions and receptors, vascular inflammation, and molecular processes which all are relevant to understand the effects of drugs. Using these surrogate end points, hypotheses can be tested in vivo in phase I and II clinical studies before starting large-scale clinical phase III or IV trials. In addition, these approaches may allow improved selection of drug therapy for a given patient. Modern techniques such as gene therapy technology provide numerous new potential mechanisms of action and targets for drug development. Device therapies and cell therapies are also under rapid development. Molecular imaging has great potential in evaluating these new therapies and selecting the patient populations and monitoring of the effect of therapy.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Drug Delivery Systems; Drug Design; Humans; Radioisotopes; Radionuclide Imaging; Radiopharmaceuticals; Technology, Pharmaceutical; Treatment Outcome

To ascertain the effectiveness of medical therapy for reducing risk in peripheral artery disease (PAD) and to model the potential impact of combining multiple efficacious approaches.. 17 electronic databases, reference lists of primary studies, clinical practice guidelines, review articles, trial registries and conference proceedings from cardiology, vascular surgery and atherosclerosis meetings were screened. Eligible studies were randomized trials or meta-analyses of randomized trials of medical therapy for PAD which reported major cardiovascular events (myocardial infarction, stroke and cardiovascular death). Baseline event rates for modelling analyses were derived from published natural history cohorts. Overall, three strategies had persuasive evidence for reducing risk in PAD: antiplatelet agents (pooled RRR 26%, 95% CI 10 to 42), statins (pooled RRR 26%, 95% CI 18 to 33) and angiotensin-converting enzyme inhibitors (individual trial RRR 25%, 95% CI 8 to 39). The estimated cumulative relative risk reduction for all three strategies was 59% (CI 32 to 76). Given a 5-year major cardiovascular event rate of 25%, the corresponding absolute risk reduction and number needed to treat to prevent one event were 15% (CI 8 to 19) and 7 (CI 5 to 12), respectively. Population level analyses suggest that increased uptake of these modalities could prevent more than 200 000 events in patients with PAD each year.. The use of multiple efficacious strategies has the potential to substantially reduce the cardiovascular burden of PAD. However, these data should be regarded as hypothetical, since they are based on mathematical modelling rather than factorial randomized trials.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Models, Statistical; Peripheral Vascular Diseases; Sensitivity and Specificity

Protective effects of each cardiovascular drug on major organ functions are reviewed. Based on these effects, proper use of the drugs is presented. It is probable that norepinephrine and dobutamine have the most protective effect against major organ dysfunctions. It has been shown that perioperative beta-blocker administration reduces cardiovascular complications. Nicorandil is likely to have ischemic preconditioning properties. In case of hypotension, low doses of noradrenaline should be administered first, and then dobutamine should be added. In case of systolic dysfunction, low doses of dobutamine should be chosen first, and then noradrenaline, and finally olprinone could be added. In case of hypotension and systolic dysfunction, combination of norepinephrine and dobutamine is the first choice. Then adrenaline could be added. When ischemic heart disease exists, nicorandil should be given. When decreasing or stabilizing heart rate is required, an ultra-short acting beta-blocker, such as landiolol, is recommended. To maintain hypotension in a certain situation, prostaglandin E1 is better to use than nicardipine, diltiazem, and nitroglycerin. It is important to administer the drugs focusing on postoperative complications and outcome.

Topics: Anesthesia; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Surgical Procedures; Catecholamines; Humans; Intraoperative Complications; Perioperative Care; Phosphodiesterase 3 Inhibitors; Phosphodiesterase Inhibitors; Postoperative Complications; Prognosis; Vasodilator Agents

Cyclic guanosine 3',5'-monophosphate (cGMP) mediates a wide spectrum of physiologic processes in multiple cell types within the cardiovascular system. Dysfunctional signaling at any step of the cascade - cGMP synthesis, effector activation, or catabolism - have been implicated in numerous cardiovascular diseases, ranging from hypertension to atherosclerosis to cardiac hypertrophy and heart failure. In this review, we outline each step of the cGMP signaling cascade and discuss its regulation and physiologic effects within the cardiovascular system. In addition, we illustrate how cGMP signaling becomes dysregulated in specific cardiovascular disease states. The ubiquitous role cGMP plays in cardiac physiology and pathophysiology presents great opportunities for pharmacologic modulation of the cGMP signal in the treatment of cardiovascular diseases. We detail the various therapeutic interventional strategies that have been developed or are in development, summarizing relevant preclinical and clinical studies.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cyclic GMP; Humans; Signal Transduction

In the last half century, phenomenal advances have been made in understanding the pathophysiology of cardiovascular disease and in developing therapies to reduce cardiovascular risk. Nevertheless, cardiovascular disease remains the leading cause of death and morbidity in the industrialized world, with rapidly rising prevalence in developing countries, accounting for approximately 30% of all deaths worldwide. Since the initial availability of statin drugs in 1987, few novel cardiovascular therapies have emerged. Whereas statins reduce the mortality and morbidity from atherosclerotic heart disease by approximately 30%, the staggering 70% residual cardiovascular risk underscores the persistent need for novel therapies. Substantial advances in genomic research offer promise to greatly facilitate cardiovascular drug development. Over the past decade, often termed "the genomics revolution," such advancements as the emergence of genome-wide genotyping in humans, the industrialization of messenger ribonucleic acid expression profiling, and the maturation of proteomic and metabolomic methodologies have been made. In addition, the advancement of informatics to allow the intersection of multiple complex datasets has led to the field of systems biology. Genomic approaches are already being utilized to drive novel compound pipelines by helping with the identification and validation of novel targets. In the future, the study of genomics is expected to support biomarker discovery and development and the identification of responder patient segments. The focus of the present review is the application of genomics to the development of novel atherosclerosis therapies.

Topics: Animals; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Forecasting; Genomics; Humans; Mice

Asymmetric dimethylarginine (ADMA), an endogenous methylated form of the amino acid L-arginine, inhibits the activity of the enzyme endothelial nitric oxide synthase, with consequent reduced synthesis of nitric oxide. ADMA is metabolised to L-citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The modulation of DDAH activity and expression plays a pivotal role in regulating intracellular ADMA concentrations, with important effects on vascular homeostasis. For example, impairment in DDAH activity, resulting in elevated ADMA concentrations and reduced nitric oxide synthesis, can promote the onset and progression of atherosclerosis in experimental models. This review discusses the current role of ADMA and DDAH in vascular health and disease, the techniques used to assess DDAH activity and expression, and the results of recent studies on pharmacological and biological agents modulating DDAH activity and expression. Suggestions for future basic and clinical research directions are also discussed.

Topics: Amidohydrolases; Animals; Arginine; Cardiovascular Agents; Cardiovascular Diseases; Disease Progression; Drug Delivery Systems; Gene Expression Regulation, Enzymologic; Humans; Nitric Oxide

LA-419, currently being developed by Lacer SA, is a thiol-containing analog of isosorbide mononitrate that is undergoing assessment in clinical trials for the treatment of chronic ischemic cardiovascular disorders. The compound was originally designed to have a reduced tendency toward tolerance sensitivity - a major limitation of established organic nitrate compounds. The rationale behind the drug design was to include an antioxidant moiety in the drug structure to combat the contribution of oxidative stress in tolerance induction. The compound is at an early stage of development, but has already provided some surprising data. First, LA-419 does not appear to require the nitroxy ester moiety for activity and its actions might not be mediated only by nitric oxide release. Second, unlike conventional nitrates, LA-419 is active in platelets, suggesting a potential role as an antithrombotic agent. Third, LA-419 has a profound impact on left ventricular hypertrophy, making the drug a plausible candidate for several additional potential therapeutic opportunities. In addition, LA-419 has demonstrated potential in the treatment of glaucoma and intestinal disorders. At the time of publication, LA-419 was in phase II clinical trials in patients with chronic ischemic cardiovascular disorders.

Topics: Animals; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Drug Tolerance; Fibrinolytic Agents; Humans; Hypertrophy, Left Ventricular; Isosorbide Dinitrate; Myocardial Ischemia; Nitric Oxide Donors; Patents as Topic; Structure-Activity Relationship; Treatment Outcome

The increasing prevalence of metabolic diseases is alarming and highlights the need for more effective and safer therapies to treat these diseases. Recent evidence from several animal studies indicates that FGF21 induces numerous beneficial metabolic changes without apparent adverse effects. These results suggest that FGF21 could be a novel and attractive drug candidate for the treatment of cardiovascular disease, obesity and type 2 diabetes. The pharmacology of FGF21, molecular mechanisms contributing to the actions of this compound, and knowledge gaps to be addressed to allow further exploration of the therapeutic potential of this molecule are discussed in this review.

Topics: Animals; Anti-Obesity Agents; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fibroblast Growth Factors; Genetic Therapy; Humans; Hypoglycemic Agents; Obesity; Signal Transduction

3'-5'-Cyclic adenosine monophosphate (cAMP) is a pleiotropic intracellular second messenger generated in response to activation of G(s) protein-coupled receptors. In the heart, cAMP mediates the catecholaminergic control on heart rate and contractility but, at the same time, it is responsible for the functional response to a wide variety of other hormones and neurotransmitters, raising the question of how the myocyte can decode the cAMP signal and generate the appropriate functional output to each individual extracellular stimulus. A growing body of evidence points to the spatial organization of the components of the cAMP signalling pathway in distinct, spatially segregated signalling domains as the key feature underpinning specificity of response and data is emerging, indicating that alteration of spatial control of the cAMP signal cascade associates with heart pathology. Most of the details of the molecular organization and regulation of individual cAMP signalling compartments are still to be elucidated but future research should provide the knowledge necessary to develop and test new therapeutic strategies that, by acting on a limited subset of downstream targets, would improve efficacy and minimize off-target effects.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cyclic AMP; Drug Discovery; Heart; Humans; Myocardium; Myocytes, Cardiac; Signal Transduction

Toll-like receptors (TLRs) are germline-encoded receptors that recognize various pathogen-associated molecular patterns (PAMPs). They are key components of the innate immunity which are activated in response to pathogens as well as non-pathogenic components of damaged tissues. TLR agonists have been developed to treat allergies, cancers, and chronic infections by upregulating the innate immune system. TLR antagonists may be used to treat a number of inflammatory conditions, such as rheumatoid arthritis and systemic lupus erythematosus. Recent research also has shown that TLRs are involved in the pathogenesis of atherosclerosis, thrombosis, myocardial remodeling, ischemic/reperfusion injury, and valvular disease. This article reviews the current experimental and clinical evidence for the role of TLRs in the cardiovascular system, and examines the mechanisms by which TLR antagonists could potentially be used in targeted therapy.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cardiovascular Diseases; Humans; Immunity, Innate; Toll-Like Receptors

Despite the FDA guidelines for studies to be performed to rule out potential cardiac toxicity, many drugs have nevertheless entered the market only to be later withdrawn from the market owing to cardiac toxicity. Cardiac toxicity may result from drugs causing impaired function or death of cardiomyocytes, valvular damage, myocardial ischemia and/or ventricular arrhythmias. Negative cardiovascular events have been implicated in 28% of drug withdrawals in the USA. The significance for patients, regulators and the pharmaceutical industry is immense.. We address whether a more rigorous and integrative approach is needed for cardiovascular safety screening of all new drug candidates. Furthermore, we will present a cardionomics approach that looks at several in vitro and in vivo models that can be applied to all drugs independent of category, therapeutic area or class.. We present examples of drugs demonstrating cardiac toxicity and provide an in-depth review of how calcium homeostasis may be a unifying theme in clinically observed cardiotoxic events. We introduce a cardionomics approach that detects clinical cardiac toxicity early in the drug discovery process, thus, preventing costly late attrition.. The consequences of a failure to detect potential cardiovascular safety issues before clinical launch can have an enormous cost for the pharmaceutical industry, when major drugs are withdrawn due to lawsuits as well as loss of time and resources. An integrated cardionomics approach may reduce the risk of drug withdrawals as a result of unexpected clinical cardiac safety issues.

Topics: Animals; Arrhythmias, Cardiac; Biomedical Research; Cardiovascular Agents; Cardiovascular Diseases; Drug Evaluation, Preclinical; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations

Inhibitors of the renin angiotensin aldosterone system (RAAS) represent some of the most widely prescribed, successful and well-tolerated therapeutics of recent times and are of proven worth in the management/prevention of cardiovascular disease and diabetic nephropathy. However, as knowledge has grown about the RAAS and its manifold alternate pathways, loci of action and dynamic response to inhibition, so has the clinical debate as how to best use existing therapeutics as well as how best to conceptualise and design RAAS inhibitors of the future.. To provide an overview of the several points of therapeutic anti-RAAS intervention, many of which have already been exploited from 'upstream' renin inhibition to 'midstream' ACE inhibition to 'downstream' angiotensin AT1 receptor blockade.. A search of patents for RAAS inhibitors recorded in 2008 was conducted along with a relevant literature search.. Each intervention has merits and demerits with implications for RAAS 'escape' phenomena, 'dual inhibition' therapy, long-term clinical efficacy and adverse drug reactions. Renin inhibitors offer the most complete RAAS inhibition, but more downstream interventions are likely to recruit supplementary anti-RAAS mediators and receptor signalling pathways. Furthermore, managing hyperkalaemia-stimulated aldosterone escape during combined ACE inhibitor and angiotensin receptor blocker treatment may realise the full clinical potential of dual inhibition therapy.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetic Retinopathy; Drug Delivery Systems; Drug Design; Humans; Patents as Topic; Renin-Angiotensin System

Probucol has a long history of clinical application with established efficacy and safety profiles. Probucol is a potent anti-oxidant drug that has been in clinical use during the past few decades for the treatment and prevention of cardiovascular diseases. Here we review the current status of knowledge on the pharmacology, clinical benefits, and the mechanism of actions of this unique drug. Probucol has diverse pharmacological properties with therapeutic effects on the cardiovascular systems. Its mechanism of pharmacologic actions at the molecular level has recently been elucidated with the new concept of HDL metabolism associated with cholesteryl ester transfer protein (CETP) or scavenger receptor class B type I (SR-BI). HDL-C reduction may not be a "side effect" but it most likely might reflect a mechanism of action of probucol. Probucol could be reconsidered as an option at least in case statins, which are known to be effective in lowering low-density lipoproteins (LDL) and coronary artery disease (CAD) risk, are not effective. In particular, a marked CAD risk reduction has been recently reported in long-term probucol treatment of patients with heterozygous familial hypercholesterolemia (FH) in Japan. Therefore, probucol could be a more common therapeutic drug for the treatment of patients with FH as well. There is more than enough reason to believe that this old drug has much more to offer than hitherto known.

Topics: Animals; Anticholesteremic Agents; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Evidence-Based Medicine; History, 20th Century; Humans; Hyperlipoproteinemia Type II; Probucol; Randomized Controlled Trials as Topic; Risk Assessment; Treatment Outcome

Cocaine is a powerful stimulant that gives users a temporary sense of euphoria, mental alertness, talkativeness, and a decreased need for food and sleep. Cocaine intoxication is the most frequent cause of drug-related death reported by medical examiners in the US, and these events are most often related to the cardiovascular manifestations of the drug. Once playing a vital role in medicine as a local anesthetic, decades of research have established that cocaine has the ability to cause irreversible structural damage to the heart, greatly accelerate cardiovascular disease, and initiate sudden cardiac death. Although pathologic findings are often reported in the literature, few images are available to support these findings, and reviews of cocaine cardiopathology are rare. We describe the major pathologic findings linked to cocaine abuse in earlier research, their underlying mechanisms, and the treatment approaches currently being used in this patient population. A MEDLINE search was conducted to identify all English language articles from January 2000 to June 2008 with the subject headings and key words 'cocaine', 'heart', 'toxicity', and 'cardiotoxicity'. Epidemiologic, laboratory, and clinical studies on the pathology, pathophysiology, and pharmacology of the effects of cocaine on the heart were reviewed, along with relevant treatment options. Reference lists were used to identify earlier studies on these topics, and related articles from Google Scholar were also included. There is an established connection between cocaine use and myocardial infarction (MI), arrhythmia, heart failure, and sudden cardiac death. Numerous mechanisms have been postulated to explain how cocaine contributes to these conditions. Among these, cocaine may lead to MI by causing coronary artery vasoconstriction and accelerated atherosclerosis, and by initiating thrombus formation. Cocaine has also been shown to block K+ channels, increase L-type Ca2+ channel current, and inhibit Na+ influx during depolarization, all possible causes for arrhythmia. Additionally, cocaine use has been associated with left ventricular hypertrophy, myocarditis, and dilated cardiomyopathy, which can lead to heart failure if drug use is continued. Certain diagnostic tools, including ECG and serial cardiac markers, are not as accurate in identifying MI in cocaine users experiencing chest pain. As a result, clinicians should be suspicious of cocaine use in their differential diagnosis of chest pain, especia

Topics: Arrhythmias, Cardiac; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Cocaine; Death, Sudden, Cardiac; Heart; Heart Failure; Humans; Myocardial Infarction; Myocardium; Practice Guidelines as Topic

A growing body of animal studies provides evidence for potential cardioprotective effects of inhibitors of the enzyme phosphodiesterase isoform 5. Infarct size reduction by administration of phosphodiesterase 5 inhibitors was described in various experimental models of ischaemia and reperfusion. Furthermore, potential beneficial effects were demonstrated in experimental models of congestive heart failure and left ventricular hypertrophy. Some of the observed effects resemble the basic mechanisms of ischaemic pre-conditioning, mimicking both acute and delayed effects. Other effects may be due to action on systemic and cardiac haemodynamics. Mechanisms and signalling pathways, characterized in some of the experimental models, appear to be complex: for instance, the rate of cyclic guanosine monophosphate (cGMP) synthesis and the functional compartmentalization of intracellular cGMP metabolism as well as interaction with ss-adrenergic and nitric oxide signalling may influence effects in different experimental settings. In this review, we discuss mechanisms, signalling pathways, and experimental limitations and touch on considerations for translation into potentially useful applications in the clinical arena.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Cardiovascular Diseases; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Heart Failure; Humans; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Signal Transduction

Junctional channels (JC) play essential roles in the normal function of the cardiovascular system, mediating the spread of the electrical impulse that triggers synchronized contraction of the cardiac chambers and contributing to the coordination of activities between cells of the arterial wall. In mammalian hearts, cells most prominently express JC built of Connexin40 (Cx40), Cx43 and Cx45, of which Cx43 is the predominant intercellular gap junction protein. Changes in cardiovascular Cx gene expression during development or in response to (patho)physiological signals are expected to be a crucial factor in normal cardiac development and functions, and several cardiac diseases, such as atrial fibrillation, hypertrophy, heart failure, atherosclerosis, etc. Although the underlying molecular mechanisms have not yet been elucidated, recent research has found a variety of novel potential therapies related to Cx43 that can help to learn more about the mechanism of those cardiovascular diseases and the signaling pathway.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Connexin 43; Gene Expression Regulation; Humans

This perspective is part of an annual series of papers discussing drugs dropped from clinical development in the previous year. Specifically, this paper focuses on the 16 cardiovascular drugs discontinued in 2008. Information for this perspective was derived from a search of the Pharmaprojects database for drugs discontinued after reaching Phase I-III clinical trials.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Contraindications; Drug Approval; Drug Industry; Humans; Pharmacology, Clinical; Time Factors

Topics: Canada; Cardiovascular Agents; Cardiovascular Diseases; Drug Costs; Drug Utilization; Humans; Prescription Drugs

Diurnal rhythms in myocardial physiology (e.g., metabolism, contractile function) and pathophyiology (e.g., sudden cardiac death) are well establish and have classically been ascribed to time-of-day-dependent alterations in the neurohumoral milieu. Existence of an intramyocellular circadian clock has recently been exposed. Circadian clocks enable the cell to anticipate environmental stimuli, facilitating a timely and appropriate response. Generation of genetically modified mice with a targeted disruption of the cardiomyocyte circadian clock has provided an initial means for deciphering the functions of this transcriptionally based mechanism and allowed predictions regarding which environmental stimuli the heart anticipates (i.e., "anticipating anticipation"). Recent studies show that the cardiomyocyte circadian clock influences myocardial gene expression, beta-adrenergic signaling, transcriptional responsiveness to fatty acids, triglyceride metabolism, heart rate, and cardiac output, as well as ischemia-reperfusion tolerance. In addition to reviewing current knowledge regarding the roles of the cardiomyocyte circadian clock, this article highlights putative frontiers in this field. The latter includes establishing molecular links between the cardiomyocyte circadian clock with identified functions, understanding the pathophysiological consequences of disruption of this mechanism, targeting resynchronization of the cardiomyocyte circadian clock for prevention/treatment of cardiovascular disease, linking the circadian clock with the cardiobeneficial effects of caloric restriction, and determining whether circadian clock genes are subject to epigenetic regulation. Information gained from studies investigating the cardiomyocyte circadian clock will likely translate to extracardiac tissues, such as skeletal muscle, liver, and adipose tissue.

Topics: Animals; Biological Clocks; Cardiovascular Agents; Cardiovascular Diseases; Circadian Rhythm; Disease Models, Animal; Energy Metabolism; Gene Expression Regulation; Humans; Myocardial Contraction; Myocytes, Cardiac; Signal Transduction

Paralleling the rise in obesity, the cardiometabolic syndrome is a rapidly growing health problem in the United States. There is a 3-fold increase in the prevalence of coronary heart disease, myocardial infarction, and stroke due to the coagulation, hemodynamic, and metabolic abnormalities seen in these individuals. The use of aspirin for secondary prevention and, to a lesser degree, primary prevention of cardiovascular events is a well-established standard of care. However, in patients with diabetes or the cardiometabolic syndrome, the role of aspirin in prevention of cardiovascular events remains controversial. In this review, the authors examine the clinical trial data on the use of aspirin in diabetes and the cardiometabolic syndrome for cardiovascular protection. They also explore, in addition to aspirin's effects on platelet aggregation, some of the mechanisms by which aspirin may favorably alter the course of atherosclerosis, effects on endothelial function, and glycemia.

Topics: Aspirin; Blood Coagulation; Blood Glucose; Blood Platelets; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Metabolic Syndrome; Treatment Outcome

Resveratrol (3,4',5 trihydroxystilbene), a naturally-occurring molecule known as a phytoalexin, is synthesized by plants in response to attacks by fungi, bacteria, or other injurious substances; it is also known to possess an array of cardioprotective effects. Recently, studies have shown resveratrol to protect against the metabolic changes associated with hypercaloric diets in mice with induced insulin resistance, hyperglycemia, and dyslipidemia. Despite impressive gains in diagnosis and treatment, cardiovascular disease (CVD) remains a serious clinical problem and threat to public health. The metabolic syndrome, which identifies persons at higher risk for diabetes mellitus and CVD, is approaching a prevalence of nearly 25% of the western world. If the metabolic syndrome can be considered a polar opposite to caloric restriction, then agents that mimic caloric restriction may offer a new therapeutic approach to preventing CVD. The authors discuss the cardioprotective effects of resveratrol and highlight its role in glucose homeostasis and lipid metabolism in mice. Armed with the ability to prevent the deleterious effects of excess caloric intake and prevent detrimental cardiovascular events, resveratrol merits proper clinical investigations for its efficacy in treating metabolic diseases and CVD.

Topics: Animals; Blood Glucose; Caloric Restriction; Cardiovascular Agents; Cardiovascular Diseases; Dietary Carbohydrates; Dietary Fats; Energy Intake; Homeostasis; Humans; Lipid Metabolism; Metabolic Syndrome; Molecular Structure; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes

Cyclooxygenase inhibitors represented extremely promising novel anti-inflammatory drugs until one of them, rofecoxib (Vioxx), was found to be associated with increased cardiovascular morbidity; however, another such drug, celecoxib (Celebrex), suffers far less from this side effect for unknown reasons and is still widely used. In this issue, Brueggemann et al. (page p. 1053) suggest a hypothesis. Celecoxib, but not rofecoxib, is shown to act as an "opener" of voltage-gated KCNQ5 K(+) channels and a blocker of "L-type" Ca(2+) channels, causing a reduction in the excitability and contractility of vascular smooth-muscle cells (VSMCs). Furthermore, VSMC tone is shown to be selectively reduced by celecoxib, resulting in dilation of blood vessels and reduction in systemic blood pressure, suggesting that the reduced work load on the heart may counteract any other deleterious effects of this class of drugs. Here, these findings are discussed in light of the role of KCNQ K(+) channels in control of excitability in general, the "lipid imbalance theory" of cyclooxygenase-2 risks, and the potential for novel therapeutic modalities for cardiovascular disease focused on ion channels in vascular smooth muscle.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Humans; Ion Channels; Muscle, Smooth, Vascular; Pyrazoles; Sulfonamides

Although having high clinical efficacy in the treatment of human epidermal growth factor receptor-2 (HER2+) metastatic breast cancer, trastuzumab has been associated with cardiotoxicity, and the etiology and pathogenesis of this condition is currently under investigation.. This paper reviews the cardiotoxicity, associated with trastuzumab use and discusses the risk assessment and management of cardiac dysfunction.. The increased risk of cardiotoxicity is lower when trastuzumab is given as monotherapy (3%-7%) compared with anthracyclines + trastuzumab therapy (27%). Type II cardiac changes occur in trastuzumab-treated patients, which do not appear to be dose-related, are not associated with histological changes, and are generally reversible. Several risk factors for cardiac events have been identified and assessing levels of troponin I and N-terminal pro-brain B-type natriuretic peptide before and after treatment with trastuzumab may allow early detection of cardiotoxicity. A symptomatic and functional evaluation scheme for patients indicated for treatment with trastuzumab has also been proposed to work alongside therapeutic options for the treatment of heart failure.. The risk of cardiac dysfunction associated with trastuzumab can be justified given the increase in overall survival. This risk is lower when trastuzumab is given as monotherapy. The paradigm for cardiologists remains the same: treat the cancer effectively whilst preventing cardiotoxicity.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Cardiovascular Agents; Cardiovascular Diseases; Female; Humans; Natriuretic Peptide, Brain; Peptide Fragments; Receptor, ErbB-2; Risk Factors; Stroke Volume; Trastuzumab; Troponin I

Despite the advances in interventional techniques, the management of stable atherosclerosis remains the domain of optimal guideline-oriented therapy. Recent studies on the effects of aggressive lipid lowering on atheroma volume changes using intravascular ultrasound indicate that it is possible to achieve atherosclerosis regression by reaching low-density lipoprotein (LDL) levels less than 75 mg/dl. The pleiotropic anti-inflammatory effects of statins contribute to the reduction of cardiovascular (CV) event observed with aggressive lipid lowering. As a second important strategy to prevent disease progression, lifestyle changes with regular physical exercise are capable of halting the atherosclerotic process and reducing angina symptoms and CV events. Optimal medical therapy, a healthy lifestyle with regular physical exercise, and coronary interventions are not mutually exclusive treatment strategies. Over the last few decades, both have proved to be effective in significantly reducing the CV mortality in the Western world. However, risk factor modification contributed to at least half the effect in the reduction of CV mortality. This figure provides an estimate of what could be achieved if we were to take risk factor modification more seriously - especially in the acute care setting. The knowledge is there: today we have a better understanding on how to stop progression and even induce regression of atherosclerosis. Much research still needs to be done and will be done. In the meantime, however, our primary focus should lie in implementing what is already known. In addition, it is essential not just to treat CV risk factors, but also to treat them to achieve the target values as set by the guidelines of European Society of Cardiology.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Disease; Diet; Evidence-Based Medicine; Exercise; Health Knowledge, Attitudes, Practice; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Life Style; Practice Guidelines as Topic; Risk Assessment; Risk Factors; Risk Reduction Behavior; Treatment Outcome

Topics: Animals; Antineoplastic Agents; Biomedical Research; Cachexia; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Genetic Therapy; Humans; Mice; MicroRNAs; Muscle, Skeletal; Neoplasms; Proteasome Endopeptidase Complex; Telomere; Ubiquitin; Ubiquitination

Topics: Adolescent; Age Factors; Cardiovascular Agents; Cardiovascular Diseases; Child; Diet; Disease Progression; Early Diagnosis; Exercise; Guideline Adherence; Humans; Life Style; Practice Guidelines as Topic; Preventive Health Services; Risk Assessment; Risk Factors; Risk Reduction Behavior

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide-ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP-1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP-1 receptors (GLP-1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP-1R agonists have wide-ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP-1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP-1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP-1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP-1 as a novel treatment for CVD.

Topics: Animals; Blood Glucose; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Receptors, Glucagon

Calcium channel blockers continue to be used for the management of a wide variety of adult and pediatric conditions including hypertension, angina pectoris, atrial arrhythmias, Raynaud phenomenon, and migraine headaches. With increased use comes increased potential for misuse and abuse. This article serves as a review of calcium channel blocker physiology with emphasis on presentation and management of the pediatric patient with calcium channel blocker toxicity.

Topics: Adult; Assisted Circulation; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Chloride; Cardiovascular Agents; Cardiovascular Diseases; Charcoal; Child, Preschool; Combined Modality Therapy; Drug Overdose; Enema; Extracorporeal Circulation; Fat Emulsions, Intravenous; Fluid Therapy; Glucagon; Heart; Humans; Hyperglycemia; Infant; Muscle, Smooth, Vascular; Plasmapheresis; Poisoning; Practice Guidelines as Topic

The cardioprotective effects of food rich in omega-3 (omega-3) polyunsaturated fatty acids (PUFA) on cardiovascular risk has been of interest from the moment when a low rate of coronary heart disease was documented in the Eskimo population. The aim of the present review is to discuss recent studies documenting multidirectional action of omega-3 PUFA due to its pleiotropic properties. Experimental studies in cellular and animal models have extensively documented the favorable effects of omega-3 PUFA (eicosapentaenoic acid and docosahexaenoic acid) on: inflammatory processes, endothelial dysfunction, platelet aggregation and arrhythmogenesis. It was reported that antiarrhythmic effects of omega-3 PUFA resulted from stabilization of cardiomyocyte membrane and inhibition of ion channels. Moreover, PUFA possess several pleiotropic properties i.e. anti-inflammatory, anti-atherogenic and antithrombotic. Anti-atherogenic effects (plaque stabilization) of omega-3 PUFA have recently been demonstrated. It was documented (OCEAN study) that eicosapentaenoic acid from a source of highly purified ethyl esters is incorporated into plaques in a relatively short period of time and these higher concentrations of omega-3 PUFA may stabilize vulnerable atherosclerotic plaques. The anti-inflammatory effect of omega-3 PUFA is associated with reduction of levels of TNF-alpha and interleukin-6. Eicosapentaenoic acid and docosahexaenoic acid inhibit arachidonic acid metabolism to inflammatory eicosanoids.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cardiovascular Diseases; Fatty Acids, Omega-3; Humans

In this review we discuss the role of pigment epithelium-derived factor (PEDF) as a possible new target molecule to therapeutically influence cardiovascular disease. PEDF is a multifunctional, pleiotropic protein with antiangiogenic, antitumorigenic, antioxidant, anti-inflammatory, antithrombotic, neurotrophic and neuroprotective properties. First identified in retinal pigment epithelium cells, it is expressed in various tissues throughout the body such as the eye, liver and adipose tissue. Recently PEDF has also been characterized in the heart. PEDF has been suggested to have a protective role in atherosclerosis, the main cause of coronary heart disease, myocardial infarction and heart failure due to its anti-inflammatory, antioxidant and antithrombotic effects in the vessel wall and platelets. Additionally PEDF has strong antiangiogenic effects by inducing apoptosis in endothelial cells and by regulating the expression of other angiogenic factors. Therefore blocking of PEDF locally for example in ischemic tissue in the heart might favour angiogenesis, induce neovascularization and lead to increased perfusion of the injured tissue. On the other hand, local overexpression of PEDF restricted to atherosclerotic lesions might block angiogenesis, inflammation and thrombosis at these sites and thus counteract destabilization and rupture of the lesion otherwise caused by inflammatory activation and excessive angiogenesis and inhibit subsequent thrombus formation.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Eye Proteins; Humans; Inflammation; Neovascularization, Pathologic; Nerve Growth Factors; Serpins

The goal of individualized drug therapy requires physicians to be able to accurately predict an individual's response to a drug. Both genetic and environmental factors are known to influence drug response. 'Pharmacogenetics' is the study of the role of inheritance in variation in drug response phenotypes. Pharmacogenetics is now moving genome-wide to become 'pharmacogenomics', resulting in the recognition of novel biomarkers for individual variation in drug response. This article reviews the development, promise and challenges facing pharmacogenomics, using examples of drugs used to treat or prevent cardiovascular disease.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Genetic Testing; Genetic Variation; Genotype; Humans; Patient Selection; Pedigree; Pharmacogenetics; Phenotype; Precision Medicine

The growing knowledge about genetic influence on cardiovascular diseases (CVD) combined with the recently generated amounts of genomic data hold promise to the identification of new markers for atherosclerotic CVD. Cardiovascular pharmacogenomics and pharmacogenetics have now the potential for leading to identification of genetic contributors and therefore to the development of predictive genetic tests that could optimize drugs efficacy and minimize toxicity. Clinical studies have shown that genetic variations within cytochromes P450 (CYPs), 3-Hydroxyl-3-Methylglutaryl Coenzyme A Reductase (HMGCR) and apolipoprotein E (APOE) genes influence individual's response to lipid lowering statins. Furthermore, development of antagonists or inhibitors of molecules such as peroxisome proliferator-activated receptors (PPARs), lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), angiotensin-converting enzyme (ACE), angiotensin receptors and tumor necrosis factor (TNF)-alpha could be another alternative to prevent atherosclerosis. In addition, novel molecules under the name of biologics including family of peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), urocortin, apelin and antimicrobial peptides (AMPs) could be considered as new targets for the prevention and treatment of CVD. In this article, we will focus mainly on recent genomic advances in the development of new markers and therapeutic agents for CVD. We present an array of molecules that could have pharmacological benefit for the treatment of heart disease. We also discuss in details new strategies including biologics, which are actually the focus of companies for clinical development of therapeutic drugs. All these efforts provide optimism and attractive promise to cure CVD.

Topics: Animals; Biological Products; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Genetic Predisposition to Disease; Genetic Testing; Genomics; Humans; Patient Selection; Peptides; Pharmacogenetics; Phenotype; Polymorphism, Genetic; Predictive Value of Tests

Vitamin E, a naturally occurring antioxidant, has been found to reduce atherosclerotic lesion formation in animal models as well as cardiovascular morbidity in several observational studies. However, a number of case-control and prospective cohort studies failed to confirm its value in the primary and secondary prevention of morbidity and mortality from coronary artery disease. Several small or larger randomized interventional trials completed to date failed to resolve the conflict. Notably, even in large, well-conducted prospective epidemiologic studies, the potential effects of residual confounding may be on the same order of magnitude as the reported benefit. The response to vitamin E supplementation in specific patient subpopulations with chronic inflammation and/or higher degrees of oxidative stress has not been studied as yet. Therefore, further large randomized interventional trials are warranted to clarify accurately the role of vitamin E in the primary and secondary prevention of atherosclerotic coronary disease in these patient groups.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Confounding Factors, Epidemiologic; Evidence-Based Medicine; Humans; Research Design; Treatment Outcome; Vitamin E

The cardiovascular effects of epoxyeicosatrienoic acids (EETs) include vasodilation, antimigratory actions on vascular smooth muscle cells and anti-inflammatory actions. These endogenous lipid mediators are broken down into diols by soluble epoxide hydrolase (sEH), and so inhibiting this enzyme would be expected to enhance the beneficial cardiovascular properties of EETs. sEH inhibitors (sEHIs) that are based on 1,3-disubstituted urea have been rapidly developed, and have been shown to be antihypertensive and anti-inflammatory, and to protect the brain, heart and kidney from damage. Although challenges for the future exist - including improving the drug-like properties of sEHIs and finding better ways to target sEHIs to specific tissues - the recent initiation of the first clinical trials of sEHIs has highlighted the therapeutic potential of these agents.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Signal Transduction

Topics: Administration, Oral; Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Anti-Arrhythmia Agents; Anticoagulants; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Cytochrome P-450 Enzyme System; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Platelet Aggregation Inhibitors; Polymorphism, Genetic

TF (tissue factor) is the main trigger of the coagulation cascade; by binding Factor VIIa it activates Factor IX and Factor X, thereby resulting in fibrin formation. Various stimuli, such as cytokines, growth factors and biogenic amines, induce TF expression and activity in vascular cells. Downstream targets of these mediators include diverse signalling molecules such as MAPKs (mitogen-activated protein kinases), PI3K (phosphoinositide 3-kinase) and PKC (protein kinase C). In addition, TF can be detected in the bloodstream, known as circulating or blood-borne TF. Many cardiovascular risk factors, such as hypertension, diabetes, dyslipidaemia and smoking, are associated with increased expression of TF. Furthermore, in patients presenting with acute coronary syndromes, elevated levels of circulating TF are found. Apart from its role in thrombosis, TF has pro-atherogenic properties, as it is involved in neointima formation by inducing vascular smooth muscle cell migration. As inhibition of TF action appears to be an attractive target for the treatment of cardiovascular disease, therapeutic strategies are under investigation to specifically interfere with the action of TF or, alternatively, promote the effects of TFPI (TF pathway inhibitor).

Topics: Blood Coagulation; Cardiovascular Agents; Cardiovascular Diseases; Humans; Metabolic Diseases; Thromboplastin

The importance of mind-body health relationships has been recognized for decades, but only recently has the wider medical and cardiovascular community become engaged in understanding and addressing the complex, bidirectional risk relationship between cardiovascular disease (CVD) and depression. Furthermore, it has become increasingly clear that there are incompletely understood sex differences in incidence and outcomes for both conditions that should guide treatment and future research efforts. This review will explore the role of depression in women as a risk factor for incident CVD, its impact on women already suffering from CVD, proposed psychobiologic mechanisms and links, and the implications of sex differences on diagnosis and treatment.

Topics: Age Factors; Behavior; Cardiovascular Agents; Cardiovascular Diseases; Causality; Depression; Female; Humans; Mass Screening; Medication Adherence; Risk Factors; Severity of Illness Index; Sex Factors; Women's Health

Recent major increases in obesity and related metabolic diseases (known as the metabolic syndrome (MetS)) because of sedentary lifestyles and overnutrition in developed and developing countries, are an exploding medical and social problem. These conditions are associated with increased risk of cardiovascular disease (CVD), the leading cause of death. Thus, it is necessary to understand the molecular basis underlying MetS and develop effective preventive and therapeutic approaches against CVD. To date, 7 angiopoietin-like proteins (Angptls) that are structurally similar to angiopoietins have been identified. However, none binds to the angiopoietin receptor, Tie2, or to the closely related Tie1 receptor, suggesting that these ligands function differently from angiopoietins. Some Angptls potently regulate angiogenesis, similar to angiopoietins, whereas others have pleiotropic activity other than angiogenesis and function in lipid and energy metabolism. In this review, we focus on the roles of Angptl2 and Angptl6/angiopoietin-like growth factor (AGF) in the development of MetS and CVD, and discuss the potential for Angptl2 and Angptl6/AGF to function as molecular targets for the prevention and treatment of both conditions.

Topics: Angiogenesis Modulating Agents; Angiopoietin-Like Protein 2; Angiopoietin-Like Protein 6; Angiopoietin-like Proteins; Angiopoietins; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Humans; Hypolipidemic Agents; Metabolic Syndrome; Signal Transduction

The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) was a 25,620 patient study program comparing telmisartan with ramipril or the combination thereof in patients at increased cardiovascular risk. Ramipril had previously been proven to prevent cardiovascular events in a similar population within the HOPE-trial. However, ramipril and other ACE inhibitors (ACE-Is) may have limited tolerability that might restrict their use in patients requiring secondary prevention, whereas angiotensin receptor blockers (ARBs) are suggested to be better tolerated. However, no ARB had been compared with the standard treatment, ramipril, in these cardiovascular patients at increased risk. ONTARGET showed that telmisartan was as effective as ramipril in preventing cardiovascular events, but was better tolerated. The combination of ramipril and telmisartan was not superior to either monotherapy. Taken together, ONTARGET demonstrated that telmisartan is as effective as ramipril in a broad cardiovascular increased-risk population in the middle of the cardiovascular continuum. In these patients who are intolerant to ACE-Is or who do not achieve blood pressure control, the ARB with the best evidence for secondary prevention is telmisartan according to the results of the ONTARGET trial.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Agents; Cardiovascular Diseases; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Telmisartan; Treatment Outcome

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Humans; Risk Factors

In traditional pure protein high-throughput drug screens, also called in vitro screens, individual compounds from a small molecule collection are tested to determine whether they inhibit the enzymatic activity or binding properties of a purified target protein. In contrast, phenotypic high-throughput drug screens, also called chemical genetic or in vivo screens, investigate the ability of individual compounds from a collection to inhibit a biological process or disease model in live cells or intact organisms. In this review, the role of phenotypic screening techniques to identify novel therapeutic agents for the treatment of cardiovascular disease will be discussed.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Cells, Cultured; Combinatorial Chemistry Techniques; Data Interpretation, Statistical; Disease Models, Animal; Drug Discovery; High-Throughput Screening Assays; Humans; Phenotype; Signal Transduction

There has been growing interest in targeting myocardial substrate metabolism for the therapy of cardiovascular and metabolic diseases. This is largely based on the observation that cardiac metabolism undergoes significant changes during both physiologic and pathologic stresses. In search for an effective therapeutic strategy, recent studies have focused on the functional significance of the substrate switch in the heart during stress conditions, such as cardiac hypertrophy and failure, using both pharmacologic and genetic approaches. The results of these studies indicate that both the capacity and the flexibility of the cardiac metabolic network are essential for normal function; thus, their maintenance should be the primary goal for future metabolic therapy.

Topics: Animals; Cardiomegaly; Cardiovascular Agents; Cardiovascular Diseases; Energy Metabolism; Fatty Acids; Genetic Therapy; Genotype; Heart Failure; Humans; Myocytes, Cardiac; Phenotype

Medical disease and the methods used to treat disease that can result in sexual problems. The prevalence and pathophysiology of sexual dysfunction have been prominent questions in medicine for more than a decade. Pertinent information related to sexual dysfunction and medical illness, with special emphasis on cardiovascular health, endocrine-related disorders, and malignancy are presented.

Topics: Antineoplastic Agents; Body Image; Cardiovascular Agents; Cardiovascular Diseases; Chronic Disease; Diabetes Complications; Female; Hormones; Humans; Hysterectomy; Mastectomy, Segmental; Metabolic Syndrome; Neoplasms; Physician-Patient Relations; Radiotherapy; Sexual Dysfunction, Physiological; Sexual Dysfunctions, Psychological

The influence of biological sex on pharmacokinetics and pharmacodynamics has been previously described for each step of the metabolic cascade of pharmaceuticals. Women and men display differences in distribution, metabolism, and excretion of drugs for several biologic reasons. Estrogens are relevant in these processes, but cannot be regarded as the only responsible mechanism. Sex differences in the incidence of adverse drug reactions and pharmacotoxicity have also been reported for several classes of drugs and specifically for several cardiovascular preparations. Given the high incidence of cardiovascular conditions and thus the broad use of these drugs in the general population, these reports have to be considered of relevance to public health. Nonetheless, increased knowledge has not translated into the development and implementation of gender-specific pharmacologic guidelines which appear as the only effective strategy to minimize the incidence of sex-specific side effects and adverse drug reactions. In the present review, we analyze the basic aspects of sex-specific pharmacodynamics and present several examples of gender dimorphism in cardiovascular drugs. We also suggest measures to analyze and possibly improve current therapeutic strategies.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Evidence-Based Medicine; Female; Health Status Disparities; Humans; Male; Sex Factors; Treatment Outcome

The 57th Annual Scientific Session of the American College of Cardiology was held in Chicago (IL, USA) between 29 March and 1 April 2008. It was attended by nearly 30,000 participants from around the world. The conference was highlighted by the presentation of 13 late-breaking clinical trials and 13 late-breaking abstracts.

Topics: Antihypertensive Agents; Atherosclerosis; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia; Hypertension; Hypolipidemic Agents; Male; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Sensitivity and Specificity; Survival Analysis; Treatment Outcome

Dementia is one of the most important neurological disorders in the elderly. Aging is associated with a large increase in the prevalence and incidence of degenerative (Alzheimer's disease) and vascular dementia, leading to a devastating loss of autonomy. In view of the increasing longevity of populations worldwide, prevention of dementia has turned into a major public health challenge. In the past decade, several vascular risk factors have been found to be associated with vascular dementia but also Alzheimer's disease. Some longitudinal studies, have found significant associations between hypertension, diabetus mellitus, and metabolic syndrome, assessed at middle age, and dementia. Studies assessing the link between hypercholesterolemia, atrial fibrillation, smoking, and dementia have given more conflicting results. Furthermore, some studies have highlighted the possible protective effect of antihypertensive therapy on cognition and some trials are evaluating the effects of statins and treatments for insulin resistance. Vascular risk factors and their treatments are a promising avenue of research for prevention of dementia, and further long-term, placebo-controlled, randomized studies, need to be performed.

Topics: Alzheimer Disease; Apolipoproteins E; Atrial Fibrillation; Cardiovascular Agents; Cardiovascular Diseases; Cognition; Dementia, Vascular; Diabetes Complications; Humans; Hypercholesterolemia; Hypertension; Metabolic Syndrome; Risk Factors; Smoking

Heme oxygenase-1, an enzyme degrading heme to carbon monoxide, iron, and biliverdin, has been recognized as playing a crucial role in cellular defense against stressful conditions, not only related to heme release. HO-1 protects endothelial cells from apoptosis, is involved in blood-vessel relaxation regulating vascular tone, attenuates inflammatory response in the vessel wall, and participates in blood-vessel formation by means of angiogenesis and vasculogenesis. The latter functions link HO-1 not only to cardiovascular ischemia but also to many other conditions that, like development, wound healing, or cancer, are dependent on neovascularization. The aim of this comprehensive review is to address the mechanisms of HO-1 regulation and function in cardiovascular physiology and pathology and to demonstrate some possible applications of the vast knowledge generated so far. Recent data provide powerful evidence for the involvement of HO-1 in the therapeutic effect of drugs used in cardiovascular diseases. Novel studies open the possibilities of application of HO-1 for gene and cell therapy. Therefore, research in forthcoming years should help to elucidate both the real role of HO-1 in the effect of drugs and the clinical feasibility of HO-1-based cell and gene therapy, creating the effective therapeutic avenues for this refined antioxidant system.

Topics: Animals; Apoptosis; Biliverdine; Carbon Monoxide; Cardiovascular Agents; Cardiovascular Diseases; Child; Diabetes Complications; Endothelium, Vascular; Enzyme Induction; Female; Genetic Therapy; Heme; Heme Oxygenase-1; Humans; Inflammation; Iron; Male; Mice; Mice, Knockout; Neovascularization, Physiologic; Rabbits; Rats; Vasomotor System

Renal artery stenosis (RAS) is usually caused by atherosclerosis or fibromuscular dysplasia. RAS leads to activation of the renin-angiotensin-aldosterone system and may result in hypertension, ischemic nephropathy, left ventricular hypertrophy and congestive heart failure. Management options include medical therapy and revascularization procedures. Recent studies have shown angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACE-I) to be highly effective in treating the hypertension associated with RAS and in reducing cardiovascular events; however, they do not correct the underlying RAS and loss of renal mass may continue. Renal artery angioplasty was first performed by Gruntzig in 1978. The routine use of stents has increased technical success rates compared with angioplasty, and surgery is now only rarely performed. Although numerous case series claimed benefit in terms of blood pressure control, no adequately powered randomized, controlled, prospective study of renal artery interventions has reported their effect on cardiovascular morbidity or mortality. The CORAL trial, an ongoing study of renal artery stent placement and optimal medical therapy (OMT) funded by the National Institutes of Health, is the first study to attempt to do so. Until the CORAL trial results are in, physicians will continue to be faced with difficult choices when determining the optimal management for RAS patients and deciding which, if any, patients should be offered revascularization.

Topics: Angioplasty, Balloon; Atherosclerosis; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Evidence-Based Medicine; Humans; Hypertension, Renal; Kidney Function Tests; Patient Selection; Radiography; Renal Artery Obstruction; Risk Assessment; Risk Factors; Stents; Treatment Outcome

The number of patients eligible for cardiovascular therapies in general is forecast to increase substantially in the coming decades. However, the current list of potential future cardiovascular blockbuster drugs is alarmingly short. There is thus a clear need for innovative strategies to increase the efficiency of drug development pipelines by establishing new sensitive biomarkers to monitor drug efficacy and safety in the context of complexity of lipoprotein metabolism targeted by the cardiovascular drugs.. Metabolomics is a discipline dedicated to the systematic study of small molecules in cells, tissues and biofluids. Since lipids (including cholesterol), as well as other metabolites, are key constituents of lipoprotein particles and are thus part of the complex lipoprotein metabolism that includes exchange of lipids and metabolites with peripheral tissues, cardiovascular drug safety and efficacy needs to be addressed in the context of systemic lipid metabolism.. Metabolomics, lipidomics in particular, is expected to make an important impact on the discovery and development of cardiovascular therapies.

Topics: Animals; Biomarkers, Pharmacological; Cardiovascular Agents; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Phenotype; Treatment Outcome

Statins lower cardiovascular risk in patients with diabetes; however, as these patients are at higher risk than other cardiovascular patients, statins merely decrease coronary event rates to the level seen in untreated nondiabetic individuals at risk for cardiovascular disease, indicating the existence of substantial residual risk. One reasonable explanation resides in the fact that statins have only limited effectiveness on hypertriglyceridemia and low HDL cholesterol, and they do not normalize the LDL size-distribution pattern. Peroxisome proliferator-activated receptor (PPAR)alpha agonists, which include fibrates, normalize this atherogenic lipid profile, as well as several cardiovascular risk markers associated with the metabolic syndrome and type 2 diabetes. In particular, hypertriglyceridemia and the ratio of small dense:large buoyant LDL particles are significantly improved. Outcome trials of PPARalpha agonists have demonstrated reductions in cardiovascular morbidity in patients with diabetes and in those with the metabolic syndrome; plaque progression is diminished, diabetic nephropathy and retinopathy are counteracted and amputation-risk decreased. The combination of fibrates with statins improves overall lipoprotein profile further. PPARalpha agonists seem particularly indicated in patients with diabetes who have residual dyslipidemia (high triglyceride and/or low HDL) despite receiving statin therapy, and patients who are nondiabetic, overweight, insulin-resistant and who have hypertriglyceridemia and/or low HDL cholesterol and chronic inflammation.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Clofibric Acid; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Lipids; PPAR alpha; Risk Assessment; Risk Factors; Treatment Outcome

Atherosclerosis can affect nearly any part of the arterial system. Therefore, it is considered as a generalized disease. As most probably similar or identical etiopathogenetic mechanisms are involved in different atherosclerotic diseases, a different effect of treatment of risk factors on atherosclerotic lesions in different parts of the vascular system is expected. Until now, great emphasis has been placed on the aggressive pharmacological management of coronary artery disease, less attention has been devoted to the management of cerebrovascular and much less to peripheral arterial disease, despite their significant morbidity and mortality. The data from recent trials have indicated that treatment of patients with antiplatelet drugs, statins, antihypertensive and antidiabetic drugs prevents the progression of coronary atherosclerosis, reduces cardiovascular events and improves prognosis of coronary patients. Subgroup analyses from large studies have also shown that treatment of risk factors for atherosclerosis with drugs reduces cardiovascular events and improves prognosis of cerebrovascular and peripheral arterial occlusive disease. Although some studies indicate that the effects of distinct preventive procedures are to some extent dependent on the locations of atherosclerotic disease, it seems that the success of preventive measures is mostly related to the progression of the disease or the risk of treated population and not on the treated vascular bed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Arterial Occlusive Diseases; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Coronary Artery Disease; Disease Progression; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Treatment Outcome

'Translation' in medicine immediately suggests 'translational research', but there are many other varieties of 'translation'. I have selected 4 translations in the field of vascular neurology in which I have been involved in different respects: (1) the translation of results from men to women, taking the example of aspirin which, in primary prevention, decreases the risk of myocardial infarction in men and the risk of cerebral infarction in women, the reason for this sex difference being so far unknown; (2) the 'inverse translational research', from bedside to bench, taking the example of the disease we have identified--CADASIL--and showing how the study of one patient and his family led to the identification of a gene, Notch3, so far unknown in humans and to the discovery of its key role in the physiology of vascular smooth muscle cells; (3) the translation from individual case reports to multidisciplinary trials taking the example of hemicraniectomy in malignant cerebral infarction and emphasizing the interest in such rare and severe conditions of pooling and reporting the results of randomized clinical trials before the results of individual trials, and (4) the translation from research to practice, emphasizing not the well-known 'evidence to practice gap' but the slippery slope of 'lack of evidence to overpractice', taking the example of patent foramen ovale closure in migraine.

Topics: Aspirin; Awards and Prizes; Biomedical Research; CADASIL; Cardiovascular Agents; Cardiovascular Diseases; Cerebral Infarction; Craniotomy; Evidence-Based Medicine; Female; Foramen Ovale, Patent; Humans; Male; Medical Records; Migraine Disorders; Myocardial Infarction; Neurology; Randomized Controlled Trials as Topic; Receptor, Notch3; Receptors, Notch; Sex Factors; Treatment Outcome

Apixaban is an oral, direct Factor Xa inhibitor that is being developed by Bristol-Myers Squibb Co and Pfizer Inc. Apixaban is currently undergoing phase III clinical trials for cerebrovascular ischemia, deep vein thrombosis and lung embolism, and phase II clinical trials for coronary artery disease.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Factor Xa Inhibitors; Humans; Patents as Topic; Pyrazoles; Pyridones; Structure-Activity Relationship

Circulating endothelial progenitor cells (EPCs) derived from bone marrow were isolated for the first time in 1997 and characterized. Recent evidence has indicated that EPCs contribute to re-endothelialization of injured vessels as well as neovascularization of ischemic lesions and that a decrease in the number of EPCs is an independent predictor of morbidity and mortality of cardiovascular diseases. These finding suggest that EPCs play a major role in the pathogenesis of atherosclerosis and cardiovascular diseases. Interestingly, the number and function of EPCs are regulated by not only various kinds of angiogenic cytokines and cardiovascular risk factors per se but also some interventions, including lifestyle modification (aerobic exercise, body weight loss, and smoking cessation) and pharmacological therapy (e.g., renin-angiotensin system inhibitor, statin, and erythropoietin). It is thought that regulation of the number and function of EPCs directly influences the maintenance and development of atherosclerosis. Therefore, it is clinically important to estimate the degree of EPC bioactivity and to increase the EPC bioactivity by appropriate interventions. In this review, we focus on the relationship between EPCs and cardiovascular risk factors and the role of EPCs in cardiovascular diseases.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Endothelial Cells; Humans; Risk Factors; Stem Cells

Metformin is now established as a first-line antidiabetic therapy for the management of type 2 diabetes. Its early use in treatment algorithms is supported by lack of weight gain, low risk of hypoglycaemia and its mode of action to counter insulin resistance. The drug's anti-atherosclerotic and cardioprotective effects have recently been confirmed in prospective and retrospective studies, and appear to reflect a collection of glucose-independent effects on the vascular endothelium, suppressant effects on glycation, oxidative stress and formation of adhesion molecules, stimulation of fibrinolysis and favourable effects on the lipid profile. Although avoidance of troublesome gastrointestinal tolerability issues requires careful dose titration, the risk of serious adverse events is considered low provided that contra-indications (especially with respect to renal function) are observed. As many of its actions go beyond glucose lowering, emerging evidence indicates potential benefits in other insulin-resistant states and possibly tumour suppression.

Topics: Administration, Oral; Blood Glucose; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Patient Selection; Practice Guidelines as Topic; Treatment Outcome

One of the greatest challenges of cardiovascular prevention is to minimize the risk of cardiovascular events through the achievement of target lipid levels. Its importance is suggested by the comprehensive meta-analyses of large scale clinical trials and the therapeutic guidelines determining everyday clinical practice. The attainment of target levels is often emphasized, nevertheless, there is a gap between theory and practice. The authors compare the goal attainment rate based on Hungarian medical literature and their own data, and analyze the possibilities of further improvement. The CEL Program evaluated the achievement rate of target total cholesterol levels in more than 10 000 patients of general practitioners in 2004, 2005 and 2006, and the ratio increased from 12% to 30% within 3 years. According to the results of the Hungarian REALITY study the rate of patients achieving the target total cholesterol levels was 21% in 2004, and it increased to 27% during a 3-year period. To this very low improving rate also belongs the fact that in 2007, when only one fourth of patients were on target levels, 87% of general practitioners and 56% of specialists reconciled themselves to it and did not propose any modification in the therapy of patients not achieving the target levels. The surveys conducted at the department of internal medicine with cardiological profile of the county hospital in Gyula proved a considerable increase in the last 7 years in the administration of drugs improving the life expectancy of cardiovascular patients (aspirin, beta-blockers, ACE-inhibitors and statins) due to the widespread application of clinical guidelines and the special attention; nowadays the administration rate is above 90% in all four groups. Nevertheless, the rate of patients achieving the LDL-cholesterol goals was 37% in the high risk and 18% in the very high risk groups in December 2007 and January 2008. The fact that in the latter group only 21% of patients received combination therapy indicates that improving this ratio may be the next step. A greater emphasis should be placed on the achievement of target levels and regular revision of applied medical therapy, particularly in the high and very high risk patients as these groups can benefit the most from it.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Anticholesteremic Agents; Aspirin; Attitude of Health Personnel; Cardiovascular Agents; Cardiovascular Diseases; Drug Therapy, Combination; Female; Humans; Hungary; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Lipids; Male; Middle Aged; Physicians; Program Evaluation

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Resistance; Humans; Pharmacogenetics; Racial Groups

Treatment of patients with in-stent restenosis (ISR) remains a challenge. We sought to compare results of sirolimus-eluting stents (SES) with those of bare-metal stents (BMS) in patients with ISR.. The results obtained in the stent arm of two randomized studies were analyzed. The RIBS I study (450 patients with ISR) allocated 224 patients to BMS; the RIBS II study (150 patients with ISR) allocated 76 patients to SES. Complete 1-year follow-up was obtained in all 300 patients treated with stents.. Although inclusion/exclusion criteria were identical in the two studies, when compared with patients in the BMS group, patients in the SES arm had more adverse baseline characteristics, more diffuse lesions, and smaller vessels. However, late angiographic findings including in-segment recurrent restenosis rate (11 vs. 38%, P < 0.001), minimal lumen diameter (2.52 vs. 1.63 mm, P < 0.001), and late loss (0.13 vs. 1.04 mm, P < 0.001) were significantly better after SES. The 1-year event-free survival was also significantly improved in the SES group (88 vs. 78%, P < 0.05), as the result of a lower requirement for repeated revascularizations (10.5 vs. 19.6%, P < 0.05). Prespecified subgroup analyses were consistent with the main outcome measures. After adjusting for (a) imbalances in baseline characteristics (restenosis OR 0.11 [95% confidence interval (CI) 0.03-0.36]; adverse events hazard ratios (HR) 0.33 [95% CI 0.13-0.84]) and (b) the propensity score (restenosis OR 0.08 [95% CI 0.03-0.28]; adverse events HR 0.24 [95% CI 0.09-0.66]), results of the SES group were superior to those obtained in the BMS group.. When compared with BMS, SES improved the long-term clinical and angiographic outcome of patients with ISR.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Cardiovascular Diseases; Coronary Angiography; Coronary Restenosis; Drug-Eluting Stents; Female; Humans; Male; Metals; Middle Aged; Odds Ratio; Prosthesis Design; Randomized Controlled Trials as Topic; Risk Assessment; Sirolimus; Stents; Time Factors; Treatment Outcome

Endovascular (EVAR) abdominal aortic aneurysm (AAA) repair has been established as a successful procedure in the short term and may constitute a viable long-term alternative to open repair (OR). The procedure has been associated with lower operative and mid-term morbidity and mortality compared to OR, but long-term results remain largely controversial. EVAR has also been associated with a significant risk of implant and procedure-related complications, such as graft thrombosis and cardiovascular events, necessitating interventional and pharmaceutical management. Medical management of patients undergoing EVAR is required for several different reasons. Patients with an AAA have an increased risk of cardiovascular death, necessitating treatment to reduce the overall risk for cardiovascular events. Treatment is in-line with the medical management of coronary artery disease including anti-platelet therapy and statins. Anti-platelet therapy is also mandatory to prevent complications such as graft-limb thrombosis and peripheral arterial disease (PAD), which is common in patients with an AAA. Especially in patients with PAD, aspirin, clopidogrel and statins remain the mainstay of medical management. Unfortunately, there is a lack of prospective randomised trials concerning the medical management of patients that have undergone abdominal aortic endo-grafting. We review the current literature on the medical treatment of patients undergoing EVAR, focusing on peri-operative management, anti-platelet agents and statins.

Topics: Aortic Aneurysm, Abdominal; Blood Vessel Prosthesis Implantation; Cardiovascular Agents; Cardiovascular Diseases; Combined Modality Therapy; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Platelet Aggregation Inhibitors; Postoperative Care; Preoperative Care; Treatment Outcome

C-reactive protein (CRP) is an acute-phase protein, which has been used in clinical practice as a non specific marker of inflammation. Many studies have shown that CRP is associated with atherosclerotic cardiovascular disease. It is currently unknown if CRP plays an active role as an etiologic factor in cardiovascular disease. The mechanisms by which CRP may contribute to the pathogenesis of cardiovascular disease are poorly understood. The effect of CRP on atherogenesis may include interactions with other factors of immunity and inflammation, such as the complement system, as well as a direct effect of CRP on the cells involved in atherosclerotic lesions. We review the literature concerning the mechanisms by which CRP may influence the development of cardiovascular disease and discuss the findings of clinical studies assessing the association between CRP and cardiovascular disease.

Topics: Animals; Atherosclerosis; Biomarkers; C-Reactive Protein; Cardiovascular Agents; Cardiovascular Diseases; Humans; Treatment Outcome

Topics: Adult; Anemia; Cardiovascular Agents; Cardiovascular Diseases; Chronic Disease; Hematinics; Humans; Kidney Diseases; Middle Aged; Practice Guidelines as Topic; Renal Dialysis; Risk Factors

Although sleep apnea is closely associated with cardiovascular disease, it remains underdiagnosed and undertreated. Obstructive sleep apnea elicits a cascade of harmful cardiovascular stimuli, and central sleep apnea is a prognostic factor for heart failure and may exert adverse effects on outcomes. The adverse effects of obstructive sleep apnea can promote the development of atherosclerosis and have also been implicated in the pathogenesis of cardiovascular disease. Sleep apnea characterized by variables of the autonomic nervous system may have a direct association with arrhythmia. Polysomnography with electroencephalography is the gold standard for assessing sleep apnea. Alternative methods of screening for OSA have recently become available. Continuous positive airway pressure for obstructive sleep apnea reduces cardiac risk and cardiovascular disease mortality. Targeting sleep apnea in the primary and/or secondary prevention of cardiovascular disease may lead to better outcomes.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Continuous Positive Airway Pressure; Electroencephalography; Heart Failure; Humans; Polysomnography; Sleep Apnea Syndromes; Sleep Apnea, Central; Treatment Outcome

Erectile dysfunction (ED) is a sensitive indicator of wider arterial insufficiency and an early correlate for the presence of ischemic heart disease. Among patients with coronary artery disease, prevalence reports of ED range from 42% to 75%. The US Food and Drug Administration has approved 3 phosphodiesterase-5 (PDE-5) inhibitors for treatment of male sexual dysfunction: sildenafil, tadalafil, and vardenafil. PDE-5 inhibitors also have cardiovascular effects. They inhibit PDE-5 enzymes in pulmonary vasculature, which causes vasodilation that decreases pulmonary vascular pressure. Sildenafil is approved for treatment of patients with pulmonary hypertension. PDE-5 inhibition with sildenafil improves cardiac output by balancing pulmonary and systemic vasodilation, and augments and prolongs the hemodynamic effects of inhaled nitric oxide in patients with chronic congestive heart failure and pulmonary hypertension. In vivo and in vitro studies are examining the possible beneficial effects of PDE-5 inhibitors in conditions such as myocardial infarction and endothelial dysfunction.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Heart Failure; Humans; Hypertension, Pulmonary; Male; Myocardial Ischemia; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Treatment Outcome

Adverse drug reactions (ADRs) occur frequently in modern medical practice, increasing morbidity and mortality and inflating the cost of care. Patients with cardiovascular disease are particularly vulnerable to ADRs due to their advanced age, polypharmacy, and the influence of heart disease on drug metabolism. The ADR potential for a particular cardiovascular drug varies with the individual, the disease being treated, and the extent of exposure to other drugs. Knowledge of this complex interplay between patient, drug, and disease is a critical component of safe and effective cardiovascular disease management. The majority of significant ADRs involving cardiovascular drugs are predictable and therefore preventable. Better patient education, avoidance of polypharmacy, and clear communication between physicians, pharmacists, and patients, particularly during the transition between the inpatient to outpatient settings, can substantially reduce ADR risk.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diagnostic Techniques, Cardiovascular; Drug Interactions; Humans; Risk Assessment; Risk Factors

In this review, we will give a critical update of published studies using ultrasound for targeted therapeutic use. We will briefly discuss the interaction mechanisms and their effects in non-invasive delivery of therapeutic agents. Moreover, the mechanisms by which ultrasonic contrast agents facilitate the delivery of drugs and genes into tissue will be discussed, together with recent applications and perspectives of targeted-microbubbles in cardiovascular medicine.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Contrast Media; Drug Delivery Systems; Extravasation of Diagnostic and Therapeutic Materials; Genetic Therapy; Humans; Microbubbles; Ultrasonography

An association has been shown between plasma renin activity (PRA) and the risk of cardiovascular disease. There is also evidence that angiotensin II exerts detrimental effects on progression and instabilization of atherosclerotic plaque. The renin-angiotensin system (RAS) can be inhibited through inhibition of angiotensin I (Ang I) generation from angiotensinogen by direct renin inhibitors, inhibition of angiotensin II (Ang II) generation from angiotensin I by angiotensin-converting enzyme inhibitors and finally by direct inhibition of the action of Ang II receptor level. Aliskiren, the first direct renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic nonpeptide. Aliskiren blocks Ang I generation, while plasma renin concentration increases because the drugs blocks the negative feed-back exerted by Ang II on renin synthesis. Because of its long pharmacological half-life, aliskiren is suitable for once-daily administration. Its through-to-peak ratio approximates 98% for the 300 mg/day dose. Because of its mechanism of action, aliskiren might offer the additional opportunity to inhibit progression of atherosclerosis at tissue level. Hypertension is an approved indication for this drug, which is also promising for the treatment of heart failure. The efficacy of this drug in reducing major clinical events is being tested in large ongoing clinical trials.

Topics: Amides; Angiotensinogen; Antihypertensive Agents; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Drug Administration Schedule; Fumarates; Humans; Prorenin Receptor; Protein Precursors; Receptors, Cell Surface; Renin; Renin-Angiotensin System; Treatment Outcome; Vacuolar Proton-Translocating ATPases

Trandolapril is a well known angiotensin converting enzyme (ACE) inhibitor with many cardiovascular (CV) indications. The objectives of this article are to review the pharmacokinetics and pharmacodynamics properties of trandolapril and to focus on its clinical relevance in cardiovascular medicine. Various populations have been studied in large clinical trials including patients with congestive heart failure (CHF) after an acute myocardial infarction (AMI), diabetics, patients with hypertension (HTN), stable coronary artery disease (CAD) and prevention of proteinuria. Long-term treatment with trandolapril in patients with reduced left ventricular function soon after AMI significantly reduced the risk of overall mortality, mortality from CV causes, sudden death, and the development of severe CHF. Treatment with trandolapril after AMI complicated by left ventricular dysfunction appears to be of considerable importance in patients with diabetes mellitus by saving lives and substantially reducing the risk of progression to severe CHF as well. Moreover, trandolapril reduces progression to proteinuria in high-risk patients. Some of the advantages of trandolapril over other ACE inhibitors are the wide spectrum of patient populations studied, the well established dosage and its proven trough-to-peak effect ratios permitting a safe once-a-day administration.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Disease; Diabetes Complications; Drug Administration Schedule; Heart Failure; Humans; Hypertension; Indoles; Myocardial Infarction; Proteinuria; Treatment Outcome; Ventricular Dysfunction, Left

Subjects with peripheral arterial disease (PAD) of the lower limbs are at high risk for cardiovascular and cerebrovascular events and the prevalence of coronary artery disease in such patients is elevated. Recent studies have shown that regular use of cardiovascular medications, such as therapeutic and preventive agents for PAD patients, seems to be promising in reducing long-term mortality and morbidity. The angiotensin-converting-enzyme (ACE) system plays an important role in the pathogenesis and progression of atherosclerosis, and ACE-inhibitors (ACE-I) seem to have vasculoprotective and antiproliferative effects as well as a direct anti-atherogenic effect. ACE-I also promote the degradation of bradykinin and the release of nitric oxide, a potent vasodilator; further, they have shown important implications for vascular oxidative stress. Other studies have suggested that ACE-I may also improve endothelial dysfunction. ACE-I are useful for reducing the risk of cardiovascular events in clinical and subclinical PAD. Particularly, one agent of the class (ie, ramipril) has shown in many studies to able to significantly reduce cardiovascular morbidity and mortality in patients with PAD.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Cardiovascular Diseases; Cell Proliferation; Endothelium, Vascular; Fibrinolysis; Humans; Lower Extremity; Oxidative Stress; Peripheral Vascular Diseases; Treatment Outcome

ST-segment elevation myocardial infarction (STEMI) is associated with high morbidity and mortality, but timely reperfusion is known to result in dramatically improved patient outcomes. As many as 40% of patients with STEMI, however, present late after symptom onset, which reduces the likelihood of them receiving reperfusion therapy. The past two decades have been plagued with controversy regarding the relative benefits of reperfusion therapy after 12 h from symptom onset. Despite considerable data supporting late reperfusion and the 'late open-artery hypothesis', recent studies have demonstrated a lack of benefit with late reperfusion. Moreover, advances in the medical management of STEMI have dramatically reduced morbidity and mortality, further challenging the need for more-invasive techniques. Numerous questions have arisen regarding the appropriate management and risk stratification of asymptomatic post-STEMI patients who present late after symptom onset. In light of recent data, we present a Review of late reperfusion in STEMI, specifically highlighting the effects of current medical therapies, risk-stratification techniques, and indications for the use of late reperfusion over medical management.

Topics: Angioplasty, Balloon, Coronary; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Exercise Test; Humans; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Patient Selection; Practice Guidelines as Topic; Risk Assessment; Risk Factors; Stents; Stroke Volume; Thrombolytic Therapy; Time Factors; Treatment Outcome; Ventricular Function, Left

Marfan syndrome (MFS) is the most common inherited disorder of connective tissue that affects multiple organ systems. This autosomal-dominant condition has an incidence of 2-3 per 10,000 individuals. Although genetic testing is available, the diagnosis is still primarily made using the Ghent criteria. Early identification and appropriate management is critical for patients with MFS who are prone to the life-threatening cardiovascular complications of aortic dissection and rupture. Advances in the understanding of the cause of MFS, early recognition of the disorder, and subsequent institution of medical and surgical therapy has resulted in dramatic improvement in the prognosis of this patient population over the past few decades. Beta-blockers have been demonstrated to slow aortic growth and thus delay the time to aortic surgery. Operative intervention has markedly changed the prognosis of patients with MFS and can be safely performed on an elective basis. Identification of presymptomatic patients is critical to reduce the frequency of catastrophic aortic events.

Topics: Adolescent; Adult; Bone and Bones; Cardiac Surgical Procedures; Cardiovascular Agents; Cardiovascular Diseases; Child; Echocardiography; Female; Humans; Lens Subluxation; Magnetic Resonance Imaging; Male; Marfan Syndrome; Pregnancy; Quality of Life; Stereotyping; Tomography, X-Ray Computed; Treatment Outcome

To review studies on the cost consequences of compliance and/or persistence in cardiovascular disease (CVD) and related conditions (hypertension, dyslipidaemia, diabetes and heart failure) published since 1995, and to evaluate the effects of noncompliance on healthcare expenditure and the cost-effectiveness of pharmaceutical interventions.. English language papers published between January 1995 and February 2007 that examined compliance/persistence with medication for CVD or related conditions, provided an economic evaluation of pharmacological interventions or cost analysis, and quantified the cost consequences of noncompliance, were identified through database searches. The cost consequences of noncompliance were compared across studies descriptively.. Of the 23 studies identified, 10 focused on hypertension, seven on diabetes, one on dyslipidaemia, one on coronary heart disease, one on heart failure and three covered multiple diseases. In studies assessing drug costs only, increased compliance/persistence led to increased drug costs. However, increased compliance/persistence increased the effectiveness of treatment, leading to a decrease in medical events and non-drug costs. This offset the higher drug costs, leading to savings in overall treatment costs. In studies evaluating the effect of compliance/persistence on the cost-effectiveness of pharmacological interventions, increased compliance/persistence appeared to reduce cost-effectiveness ratios, but the extent of this effect was not quantified.. Noncompliance with cardiovascular and antidiabetic medication is a significant problem. Increased compliance/persistence leads to increased drug costs, but these are offset by reduced non-drug costs, leading to overall cost savings. The effect of noncompliance on the cost-effectiveness of pharmacological interventions is inconclusive and further research is needed to resolve the issue.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cost of Illness; Cost-Benefit Analysis; Drug Costs; Health Care Costs; Health Promotion; Humans; Patient Compliance

Starting in the 1970s the hypothesis that the low mortality from coronary heart disease among the Greenland Eskimos was due to their high consumption of n-3 fish oil fatty acids, initiated many studies to find if the n-3 polyunsaturated fatty acids in fish oils (PUFAs) could prevent cardiac atherosclerosis. To date this possibility has not achieved clinical recognition. The recent literature shows an increase of intervention studies to learn if the fish oil fatty acids can reduce mortality from sudden cardiac death, and the mechanism(s) of such a protective effect. Indeed the most definite beneficial cardiac action of these n-3 PUFAs seems now to be their ability in the short term to prevent sudden cardiac death. It is apparent that over long periods of time the n-3 fish oil fatty acids also prevent atherosclerosis. Definition of the fatty acids to which I will be referring in the text: n-6 (omega-6) polyunsaturated fatty acids; linoleic acid (18:2n-6, LA); arachidonic acid (C20:4n-6, AA). n-3 (omega-3) fatty acids; alpha-linolenic acid (18:3n-3, ALA); eicosapentaenoic acid (20:5n-3, EPA); docosahexaenoic acid (C22:6n-3, DHA). The bold, underlined abbreviation will appear in the text to identify the fatty acid being discussed.

Topics: Animals; Atherosclerosis; Calcium Channels, L-Type; Cardiovascular Agents; Cardiovascular Diseases; Cells, Cultured; Death, Sudden, Cardiac; Dogs; Electrophysiology; Fatty Acids, Omega-3; Fish Oils; Humans; Myocytes, Cardiac; Rats

The research, development and use of natural products as therapeutic agents, especially those derived from plants, have been increasing in recent years. There has been great deal of focus on the naturally occurring antispasmodic phytochemicals as potential therapy for cardiovascular diseases. Naturally occurring diterpenes exert several biological activities such as anti-inflammatory action, antimicrobial and antispasmodic activities. Several diterpenes have been shown to have pronounced cardiovascular effects, for example, grayanotoxin I produces positive inotropic responses, forskolin is a well-known activator of adenylate cyclase, eleganolone and 14-deoxyandrographolide exhibit vasorelaxant properties and marrubenol inhibits smooth muscle contraction by blocking L-type calcium channels. In the last few years, we have investigated the biological activity of kaurane and pimarane-type diterpenes, which are the main secondary metabolites isolated from the roots of Viguiera robusta and V. arenaria, respectively. These diterpenoids exhibit vasorelaxant action and inhibit the vascular contractility mainly by blocking extracellular Ca(2+) influx. Moreover, kaurane and pimarane-type diterpenes decreased mean arterial blood pressure in normotensive rats. Diterpenes likely fulfil the definition of a pharmacological preconditioning class of compounds and give hope for the therapeutic use in cardiovascular diseases. This article will review patents, structure-activity relationship, pharmacology, antihypertensive efficiency, and the vascular mechanisms underlying the effects of diterpenes. Careful examination of the cardiovascular effects exhibited by kaurane and pimarane-type diterpenes will be provided.

Topics: Animals; Calcium; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Diterpenes; Humans; Muscle Contraction; Muscle, Smooth; Patents as Topic; Plants, Medicinal

Urokinase (UK) [EC 3.4.99.26] is a serine protease that activates plasminogen to plasmin, which in turn degrades fibrin clots. Hence, UK finds its value as an important anti-thromboembolic drug. Plasmin has diverse physiological roles apart from its fibrinolytic role in the regulation of blood clotting. It has been implicated in complement activation, cell migration, wound healing, and generation of localized extracellular proteolysis during tissue remodelling, pro-hormone conversion, carcinogenesis and neoplasia. Among the plasminogen activators, UK provides a superior alternative for the simple reasons of its being more potent as compared to tissue-plasminogen activator and non-antigenic by virtue of its human origin unlike streptokinase. Based on these observations, UK is a very popular cardiovascular agent. Hence, UK, as one of the most potent plasminogen activators is attracting a great deal of attention. We will summarize recent patents related to the occurrence, mechanism of action, structure and function, physico-chemical properties, in vitro production, cloning and expression, purification and applications of UK.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Chemical Phenomena; Chemistry, Physical; Humans; Patents as Topic; Plasminogen Activators; Urokinase-Type Plasminogen Activator

Cardiovascular diseases are a group of multifactorial and complex debilitating diseases facing limitations in classical pharmacology. Instead of drug-targeting the consequences, the origin of the disease (i.e. cardiomyocytes degeneration) represents a better although challenging target. Indeed, the human heart is not or poorly able to regenerate. The loss of cardiomyocytes, occurring in many ischemic or genetic cardiac diseases, replaced by fibroblasts leads to a lower response of the myocardium to the contractile demand. Following a transient compensatory hypertrophic phase, and despite the intervention of pharmacological agents to limit the contractile demand, including beta-adrenoceptors blockers or inhibitors of the conversion enzyme, the contractile force developed reaches a limitation dropping the myocardium into a failing stage. Thus, myocardial regeneration has been envisioned using 'pharmacological' agents, genes, or stem cells. For the past decade, both gene therapy and more recently cell therapy have been tested in clinical trials to relieve some aspects of heart weakness or to compensate myocardial degeneration. Protein-based and miRNA-based regenerative therapies are also emerging from experimental animal studies. This review brings an update on the most recent research strategies to regenerate the diseased myocardium. The remaining challenges of gene-based, cell-based, or protein-based therapies to relieve heart failure are discussed.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Genetic Therapy; Humans; MicroRNAs; Proteins; Regeneration; Stem Cell Transplantation

The first therapeutic aptamer was approved for human use in 2004, and a range of chemical substitutions that improve the drug-like properties of aptamers has recently been shown to increase the utility of this modality. Currently there are both anticoagulant and antithrombotic aptamers in the clinic, and additionally there are a number of earlier stage projects in which a variety of cardiovascular targets are inhibited by specific aptamers and for which a wide range of therapeutic applications has been suggested.

Topics: Animals; Anticoagulants; Aptamers, Nucleotide; Cardiovascular Agents; Cardiovascular Diseases; Cell Adhesion; Drug Delivery Systems; Fibrinolytic Agents; Humans

Peripheral arterial occlusive disease (PAD) is a highly prevalent atherosclerotic syndrome associated with significant morbidity and mortality. It is defined by atherosclerotic obstruction of the abdominal aorta and arteries to the legs that reduces arterial flow during exercise and/or at rest, and is a common manifestation of systemic atherosclerosis. PAD represents a marker for premature cardiovascular events, and in patients with PAD, even in the absence of a history of myocardial infarction (MI) or ischemic stroke, they have approximately the same relative risk of death from cardiovascular causes as do patients with a history of coronary or cerebrovascular disease. In addition, their death rate from all causes is approximately equal in men and women and is elevated even in asymptomatic patients. The major risk factors for PAD are the well defined atherosclerotic risks such as diabetes mellitus, cigarette smoking, advanced age, hyperlipidemia, and hypertension. Due to the presence of these risk factors, the systemic nature of atherosclerosis, and the high risk of ischemic events, patients with PAD should be candidates for aggressive secondary prevention strategies including aggressive risk factor modification, antiplatelet therapy, lipid lowering therapy and antihypertensive treatment. This article reviews the current medical treatment and risk factor modification of patients with PAD.

Topics: Age Factors; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Complications; Disease Progression; Drugs, Investigational; Exercise Therapy; Female; Humans; Hyperhomocysteinemia; Hyperlipidemias; Hypertension; Inflammation; Intermittent Claudication; Male; Peripheral Vascular Diseases; Renal Insufficiency, Chronic; Risk Factors; Smoking; Smoking Cessation; Treatment Outcome

Apoptosis, a form of programmed cell death (PCD), plays an important role in the initiation and progression of a number of cardiovascular disease, such as heart failure, myocardial infarction, and atherosclerosis. One of the most prominent characteristics of apoptosis is the externalisation of phosphatidylserine (PS), a plasma cell membrane phospholipid, which in healthy cells only is present on the inner leaflet of the plasma cell membrane. Annexin A5, a 35 kD plasma protein, has strong affinity for PS in the nano-molar range. Through the coupling of Annexin A5 to contrast agents, visualization of apoptotic cell death in vivo in animal models and in patients has become feasible. These imaging studies have provided novel insight into the extent and kinetics of apoptosis in cardiovascular disease. Furthermore, Annexin A5 imaging has proven to be a suitable imaging biomarker for the evaluation of cell death modifying compounds and plaque stabilizing strategies. Recent insight in PS biology has shown that PS externalisation not only occurs in apoptosis, but is also observed in activated macrophages and stressed cells. In addition, it has been shown that Annexin A5 not only binds to exteriorized PS, but is also internalized through an Annexin A5 specific mechanism. These latter findings indicate that Annexin A5 imaging is not exclusively valuable for apoptosis detection, but can also be used to visualize inflammation and cell stress. This will open novel opportunities for imaging and drug delivery strategies. In this review we will discuss the introduction of Annexin A5 in preclinical and clinical imaging studies and provide an outlook on novel opportunities of Annexin A5 based targeting of PS.

Topics: Animals; Annexin A4; Annexin A5; Apoptosis; Atherosclerosis; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Fluorescent Dyes; Heart Failure; Humans; Microscopy, Fluorescence; Myocardial Ischemia; Radiopharmaceuticals; Risk Assessment; Swine; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

Functional studies can be utilized to give importance/relevance to clinical associations. Once a clinical genetic or pharmacogenetic association is found, molecular studies can be utilized to explore the mechanism for the association. By employing cells in culture or transgenic mice modified with specific variant genes or sequence polymorphisms of interest, pathophysiological processes and response to pharmacological agents may be tested under conditions that are not approachable in human patients. These mechanistic studies may be particularly important when it comes to pharmacogenetic associations by providing significant, clinically relevant insights into the variable responses patients show to drug therapy.

Topics: 2',5'-Oligoadenylate Synthetase; Animals; Biotransformation; Cardiovascular Agents; Cardiovascular Diseases; Computational Biology; Genetic Testing; Genomics; Genotype; Humans; Mice; Molecular Biology; Patient Selection; Pharmacogenetics; Phenotype; Polymorphism, Single Nucleotide; PPAR gamma; Receptors, Adrenergic, beta-1; Treatment Outcome

Folic acid (FA) is a member of the B-vitamin family with cardiovascular roles in homocysteine regulation and endothelial nitric oxide synthase (eNOS) activity. Its interaction with eNOS is thought to be due to the enhancement of tetrahydrobiopterin bioavailability, helping maintain eNOS in its coupled state to favor the generation of nitric oxide rather than oxygen free radicals. FA also plays a role in the prevention of several cardiac and noncardiac malformations, has potent direct antioxidant and antithrombotic effects, and can interfere with the production of the endothelial-derived hyperpolarizing factor. These multiple mechanisms of action have led to studies regarding the therapeutic potential of FA in cardiovascular disease. To date, studies have demonstrated that FA ameliorates endothelial dysfunction and nitrate tolerance and can improve pathological features of atherosclerosis. These effects appear to be homocysteine independent but rather related to their role in eNOS function. Given the growing evidence that nitric oxide synthase uncoupling plays a major role in many cardiovascular disorders, the potential of exogenous FA as an inexpensive and safe oral therapy is intriguing and is stimulating ongoing investigations.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Folic Acid; Heart Defects, Congenital; Hemodynamics; Homocysteine; Humans; Nitric Oxide; Nitric Oxide Synthase Type III

In contrast with the short research history of the enzymatic synthesis of nitric oxide (NO), the introduction of nitrate-containing compounds for medicinal purposes marked its 150th anniversary in 1997. Glyceryl trinitrate (nitroglycerin) is the first compound of this category. On October 12, 1998, the Nobel Assembly awarded the Nobel Prize in Medicine or Physiology to scientists Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning NO as a signaling molecule in the cardiovascular system. NO-mediated signaling is a recognized component in various physiologic processes (eg, smooth muscle relaxation, inhibition of platelet and leukocyte aggregation, attenuation of vascular smooth muscle cell proliferation, neurotransmission, and immune defense), to name only a few. NO has also been implicated in the pathology of many inflammatory diseases, including arthritis, myocarditis, colitis, and nephritis and a large number of pathologic conditions such as amyotrophic lateral sclerosis, cancer, diabetes, and neurodegenerative diseases. Some of these processes (eg, smooth muscle relaxation, platelet aggregation, and neurotransmission) require only a brief production of NO at low nanomolar concentrations and are dependent on the recruitment of cyclic guanosine monophosphate (cGMP)-dependent signaling. Other processes are associated with direct interaction of NO or reactive nitrogen species derived from it with target proteins and requires a more sustained production of NO at higher concentrations but do not involve the cGMP pathway.

Topics: Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Endothelium; Humans; Hypertension; Nitric Oxide; Reactive Nitrogen Species; Reactive Oxygen Species; Signal Transduction

Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, stroke, blindness, and end-stage renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Recent clinical studies have substantiated the concept of "hyperglycemic memory" in the pathogenesis of cardiovascular disease (CVD) in diabetes. Indeed, the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, has revealed that intensive therapy during the DCCT reduces the risk of cardiovascular events by about 50% in type 1 diabetic patients 11 years after the end of the trial. Among various biochemical pathways activated under diabetic conditions, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory "hyperglycemic memory." Further, there is a growing body of evidence that AGEs play an important role in CVD in diabetes. These observations suggest that the inhibition of AGEs formation may be a promising target for therapeutic intervention in diabetic vascular complications. Therefore, in this article, we review several agents with inhibitory effects on AGEs formation and their therapeutic implications in CVD in diabetes.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Glycation End Products, Advanced; Humans; Renin-Angiotensin System

Bone marrow-derived mononuclear cells differentiate into endothelial cells in adult animals, including humans. These cells, endothelial progenitor cells (EPCs), play central roles in neovascularization in a variety of physiological and pathological processes. EPCs numbers are clinically relevant; in patients with vascular disease, EPC numbers are predictive of hard clinical endpoints and correlate with vascular health in patients without manifest atherosclerosis. EPCs express CXCR4 which allows homing to sites of neovascularization. The homing signal released by the target tissues is SDF-1 which is the ligand for CXCR4. With release of SDF-1 and reversal of the marrow/periphery gradient, EPCs are mobilized to the periphery where they are recruited to SDF-1 expressing tissues. The SDF-1/CXCR4 axis is the final common pathway for EPC mobilization by hypoxia, angiogenic peptides and G-CSF. Expression of SDF-1 in target tissues and CXCR4 in EPCs as well as angiogenic cytokines such as VEGF are regulated by hypoxia inducible factor-1 alpha (HIF-1 alpha). This paper discusses evidence suggesting that depressed HIF-1 alpha-mediated gene programming is the most fundamental of all cardiovascular risk factors and discusses the manipulation of this system with existing drugs such as cobalt or hydralazine. By stabilizing HIF-1 alpha protein, these compounds will enhance EPC mobilization and function, thereby improving cardiovascular health overall. This paper discusses why previous studies with EPC transplantation or mobilization with G-CSF have had negative results and proposes the use of Cobalt and Hydralazine to enhance EPC function to overcome the dysfunctional EPC phenotype that is seen in patients with vascular disease or cardiovascular risk factors.

Topics: Angiogenic Proteins; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cell Hypoxia; Cell Movement; Chemokine CXCL12; Cobalt; Endothelial Cells; Gene Expression; Humans; Hydralazine; Hypoxia-Inducible Factor 1, alpha Subunit; Monocytes; Myocardial Infarction; Neovascularization, Physiologic; Oxygen; Receptors, CXCR4; Risk Factors; Signal Transduction; Stem Cell Transplantation; Stem Cells; Wound Healing

End stage kidney disease (ESKD) is associated with a 10- to 20-fold increased risk of cardiovascular mortality compared with age- and sex-matched controls without CKD. In spite of this marked increase in risk, the vast majority of cardiovascular intervention clinical trials to date have specifically excluded subjects with CKD. The aim of this paper is to critically review the recently published clinical trial evidence that cardiac outcomes in CKD patients are modified by cardiovascular risk factor interventions, including erythropoiesis stimulating agent therapy (US Normal Hematocrit, CHOIR and CREATE trials), statins (PPP, 4D and ALERT), fibrates (VA-HIT), folic acid (ASFAST, US folic acid trial, HOST), anti-oxidative stress therapy (SPACE, HOPE and ATIC), N-acetylcysteine, sevelamer (D-COR), cinacalcet (Cunningham meta-analysis), carvedilol, angiotensin converting enzyme inhibitor (FOSIDIAL), telmisartan, aspirin (HOT study re-analysis) and multidisciplinary multiple cardiovascular risk factor intervention clinics (LANDMARK). Although none of these studies could be considered conclusive, the negative trials to date should raise significant concerns about the heavy reliance of current clinical practice guidelines on extrapolation of findings from cardiovascular intervention trials in the general population. It may be that cardiovascular disease in dialysis populations is less amenable to intervention, either because of the advanced stage of CKD or because the pathogenesis of cardiovascular disease in CKD patients is different to that in the general population. Further large, well-conducted, multi-centre randomised controlled trials in this area are urgently required.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Hematologic Agents; Humans; Kidney Failure, Chronic; Risk Factors

Cardiovascular risk prediction relies on classical risk factors such as age, gender, lipids, hypertension, smoking and diabetes. Although the value of such scales of risk is high for populations, its value for individual is reduced and too much influenced by non-modifiable risk factors (age and gender). Biomarkers of risk have been deceiving and genome wide scan approach is too recent. Target organ damage may help in selecting patients at high risk and in determining intervention. Aortic pulse wave velocity, an index of aortic stiffness, has been widely validated as providing additional risk predictions beyond and above classical risk factors, and has now entered into official guidelines. Many interventions (dietary, behaviour, drug treatment) were shown to influence arterial stiffness positively, but little evidence of a direct effect of intervention on arterial stiffness independent of blood pressure is available. New pharmacological targets and new drugs need to be identified. To become a surrogate endpoint for drug development, there is a need to demonstrate that regression arterial stiffness is associated with improved outcome. In parallel to this demonstration, points to be improved are the homogenization and spreading of the technique of measurement, the establishment of a reference value database.

Topics: Animals; Arteries; Blood Flow Velocity; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Carotid Arteries; Drug Design; Femoral Artery; Humans; Prognosis; Pulse; Risk Factors

Genome-wide gene-expression data from DNA-microarray technology and molecular-network data from computational text-mining have led to a paradigm shift in biological research. However, interpretation of the huge amount of data is a bottleneck. We have developed an informatics system, which we refer to as bioSpace Explorer, that can extract pathways and molecules of interest from genome-wide data and show the mutual relationships among these pathways and molecules. Differentiation of 3T3-L1 cells into adipocytes and the action of a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist or alpha-linolenic acid on this process was analyzed with bioSpace Explorer. The results suggested a biological basis for adipocyte differentiation and a strategy to enhance lipid oxidation in adipocytes. Clustered changes of molecules were apparent in the insulin, Wnt, and PPARgamma signaling pathways and in the lipogenesis, lipid oxidation, and lipid transport pathways during cell differentiation. A PPARgamma agonist enhanced lipid oxidation in adipocytes and alpha-linolenic acid gave similar results to the PPARgamma agonist. An analysis of sex hormone and thyroid hormone, in addition to PPARgamma signaling, suggested that these molecules are important for enhancement of lipid oxidation in adipocytes. The results indicate the utility of bioSpace Explorer for biological research on genome-wide molecular networks.

Topics: 3T3-L1 Cells; Adipocytes; alpha-Linolenic Acid; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cell Differentiation; Computational Biology; Databases, Genetic; Gene Expression Profiling; Gene Regulatory Networks; Humans; Lipid Metabolism; Mice; Oligonucleotide Array Sequence Analysis; Oxidation-Reduction; Pharmacogenetics; PPAR gamma; Signal Transduction

The most important strategies in pharmacogenomics are gene expression profiling and the network analysis of human disease models. We have previously discovered novel drug target candidates in cardiovascular diseases through investigations of these pharmacogenomics. The significant induction of S100C mRNA and protein expression was detected in the rat pulmonary hypertension and myocardial infarction model. We also found increased taurine in hypoxia, a calcium-associated cytoprotective compound, to suppress the hypoxia-induced S100C gene expression and vascular remodeling. These results suggest that S100C may be one of the potential novel drug targets in hypoxic or ischemic diseases. Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage causes cerebral ischemia and infarction. Using a DNA microarray, a prominant upregulation of heme oxygenase-1 (HO-1) and heat shock protein (HSP) 72 mRNAs were observed in the basilar artery of a murine vasospasm model. Antisense HO-1 and HSP 72 oligodeoxynucleotide inhibited HO-1 and HSP 72 induction, respectively, and significantly aggravated cerebral vasospasm. Moreover, we have also developed a unique heart failure model in zebrafish and identified several candidate genes as novel drug targets. These results suggest that pharmacogenomic network analysis has the potential to bridge the gap between in vitro and in vivo studies and could define strategies for identifying novel drug targets in various cardiovascular diseases.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Drug Evaluation, Preclinical; Gene Expression Profiling; Gene Regulatory Networks; Genetic Therapy; Heart Failure; Heme Oxygenase-1; HSP72 Heat-Shock Proteins; Humans; Hypertension, Pulmonary; Pharmacogenetics; Rats; S100 Proteins; Vasospasm, Intracranial; Zebrafish

We assessed the outcomes in diabetic patients undergoing percutaneous coronary intervention (PCI) using sirolimus-eluting stents (SES) as a function of treatment with glycoprotein (GP) IIb/IIIa inhibitors.. Of 551 diabetic patients treated with a SES in nine trials (RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS, REALITY, SVELTE, DIRECT, SIRIUS 2.25, and SIRIUS 4.0), 187 patients (33.9%) were administered GP IIb/IIIa inhibitors during PCI. GP IIb/IIIa blockade was associated with lower rates of myocardial infarction (MI) at 30 days (1.1% vs. 3.3%, P = 0.12) and at 1 year (1.1% vs. 4.7%, P = 0.04), and composite endpoint of cardiac death/MI at 1 year (2.2% vs. 6.2%, P = 0.05). Benefit from GP IIb/IIIa inhibitors was confined to 128 insulin-treated diabetics who had remarkable reduction in MI (0.0% vs. 6.3%, P = 0.04) and cardiac death/MI at 30 days (0.0% vs. 7.6%, P = 0.05) and at 1-year (0.0% vs. 13.4%, P = 0.01 and 0.0% vs. 15.7%, P = 0.0005, respectively). When treated with GP IIb/IIIa inhibitors, insulin-requiring diabetics had similar rates of 1-year death/MI when compared with the nondiabetic patients (0% vs. 4.7%, P = 0.13, respectively). There were no significant differences in outcomes as a function of GP IIb/IIIa blockade in diabetics not treated with insulin.. In this analysis, outcomes of insulin requiring diabetic patients undergoing PCI with SES were considerably improved with adjunctive GP IIb/IIIa inhibitors by decreasing the rates of MI and composite endpoint of cardiac death/MI.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Cardiovascular Diseases; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus, Type 1; Drug-Eluting Stents; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Proportional Hazards Models; Risk Assessment; Sirolimus; Time Factors; Treatment Outcome

There is a large inter-patient variability concerning the response to drug therapy and a great interest for determining the causes of this variability. This review takes into discussion some aspects of cardiovascular drugs metabolism and transport, pointing out the effects of genetic variation. Isoenyzmes belonging to the Cytochrome P450 super family have an important role in cardiovascular drug metabolism, namely CYP 1A2; CYP 3A; CYP 2C19; CYP2C9; CYP 2D6, involved in the oxidative phase and also N-acetyltransferase 2, involved in the conjungative phase of the metabolism. P-glycoprotein is implied in cardiovascular drug transport. Polymorphisms of those enzymes and transport protein result in different phenotypes, that is the case of CYP isoenyzmes with abolished, low or increased activity and in the case of N-acetyltransferase 2, slow, intermediate and rapid acetylator phenotypes. There is hope that, in the future, a more individualized treatment of a certain disease, with minimum adverse effects and a maximum therapeutic effect, will be available, by means of genetic testing.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cytochrome P-450 Enzyme System; Humans; Metabolic Detoxication, Phase I; Metabolic Detoxication, Phase II; Pharmacogenetics

The customary interpretation of active-controlled noninferiority trials is founded on a number of unverifiable assumptions. These assumptions can be circumvented, and the semantic and statistic interpretation of the trials placed on a more rational foundation, if treatment comparisons are analyzed from a Bayesian perspective. In conclusion, the resultant probabilistic measures thereby render the meaning of noninferiority more transparent and clinically relevant.

Topics: Bayes Theorem; Cardiovascular Agents; Cardiovascular Diseases; Data Interpretation, Statistical; Endpoint Determination; Humans; Likelihood Functions; Odds Ratio; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

The important role of the vascular endothelium in cardiovascular health is increasingly recognized. However, mature endothelial cells possess limited regenerative capacity. There is therefore much interest in circulating endothelial progenitor cells (EPCs) among the scientific community, especially into their purported role in maintenance of endothelial integrity and function, as well as postnatal neovascularization. It has been suggested that these cells might not only be responsible for the continuous recovery of the endothelium after injury/damage, but also might take part in angiogenesis, giving the hope of new treatment opportunities. Indeed, there is accumulating evidence showing reduced availability and impaired EPC function in the presence of both cardiovascular disease and associated comorbid risk factors. Thus, many studies into the potential for use of EPCs in the clinical setting are being undertaken. The goal of this review article is to provide an overview of data relevant to the clinical role of EPCs and perspectives for treatment of cardiovascular disorders.

Topics: Aging; Animals; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Endothelial Cells; Humans; Neovascularization, Physiologic; Risk Factors; Stem Cell Transplantation; Stem Cells; Treatment Outcome

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Carrier Proteins; Drug Therapy; Humans; Informatics; Lung Diseases; Neoplasms; Pharmaceutical Preparations; Pharmacogenetics; Platelet Aggregation Inhibitors; Polymorphism, Single Nucleotide; Substance-Related Disorders

Percutaneous intervention using balloon angioplasty accompanied by stent implantation has become the predominant procedure to treat occlusive coronary and peripheral vascular disease. Unfortunately, restenosis associated with intimal hyperplasia and arterial remodeling at the stented site occurs within 6 months in 20 to 30% of cases. To address this problem, the concept of utilizing a stent as the vehicle to deliver agents locally and limit the overexuberant tissue response related to its placement has been developed. Targeting excess arterial wall smooth muscle cell proliferation, preclinical studies have demonstrated the efficacy of two drugs, paclitaxel and rapamycin, in both in vitro and in vivo animal studies. Early, as well as large, randomized clinical studies using polymer-coated, drug-eluting stents have clearly demonstrated a significant and dramatic efficacy in reducing restenosis rates and improving clinical outcomes compared with the use of the bare stent for revascularization procedures. Despite the low incidence of late thrombosis associated with the rapamycin- and paclitaxel-eluting stents, some concerns remain (such as the need for sustained anticoagulant therapy), providing the impetus for developing coated stents that promote rather than inhibit endothelial healing in order to limit the restenotic response.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Coronary Restenosis; Drug Design; Drug Evaluation, Preclinical; Humans; Models, Biological; Randomized Controlled Trials as Topic; Stents

Integrins are the principle mediators of molecular dialog between a cell and its extracellular matrix environment. The unique combinations of integrin subunits determine which extracellular matrix molecules are recognized by a cell. Recent studies have demonstrated that remodeling in heart and vasculature is linked to alterations in extracellular matrix and integrin expression. The roles of integrins in controlling cellular behavior have made these molecules highly attractive drug targets. New insights into mechanisms whereby the extracellular matrix takes part in the control of smooth muscle cell proliferation and cardiac growth suggest a number of putative targets for future therapies that can be applied to increase plaque stability, prevent the clinical consequences of atherosclerosis and improve outcomes after interventional procedures such as cardiac transplantation. Therapeutic candidates include antibodies, cyclic peptides, peptidomimetics and small molecules. The integrin inhibitors Integrilin and ReoPro have been approved as blood thinners in cardiovascular disease, and newer agents are undergoing testing. Although integrin function is important in the cardiovascular system, there are wide gaps in knowledge. In this review, we discuss the primary mechanisms of action and signaling of integrins in the cardiac and vascular system in normal and pathological states, as well as therapeutic strategies for targeting these molecules in the cardiovascular system.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Endothelium, Vascular; Extracellular Matrix; Humans; Integrins; Randomized Controlled Trials as Topic; Signal Transduction

LDL-lowering therapies, predominantly involving statins, have been shown to significantly reduce cardiovascular events in asymptomatic subjects as well as in subjects with clinically established atherosclerotic cardiovascular disease. However, despite statin therapy, significant number of cardiovascular events continue to occur indicating the need for additional targets for atherosclerosis management. A number of pre-clinical studies have suggested that several HDL based therapies have the potential to stabilize or regress atherosclerosis consistent with epidemiologic evidence of an inverse relationship between coronary heart disease and HDL cholesterol levels. One such therapeutic approach involves direct infusion of HDL or HDL like molecules for rapid remodeling and stabilization of atherosclerosis. Pre-clinical and proof of concept type preliminary clinical studies suggest the feasibility and potential efficacy of this emerging new therapeutic paradigm.

Topics: Animals; Apolipoprotein A-I; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Humans; Infusions, Intravenous; Lipoproteins, HDL; Rupture, Spontaneous; Treatment Outcome

Atherosclerosis is currently viewed as an inflammatory disease in which the initiation and progression of the atherosclerotic plaque towards a rupture prone, unstable plaque is driven by leukocyte recruitment mediated by various inflammatory mediators. Recently, interest in chemotactic cytokines or chemokines with regard to atherosclerosis has been growing as chemokines mediate the influx of leukocytes that is typical of atherothrombosis. The activity of the majority of chemokines is overlapping and chemokines are not only produced by the various cellular constituents of the atherosclerotic plaque but also by activated platelets. Consequently, the direct influence of individual chemokines on plaque destabilisation and rupture is widespread and rather unclear. Experimental research has already established the role of a number of chemokines in advanced atherosclerosis. Nevertheless, given the complexity and size of the chemokine family, further screening of cardiovascular disease for chemokine level and genetic polymorphisms for chemokines will be warranted as the search for viable biomarkers of plaque destabilization as well as novel therapeutic targets for specific atheroregressive therapeutic compounds is ongoing. With regard to the latter, clinical trials with specific chemokine inhibitory strategies, like chemokine receptor antagonists, are already underway in other inflammatory disorders. Summarizing, chemokine inhibition likely constitutes an important therapeutic option next to already established drugs in the management of cardiovascular disease.

Topics: Animals; Atherosclerosis; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Chemokines; Disease Progression; Drug Design; Humans; Receptors, Chemokine; Rupture, Spontaneous

Risk factors for atherosclerotic cardiovascular disease (CVD) are highly co-prevalent but poorly identified and treated. The Screening for Heart Attack Prevention and Education (SHAPE) Task Force from the Association for Eradication of Heart Attack (AEHA) has recently proposed a new strategy that recommends screening for subclinical atherosclerosis and implementing aggressive treatment of "vulnerable patients". The Task Force has also envisioned future developments that may shift mass screening strategies to mass prophylactic therapy. The "Polypill" concept, introduced by Wald and Law suggests a combination of statin, low-dose antihypertensives, aspirin and folic acid, in a single pill, taken prophylactically by high risk population can cut CVD event rates by as much as 80%. In this communication, we review the challenges and promises of such a strategy. "Polypill" is but one of an astronomical number of possible multiconstituent pills (MCCP). Attractive as the MCCP concept is, it lacks evidence from randomized controlled trials, and begs numerous questions about the credibility of the concept, the design and synthesis of such complex pills, pharmacokinetics, pharmacodynamics, bioequivalence, "class" vs. unique properties, interactions, evidence of clinical efficacy and safety, regulatory approval, post-marketing surveillance, prescription vs. over-the-counter use, responsibility for initiating and monitoring therapy, patient education, counterfeiting and importation, reimbursement, advertisement, patent protection, commercial viability, etc. If these issues are favorably addressed, MCCP stand to dramatically change the manner in which CVD is prevented particularly in developing societies. Notwithstanding, assuming low commercial interests, realizing the promises of MCCP will demand serious attention from national public health policymakers. The clinical and regulatory implications of population-based secondary prevention (which rely on a different evidence base, and in which entirely different risk-benefit and cost-effectiveness considerations apply) remain issues for active debate.

Topics: Antihypertensive Agents; Aspirin; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Drug Therapy; Folic Acid; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Platelet Aggregation Inhibitors; Primary Prevention; Vitamin B Complex

This paper will review the role of the sympathetic nervous system in the pathogenesis of the metabolic syndrome as well as its importance as target of non-pharmacologic and pharmacologic treatment.. Several indices of adrenergic drive, such as plasma norepinephrine, norepinephrine spillover from adrenergic nerve terminals and efferent postganglionic muscle sympathetic nerve traffic, have all shown an increase in the different conditions clustering in metabolic syndrome, such as obesity, hypertension and insulin resistance state. This increase: 1) appears to be potentiated in the metabolic syndrome; and 2) contributes to a large extent at the cardiovascular structural and functional alterations typical of the disease. Based on this evidence, non-pharmacologic life-style interventions as well as drug treatment procedures used in the therapeutic approach to the metabolic syndrome should be aimed at exerting not only favourable haemodynamic and metabolic effects but also pronounced sympathoinhibition.. The data reviewed in this paper strongly support the relevance of the sympathetic nervous system in the pathogenesis of the metabolic syndrome and the importance of the sympathomodulation as a specific aim of therapeutic intervention.

Topics: Adrenergic Fibers; Blood Pressure; Blood Vessels; Cardiomegaly; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Health Behavior; Humans; Hypertension; Life Style; Metabolic Syndrome; Obesity; Risk Factors; Sympathetic Nervous System

Despite their presence in many tissues and their potential implication in various disease states, low-voltage activated T-type calcium channels (T-channels) have only recently become targets of interest. Unfortunately, the lack of selective T-channel blockers has hampered further characterisation of these channels. The recent availability of cloned T-channels, the Ca(V)3 proteins, facilitates identification of novel T-channel blockers. Also, studies performed in knockout animals have fostered novel interest. Selective inhibition of T-channels may have clinical importance in cardiovascular diseases, some forms of epilepsy, sleep disorders, pain and possibly cancer. This review focuses on novel research approaches to discover potent and selective T-channel modulators. These molecules may be potential drugs for treating human diseases, as well as important tools to decipher the physiological role of these channels.

Topics: Analgesics; Animals; Anticonvulsants; Arachidonic Acids; Autistic Disorder; Calcium; Calcium Channel Blockers; Calcium Channels, T-Type; Cardiovascular Agents; Cardiovascular Diseases; Cations; Drug Design; Endocannabinoids; Epilepsy; Humans; Mice; Mice, Knockout; Polyunsaturated Alkamides; Scorpion Venoms; Sleep Disorders, Intrinsic

The development of personalized medicine will require improved knowledge of biological variability, particularly concerning the important impact of each individual's genetic makeup. A five-step strategy can be followed when trying to identify genes and gene products involved in differential responses to cardiovascular drugs: 1) Pharmacokinetic-related genes and phenotypes; (2) Pharmacodynamic targets, genes and products; (3) Cardiovascular diseases and risks depending on specific or large metabolic cycles; (4) Physiological variations of previously identified genes and proteins; (5) Environmental influences on them. After summarizing the most well known genes involved in drug metabolism, we used statins as an example. In addition to their economic impact, statins are generally considered to be of significant importance in terms of public health. Individuals respond differently to these drugs depending on multiple polymorphisms. Applying a pharmacoproteomic strategy, it is important to use available information on peptides, proteins and metabolites, generally gene products, in each of the five steps. A profiling approach dealing with genomics as well as proteomics is useful. In conclusion, the ever growing volume of available data will require an organized interpretation of variations in DNA and mRNA as well as proteins, both on the individual and population level.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pharmacogenetics; Proteomics

The cardiovascular complications of Marfan syndrome (MFS) remain the primary source of morbidity and mortality in affected patients. Over the last decade, the underlying pathogenesis of these cardiovascular abnormalities has been the focus of much research. Such research has shed light on the potential role of several novel medical therapies and their ability to prevent cardiovascular disease progression. This paper summarizes the research underlying new medical therapies and provides a review of the scientific foundation underlying all current medical therapies used for prevention of cardiovascular disease in patients with MFS, including beta-adrenoceptor antagonists, calcium channel antagonists, ACE inhibitors, and angiotensin receptor antagonists.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Aortic Diseases; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Humans; Marfan Syndrome

The use of cardiovascular medications can have a variety of neuropsychiatric consequences. Many cardiovascular agents cause higher rates of fatigue and sedation than placebo, and case reports of medication-induced mood syndromes, psychosis, and cognitive disturbances exist for many cardiovascular drugs. Depression has been associated with P3-blockers, methyldopa, and reserpine, but more recent syntheses of the data have suggested that these associations are much weaker than originally believed. Though low cholesterol levels have been associated with depression and suicide, lipid-lowering agents have not been associated with these adverse effects. Finally, cardiovascular medications may have beneficial neuropsychiatric consequences; for example, the use of clonidine in patients with attention deficit-hyperactivity disorder, the use of prazosin for patients with post-traumatic stress disorder; and the use of propranolol for performance anxiety and akathisia.

Topics: Adrenergic beta-Antagonists; Anxiety Disorders; Attention Deficit Disorder with Hyperactivity; Cardiovascular Agents; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mental Disorders; Mood Disorders; Stress Disorders, Post-Traumatic

Medical management of patients with abdominal aortic aneurysm (AAA) is required for several different reasons. Since these patients have an increased risk of cardiovascular death therapy to reduce cardiovascular events is essential. Treatment is in line with the medical management of coronary artery disease including smoking cessation, statins and anti-platelet therapy. Some of these therapies also will slow aneurysm growth. Currently there is no proven focused therapy that reduces aneurysm growth, but the emerging strategies are discussed. Medical management also is required to reduce peri-operative risks and stabilise endovascular aneurysm repair. Whilst some of the therapies targeting cardiovascular risk reduction may be helpful, other emerging strategies are discussed.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Bacterial Agents; Aortic Aneurysm, Abdominal; Aortic Rupture; Cardiovascular Agents; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Matrix Metalloproteinase Inhibitors; Perioperative Care; Practice Guidelines as Topic; Protease Inhibitors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Treatment Outcome; Vascular Surgical Procedures

1. Arteries become stiffer with increasing age and various disease states. A complete description of arterial mechanical properties in vivo is not possible, although a number of methods have been used. 2. Detailed discussion in the present review is limited to pulse wave velocity and estimates of central waveform morphology derived by the application of a generalized arterial transfer function. 3. Many drugs affect these parameters, either increasing or decreasing apparent stiffness. However, the extent to which changes reflect changes in blood pressure rather than more fundamental vessel wall properties remains unclear. Similarly, it is as yet unknown whether determining the need for, or assessing the effectiveness of, drug treatment by the assessment of arterial mechanical properties will offer any advantage and the usefulness of these techniques as routine clinical tools remains to be established.

Topics: Arteries; Biomechanical Phenomena; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Compliance; Drug Evaluation, Preclinical; Humans; Pulsatile Flow; Research Design

Raised plasma fibrinogen levels are associated with an increased risk of vascular events. This may be mediated by adverse effects of fibrinogen on plasma viscosity, coagulation, platelet activity, inflammation and atherogenesis. However, there is as yet no drug that specifically lowers plasma fibrinogen levels on a long-term basis. Thus, we do not have intervention trials demonstrating that lowering plasma fibrinogen levels will result in a decreased risk of vascular events. However, such a trial may never happen unless a specific agent is discovered or designed. Several drugs that are used in vascular disease prevention (e.g. lipid lowering agents and antihypertensives) may influence plasma fibrinogen levels. Whether such an additional effect accounts for variations in the benefit resulting from the use of different drugs within the same class remains to be established. The debate continues as to whether fibrinogen is just a marker of vascular risk or whether lowering its circulating levels will result in a significant decrease in clinically relevant endpoints. Whatever the case, the measurement of plasma fibrinogen levels is likely to provide a more comprehensive estimation of risk.

Topics: Biomarkers; Blood Coagulation; Cardiovascular Agents; Cardiovascular Diseases; Fibrinogen; Humans; Risk Assessment; Risk Factors; Up-Regulation

Since the first description of putative progenitor endothelial cells mobilized from bone marrow by stimuli like ischemia and cytokines, several studies in animals have confirmed their role in neovascularization of ischemic organs. In ischemic myocardium endothelial progenitor cells can prevent cardiomyocyte apoptosis, reduce remodeling and improve cardiac function. These observations led to the hypothesis of endothelial progenitor cells as possible cell-based therapy in patients by autologous transplantation in ischemic tissue or by improving peripheral circulating numbers with mobilization by cytokines. Early trials, including a randomized one, suggest that the intracoronary autologous bone marrow cell transfer after myocardial infarction exerts at least short term functional benefits. Since endothelial damage and dysfunction play a critical role in atherosclerosis disease, research interest was addressed to evaluate the role of progenitor endothelial cells in vascular endothelial layer maintenance. Opposing to local resident endothelial cells poor proliferation rate, progenitor endothelial cells regenerative capacity, homing and integration into blood vessels have been interpreted as a protective role of these cells in vascular homeostasis. Indeed, the number and function of endothelial progenitor cells relate with the progression of atherosclerosis; the accumulation of cardiovascular risk factors or an increased overall risk are inversely associated with endothelial progenitor cells number and function. Finally, recent studies have shown a role of progenitor cells numbers to predict cardiovascular events, raising endothelial progenitor cells to the podium of novel prognostic biomarker.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cell Count; Cell Culture Techniques; Cell Separation; Endothelial Cells; Endothelium, Vascular; Humans; Phenotype; Prognosis; Risk Factors; Stem Cells

Endothelial dysfunction is a well documented early phenomenon in atherosclerosis. Because it may precede structural changes and clinical manifestations, major research efforts have focused on the detection of endothelial dysfunction in humans. The utility of such tests in clinical practice critically depends on the proof of their prognostic value, their safety and reproducibility. First data supporting the prognostic impact of endothelial function have come from studies using intracoronary infusion of acetylcholine, a test clearly too invasive to be performed in asymptomatic subjects. Therefore, non-invasive techniques such as flow-mediated vasodilation of the brachial artery and strain-gauge venous plethysmography of the forearm have been developed. Numerous studies in a variety of patient populations have been performed to evaluate the prognostic value of these methods. This review summarizes the current status of endothelial dysfunction as an early parameter of atherosclerosis and its potential use in the clinical arena. The value of endothelial function as a surrogate endpoint in cardiovascular studies is critically reviewed.

Topics: Acetylcholine; Atherosclerosis; Brachial Artery; Cardiovascular Agents; Cardiovascular Diseases; Diagnostic Techniques, Cardiovascular; Endothelium, Vascular; Forearm; Humans; Plethysmography; Prognosis; Regional Blood Flow; Risk Assessment; Risk Factors; Treatment Outcome; Ultrasonography; Vasodilation; Vasodilator Agents; Veins

Knowledge about the function of endothelial nitric oxide synthase (eNOS), and its regulation in pathophysiological states has tremendously increased. It is now clear that diminished activity of nitric oxide (NO) contributes to endothelial dysfunction, which is a characteristic of impeding atherosclerosis. This review aims to summarize the available knowledge about the impact of important cardiovascular risk factors on NO production by eNOS. There are 4 principle causes of diminished NO bio-activity: decreased expression and/or activity of the eNOS enzyme, eNOS uncoupling, enhanced breakdown or scavenging of NO and impaired transmission of NO-mediated signaling events (failure of the effector mechanisms). From the analysis, it becomes clear, that several aspects of eNOS functionality have only scarcely been tested under conditions of increased (experimental) cardiovascular risk. These aspects include palmitoylation, myristoylation and phosphorylation of the eNOS enzyme. Clear is that enhanced production of reactive oxygen species (ROS) and eNOS uncoupling are relatively important causes of reduced NO-bioactivity in cardiovascular disease states. Ideally, eNOS is sufficiently expressed, produces NO sufficiently and not abundantly, does not produce superoxide and is not scavenged by ROS; the produced NO then reaches its signaling target, mainly soluble guanylyl cyclase (sGC) and elicits a cellular response. Considering which aspects of eNOS are now assessable in a clinical setting and which therapeutic measures are available, there is a great challenge ahead.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Gene Expression Regulation, Enzymologic; Guanylate Cyclase; Humans; Kidney Diseases, Cystic; Myristic Acid; Nitric Oxide; Nitric Oxide Synthase Type III; Palmitic Acid; Phosphorylation; Protein Processing, Post-Translational; Reactive Oxygen Species; Receptors, Cytoplasmic and Nuclear; Risk Factors; Signal Transduction; Soluble Guanylyl Cyclase

The aim of this chapter is to present and identify potential pharmacological targets in endothelial cell-monocyte interactions leading to vascular syndrome and involving inflammation, coagulation, vascular remodelling and thrombosis. Increasing evidence is indicating that endothelial cells play a key role in atherothombosis by their capacity to attract, bind and allow the extravasation of monocytes to sites of inflammation. Surface expression and/or activation of constituent cell adhesion molecules (for e.g. P-selectin, E-selectin, ICAM-1, and VCAM-1) on endothelial cells together with chemokines such as CXCL8 (IL-8), Platelet-activating factor (PAF), CCL2 and CCL5 (Table 1) allow the rolling, adhesion and extravasation of monocytes. This review focuses on pharmacological targets implicated in endothelial cells interactions with monocytes/macrophages in vascular disease states and on cutting edge genomic tools for the identification and characterization of such targets.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Communication; Chemokines; Endothelial Cells; Genomics; Humans; Inflammation; Intercellular Adhesion Molecule-1; Macrophages; Membrane Glycoproteins; Monocytes; P-Selectin; Platelet Activating Factor; Platelet Endothelial Cell Adhesion Molecule-1; Signal Transduction; Vascular Cell Adhesion Molecule-1

1. Oestrogen deficiency causes progressive reduction in endothelial function. Despite the benefits of hormone-replacement therapy (HRT) evident in earlier epidemiological studies, recent randomized trials of HRT for the prevention of heart disease found no overall benefit. Instead, HRT users had higher incidences of stroke and heart attack. Most women discontinue HRT because of its many side-effects and/or the increased risk of breast and uterine cancer. This has contributed to the development of selective oestrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, as alternative oestrogenic agents. 2. A SERM is a molecule that binds with high affinity to oestrogen receptors but has tissue-specific effects distinct from oestrogen, acting as an oestrogen agonist in some tissues and as an antagonist in others. Clinical and animal studies suggest multiple cardiovascular effects of SERMs. For example, raloxifene lowers serum levels of cholesterol and homocysteine, attenuates oxidation of low-density lipoprotein, inhibits endothelial-leucocyte interaction, improves endothelial function and reduces vascular smooth muscle tone. 3. Available evidence suggests that raloxifene and tamoxifen are capable of acting directly on both endothelial cells and the underlying vascular smooth muscle cells and cause a multitude of favourable modifications of the vascular wall, which jointly contribute to improved local blood flow. The outcome of the Raloxifene Use for the Heart (RUTH) trial will determine whether raloxifene, currently approved for the treatment of post-menopausal osteoporosis, could substitute for HRT in alleviating cardiovascular symptoms in post-menopausal women.

Topics: Animals; Atherosclerosis; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Circulation; Collateral Circulation; Coronary Circulation; Endothelium, Vascular; Estrogen Replacement Therapy; Female; Humans; Nitric Oxide; Pulmonary Circulation; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Vasodilation

Cannabinoid drugs exert their effects primarily through activation of cannabinoid CB1 and CB2 receptors. Both CB1 and CB2 receptors have been implicated in a number of cardiovascular processes, including vasodilation, cardiac protection, modulation of the baroreceptor reflex in the control of systolic blood pressure, and inhibition of endothelial inflammation and the progress of atherosclerosis in a murine model. These effects are mainly mediated through central and peripheral nervous system CB1 receptors, vascular CB1 receptors and immune cell CB2 receptors. Relevant cellular effects include: the inhibition of neurotransmitter release in the nucleus tractus solitarius and in peripheral adrenergic neurons; regulation of NOS activity in vascular beds; inhibition of vascular smooth muscle cell excitability; regulation of endothelial cell migration and proliferation; and effects on immune cell proliferation, activation, and inflammatory functions. We review the pre-clinical evidence for beneficial effects of cannabinoid drugs in a range of vascular and cardiovascular pathologies. We also discuss the clinically relevant potential of cannabinoids.

Topics: Animals; Anti-Obesity Agents; Cannabinoid Receptor Modulators; Cannabinoids; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Risk Factors; Treatment Outcome

After Murry et al (Circulation 1986;74:1124) described ischemic preconditioning in 1986, numerous pharmacologic agents with effects simulating ischemic preconditioning have been identified. With the exception of beta-blockers, most such agents have no proven clinical benefit in the setting of myocardial ischemia. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been consistently demonstrated to reduce myocardial injury, morbidity, and mortality in the clinical setting, both perioperatively and after percutaneous coronary intervention. Although the precise mechanism underlying their additional protective effect is not yet fully understood, it appears to be immediate in action and independent of cholesterol lowering. Experimental data from several animal models of ischemia and reperfusion have demonstrated an infarct size reduction with prior statin administration. At the cellular level, statins activate the phosphoinositol-3 kinase and Akt signaling cascade. Statins also increase expression and activity of endothelial nitric oxide synthase, inducible nitric oxide synthase, ecto-5'-nucleotidase, cyclooxygenase-2, and other prostaglandin synthesis pathway enzymes. However, when given by oral route to animals, relatively high dose of statins is needed to exert maximal protective effect. Understanding the underlying mechanism may enable to maximize the protective effect by using drug combination with synergistic activity and to avoid medications that may interfere with the protective effect of statins (ie, selective and nonselective cyclooxygenase-2 inhibition). Future clinical applications include preoperative and periprocedural risk reduction.

Topics: Angioplasty, Balloon, Coronary; Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemic Preconditioning, Myocardial; Surgical Procedures, Operative

Cardiac disorders complicate less than 1% of all pregnancies. Physiologic changes in pregnancy may mimic heart disease. In order to differentiate these adaptations from pathologic conditions, an in-depth knowledge of cardiovascular physiology is mandatory. A comprehensive history, physical examination, electrocardiogram, chest radiograph, and echocardiogram are sufficient in most cases to confirm the diagnosis. Care of women with cardiac disease begins with preconception counseling. Severe lesions should be taken care of prior to contemplating pregnancy. Management principles for pregnant women are similar to those for the non-pregnant state. A team approach comprised of a maternal fetal medicine specialist, cardiologist, neonatologist, and anesthesiologist is essential to assure optimal outcome for both the mother and the fetus. Although fetal heart disease complicates only a small percentage of pregnancies, congenital heart disease causes more neonatal morbidity and mortality than any other congenital malformation. Unfortunately, screening approaches for fetal heart disease continue to miss a large percentage of cases. This weakness in fetal screening has important clinical implications, because the prenatal detection and diagnosis of congenital heart disease may improve the outcome for many of these fetal patients. In fact, simply the detection of major heart disease prenatally can improve neonatal outcome by avoiding discharge to home of neonates with ductal-dependent congenital heart disease. Fortunately, recent advances in screening techniques, an increased ability to change the prenatal natural history of many forms of fetal heart disease, and an increasing recognition of the importance of a multidisciplinary, team approach to the management of pregnancies complicated with fetal heart disease, together promise to improve the outcome of the fetus with congenital heart disease.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Delivery, Obstetric; Female; Fetal Diseases; Humans; Pregnancy; Pregnancy Complications, Cardiovascular; Prenatal Diagnosis; Risk Factors

Endothelial dysfunction is universal in diabetes, being intimately involved with the development of cardiovascular disease. The pathogenesis of endothelial dysfunction in diabetes is complex. It is initially related to the effects of fatty acids and insulin resistance on 'uncoupling' of both endothelial nitric oxide synthase activity and mitochondrial function. Oxidative stress activates protein kinase C (PKC), polyol, hexosamine and nuclear factor kappa B pathways, thereby aggravating endothelial dysfunction. Improvements in endothelial function in the peripheral circulation in diabetes have been demonstrated with monotherapies, including statins, fibrates, angiotensin-converting enzyme (ACE) inhibitors, metformin and fish oils. These observations are supported by large clinical end point trials. Other studies show benefits with certain antioxidants, L-arginine, folate, PKC-inhibitors, peroxisome proliferator activated receptor (PPAR)-alpha and -gamma agonists and phosphodiesterase (PDE-5) inhibitors. However, the benefits of these agents remain to be shown in clinical end point trials. Combination treatments, for example, statins plus ACE inhibitors and statins plus fibrates, have also been demonstrated to have additive benefits on endothelial function in diabetes, but there are no clinical outcome data to date. Measurement of endothelial dysfunction in cardiovascular research can provide fresh opportunities for exploring the mechanism of benefit of new therapeutic regimens and for planning and designing large clinical trials.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Endothelium, Vascular; Humans; Hypoglycemic Agents; Signal Transduction; Treatment Outcome

The structural and functional integrity of the vascular endothelium plays a critical role in vascular homeostasis. Insulin resistance, an important risk factor for cardiovascular disease, is thought to promote atherosclerosis through a reciprocal relationship with endothelial dysfunction. In health, cumulative damage to endothelial cells incurred by exposure to risk factors is mitigated by endogenous reparative processes. Disruption of the balance between endothelial damage and repair may mediate atherosclerotic progression. Bone marrow-derived 'endothelial progenitor cells' (EPC) have been identified as significant contributors to endogenous vascular repair. Insulin resistance is associated with a spectrum of biochemical abnormalities which have the potential to reduce the availability of EPCs and diminish their capacity for vascular repair. Many lifestyle and pharmacological interventions which improve insulin resistance also increase the numbers and functionality of EPCs. Cell-based therapies may also hold promise for the prevention and treatment of cardiovascular disease.

Topics: Animals; Apoptosis; Cardiovascular Agents; Cardiovascular Diseases; Cell Proliferation; Diabetes Complications; Endothelium, Vascular; Humans; Hypoglycemic Agents; Insulin Resistance; Life Style; Regeneration; Risk Factors; Stem Cell Transplantation; Stem Cells

Topics: Alcohol Drinking; Cardiac Rehabilitation; Cardiovascular Agents; Cardiovascular Diseases; Counseling; Diet; Exercise; Family Practice; Humans; Life Style; Practice Guidelines as Topic; Practice Patterns, Physicians'; Quality of Health Care; Smoking Cessation

Peripheral arterial disease (PAD) encompasses the vascular diseases caused primarily by atherosclerosis and thromboembolic pathophysiological processes that alter the normal structure and function of the aorta, its visceral arterial branches and the arteries of the upper and lower extremities. PAD is associated with an increased risk for cardiovascular morbidity and mortality. The goals for pharmacological therapy in PAD should focus on reducing cardiovascular risk, improving walking distance and preventing critical limb ischaemia. Exercise training plays a key role in the therapeutic assessment, as well stopping smoking. Antiplatelet therapy (aspirin) should be given to every PAD patient if there are no contraindications. Neither their combination nor anticoagulant therapy has shown additional benefit in PAD patients. Several pharmacological agents have been developed to improve the functional state of the claudicant and to relieve the symptoms. Many studied drugs have shown either no, a small or a potential benefit. With future development of new drugs for PAD, there is an absolute need for very strict well-designed protocols in order to evaluate the claudication distance, the progression of the disease and the reduction in cardiovascular morbidity and mortality. New developments should focus on improvement of endothelial function, vascular repair and enhancement of collateral circulation.

Topics: Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Exercise Therapy; Fibrinolytic Agents; Humans; Hypolipidemic Agents; Intermittent Claudication; Life Style; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Risk Factors; Smoking Cessation; Treatment Outcome

Sudden cardiac death is a major clinical problem, causing 300,000 to 400,000 deaths annually and 63% of all cardiac deaths. Despite the overall decrease in cardiovascular mortality, the proportion of cardiovascular death from sudden cardiac death has remained constant. Survival rates among patients who have out-of-hospital cardiac arrest vary from 5% to 18%, depending on the presenting rhythm. The latest guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care published by the American Heart Association include substantial changes to the algorithms for basic life support and advanced cardiovascular life support. For unwitnessed cardiac arrest, immediate defibrillation of the patient is no longer recommended. Rather, 2 minutes of CPR before defibrillation is now recommended. People in cardiac arrest should no longer receive stacked shocks. The compression-ventilation ratio has been changed from 15:2 to 30:2. This article is a contemporary review of the management of CPR and emergency cardiovascular care. It examines current practice and data supporting use of CPR, along with changes in the management of sudden cardiac death.

Topics: Cardiopulmonary Resuscitation; Cardiovascular Agents; Cardiovascular Diseases; Electric Countershock; Emergency Medical Services; Heart Arrest; Humans

Topics: Arrhythmias, Cardiac; Atrial Fibrillation; Cardiovascular Agents; Cardiovascular Diseases; Female; Humans; Male; Myocardial Ischemia

This article discusses the use of nanotechnology in drug delivery approaches. Magnetic nanotechnology is finding wide applications in medicine, most notably in MRI and magnetic separation. The impedance biosensor is expected to find applications in monitoring cytokines in cancer, bone turnover markers in osteoporosis, and understanding neural-degenerative diseases.

Topics: Animals; Antineoplastic Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Carriers; Drug Delivery Systems; Humans; Nanomedicine; Nanostructures; Neoplasms

Tetrahydrobiopterin is the reduced unconjugated pterin that serves as an essential cofactor for the normal enzymatic function of the aromatic amino acid hydroxylases and for the nitric oxide synthases (NOS). Its role in the latter biochemistry is being increasing appreciated, as depletion or oxidation of BH4 results in a condition of NOS uncoupling, resulting in a nitroso-oxidative imbalance. Recent experimental studies support an important pathophysiologic role of BH4 deficiency as well as the therapeutic potential of BH4 repletion for hypertension, endothelial dysfunction, atherosclerosis, diabetes, cardiac hypertrophic remodeling, and heart failure. In addition to BH4, studies are also examining the potential role of folic acid therapy, because folic acid can enhance BH4 levels and the NOS coupling state. This review summarizes these recent studies focusing on the biochemistry and pharmacology of BH4 and its potential role for treating cardiovascular disease.

Topics: Animals; Biopterins; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus; Endothelium, Vascular; Folic Acid; Humans; Nitric Oxide Synthase

The Na(+)/Ca(2+) exchanger (NCX) is a bidirectional transporter that normally extrudes Ca(2+) from the cell (forward mode), but also brings Ca(2+) into the cell (reverse mode) under special conditions such as intracellular Na(+) (Na(+)(i)) accumulation or membrane depolarization. There are three mammalian NCX isoforms: NCX1 is widely expressed in the heart, kidney, brain, blood vessels, and so on; whereas the expression of NCX2 and NCX3 is limited mainly to the brain and skeletal muscle. The pharmacology of NCX inhibitors has been studied extensively since the development of KB-R7943, a prototype benzyloxyphenyl NCX inhibitor, in 1996. Currently, experiments are actively progressing with more selective inhibitors: SEA0400, SN-6, and YM-244769. Intriguingly, the inhibitory potency of benzyloxyphenyl NCX inhibitors is directly coupled to the rate of Na(+)(i)-dependent inactivation. Therefore, the benzyloxyphenyl inhibitors are apparently dormant during the forward mode under normal conditions (low Na(+)(i)), but become effective during the reverse mode under pathological conditions (high Na(+)(i)). This should be an ideal profile for calcium regulators against Na(+)(i)-related diseases, such as ischemia/reperfusion injuries, salt-dependent hypertension, and digitalis arrhythmia. Existing ion channel blockers, such as amiodarone, dronedarone, bepridil, aprindine, and cibenzoline, have been found to have an NCX inhibitory action. It is possible that this property is partly responsible for their antiarrhythmic and cardioprotective effects. This article presents the characteristics of selective and non-selective NCX inhibitors and their therapeutic potential as a new calcium regulator.

Topics: Animals; Calcium; Calcium Signaling; Cardiovascular Agents; Cardiovascular Diseases; Humans; Ion Channels; Sodium-Calcium Exchanger; Structure-Activity Relationship

Cardiovascular disease (CVD) is the most common cause of death in women but some of the challenges of management differ from those in men. This article addresses the gender-specific issues of cardiovascular management, with emphasis on ischaemic heart disease and modification of coronary risk factors. Women with ischaemic heart disease present later than men, and are therefore older and more likely to suffer from co-morbidities such as diabetes and hypertension. Proven CVD risk factors in women can be divided into those that are modifiable and those that are non-modifiable. The former include diabetes, dyslipidaemia, hypertension, smoking, obesity, sedentary lifestyle and poor nutrition; the latter include family history of heart disease and older age at presentation. It is this difference in age and general health that explains much of the variability in response to treatment. Pharmacotherapy, percutaneous intervention, surgical revascularization, and cardiac rehabilitation and disease prevention are discussed.

Topics: Cardiac Catheterization; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Coronary Artery Bypass; Dyslipidemias; Female; Health Knowledge, Attitudes, Practice; Humans; Hypertension; Life Style; Obesity; Postmenopause; Primary Prevention; Risk Factors; Sex Factors; Smoking; Stress, Psychological; United States; Women's Health

Recent trials of patients with cardiovascular disease (CVD) have provided a wealth of data regarding diagnosis, risk factors, and treatment. Aggressive risk factor management has been shown to improve patient survival, reduce recurrent events and the need for interventional procedures, and improve the quality of life in patients with known CVD. There have been impressive reductions in blood pressure and low-density lipoprotein cholesterol levels, and improved diabetes control. Medical therapy with options such as angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and aspirin has been shown to have positive effects. Patients in current trials are more likely to be receiving appropriate treatment upon study entry than were patients in older trials. Changes in the risk profile of high-risk patients have reduced the overall rates of cardiovascular events and will continue to affect outcomes in randomized clinical trials. Such changes should be considered in the design of new clinical trials and in the interpretation of current data.

Topics: American Heart Association; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Anticholesteremic Agents; Antihypertensive Agents; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Cholesterol, LDL; Clinical Trials as Topic; Humans; Hypercholesterolemia; Hypertension; Models, Cardiovascular; Odds Ratio; Patient Selection; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Research Design; Risk Assessment; Risk Factors; United States

To examine the appropriateness of cardiovascular (CV) medication prescribing of patients admitted to a geriatric psychiatry ward. Secondary aims included examining: 1) if differences in CV medication prescribing existed between admission and discharge and 2) if differences in CV medication prescribing existed between patients with and without dementia.. Cross-sectional study.. Inpatient geriatric psychiatry unit within a regional medical center.. 197 patients admitted between June 2005 and May 2006.. Changes in CV medication prescribing from admission to discharge.. On admission, the percent of patients receiving appropriate CV medications for general CV prevention, atrial fibrillation, coronary-artery disease, and heart failure ranged from 33% to 56%. With the exception of the treatment of heart failure, no significant improvements in appropriate CV medication prescribing were noted at the time of discharge. No differences in CV medication prescribing were found between patients with and without dementia.. Despite the known benefits of numerous CV medications in older adults, many patients admitted to a geriatric psychiatry ward were not prescribed optimal pharmacotherapeutic regimens on admission or had their medications changed by the time of discharge.

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Cross-Sectional Studies; Dementia; Drug Monitoring; Drug Utilization; Female; Humans; Male; North Carolina; Patient Admission; Patient Discharge; Practice Patterns, Physicians'; Psychiatric Department, Hospital

The small GTPase Rho and its downstream effector Rho-kinase contribute to agonist-induced vascular contraction via Ca2+ sensitization. Reasonably selective pharmacological inhibitors of these proteins have been developed and are now widely used experimentally to investigate the role of this signaling pathway in vascular function. Rho and Rho-kinase have attracted increasing clinical interest as a result of emerging evidence for their roles in the pathogenesis of several cardiovascular disorders, including hypertension, coronary and cerebral vasospasm, atherosclerosis and diabetes, and are now considered important future therapeutic targets. A major challenge lies in further developing selective inhibitors of this pathway beyond experimental use. Consideration should perhaps also be given to widening the application of existing clinical drugs now known to also interfere with Rho-Rho-kinase signaling.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Intracellular Signaling Peptides and Proteins; Muscle Tonus; Muscle, Smooth, Vascular; Protein Serine-Threonine Kinases; rho GTP-Binding Proteins; rho-Associated Kinases

Age is well recognized as a powerful prognostic factor in the setting of cardiovascular disease. With the aging of the US population, it is projected that more than 50 million people will be aged over 65 years by the year 2020. This growing elderly population has increased rates of morbidity and mortality owing to cardiovascular disease; however, proven therapies for prevention and treatment are often underused in older patients, largely because physicians perceive them as being frail and have limited understanding of age-related unique adverse and therapeutic effects. Advancing age is associated with a number of physiologic and pathophysiologic changes that impact the toxic effects, efficacy and dosing of many medications. Decreases in lean muscle mass affect the volume of distribution, and reductions in hepatic function affect the metabolism of many medications. Age-related reductions in renal function might have the most profound impact on the safety profile and dosing of medications in elderly patients. The strong association between renal and cardiovascular disease makes recognition of renal dysfunction and appropriate dose adjustment particularly important in elderly patients with cardiovascular disease. This article reviews current approaches to the estimation of renal function, and unique considerations related to prescribing medication for elderly patients with concomitant renal and cardiovascular disease.

Topics: Aged; Aging; Cardiovascular Agents; Cardiovascular Diseases; Humans; Kidney; Kidney Function Tests; Renal Insufficiency, Chronic

For more than 10 years, preventive cardiology has obtained many positive results. Cardiologists can alter the prognosis of cardiovascular disease in primary and secondary prevention. In primary prevention or during the chronic phases of coronary artery disease, prevention is mainly based on drugs. However, prevention can be achieved only if patients have a good understanding of their disease, fair relationships with their physicians and a strict compliance with their treatments. Patient education is useful for the patient in order to control cardiovascular risk. In France, the PEGASE program evaluates the efficacy of an educational program in high risk patients. The final objective of this program is to spread this educational program for high risk patients to cardiologists all over the country.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Disease; France; Humans; Patient Education as Topic; Risk Assessment

Although the year 2005 has reinforced the therapeutic advances of 2004, with confirmation of certain concepts, the 'coxib affair' has continued to provoke arguments between pharmaceutical companies, licensing agencies as well as patients, some of whom have amalgamated into consumer groups to reject en masse placing any responsibility on the prescribers in favour of an attack on the drug licensing process itself. Among the cardiovascular drugs that will soon be licensed, only ivabradine in stable angina, and remodulin in primary pulmonary arterial hypertension are new. The therapeutic advances in 2005 regarding platelet aggregation and blood coagulation have been significant, in the human, scientific and commercial context, while hypertension has not been ignored. Another new development is the ever more precise notion of the metabolic syndrome, a target of choice for the pharmaceutical industry. The potential range of applications has been widened to include obesity, hypertension, diabetes, HDL cholesterol... The licensing authorities find themselves facing a hurdle to overcome, with novel combinations of drugs (ACE inhibitors, calcium blockers/statins, statins/aspirin, ARA2/calcium blockers...).

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Approval; Humans; Publishing

Topics: Algorithms; Cardiovascular Agents; Cardiovascular Diseases; Cilostazol; Humans; Risk Assessment; Tetrazoles; Vasodilator Agents

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Complications; Humans; Hypercholesterolemia; Hypertension; Life Style; Male; Mental Health; Obesity; Risk Factors; Smoking; United States

The prevalence of diabetes mellitus is increasing worldwide. Among other complications, diabetes is associated with the risk of coronary heart disease (CHD) that is thought to be equal to the risk of CHD in subjects without diabetes with previous myocardial infarction. Studies have shown that CHD risk factors start to increase long before the onset of clinical diabetes. Furthermore, the risk factors that are present in prediabetic individuals are also components of the highly prevalent metabolic syndrome. This suggests that treatment of CHD risk factors may effectively reduce the incidence of type 2 diabetes. Lifestyle interventions have proved effective in preventing the onset of type 2 diabetes in subjects with impaired glucose tolerance. A number of post hoc studies have reported consistent reductions in the incidence of type 2 diabetes in hypertensive patients treated with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). As a result of these positive data, ongoing prospective studies are investigating whether antihypertensive agents prevent or delay the onset of diabetes in patients at risk. Telmisartan, a selective oral ARB that is indicated for first-line therapy of essential hypertension, may provide improved tolerability compared with ACE inhibitors. Therefore, the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) program is investigating the effectiveness of telmisartan in the prevention or delay of type 2 diabetes. The program comprises ONTARGET and the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease (TRANSCEND).

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Female; Humans; Life Style; Male; Metabolic Syndrome; Risk Assessment; Risk Factors

Bone morphogenetic proteins (BMPs) and growth differentiation factors (GDFs) control the development and homeostasis of multiple tissue types in many organisms, from humans to invertebrates. These morphogens are expressed in a tissue-specific manner and they signal by binding to serine-threonine kinase receptors, resulting in coordinated changes in gene expression that regulate the differentiation and development of multiple tissue types. In addition, these proteins are regulated post-transcriptionally through binding to several soluble proteins. In this review we focus on a subset of BMPs and GDFs that have been implicated in the pathophysiology of type 2 diabetes and cardiovascular disease.

Topics: Animals; Atherosclerosis; Bone Morphogenetic Protein 7; Bone Morphogenetic Protein Receptors; Bone Morphogenetic Proteins; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Growth Differentiation Factor 3; Humans; Hypertension, Pulmonary; Hypoglycemic Agents; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Metabolic Diseases; Signal Transduction; Transforming Growth Factor beta

The manifestations of cardiovascular diseases differ between men and women, as do outcomes after therapeutic interventions. It is important that those involved in drug discovery and development, as well as disease treatment, are aware of these differences because such variations are likely to have an increasing role in therapeutic decisions in the future. Here, I review gender differences in the most frequent cardiovascular diseases and their underlying sex-dependent molecular pathophysiology, and discuss gender-specific effects of current cardiovascular drugs and the implications for novel strategies for drug development.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Evaluation, Preclinical; Female; Humans; Male; Sex Factors

To review the evidence for ethnic differences in susceptibility to adverse drug reactions (ADRs) to cardiovascular drugs.. Systematic review and meta-analysis.. We searched Medline and Embase to March 2005. Reference lists of identified articles were hand searched for further relevant articles.. Studies were eligible for inclusion if they included at least two ethnic groups and one or more ADRs. We excluded case reports and case series.. 564 studies contained some description of ethnicity and an ADR, and 132 of them related to cardiovascular therapies. Twenty four studies provided data for ADRs for at least two ethnic groups and were therefore eligible for inclusion. In pooled analyses the relative risk of angio-oedema from angiotensin converting enzyme (ACE) inhibitors in black compared with non-black patients was 3.0 (95% confidence interval 2.5 to 3.7); the relative risk of cough from ACE inhibitors was 2.7 (1.6 to 4.5) in East Asian compared with white patients; and the relative risk of intracranial haemorrhage with thrombolytic therapy was 1.5 (1.2 to 1.9) in black compared with non-black patients.. Patients from different ethnic groups have different risks for important ADRs to cardiovascular drugs. Ethnic group may therefore be one determinant of harms of a given treatment in the individual patient, either because it acts as a surrogate measure of genetic make up or because cultural factors alter the risk. Data are sparse, and regulators should consider asking for better data before licensing.

Topics: Adverse Drug Reaction Reporting Systems; Angiotensin-Converting Enzyme Inhibitors; Bias; Cardiovascular Agents; Cardiovascular Diseases; Confounding Factors, Epidemiologic; Ethnopharmacology; Humans; Risk Factors; Thrombolytic Therapy

Immunopharmacological studies show that medicines used in cardiovascular diseases (atherosclerosis, ischaemic heart disease, heart failure) can exert immunomodulatory effects on proinflammatory cytokines. In the paper the influence of statins, fibrates, angiotensin converting enzyme inhibitors (ACEI), beta-blockers, calcium channel blockers and phosphodiesterase inhibitors on the activity of cytokines was introduced.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Atherosclerosis; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Cytokines; Heart Failure; Humans; Immunologic Factors; Myocardial Ischemia; Phosphodiesterase Inhibitors

Endothelial nitric oxide synthase (eNOS) is an enzyme that plays a critical role in normal cardiovascular function. Caveolae are structures within the surface membrane of cells in which many signaling and second messenger pathways, including nitric oxide, are regulated. Many interventions in cardiovascular disease act, in part, either by changing factors that directly influence eNOS, or by changing a complex set of proteins that act indirectly on caveolae, to alter eNOS activity. In this review, we will focus on the regulation of eNOS activity by circulating factors which are altered in cardiovascular disease and the effects of pharmacological interventions that act partially through effects on eNOS.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Caveolae; Endothelium, Vascular; Humans; Nitric Oxide; Nitric Oxide Synthase Type III; Signal Transduction

Adiponectin is an adipose tissue-derived plasma protein which has a reduced concentration in subjects with obesity-related diseases. Adiponectin has antidiabetic and anti-inflammatory characteristics, which lead to beneficial actions on various obesity-linked complications. Recent experimental findings have shown that adiponectin contributes to protection against cardiac remodelling after pressure overload and cardiac injury following ischaemia-reperfusion. Thus, adiponectin could emerge as a potential cardioprotective agent for the treatment of several pathological heart conditions.

Topics: Adiponectin; Cardiotonic Agents; Cardiovascular Agents; Cardiovascular Diseases; Humans

Toll-like receptors (TLRs) form a family of pattern recognition receptors that have emerged as key mediators of innate immunity. These receptors sense invading microbes and initiate the immune response. TLR-mediated inflammation is an important pathogenic link between innate immunity and a diverse panel of clinical disorders. Among the processes in which TLRs play a role are cardiovascular disorders such as cardiac ischaemia, coronary artery disease, ventricular remodelling, cancer angiogenesis or transplant rejection. From these, many important opportunities for disease modification through TLR signalling manipulation can be imagined. Their role as potential targets for therapeutic intervention is just beginning to be appreciated and this article reviews the current status of these treatment strategies for cardiovascular disease.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiac Output, Low; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Genetic Predisposition to Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Ligands; Polymorphism, Genetic; Signal Transduction; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 5

Cardiovascular disease continues to be a tremendous worldwide problem, and drug therapy is a major modality to attenuate its burden. At present, conditions such as hypertension, dyslipidaemia and heart failure are pharmacologically managed with an empirical trial-and-error approach. However, it has been suggested that this approach fails to adequately address the therapeutic needs of many patients, and pharmacogenetics has been offered as a tool to enhance patient-specific drug therapy. This review outlines pharmacogenetic studies of common cardiovascular drugs, such as diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins and warfarin, ultimately highlighting considerations for future research and practice.

Topics: Anticoagulants; Cardiovascular Agents; Cardiovascular Diseases; Chronic Disease; Humans; Hypertension; Pharmacogenetics

Mortality and morbid events are insensitive guides to the efficacy and safety of interventions in chronic cardiovascular disease (CVD). To enhance the ability to find new and effective long-term treatments, especially for the early stages of CVD, a revised strategy for clinical trials should emphasize efficacy on disease progression while monitoring symptoms and quality of life as guides to clinical benefit. Mortality, which is uncommon except in acute or advanced disease, provides at best a crude guide to net efficacy and safety. It must be monitored to support demonstrated efficacy on disease progression without adverse safety effects. This revised approach, made possible by our enhanced ability to monitor the progression of disease, should make it possible to study earlier disease and to improve cardiovascular health while reducing health care costs.

Topics: Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Chronic Disease; Clinical Trials as Topic; Disease Progression; Humans; Research Design; Safety; Treatment Outcome

With an increasing burden of cardiovascular disease and many promising novel treatments in development, the need for efficient systems to evaluate treatments has never been greater. To understand whether a treatment should be used in practice, we need to know whether it makes patients live longer, feel better, prevents adverse events, or does these things with better tolerability or lower cost. But therapeutic development is expensive, inefficient, and is generally focused on short-term treatment effects, rather than on prevention and on long-term impact. Could measures of disease progression, combined with trends on clinical outcomes and post-marketing surveillance to assess safety, serve as the foundation for therapeutic development? Experience and principles of clinical research tell us no. Especially in the field of heart failure, numerous treatments have appeared promising based on disease markers, yet caused harm when tested in studies that assessed clinical outcomes. The intersection of complex human disease, intended and unintended targets of therapy, and overall risk and benefit make it impossible to accurately predict the effect on clinical outcomes based on impact on a disease marker. While reliable measures of disease progression are important to guide which treatments to study in trials, clinical outcome trials must remain the basis for informing clinicians on which treatments improve clinical outcomes. Improved reliability and capacity require the development of more efficient clinical trial methods, streamlined regulatory processes, rational use of privacy protection, leveraging of electronic medical records, and recruitment of a larger proportion of the clinical community to participate in clinical trials.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Disease Progression; Humans; Treatment Outcome

Chronic low-grade inflammation was recognized during the past decade as an important risk factor for the development of atherosclerosis and, more recently, for the development of heart failure. Patients with rheumatoid arthritis (RA) are at increased risk of morbidity and mortality from ischemic cardiovascular events and heart failure. Epidemiologic and clinical studies indicate that RA is an independent risk factor for cardiovascular disease, which suggests that chronic exposure to high levels of inflammatory mediators contributes to this enhanced risk. The relative contribution of conventional risk factors to the acceleration of cardiovascular disease does not seem to be increased in patients with RA compared with control populations. Nonetheless, some preclinical laboratory measures of risk factors (e.g. insulin sensitivity) are adversely modulated in the context of the highly inflammatory rheumatoid microenvironment. Discerning the net effect of RA therapies on cardiovascular disease is also challenging because, theoretically, their biologic effects could either promote or attenuate atherosclerosis and ventricular dysfunction; however, available data suggest a beneficial effect on cardiovascular morbidity and mortality in patients with RA. This review provides an overview of the potential influence of RA and its treatment on the development and progression of cardiovascular disease, and outlines some preliminary recommendations for prevention and management of this complication in patients with RA.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Cardiovascular Agents; Cardiovascular Diseases; Disease Progression; Humans; Incidence; Prevalence; Prognosis; Risk Factors

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Multigene Family; Pharmacogenetics; Polymorphism, Genetic

The First Hungarian Therapeutic Consensus Conference took place on 3rd Nov. 2003 with the participation of 9 medical societies. Over the past 2 years the results of new major studies have been published and the American ATP III has also updated its guidelines issued in 2004. Based on the above proposals, the Second Hungarian Therapeutic Consensus Conference held on 3rd Nov. 2005 partly confirmed its earlier suggestions, but made some changes as well. Within the high risk category the Conference optionally created a very high risk group from those patients who - in addition to their cardiovascular disease--have either diabetes or metabolic syndrome or acut coronaria syndrome or who are chain smokers. We have included - as a complement - into the asymptomatic high risk category such newly emerging risk factors, one of which already in itself means high risk: ankle/arm index < or = 0.9, GFR <60 ml/min, microalbuminuria (30-300 mg), preclinical atherosclerosis (plaque). Besides, 4 other risk factors were also categorised such as Lp/a (> or = 30 mg/dl), CRP (> or = 3mg/l), homocysteine (> or = 12 micromol), familiarity--atherogenic gene constellation, but only the presence of at least two of these verify high risk. In very high risk group the goals of 3.5 mmol/l and 1.8 mmol/l were determined as therapeutic option. The goal in obese patients--expressed earlier only in BMI--can now be equally determined by the abdominal circumference (94 cm for men, 80 cm for women respectively). ACE inhibitors were recommended earlier as a preventive therapy in case of dysfunction of the left ventricle, while at present they are suggested for all patients with cardiovascular disease. In the recent recommendations guidelines related to nutrition, smoking, exercise have also been included.

Topics: Abdominal Fat; Acute Disease; Albuminuria; Atherosclerosis; Body Mass Index; Cardiovascular Agents; Cardiovascular Diseases; Consensus Development Conferences as Topic; Coronary Disease; Diabetes Complications; Dyslipidemias; Exercise; Feeding Behavior; Female; Humans; Hungary; Hypertension; Life Style; Male; Metabolic Syndrome; Obesity; Practice Guidelines as Topic; Risk Assessment; Risk Factors; Smoking Cessation; Societies, Medical; Therapeutics

Failure of the cardiovascular system is the main reason for mortality in industrialized countries, and is a major cause of chronic morbidity. As most of the numerous ways in which it can fail will manifest in the second half of life and are exacerbated by old age, this situation is not likely to change in the near future unless fundamentally new ways of treating or preventing hypertension, atherosclerosis, myocardial infarction, chronic heart failure and cardiac arrhythmia are found. This prospect keeps the pharmaceutical industry on a constant, intense search for new therapeutic targets, new drugs, and new ways to identify such targets and drugs, as well as monitoring patient responses to drugs. This summary highlights the most interesting developments seen in cardiovascular and renal patents (other than those claiming formulations or combinations of known drugs) published during the first half of 2006.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cell- and Tissue-Based Therapy; Disease Models, Animal; Drug Delivery Systems; Drug Design; Genetic Therapy; Humans; Kidney Diseases; Renal Agents; RNA, Small Interfering

Phosphodiesterase 5 inhibitors, such as sildenafil, vardenafil and tadalafil, are now approved for the treatment of erectile dysfunction. They inhibit the cGMP-specific isoform 5 of phosphodiesterase, resulting in cGMP accumulation, which, for example in smooth muscle cells, reduces muscular tone. In the cardiovascular system, they slightly reduce arterial systemic blood pressure. This moderate effect was also shown in combination with many antihypertensive drugs. But the important contraindication is the concomitant use of PDE 5 inhibitors with any drug serving as a nitric oxide donor, as this combination can lead to significant arterial hypotension. Caution is needed in patients on alpha-blocking agents. In general, this class of drugs was not shown to exhibit direct deleterious effects on the myocardium or promote arrhythmias. Furthermore, statistical evaluations did not demonstrate an increased risk for patients taking PDE 5 inhibitors in comparison with an adequate control population. Many patients suffering from erectile dysfunction may be characterized by multiple cardiovascular risk factors or even ischemic heart disease, suggesting an increased baseline risk. While in many forms of erectile dysfunction, these agents seem to be very effective, it becomes clear that endothelial dysfunction is an attractive target of PDE 5 inhibitors and may also be the underlying cause in many types of erectile dysfunction. In addition, these agents seem to be very effective in lowering pulmonary arterial pressure, which might provide the opportunity to treat primary and some forms of secondary pulmonary hypertension, perhaps in combination with inhaled nitric oxide or other pulmonary arterial vasodilators. Sildenafil was approved for treatment of primary arterial hypertension in the U.S. in June 2005. Recently, direct cardioprotective effects were described in animal research, resembling preconditioning-like effects, which may, under certain conditions, also be applicable in clinical research.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Phosphodiesterase Inhibitors

Pharmacological and non-pharmacological interventions to improve function and quality of life in patients with claudication are being evaluated in clinical research trials. An important component of clinical development programs is assessing the safety of the intervention and monitoring for adverse impact of the therapy on research participants. The conduct of both of these safety assessments is facilitated by the ability to estimate the anticipated rates of cardiovascular events and death in the target population. To obtain estimates of these rates, data were abstracted from randomized, double-blind, placebo-controlled trials performed in patients with claudication and designed to show functional improvement, and which have been published since 1990. Patient-year exposures and the number of deaths, serious adverse events and cardiovascular serious adverse events in the placebo arms of these trials were tabulated, and summed event rates calculated. The mortality rate was 1.9 deaths per hundred patient-years (27 deaths observed in 1446 patient-years). The mortality rate in claudication trials is lower than that reported in natural history studies. Cardiovascular serious adverse events in claudication trials were observed at a rate of 8.5 per hundred patient-years (65 events in 762 patient-years). Thus, cardiovascular morbidity and mortality should be expected in clinical trials enrolling claudicants. The current analyses provide benchmark data for ensuring that development programs are large enough to allow meaningful safety conclusions, and to assist in data and safety monitoring of these trials.

Topics: Adverse Drug Reaction Reporting Systems; Cardiovascular Agents; Cardiovascular Diseases; Humans; Intermittent Claudication; Linear Models; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Research Design; Risk Factors

Lipoprotein(a) (Lp(a)) is of interest to both basic researchers who endeavour to understand the mechanism of action of this unique lipoprotein, as well as to clinicians who are interested in the contribution of Lp(a) to cardiovascular risk profiles. The Lp(a) particle contains a moiety that is indistinguishable from circulating LDL, covalently linked to the unique glycoprotein component apolipoprotein(a) (apo(a)). Since the 1970s, epidemiological data have been accumulated that, on balance, indicate that elevated plasma Lp(a) concentrations are an independent risk factor for vascular diseases. Apo(a) is highly homologous to the fibrinolytic proenzyme plasminogen, containing many tandemly-repeated kringle motifs similar to several of those found in the plasminogen molecule; the size of the kringle domain in apo(a) gives rise to Lp(a) isoform size heterogeneity which is a hallmark of this lipoprotein. The similarity between Lp(a) and plasminogen led to speculation of a bridging role for Lp(a) in atherothrombotic disease based on the duality of the structure of this lipoprotein. In this scenario, LDL would contribute to the proatherosclerotic properties of the particle, while apo(a) would interfere with the normal fibrinolytic functions of plasminogen, thereby inhibiting the breakdown of thrombi formed in the vasculature. Many in vitro and in vivo studies have suggested a prothrombotic role for Lp(a) which is attributable to the apo(a) component of the particle. However, there are a number of unique properties that apo(a) confers to Lp(a) which are independent of its similarity to plasminogen. These include the ability of apo(a)/Lp(a) to affect platelet function, to contribute to endothelial dysfunction, and to inhibit the clearance of chylomicron remnant particles in a transgenic mouse model. Very recent data have revealed a potential role for Lp(a) in the preferential binding of oxidized phospholipid adducts through one of the kringle motifs in apo(a). Many questions remain to be answered regarding the role of Lp(a) in atherothrombotic disease. This article will review the relevant literature concerning the contribution of Lp(a) to risk for both atherosclerotic and purely thrombotic disorders, as well as the proposed mechanisms of Lp(a) pathogenicity related to the structure of this lipoprotein. Emerging areas of interest in the field including the role of apo(a) isoform size as a risk factor for CHD - independent of Lp(a) levels - will also be discussed,

Topics: Animals; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Humans; Isomerism; Lipoprotein(a); Risk Factors

Cardiovascular disease (CVD) is the most critical global health threat, which contributes more than one third of global morbidity. CVD includes heart disease, vascular disease, atherosclerosis, stroke and hypertension. The most important independent risk factors for CVD include dyslipidemia along with hypertension, obesity, sedentary lifestyle, diabetes and chronic inflammation. These factors are directly regulated by diet, metabolism and physical activity. Diets rich in fat and carbohydrate coupled to sedentary lifestyles have contributed to the increase in dyslipidemia, type 2 diabetes, obesity and CVD in the world. Discovery of Peroxisome Proliferator Activated Receptors (PPARs) as a key regulator of metabolic pathways has led to significant insight into the mechanisms regulating these processes. Three PPAR subtypes, encoded by distinct genes, are designated as PPAR-alpha, PPAR-delta (also know as beta) and PPAR-gamma. PPARs act as nutritional sensors that regulate a variety of homeostatic functions including metabolism, inflammation and development. PPAR-alpha is the main metabolic regulator for catabolism whereas PPAR-gamma regulates anabolism or storage. PPARs are expressed in the cardiovascular system such as endothelial cells, vascular smooth muscle cells and monocytes/macrophages. It has been shown that they play an important role in the modulation of inflammatory, fibrotic and hypertrophic responses. In 1997, a Glaxo patent described that Troglitazone (first PPAR-gamma ligand to reach market) reduced TNF-induced VCAM1 expression in HUVECs indicating the potential benefit in atherosclerosis. A series of patents from Eli Lilly and Dr. Reddy's Laboratories Ltd. between 1999 and 2005 described a variety of PPAR-alpha and -alpha,gamma dual ligands in a number of patents having glucose, triglyceride, cholesterol lowering, HDL elevating and body weight reducing activity. Patents from Metabolex and Tularik in 2001 and 2002 described the beneficial effects of SPPARM molecules for insulin resistance and diabetes, without showing concern on PPAR-gamma related side effects such as edema and body weight. GSK and Takeda described the potential effects of PPAR-delta modulators during 2001 to 2004 in few patents. Several clinical and preclinical studies have demonstrated the beneficial effects of PPAR ligands on various cardiovascular risk factors. This review intends to capture some of the key studies in this area as is described in some recent patents and lit

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Peroxisome Proliferator-Activated Receptors; PPAR alpha; PPAR delta; PPAR gamma; Risk Factors

Apoptosis, or programmed cell death, is an active form of cell death, distinct from necrosis, through which multicellular organisms dispose of cells efficiently. Implication of apoptosis in the initiation and progression of many cardiovascular diseases, such as heart failure, systemic hypertension, coronary artery disease, has raised the possibility to elaborate new classes of medication to modulate this process. We review the most important drugs used in cardiovascular diseases and their interference with apoptosis, demonstrated by clinical studies as well as the involved mechanisms. We also analyze new molecules which protect cells from apoptosis and may therefore be clinically useful, as a new class of medication.

Topics: Apoptosis; Cardiovascular Agents; Cardiovascular Diseases; Humans

Rho-kinase is a signaling molecule that occurs downstream of the small GTPase Rho, which mediates various cellular functions. The Rho/Rho-kinase pathway plays an important role in pathophysiology and progression of various cardiovascular diseases such as hypertension, coronary vasospasm, angina pectoris, and restenosis after percutaneous coronary intervention, all of which are related to arteriosclerosis/atherosclerosis changes of the vasculature. Activation of the Rho/Rho-kinase pathway contributes to inflammatory and proliferative changes of the blood vessels and affects cardiac myocytes. Evidence from in vitro and in vivo studies suggests that Rho-kinase inhibitors have beneficial effects on cardiovascular diseases, particularly arteriosclerosis and coronary vasospasm. Furthermore, activation of the Rho/Rho-kinase pathway contributes to blood pressure regulation via the central sympathetic nervous system. There is evidence to suggest that Rho-kinase is involved in angiotensin II-induced cardiac hypertrophy and endothelial dysfunction, and preliminary data indicate that inhibition of Rho-kinase may be beneficial in vascular disorders such as pulmonary arterial hypertension and erectile dysfunction. Fasudil is currently the only Rho-kinase inhibitor available for clinical use and it is approved in Japan for the prevention of vasospasm in patients with subarachnoid hemorrhage. Emerging clinical data have shown that oral fasudil 80 mg three times daily is effective in preventing myocardial ischemia in patients with stable angina pectoris. Rho-kinase represents a new target for the management of cardiovascular diseases and further studies are needed to define the therapeutic potential of Rho-kinase inhibitors.

Topics: Angina Pectoris; Brain; Cardiovascular Agents; Cardiovascular Diseases; Humans; Hypertension; Intracellular Signaling Peptides and Proteins; Protein Serine-Threonine Kinases; Randomized Controlled Trials as Topic; rho-Associated Kinases

There is a plausible biological basis for the association between psychiatric morbidity and cardiovascular disease. Anxiety, panic disorder, and depression are common in patients with coronary heart disease and hypertension. Despite this evidence there is poor recognition of anxiety disorders and depression in primary care and hospital medical practice. Concern also surrounds the use of psychotropic drugs in patients with cardiovascular disease. In the first of the two articles on this subject, we highlighted the current evidence regarding the association between cardiovascular and psychotropic conditions. In this second article, we discuss the interaction of the drugs used in the management of these two varied but commonly coexistent group of diseases as well as their relative effects on either system. Finally, we summarise the data regarding the safe use of these medications based on the recommendations from the currently available evidence.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Humans; Mental Disorders; Psychotropic Drugs

Endothelin (ET) is among the strongest endogenous vasoconstrictors known and a potent mitogen. A rich body of experimental evidence suggests that ET contributes to vascular remodeling and end-organ damage in several cardiovascular conditions. Therefore, blockade of ET receptors has been suggested as an attractive target in a number of acute and chronic cardiovascular indications, including pulmonary arterial hypertension (PAH), systemic hypertension, and heart failure. To date, clinical studies have confirmed expectations in PAH and yielded promising initial results in systemic hypertension, which are currently awaiting confirmation in large-scale trials. In contrast, no added benefit could be demonstrated in large clinical trials on top of current standard treatment in both acute and chronic heart failure. Further clinical development in heart failure has therefore been suspended. Other indications that are currently being studied clinically or would possibly merit clinical trials include acute myocardial ischemia and reperfusion, cerebral vasospasm after intracranial bleeding, glaucoma, acute severe pancreatitis, systemic sclerosis, (diabetic) renal failure, restenosis after angioplasty/stent implantation, and late transplant rejection. This article critically reviews the available clinical data on ET receptor antagonism in cardiovascular indications against the background of the underlying preclinical research.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Endothelin Receptor Antagonists; Heart Failure; Hemodynamics; Humans; Hypertension; Hypertension, Pulmonary; Ventricular Remodeling

Use of herbal medicines among patients under cardiovascular pharmacotherapy is widespread. In this paper, we have reviewed the literature to determine the possible interactions between herbal medicines and cardiovascular drugs. The Medline database was searched for clinical articles published between January 1996 and February 2003. Forty-three case reports and eight clinical trials were identified. Warfarin was the most common cardiovascular drug involved. It was found to interact with boldo, curbicin, fenugreek, garlic, danshen, devil's claw, don quai, ginkgo, papaya, lycium, mango, PC-SPES (resulting in over-anticoagulation) and with ginseng, green tea, soy and St. John's wort (causing decreased anticoagulant effect). Gum guar, St. John's wort, Siberian ginseng and wheat bran were found to decrease plasma digoxin concentration; aspirin interactions include spontaneous hyphema when associated with ginkgo and increased bioavailability if combined with tamarind. Decreased plasma concentration of simvastatin or lovastatin was observed after co-administration with St. John's wort and wheat bran, respectively. Other adverse events include hypertension after co-administration of ginkgo and a diuretic thiazide, hypokalemia after liquorice and antihypertensives and anticoagulation after phenprocoumon and St. John's wort. Interaction between herbal medicine and cardiovascular drugs is a potentially important safety issue. Patients taking anticoagulants are at the highest risk.

Topics: Anticoagulants; Antihypertensive Agents; Biological Availability; Blood Coagulation; Cardiotonic Agents; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Herb-Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Phytotherapy; Plant Preparations; Plants, Medicinal; Platelet Aggregation Inhibitors; Risk Factors

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diabetes Complications; Dyslipidemias; Female; Heart Failure; Humans; Hypertension; Risk Factors; Smoking; Women's Health

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cost-Benefit Analysis; Drug Costs; Health Expenditures; Humans; United States

Optimal care of lupus nephritis patients should include the treatment of proteinuria and hypertension, other measures to delay the progression of chronic kidney disease, the vigorous management of cardiovascular risk factors and finally, the treatment of advanced chronic kidney disease and its consequences. These topics are briefly reviewed in the present paper, with particular emphasis on the recent progresses in antiproteinuric treatment.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Disease Progression; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Lupus Nephritis; Patient Care; Proteinuria; Risk Factors

Regulator of G-protein-signaling (RGS) proteins play a key role in the regulation of G-protein-coupled receptor (GPCR) signaling. The characteristic hallmark of RGS proteins is a conserved approximately 120-aa RGS region that confers on these proteins the ability to serve as GTPase-activating proteins (GAPs) for G(alpha) proteins. Most RGS proteins can serve as GAPs for multiple isoforms of G(alpha) and therefore have the potential to influence many cellular signaling pathways. However, RGS proteins can be highly regulated and can demonstrate extreme specificity for a particular signaling pathway. RGS proteins can be regulated by altering their GAP activity or subcellular localization; such regulation is achieved by phosphorylation, palmitoylation, and interaction with protein and lipid-binding partners. Many RGS proteins have GAP-independent functions that influence GPCR and non-GPCR-mediated signaling, such as effector regulation or action as an effector. Hence, RGS proteins should be considered multifunctional signaling regulators. GPCR-mediated signaling is critical for normal function in the cardiovascular system and is currently the primary target for the pharmacological treatment of disease. Alterations in RGS protein levels, in particular RGS2 and RGS4, produce cardiovascular phenotypes. Thus, because of the importance of GPCR-signaling pathways and the profound influence of RGS proteins on these pathways, RGS proteins are regulators of cardiovascular physiology and potentially novel drug targets as well.

Topics: 14-3-3 Proteins; Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Gene Expression Regulation; GTP-Binding Protein alpha Subunits; Heart; Humans; Mice; Multigene Family; Myocardium; Protein Binding; Protein Isoforms; Protein Processing, Post-Translational; Protein Structure, Tertiary; Rats; Receptors, G-Protein-Coupled; RGS Proteins; Signal Transduction; Subcellular Fractions; Substrate Specificity

The incidence of cardiovascular disease is increasing with the aging population. This has stimulated a need for innovative means to evaluate and develop therapeutic strategies intended to improve patient care. Positron emission tomography (PET) imaging is an advanced nuclear imaging technology. The advantage of PET over other non-invasive imaging modalities is its ability to accurately measure tissue concentrations of specific radiolabeled compounds. These radioligands can be used as molecular probes to quantify physiological processes and the effects of therapy. Molecular imaging with PET has been applied to evaluate new and established drugs and therapies, as well as their effects on physiological parameters. New radiolabeled receptor ligands will also allow in vivo pharmacokinetic studies following drug treatment, yielding insights into drug delivery, optimal drug occupancy, and mechanism of action at the receptor level. These exciting tissue pharmacokinetic data could revolutionize evaluation of drug therapies in cardiovascular diseases. In addition, serial evaluations of these processes are now possible in both animals and humans permitting sensitive means to evaluate disease progression and therapies. New tools for imaging such as PET/CT and small animal PET broaden the potential of PET in drug evaluation. This review will describe the accuracy of PET as a non-invasive modality to quantify various parameters, and the application of PET in evaluating new and established therapies. This paper will also review the application of receptor ligand imaging and the principles of using surrogate physiological end-points in early drug development and evaluation.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Coronary Circulation; Diagnostic Imaging; Drug Evaluation, Preclinical; Genetic Therapy; Humans; Neurotransmitter Agents; Positron-Emission Tomography; Receptors, Cell Surface; Stress, Physiological

People with type 2 diabetes generally carry an array of risk factors for cardiovascular disease (CVD), including hyperglycaemia, dyslipidaemia, alterations in inflammatory mediators and coagulation/thrombolytic parameters, as well as other 'non-traditional' risk factors, many of which may be closely associated with insulin resistance. Consequently, rates of CVD mortality and morbidity are particularly high in this population. Targeting hyperglycaemia alone does not reduce the excess risk in diabetes, highlighting the need for aggressive treatment of other risk factors.. This is a review of cardiovascular risk markers in diabetes, based on MEDLINE and EMBASE literature searches (1994-2004).. Although, the current use of statin therapy is effective at reducing low-density lipoprotein (LDL)-cholesterol, residual risk remains from other independent lipid and non-lipid factors. The peroxisome proliferator-activated receptor-gamma(PPARgamma) appears to be intimately involved in regulating risk markers at multiple levels. Ligands that activate PPARgamma, which include the thiazolidinedione (TZD) insulin-sensitizing agents used to manage type 2 diabetes, display a number of potential anti-atherogenic properties, including effects on high-density lipoprotein (HDL) cholesterol and triglycerides, as well as other beneficial non-lipid effects, such as regulating levels of mediators involved in inflammation and endothelial dysfunction. Data from several sources suggest that simple strategies combining TZDs and statins could have complementary effects on CVD risk factors profiles in diabetes, alongside the ability to control glycaemia.. It is hoped that studies currently underway will provide insights into the value of such treatment approaches in terms of reducing the excess CVD risk, morbidity and mortality associated with type 2 diabetes.

Topics: Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin Resistance; PPAR gamma; Risk; Thiazolidinediones

Outcome studies are used to measure clinically meaningful primary end points, such as mortality and cardiovascular morbidity. However, few outcome trials have been conducted exclusively in people with diabetes; the majority of conventional diabetes trials use surrogate end points that may or may not translate into clinical benefits. Our current knowledge of the effects of pharmacotherapies on cardiovascular risk in patients with diabetes has been gained from subgroups included in large-scale studies. Several trials with lipid-modifying, antiplatelet and/or antihypertensive therapy, for example the recent Collaborative AtoRvastatin Diabetes Study, have included sufficient numbers of patients with diabetes to indicate that effective management can reduce cardio vascular risk in this patient population. The United Kingdom Diabetes Study and the Diabetes Control and Complications Trial provide important, but inconclusive data on the impact of glucose-lowering therapy on the incidence of cardiovascular complications in diabetes. Thiazolidinediones have only become available during the past few years, thus their effects were not assessed in these landmark trials. Ongoing studies in diabetic populations at high risk for further macrovascular events, such as the PROspective pioglitAzone Clinical Trial In macroVascular Events, have been designed to assess the effect of thiazolidinediones on cardiovascular outcome in patients with diabetes and should help to reinforce the importance of broad-based treatment of the multiple metabolic risk factors for cardiovascular disease in people with diabetes.. This paper (based upon MEDLINE and EMBASE literature searches in the year range 1990-2005) reviews what we have learned from outcome studies up to the end of 2004 and looks at what we hope to learn from ongoing studies.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Clofibric Acid; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Outcome Assessment, Health Care; Platelet Aggregation Inhibitors; Risk Reduction Behavior; Thiazolidinediones

Vitamin D3 is modified by vitamin D3-25-hydroxylase in the liver, and 25-hydroxyvitamin D3-1alpha-hydroxylase in the kidney, to form the active metabolite, 1,25-dihydroxyvitamin D3. Chronic kidney disease (CKD) is characterized by reduced synthesis of 1,25-dibydroxyvitamin D3, inadequate renal phosphate clearance and calcium imbalance, secondary hyperparathyroidism (SHPT) and bone disease. CKD patients encounter a much higher risk of cardiovascular disease (CVD) than the general public. The cardiovascular risk factors for CKD patients include conventional factors such as age, gender, hypertension, diabetes, dyslipidemia and smoking, and non-conventional factors, such as anemia, uremia, reduced vascular compliance, inflammation and various hormonal factors. Several vitamin D analogs are currently available for the treatment of SHPT, and recent clinical data show that these analogs provide survival benefit for CKD patients in the order of paricalcitol > calcitriol > no vitamin D analog, independent of parathyroid hormone and calcium. Moreover, the survival benefit seems to be associated with cardiovascular causes. The observations made from these clinical studies raised intriguing questions about the involvement of the vitamin D receptor locus (VDR) in the cardiovascular system. This review discusses recent data regarding the role of vitamin D and its analogs in the CVD associated with CKD.

Topics: Calcitriol; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Failure, Chronic; Vitamin D

Erectile dysfunction is common and closely associated with age and risk factors for cardiovascular disease. The oral selective inhibitors of phosphodiesterase type 5 (PDE5) have become the treatments of choice, owing to their convenience, general safety, and broad-spectrum effectiveness. For the same reasons, they have greatly simplified the workup. Thus, the general practitioner has gradually replaced the urologist for the initial management of erectile dysfunction and the proper evaluation of cardiac status before starting treatment with the PDE5 inhibitors. The following review provides a practical approach for the management of erectile dysfunction in primary care.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Contraindications; Drug Interactions; Erectile Dysfunction; Humans; Interprofessional Relations; Male; Phosphodiesterase Inhibitors; Physicians, Family; Piperazines; Practice Patterns, Physicians'; Purines; Risk Factors; Sildenafil Citrate; Sulfones

Urotensin II is the most potent vasoconstrictor known. Paradoxically, urotensin II also possesses vasodilator activity in certain vascular beds. While much is still to be learnt regarding urotensin II's actions on vascular tone, it is now clear that it mediates its effects by interacting with a specific G-protein-coupled receptor. The presence of urotensin II and its receptor in both vertebrate and invertebrate species suggests an evolutionarily conserved role in normal physiology although evidence is mounting for both species-specific as well as disease-specific effects of this peptide. This somatostatin-like peptide was originally thought to reside solely in compartments of the central nervous system. However, recent evidence implicated urotensin II in the pathogenesis of a variety of disease processes ranging from hypertension to hepatic cirrhosis. Increased expression of this peptide has been noted in cardiac, renal and hepatic disease. While the contribution of urotensin II to these diseases remains unclear, the advent of urotensin II antagonists allows for not only the possibility of a new range of therapeutic drugs but also new avenues of investigation and further mechanistic insights into the pathophysiology of these disease processes.

Topics: Amino Acid Sequence; Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Humans; Molecular Sequence Data; Receptors, G-Protein-Coupled; Urotensins

Dexrazoxane (Cardioxane, Zinecard, a cyclic derivative of edetic acid, is a site-specific cardioprotective agent that effectively protects against anthracycline-induced cardiac toxicity. Dexrazoxane is approved in the US and some European countries for cardioprotection in women with advanced and/or metastatic breast cancer receiving doxorubicin; in other countries dexrazoxane is approved for use in a wider range of patients with advanced cancer receiving anthracyclines. As shown in clinical trials, intravenous dexrazoxane significantly reduces the incidence of anthracycline-induced congestive heart failure (CHF) and adverse cardiac events in women with advanced breast cancer or adults with soft tissue sarcomas or small-cell lung cancer, regardless of whether the drug is given before the first dose of anthracycline or the administration is delayed until cumulative doxorubicin dose is > or =300 mg/m2. The drug also appears to offer cardioprotection irrespective of pre-existing cardiac risk factors. Importantly, the antitumour efficacy of anthracyclines is unlikely to be altered by dexrazoxane use, although the drug has not been shown to improve progression-free and overall patient survival. At present, the cardioprotective efficacy of dexrazoxane in patients with childhood malignancies is supported by limited data. The drug is generally well tolerated and has a tolerability profile similar to that of placebo in cancer patients undergoing anthracycline-based chemotherapy, with the exception of a higher incidence of severe leukopenia (78% vs 68%; p < 0.01). Dexrazoxane is the only cardioprotective agent with proven efficacy in cancer patients receiving anthracycline chemotherapy and is a valuable option for the prevention of cardiotoxicity in this patient population.

Topics: Anthracyclines; Antineoplastic Agents; Cardiovascular Agents; Cardiovascular Diseases; Humans; Neoplasms; Randomized Controlled Trials as Topic; Razoxane

Epidemiology and prevention of coronary artery disease. The author summarizes the most important risk factors of atherosclerosis and epidemiological data of coronary heart disease. According to epidemiological data during the next 10-20 years cardiovascular diseases will be the leading cause of death all around the world. Smoking is the most important risk factor causing half of all avoidable death, half of these deaths caused by cardiovascular diseases. Three strategies of prevention are discussed: population strategies, high risk strategy and secondary prevention. All of these preventive strategies should be implemented to reach the goal. During the last years many drug studies were finished proving the effectiveness of aspirin, statins, ACE inhibitors and beta blockers as an effective tool of prevention.

Topics: Arteriosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Coronary Disease; Humans; Hungary; Primary Prevention; Risk Factors; Smoking

The BEACH program, a continuous national study of general practice activity in Australia, gives us an analysis of the management of cardiovascular conditions in general practice. This provides a backdrop against which articles in this issue of Australian Family Physician can be further considered.

Topics: Adult; Age Distribution; Aged; Australia; Cardiovascular Agents; Cardiovascular Diseases; Family Practice; Female; Humans; Male; Middle Aged; Practice Patterns, Physicians'; Referral and Consultation; Sex Distribution

Cardiovascular diseases are the leading cause of death in Western countries, and that is true for Hungary as well, and so will be the case in developing countries in 2025. Cardiovascular diseases kill more than 950000 people only in the USA. 50% of cardiovascular mortality is due to ischemic heart disease, stroke is responsible for 20%. The annual cost of the treatment of cardiovascular illnesses takes more than 330 billion dollars. All these data underline the importance of these illnesses. The aim of cardiovascular prevention is to reduce the incidence of first or recurrent events due to ischemic heart disease, ischemic stroke or peripheral artery disease, especially early deaths and disability. In the following article the medical aspects of cardiovascular prevention are summarized. Lifestyle changes and special treatment of particular risk factors are out of scope of this review.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Cardiovascular Diseases; Estrogen Replacement Therapy; Humans; Hypolipidemic Agents; Incidence; Platelet Aggregation Inhibitors; Primary Prevention; Secondary Prevention

Differences in pharmacokinetics, pharmacodynamics, and physiology contribute to the phenomenon that women and men frequently respond differently to cardiovascular drugs. Hormonal influences, in addition, can play an important role: for example, the menstrual cycle, menopause, and pregnancy--as a result of fluctuations in concentrations of sexual steroids, and of changes in total body water--can be associated with gender-specific differences in the plasma levels of cardiovascular drugs. Clinical relevance accordingly results, especially for substances with a narrow therapeutic margin. This review treats the most important pharmacodynamic gender-relevant differences in this context, and surveys available evidence on the benefits of therapy of chronic cardiovascular diseases in women. On the whole, the study situation for women is appreciably less favourable than for men: owing to the fact that women are under-represented in most studies, and that few gender-specific analyses have been conducted.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Aspirin; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Chronic Disease; Clopidogrel; Digitalis Glycosides; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Sex Factors; Ticlopidine; Women's Health

Crataegus oxyacantha (Aubepine, Hawthorn), was used by european herbalist in the first century A. D. It went out fashion as a medicine until the 19th century for heart disease. The leaves, flowers, and berries of hawthorn contain a variety of bioflavonoid-like complexes that appear to be primarily responsible for the cardiac actions of the plant. Bioflavonoids found in C. oxyacantha include oligomeric procyanidins (OPCc), vitexin, quercetin, and hyperoside. The action of these compounds on the cardiovascular system has led to the development of leaf and flower extracts. As described in French pharmacopea, the hyperoside is the marker for quality control.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Crataegus; Flowers; France; Heart Failure; Humans; Phytotherapy; Plant Extracts; Plants, Medicinal

The aim of this article was to review the importance of the clinical identification of persons with cardiovascular autonomic neuropathy (CAN) and discuss potential treatment interventions.. A MEDLINE search was conducted for articles published during the last 20 yr. In addition, subsequent references of retrieved articles were reviewed. Search strategies included using key terms such as CAN, heart rate variability, orthostatic hypotension, and diabetes mellitus.. CAN is a common form of diabetic autonomic neuropathy and causes abnormalities in heart rate control as well as central and peripheral vascular dynamics. The clinical manifestations of CAN include exercise intolerance, intraoperative cardiovascular lability, orthostatic hypotension, painless myocardial ischemia, and increased risk of mortality. CAN contributes to morbidity, mortality, and reduced quality of life for persons with diabetes. The American Diabetes Association has recently published a statement that provides guidelines for prevention, detection, and management of neuropathy, including CAN, for healthcare providers who care for patients with diabetes. Algorithms for the evaluation and treatment of the patient with CAN, even if the patient is asymptomatic, are provided in this review.. Once CAN is identified in a patient with diabetes, healthcare providers may consider altering the prescribed exercise regimen, increasing surveillance for cardiac ischemia, carefully reexamining the list of prescribed medications, and aggressively treating cardiovascular risk factors (e.g. hypertension) that may be associated with the development of CAN.

Topics: Autonomic Nervous System Diseases; Cardiovascular Agents; Cardiovascular Diseases; Diabetic Neuropathies; Humans

Recent studies have highlighted the relation between erectile dysfunction (ED) and cardiovascular disease. In particular, the role of endothelial dysfunction and nitric oxide in ED and atherosclerotic disease has been elucidated. Given the large number of men receiving medical treatment for ED, concerns regarding the risk for sexual activity triggering acute cardiovascular events and potential risks of adverse or unanticipated drug interactions need to be addressed. A risk stratification algorithm was developed by the First Princeton Consensus Panel to evaluate the degree of cardiovascular risk associated with sexual activity for men with varying degrees of cardiovascular disease. Patients were assigned to 3 categories: low, intermediate (including those requiring further evaluation), and high risk. This consensus study from the Second Princeton Consensus Conference corroborates and clarifies the algorithm and emphasizes the importance of risk factor evaluation and management for all patients with ED. The panel reviewed recent safety and drug interaction data for 3 phosphodiesterase (PDE)-5 inhibitors (sildenafil, tadalafil, vardenafil), with emphasis on the safety of these agents in men with ED and concomitant cardiovascular disease. Increasing evidence supports the role of lifestyle intervention in ED, specifically weight loss and increased physical activity, particularly in patients with ED and concomitant cardiovascular disease. Special management recommendations for patients taking PDE-5 inhibitors who present at the emergency department and other emergency medical situations are described. Finally, further research on the role of PDE-5 inhibition in treating patients with other medical or cardiovascular disorders is recommended.

Topics: Age Distribution; Aged; Angina Pectoris; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Coronary Disease; Drug Interactions; Erectile Dysfunction; Humans; Incidence; Male; Middle Aged; Piperazines; Prognosis; Purines; Risk Assessment; Severity of Illness Index; Sildenafil Citrate; Sulfones; Survival Rate

To review the antihypertensive, cardiovascular and pleiotropic effects of angiotensin-receptor blockers (ARBs).. ARBs are the most recently approved class of antihypertensive agents. They selectively block the angiotensin II type 1 receptor, thus inhibiting most of the deleterious effects of angiotensin II. In addition to blood-pressure control, other benefits may be gained using ARBs. This is because the renin-angiotensin system plays a crucial role in circulatory homoeostasis, and in patients with atherosclerosis, diabetes or hypertension, angiotensin II contributes to the pathophysiology of disease. Evidence-based medicine includes well-controlled studies with mortality and morbidity endpoints in patients with a variety of conditions including hypertension, type 2 diabetes, stroke, renal disease, heart failure, left-ventricular hypertrophy and coronary heart diseases. In addition to these hard endpoints, it has been shown that treatment with ARBs prevents the development of type 2 diabetes, ameliorates coronary and peripheral vascular endothelial dysfunction and decreases plasma levels of several markers of vascular inflammation.. ARBs are first-line agents for the treatment of hypertension and cardiovascular diseases. Blocking the renin-angiotensin system with these agents has special advantages due to specific vascular and antiatherosclerotic effects, which contribute to a better cardiovascular and renal protection in patients at risk from or with cardiovascular disease.

Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Coronary Disease; Diabetes Mellitus, Type 2; Endothelium, Vascular; Heart Failure; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Diseases

Rho kinase (ROCK) belongs to a family of Ser/Thr protein kinases that are activated via interaction with the small GTP-binding protein RhoA. Growing evidence suggests that RhoA and ROCK participate in a variety of important physiological functions in vasculature including smooth muscle contraction, cell proliferation, cell adhesion and migration, and many aspects of inflammatory responses. As these processes mediate the onset and progression of cardiovascular disease, modulation of the Rho/ROCK signalling pathway is a potential strategy for targeting an array of cardiovascular indications. Two widely employed ROCK inhibitors, fasudil and Y-27632, have provided preliminary but compelling evidence supporting the potential cardiovascular benefits of ROCK inhibition in preclinical animal disease models and in the clinic. This review summarises the molecular biology of ROCK and its biological functions in smooth muscle, endothelium and other vascular tissues. In addition, there will be a focus on recent progress demonstrating the benefits of ROCK inhibition in several animal models of cardiovascular diseases. Finally, recent progress in the identification of novel ROCK inhibitors and challenges associated with their development for clinical use will be discussed.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Intracellular Signaling Peptides and Proteins; Protein Serine-Threonine Kinases; rho-Associated Kinases; Substrate Specificity

RTRs are at high risk for ischemic heart disease and heart failure. Although some differences pertain, most of the major risk factors are similar to those in the general population. It is highly probable that interventions of proven benefit in the general population will also be of benefit in RTRs. A combination of lifestyle modifications (smoking cessation, maintenance of ideal bodyweight, healthy diet), aggressive blood pressure control (<130/80 mm Hg), use of ACE inhibitors or ARBs, lipid lowering with statins, antiplatelet therapy for diabetics and those with established coronary disease, and beta blockers for CHF or after myocardial infarction is likely to have a major benefit on patient survival and cardiac morbidity among transplant recipients. Coronary revascularization should be considered for the same indications as in the general population.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Kidney Transplantation; Myocardial Revascularization; Risk Factors; Risk Reduction Behavior

Endothelial progenitor cells (EPC) are bone marrow derived cells with the potential to differentiate into mature functional endothelial cells. First clinical trials have been performed investigating the effects of EPC transplantation into cardiac ischemic areas after myocardial infarction, in patients with peripheral atherovascular disease or on endothelialisation of artificial heart valves. Next to EPC transplantation, the pharmacological mobilisation and functional modification of EPC may also play a major role in future therapies. Studies have raised the concern that patients with coronary heart disease or severe heart failure may suffer from decreased amounts and impaired function of peripheral circulating EPC. Drug induced mobilization of EPC and normalization of EPC function may therefore improve prognosis of certain cardiovascular diseases. The underlying molecular events of a disturbed mobilisation, differentiation, homing and/or function of EPC are not well understood. In the present review we will highlight the current knowledge of the role of EPC dysfunction in various cardiovascular diseases and focus on potential causally related molecular mechanisms, which might be novel drug targets.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Endothelial Cells; Endothelium, Vascular; Humans; Stem Cells

Endothelin-1 (ET-1), the predominant isoform of the endothelin peptide family, has potent vasoconstrictor, mitogenic, pro-inflammatory and antinatriuretic properties which have been implicated in the pathophysiology of a number of cardiovascular diseases. ET-1 effects are mediated through activation of the G-protein-coupled ETA and ETB receptors, which are found in a variety of cells including endothelial, vascular smooth muscle and mesangial cells. Overexpression of ET-1 has been consistently described in salt-sensitive models of hypertension and in models of renal failure, and has been associated with disease progression. The development of a range of peptidic and nonpeptidic ET-1 receptor antagonists represents an exciting breakthrough in cardiovascular therapeutics. Endothelin antagonists improve endothelium-dependent relaxation and ameliorate vascular and cardiac hypertrophy as well as glomerulosclerosis; interestingly, these beneficial effects seem to occur independently of their capacity to lower blood pressure. The comparison between selective ETA and combined ETA/ETB antagonists in experimental models of cardiovascular diseases reveals no differences in terms of their effects on blood pressure, LV hemodynamics or remodeling. In the case of salt-sensitive hypertension, ETA receptor blockade leads to the prevention of vascular hypertrophy and renal function improvement, being likely that these effects are also mediated by ETB receptors based on the fact that the concomitant blockade of ETB receptors prevents the beneficial effects of ETA antagonists. As a whole, the available data indicate that the use of ET-1 receptor antagonists might be of therapeutic interest to prevent hypertension induced end-organ damage; however, the comparative efficacy of selective ETA vs. dual ETA/ETB blockade to prevent target organ injuries in humans still remains to be investigated.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Endothelin Receptor Antagonists; Endothelins; Humans

New therapeutic options such as the highly active antiretroviral therapy (HAART) have significantly improved morbidity and mortality of HIV-infected patients. Consequently, age-related diseases become more manifest. In addition, HIV infection itself causes certain cardiovascular morbidity. Therefore, treatment of cardiovascular symptoms of HIV-positive patients becomes more and more important. Pharmacotherapy in these patients is complex and requires polypharmacy with drugs carrying a high risk of drug-drug interactions.

Topics: Anti-Retroviral Agents; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Drug Interactions; HIV Infections; Humans; Practice Guidelines as Topic; Practice Patterns, Physicians'

The diagnoses and subsequent treatment of poisoned patients manifesting cardiovascular compromise challenges the most experienced emergency physician. Numerous drugs and chemicals cause cardiac and vascular disorders. Despite widely varying indications for therapeutic use, many agents share a common cardiovascular pharmacologic effect if taken in overdose. Standard advanced cardiac life support protocol care of these patients may not apply and may even result in harm if followed. This chapter discusses com-mon cardiovascular toxins and groups them into their common mechanisms of toxicity. Multiple agents exist that result in human cardiovascular toxicity. The management of the toxicity of each agent should follow a rationale approach. The first step in the care of all poisoned patients focuses on good supportive care.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Toxicology

Cardiovascular disease (CVD) is the major cause of death in developed countries and is rapidly becoming the major cause of death in the developing world. The increasing rates of obesity and type 2 diabetes, however, may slow the current favorable trends for deaths attributable to CVD in many developed countries. To improve control of risk factors for CVD, Wald and Law proposed a "polypill," containing a statin, a diuretic, a beta-blocker, an angiotensin-converting enzyme inhibitor, aspirin, and folic acid. This combination pharmacotherapy (CP) could be made widely available without treating specific risk factors or individuals. A workshop sponsored by the Centers for Disease Control and Prevention reviewed the concept of CP for both primary and secondary prevention. Combination pharmacotherapy may prove to be efficacious but may also have side effects and poor adherence, which may be greater than or less than that of other preventive approaches. Randomized trials are needed to study these issues, although the design for such trials is uncertain. The ability of CP to prevent CVD in a cost-effective manner must be demonstrated. Minority groups and people with low socioeconomic status in the United States have an increased risk for CVD, and the effectiveness of such pharmacotherapy must be considered for these populations. Combination pharmacotherapy may prove especially effective in the developing world, where studies of CP may precede those done in wealthier countries. Combination pharmacotherapy may have tremendous potential, but additional study and detailed evaluation are necessary.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Developing Countries; Drug Therapy, Combination; Health Care Costs; Humans; Life Style; Patient Compliance; Socioeconomic Factors

Metabolic syndrome is a constellation of clinical findings that identify individuals at higher than normal risk of developing diabetes mellitus or cardiovascular disease. There are two principal definitions, one emerging from the American National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, and the other from the World Health Organization. Both definitions share the common elements of abdominal obesity, hypertriglyceridaemia, low HDL-cholesterol, hypertension and abnormal glucose regulation. The syndrome is relatively common across continents, and also among those without marked obesity. It is even more common among patients with major mental health disorders such as schizophrenia. Metabolic syndrome can be used to assess risk for cardiovascular disorder and death, and is an alternative to Framingham Risk Calculations. C-reactive protein may play an additional role in risk prediction. Ongoing monitoring for all components of the metabolic syndrome is necessary. Individuals at high risk require multimodal interventions, including lifestyle interventions and targeted medications as appropriate.

Topics: Adult; Antipsychotic Agents; C-Reactive Protein; Cardiovascular Agents; Cardiovascular Diseases; Diet; Exercise; Female; Humans; Life Style; Male; Metabolic Syndrome; Middle Aged; Risk Assessment; Risk Factors; Risk Reduction Behavior; Schizophrenia; Schizophrenic Psychology; Terminology as Topic; Time Factors; Treatment Outcome

The increased expression and activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex has emerged as a major common factor in the etiology of all forms of cardiovascular diseases since the upregulation of intravascular NADPH oxidase results in the formation of superoxide (O(2)(-)), which in turn promotes vasculopathy. An ever-increasing number of drugs commonly used in cardiovascular medicine have been shown to influence NADPH oxidase expression and activity. These include nitric oxide donors, nitroaspirin, eicosanoids, phosphodiesterase inhibitors, corticosteroids, antioxidants, and specific inhibitors. The objective of this review is to discuss these drugs in relation to the mechanisms underlying their effects on NADPH oxidase activity and the expression and therapeutic implications of these effects.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Eicosanoids; Erectile Dysfunction; Glucocorticoids; Humans; Male; NADPH Oxidases; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Up-Regulation

Pharmacogenomics is the study of how an individual's genetic inheritance affects the body's response to drugs. Pharmacogenomics holds the promise that drugs might one day be tailor-made for individuals and adapted to an individual's genetic makeup. Several studies have shown that both adverse and beneficial responses to cardiovascular drugs can be influenced by single nucleotide polymorphisms in genes coding for metabolising enzymes, drug transporters and drug targets. Despite the large amount of data about gene-drug interactions, the translation of pharmacogenomics in clinical practise is slow. To improve this, there is a need of new technology and large prospective trials allowing for simultaneous analysis of multiple genetic variants in molecular pathways that could affect drug disposition and action.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide

The peroxisome proliferator-activated receptors (PPARs) comprise a group of related transcription factors that serve to regulate a number of cellular processes that are central to cardiovascular health and disease. Two large bodies of work strongly implicate the PPARs as key factors in normal cardiovascular physiology and in cardiovascular pathophysiology: i) studies demonstrating associations between PPAR and abnormal cardiovascular phenotypes; and ii) pharmacological studies assessing the effects of specific PPAR agonists in clinical trials. With the abundance of data available from these studies as a background, PPAR pharmacogenetics has become a promising and rapidly-advancing field. This review summarises the current state of understanding of PPAR pharmacogenetics and its profound implications for the individualisation of therapy for patients with a diverse group of cardiovascular diseases.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Gene Targeting; Humans; Peroxisome Proliferator-Activated Receptors; Pharmacogenetics

Personalized medicine is based on a better knowledge of biological variability, considering the important part due to genetics. When trying to identify involved genes and their products in differential cardiovascular drug responses, a five-step strategy is to be followed: 1) Pharmacokinetic-related genes and phenotypes (2) Pharmacodynamic targets, genes and products (3) Cardiovascular diseases and risks depending on specific or large metabolic cycles (4) Physiological variations of previously identified genes and proteins (5) Environment influences on them. After summarizing the most well-known genes involved in drug metabolism, we will take as example of drugs, the statins, considered as very important drugs from a Public-Health standpoint, but also for economical reasons. These drugs respond differently in human depending on multiple polymorphisms. We will give examples with common ApoE polymorphisms influencing the hypolipemic effects of statins. These drugs also have pleiotropic effects and decrease inflammatory markers. This illustrates the need to separate clinical diseases phenotypes in specific metabolic pathways, which could propose other classifications, of diseases and related genes. Hypertension is also a good example of clinical phenotype which should be followed after various therapeutic approaches by genes polymorphisms and proteins markers. Gene products are under clear environmental expression variations such as age, body mass index and obesity, alcohol, tobacco and dietary interventions which are the first therapeutical actions taken in cardiovascular diseases. But at each of the five steps, within a pharmacoproteomic strategy, we also need to use available information from peptides, proteins and metabolites, which usually are the gene products. A profiling approach, i.e., dealing with genomics, but now also with proteomics, is to be used. In conclusion, the profiling, as well as the large amount of data, will more than before render necessary an organized interpretation of DNA, RNA as well as proteins variations, both at individual and population level.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Genotype; Humans; Models, Biological; Pharmacogenetics; Phenotype; Proteomics

An increasing number of elderly patients are exposed to cardiovascular drugs for the treatment of acute and/or chronic conditions. This is a result of the progressive aging of the population, a common feature in most industrialised countries, and an improvement in primary and secondary cardiovascular prevention strategies with increased survival rates. Traditionally, most elderly patients receiving cardiovascular drugs had advanced cardiac, liver and kidney disease that significantly influenced drug pharmacokinetic and pharmacodynamic parameters. Currently, however, many patients without significant organ impairment receive cardiovascular therapy for primary or early secondary prevention (i.e. increased vascular risk, asymptomatic left ventricular dysfunction, poststroke phase, type 2 diabetes mellitus), highlighting the need for a better understanding of specific age-related pharmacokinetic and pharmacodynamic effects. A systematic review has been conducted on the specific effects of aging, in the absence of major co-morbidities, on the pharmacokinetic and pharmacodynamic properties of traditional and newer cardiovascular drugs. Currently, the evidence available is poor or nonexisting for several drugs and mainly derived from very small and underpowered studies, thus limiting data interpretation. In particular, there is very little information on patients >80 years of age, thus raising important concerns about the correct use of these drugs in this constantly growing population.

Topics: Aged; Aged, 80 and over; Aging; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Clinical Trials as Topic; Humans

This article reviews the various cardiovascular drugs for newborns, including antiarrhythmics, antihypertensives, inotropes, and pulmonary vasodilators. Antiarrhythmic drugs are classified according to their mechanisms of action, such as effects on ion channels, duration of repolarization, and receptor interaction, which help with understanding the effects of individual antiarrhythmic drugs and selection of drugs for specific arrhythmias. Drug treatment for hypertension should start with a single drug from one of the following classes: ACE inhibitors, angiotensin-receptor antagonists, beta-receptor antagonists, calcium channel blockers, or diuretics. The inotropic drug should be selected according to its specific pharmacologic properties and the specific cardiovascular abnormality to be corrected. An effective pulmonary vasodilator must dilate the pulmonary vasculature more than the systemic vasculature.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Infant, Newborn; Infant, Newborn, Diseases

Topics: Amiodarone; Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Humans; Hypothyroidism; Risk Factors; Thyroxine

In the past 12 months, the FDA has approved important new pharmaceutical drugs and devices of particular interest to primary health care providers. The drugs include: Oxytrol (for urinary incontinence), Valtrex (for reducing the risk of heterosexual transmission of genital herpes), Femring (for vaginal delivery of hormone therapy), Uroxatral (for benign prostatic hypertrophy), Levitra (for erectile dysfunction), Flumist (for preventing influenza), Xolair (for asthma), Raptiva (for psoriasis), Cubicin (for skin infections), Crestor (for hypercholesterolemia), and Coreg (for severe heart failure).

Topics: Acyclovir; Cardiovascular Agents; Cardiovascular Diseases; Dermatologic Agents; Drug Approval; Estrogen Replacement Therapy; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Immunologic Factors; Male; Mandelic Acids; Skin Diseases; Valacyclovir; Valine; Women's Health

The use of complementary and alternative medical (CAM) practices in the United States is growing rapidly. In this manuscript, we review some of the most commonly used biologically based approaches, including herbs, supplements, and other pharmacological therapies, that are encountered in caring for patients with cardiovascular disease, focusing on potential effects, adverse effects, and treatment interactions.. Between November 2002 and April 2003, we searched Medline and the National Center for Complementary and Alternative Medicine (NCCAM) web site and its various references and several complementary medicine text books. The key words used were: "cardiovascular diseases," "coronary disease," "heart failure, congestive," "complementary and alternative medicine," "complementary therapies," "drug interactions," and "plants, medicinal." A keyword search of each individual supplement identified was also performed. Additionally, we relied on expert opinion in the field.. Potentially serious adverse effects and interactions with conventional cardiovascular therapies exist for many herbs and supplements. There are currently scarce mechanistic data and very limited data on the effect of CAM therapies on clinical outcomes.. Randomized clinical trials with adequate power to detect effects of CAM therapies on clinical outcomes and safety are needed. Until these data are available, clinicians must be aware of the increasing use of CAM approaches by their patients and the potential for interactions with conventional therapies and should focus on treatment with proven, evidence-based strategies.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Complementary Therapies; Drug Interactions; Humans; Phytotherapy; Plant Preparations

Topics: Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Contraindications; Diet; Estrogen Replacement Therapy; Evidence-Based Medicine; Exercise; Expert Testimony; Female; Forecasting; Health Priorities; Humans; Hyperlipidemias; Hypertension; Life Style; Patient Education as Topic; Risk Factors; Smoking Cessation

Protein kinases are enzymes that covalently modify proteins by attaching phosphate groups (from ATP) to serine, threonine, and/or tyrosine residues. In so doing, the functional properties of the protein kinase's substrates are modified. Protein kinases transduce signals from the cell membrane into the interior of the cell. Such signals include not only those arising from ligand-receptor interactions but also environmental perturbations such as when the membrane undergoes mechanical deformation (ie, cell stretch or shear stress). Ultimately, the activation of signaling pathways that use protein kinases often culminates in the reprogramming of gene expression through the direct regulation of transcription factors or through the regulation of mRNA stability or protein translation. Protein kinases regulate most aspects of normal cellular function. The pathophysiological dysfunction of protein kinase signaling pathways underlies the molecular basis of many cancers and of several manifestations of cardiovascular disease, such as hypertrophy and other types of left ventricular remodeling, ischemia/reperfusion injury, angiogenesis, and atherogenesis. Given their roles in such a wide variety of disease states, protein kinases are rapidly becoming extremely attractive targets for drug discovery, probably second only to heterotrimeric G protein-coupled receptors (eg, angiotensin II). Here, we will review the reasons for this explosion in interest in inhibitors of protein kinases and will describe the process of identifying novel drugs directed against kinases. We will specifically focus on disease states for which drug development has proceeded to the point of clinical or advanced preclinical studies.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Gene Expression Regulation; Humans; MAP Kinase Signaling System; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Protein Processing, Post-Translational; Rabbits; Signal Transduction

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cytochrome P-450 Enzyme System; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide; Treatment Outcome

To discuss the role of CD40 ligand (CD40L) in atherosclerosis and acute coronary syndromes (ACS), as well as describe relevant clinical literature evaluating the effects of pharmacotherapeutic agents on CD40L expression and soluble CD40L levels.. A MEDLINE and EMBASE search (1966-September 2003) was conducted using the key terms CD40, CD40 ligand, platelets, inflammation, and drug therapy. Additional primary literature was identified by reviewing the reference lists of relevant original and review papers.. All articles identified in the search were evaluated, and those deemed relevant were incorporated into the review.. CD40L is a transmembrane protein expressed on T cells, B cells, mast cells, basophils, eosinophils, natural killer cells, macrophages, endothelial cells, vascular smooth muscle cells, and activated platelets. It is also found in plasma as a soluble protein, sCD40L. As a consequence of CD40L binding to its receptor (CD40), several inflammatory processes are initiated. Studies have demonstrated elevated CD40L levels in patients with hypercholesterolemia and ACS, and elevated sCD40L levels have been associated with increased risk of cardiovascular events. Statins, glitazones, glycoprotein IIb/IIIa inhibitors, and clopidogrel have been demonstrated to effectively reduce CD40L levels both in vitro and in vivo. Abciximab has been shown to reduce the occurrence of death or myocardial infarction during 6 months of follow-up in patients with ACS who had the highest levels of sCD40L.. The proinflammatory and procoagulant protein CD40L represents a novel target in the treatment of atherosclerosis and ACS. A number of therapeutic agents have been shown to modulate the expression of CD40L, findings that could have important clinical applications.

Topics: Cardiovascular Agents; Cardiovascular Diseases; CD40 Ligand; Clinical Trials as Topic; Clopidogrel; Coronary Artery Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Thiazolidinediones; Ticlopidine

Phytoestrogenic molecules have received a great deal of attention over the last few years because of their potentially preventive roles against a few of today's most prevalent chronic diseases, namely cardiovascular diseases, osteoporosis and hormone related cancers. Of the several phytoestrogens, genistein in particular has been shown to be the most efficacious in animal models and experimental studies. Genistein in vitro relaxes rat arteries by a nitric oxide dependent mechanism and enhances the dilator response to acetylcholine of atherosclerotic arteries. Genistein supplementation improves endothelial dysfunction induced by oophorectomy in rats and reduces infarct size in an experimental model of myocardial ischaemia-reperfusion injury. Furthermore, genistein in postmenopausal women increases plasma nitric oxide breakdown products, reduces endothelin-1 levels and improves endothelial dependent vasodilation in post-menopausal women. All these findings, taken together, would suggest that this molecule might represent an attractive alternative for cardiovascular protection.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Female; Genistein; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Postmenopause

The phytoantitoxin resveratrol is a plant-derived polyphenol with phytoestrogenic properties. Resveratrol protects the cardiovascular system by mechanisms that include defense against ischemic-reperfusion injury, promotion of vasorelaxation, protection and maintenance of intact endothelium, anti-atherosclerotic properties, inhibition of low-density lipoprotein oxidation, suppression of platelet aggregation, and estrogen-like actions. The purpose of this article is to review the mechanisms of these effects.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Cell Division; Humans; Phytoestrogens; Resveratrol; Signal Transduction; Stilbenes

Grapefruit juice can alter oral drug pharmacokinetics by different mechanisms. Irreversible inactivation of intestinal cytochrome P450 (CYP) 3A4 is produced by commercial grapefruit juice given as a single normal amount (e.g. 200-300 mL) or by whole fresh fruit segments. As a result, presystemic metabolism is reduced and oral drug bioavailability increased. Enhanced oral drug bioavailability can occur 24 hours after juice consumption. Inhibition of P-glycoprotein (P-gp) is a possible mechanism that increases oral drug bioavailability by reducing intestinal and/or hepatic efflux transport. Recently, inhibition of organic anion transporting polypeptides by grapefruit juice was observed in vitro; intestinal uptake transport appeared decreased as oral drug bioavailability was reduced. Numerous medications used in the prevention or treatment of coronary artery disease and its complications have been observed or are predicted to interact with grapefruit juice. Such interactions may increase the risk of rhabdomyolysis when dyslipidemia is treated with the HMG-CoA reductase inhibitors atorvastatin, lovastatin, or simvastatin. Potential alternative agents are pravastatin, fluvastatin, or rosuvastatin. Such interactions might also cause excessive vasodilatation when hypertension is managed with the dihydropyridines felodipine, nicardipine, nifedipine, nisoldipine, or nitrendipine. An alternative agent could be amlodipine. In contrast, the therapeutic effect of the angiotensin II type 1 receptor antagonist losartan may be reduced by grapefruit juice. Grapefruit juice interacting with the antidiabetic agent repaglinide may cause hypoglycemia, and interaction with the appetite suppressant sibutramine may cause elevated BP and HR. In angina pectoris, administration of grapefruit juice could result in atrioventricular conduction disorders with verapamil or attenuated antiplatelet activity with clopidrogel. Grapefruit juice may enhance drug toxicity for antiarrhythmic agents such as amiodarone, quinidine, disopyramide, or propafenone, and for the congestive heart failure drug, carvediol. Some drugs for the treatment of peripheral or central vascular disease also have the potential to interact with grapefruit juice. Interaction with sildenafil, tadalafil, or vardenafil for erectile dysfunction, may cause serious systemic vasodilatation especially when combined with a nitrate. Interaction between ergotamine for migraine and grapefruit juice may cause gangrene or stroke. In

Topics: Beverages; Cardiovascular Agents; Cardiovascular Diseases; Citrus paradisi; Food-Drug Interactions; Humans

Topics: Cardiovascular Agents; Cardiovascular Diseases; Family Practice; Humans; Hyperlipidemias; Hypertension; Life Style; Metabolic Syndrome; Obesity; Risk Factors

Kinins are located in the vascular smooth muscle and the heart, and are the most potent biologically active polypeptides. Pharmacological studies of cardiovascular disorders, including hypertension, cardiac failure, ischemia, myocardial infarction and left ventricular hypertrophy, indicate that reduced activity of the local kallikrein-kinin system (KKS) may be instrumental in the induction of these disorders. The ability of kallikrein gene delivery and bradykinin (BK) B2 receptor agonists to produce a wide spectrum of beneficial effects make them excellent candidate therapies for the treatment of hypertension, and cardiovascular and renal diseases. In addition, strategies that activate kinin receptors may be applicable to the treatment of cardiovascular and renal disorders. However, one major challenge of this approach is the unanswered question of whether there is a sufficiently safe therapeutic index between the potential cardioprotective and pro-inflammatory effects following administration of BK B2 receptor agonists.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Kallikrein-Kinin System; Receptors, Bradykinin

Vitamin D3 plays a key role in regulating calcium and mineral homeostasis in support of normal development and maintenance of bone. The classic effects of vitamin D3 include promoting absorption of dietary calcium in the gut and, through its actions as a steroid endocrine hormone, regulating the synthesis and secretion of parathyroid hormone. The effects of the vitamin D3 system are mediated through the highly regulated generation of the potent, active metabolite 1,25-dihydroxyvitamin D3 (calcitriol). Vitamin D3 exerts its effects through the vitamin D3 receptor (VDR), a ligand-activated nuclear receptor expressed in a wide array of tissue and cell types. Studies performed in mice rendered deficient for VDR suggest that calcitriol and VDR may inhibit the renin-angiotensin system and reduce blood pressure in the long-term. Clinical studies suggest that administration of vitamin D3 analogs produces differential benefit with regards to mortality in dialysis patients; other studies suggest that vitamin D3 analogs may provide cardiovascular benefit in both dialysis and nondialysis patients. This paper reviews clinical and preclinical studies, which suggest that vitamin D3 analogs may provide therapeutic utility in the treatment of cardiovascular disease independent of those mechanisms typically associated with the vitamin D3 endocrine system.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cholecalciferol; Clinical Trials as Topic; Heart Failure; Humans; Hypertension; Parathyroid Hormone

Neuropeptide Y (NPY), a sympathetic co-transmitter, acts through multiple G protein-coupled receptors (Y1 to y6) to elicit its vast range of effects in the cardiovascular, immune, and central and peripheral nervous systems. Initially, the focus of the function of NPY in the cardiovascular system involved its acute actions, such as vasoconstriction via the Y1 receptor. However, recent studies have shown that NPY is a potent growth and angiogenic factor, which acts on multiple receptor subtypes. To be more specific, NPY-mediated vascular smooth muscle cell growth, leading to neointima formation, involves Y1 and Y1 receptors, while the angiogenic effects of NPY include Y2 and Y5 receptor activation. The presence of dipeptidyl peptidase IV also influences the cardiovascular responses of NPY by acting as a converting enzyme, shifting NPY activities away from Y1. Thus, agonists and antagonists aimed at the NPY system represent a new avenue for drug treatment, which may help alleviate several cardiovascular disorders in which vascular remodeling plays a major role, such as atherosclerosis, restenosis following balloon angioplasty, hypertension and peripheral vascular disease.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Muscle, Smooth, Vascular; Neuropeptide Y; Receptors, Neuropeptide Y; Tunica Intima

Pfizer, following its acquisition of Esperion Therapeutics in the first quarter of 2004, is developing ETC-588 as a potential acute treatment for ischemia caused by atherosclerosis. Enrollment in phase II trials in patients with acute coronary syndrome is complete.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Phosphatidylcholines; Randomized Controlled Trials as Topic

Patients differ in their response to drugs. Part of this variability may reflect genetically-determined characteristics of target genes or metabolizing enzymes. A knowledge of an individual's genetic makeup could allow drug therapy to be targeted at those most likely to benefit.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Drug Resistance; Drug Tolerance; Gene Targeting; Genome, Human; Humans

Advanced glycation end product (AGE) formation that occurs with aging and diabetes leads to the cross-linking of proteins and subsequent changes in the physicochemical properties of tissues. Cellular responses to AGE that lead to either pathological conditions or removal of AGE are mediated by a number of receptors that have been identified on various cell types such as macrophages, endothelial cells, and smooth-muscle cells. Mechanisms by which AGE affect the cardiovascular system include AGE cross-linking of long-lived proteins such as collagen and elastin and altered cellular responses. Alagebrium (3-phenacyl-4,5-dimethylthiazolium chloride, ALT-711) is the first drug in a new class of thiazolium therapeutic agents that break established AGE cross-links between proteins. In animal studies, alagebrium was effective in reducing large artery stiffness, slowing pulse-wave velocity, enhancing cardiac output, and improving left ventricular diastolic distensibility. In human studies to determine safety and efficacy, alagebrium was safe and well tolerated. In the first phase 2 clinical study, alagebrium improved arterial compliance in elderly patients with vascular stiffening. In two subsequent phase 2 clinical studies, one addressing diastolic heart failure and the other addressing systolic hypertension, alagebrium was effective in improving cardiac function and uncontrolled systolic blood pressure, particularly in more severely affected patients. Additional clinical studies to determine the utility of alagebrium in treating cardiovascular disorders associated with aging are in progress.

Topics: Aging; Animals; Blood Pressure; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Glycation End Products, Advanced; Heart Failure; Humans; Hypertension; Thiazoles

To analyze cardiovascular disease (CVD) along wit it's contributing risk factors in women with diabetes mellitus (DM) and from this, to recommend prevention strategies.. A review of pertinent studies serves as the basis for the analysis and recommendations of prevention strategies in this group.. Women with (DM) show a higher morbidity and mortality from CVD. The presence of DM confers these individuals the same risk of having a coronary event as present in a non-diabetic person who has suffered a previous myocardial infarction. Arterial hypertension, a characteristic dyslipidaemia (hypertrigliceridemia, low level of high density lipoprotein cholesterol and elevated low density lipoprotein cholesterol), obesity, microalbuminuria, platelet hyperaggregability and endothelial dysfunction converge conferring the women with DM a higher susceptibility to atherosclerosis. Recommendations include: lifestyle intervention weight reduction, increase in physical activity and smoking cessation. Women with DM should target to lower the LDL-C to a level below 100 mg/dl, the blood pressure level to below 130/80 mm Hg and triglycerides to less than 150 mg/dl. The goal is to raise HDL-C to a level over 45 mg/dl and reduce hemoglobin A1c (HbAlc) levels to below seven (7%) percent. Women with DM should use aspirin on a daily basis, unless contraindicated. These actions may lead to the reduction of the burden of CVD in women with DM.. This article summarizes the recent salient features of CVD in women with DM with emphasis on preventive measures as well as on the understanding of prevailing guidelines established under the principles of evidence based medicine.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Female; Guidelines as Topic; Humans; Risk Factors

At the beginning of a new millennium, several important questions have come to the fore connected with the utilization of natural resources for the investigation of new medicaments (necessity of cooperation of both highly developed and developing countries in the protection of natural resources, necessity to justly evaluate and reward the contributions of the individual cultures in the case that a knowledge of traditional medicine was employed in the development of a new medicament, necessity to achieve the maximal chemical variety of real and virtual libraries of substances from which potential drugs are selected for screening tests). The research of chalcones and its analogues which are relatively easily available not only by isolation from natural material, but also by the methods of classical and combinatorial synthesis should not be substantially affected by the above-described changes. The present communication links up with previous papers (Opletalová, V., Sedivý, D.: Ces. slov. Farm. 48, 252 (1999); Opletalová, V.: Ces. slov. Farm. 49, 278 (2000); Opletalová, V. et al.: Folia Pharm. Univ. Carol. 25, 21 (2000)) and is devoted to the stabilizing action of chalcones on the vascular wall, vasodilating and anti-aggregating effects, and a favourable effect of their antioxidative activity on the functions of the cardiovascular system. The introduction also briefly discusses the nomenclature of this group of compounds.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Chalcone; Humans

Cardiovascular diseases represent a widespread heterogeneous group of conditions that have significant morbidity and mortality. The various diseases and their treatments can have an impact upon the periodontium and the delivery of periodontal care.. In this paper we consider three main topics and explore their relationship to the periodontist and the provision of periodontal treatment.. The areas reviewed include the effect of cardiovascular drugs on the periodontium and management of patients with periodontal diseases; the risk of infective endocarditis arising from periodontal procedures; the inter-relationship between periodontal disease and coronary artery disease.. Calcium-channel blockers and beta-adrenoceptor blockers cause gingival overgrowth and tooth demineralisation, respectively. Evidence suggests that stopping anticoagulant therapy prior to periodontal procedures is putting patients at a greater risk of thromboembolic disorders compared to the risk of prolonged bleeding. The relationship between dentistry and infective endocarditis remains a controversial issue. It would appear that spontaneous bacteraemia arising from a patient's oral hygiene practices is more likely to be the cause of endocarditis than one-off periodontal procedures. The efficacy of antibiotic prophylaxis is uncertain (and unlikely to be proven), and the risk of death from penicillin appears to be greater than the risk of death arising from infective endocarditis. Finally, the association between periodontal disease and coronary artery disease has been explored and there seem to be many issues with respect to data handling interpretation. Many putative mechanisms have been suggested; however, these only further highlight the need for intervention studies.

Topics: Bacteremia; Cardiovascular Agents; Cardiovascular Diseases; Coronary Disease; Endocarditis, Bacterial; Humans; Periodontal Diseases; Periodontium; Risk Factors

Topics: Arteriosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Embolism; Endocarditis, Bacterial; Eye Diseases; Giant Cell Arteritis; Humans; Medical History Taking; Ocular Hypertension; Retinal Vein Occlusion; Syndrome

Anticoagulants and antithrombotic drugs have played a key role in the prophylaxis, treatment and surgica/interventional management of thrombotic and cardiovascular disorders. There are several newer drugs which are currently developed for the anticoagulant management of cardiovascular diseases in both the medical and surgical indications. These include the low molecular weight heparins (LMWHs), antithrombin agents such as the Hirudin, Hirulog and Argatroban and indirect and direct anti-Xa drugs, represented by Pentasaccharide (Arixtra) and DX 9065a, respectively. Several other agents such as the natural and recombinant anti-Xa drugs and anti-tissue factor agents are also developed. The antiplatelet agents include Clopidogrel, Cilostazol, Anplag and GP IIb/IIIa inhibitors. For the subcutaneous indications, unfractionated heparin is gradually replaced by the low molecular weight heparins (LMWHs). LMWHs such as the Enoxaparin and Dalteparin are commonly used for the management of acute coronary syndrome. These drugs have been approved for the treatment of unstable angina and are currently undergoing rigorous trials for interventional indications. Arixtra is also developed for various subcutaneous indications. However, it exhibits lower anticoagulant effects and may not be optimal for intravenous and interventional purposes. At a higher dosage when administered intravenously the LMWHs produce varying degrees of anticoagulation at relatively lower activated clotting times (150-200). Several studies in vascular and cardiovascular interventions have shown that even at a relatively lower anticoagulant level the LMWHs are as effective as unfractionated heparin at the recommended dosages which produce a relatively higher level of anticoagulation (ACT > 200 secs.). Thus, these agents are currently developed for interventional and surgical indications. It should be emphasized that different LMWHs produce different degrees of anticoagulation and should therefore be individually optimized for a given interventional or surgical purposes. At a relatively high dosage the levels of LMWHs can be measured by using the ACT and APTT. When administered with such GP IIb/IIIa inhibitors as the Abciximab, Aggrastat or Eptifibratide, these drugs may require dosage adjustment However, since the introduction of the front loading of Clopidogrel, the unqualified use of GP IIb/IIIa is debated. LMWHs will find expanded indications in both the medical and surgical management of patients w

Topics: Anticoagulants; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Factor Xa Inhibitors; Fibrinolytic Agents; Forecasting; Heparin, Low-Molecular-Weight; Humans; Platelet Aggregation Inhibitors; Thrombin; Thrombosis

Purine receptor subtypes are expressed with some selectivity on different types of cells in the cardiovascular system and are possible targets for therapeutic strategies in cardiovascular diseases. The considerable efforts of the clinical biochemists working in this field is leading to a promising emergence of subtype-specific P2 ligands. This will open up new avenues for research into the physiological roles of purine receptors and their therapeutic potential.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Drug Design; Humans; Nucleotidases; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Purinergic P2 Receptor Agonists; Purinergic P2 Receptor Antagonists; Purines; Pyrimidines; Receptors, Purinergic P1; Receptors, Purinergic P2; Signal Transduction

Topics: C-Reactive Protein; Cardiovascular Agents; Cardiovascular Diseases; Humans; Incidence; Metabolic Diseases; Predictive Value of Tests; Risk

Activation of vascular NAD(P)H oxidases and the production of reactive oxygen species (ROS) by these enzyme systems are common in cardiovascular disease. In the past several years, a new family of NAD(P)H oxidase subunits, known as the non-phagocytic NAD(P)H oxidase (NOX) proteins, have been discovered and shown to play a role in vascular tissues. Recent studies make clearer the mechanisms of activation of the endothelial and vascular smooth muscle NAD(P)H oxidases. ROS produced following angiotensin II-mediated stimulation of NAD(P)H oxidases signal through pathways such as mitogen-activated protein kinases, tyrosine kinases and transcription factors, and lead to events such as inflammation, hypertrophy, remodeling and angiogenesis. Studies in mice that are deficient in p47(phox) and gp91(phox) (also known as NOX2) NAD(P)H oxidase subunits show that ROS produced by these oxidases contribute to cardiovascular diseases including atherosclerosis and hypertension. Recently, efforts have been devoted to developing inhibitors of NAD(P)H oxidases that will provide useful experimental tools and might have therapeutic potential in the treatment of human diseases.

Topics: Angiotensin II; Animals; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Enzyme Activation; Humans; Mice; NADPH Oxidases; Reactive Oxygen Species

Although cardiovascular disease continues to be the major cause of morbidity and mortality in diabetes, the understanding that multiple risk factor intervention is the cornerstone of diabetes management is leading to significant benefits for patients. Aggressive goal setting for modifiable cardiovascular risk factors that cluster in patients with diabetes, such as dyslipidemia, hypertension, and a procoagulant state, and judicious selection of efficacious therapies have been shown to produce significant reductions in cardiovascular events, and in some cases mortality, in controlled clinical trials. Although effective control of hyperglycemia per se has at most modest impact, the choice and application of antihyperglycemic therapies add to the benefit. In addition, newer agents and early intervention in prediabetic and diabetic individuals hold promise for even greater success in the prevention of this important complication of diabetes.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Humans; Hypoglycemic Agents

The adhesion molecule P-selectin (CD62P) is of interest because of its role in modulating interactions between blood cells and the endothelium, and also because of the possible use of the soluble form as a plasma predictor of adverse cardiovascular events. Although present on the external cell surface of both activated endothelium and activated platelets, it now seems clear that most, if not all, of the measured plasma P-selectin is of platelet origin. P-selectin is partially responsible for the adhesion of certain leukocytes and platelets to the endothelium. Animal models have also shown the important role of P-selectin in the process of atherogenesis. For example, increased P-selectin expression has been demonstrated on active atherosclerotic plaques; in contrast, fibrotic inactive plaques lack P-selectin expression, and animals lacking P-selectin have a decreased tendency to form atherosclerotic plaques. Increased levels of soluble P-selectin in the plasma have also been demonstrated in a variety of cardiovascular disorders, including coronary artery disease, hypertension and atrial fibrillation, with some relationship to prognosis. The objective of this review is to provide an overview of the current literature on this molecule and thus present a concise view of its potential in dissecting the pathophysiology of atherosclerosis. In doing so we shall focus primarily on human biology but will note a small number of excellent lessons provided by non-human work.

Topics: Arteriosclerosis; Blood Platelets; Cardiovascular Agents; Cardiovascular Diseases; Cross-Sectional Studies; Endothelial Cells; Endothelium, Vascular; Humans; P-Selectin; Risk Factors

Prevalence of cardiovascular diseases increases with advancing age. Moreover, these patients are getting older and older. Therefore, pharmacotherapy of the elderly becomes a major objective in clinical cardiology. Pharmacodynamic and pharmacokinetic changes in the elderly can interfere with a sufficient treatment of cardiovascular diseases and moreover, multiple drug usage is a considerable risk factor of possible drug-drug interactions. Furthermore, treatment of cardiovascular diseases as hypertension, heart failure or coronary heart disease in the elderly according to the international guidelines is often limited due to co-morbidities restricting usage of the appropriate medication. This review addresses both, the treatment of cardiovascular diseases in the elderly and the pharmacological characteristics of frequently used drugs.

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Humans; Risk Factors

Cardiovascular therapeutics is a vast and evolving area for researchers, primary care physicians and specialists. To help keep you up-to-date with the latest advances worldwide on all aspects of drug therapy and management of cardiovascular disorders, this section of the journal brings you information selected from the drug therapy reporting service Inpharma Weekly. The following reports are selected from the latest issues, summarizing the most important research and development news, clinical studies, treatment guidelines, pharmacoeconomic and adverse reaction news, and expert opinion pieces published across a broad range of literature sources.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Evidence-Based Medicine; Humans

The genetic polymorphisms that may affect individual responses to cardiovascular agents are reviewed, and the application of pharmacogenetics to cardiovascular disease management is discussed. Pharmacogenetics is the search for genetic polymorphisms that affect responses to drug therapy. Investigators have found many associations between genetic polymorphisms and responses to cardiovascular drugs. Some of these relationships have been demonstrated in large patient populations, such as patients with ischemic heart disease receiving statins. Study data consistently show a greater response to statins in ischemic heart disease patients with genotypes associated with worse prognoses. Studies of other polymorphisms, such as those in the genes encoding anglotensin-converting enzyme and beta 1-adrenergic receptors, have less consistently found relationships between these variations and cardiovascular drug responses. For gene-drug response associations for which the data are inconsistent, the interaction of multiple polymorphisms in multiple genes coding for proteins affected by drug therapy or influencing drug metabolism may prove to have a greater influence on drug responses than any one polymorphism. Once the polymorphisms that best determine the response to a particular drug are known and tests to rapidly identify these variations are available, individual patients may be screened for genetic polymorphisms before drug therapy is begun and the information used to choose agents with the greatest potential for efficacy and least potential for toxicity. Pharmacogenetics has many possible applications in the drug therapy of cardiovascular diseases. Much more must be learned, however, before pharmacogenetic factors can be routinely incorporated into therapeutic decisions.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Pharmacogenetics; Polymorphism, Genetic; Receptors, Adrenergic, beta; Renin-Angiotensin System

Endothelial production of nitric oxide (nitrogen monoxide, NO) has become a major research area in vascular biology. Some of the most important effects that NO exerts in the vascular wall are potentially vasoprotective, because these effects maintain important physiological functions such as vasodilation, anticoagulation, leucocyte adhesion, smooth muscle proliferation, and the antioxidative capacity. During the last 2 decades it has become apparent that a variety of diseases are associated with an impairment of endothelium-dependent NO activity. One of the major causes is believed to be an increased production of reactive oxygen species, in particular superoxide, which have been shown to interfere with many steps of the NO--cyclic guanosine monophosphate (cGMP) pathway. This phenomenon has been found in diverse conditions such as atherosclerosis, hypertension, diabetes, hypercholesterolemia, heart failure, and cigarette smoking. The aim of this review is to examine the cellular and molecular mechanisms whereby NO exerts potentially vasoprotective effects and to discuss pharmacologic approaches targeting the NO pathway in view of their potential to improve endothelial function and to reduce the progression of atherosclerotic vascular disease. We conclude that there is compelling evidence for vasoprotective actions of NO which are mediated by cGMP-dependent and cGMP-independent mechanisms. These effects may contribute to the beneficial effects of established drugs such as ACE inhibitors or statins. Unfortunately, clinical data on the effect of long-term treatment with nitrates on the progression of coronary artery disease are lacking. Finally, L-arginine or new activators of the NO pathway may become therapeutic options in the future.

Topics: Blood Coagulation; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Humans; Nitric Oxide; Vasodilation

Cardiovascular disease is the leading cause of death in patients aged 65 and above. Although elderly persons represent only 12.4% of the US population, they account for about a third of drug expenditures. However the appropriate use of cardiovascular medications in these patients has been shown to reduce the rate of cardiovascular morbidity and mortality. The normal aging and the disease process in the elderly result in significant changes at the structural and molecular level in the elderly. The changes that take place in the autonomic nervous system, the kidneys, and the liver in the elderly modify the metabolism and clinical effects of most medications. Elderly patients are also susceptible to side effects and adverse drug reactions. Physicians should have a clear understanding of the normal aging processes, the abnormal changes due to disease process and the changes in the pharmacology of drugs in the elderly to deliver proper care to the elderly patient.

Topics: Aged; Aging; Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Humans

A high standard of proof of efficacy and safety is required in clinical trials. This standard requires careful translation into practice, combining an evidence-based approach with clinical experience and judgment to maximise patient benefits and minimise harms. The tendency to extend application of new treatments to patient groups other than those for whom reliable data exist should be avoided. Equally, extrapolation of the data to agents of the same class untested for particular indications should not occur. If the considerable potential benefits of modern cardiovascular therapeutics are to be maximised and harms avoided, clinicians should observe these principles carefully as new treatments become accessible and are applied.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Evidence-Based Medicine; Humans; Patient Selection; Treatment Outcome

Angiotensin-receptor blockers have been part of the antihypertensive treatment armamentarium since the mid-1990s. During this period, the number of agents has increased greatly, as has the number of indications for which these drugs are being tested in randomized controlled clinical trials. Beginning as efficacious and very well tolerated antihypertensives, angiotensin-receptor blockers have been shown to have benefits in patients with diabetes and heart failure that are not only attributable to the reduced blood pressure, as supported by recently concluded trials. The expanding treatment areas with these agents widen the interest in their applicability across the entire cardiovascular continuum. A number of large-scale studies set to report within the next few years will further determine the effects of angiotensin-receptor blockers in a range of cardiovascular indications beyond hypertension.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Failure; Humans; Myocardial Infarction; Renin-Angiotensin System

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Oligonucleotide Array Sequence Analysis

The completion of sequencing of the human genome will be the vanguard for numerous advances in medicine. The first discernible application is likely to occur in pharmacogenomics, a field focused on the influence of genetic differences on the variability in patients' response to medications. While an inherited basis for drug response has been recognized for some time, it is the confluence of molecular biology, high-throughput genotyping, and bioinformatics that has made it practical to study the genetic basis of variability to medications on a large scale. Pharmacogenomics may enable clinicians to prospectively identify patients most likely to derive benefit from a drug, with minimal likelihood of adverse events. This DNA-based approach to predicting clinical drug efficacy and toxicity would shift the current prescribing paradigm from its empirical nature to a more patient-specific model, ushering in a new era of personalized medicine. Polymorphisms in drug metabolizing enzymes, drug targets, and disease pathogenesis genes are associated with therapeutic effect to cardiovascular pharmacotherapy. Moreover, pharmacogenomics and functional genomics are expected to have a profound impact on the process of drug discovery and development. Finally, pharmacogenomics is likely to transform the way clinical trials are conducted by allowing for the selection of a more homogeneous study population, thereby reducing the size and cost of clinical investigation.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Drug Design; Genome, Human; Humans; Pharmacogenetics; Polymorphism, Genetic

Type 2 diabetes increases the risk of cardiovascular disease two- to fourfold compared to the risk in nondiabetic subjects. Although type 2 diabetes is associated with a clustering of risk factors, the cause for an excess risk of cardiovascular disease remains unknown. Lipid and lipoprotein abnormalities in type 2 diabetes include particularly elevated levels of total and very low-density lipoprotein triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol. Total and low-density lipoprotein (LDL) cholesterol levels are usually normal if glycemic control is adequate but LDL particles are small and dense. According to prospective population-based studies, total cholesterol is a similar risk factor for coronary heart disease (CHD) in patients with type 2 diabetes as it is in nondiabetic subjects. High total triglycerides and low HDL cholesterol may be even stronger risk factors for CHD in patients with type 2 diabetes than in nondiabetic subjects. Recent drug treatment trials have indicated that the lowering of total and LDL cholesterol by statins, and the lowering of total triglycerides and the raising of HDL cholesterol by fibrates, are at least as beneficial in diabetic patients as in nondiabetic subjects in the prevention of cardiovascular disease.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clofibric Acid; Diabetes Mellitus, Type 2; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Lipids; Lipoproteins

Women frequently chose alternatives to hormone replacement therapy (HRT) for treatment of menopause even though medical indications for estrogens may be present. Prior breast cancer or fear of breast cancer is a major consideration. This review of alternatives to estrogen discusses the evidence linking breast cancer to HRTs and compares potential risks and benefits of HRT to nonHRT alternatives for relief of vasomotor symptoms, vaginal atrophy, neurocognitive changes and prevention of heart disease and osteoporosis. Practical guidelines are suggested for use of alternatives for each problem.

Topics: Aged; Antidepressive Agents; Atrophy; Bone Density; Bone Resorption; Breast Neoplasms; Calcitonin; Calcium; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Contraindications; Diphosphonates; Double-Blind Method; Estrogen Replacement Therapy; Estrogens; Estrogens, Non-Steroidal; Female; Fractures, Bone; Hot Flashes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Isoflavones; Life Style; Menopause; Mental Disorders; Meta-Analysis as Topic; Middle Aged; Multicenter Studies as Topic; Osteoporosis, Postmenopausal; Phytoestrogens; Phytotherapy; Plant Preparations; Randomized Controlled Trials as Topic; Risk; Safety; Selective Estrogen Receptor Modulators; Urothelium; Vagina

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans

To review use of alternative pharmacotherapy (AP) in patients with cardiovascular disease (CVD) and significant drug interactions between AP and traditional CVD medications.. A literature search of MEDLINE and the National Complementary and Alternative Medicine database was done using these search terms: supplements, vitamins, garlic, fish oil, L-arginine, soy, coenzyme Q10, herbs, phytosterols, chelation therapy, alternative medicine, and CVD.. English human clinical trials measuring surrogate and clinical end points.. Antioxidants have not been consistently proven beneficial in reducing cardiovascular mortality. Fish oils may be beneficial in patients with hypertension and hypercholesterolemia, but therapeutic doses need to be defined. Use of coenzyme Q10 in patients with heart failure has not demonstrated consistent benefits. Garlic may lower blood pressure and cholesterol levels, but also may increase bleeding, so its use in CVD patients should be monitored. Clinical studies with small sample sizes have demonstrated that L-arginine may be useful to prevent and treat CVD. The Food and Drug Administration recommends 25 g/day of soy protein as part of a diet low in saturated fats for cholesterol reduction. Plant sterols are recommended by the American Heart Association and the National Cholesterol Education Program Expert Panel as adjunct therapy to reduce low-density lipoprotein. No data support use of chelation therapy. Some APs interact with common prescription CVD medications (eg, gingko and ginseng with warfarin, St. John's Wort with digoxin).. The benefits of APs as part of the treatment for CVD are controversial. Routine use is not recommended.

Topics: Antioxidants; Arginine; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Coenzymes; Complementary Therapies; Dietary Supplements; Drug Interactions; Education, Pharmacy, Continuing; Fish Oils; Garlic; Humans; Plant Preparations; Soybean Proteins; Sterols; Ubiquinone

Topics: Antihypertensive Agents; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Circadian Rhythm; Death, Sudden, Cardiac; Humans; Hypertension; Kidney Failure, Chronic; Myocardial Infarction

This short review describes the effects of drugs and nonpharmacologic treatments on large artery stiffness in clinical trials. Arterial stiffness is generally accepted as a predictive factor for cardiovascular morbidity and mortality. The drug-induced reduction in arterial stiffness may parallel the reduction in cardiovascular work. This review summarizes the discussion of a task force that worked on the therapeutic aspects during a Consensus Conference on the 'Clinical applications of arterial stiffness," held in Paris on June 17, 2000. The effects of drugs on arterial stiffness are detailed in patients with hypertension, heart failure, and other arterial diseases. Other issues are raised, including the reversibility of arterial changes following pharmacologic treatment, and the possibility for nonpharmacologic treatment to be effective on arterial stiffness. Directions for future therapeutic trials are suggested.

Topics: Arteries; Cardiovascular Agents; Cardiovascular Diseases; Elasticity; Humans

Topics: Athletic Injuries; Cardiovascular Agents; Cardiovascular Diseases; Clinical Laboratory Techniques; Diagnosis, Differential; Female; Humans; Magnetic Resonance Angiography; Marfan Syndrome; Pregnancy; Pregnancy Complications; Risk Factors

One of the aims of transplantation is to restore the potential for a full life to individuals with ESRD. To obtain this strategies that allow better and longer allograft function and a reduction in adverse events that lead to premature death are required. To this end, the recommendations below showed reduce cardiovascular disease and help present and future transplant recipients live a full life. Focusing on traditional risk factors (hypertension, hyperlipidemia, discontinuation of smoking, and prevention and treatment of diabetes mellitus) in patients at risk and striving for the recommended targets will have the greatest clinical benefit. These strategies should begin in the pre-dialysis and dialysis phases in order to reduce the cumulative burden of disease. Failing this, early and hopefully pre-emptive transplantation should be the goal.

Topics: Arteriosclerosis; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Cost-Benefit Analysis; Diabetes Mellitus; Heart Function Tests; Humans; Hyperlipidemias; Hypertension; Hypertrophy, Left Ventricular; Hypoglycemic Agents; Hypolipidemic Agents; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Life Expectancy; Pancreas Transplantation; Postoperative Complications; Prevalence; Renal Dialysis; Risk Reduction Behavior; Smoking Cessation; Treatment Outcome

Medical errors in the care of patients may account for 44,000 to 98,000 deaths per year, and 7,000 deaths per year are attributed to medication errors alone. Increasing awareness among health care providers of potential errors is a critical step toward improving the safety of medical care. Because today's medications are increasingly complex, approved at an accelerated rate, and often have a narrow therapeutic window with only a small margin of safety, patient and provider education is critical in assuring optimal therapeutic outcomes. Providers can use electronic resources such as Web sites to keep informed on drug-drug, drug-food, and drug-nutritional supplements interactions.

Topics: California; Cardiovascular Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Medication Errors; Risk Assessment; Risk Factors; Survival Analysis

Cardiovascular disease is a common comorbidity and a major cause of mortality in patients with chronic renal disease. Drug regimens in patients with cardiovascular disease are frequently complex and can be significantly affected by alterations in renal function. In addition, several cardiovascular drugs directly affect renal function and the management of patients with renal disease. This article reviews the impact of renal disease on the pharmacokinetics of cardiovascular drugs and identifies clinically important interactions between these and other drugs commonly used in the management of chronic renal disease. Several classes of cardiovascular drugs are also discussed in relationship to their differential effects on the management and progression of renal disease.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Humans; Kidney Failure, Chronic

This self-directed learning module highlights cardiac rehabilitation issues facing able-bodied populations. It is part of the chapter on cardiovascular, pulmonary, and cancer rehabilitation in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article focuses on various aspects of the management of cardiac disease and rehabilitation, including medication, exercise, risk-factor modification, secondary prevention, and surgery. Topics discussed include myocardial infarction, coronary artery disease, cardiomyopathy, and angina. New advances covered in this article include the various phases of cardiac rehabilitation, data on lifestyle adaptations for cardiac disease, and recent surgical advances for the treatment of severe heart failure.. To review aspects of the management of cardiac disease and rehabilitation, including medication, exercise, risk-factor modification, secondary prevention, and surgery.

Topics: Aged; Cardiac Rehabilitation; Cardiovascular Agents; Cardiovascular Diseases; Exercise Therapy; Female; Humans; Life Style; Male; Middle Aged; Myocardial Revascularization; Patient Care Planning; Physical and Rehabilitation Medicine; Risk Factors

In cardiovascular pharmacotherapy, the main focus is now on statins (HMG-CoA-reductase inhibitors) because of their antihyperlipidaemic and antiatherogenic effect. They are suggested to be beneficial also in senile dementia, stroke and osteoporosis and they can reduce incidence of ventricular arrhythmias in patients with cardioverter-defibrillator. In chronic heart failure, statins should be used with caution since reduced cholesterol levels relate to impaired survival. As an alternative to statins and fibrates, niacin therapy may be considered. ACE inhibitors are of proven benefit for patients with left ventricular dysfunction after acute myocardial infarction; however, in long-term treatment, their protective activity is not superior to that of beta-blockers, diuretics and clonidine. Ca-channel antagonists slightly increase the incidence of cardiovascular complications but reduce the incidence of stroke in high-risk patients. Biventricular pacing has been used with success in patients with severe heart failure and conduction disturbances, and the first permanent artificial ventricle was implanted to a patient with irreversible terminal heart failure in summer 2000. Cardiospecific troponin I may be an uninvasive marker of a procoagulant status indicating e.g. graft failure after cardiac transplantation; T-cadherin belongs to the cell-adhesion molecules and has a role in maintenance of cellular contacts which are critical for the vessel wall architecture. Etamoxir, originally developed for the treatment of diabetes II, has recently been shown to be a potential novel drug for heart failure. Routine use of nitric oxide after congenital heart surgery lessens the risk of pulmonary hypertensive crises.

Topics: Cardiac Pacing, Artificial; Cardiovascular Agents; Cardiovascular Diseases; Humans

Transdermic estrogens share many of the oral estrogens cardiovascular effects, but so far there are no studies proving that they have a cardioprotective effect neither in animals nor in human beings. The doubt is outlined moreover, when most of the investigations performed with oral estrogens in animals show an antiatherogenic effect, while the few experimental studies that hare been carried out with estrogen patches show contradictory results. We will have to wait for more extensive clinical trials to be able to know if the transdermic estrogens are really cardioprotective, however if we want to achieve some cardiovascular risk improvement with the current knowledge we will probably have to support the use of oral estrogens.

Topics: Administration, Cutaneous; Animals; Cardiovascular Agents; Cardiovascular Diseases; Climacteric; Coronary Artery Disease; Estradiol; Estrogen Replacement Therapy; Estrogens; Female; Humans

Topics: Animals; Biological Factors; Cardiovascular Agents; Cardiovascular Diseases; Combinatorial Chemistry Techniques; Disease Models, Animal; Drug Design; Gene Expression Profiling; Genes; Genomics; Humans; Proteins; Proteome; Structure-Activity Relationship

Interethnic or racial differences are associated with enzyme polymorphisms, which are tiny variations in individuals in the physiology, absence, or presence of drug-metabolizing enzymes. The largest class of cardiovascular drugs investigated in pharmacogenetic studies is the antihypertensives. A number of studies have examined the best choices of antihypertensives for individuals within selected racial and ethnically defined populations. There is a fairly strong consensus about the pattern of antihypertensive treatment for black patients, but clear treatment directives for antihypertensive patients with other cultural affiliations have not emerged. Less information is reported about racial, ethnic, or cultural differences in effectiveness for other cardiovascular drugs. Nurses should consider whether the ethnic or racial affiliation of the patient places him or her more at risk for impaired drug metabolism. This article contains a guide for nursing assessment of culturally important factors related to polymorphisms.

Topics: Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Ethnicity; Humans; Nursing Assessment; Patient Education as Topic; Polymorphism, Genetic; Racial Groups

Blockade of the renin-angiotensin-aldosterone cascade is now recognised as a very effective approach to treat hypertensive, heart failure and high cardiovascular risk patients and to retard the development of renal failure. The purpose of this review is to discuss the state of development of currently available drugs blocking the renin-angiotensin system, such as angiotensin converting enzyme (ACE) inhibitors, renin inhibitors and angiotensin II receptor antagonists, with a special emphasis on the results of the most recent trials conducted with AT(2) receptor antagonists in heart failure and Type 2 diabetes. In addition, the future perspectives of drugs with dual mechanisms of action, such as NEP/ACE inhibitors, also named vasopeptidase inhibitors, are presented.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Protease Inhibitors; Renin

Topics: Antihypertensive Agents; Arterioles; Arteriosclerosis; Basement Membrane; Bone Remodeling; Calcinosis; Calcium; Cardiovascular Agents; Cardiovascular Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Diagnostic Tests, Routine; Disease Progression; Humans; Hyperparathyroidism; Hypertension; Hypertrophy, Left Ventricular; Kidney Transplantation; Osteoblasts; Renal Dialysis; Uremia; Vascular Diseases; Venules; Vitamin D

Recent advances in our understanding of the hepatic cytochrome P450 inhibitory effects of the newer antidepressants have increased concern about drug interactions in the practice of psychiatry. The authors summarize the potential interactions of psychoactive drugs with cardiovascular medications. Practicing psychiatrists encounter many patients with cardiovascular disease, and an awareness of these interactions will improve knowledgeable prescribing for medically ill patients with comorbid mental disorders.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cytochrome P-450 Enzyme System; Drug Interactions; Formularies as Topic; Humans; Mental Disorders; Psychiatry; Psychotropic Drugs; United States

Endothelial cells play a key role in cardiovascular homeostasis by producing several vasoactive agents, which modulate basal vascular tone and structure. Traditional risk factors of atherosclerosis contribute to endothelial dysfunction through different mechanisms such as oxidative stress, modulation of constitutive nitric oxide synthase, activation of angiotensin-converting enzyme and presumably endothelin-1. The purpose of this review was to evaluate the results of experimental and human studies on several treatment options that could improve endothelial function. However, further studies are needed to evaluate whether these different classes of drugs may improve both vascular injury and cardiovascular morbidity and mortality.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Diabetic Angiopathies; Endothelium, Vascular; Humans; Risk Factors

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans

The variability in the individual response to drugs may be due either to interindividual variations in the pharmacokinetics of the drugs or to the heterogeneity of the mechanism(s) underlying the diseases, or both. In both cases, genetic heterogeneity is involved in the metabolism of cardiovascular drugs and pathogenesis of inherited cardiovascular disorders. Molecular genetic technologies can now provide sensitive and efficient genetic testing, not only to identify polymorphic drug metabolism genes, but also to identify disease-associated genes for diagnosis and risk stratification of many hereditary cardiovascular diseases. In this review, we discuss the polymorphic metabolism of cardiovascular drugs and the molecular genetics of cardiovascular diseases in relation to the genes determining the responsiveness to a given drug.

Topics: Adrenergic beta-Antagonists; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Cytochrome P-450 Enzyme System; Genetic Variation; Humans; Molecular Biology; Pharmacogenetics; Polymorphism, Genetic; Potassium Channel Blockers; Sodium Channel Blockers; Vasodilator Agents

Topics: Biological Availability; Cardiovascular Agents; Cardiovascular Diseases; Drug Administration Routes; Humans; Perioperative Care; Practice Guidelines as Topic

Topics: Cardiovascular Agents; Cardiovascular Diseases; Genetic Therapy; Humans; Molecular Biology; Oligonucleotides, Antisense

Topics: Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Death, Sudden, Cardiac; Humans

The molecular understanding of platelet function, together with an appreciation of the role of platelet thrombus in the pathogenesis of acute coronary syndromes (ACS) and abrupt vessel closure following coronary intervention, lead to the development of the class of agents now referred to as platelet glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors. Currently three parenteral GP IIb/IIIa inhibitors are licensed for use in patients undergoing coronary intervention or as empirical therapy in non-ST elevation ACS (unstable angina and non-Q wave myocardial infarction). Clinical trials using these agents in patients undergoing coronary interventions have demonstrated a consistent reduction in ischaemic end points at 30 days that is sustained during long-term follow-up. Similar benefits have been found in patients with ACS who are managed medically or who proceed to revacularization. Studies using prolonged platelet inhibition using oral GP IIb/IIIa inhibitors in patients following coronary intervention or with ACS have produced disappointing results. Further investigation with existing and newer oral agents are ongoing. The use of GP IIb/IIIa inhibitors in combination with fibrinolytic agents for optimal reperfusion in patients with acute ST-elevation myocardial infarction (MI) is an active area of interest. Angiographic outcomes with this approach have been encouraging and clinical outcome data are awaited. Beyond efficacy, GP IIb/IIIa inhibitors have proven to be safe for clinical use. Haemorrhagic complications and thrombocytopenia are the most common adverse events, though infrequent. Unresolved issues regarding drug dosing, monitoring of effect, duration of therapy, head-to-head comparisons of agents, and use of adjunctive therapies are the subject of ongoing studies.

Topics: Animals; Antibodies; Blood Platelets; Cardiovascular Agents; Cardiovascular Diseases; Humans; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex

Despite the relative paucity of drug trials in the old and especially the very old (> 85 years), some general principles of pharmacology in the aging patient can be taken from available data and clinical experience. The pharmacokinetic changes most consistently seen with aging occur in the volume of distribution, clearance, and half-life of a drug. Renal drug clearance is consistently diminished with aging. Hepatic metabolism is more variably affected, and in contrast to renal clearance, no reliable formula exists to estimate hepatic drug clearance. Pharmacodynamic changes, although present, are less well studied or described in the elderly. Drug interactions and adverse drug reactions increase with increasing numbers of medications prescribed and represent a complex interplay of age, underlying disease, and number and types of medications. The clinical caveats that apply to drug prescription in the very old include reduced starting doses with slow incremental increases; elimination of unnecessary medications; and anticipating and monitoring for drug interactions and ADRs, especially when prescribing warfarin, digoxin, and amiodarone. Future studies that look at the aging patient in the presence of effects of age, physiology, gender, comorbid illness, and multiple drug therapies may help evolve a new set of paradigms for geriatric drug prescribing.

Topics: Aged; Aged, 80 and over; Aging; Cardiovascular Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Interactions; Humans; Kidney; Liver

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cost-Benefit Analysis; Developed Countries; Economics, Pharmaceutical; Humans; Models, Economic; Randomized Controlled Trials as Topic

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Hypercholesterolemia; Recurrence; Risk Factors

Several receptors activated by extracellular nucleotides (ATP, ADP, UTP and UDP) have recently been cloned. These P2 receptors mediate a multitude of cardiovascular effects such as positive inotropic effects in the heart, platelet aggregation, release of endothelial factors, growth stimulation of vascular smooth muscle cells, vasomotor effects and blood pressure regulation. The physiological and pathophysiological importance of P2 receptors is established, and the first P2 receptor antagonists (ticlopidine and clopidrogel) are already in clinical use as inhibitors of platelet aggregation in the prevention of ischaemic heart disease and stroke. The development of selective antagonists for other P2 receptor subtypes will lead to better understanding of cardiovascular disease processes and yield new therapeutic options.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Research

There has been much interest in the effect of sex hormones on cardiovascular risk factors and as a therapeutic modality in both men and women. In this article, testosterone is considered as a possible therapy for cardiovascular disease. It has been shown that the level of serum testosterone decreases in men as they age. Healthy men with low testosterone levels have increased cardiovascular risk factors, including high fasting and 2-hour plasma glucose, serum triglycerides, total cholesterol and low-density lipoprotein (LDL) cholesterol, and apo A-I lipoprotein. Injections of testosterone to raise the levels to midnormal range have been shown to decrease total cholesterol and LDL cholesterol, while increasing high-density lipoprotein (HDL) cholesterol. Testosterone affects the clotting system by increasing thromboxane A (2) receptor activity and platelet aggregability. Testosterone has also been shown to augment the fibrinolytic system and antithrombin III activity. In men, testosterone has been shown to have antianginal effects, and endogenous levels have an inverse relationship to systolic blood pressure. Testosterone can be given in oral, injectable, pellet, and transdermal patch forms. There may be a role in administering testosterone to return men to normal physiologic range who have low serum levels. This treatment increases the risk of prostatic cancer, benign prostatism, erythrocytosis, and edema. No long-term studies of the effects of long-term testosterone replacement have been undertaken, so it is difficult to recommend this treatment as yet, but it is being considered as a therapy for augmenting skeletal muscle strength in patients with congestive heart failure.

Topics: Anabolic Agents; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Female; Gonadal Steroid Hormones; Humans; Male; Testosterone

A chronobiological considerations of time-dependent incidents of cardiovascular diseases including triggering mechanisms and their role in chronotherapy are presented in the article. Circadian and seasonal variation has been demonstrated especially in myocardial infarction, stable and unstable angina pectoris, sudden cardiac death and stroke. Chronopharmacological considerations of therapy of coronary heart disease and hypertension are also reviewed.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Circadian Rhythm; Humans; Seasons

For many years, it was thought that acute cardiovascular events occurred in a random fashion. However, over the past 13 years or so, a significant amount of research, both retrospective and prospective, has shown that there is an excess of ischaemic activity, arrhythmic activity and acute cardiovascular events in the first few hours after waking and commencing activity. This excess may well be at least partly linked to the known physiological changes which occur after waking, including a surge in heart rate, blood pressure and catecholamine release, activation of the renin-angiotensin system, an increase in platelet aggregability on assuming the upright posture, and the final trough in the fibrinolytic system. Because of the relatively short half-life and duration of the therapeutic effect (<24 h) of many anti-ischaemic and anti-arrhythmic agents, it is likely that single day agents taken in the morning will have reached subtherapeutic levels at the time of waking and commencing activity the following morning. As many patients do not take their daily (morning) medication immediately on rising, and allowing for time for adsorption, it is likely that, despite our knowledge of "circadian variations" in both physiological responses and pathophysiological events in the morning waking hours, patients are in fact at least protection at this particular high-risk time of the 24 h day. With our knowledge about when events are more likely to happen, we should consider carefully the timing of administration of medications, having factored in the likely length of therapeutic effect in each instance. It is likely that the almost universal inability to demonstrate prognostic benefit with many anti-ischaemic and anti-arrhythmic agents to date relates at least in part to a lack of appropriate "protection" at the time of apparent greatest risk in the patient with cardiovascular disease. Intelligent prescribing might indeed improve outcome, and even in the absence of proof on this regard, it would seem appropriate that we at least strive to achieve such an outcome.

Topics: Acute Disease; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Circadian Rhythm; Clinical Trials as Topic; Humans; Time Factors

The purpose of this manuscript is to review the available antagonists of platelet glycoprotein (GP) IIb/IIIa. The critical role of platelet aggregation in the pathogenesis of acute coronary syndromes of unstable angina and non-Q-wave myocardial infarction, as well as in mediating abrupt vessel closure and periprocedural infarction after percutaneous coronary interventions, has been recognised recently. Platelet aggregation is mediated through expression of activated GP IIb/IIIa and its subsequent binding to circulating fibrinogen. Inhibition of this interaction with one of 3 commercially available agents has been demonstrated to reduce ischaemic complications of coronary intervention and to reduce the rates of death and myocardial infarction in patients with acute coronary syndromes. Differential pharmacological characteristics of the drugs abciximab, tirofiban and eptifibatide are described and the trials which have defined their role in the management of ischaemic heart disease are reviewed.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Platelet Glycoprotein GPIIb-IIIa Complex

This paper, the second in a series of 2, reviews major developments and trends in the current healthcare arena that will affect cardiovascular disease (CVD) treatment over the next 10 years. The paper also discusses the implications and future outlook for cardiovascular services in a managed care environment.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Evidence-Based Medicine; Forecasting; Health Care Sector; Humans; Managed Care Programs; Medical Laboratory Science; Practice Guidelines as Topic; Socioeconomic Factors; United States

Micro-organisms continue to provide an important source of chemical diversity for the discovery of compounds with new biological activities. Microbial metabolites discovered recently using assays to detect compounds with potential pharmacological utility are surveyed and found to represent an extensive range of structural types produced by a wide variety of organisms. Assays used for screening samples produced by microbial processes must be robust, sensitive and specific and able to operate above a background of potential interferences from a number of sources. Discovery assays currently in use fall into three main categories cell-based, receptor-ligand interaction and enzyme inhibition assays. Trends in the use of these assays and new developments in assay technology applicable to the screening of microbial samples are examined with particular reference to the high throughput screening environment. For microbial screening to be a competitive route to new drug leads, the disciplines involved must be engineered into a seamlessly integrated process to deliver novel compounds with the required biological properties rapidly.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Cardiovascular Agents; Cardiovascular Diseases; Chemistry, Pharmaceutical; Drug Evaluation, Preclinical; Guinea Pigs; Humans; Industrial Microbiology; Inflammation; Neoplasms, Experimental; Neovascularization, Pathologic; Nerve Growth Factors; Platelet Aggregation Inhibitors; Rats; Receptors, Drug

Effects of sleeping and awaking on blood pressure, heart rate and heart rate variability were shown in normal and a diabetic patient using an ambulatory blood pressure monitor (ABPM), Holter recorder and an accelerometer indicating body motion and posture. From the circadian variation of blood pressure and autonomic nerve function, optimal treatments to protect cardio-vascular accidents were discussed. For the assessments of medication and selection of drugs, ABPM and Holter recording with simultaneous measurement of physical activity are useful.

Topics: Activities of Daily Living; Autonomic Nervous System; Blood Pressure Monitoring, Ambulatory; Cardiovascular Agents; Cardiovascular Diseases; Chronotherapy; Electrocardiography, Ambulatory; Hemodynamics; Humans

Various drug delivery systems are available when cardiovascular drugs are used. Various kinds of receptor inhibitors such as beta blockade or angiotensin II receptor inhibitor are frequently used in the daily cardiovascular clinic. Several different routes of drug administration exist. Conventional tablet or its liquid spray by sublingual or lingual administration is rapidly absorbed and specified oral tablet or transdermal patch for maintaining longtime is slowly absorbed from the digestive tract or skin. Some drugs have different type of tablets for obtaining different pharmacodynamics. Nifedipine has 3 kinds of tablets showing short, long and very long-time effect. Recent advance in drug delivery system makes possible to administer the drug to the small local area through stent or balloon catheter at the coronary interventional therapy.

Topics: Angioplasty, Balloon, Coronary; Cardiovascular Agents; Cardiovascular Diseases; Drug Administration Routes; Drug Delivery Systems; Humans; Recurrence; Stents

The treatment for asthma usually involves a combination of drugs used for bronchodilation and to treat underlying airway inflammation. When asthma is severe, the regimen used to treat asthma can become quite complicated, often using as many as 3 or 4 separate pharmacological agents. As patients with asthma get older, their medication regimen can become even more complex with the development of numerous other age-related diseases requiring their own list of medications. Diseases of the joints, diseases of the eye, cardiovascular disease, neurological disease and urological problems represent the most common conditions that patients develop, at times needing medications which might interfere with asthma management. Many of these diseases require the use of nonsteroidal anti-inflammatory agents, well known to provoke wheezing in patients with intrinsic asthma, and diseases of the eye and cardiovascular system frequently require use of beta-blockers which can cause or exacerbate asthma. Managing patients with asthma who have other diseases requires constant supervision of their medication usage and careful and cautious review of the entire list of medications at each presentation.

Topics: Adrenergic beta-Antagonists; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Bone Diseases; Cardiovascular Agents; Cardiovascular Diseases; Eye Diseases; Humans

In what concerns the appropriate usage of drugs in the treatment of cardiovascular diseases, this paper provides a set of concepts and guidelines to aid the clinician in the choice of drug, the appropriate dose, the form of administration and the assessment of results. Therefore, the concepts of pharmacokinetics and pharmacodynamics which condition the administration regimen are also presented, as well as the notions of bioavailability, halflife and clearance in the light of the theory of the two compartments, quoting examples in the various pharmacologic groups currently used in cardiology. The main forms of administration and the respective indications are analysed and the concepts of tolerance, hypersensitivity and intolerance to a drug are also discussed. The importance of the major clinical trials in the assessment of the effects of drugs is supported, which consubstantiates the clinical decision based on scientific evidence. The notions of the efficacy and benefit of a treatment are presented, with examples of some recent clinical trials. The paper ends with a reference to the drug surveillance and cost-benefit studies.

Topics: Biological Availability; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Half-Life; Humans

In toxicity studies, the examination of tissue sections for pathological changes is the principle method for the identification of organ toxicity and characterisation of the hazard of novel drugs for humans. Study of the patterns of pathological alterations also represents an important means of developing an understanding of the mechanism of toxicity. However as pathological change frequently represents a final common expression of diverse processes, additional functional information is often required for a clear understanding of the mechanisms of toxicity. This is exemplified in the evaluation of the effects of drugs on the beagle dog cardiovascular system where an understanding of mechanisms is crucial in the assessment of human risk. Particular patterns of drug-induced structural change in the myocardium or blood vessels are frequently linked to specific mechanisms of toxicity. However, assessment based on the interpretation of patterns of cardiovascular pathology alone may be misleading. Quite different changes in cardiac and vascular function or direct cellular toxicity may also be manifest by pathological features in common. Therefore, a clear understanding of mechanism frequently requires additional in vivo or in vitro physiological, pharmacological, biochemical or other mechanistic information. The beagle dog remains an important model for the study of cardiovascular toxicity because in this species, haemodynamic changes and pathological alterations can be related in a way that provides the basis for the safe study in humans of novel drugs with cardiovascular activity.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Coronary Vessels; Disease Models, Animal; Dogs; Heart Atria; Heart Valves; Heart Ventricles; Humans; Ischemia; Myocardium; Species Specificity

Among cardiovascular diseases, hypertension, angina pectoris, acute myocardial infarction and ischemic stroke present a circadian pattern with a greater incidence of unfavourable events between awakening and noon. Chronotherapy aims to use drugs that release their active principles at different times during the day, according to biological needs. In chronotherapy of cardiovascular diseases, a particular attention has been paid to slow-release drugs that assure a 24 hours therapeutic effect with once a day administration. In primary hypertension well controlled by monotherapy (dipper hypertensives), the morning administration of long-acting beta-blockers and calcium antagonists has shown to control blood pressure over 24 hours, whereas ACE-inhibitors have proved more effective when administered at evening. In secondary hypertension (non dipper hypertensives) the administration of calcium antagonists is more effective at evening. Patients with severe hypertension need polytherapy. In that case, at least one of the antihypertensive drugs should be given at evening to lower night blood pressure values, which are particularly elevated also during sleep, and so to prevent an excessive blood pressure rise on awakening. In chronic monotherapy of ischemic heart disease, long-acting beta-blockers and calcium antagonists have shown to be equally effective when they are administered at morning, whereas slow-release nitrates, which need a nitrate-free interval, are to be administered either at morning or at evening, according to the expected time of onset of anginal pain. ASA seems to reduce the morning incidence of acute myocardial infarction, while tissue-type plasminogen activator presents a circadian variation of its thrombolytic activity with a higher efficacy between noon and midnight.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Chronotherapy; Humans

Cardiovascular complications are common and varied in neuromuscular diseases. Knowledge of the complications specific to each disease is essential for appropriate screening for cardiovascular disease. Appropriate treatment of complications varies between neuromuscular diseases and draws primarily on experience from patients without neuromuscular disease. This article details the known cardiovascular complications and treatments for some of the major neuromuscular diseases.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Echocardiography; Electrocardiography; Humans; Neuromuscular Diseases; Oxygen Inhalation Therapy; Physical and Rehabilitation Medicine

Topics: Cardiovascular Agents; Cardiovascular Diseases; Humans; Quality of Life; Surveys and Questionnaires; Treatment Outcome

Topics: Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Contraindications; Humans

Sexual difficulties are highly prevalent in male patients with cardiovascular diseases, such as hypertension, atherosclerosis, and hypercholesterolemia. Recently, several studies have been conducted on the effects of cardiovascular diseases, as well as associated drug and nondrug treatments, on nocturnal penile tumescence (NPT) and other measures of sexual function. Although an overall trend has been observed toward decreased NPT in patients with chronic hypertension and other cardiovascular conditions, design and methodological difficulties have been noted in most studies, and results have been generally, inconclusive. Similarly, antihypertensive drugs such as beta-blockers and diuretics have been associated with diminished NPT in several studies, although methodological problems have again been noted. Furthermore, the mechanism of action of antihypertensive drugs on sleep-related erections has not been determined. Most recently, a positive effect of cholesterol-lowering drugs (pravastatin, lovastatin) on NPT has been observed in middle-aged males with chronic hypercholesterolemia. Additional studies of the effects of cardiovascular disease on NPT and other measures of sexual function are needed.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Erectile Dysfunction; Humans; Impotence, Vasculogenic; Male; Penile Erection; Randomized Controlled Trials as Topic; Sleep, REM

Topics: Aging; Animals; Blood Pressure; Blood Vessels; Cardiovascular Agents; Cardiovascular Diseases; Compliance; Exercise; Humans; Menopause; Risk Factors; Smoking; Stress, Mechanical

Topics: Antioxidants; Cardiovascular Agents; Cardiovascular Diseases; Diet; Humans; Vitamin E

A number of pharmacologic interventions are now recommended for the prevention of cardiovascular disease, based on the results of randomized controlled trials. These include antihypertensive drugs, lipid-lowering agents, antiplatelet and anticoagulant drugs, estrogen replacement therapy, beta-blockers, and angiotensin converting enzyme (ACE) inhibitors. It is likely that additional pharmacologic interactions will soon be proven efficacious. Despite the strength of this evidence and the development of clinical guidelines incorporating their use, a surprisingly low proportion of patients are actively treated with these agents. There may be a variety of explanations for this, including barriers at the level of the patient, health care provider, and health care institution. Finally, a number of questions remain as to the optimal combination of interventions, both behavioral and pharmacologic, which will yield maximal reduction in risk. The description of factors which reduce the effectiveness of pharmacologic interventions below the efficacy demonstrated in randomized clinical trials should be a fertile area for epidemiologic and behavioral research.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Combined Modality Therapy; Humans; Life Style; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Risk Factors

The efficacy of cardiovascular risk-reduction programs has been established. However, the extent to which risk-reduction interventions are effective may depend on adherence. Non-compliance, or non-adherence, may occur with any of the recommended or prescribed regimens and may vary across the treatment course. Compliance problems, whether occurring early or late in the treatment course, are clinically significant, as adherence is one mediator of the clinical outcome. This article, which is based on a review of the empirical literature of the past 20 years, addresses compliance across four regimens of cardiovascular risk reduction: pharmacological therapy, exercise, nutrition, and smoking cessation. The criteria for inclusion of a study in this review were: (a) focus on cardiovascular disease risk reduction; (b) report of a quantitative measure of compliance behavior; and (c) use of a randomized controlled design. Forty-six studies meeting these criteria were identified. A variety of self-report, objective, and electronic measurement methods were used across these studies. The interventions employed diverse combinations of cognitive, educational, and behavioral strategies to improve compliance in an array of settings. The strategies demonstrated to be successful in improving compliance included behavioral skill training, self-monitoring, telephone/mail contact, self-efficacy enhancement, and external cognitive aids. A series of tables summarize the intervention strategies, compliance measures, and findings, as well as the interventions demonstrated to be successful. This review reflects the progress made over two decades in compliance measurement and research and, further, advances made in the application of behavioral strategies to the promotion of cardiovascular risk reduction.

Topics: Behavior Therapy; Cardiovascular Agents; Cardiovascular Diseases; Diet, Fat-Restricted; Exercise; Humans; Patient Compliance; Risk Factors; Smoking Cessation; Treatment Outcome

The incidence of cardiovascular events during travel is rising with the age of the population and number of traveling seniors. Cardiovascular events are the second most frequent reason for medical evacuation and the cause of 50% of deaths recorded during commercial air travel. In most cases the underlying disorder is coronary artery disease which is readily destabilized by stress and fatigue associated with travel. Inflight conditions that can cause problems include altitude-related hypoxia, pressurization, and cramped seating in most sections of the plane. Upon arrival the traveler is exposed to a variety of climatic, food, and environmental factors that can trigger manifestations of latent heart disease. Prophylactic drugs for tropical infectious disease (especially antimalarials of the quinidine group) should be used with caution due to possible adverse interaction with medications used to treat heart disease. A pre-travel examination is necessary to ascertain cardiovascular status and define simple preventive precautions.

Topics: Age Distribution; Anti-Infective Agents; Cardiovascular Agents; Cardiovascular Diseases; Cause of Death; Drug Interactions; Humans; Incidence; Risk Factors; Travel

For proper drug development, targeting and testing the use of suitable animal models that are well controlled with regard to duration, degree, and stage of the disease are vitally needed. Furthermore reliable phenotyping and genotyping with regard to functional physiology as well as cellular biochemistry and molecular biology are vital to early decision making in drug discovery, development, and successful clinical development. The use of animal models allows the design of clinical trials without the complication of having to impose "accepted treatment modalities" on top of investigative agents. With the availability of human myocardium for study as a result of cardiac transplantation programs, experimental findings previously reported in several animal models of heart disease have been questioned with regard to suitability for comparison to the human condition. With the development and application of sophisticated techniques and biochemical assays to the study of heart tissue several adaptive changes have been identified and labeled "markers of heart failure." Several animal models share some of these adaptive changes in common with failing human myocardium, but not others. The goal of this report is to point out similarities and differences reported to date in failing and nonfailing human myocardium to that reported in animal models of human heart disease. This discussion indicates important dissimilarities found in several key animal models that have resulted in the development of cardioactive agents and therapeutic interventions for the treatment of human heart disease and the unexpected outcomes. Although focusing on heart failure, a vital goal of this report is to emphasize some key principles supporting the need for clear, comprehensive, and unbiased evaluation of animal models currently in use to study any disease condition, as well as the need for further model development and study in open collaborative efforts.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Disease Models, Animal; Drug Industry; Humans

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Risk Factors

Despite the public perception that heart disease primarily affects men, as women age, their risk equals and eventually outpaces that of men. Gender-specific differences in cardiovascular diseases have been reported related to onset, diagnosis, therapy, pharmacokinetics, adverse drug reactions, and mortality rates, but most of these differences are unexplained. Research in coronary heart disease has been performed almost exclusively in men, but the findings have been used to set standards for both sexes. Studies suggest a 50% reduction in heart disease risk among women receiving postmenopausal hormone replacement therapy.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Female; Humans; Male; Risk Factors; Sex Characteristics

Topics: Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Catecholamines; Fibrinolytic Agents; Humans; Nitric Oxide; Platelet Aggregation Inhibitors; Sympatholytics; Sympathomimetics

Cardiovascular diseases involve changes in the structure of the heart and blood vessels. Normal structure is maintained by a sophisticated set of mechanical and cellular "checks and balances." A disturbance of these checks and balances induces a remodeling process. The most distinguished features of this process are phenotypic modulation of various cell types in the cardiovascular system; cellular hyperplasia and hypertrophy; and extracellular matrix production, deposition, and degradation. Optimal pharmacotherapy of cardiovascular diseases should be aimed at correcting structural abnormalities in the heart and blood vessels. This goal can be achieved by influencing mechanical stresses on the cardiovascular system or by interfering with the chemical mediators of the remodeling process. Many existing groups of cardiovascular drugs, such as angiotensin-converting enzyme inhibitors, calcium-antagonists, alpha- and beta-adrenoceptor antagonists, and antithrombotic drugs, influence cardiovascular remodeling. New approaches involve the development of drugs acting on peptidergic mediators of cardiovascular remodeling.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Forecasting; Humans

One of every four persons in the Western industrialised nations has cardiovascular disease. The perioperative setting in those patients is associated with the risk of myocardial ischaemia (PMI) and myocardial infarction, and also with the risk of perioperative stroke and dysfunction of the central nervous system (CNS). Perioperative cardiovascular morbidity represents a major healthcare challenge. The relevance of PMI is well documented. It has been demonstrated in early trials that both myocardial ischaemia and infarction are preventable in high-risk patients undergoing surgery, and that therapeutic agents such as adenosine-related agents, alpha 2-agonists, and other stress modulators can be safely administered to these patients. Regarding perioperative stroke, approximately 3 to 7% of patients undergoing cardiac surgery suffer stroke, with an additional 30% or more suffering in-hospital CNS dysfunction, and 10% suffering moderately severe long-term CNS dysfunction. Few data are available for noncardiac surgery. The number of outcome studies addressing prophylactic or therapeutic options in these patients is quite limited. In fact, only one recent study has established that perioperative stroke is preventable with the use of an adenosine-regulating agent. Thus, it appears that it may be possible to prevent stroke, even though these results require confirmation. Because of the aging of our population, and the medical, financial and social impact of cardiovascular disease, the development of anti-ischaemic therapy, particularly in the surgical patient, will be a critical area of medical research for the next several decades.

Topics: Anesthesia, General; Brain Damage, Chronic; Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Humans; Intraoperative Complications; Myocardial Infarction; Myocardial Ischemia; Postoperative Complications; Premedication; Risk Factors

There is a fascinating and exceedingly important area of medicine that most of us have not been exposed to at any level of our medical training. This relatively new area is termed chronobiology; that is, how time-related events shape our daily biologic responses and apply to any aspect of medicine with regard to altering pathophysiology and treatment response. For example, normally occurring circadian (daily cycles, approximately 24 hours) events, such as nadirs in epinephrine and cortisol levels that occur in the body around 10 PM to 4 AM and elevated histamine and other mediator levels that occur between midnight and 4 AM, play a major role in the worsening of asthma during the night. In fact, this nocturnal exacerbation occurs in the majority of asthmatic patients. Because all biologic functions, including those of cells, organs, and the entire body, have circadian, ultradian (less than 22 hours), or infradian (greater than 26 hours) rhythms, understanding the pathophysiology and treatment of disease needs to be viewed with these changes in mind. Biologic rhythms are ingrained, and although they can be changed over time by changing the wake-sleep cycle, these alterations occur over days. However, sleep itself can adversely affect the pathophysiology of disease. The non-light/dark influence of biologic rhythms was first described in 1729 by the French astronomer Jean-Jacques de Mairan. Previously, it was presumed that the small red flowers of the plant Kalanchoe bloss feldiuna opened in the day because of the sunlight and closed at night because of the darkness. When de Mairan placed the plant in total darkness, the opening and closing of the flowers still occurred on its intrinsic circadian basis. It is intriguing to think about how the time of day governs the pathophysiology of disease. On awakening in the morning, heart rate and blood pressure briskly increase, as do platelet aggregability and other clotting factors. This can be linked to the acrophase (peak event) of heart attacks. During the afternoon we hit our best mental and physical performance, which explains why most of us state that "I am not a morning person." Even the tolerance for alcohol varies over the 24-hour cycle, with best tolerance around 5 pm (i.e. "Doctor, I only have a couple of highballs before dinner"). Thus, all biologic functions, from those of the cell, the tissue, the organs, and the entire body, run on a cycle of altering activity and function.(ABSTRACT TRUNCATED AT 400 W

Topics: Arthritis; Autonomic Nervous System Diseases; Cardiovascular Agents; Cardiovascular Diseases; Chronobiology Phenomena; Circadian Rhythm; Endocrine System Diseases; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hypersensitivity; Kidney Diseases; Male; Nervous System Diseases; Neuromuscular Diseases; Phototherapy; Respiratory Physiological Phenomena; Respiratory Tract Diseases; Sleep; Sleep Apnea Syndromes

Many patients who are referred for physical therapy take medications that affect either their physiological responses to exercise or their ability to exercise. The purpose of this article is to discuss how medications potentially can affect cardiovascular responses to exercise. The effects of selected medications on heart rate, blood pressure, and electrocardiographic responses during exercise; on exercise performance; and on training adaptations are discussed. The types of medications included in this review are beta-adrenergic receptor antagonists, vasodilators, diuretics, digitalis, and antiarrhythmic agents. The mechanisms of action and the clinical indications are described for each category of drugs. Ways in which each of the categories of drugs interacts with exercise responses, exercise performance, and training adaptations are described. Knowledge of a person's medications can provide valuable information on current physical condition and medical history and can alert therapists as to how exercise responses may be altered. Potential complications that are likely to occur during exercise can be identified, facilitating the design of safe and effective treatment programs.

Topics: Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cardiovascular System; Digitalis Glycosides; Diuretics; Exercise; Hemodynamics; Humans; Vasodilator Agents

Physiological functions as well as pathophysiological events--angina pectoris, myocardial infarction, sudden cardiac death--display pronounced circadian rhythms. Clinical studies also give evidence for a circadian phase dependency in the pharmacokinetics of cardio-vascular active drugs. Thus, a circadian phase dependency in the dose-response relationship of drugs has to be taken into account.

Topics: Animals; Biological Availability; Biological Clocks; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Circadian Rhythm; Dose-Response Relationship, Drug; Drug Administration Schedule; Hemodynamics; Humans; Hypertension; Rats

Topics: Cardiovascular Agents; Cardiovascular Diseases; Circadian Rhythm; Drug Administration Schedule; Humans

During the last decade, several epidemiological studies have reliably demonstrated that plasma fibrinogen is a strong and independent risk factor for cardiovascular disease that is at least as important as more traditional risk factors for the disease. The deleterious effects of this protein seem to be mediated through its role in hemorrheology, hemostasis, and the atherogenic process itself. According to prospective epidemiological studies, the risk of developing a cardiovascular event such as ischemic heart disease or stroke is 1.8 to 4.1 times higher in subjects with fibrinogen levels in the top third than in those with levels in the lower third. Epidemiological studies, clinical trials, pathophysiology, and therapeutical possibilities are reviewed in this paper.

Topics: Adult; Aged; Cardiovascular Agents; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Europe; Female; Fibrinogen; Humans; Male; Middle Aged; Prospective Studies; Risk Factors; United States

Current medical practice recommends the use of alternatives to estrogen-replacement therapy for the treatment of menopausal sequelae in younger women with breast cancer, although this clinical recommendation is undergoing reappraisal. Until prospective randomized studies addressing hormone use in this population are available, estrogen use in breast cancer patients will remain controversial. Because estrogen-replacement therapy is not the standard of practice and there is limited information available on nonestrogen therapies, women with breast cancer who are menopausal may not be prescribed or counseled about nonestrogen options. The efficacy, safety, and extent of use of most nonestrogen treatment modalities (other hormonal preparations, nonhormonal drugs, homeopathic preparations, and non-drug treatments) are not well documented and, unlike estrogen, many are selective in their benefit and do not share estrogen's universal impact. The use of several nonestrogen approaches for the prevention and treatment of osteoporosis has been promising. Traditional recommendations to maintain skeletal integrity, such as weight-bearing exercise; a diet rich in calcium and limited in caffeine, alcohol, and protein; avoidance of smoking; and measures to minimize trauma have been expanded to include the use or investigation of drugs (either alone or in combination). These drugs include progestins, vitamin D metabolites, injectable and intranasal synthetic salmon calcitonin, bisphosphonates, sodium fluoride, parathyroid hormone, growth factors, tamoxifen, etc. Strict control of the known risk factors, such as smoking, dyslipidemia, and hypertension as well as exercise, weight control, and the use of tamoxifen, are employed for the prevention and treatment of cardiovascular complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Age Factors; Antineoplastic Agents; Atrophy; Biological Factors; Breast Neoplasms; Calcitonin; Cardiovascular Agents; Cardiovascular Diseases; Complementary Therapies; Female; Flushing; Humans; Life Style; Menopause, Premature; Mental Disorders; Middle Aged; Osteoporosis, Postmenopausal; Ovariectomy; Plant Extracts; Primary Ovarian Insufficiency; Progestins; Risk Factors; Survivors; Tamoxifen; Vagina

Topics: Cardiotonic Agents; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Cost-Benefit Analysis; Fibrinolytic Agents; Heart Failure; Humans; Hypertension; Hypertrophy, Left Ventricular; Sociology

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Humans; Quality of Life

Indicators such as lowering of blood pressure in hypertension, alleviation of chest pain in angina pectoris, improvement in rest or exertional dyspnea from congestive heart failure (CHF) and suppression of ventricular arrhythmia are widely used in the management of cardiovascular diseases. There are often strong associations between the physiological indicators and the long-term clinical outcomes of cardiovascular disease such as stroke, myocardial infarction, sudden death and all-cause mortality. Physicians have assumed reasonably that early improvements in physiological markers will lead invariably to better long-term clinical outcomes. In recent years, a number of large clinical trials have demonstrated that short-term physiological improvements are not necessarily linked to better long-term clinical outcomes, but may be associated with less benefit than expected or even with detrimental outcomes. Management of cardiovascular diseases is complicated by the possibility that beneficial effects of a particular drug may be offset by its negative actions on the cardiovascular system. Effective antihypertensives may depress cardiac contractility; inotropes enhance left ventricular contractility in CHF, but may increase the risk of serious ventricular dysrhythmia; drugs which suppress ventricular arrhythmia may precipitate CHF or even excite pro-arrhythmic effects. Physicians must be conscious of this interplay of potentially beneficial and deleterious effects when cardiovascular drugs are prescribed. It is important in the analysis of large clinical trials of cardiovascular drugs to identify those situations in which the drug exhibits more benefit than harm and to determine, if possible, those aspects of drug action, drug dosage and population characteristics which contribute to the beneficial and detrimental actions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Arrhythmias, Cardiac; Cardiovascular Agents; Cardiovascular Diseases; Heart Failure; Humans; Hypertension; Myocardial Ischemia; Treatment Outcome

Topics: Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Humans; Vasoconstriction; Vasodilation

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Humans

The endothelins are a family of novel 21 amino-acid peptides and are the most potent vasoconstrictor substances yet discovered. The endothelins not only produce prolonged pressor responses in intact animals but they also constrict large and small arterial and venous vessels studied as isolated vascular preparations, influence autonomic transmission, exert positive inotropic effects on the heart and have been shown to be capable of releasing EDRF, prostanoids and atrial natriuretic factor. Release of endothelins occurs after de novo synthesis which may be stimulated by various agonists, fluid-flow and possibly hypoxia. The endothelins have been implicated in the pathophysiology of a variety of cardiovascular disorders but their precise role remains to be elucidated.

Topics: Amino Acid Sequence; Animals; Binding Sites; Cardiovascular Agents; Cardiovascular Diseases; Endothelins; Humans; Molecular Sequence Data; Myocardial Contraction; Receptors, Cell Surface; Receptors, Endothelin; Structure-Activity Relationship; Vasoconstriction

Cardiac diseases of cattle may involve valvular structures, myocardium, pericardium, or blood vessels and are manifested by the clinical signs of cardiac dysrhythmias, cardiac murmurs, generalized edema, muffled heart sounds, jugular venous distention, jugular venous pulsations, pulmonary edema, pleural effusion, or ascites. Digoxin, quinidine, and furosemide can be used effectively to control signs of CHF and cardiac arrhythmias. Combination antimicrobial therapy can be successful for cows with infective endocarditis and thrombophlebitis. Pericardial fluid drainage may temporarily improve cattle with traumatic pericarditis or lymphosarcoma so that short-term goals may be reached.

Topics: Animals; Cardiac Glycosides; Cardiovascular Agents; Cardiovascular Diseases; Cattle; Cattle Diseases; Diuretics; Quinidine

Topics: Cardiovascular Agents; Cardiovascular Diseases; Contraindications; Dose-Response Relationship, Drug; Drug Evaluation; Female; Fetus; Humans; Pregnancy; Pregnancy Complications, Cardiovascular

The therapeutic management of elderly patients should be extremely careful, particularly in those over 75 years of age. As a matter of fact, in such patients a steep increase of the risk of comorbidity and of dependence has been evidenced. This implies a more complex therapeutic management, that must be oriented to the amelioration of quality of life more than to the resolution of the single pathologies. However, all the intervention trials so far conducted excluded such patients. Therefore, they cannot be considered representative of the geriatric epidemiological reality. As a result, there is virtually no useful information on the efficacy and safety of cardiovascular drugs in patients over 75 years of age. However, the following items should be pointed out: only drugs whose efficacy has been proved should be used, and only after a thorough diagnosis; a multidimensional evaluation should be performed, also addressing psychological, social, environmental and economical factors that could affect the clinical course; the risks and benefits of any therapy should be considered, particularly in the presence of comorbidity, as the number of assumed drugs directly correlates with the risk of developing adverse reactions; drugs should be dosed according to renal function and body weight, possibly starting with half the dosage of younger patients; after starting the therapy, patients should be kept under strict clinical control, and every new symptom should be considered an adverse reaction, unless it will not disappear after withdrawal of the drug; serum drug concentration should be monitored whenever possible, given its larger variability in advanced age.

Topics: Aged; Aged, 80 and over; Cardiovascular Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Frail Elderly; Humans

Syncope usually has a cardiovascular source, so neurologic evaluation has a low diagnostic yield in these patients. Cardiac arrhythmias in persons with or without structural heart disease can produce syncope. Neurocardiogenic dysfunction that results in diminished venous return and hypercontractility is another frequent cause. Postural hypotension or left ventricular outflow obstruction may also be to blame. Careful history taking and physical examination, head-up tilt testing, echocardiography or radionuclide isotope imaging, and electrophysiologic study are often diagnostic. However, syncope remains undiagnosed in some patients, and they may require periodic reassessment. Treatment options are available for most cardiovascular disorders, among them use of pharmacologic agents; catheter, surgical, or radio-frequency modification of certain tachycardias; and permanent pacing.

Topics: Cardiac Pacing, Artificial; Cardiovascular Agents; Cardiovascular Diseases; Echocardiography; Education, Medical, Continuing; Electrocoagulation; Electrophysiology; Humans; Radionuclide Imaging; Syncope

The therapeutic goals for the patient with angina pectoris are to minimize the frequency and severity of angina and to improve functional capacity at a reasonable cost and with as few side effects as possible. An integrated approach necessitates attention to conditions that might be aggravating angina, such as anemia or hypertension. Alterations in life-style and personal habits, such as cessation of cigarette smoking, are often necessary and should be continually reinforced by the physician. Certain concomitant diseases, such as chronic obstructive pulmonary disease, may influence the selection of drug therapy. Nitrates, beta-adrenergic blockers, and calcium entry blockers are the major classes of drugs that can be used alone or in combination in a program that is designed for the individual patient.

Topics: Adrenergic beta-Antagonists; Angina Pectoris; Calcium Channel Blockers; Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Humans; Nitrates; Nitroglycerin

Drugs used to treat cardiovascular diseases have low therapeutic indices, may produce the very pathophysiologic effects that it is hoped they will reverse, and are used commonly in aged animals with multisystemic diseases for which they are receiving other compounds. These factors predispose to undesirable drug reactions and interactions. It is difficult to determine, a priori, which animals will respond with profound toxic manifestations; therefore, resuscitative measures, including drugs and devices, must be available at all times, and the clinician must be schooled in their use. In particular, class IA antiarrhythmics, digitalis glycosides, and antineoplastic compounds, all used relatively frequently, have great potential for producing toxicosis. An important role of the clinician with regard to cardiovascular toxicology lies in providing consultation to both the pharmaceutical industry and governmental regulatory agencies. Because the worst aspects of cardiovascular toxicosis lie in electrical disturbances of the heart, and because electrocardiography is the best method for studying these electrical properties, the clinician and adviser to the pharmaceutical industry and the FDA must be well schooled in electrocardiography.

Topics: Animals; Anti-Arrhythmia Agents; Cardiovascular Agents; Cardiovascular Diseases; Digitalis Glycosides; Dog Diseases; Dogs; Doxorubicin

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Interactions; Humans

Dietary magnesium (Mg) deficiency is more prevalent than generally suspected and can cause cardiovascular lesions leading to disease at all stages of life. The average American diet is deficient in Mg, especially in the young, in alcoholic persons, and in those under stress or with diseases or receiving certain drug therapies, who have increased Mg needs. Otherwise normal, Mg-deficient diets cause arterial and myocardial lesions in all animals studied, and diets that are atherogenic, thrombogenic and cardiovasopathic, as well as Mg-deficient, intensify the cardiovascular lesions, whereas Mg supplementation prevents them. Diuretics and digitalis can intensify an underlying Mg deficiency, leading to cardiac arrhythmias that are refractory unless Mg is added to the regimen. Potassium (K) depletion in diuretic-treated hypertensive patients has been linked to an increased incidence of ventricular ectopy and sudden death. K supplementation alone is not the answer. Mg has been found to be necessary to intracellular K repletion in these patients. Because patients with congestive heart failure and others receiving diuretic therapy are also prone to chloride loss leading to metabolic alkalosis that also interferes with K repletion, the addition of Mg and chloride supplements in addition to the K seems prudent.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Chlorides; Diet; Female; Heart Diseases; Humans; Hypertension; Magnesium; Magnesium Deficiency; Potassium; Pregnancy; Stress, Physiological

Topics: Asthma; Bronchodilator Agents; Cardiovascular Agents; Cardiovascular Diseases; Circadian Rhythm; Drug Administration Schedule; Humans

A consensus meeting on persons with a cardiovascular disease engaging in sports was held on 25 November 1988. The purpose was to arrive at uniformity in counselling and attendance. For these purposes, the exercise tolerance of the cardiovascular patients has to be weighed against the expected work load. The recommendations should be based on examinations suitable to the nature of the disorder. Guidelines for performance- and recreation-directed athletic activities are presented for a number of cardiovascular diseases. In counselling and attendance the medication used should also be taken into account. Expertise in counselling and attendance is of great importance for prevention of injuries. This is mostly achieved by team work with the sports physician coordinating.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Counseling; Hemodynamics; Humans; Netherlands; Physical Examination; Physical Exertion; Physical Fitness; Sports

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Evaluation; Female; Fetus; Humans; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications, Cardiovascular

Early observations that the regular use of aspirin (acetylsalicylic acid, ASA), a nonsteroidal anti-inflammatory agent, seemed to protect against myocardial infarction and reduce platelet aggregation made this substance the most frequently used drug in large clinical trials. The objectives of these studies were to reduce thromboembolic complications in arterial cardiovascular diseases (prevention of myocardial infarction in unstable angina, secondary prevention of acute myocardial infarction, and increased patency of aortocoronary bypass grafts) and to reduce platelet deposition on artificial surfaces (artificial heart valves and hemodialysis shunts). Despite the recent synthesis of more selective inhibitors of arachidonic acid metabolism in blood platelets, and a multitude of questions concerning optimal dose, schedule, and mode of action that still remain open, ASA continues to be the most frequently used drug in arterial vascular disorders. Because of the frequent and potentially serious side effects of aspirin, mainly on the gastrointestinal tract, less toxic ways of inhibiting eicosanoid metabolism in blood platelets are attracting more and more interest. Among these, the alimentary substitution of omega-3 fatty acids for a competitive inhibition of the omega-6-arachidonic acid metabolism seems the most promising. Results with fish-oil diet raise the question of whether substitution of polyunsaturated lipid acids influence only platelet metabolism, or whether the action of "anti-platelet" drugs or diet in cardiovascular disorders is mediated primarily by leukocytes or monocytes. This new dietary principle, which possibly corrects only a poor alimentary habit of civilization, could open simple and adequate ways for even a primary prophylaxis of vascular disease by diet alone or, at least for therapeutic aims, in combination with drugs.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Diet; Humans

Topics: Cardiovascular Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Emergencies; Humans

Knowledge of the dosage, rate and route of administration, and potential side effects of drugs used to treat cardiac disease in horses has been refined. The judicious use of these drugs can increase exercise capacity, improve health, and potentially prolong life. Currently, antiarrhythmics (quinidine, lidocaine), positive inotropies (digoxin), and diuretics (furosemide) are the primary agents used to treat cardiovascular disease in horses. The development of newer drugs (verapamil, milrinone, bumetanide) and their usefulness in therapy for horses with cardiovascular disease require further investigation.

Topics: Animals; Arrhythmias, Cardiac; Cardiovascular Agents; Cardiovascular Diseases; Edema; Female; Heart Rate; Horse Diseases; Horses; Male; Myocardial Contraction

Diuretics are the mainstay of drug therapy in the treatment of many cardiovascular disorders. However, perusal of knowledge of their haemodynamic activities in heart failure and hypertension reveals major gaps. In left ventricular failure complicating acute myocardial infarction, intravenous frusemide reduces the elevated left heart filling pressure with little change in systemic blood pressure, heart rate or cardiac output, and restores the ability of the left heart to handle an acute increase in filling volume. But there is little knowledge of the haemodynamic effects of other intravenous diuretics, oral diuretics or diuretics other than those acting on the loop of Henle in this emergency clinical situation. Even less information is available on the haemodynamic effects of diuretics in patients in chronic heart failure. In patients with valvular heart disease, parenteral mercury and oral thiazides reduce right heart and pulmonary vascular pressures with variable (dose-dependent?) changes in cardiac output. Information on the effect of loop diuretics, the comparative effects of intravenous versus oral routes of administration and dose-response correlations are all lacking. In hypertension, the dose-blood pressure lowering response relationship of orally administered diuretics is relatively flat. The majority of information relates to oral thiazides; there is little reliable information on the anti-hypertensive efficacy of the loop diuretics. The acute and chronic effects of the majority of commonly used diuretics on cardiac and peripheral vascular functions is unexplained. More is known of their potentially adverse metabolic effects than of their possible circulatory benefits in hypertensive patients. Many unwanted side-effects of these drugs have been described; their potential importance is related directly to the disease state and doses in which they are used. In acute heart failure, their potential danger is probably minimal. In the treatment of chronic heart failure their most sinister potential is in the excessive secretion of potassium and magnesium. In hypertensive patients their long-term administration in high-doses may lead to undesirable metabolic effects that tend to offset their blood pressure lowering activity. Despite their drawbacks, diuretics continue to provide the natural first-line treatment of choice of these common cardiovascular syndromes. But more information on their mechanisms of vascular activities and the differences in non-d

Topics: Angina Pectoris; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Chronic Disease; Diuretics; Drug Interactions; Heart Failure; Humans; Hypertension; Kidney Diseases; Socioeconomic Factors

Topics: Aged; Antidepressive Agents, Tricyclic; Cardiovascular Agents; Cardiovascular Diseases; Heart Diseases; Humans; Mental Disorders

Topics: Adrenergic beta-Antagonists; Analgesics, Opioid; Anti-Arrhythmia Agents; Atropine; Calcium Channel Blockers; Cardiotonic Agents; Cardiovascular Agents; Cardiovascular Diseases; Digitalis Glycosides; Emergency Medical Services; Heart Diseases; Heparin; Humans; Lidocaine; Nitroprusside; Oxygen Inhalation Therapy; Vasodilator Agents

At least 10% of the American population medically use prescribed psychopharmacological medications; and such psychotropic medications account for approximately 20% of all prescriptions in this country. Furthermore, there is widespread illicit use of psychoactive drugs, including narcotics, psychostimulants, and central nervous system depressants. All of these agents have potent effects on the cardiovascular system and, in addition, may undergo numerous drug-drug interactions with cardiovascular medications. Givaen the high incidence of both cardiovascular disease and psychoactive drug use in the United States, it is likely that clinicians manage many patients with cardiovascular disease, possibly receiving cardiovascular medications, and also needing psychopharmacological interventions. Consequently, the authors have reviewed the pharmacology of the major classes of psychoactive agents: (I & II) Antidepressants (tricyclic antidepressants and monoamine oxidase inhibitors); (III) Lithium Carbonate; (IV) Major Tranquilizers (phenothiazines, thioxanthenes, butryophenones, reserpine); and (V) Minor Tranquilizers, Sedatives, and Hypnotics (benzodiazepines and barbiturates) with respect to their cardiotoxicity, cardiovascular side effects, and drug-drug interactions. Management of the cardiovascular complications of psychotropic overdose is discussed, as well as potential therapeutic uses of psychopharmacological medications in patients with cardiovascular pathology.

Topics: Adrenergic alpha-Antagonists; Anti-Anxiety Agents; Antipsychotic Agents; Arrhythmias, Cardiac; Autonomic Nervous System; Basal Ganglia Diseases; Benzodiazepines; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Chlorpromazine; Coronary Circulation; Drug Interactions; Electroencephalography; Humans; Neuromuscular Blocking Agents; Reserpine; Tranquilizing Agents

Most patients with comorbid sleep apnea (OSA), cardiovascular (CV) disease, and/or cerebrovascular (CeV) disease simultaneously take medications. Whether OSA and continuous positive airway pressure (CPAP) interact with CV/CeV medications remains unknown. This study aimed to determine the interaction among OSA, CPAP, and CV/CeV medications; the effects of medications on major adverse cardiac and cerebrovascular events, and survival in patients with comorbid OSA and CV/CeV.. This was a post hoc analysis of the data from one center of the Sleep Apnea Cardiovascular Endpoints Study. Participants (aged 45-75 years) with comorbid OSA and CV/CeV were randomized to receive usual care with or without CPAP from December 2008 to November 2013. The primary endpoint was death and the secondary endpoint was a composite of death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, and transient ischemic attack.. In total, 131 patients were analyzed. Sixty-three were in the CPAP group and 68 were in the usual care group, 41 had good adherence to CPAP (65.1%), and the median follow-up time was 43.0 (35.0, 54.0) months. In Cox regression analysis, ACE inhibitors and nitrates were independent factors for decreased survival in patients with comorbid OSA and CV/CeV (chi-square = 22.932, P = 0.003; ACE inhibitors: OR 7.241, P = 0.048, 95% CI 1.016-51.628; nitrates: OR 18.012, P = 0.011, 95% CI 1.923-168.750). ACE inhibitors increased mortality and secondary endpoints in the CPAP group (chi-square = 4.134, P = 0.042) but not in patients with good CPAP adherence. Clopidogrel and nitrates decreased survival in usual care group (clopidogrel: chi-square = 5.312, P = 0.021; nitrates: chi-square = 6.417, P = 0.011), but not in CPAP group.. OSA may predispose patients with CV/CeV and CV/CeV medications to a negative effect. CPAP treatment may neutralize the negative effects of OSA by relieving chronic intermittent hypoxia. Trial registration ClinicalTrials.gov (NCT00738179, first registration date: 20/08/2008).

Topics: Adrenergic beta-Antagonists; Aged; Cardiovascular Agents; Cardiovascular Diseases; Cerebrovascular Disorders; Comorbidity; Continuous Positive Airway Pressure; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Male; Middle Aged; Nitrates; Proportional Hazards Models; Risk Factors; Sleep Apnea, Obstructive; Survival Analysis

Sodium tanshinone IIA sulfonate (STS) has been widely used by Chinese medicine practitioners for chronic cardiovascular diseases. However, its direct clinical efficacy in patients with acute coronary syndrome following percutaneous coronary intervention (PCI) has not been reported yet. The present trial aimed to investigate potential cardioprotection of STS in patients undergoing PCI for non-ST elevation acute coronary syndrome (NSTE-ACS).. In a randomized, double-blind, placebo-controlled trial, 372 patients with NSTE-ACS were randomly assigned to receive STS (n = 192) or saline (n = 180) for 2 days before and 3 days after PCI along with standard therapy. The primary endpoint was the composite incidence of major adverse cardiac events (MACEs), including death, non-fatal myocardial infarction, repeated revascularization of the target vessel, and stent thrombosis, within 30 days after PCI.. The 30-day MACEs occurred in 18.8% of the patients in the STS group and in 27.2% of the patients in the control group (P = 0.038); this difference was mostly driven by reduction of myocardial infarction incidence (17.2% vs. 26.7%, P = 0.027). Post-procedural elevation of troponin-I was also significantly lower in the STS group (26.56% vs. 47.78%, P < 0.001). Multivariable analysis identified STS as a predictor of decreased risk of MACE occurrence (odds ratio: 0.60, 95% confidence interval: 0.36 to 0.99; P = 0.045).. Addition of STS to the standard treatments recommended by the current practice guidelines in patients with NSTE-ACS undergoing PCI could reduce myocardial injury and the occurrence of short-term cardiovascular events, primarily driven by non-fatal myocardial infarction.. ChiCTR-TRC-14005182.

Topics: Acute Coronary Syndrome; Aged; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Double-Blind Method; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Phenanthrenes

Adherence to medications remains poor despite numerous efforts to identify and intervene upon nonadherence. One potential explanation is the limited focus of many interventions on one barrier. Little is known about the prevalence and impact of having multiple barriers in contemporary practice. Our objective was to quantify adherence barriers for patients with poorly controlled cardiometabolic condition, identify patient characteristics associated with having multiple barriers, and determine its impact on adherence. We used a linked electronic health records and insurer claims dataset from a large health system from a recent pragmatic trial. Barriers to medication taking before the start of the intervention were elicited by clinical pharmacists using structured interviews. We used multivariable modified Poisson regression models to examine the association between patient factors and multiple barriers and multivariable linear regression to evaluate the relation between multiple barriers and claims-based adherence. Of the 1,069 patients (mean: 61 years of age) in this study, 25.1% had multiple barriers to adherence; the most common co-occurring barriers were forgetfulness and health beliefs (31%, n = 268). Patients with multiple barriers were more likely to be non-white (relative risk [RR] 1.57, 95% confidence interval [CI] 1.21 to 1.74), be single/unpartnered (RR 1.36, 95% CI 1.06 to 1.74), use tobacco (RR 1.54, 95% CI 1.13 to 2.11), and have poor glycemic control (RR 1.77, 95% CI 1.31 to 2.39) versus those with 0 or 1 barrier. Each additional barrier worsened average adherence by 3.1% (95% CI -4.6%, -1.5%). In conclusion, >25% of nonadherent patients present with multiple barriers to optimal use, leading to meaningful differences in adherence. These findings should inform quality improvement interventions aimed at nonadherence.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Female; Follow-Up Studies; Humans; Male; Medication Adherence; Middle Aged; Prevalence; Retrospective Studies; Surveys and Questionnaires

This study assessed baseline cardiovascular (CV) risk factors, concomitant CV medication use, risk of major adverse cardiac events-plus (MACE-plus), and bleeding adverse events (AEs) in patients with idiopathic pulmonary fibrosis (IPF) in three randomized, placebo-controlled phase III trials of pirfenidone.. Patients in the pirfenidone phase III trials were included. Patients with unstable or deteriorating cardiac disease within 6 months before enrollment were ineligible. Medical history at baseline and concomitant CV medication use during treatment were reported. A retrospective, blinded review of AE preferred terms was conducted to identify MACE-plus and bleeding events. Subgroup analyses examined the impact of concomitant CV medication use on how pirfenidone treatment affected clinical outcomes.. In total, 1247 patients were included [n = 623 pirfenidone (2403 mg/day) and n = 624 placebo]. The median age was 68 years, 74% were male, and 65% were current/former smokers. Commonly reported CV risk factors included hypertension (52%), obesity (44%), hypercholesterolemia (23%), and hyperlipidemia (23%). Pre-existing cardiac disorders included coronary artery disease (16%), myocardial infarction (5%), and atrial fibrillation (5%). Lipid-modifying agents (60%), antithrombotic agents (54%), and renin-angiotensin inhibitors (39%) were commonly used concomitant CV medications. The incidences of MACE-plus and bleeding events were similar between the pirfenidone and placebo groups (1.8% and 2.9% for MACE-plus events and 3.7% and 4.3% for bleeding events, respectively). Except for patients receiving heparin, pirfenidone had a beneficial effect compared with placebo on efficacy outcomes regardless of concomitant CV medications.. CV risk factors and comorbidities and use of concomitant CV medications are common in patients with IPF. Pirfenidone did not appear to increase the risk of CV or bleeding events. Use of several concomitant CV medications, including warfarin, did not appear to adversely impact pirfenidone's beneficial effect on efficacy outcomes.. NCT00287716, NCT00287729, and NCT01366209.. F. Hoffmann-La Roche Ltd. and Genentech, Inc.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Atrial Fibrillation; Cardiovascular Agents; Cardiovascular Diseases; Coronary Artery Disease; Female; Hemorrhage; Humans; Idiopathic Pulmonary Fibrosis; Male; Middle Aged; Pyridones; Retrospective Studies; Risk Factors; Treatment Outcome; Warfarin

A fixed-dose combination therapy (polypill strategy) has been proposed as an approach to reduce the burden of cardiovascular disease, especially in low-income and middle-income countries (LMICs). The PolyIran study aimed to assess the effectiveness and safety of a four-component polypill including aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan for primary and secondary prevention of cardiovascular disease.. The PolyIran study was a two-group, pragmatic, cluster-randomised trial nested within the Golestan Cohort Study (GCS), a cohort study with 50 045 participants aged 40-75 years from the Golestan province in Iran. Clusters (villages) were randomly allocated (1:1) to either a package of non-pharmacological preventive interventions alone (minimal care group) or together with a once-daily polypill tablet (polypill group). Randomisation was stratified by three districts (Gonbad, Aq-Qala, and Kalaleh), with the village as the unit of randomisation. We used a balanced randomisation algorithm, considering block sizes of 20 and balancing for cluster size or natural log of the cluster size (depending on the skewness within strata). Randomisation was done at a fixed point in time (Jan 18, 2011) by statisticians at the University of Birmingham (Birmingham, UK), independent of the local study team. The non-pharmacological preventive interventions (including educational training about healthy lifestyle-eg, healthy diet with low salt, sugar, and fat content, exercise, weight control, and abstinence from smoking and opium) were delivered by the PolyIran field visit team at months 3 and 6, and then every 6 months thereafter. Two formulations of polypill tablet were used in this study. Participants were first prescribed polypill one (hydrochlorothiazide 12·5 mg, aspirin 81 mg, atorvastatin 20 mg, and enalapril 5 mg). Participants who developed cough during follow-up were switched by a trained study physician to polypill two, which included valsartan 40 mg instead of enalapril 5 mg. Participants were followed up for 60 months. The primary outcome-occurrence of major cardiovascular events (including hospitalisation for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularisation procedures, and non-fatal and fatal stroke)-was centrally assessed by the GCS follow-up team, who were masked to allocation status. We did intention-to-treat analyses by including all participants who met eligibility criteria in the two study groups. The trial was registered with ClinicalTrials.gov, number NCT01271985.. Between Feb 22, 2011, and April 15, 2013, we enrolled 6838 individuals into the study-3417 (in 116 clusters) in the minimal care group and 3421 (in 120 clusters) in the polypill group. 1761 (51·5%) of 3421 participants in the polypill group were women, as were 1679 (49·1%) of 3417 participants in the minimal care group. Median adherence to polypill tablets was 80·5% (IQR 48·5-92·2). During follow-up, 301 (8·8%) of 3417 participants in the minimal care group had major cardiovascular events compared with 202 (5·9%) of 3421 participants in the polypill group (adjusted hazard ratio [HR] 0·66, 95% CI 0·55-0·80). We found no statistically significant interaction with the presence (HR 0·61, 95% CI 0·49-0·75) or absence of pre-existing cardiovascular disease (0·80; 0·51-1·12; p. Use of polypill was effective in preventing major cardiovascular events. Medication adherence was high and adverse event numbers were low. The polypill strategy could be considered as an additional effective component in controlling cardiovascular diseases, especially in LMICs.. Tehran University of Medical Sciences, Barakat Foundation, and Alborz Darou.

Topics: Adult; Aged; Anticholesteremic Agents; Antihypertensive Agents; Aspirin; Atorvastatin; Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Cholesterol, LDL; Diabetes Mellitus; Drug Combinations; Enalapril; Female; Humans; Hydrochlorothiazide; Male; Medication Adherence; Middle Aged; Platelet Aggregation Inhibitors; Secondary Prevention; Valsartan

In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.. In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.. Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.).

Topics: Aged; Benzhydryl Compounds; Cardiovascular Agents; Cardiovascular Diseases; Combined Modality Therapy; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Heart Failure; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Ventricular Dysfunction, Left

Non-adherence has been well recognized for years to be a common issue that significantly impacts clinical outcomes and health care costs. Medication adherence is remarkably low even in the controlled environment of clinical trials where it has potentially complex major implications. Collection of non-adherence data diverge markedly among cardiovascular randomized trials and, even where collected, is rarely incorporated in the statistical analysis to test the consistency of the primary endpoint(s). The imprecision introduced by the inconsistent assessment of non-adherence in clinical trials might confound the estimate of the calculated efficacy of the study drug. Hence, clinical trials may not accurately answer the scientific question posed by regulators, who seek an accurate estimate of the true efficacy and safety of treatment, or the question posed by payers, who want a reliable estimate of the effectiveness of treatment in the marketplace after approval. The Non-adherence Academic Research Consortium is a collaboration among leading academic research organizations, representatives from the U.S. Food and Drug Administration and physician-scientists from the USA and Europe. One in-person meeting was held in Madrid, Spain, culminating in a document describing consensus recommendations for reporting, collecting, and analysing adherence endpoints across clinical trials. The adoption of these recommendations will afford robustness and consistency in the comparative safety and effectiveness evaluation of investigational drugs from early development to post-marketing approval studies. These principles may be useful for regulatory assessment, as well as for monitoring local and regional outcomes to guide quality improvement initiatives.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Case-Control Studies; Consensus; Decision Making; Health Care Costs; Humans; Intention to Treat Analysis; Medication Adherence; Physicians; Placebos; Risk Assessment; Safety; Societies, Scientific; Spain; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Aged; Biomarkers; Blood Pressure; Cardiac Rehabilitation; Cardiovascular Agents; Cardiovascular Diseases; Cholesterol; Denmark; Female; Follow-Up Studies; Glycated Hemoglobin; Health Equity; Humans; Life Style; Male; Medication Adherence; Middle Aged; Myocardial Infarction; Prospective Studies; Risk Factors; Secondary Prevention; Smoking; Social Support; Socioeconomic Factors

The use of cardiovascular medication for the primary prevention of cardiovascular disease (CVD) is potentially inappropriate when potential risks outweigh the potential benefits. It is unknown whether deprescribing preventive cardiovascular medication in patients without a strict indication for such medication is safe and cost-effective in general practice.. In this pragmatic cluster randomised controlled non-inferiority trial, we recruited 46 general practices in the Netherlands. Patients aged 40-70 years who were using antihypertensive and/or lipid-lowering drugs without CVD and with low risk of future CVD were followed for 2 years. The intervention was an attempt to deprescribe preventive cardiovascular medication. The primary outcome was the difference in the increase in predicted (10-year) CVD risk in the per-protocol (PP) population with a non-inferiority margin of 2.5 percentage points. An economic evaluation was performed in the intention-to-treat (ITT) population. We used multilevel (generalised) linear regression with multiple imputation of missing data.. Of 1067 participants recruited between 7 November 2012 and 18 February 2014, 72% were female. Overall, their mean age was 55 years and their mean predicted CVD risk at baseline was 5%. Of 492 participants in the ITT intervention group, 319 (65%) quit the medication (PP intervention group); 135 (27%) of those participants were still not taking medication after 2 years. The predicted CVD risk increased by 2.0 percentage points in the PP intervention group compared to 1.9 percentage points in the usual care group. The difference of 0.1 (95% CI -0.3 to 0.6) fell within the non-inferiority margin. After 2 years, compared to the usual care group, for the PP intervention group, systolic blood pressure was 6 mmHg higher, diastolic blood pressure was 4 mmHg higher and total cholesterol and low-density lipoprotein-cholesterol levels were both 7 mg/dl higher (all P < 0.05). Cost and quality-adjusted life years did not differ between the groups.. The results of the ECSTATIC study show that an attempt to deprescribe preventive cardiovascular medication in low-CVD-risk patients is safe in the short term when blood pressure and cholesterol levels are monitored after stopping. An attempt to deprescribe medication can be considered, taking patient preferences into consideration.. This study was registered with Dutch trial register on 20 June 2012 ( NTR3493 ).

Topics: Adult; Aged; Antihypertensive Agents; Cardiovascular Agents; Cardiovascular Diseases; Chemoprevention; Cluster Analysis; Deprescriptions; Female; General Practice; Humans; Male; Middle Aged; Netherlands; Primary Prevention; Prognosis; Quality-Adjusted Life Years; Risk Factors

Tobacco use and tobacco-related diseases disproportionately affect Alaska Native (AN) people. Using telemedicine, this study aims to identify culturally-tailored, theoretically-driven, efficacious interventions for tobacco use and other cardiovascular disease (CVD) risk behaviors among AN people in remote areas.. Randomized clinical trial with two intervention arms: 1) tobacco and physical activity; 2) medication adherence and a heart-healthy AN diet.. Participants are N = 300 AN men and women current smokers with high blood pressure or high cholesterol.. All participants receive motivational, stage-tailored, telemedicine-delivered counseling sessions at baseline and 3, 6, and 12 months follow-up; an individualized behavior change plan that is updated at each contact; and a behavior change manual. In Group 1, the focus is on tobacco and physical activity; a pedometer is provided and nicotine replacement therapy is offered. In Group 2, the focus is on medication adherence for treating hypertension and/or hypercholesterolemia; a medication bag and traditional food guide are provided.. With assessments at baseline, 3, 6, 12, and 18 months, the primary outcome is smoking status, assessed as 7-day point prevalence abstinence, biochemically verified with urine anabasine. Secondary outcomes include physical activity, blood pressure and cholesterol, medication compliance, diet, multiple risk behavior change indices, and cost-effectiveness.. The current study has the potential to identify novel, feasible, acceptable, and efficacious interventions for treating the co-occurrence of CVD risk factors in AN people. Findings may inform personalized treatment and the development of effective and cost-effective intervention strategies for use in remote indigenous communities more broadly. Clinical Trial Registration # NCT02137902.

Topics: Adult; Alaskan Natives; Behavior Control; Cardiovascular Agents; Cardiovascular Diseases; Distance Counseling; Exercise; Female; Humans; Male; Medication Adherence; Quality of Life; Risk Factors; Risk Reduction Behavior; Smoking Cessation; Telemedicine; Tobacco Use Disorder

Patients with chronic kidney disease (CKD) are at high risk for developing cardiovascular events. However, limited evidence is available regarding the use of aspirin in CKD patients to decrease cardiovascular risk and to slow renal disease progression.. Prospective, multicenter, open-label randomized controlled trial.. One hundred eleven patients with estimated glomerular filtration rate (eGFR) 15-60 ml/min/1.73 m. Aspirin treatment (100 mg/day) (n = 50) or usual therapy (n = 61). Mean follow-up time was 64.8 ± 16.4 months.. The primary endpoint was composed of cardiovascular death, acute coronary syndrome (nonfatal MI, coronary revascularization, or unstable angina pectoris), cerebrovascular disease, heart failure, or nonfatal peripheral arterial disease. Secondary endpoints were fatal and nonfatal coronary events, renal events (defined as doubling of serum creatinine, ≥ 50% decrease in eGFR, or renal replacement therapy), and bleeding episodes.. During follow-up, 17 and 5 participants suffered from a primary endpoint in the control and aspirin groups, respectively. Aspirin did not significantly reduce primary composite endpoint (HR, 0.396 (0.146-1.076), p = 0.069. Eight patients suffered from a fatal or nonfatal coronary event in the control group compared to no patients in the aspirin group. Aspirin significantly reduced the risk of coronary events (log-rank, 5.997; p = 0.014). Seventeen patients in the control group reached the renal outcome in comparison with 3 patients in the aspirin group. Aspirin treatment decreased renal disease progression in a model adjusted for age, baseline kidney function, and diabetes mellitus (HR, 0.272; 95% CI, 0.077-0.955; p = 0.043) but did not when adjusted for albuminuria. No differences were found in minor bleeding episodes between groups and no major bleeding was registered.. Small sample size and open-label trial.. Long-term treatment with low-dose aspirin did not reduce the composite primary endpoint; however, there were reductions in secondary endpoints with fewer coronary events and renal outcomes. ClinicalTrials.gov Identifier: NCT01709994.

Topics: Aged; Aspirin; Cardiovascular Agents; Cardiovascular Diseases; Disease Progression; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Kidney; Male; Middle Aged; Primary Prevention; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors; Spain; Time Factors; Treatment Outcome

Individual risk factor control improves survival in patients with stable ischemic heart disease (SIHD). It is uncertain if multiple risk factor control further extends survival.. This study determined whether a greater number of risk factors at goal predicted improved survival in SIHD patients.. Of 2,287 participants in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, 2,102 (92%) had complete ascertainment of 6 pre-specified risk factors: systolic blood pressure, low-density lipoprotein cholesterol, smoking, physical activity, diet, and body mass index. Participants received interventions to control these risk factors. The outcome measure was mortality.. During a mean follow-up of 6.8 years, 473 (22.5%) subjects died. In univariate analysis, the greater the number of risk factors controlled, the higher the probability of survival (unadjusted log rank: p < 0.001). In multivariate analysis, the strongest predictors at 1 year of improved survival were being a nonsmoker, regular physical activity, having a systolic blood pressure <130 mm Hg, and following the American Heart Association Step 2 diet. Baseline risk factor values and evidence-based medications did not independently predict survival once risk factor control at 1 year was included in the model. Having 4 to 6 risk factors compared with 0 to 1 risk factor at goal predicted lower mortality (hazard ratios for 4 and 6 controlled risk factors: 0.64; 95% confidence interval: 0.41 to 0.98, and 0.27; 95% confidence interval: 0.09 to 0.79, respectively).. The greater the number of risk factors in control, the higher the probability of survival in patients with SIHD. More effective strategies are needed to achieve comprehensive risk factor control, including healthy behaviors. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE]; NCT00007657).

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Cholesterol, LDL; Cohort Studies; Exercise; Female; Follow-Up Studies; Health Behavior; Humans; Male; Middle Aged; Risk Factors; Risk Reduction Behavior; Smoking Cessation; Survival Rate

Signs and symptoms of heart failure can occur at any time. Differences between acute heart failure (AHF) patients who present at nighttime vs daytime and their outcomes have not been well studied. Our objective was to determine if there are differences in baseline characteristics and clinical outcomes between AHF patients presenting during daytime vs nighttime hours within an international, clinical trial.. This is a post hoc analysis of the RELAX AHF trial, which randomized 1,161 AHF patients to serelaxin vs placebo, both in addition to usual AHF therapy. Prespecified end points of the primary trial were used: dyspnea, 60-day heart failure/renal failure rehospitalization or cardiovascular (CV) death, and 180-day CV death. Both unadjusted and adjusted analyses for outcomes stratified by daytime vs nighttime presentation were performed.. Of the 1,161 RELAX-AHF patients, 775 (66.8%) patients presented during daytime and 386 (33.2%) at nighttime. Baseline characteristics were largely similar, although daytime patients were more likely to be male, have greater baseline body weight, have higher New York Heart Association class, have history of atrial fibrillation, and have more peripheral edema compared with nighttime patients. No differences in dyspnea relief or 60-day outcomes were observed. However, daytime presentation was associated with greater risk for 180-day CV death after adjustment (hazard ratio 2.28, 95% CI 1.34-3.86; c statistic = 0.82, 95% CI 0.78-0.86).. In this secondary analysis of the RELAX-AHF trial, baseline characteristics suggest that daytime-presenting patients may have more gradual worsening of chronic HF. Patients with AHF who presented at night had less risk for 180-day CV death, but similar risk for 60-day CV death or rehospitalization and symptom improvement for patients who presented during the daytime.

Topics: Acute Disease; Aged; Cardiovascular Agents; Cardiovascular Diseases; Double-Blind Method; Female; Heart Failure; Humans; Male; Prognosis; Recombinant Proteins; Relaxin; Risk Factors; Time Factors

Fixed dose combinations of cardiovascular therapy ('polypills') have now been launched in several dozen countries. There is considerable clinical interest in the effects of switching to polypill-based care from typical current treatment regimens, especially if polypills contain components at sub-maximal dosage.. The SPACE Collaboration includes three trials of polypill based care vs usual care in patients with established CVD or at high calculated risk. Individual patient data for 3140 trial participants were combined. Patients were categorized according to the potency of the statin and the number of BP lowering medications they were taking at baseline. Effects on adherence to anti-platelet medication, systolic blood pressure (SBP) and LDL cholesterol stratified by baseline potency of medication were determined using fixed effects models.. Randomisation to the polypill group was associated with improved SBP at 12months, but this improvement varied according to baseline BP regimen: -3.3, -5.9, -2.5 and +1mmHg for patients taking 0, 1, 2 and 3+ BP lowering medications at baseline. For changes in LDL cholesterol at 12months, significant improvements in LDL cholesterol were seen for those taking no statin (-0.21mmol/L; 95% CI: -0.34 to -0.07), less potent statin (-0.16mmol/L; 95% CI: -0.29 to -0.04) and equipotent statins (-0.14mmol/L; 95% CI -0.26 to -0.02) at baseline.. The adherence benefits of polypills tend to offset the loss of potency from use of individual components with lower dose potency, and to facilitate improvements in multiple risk factors.

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Databases, Factual; Drug Combinations; Drug Substitution; Female; Humans; Male; Middle Aged

Recent data indicate that fixed-dose combination (FDC) pills, polypills, can produce sizeable risk factor reductions. There are very few published data on the consistency of the effects of a polypill in different patient populations. It is unclear for example whether the effects of the polypill are mainly driven by the individuals with high individual risk factor levels. The aim of the present study is to examine whether baseline risk factor levels modify the effect of polypill treatment on low-density lipoprotein (LDL)-cholesterol, blood pressure (BP), calculated cardiovascular relative risk reduction and adverse events.. This paper describes a post-hoc analysis of a randomised, placebo-controlled trial of a polypill (containing aspirin 75 mg, simvastatin 20 mg, lisinopril 10 mg and hydrochlorothiazide 12.5 mg) in 378 individuals without an indication for any component of the polypill, but who had an estimated five-year risk for cardiovascular disease ≥7.5%. The outcomes considered were effect modification by baseline risk factor levels on change in LDL-cholesterol, systolic BP, calculated cardiovascular relative risk reduction and adverse events.. The mean LDL-cholesterol in the polypill group was 0.9 mmol/l (95% confidence interval (CI): 0.8-1.0) lower compared with the placebo group during follow-up. Those with a baseline LDL-cholesterol >3.6 mmol/l achieved a greater absolute LDL-cholesterol reduction with the polypill compared with placebo, than patients with an LDL-cholesterol ≤3.6 mmol/l (-1.1 versus -0.6 mmol/l, respectively). The mean systolic BP was 10 mm Hg (95% CI: 8-12) lower in the polypill group. In participants with a baseline systolic BP >135 mm Hg the polypill resulted in a greater absolute systolic BP reduction with the polypill compared with placebo, than participants with a systolic BP ≤ 135 mm Hg (-12 versus -7 mm Hg, respectively). Calculated from individual risk factor reductions, the mean cardiovascular relative risk reduction was 48% (95% CI: 43-52) in the polypill group. Both baseline LDL-cholesterol and estimated cardiovascular risk were significant modifiers of the estimated cardiovascular relative risk reduction caused by the polypill. Adverse events did not appear to be related to baseline risk factor levels or the estimated cardiovascular risk.. This study demonstrated that the effect of a cardiovascular polypill on risk factor levels is modified by the level of these risk factors. Groups defined by baseline LDL-cholesterol or systolic BP had large differences in risk factor reductions but only moderate differences in estimated cardiovascular relative risk reduction, suggesting also that patients with mildly increased risk factor levels but an overall raised cardiovascular risk benefit from being treated with a polypill.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Cardiovascular Diseases; Diuretics; Dose-Response Relationship, Drug; Drug Combinations; Female; Follow-Up Studies; Global Health; Humans; Hydrochlorothiazide; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lisinopril; Male; Medication Adherence; Middle Aged; Morbidity; Risk Assessment; Risk Factors; Simvastatin; Time Factors; Treatment Outcome

The aim of this study was to evaluate whether Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification could predict mortality risk factors and whether baseline treatment intensity would relate to mortality within each group, using data from TIOSPIR(®), the largest randomized clinical trial in COPD performed to date.. A total of 17,135 patients from TIOSPIR(®) were pooled and grouped by GOLD grading (A-D) according to baseline Medical Research Council breathlessness score, exacerbation history, and spirometry. All-cause mortality and adjudicated cardiovascular (CV) and respiratory mortality were assessed.. Of the 16,326 patients classified, 1,248 died on treatment. Group B patients received proportionally more CV treatment at baseline. CV mortality risk, but not all-cause mortality risk, was significantly higher in Group B than Group C patients (CV mortality - hazard ratio [HR] =1.74, P=0.004; all-cause mortality - HR =1.18, P=0.11). Group D patients had a higher incidence of all-cause mortality than Group B patients (10.9% vs 6.6%). Similar trends were observed regardless of respiratory or CV medication at baseline. In contrast, respiratory deaths increased consistently from Groups A-D (0.3%, 0.8%, 1.6%, and 4.2% of patients, respectively).. The data obtained from the TIOSPIR(®) trial, supporting earlier studies, suggest that proportionally more CV medication and CV deaths occur in GOLD Group B COPD patients, although deaths attributed to respiratory causes are more prevalent in Groups C and D.

Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Disease Progression; Dyspnea; Female; Humans; Incidence; Male; Middle Aged; Patient Outcome Assessment; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Respiratory System Agents; Risk Assessment; Risk Factors; Severity of Illness Index; Spirometry; Symptom Flare Up

The purpose of this study was to investigate the consistency of the proportional effect of fixed-dose combination therapy (the 'polypill') on the use of recommended cardiovascular preventative medications among indigenous Māori and non-indigenous adults in New Zealand.. We randomised Māori and non-Māori primary care patients at high risk of cardiovascular disease (either because of a prior event or with an estimated 5-year risk of a first event of at least 15%) to a polypill (containing aspirin, statin and two antihypertensives) or usual care for a minimum of 12 months. All patients had indications for all polypill components according to their general practitioner, and all medications (including the polypill) were prescribed by the patient's general practitioner and dispensed at community pharmacies. The main outcome for this study was the use of all recommended medications (antiplatelet, statin and two antihypertensives) at 12 months. Heterogeneity in the effect of polypill-based care compared with usual care on this outcome by ethnicity was assessed by logistic regression.. Baseline use of recommended medications was 36% (93/257) among Māori and 51% (130/156) among non-Māori participants. Polypill-based care was associated with an increase in the use of recommended medications among Māori (relative risk [RR]: 1.87; 95% confidence interval [CI]: 1.50-2.34) and non-Māori (RR: 1.66; 95% CI: 1.37-2.00) when compared with usual care at 12 months, and there was no statistically significant heterogeneity in this outcome by ethnicity (p = 0.92).. Polypill-based care is likely to reduce absolute inequities between Māori and non-Māori in the use of recommended cardiovascular preventative medications given baseline absolute differences and the consistency of the proportional effect of this intervention by ethnicity in this pragmatic trial in primary care.

Topics: Cardiovascular Agents; Cardiovascular Diseases; Drug Combinations; Ethnicity; Female; Follow-Up Studies; Humans; Male; Middle Aged; Morbidity; New Zealand; Retrospective Studies; Risk Assessment; Time Factors; Treatment Outcome

The use of preventive cardiovascular medication by patients with low cardiovascular disease (CVD) risk is potentially inappropriate.. The aim of this study was to identify barriers to and enablers of deprescribing potentially inappropriate preventive cardiovascular medication experienced by patients and general practitioners (GPs).. A total of 10 GPs participating in the ECSTATIC trial (Evaluating Cessation of STatins and Antihypertensive Treatment In primary Care) audiotaped deprescribing consultations with low-CVD-risk patients. After initial conventional content analysis, 2 researchers separately coded all barriers to and enablers of deprescribing medication using framework analysis. We performed a within-case and cross-case analysis to explore barriers and enablers among both patients and GPs.. Patients (n = 49) and GPs (n = 10) expressed barriers and enablers with regard to the appropriateness of the medication and the deprescribing process. A family history for CVD was identified as a barrier to deprescribing medication for both patients and GPs. Patients feared possible consequences of deprescribing and were influenced by the opinion of their GP. Additionally, a presumed disapproving opinion from specialists influenced the GPs' willingness to deprescribe medication.. Patients appreciated discussing their doubts regarding deprescribing potentially inappropriate preventive cardiovascular medication. Furthermore, they acknowledged their GP's expertise and took their opinion toward deprescribing into consideration. The GPs' decisions to deprescribe were influenced by the low CVD risk of the patients, additional risk factors, and the alleged specialist's opinion toward deprescribing. We recommend deprescribing consultations to be patient centered, with GPs addressing relevant themes and probable consequences of deprescribing preventive cardiovascular medication.

Topics: Adult; Cardiovascular Agents; Cardiovascular Diseases; Deprescriptions; Female; General Practitioners; Humans; Male; Middle Aged; Potentially Inappropriate Medication List; Practice Guidelines as Topic; Practice Patterns, Physicians'; Risk Factors