cardiovascular-agents and Atherosclerosis

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

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

The resolution of inflammation (or inflammation-resolution) is an active and highly coordinated process. Inflammation-resolution is governed by several endogenous factors, and specialized pro-resolving mediators (SPMs) are one such class of molecules that have robust biological function. Non-resolving inflammation is associated with a variety of human diseases, including atherosclerosis. Moreover, non-resolving inflammation is a hallmark of ageing, an inevitable process associated with increased risk for cardiovascular disease. Uncovering mechanisms as to why inflammation-resolution is impaired in ageing and in disease and identifying useful biomarkers for non-resolving inflammation are unmet needs. Recent work has pointed to a critical role for balanced ratios of SPMs and pro-inflammatory lipids (i.e. leucotrienes and/or specific prostaglandins) as a key determinant of timely inflammation resolution. This review will focus on the accumulating findings that support the role of non-resolving inflammation and imbalanced pro-resolving and pro-inflammatory mediators in atherosclerosis. We aim to provide insight as to why these imbalances occur, the importance of ageing in disease progression, and how haematopoietic function impacts inflammation-resolution and atherosclerosis. We highlight open questions regarding therapeutic strategies and mechanisms of disease to provide a framework for future studies that aim to tackle this important human disease.

Topics: Animals; Anti-Inflammatory Agents; Arteries; Atherosclerosis; Cardiovascular Agents; Humans; Immune System; Inflammation; Inflammation Mediators; Plaque, Atherosclerotic; Signal Transduction

Cardiovascular diseases (CVD) have overtaken infectious diseases and are currently the world's top killer. A quite strong linkage between this type of ailments and elevated plasma levels of triglycerides (TG) has been always noticed. Notably, this risk factor is mired in deep confusion, since its role in atherosclerosis is uncertain. One of the explanations that aim to decipher this persistent enigma was provided by apolipoprotein C-III (apoC-III), a small protein historically recognized as an important regulator of TG metabolism. Preeminently, hundreds of studies have been carried out in order to explore the APOC3 genetic background, as well as to establish a correlation between its variants and dyslipidemia-related disorders, pointing to an earnest predictive power for future outcomes. Among several polymorphisms reported within the APOC3, the SstI site in its 3'-untranslated region (3'-UTR) was the most consistently and robustly associated with an increased CVD risk. As more genetic data supporting its importance in cardiovascular events aggregate, it was declared, correspondingly, that apoC-III exerts various atherogenic effects, either by intervening in the function and catabolism of many lipoproteins, or by inducing endothelial inflammation and smooth muscle cells (SMC) proliferation. This review was designed to shed the light on the structural and functional aspects of the APOC3 gene, the existing association between its SstI polymorphism and CVD, and the specific molecular mechanisms that underlie apoC-III pathological implications. In addition, the translation of all these gathered knowledges into preventive and therapeutic benefits will be detailed too.

Topics: 3' Untranslated Regions; Apolipoprotein C-III; Atherosclerosis; Cardiovascular Agents; Clinical Trials as Topic; Gene Expression; Humans; Hyperlipoproteinemia Type I; Hypertriglyceridemia; Oligonucleotides; Plaque, Atherosclerotic; Polymorphism, Genetic; Risk Factors; Triglycerides

The use of medicinal plants as a therapy alternative is old as human existence itself. Nowadays, the search for effective molecules for chronic diseases treatments has increased. The cardiometabolic disorders still the main cause of death worldwide and plants may offer potential pharmacological innovative approaches to treat and prevent diseases. In the range of plant molecules are inserted the terpenes, which constituent essential elements with several pharmacological characteristics and applications, including cardiovascular and metabolic properties. Thus, the aim of the present review is to update the terpenes use on chronic disorders such as obesity, diabetes, hypertension and vascular conditions. The review includes a brief terpenes description based on the scientific literature in addition to data collected from secondary sources such as books and conference proceedings. We concluded that terpenes could act as adjuvant or main alternative treatment (when started earlier) to improve cardiometabolic diseases, contributing to reduce side effects of conventional drugs, in addition to preserving ethnopharmacological knowledge.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Chemotherapy, Adjuvant; Diabetes Mellitus; Disease Models, Animal; Ethnopharmacology; Humans; Hypertension; Obesity; Plant Extracts; Plants, Medicinal; Stereoisomerism; Terpenes

Since the outbreak of coronavirus disease 2019 (COVID-19) in 2019, it is gaining worldwide attention at the moment. Apart from respiratory manifestations, neurological dysfunction in COVID-19 patients, especially the occurrence of cerebrovascular diseases (CVD), has been intensively investigated. In this review, the effects of COVID-19 infection on CVD were summarized as follows: (I) angiotensin-converting enzyme 2 (ACE2) may be involved in the attack on vascular endothelial cells by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), leading to endothelial damage and increased subintimal inflammation, which are followed by hemorrhage or thrombosis; (II) SARS-CoV-2 could alter the expression/activity of ACE2, consequently resulting in the disruption of renin-angiotensin system which is associated with the occurrence and progression of atherosclerosis; (III) upregulation of neutrophil extracellular traps has been detected in COVID-19 patients, which is closely associated with immunothrombosis; (IV) the inflammatory cascade induced by SARS-CoV-2 often leads to hypercoagulability and promotes the formation and progress of atherosclerosis; (V) antiphospholipid antibodies are also detected in plasma of some severe cases, which aggravate the thrombosis through the formation of immune complexes; (VI) hyperglycemia in COVID-19 patients may trigger CVD by increasing oxidative stress and blood viscosity; (VII) the COVID-19 outbreak is a global emergency and causes psychological stress, which could be a potential risk factor of CVD as coagulation, and fibrinolysis may be affected. In this review, we aimed to further our understanding of CVD-associated COVID-19 infection, which could improve the therapeutic outcomes of patients. Personalized treatments should be offered to COVID-19 patients at greater risk for stroke in future clinical practice.

Topics: Anticoagulants; Antiviral Agents; Atherosclerosis; Cardiovascular Agents; COVID-19; COVID-19 Drug Treatment; Disseminated Intravascular Coagulation; Extracellular Traps; Hemorrhage; Humans; Hyperglycemia; Inflammation; Renin-Angiotensin System; SARS-CoV-2; Stroke; Thrombosis

Atherosclerosis is the leading cause of death in developed countries. The pathogenetic mechanism relies on a macrophage-based immune reaction to low density lipoprotein (LDL) deposition in blood vessels with dysfunctional endothelia. Thus, atherosclerosis is defined as a chronic inflammatory disease. A plethora of cardiovascular drugs have been developed and are on the market, but the major shortcoming of standard medications is that they do not address the root cause of the disease. Statins and thiazolidinediones that have recently been recognized to exert specific anti-atherosclerotic effects represent a potential breakthrough on the horizon. But their whole potential cannot be realized due to insufficient availability at the pathological site and severe off-target effects. The focus of this review will be to elaborate how both groups of drugs could immensely profit from nanoparticulate carriers. This delivery principle would allow for their accumulation in target macrophages and endothelial cells of the atherosclerotic plaque, increasing bioavailability where it is needed most. Based on the analyzed literature we conclude design criteria for the delivery of statins and thiazolidinediones with nanoparticles for anti-atherosclerotic therapy. Nanoparticles need to be below a diameter of 100 nm to accumulate in the atherosclerotic plaque and should be fabricated using biodegradable materials. Further, the thiazolidinediones or statins must be encapsulated into the particle core, because especially for thiazolidindiones the uptake into cells is prerequisite for their mechanism of action. For optimal uptake into targeted macrophages and endothelial cells, the ideal particle should present ligands on its surface which bind specifically to scavenger receptors. The impact of statins on the lectin-type oxidized LDL receptor 1 (LOX1) seems particularly promising because of its outstanding role in the inflammatory process. Using this pioneering concept, it will be possible to promote the impact of statins and thiazolidinediones on macrophages and endothelial cells and significantly enhance their anti-atherosclerotic therapeutic potential.

Topics: Atherosclerosis; Cardiovascular Agents; Endothelial Cells; Humans; Lipoproteins, LDL; Nanotechnology; Plaque, Atherosclerotic

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

Coronary artery disease is the leading cause of morbidity and mortality worldwide. The most common pathophysiologic substrate is atherosclerosis which is an inflammatory procedure that starts at childhood and develops throughout life. Endothelial dysfunction is associated with the initiation and progression of atherosclerosis and is characterized by the impaired production of nitric oxide. In general, endothelial dysfunction is linked to poor cardiovascular prognosis and different methods, both invasive and non-invasive, have been developed for its evaluation. Ultrasound evaluation of flow mediated dilatation of the branchial artery is the most commonly used method to assessed endothelial function while intracoronary administration of vasoactive agents may be also be used to test directly endothelial properties of the coronary vasculature. Endothelial dysfunction has also been the subject of therapeutic interventions. This review article summarizes the knowledge about evaluation of endothelial function in acute coronary syndromes and stable coronary artery disease and demonstrates the current therapeutic approaches against endothelial dysfunction.

Topics: Atherosclerosis; Cardiovascular Agents; Coronary Artery Disease; Coronary Vessels; Endothelium, Vascular; Humans; Nitric Oxide; Vasodilation

Topics: Animals; Anti-Inflammatory Agents; Arteries; Atherosclerosis; Biomarkers; Cardiovascular Agents; Humans; Inflammation; Inflammation Mediators; Molecular Targeted Therapy; Plaque, Atherosclerotic; Signal Transduction

Abdominal aortic aneurysms (AAA) pose a considerable health burden and at present are only managed surgically since there is no proven pharmacotherapy that will retard their expansion or reduce the incidence of fatal rupture. This pathology shares several pathophysiological mechanisms with atherosclerosis, such as macrophage infiltration, inflammation, and degradation of extracellular matrix. Therefore, therapeutic targets proven effective in the treatment of atherosclerosis could also be considered for treatment of AAA. Different members of the nuclear receptor (NR) superfamily have been extensively studied as potential targets in the treatment of cardiovascular disease (CVD) and therefore might also be suited for AAA treatment. In this context, this review summarizes the role of different NRs in CVD, mostly atherosclerosis, and discusses in detail the current knowledge of their implications in AAA. From this overview it becomes apparent that NRs that were attributed a beneficial or adverse role in CVD have similar roles in AAA. Together, this overview provides compelling evidence to consider several NRs as attractive targets for future treatment of AAA.

Topics: Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Atherosclerosis; Cardiovascular Agents; Humans; Receptors, Cytoplasmic and Nuclear; Signal Transduction

The potential of CD31 as a therapeutic target in atherosclerosis has been considered ever since its cloning in the 1990s, but the exact role played by this molecule in the biologic events underlying atherosclerosis has remained controversial, resulting in the stalling of any therapeutic perspective. Due to the supposed cell adhesive properties of CD31, specific monoclonal antibodies and recombinant proteins were regarded as blocking agents because their use prevented the arrival of leukocytes at sites of acute inflammation. However, the observed effect of those compounds likely resulted from the engagement of the immunomodulatory function of CD31 signaling. This was acknowledged only later though, upon the discovery of CD31's 2 intracytoplasmic tyrosine residues called immunoreceptor tyrosine inhibitory motifs. A growing body of evidence currently points at a therapeutic potential for CD31

Topics: Animals; Arteries; Atherosclerosis; Cardiovascular Agents; Coronary Artery Disease; Drug-Eluting Stents; Humans; Immunologic Factors; Molecular Targeted Therapy; Percutaneous Coronary Intervention; Plaque, Atherosclerotic; Platelet Endothelial Cell Adhesion Molecule-1; Prosthesis Design; Signal Transduction

Atherosclerosis (AS), a typical chronic inflammatory vascular disease, is the main pathological basis of ischemic cardio/cerebrovascular disease (CVD). Long-term administration was characterized with low efficacy and serious side effects, while the macrophages with attractive intrinsic homing target have great potential in the efficient and safe management of AS. In this review, we focused on the systematical summary of the macrophage-based therapies in AS management, including macrophage autophagy, polarization, targeted delivery, microenvironment-triggered drug release, and macrophage- or macrophage membrane-based drug carrier. In conclusion, macrophage-based therapies have great promise to effectively manage AS in future research and clinic translation.

Topics: Animals; Atherosclerosis; Autophagy; Cardiovascular Agents; Cell Membrane; Disease Models, Animal; Drug Carriers; Humans; Inflammasomes; Macrophage Activation; Macrophages

With the advancement of science and technology, the living standards of human beings have continuously improved, but the incidence and mortality from atherosclerosis worldwide have also increased by year. Although interventional surgery and the continuous development of new drugs have significant therapeutic effects, their side effects cannot be ignored. Polydatin, an active ingredient isolated from the natural medicine Polygonum cuspidatum, has been shown to have a prominent role in the treatment of cardiovascular diseases. Polydatin treats atherosclerosis mainly from three aspects: anti-inflammatory, regulating lipid metabolism and anti-oxidative stress. This article will review the pharmacological mechanism of polydatin in anti-atherosclerosis, the biological characteristics of Polygonum cuspidatum, the toxicology and pharmacokinetics of polydatin and will provide ideas for further research.

Topics: Animals; Anti-Inflammatory Agents; Anticholesteremic Agents; Antioxidants; Arteries; Atherosclerosis; Cardiovascular Agents; Glucosides; Humans; Inflammation Mediators; Lipid Metabolism; Oxidative Stress; Plaque, Atherosclerotic; Signal Transduction; Stilbenes

Atherosclerosis is a chronic disease characterized by lipid accumulation and chronic inflammation of the arterial wall, which is the pathological basis for coronary heart disease, cerebrovascular disease and thromboembolic disease. Currently, there is a lack of low-cost therapeutic agents that effectively slow the progression of atherosclerosis. Therefore, the development of new drugs is urgently needed. The research and development of marine-derived drugs have gained increasing interest from researchers across the world. Many marine organisms provide a rich material basis for the development of atherosclerotic drugs. This review focuses on the latest technological advances in the structures and mechanisms of action of marine-derived anti-atherosclerotic substances and the challenges of the application of these substances including marine polysaccharides, proteins and peptides, polyunsaturated fatty acids and small molecule compounds. Here, we describe the theoretical basis of marine biological resources in the treatment of atherosclerosis.

Topics: Animals; Aquatic Organisms; Atherosclerosis; Cardiovascular Agents; Fatty Acids, Unsaturated; Humans; Molecular Structure; Polysaccharides; Proteins; Structure-Activity Relationship

Reactive oxygen species (ROS) are natural byproducts of oxygen metabolism in the cell. At physiological levels, they play a vital role in cell signaling. However, high ROS levels cause oxidative stress, which is implicated in cardiovascular diseases (CVD) such as atherosclerosis, hypertension, and restenosis after angioplasty. Despite the great amount of research conducted to identify the role of ROS in CVD, the image is still far from being complete. A common event in CVD pathophysiology is the switch of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype. Interestingly, oxidative stress is a major contributor to this phenotypic switch. In this review, we focus on the effect of ROS on the hallmarks of VSMC phenotypic switch, particularly proliferation and migration. In addition, we speculate on the underlying molecular mechanisms of these cellular events. Along these lines, the impact of ROS on the expression of contractile markers of VSMCs is discussed in depth. We conclude by commenting on the efficiency of antioxidants as CVD therapies.

Topics: Angiotensin II; Antioxidants; Atherosclerosis; Biomarkers; Cardiovascular Agents; Cell Cycle Proteins; Cell Movement; Cell Proliferation; Fibroblast Growth Factors; Gene Expression Regulation; Graft Occlusion, Vascular; Humans; Hypertension; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NADPH Oxidases; Oxidative Stress; Phenotype; Reactive Oxygen Species; Signal Transduction

Recent reports have established atherosclerosis (AS) as a major factor in the pathogenetic process of cardiovascular diseases such as ischemic stroke and coronary heart disease. Although the possible pathogenesis of AS remains to be elucidated, a large number of investigations strongly suggest that the inhibition of toll-like receptors (TLRs) alleviates the severity of AS to some extent by suppressing vascular inflammation and the formation of atherosclerotic plaques. As pattern recognition receptors, TLRs occupy a vital position in innate immunity, mediating various signaling pathways in infective and sterile inflammation. This review summarizes the available data on the research progress of AS and the latest antiatherosclerotic drugs associated with TLR pathway.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Humans; Immunity, Innate; Inflammation; Signal Transduction; Toll-Like Receptors

During atherosclerosis, the gradual accumulation of lipids into the subendothelial space of damaged arteries results in several lipid modification processes followed by macrophage uptake in the arterial wall. The way in which these modified lipoproteins are dealt with determines the likelihood of cholesterol accumulation within the monocyte-derived macrophage and thus its transformation into the foam cell that makes up the characteristic fatty streak observed in the early stages of atherosclerosis. The unique expression of chemokine receptors and cellular adhesion molecules expressed on the cell surface of monocytes points to a particular extravasation route that they can take to gain entry into atherosclerotic site, in order to undergo differentiation into the phagocytic macrophage. Indeed several GWAS and animal studies have identified key genes and proteins required for monocyte recruitment as well cholesterol handling involving lipid uptake, cholesterol esterification and cholesterol efflux. A re-examination of the previously accepted paradigm of macrophage foam cell origin has been called into question by recent studies demonstrating shared expression of scavenger receptors, cholesterol transporters and pro-inflammatory cytokine release by alternative cell types present in the neointima, namely; endothelial cells, vascular smooth muscle cells and stem/progenitor cells. Thus, therapeutic targets aimed at a more heterogeneous foam cell population with shared functions, such as enhanced protease activity, and signalling pathways, mediated by non-coding RNA molecules, may provide greater therapeutic outcome in patients. Finally, studies targeting each aspect of foam cell formation and death using both genetic knock down and pharmacological inhibition have provided researchers with a clearer understanding of the cellular processes at play, as well as helped researchers to identify key molecular targets, which may hold significant therapeutic potential in the future.

Topics: Animals; Apoptosis; Atherosclerosis; Cardiovascular Agents; Cholesterol; Foam Cells; Genetic Predisposition to Disease; Humans; Molecular Targeted Therapy; Necrosis; Phenotype; Plaque, Atherosclerotic; Risk Factors; Signal Transduction

Notwithstanding the intense efforts into the understanding and prevention of cardiovascular disease (CVD), its complex pathology remains the leading cause of mortality worldwide. The pivotal role of epigenetic changes in the control of gene expression has been profiled in several diseases, such as cancer and inflammatory disorders. In the last decade, increasing evidence has also linked aberrant epigenetic modulation as a contributor to CVD development. Differential profiles of DNA methylation, histone methylation and acetylation have consistently been observed in tissues and cells (comprising the aortic lesions, vascular endothelium and monocytes) from patients with CVD. This highlights the therapeutic potential of epigenetic drugs for cardiovascular treatment.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Chromatin Assembly and Disassembly; DNA Methylation; DNA Modification Methylases; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Plaque, Atherosclerotic; Transcription, Genetic

Sphingolipids, such as sphingomyelins, ceramides, glycosphingolipids, and sphingosine-1-phosphates (S1P) are a large group of structurally and functionally diverse molecules. Some specific species are found associated with atherogenesis and provide novel therapeutic targets. Herein, we briefly review how sphingolipids are implicated in the progression of atherosclerosis and related diseases, and then we discuss the potential therapy options by targetting several key enzymes in sphingolipid metabolism.

Topics: Atherosclerosis; Cardiovascular Agents; Ceramides; Humans; Molecular Targeted Therapy; Sphingolipids; Sphingomyelin Phosphodiesterase; Sphingomyelins

Topics: Aspirin; Atherosclerosis; Cardiovascular Agents; Cause of Death; Evidence-Based Medicine; Hemorrhage; Humans; Primary Prevention; Protective Factors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

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

Approximately 40% of heart attack survivors remain at increased risk of recurrent cardiovascular events, despite the current treatment options showing that atherothrombosis is not exclusively a disorder of lipoprotein aggregation in the arterial wall. Clinical and experimental data suggest that inflammation plays an important role in atherothrombosis independent of the cholesterol level. Acute-phase reactants, such as C-reactive protein, increase in patients with coronary artery disease and are known to predict adverse outcomes in such patients. The recent CANTOS trial published in The New England Journal of Medicine provides evidence that interleukin-1β along with other cytokines play central roles in the inflammatory reaction that drives the interleukin-6 signaling pathway and have profound effects on cardiovascular outcomes. Several other ongoing studies are focused on multiple immune mediators involved in this process to support the inflammatory hypothesis of cardiovascular diseases. These new classes of drugs could represent the biggest breakthrough in cardiovascular medicine, which could have the greatest impact on cardiovascular mortality since the advent of statins. The drug canakinumab has shown promise in lowering atherosclerosis, and other drugs, such as colchicine and methotrexate, are gaining interest and are being investigated in multiple ongoing trials. A major concern is the affordability of these drugs, as most cardiovascular diseases are noted among people of lower socioeconomic statuses. The LoDoCo trial showed some benefits of colchicine, and whether this old drug can be marketed with a new label for cardiovascular disease remains in question. Therefore, a clear understanding of the different inflammatory pathways involved in atherosclerosis is needed to help develop more effective treatment modalities that will benefit humankind.

Topics: Animals; Anti-Inflammatory Agents; Arteries; Atherosclerosis; Cardiovascular Agents; Humans; Inflammation Mediators; Plaque, Atherosclerotic; Signal Transduction

Plasma HDL levels have an inverse relationship to coronary artery disease (CAD) risk, which led to the idea that increasing HDL levels therapeutically would ameliorate atherosclerosis. Human genetic deficiency of CETP caused markedly elevated HDL and moderately reduced non-HDL cholesterol levels, suggesting that CETP inhibitors might produce cardiovascular benefit. The CETP inhibitor anacetrapib reproduced the phenotype of homozygous CETP deficiency and showed a highly significant benefit for CAD in the REVEAL trial. However, the magnitude of this effect was moderate, and the mechanism of benefit remains unclear. Insights into the mechanisms underlying macrophage cholesterol efflux and reverse cholesterol transport have come from monogenic human disorders and transgenic mouse studies. In particular, the importance of the ATP binding cassette transporters ABCA1 and ABCG1 in promoting cholesterol efflux from myeloid and other hematopoietic cells has been shown and linked to aberrant myelopoiesis and macrophage inflammation. Recent studies have shown that myeloid deficiency of ABCA1 and ABCG1 leads to macrophage and neutrophil inflammasome activation, which in turn promotes atherosclerotic plaque development and notably the formation of neutrophil extracellular traps (NETs) in plaques. In addition, clonal hematopoiesis has emerged as an important CAD risk factor, likely involving macrophage inflammation and inflammasome activation. Further elucidation of the mechanisms linking plaque accumulation of cholesterol and oxidized lipids to myeloid cell inflammation may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for CAD.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Cholesterol Ester Transfer Proteins; Coronary Artery Disease; Enzyme Inhibitors; Genetic Predisposition to Disease; Humans; Inflammasomes; Inflammation; Lipoproteins, HDL; Macrophages; Neutrophils; Phenotype; Up-Regulation

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

C1q tumor necrosis factor-related protein 9 (CTRP9), a newly discovered adipokine, is the closest paralog of adiponectin. After proteolytic cleavage, it can release the globular domain (gCTRP9) that serves as the major circulatory isoform. Upon binding to adiponectin receptor 1 (AdipoR1) and N-cadherin, CTRP9 can activate a variety of signaling pathways to regulate glucose and lipid metabolism, vascular relaxation and cell differentiation. Circulating CTRP9 levels are significantly decreased in patients with coronary atherosclerosis disease. Data obtained from in vitro experiments and animal models suggest that CTRP9 exerts an atheroprotective effect by altering multiple pathological processes involved in atherosclerosis, including inflammation, foam cell formation, endothelial dysfunction, insulin resistance, and vascular smooth muscle cell dedifferentiation, proliferation and migration. In this review, we summarize the latest advances regarding the roles of CTRP9 in atherosclerosis with an emphasis on its potential as a novel therapeutic target in cardiovascular disease.

Topics: Adiponectin; Animals; Anti-Inflammatory Agents; Antigens, CD; Arteries; Atherosclerosis; Cadherins; Cardiovascular Agents; Glycoproteins; Humans; Receptors, Adiponectin; Signal Transduction; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

Perivascular adipose tissue (PVAT), the adipose tissue that surrounds most of the vasculature, has emerged as an active component of the blood vessel wall regulating vascular homeostasis and affecting the pathogenesis of atherosclerosis. Although PVAT characteristics resemble both brown and white adipose tissues, recent evidence suggests that PVAT develops from its own distinct precursors implying a closer link between PVAT and vascular system. Under physiological conditions, PVAT has potent anti-atherogenic properties mediated by its ability to secrete various biologically active factors that induce non-shivering thermogenesis and metabolize fatty acids. In contrast, under pathological conditions (mainly obesity), PVAT becomes dysfunctional, loses its thermogenic capacity and secretes pro-inflammatory adipokines that induce endothelial dysfunction and infiltration of inflammatory cells, promoting atherosclerosis development. Since PVAT plays crucial roles in regulating key steps of atherosclerosis development, it may constitute a novel therapeutic target for the prevention and treatment of atherosclerosis. Here, we review the current literature regarding the roles of PVAT in the pathogenesis of atherosclerosis.

Topics: Adipokines; Adipose Tissue; Adiposity; Animals; Anti-Inflammatory Agents; Atherosclerosis; Blood Vessels; Cardiovascular Agents; Energy Metabolism; Humans; Inflammation Mediators; Protective Factors; Risk Factors; Signal Transduction; Thermogenesis

The increasing prevalence of atherosclerosis has become a worldwide health concern. Although significant progress has been made in the understanding of atherosclerosis pathogenesis, the underlying mechanisms are not fully understood. Recent studies suggest dipeptidyl peptidase-4 (DPP4), a regulator of inflammation and metabolism, may be involved in the development of atherosclerotic diseases. There has been increasing clinical and pre-clinical evidence showing DPP4-incretin axis is involved in cardiovascular disease. Although the cardiovascular outcome of DPP4 inhibition or incretin analogues has been or being evaluated by several large scale clinical trials, the exact role of DPP4 in atherosclerotic diseases is not completely understood. In the current review, we will summarize the recent advances in direct and indirect regulatory role of DPP4 in atherosclerosis.

Topics: Animals; Arteries; Atherosclerosis; Cardiovascular Agents; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incretins; Plaque, Atherosclerotic; Signal Transduction

Dipeptidyl peptidase IV (DPP-IV) has been revealed as an adipokine with potential relevance in cardiovascular disease (CVD), while clinically used DPP-IV inhibitors have demonstrated beneficial cardiovascular effects in several experimental studies. Perivascular adipose tissue (PVAT) is a unique adipose tissue depot in close anatomical proximity and bidirectional functional interaction with the vascular wall, which is a source of DPP-IV and its biology may be influenced by DPP-IV inhibition. Recently, DPP-IV inhibition has been associated with decreased local inflammation and oxidative stress both in the vascular wall and the PVAT, potentially regulating atherogenesis progression in vivo. DPP-IV inhibition may thus be a promising target in cardiovascular disease. However, the exact pleiotropic mechanisms that underlie the cardiovascular effects of DPP-IV inhibition need to be clarified, while the in vivo benefit of DPP-IV inhibition in humans remains unclear.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents; Antioxidants; Atherosclerosis; Blood Vessels; Cardiovascular Agents; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Oxidative Stress; Signal Transduction

Vasa vasorum are blood microvessels which penetrate the adventitia and outer layers of the media of large blood vessels, supplying them with nutrients and oxygen. A growing body of evidence suggests that vasa vasorum play a central role in the pathogenesis of atherosclerosis. In this review, we will make a case for the role of microvascular dysfunction in the initiation of disease. When seen through this lens, new therapeutic opportunities for prevention can be envisioned. In particular, we discuss how targeting the cellular metabolism and epigenetic machinery of vasa vasorum neovessels could be harnessed to render vasa vasorum endothelial cells less sensitive to atherogenic stimuli.

Topics: Animals; Atherosclerosis; Capillary Permeability; Cardiovascular Agents; Epigenesis, Genetic; Humans; Inflammation Mediators; Microcirculation; MicroRNAs; Neovascularization, Pathologic; Signal Transduction; Vasa Vasorum

It is well established that diabetes mellitus accelerates atherosclerotic vascular disease. Endothelial injury has been proposed to be the initial event in the pathogenesis of atherosclerosis. Endothelium not only acts as a semi-selective barrier but also serves physiological and metabolic functions. Diabetes or high glucose in circulation triggers a series of intracellular responses and organ damage such as endothelial dysfunction and apoptosis. One such response is high glucose-induced chronic endoplasmic reticulum stress in the endothelium. The unfolded protein response is an acute reaction that enables cells to overcome endoplasmic reticulum stress. However, when chronically persistent, endoplasmic reticulum stress response could ultimately lead to endothelial dysfunction and atherosclerosis. Herein, we discuss the scientific advances in understanding endoplasmic reticulum stress-induced endothelial dysfunction, the pathogenesis of diabetes-accelerated atherosclerosis and endoplasmic reticulum stress as a potential target in therapies for diabetic atherosclerosis.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Diabetic Angiopathies; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Endothelial Cells; Endothelium, Vascular; Humans; Plaque, Atherosclerotic; Signal Transduction

Compelling experimental results have substantiated the immune-driven inflammatory nature of atherosclerosis. Most of the scientific advances over the past decades have been achieved by relying on transgenic animal models that have been employed with increasing levels of sophistication. However, recent failures in translating various anti-inflammatory therapeutic strategies for use in humans might raise some skepticism with regards to an inflammatory causality underlying human atherosclerosis. By applying a dialectical approach, this Perspective aims to challenge and deduce the nature of atherosclerosis by reviewing results exclusively derived from human studies and recent clinical trials, as "things may not always be, what they appear".

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Humans; Inflammation; Inflammation Mediators; Lipids; Plaque, Atherosclerotic; Signal Transduction

High-density lipoprotein (HDL) is considered an anti-atherogenic lipoprotein species due to its role in reverse cholesterol transport. HDL delivers cholesterol esters to the liver through selective uptake by scavenger receptor class B type I (SR-BI). In line with the protective role for HDL in the context of cardiovascular disease, studies in mice and recently also in humans have shown that a disruption of normal SR-BI function predisposes subjects to the development of atherosclerotic lesions and cardiovascular disease. Although SR-BI function has been studied primarily in the liver, it should be acknowledged that the SR-BI protein is expressed in multiple tissues and cell types across the body, albeit at varying levels between the different tissues. Given that SR-BI is widely expressed throughout the body, multiple cell types and tissues can theoretically contribute to the atheroprotective effect of SR-BI. In this review the different functions of SR-BI in normal physiology are highlighted and the (potential) consequences of cell type-specific disruption of SR-BI function for atherosclerosis and cardiovascular disease susceptibility discussed. It appears that hepatocyte and platelet SR-BI inhibit respectively the development of atherosclerotic lesions and thrombosis, suggesting that SR-BI located on these cell compartments should be regarded as being a protective factor in the context of cardiovascular disease. The relative contribution of SR-BI present on endothelial cells, steroidogenic cells, adipocytes and macrophages to the pathogenesis of atherosclerosis and cardiovascular disease remains less clear, although proper SR-BI function in these cells does appear to influence multiple processes that impact on cardiovascular disease susceptibility.

Topics: Animals; Arteries; Atherosclerosis; Cardiovascular Agents; CD36 Antigens; Disease Models, Animal; Drug Design; Humans; Mice, Transgenic; Molecular Targeted Therapy; Plaque, Atherosclerotic; Signal Transduction

Coronary heart disease and ischaemic stroke caused by atherosclerosis are leading causes of illness and death worldwide. Small animal models have provided insight into the fundamental mechanisms driving early atherosclerosis, but it is increasingly clear that new strategies and research tools are needed to translate these discoveries into improved prevention and treatment of symptomatic atherosclerosis in humans. Key challenges include better understanding of processes in late atherosclerosis, factors affecting atherosclerosis in the coronary bed, and the development of reliable imaging biomarker tools for risk stratification and monitoring of drug effects in humans. Efficient large animal models of atherosclerosis may help tackle these problems. Recent years have seen tremendous advances in gene-editing tools for large animals. This has made it possible to create gene-modified minipigs that develop atherosclerosis with many similarities to humans in terms of predilection for lesion sites and histopathology. Together with existing porcine models of atherosclerosis that are based on spontaneous mutations or severe diabetes, such models open new avenues for translational research in atherosclerosis. In this review, we discuss the merits of different animal models of atherosclerosis and give examples of important research problems where porcine models could prove pivotal for progress.

Topics: Animals; Animals, Genetically Modified; Atherosclerosis; Cardiovascular Agents; Diagnostic Imaging; Disease Models, Animal; Drug Discovery; Drug Evaluation, Preclinical; Forecasting; Genetic Engineering; Humans; Mice; Rabbits; Swine; Swine, Miniature

Autophagy is an evolutionarily conserved catabolic process whereby the cytoplasmic contents of a cell are sequestered within autophagosomes through a lysosome-dependent pathway. Increasing evidence shows that this process is of great importance in a wide range of diseases, including atherosclerosis (AS). Autophagy can be modulated in advanced AS plaques by cytokines, reactive lipids, lipopolysaccharides, advanced glycation end products, and microRNAs. Autophagy exerts both protective and detrimental functions in vascular disorders. However, despite an increasing interest in autophagy, it remains an underestimated and overlooked phenomenon in AS. Therefore, the precise role of autophagy and its relationship with apoptosis need to be described. This review highlights recent findings on the autophagy activities and signaling pathways in endothelial cells, macrophages, and smooth muscle cells that are accompanied by apoptosis in AS. We conclude with recent studies on autophagy modulation as a new therapeutic approach to treat AS.

Topics: Animals; Apoptosis; Atherosclerosis; Autophagy; Cardiovascular Agents; Drug Discovery; Endothelial Cells; Humans; Macrophages; Molecular Targeted Therapy; Myocytes, Smooth Muscle; Signal Transduction

The metabolic syndrome is a multiplex risk factor for atherosclerotic cardiovascular disease and type 2 diabetes. It is composed of atherogenic dyslipidemia, elevated blood pressure, insulin resistance and elevated glucose, a pro-thrombotic state, and a pro-inflammatory state. Excess energy intake and concomitant obesity are the major drivers of the syndrome. Lifestyle intervention can reverse metabolic risk factors, but at times, drug therapies or bariatric surgery may be required to control more overt risk factors.

Topics: Atherosclerosis; Bariatric Surgery; Cardiovascular Agents; Dyslipidemias; Humans; Hyperglycemia; Hypertension; Hypoglycemic Agents; Hypolipidemic Agents; Metabolic Syndrome; Obesity; Risk Factors; Risk Reduction Behavior; 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

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein that belongs to the tumour necrosis factor (TNF) cytokine superfamily. TRAIL is expressed by numerous cell types including vascular cells, immune cells and adipocytes. Although originally thought to induce apoptosis in malignant or transformed cells only, it is now known that TRAIL can bind up to 5 distinct receptors to activate complex signalling pathways, and is capable of exerting pleiotropic effects in non-transformed cells. In this respect, a number of clinical and animal studies point to the potential vasoprotective influence of TRAIL, with TRAIL deficiency being linked to accelerated atherosclerosis and vascular calcification. Moreover, exogenous TRAIL administration has been shown to exhibit anti-atherosclerotic activity in-vivo. In-vitro studies on TRAIL in this context have yielded conflicting results however, with evidence of both pro-atherogenic and vasoprotective effects ascribed to TRAIL. Notwithstanding these various studies, mechanistic information on the precise nature of TRAIL-mediated injury/protection within the vasculature, as well as the identity of the downstream molecular/cellular targets of TRAIL, is still quite limited. In this review, we will summarize our current knowledge of TRAIL regulation, signalling mechanisms, and its apparent involvement in CVD pathogenesis as a prelude to examining the existing evidence for TRAIL-mediated vasoprotection. To this end, extensive in vitro, in vivo, and clinical studies will be reviewed and critical findings highlighted.

Topics: Animals; Apoptosis; Atherosclerosis; Blood Vessels; Cardiovascular Agents; Humans; Protective Factors; Risk Factors; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand

Atherosclerosis is a leading cause of vascular disease worldwide. Its major clinical manifestations include ischemic heart disease, ischemic stroke, and peripheral arterial disease. In high-income countries, there have been dramatic declines in the incidence and mortality from ischemic heart disease and ischemic stroke since the middle of the 20th century. For example, in the United Kingdom, the probability of death from vascular disease in middle-aged men (35-69 years) has decreased from 22% in 1950 to 6% in 2010. Most low- and middle-income countries have also reported declines in mortality from stroke over the last few decades, but mortality trends from ischemic heart disease have been more varied, with some countries reporting declines and others reporting increases (particularly those in Eastern Europe and Asia). Many major modifiable risk factors for atherosclerosis have been identified, and the causal relevance of several risk factors is now well established (including, but not limited to, smoking, adiposity, blood pressure, blood cholesterol, and diabetes mellitus). Widespread changes in health behaviors and use of treatments for these risk factors are responsible for some of the dramatic declines in vascular mortality in high-income countries. In order that these declines continue and are mirrored in less wealthy nations, increased efforts are needed to tackle these major risk factors, particularly smoking and the emerging obesity epidemic.

Topics: Atherosclerosis; Cardiovascular Agents; Comorbidity; Global Health; Humans; Life Style; Preventive Health Services; Prognosis; Risk Assessment; Risk Factors; Risk Reduction Behavior; Time Factors

Vascular calcification (VC), a disorder that causes blood vessel hardening and dysfunction, is a significant risk factor for type-2 diabetes mellitus (T2DM), which invariably manifests associated cardiovascular complications. Although the clinical effects of VC have been well-documented, the precise cellular events underlying the manifestation and progression of VC are only now coming to light. Current research models indicate that VC likely involves signalling pathways traditionally associated with bone remodelling, such as the OPG/RANKL/TRAIL signalling system. In this respect, receptor activator of NF-κB ligand (RANKL) promotes VC whilst osteoprotegerin (OPG) acts as a RANKL decoy receptor to block this effect, events that contrast with the known functional influence of these proteins during bone metabolism. Moreover, evidence suggests that tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), an alternative decoy ligand for OPG, may exert an anti-calcific influence within the vasculature. In the current review, we conduct a timely examination of this complex VC pathology from both mechanistic and therapeutic perspectives. Our objectives are twofold: (i) to critically assess our current understanding of both osteogenic and vascular calcification pathways, with particular focus on the co-interactive roles of OPG, RANKL, and TRAIL. Extensive in vitro, in vivo, and clinical studies will therefore be reviewed and critical findings highlighted; and (ii) to examine a range of therapeutic approaches of potential relevance to VC pathology. In this regard, a clear focus on VC as it applies to T2DM and cardiovascular disease (and particularly atherosclerosis) will be maintained.

Topics: Animals; Arteries; Atherosclerosis; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Osteoblasts; Osteoclasts; Osteogenesis; Osteoprotegerin; Plaque, Atherosclerotic; RANK Ligand; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Vascular Calcification

Numerous epidemiological studies and clinical trials have reported the health benefits of omega-3 polyunsaturated fatty acids (PUFA), including a lower risk of coronary heart diseases. This review mainly focuses on the effects of alpha-linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on some risk factors associated with atherothrombosis, including platelet activation, plasma lipid concentrations and oxidative modification of low-density lipoproteins (LDL). Special focus is given to the effects of marine PUFA on the formation of eicosanoids and docosanoids, and to the bioactive properties of some oxygenated metabolites of omega-3 PUFA produced by cyclooxygenases and lipoxygenases. The antioxidant effects of marine omega-3 PUFA at low concentrations and the pro-oxidant effects of DHA at high concentrations on the redox status of platelets and LDL are highlighted. Non enzymatic peroxidation end-products deriving from omega-3 PUFA such as hydroxy-hexenals, neuroketals and EPA-derived isoprostanes are also considered in relation to atherosclerosis. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".

Topics: alpha-Linolenic Acid; Animals; Atherosclerosis; Cardiovascular Agents; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Humans; Oxidation-Reduction; Risk Assessment; Risk Factors; Thrombosis; Treatment Outcome

Coronary artery disease (CAD) and acute myocardial infarction (AMI) are inflammatory pathologies, involving interleukins (ILs), such as IL-1β, IL-6 and tumor necrosis factor (TNF)-α, and acute phase proteins production, such as for C reactive protein (CRP). The process begins with retention of low-density lipoprotein (LDL) and its oxidation inside the intima, with the formation of the "foam cells." Toll-like receptors and inflamassomes participate in atherosclerosis formation, as well as in the activation of the complement system. In addition to innate immunity, adaptive immunity is also associated with atherosclerosis through antigen-presenting cells, T and B lymphocytes. AMI also increases the expression of some ILs and promotes macrophage and lymphocyte accumulation. Reperfusion increases the expression of anti-inflammatory ILs (such as IL-10) and generates oxygen free radicals. Although CAD and AMI are inflammatory disorders, the only drugs with anti-inflammatory effect so far widely used in ischemic heart disease are aspirin and statins. Some immunomodulatory or immunosuppressive promising therapies, such as cyclosporine and colchicine, may have benefits in CAD. Methotrexate also has potential cardioprotective anti-inflammatory effects, through increased adenosine levels. The TETHYS trial (The Effects of mETHotrexate Therapy on ST Segment Elevation MYocardial InfarctionS trial) will evaluate low-dose methotrexate in ST elevation AMI. The CIRT (Cardiovascular Inflammation Reduction Trial), in turn, will evaluate low-dose methotrexate in patients with a high prevalence of subclinical vascular inflammation. The CANTOS (The Canakinumab Antiinflammatory Thrombosis Outcomes Study) will evaluate canakinumab in patients with CAD and persistently elevated CRP. The blockage of other potential targets, such as the IL-6 receptor, CC2 chemokine receptor and CD20, could bring benefits in CAD.

Topics: Acute Coronary Syndrome; Adaptive Immunity; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Cardiovascular Agents; Coronary Artery Disease; Coronary Thrombosis; Endothelium, Vascular; Evidence-Based Medicine; Humans; Immunity, Innate; Models, Immunological; Myocardial Infarction; Myocardial Reperfusion Injury; Vasculitis

Atherosclerosis is the main pathophysiological process underlying acute cardiovascular diseases. Life-threatening conditions, such as myocardial infarction and ischemic stroke, are provoked by the sudden rupture of vulnerable atherosclerotic plaques, characterized by thin, highly inflamed and collagen-poor fibrous cap. Whereas both innate and adaptive inflammation progressively emerged as driving force of this processes, less is known about the involvement of neutrophils (PMNs). Advances in laboratory techniques during the last two decades disclosed that PMNs play a crucial role in promoting plaque vulnerability by the release of different enzymes, such as gelatinases (matrix metalloproteinases) collagenases, elastase and myeloperoxidase. Accordingly, circulating levels of PMNs and their products have been investigated as potential markers of plaque instability in both primary and secondary prevention on cardiovascular diseases. In addition, the development of different classes of drugs targeting PMNs activation is emerging as an interesting field of research. This narrative review will provide an update on the role of PMNs in promoting plaque vulnerability also discussing the potential effects of therapeutic strategies targeting PMN on plaque vulnerability.

Topics: Animals; Anti-Inflammatory Agents; Arteries; Atherosclerosis; Cardiovascular Agents; Disease Progression; Humans; Neutrophil Activation; Neutrophils; Plaque, Atherosclerotic; Rupture, Spontaneous

Sodium-hydrogen exchangers (NHEs) and aquaporins (AQPs) are key regulators of cell volume and intracellular ions both in physiological and pathological conditions. By directly affecting water and ion exchanges across the plasma membrane, NHEs and AQPs, particularly isoforms 1, can also influence vascular tone and the cytoskeleton, respectively, in response to several types of stimuli, such as hypertonic stress. NHE-1 and AQP1 are mainly expressed in tissues of the cardiovascular system. Their excessive activation in response to elevated extracellular osmolarity, as occurring in diabetic hyperglycemia, can be deleterious both for micro- and macrovascular endothelial cells. Although NHE-1 and AQP1 regulate the intracellular volume and ions, they also influence the activation of hypertonicity-responsive genes and cell functions involved in glucotoxicity and vascular injury. Because of the involvement of NHEs and AQPs in micro- and macrovascular disease, including arterial hypertension and atherosclerotic plaque destabilization, research has focused on developing inhibitors of these transporters. We here review current knowledge of NHEs and AQPs investigating biological aspects and mechanisms of their regulation, including their potential as target for developing new drugs that could target diabetic atherosclerosis.

Topics: Animals; Aquaporin 1; Atherosclerosis; Cardiovascular Agents; Cation Transport Proteins; Diabetic Angiopathies; Humans; Molecular Targeted Therapy; Osmoregulation; Signal Transduction; Sodium-Hydrogen Exchanger 1; Sodium-Hydrogen Exchangers

Autophagy is a cellular catabolic process responsible for the destruction of long-lived proteins and organelles via lysosome-dependent pathway. This process is of great importance in maintaining cellular homeostasis, and deregulated autophagy has been implicated in the pathogenesis of a wide range of diseases. A growing body of evidence suggests that autophagy can be activated in vascular disorders such as atherosclerosis. Autophagy occurs under basal conditions and mediates homeostatic functions in cells but in the setting of pathological states up-regulated autophagy can exert both protective and detrimental functions. Therefore, the precise role of autophagy and its relationship with the progression of the disease need to be clarified. This review highlights recent findings regarding autophagy activity in vascular cells and its potential contribution to vascular disorders with a focus on atherogenesis. Finally, whether the manipulation of autophagy represents a new therapeutic approach to treat or prevent vascular diseases is also discussed.

Topics: Animals; Atherosclerosis; Autophagy; Blood Vessels; Cardiovascular Agents; Humans; Macrophages; Signal Transduction

Recent large epidemiological studies have confirmed that an elevated resting heart rate is an independent predictor of cardiovascular and overall mortality in the general population as well as in patients with hypertension, coronary heart disease and chronic heart failure. Pathophysiological studies indicate that a higher heart rate has detrimental effects that favor myocardial ischemia, ventricular arrhythmias, as well as an increase in vascular oxidative stress, endothelial dysfunction and atherosclerosis progression. Benefits of heart rate lowering drugs, such as beta-blockers and ivabradine, in reducing overall and cardiovascular-related mortality, have been demonstrated particularly in patients with coronary heart disease and heart failure. However, despite these evidences, resting heart rate is still an overlooked cardiovascular risk factor.

Topics: Adrenergic beta-Antagonists; Arrhythmias, Cardiac; Atherosclerosis; Benzazepines; Cardiovascular Agents; Clinical Trials as Topic; Heart Failure; Heart Rate; Humans; Hypertension; Ivabradine; Myocardial Ischemia; Risk Factors

Platelet-derived growth factor (PDGF) represents one of the most prominent inducer of smooth muscle cell (SMC) migration and proliferation. Homo- and heterodimers of PDGF-A, PDGF-B, PDGF-C and PDGF-D subunits act by binding to homo- or heterodimers of the PDGF tyrosine kinase receptors, PDGFR-α and PDGFR-β. The essential role of PDGFR signaling on restenosis post-angioplasty or atherosclerosis has been demonstrated by using blocking antibodies to PDGF or the tyrosine kinase inhibitor imatinib. More specifically, molecular studies have defined the intracellular signaling pathways activated by PDGF, inducing the cell cycle progression and the migration of SMCs. Considering the relevant role of PDGF in atherogenesis, several studies have been performed to investigate the effect of naturally occurring compounds on both in vitro and in vivo experimental models of atherogenesis. The present review will briefly summarize the pathophysiological role of PDGF and the studies of natural inhibitors tested in in vivo experimental models of restenosis in response to vascular injury and/or atherosclerosis.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Cell Movement; Cell Proliferation; Humans; Molecular Targeted Therapy; Muscle, Smooth, Vascular; Phytotherapy; Plant Extracts; Plants, Medicinal; Plaque, Atherosclerotic; Receptors, Platelet-Derived Growth Factor; Signal Transduction

The G protein-coupled estrogen receptor (GPER) is a 7-transmembrane receptor implicated in rapid estrogen signaling. Originally cloned from vascular endothelial cells, GPER plays a central role in the regulation of vascular tone and cell growth as well as lipid and glucose homeostasis. This review highlights our knowledge of the physiological and pathophysiological functions of GPER in the pancreas, peripheral and immune tissues, and the arterial vasculature. Recent findings on its roles in obesity, diabetes, and atherosclerosis, including GPER-dependent regulation of lipid metabolism and inflammation, are presented. The therapeutic potential of targeting GPER-dependent pathways in chronic diseases such as coronary artery disease and diabetes and in the context of menopause is also discussed.

Topics: Animals; Anti-Obesity Agents; Atherosclerosis; Cardiovascular Agents; Diabetes Mellitus; Humans; Hypoglycemic Agents; Ligands; Lipid Metabolism; Models, Biological; Molecular Targeted Therapy; Obesity; Organ Specificity; Receptors, Estrogen; Receptors, G-Protein-Coupled; Signal Transduction

Atherosclerosis is a multifactorial condition characterized by endothelial injury, fatty streak deposition, and stiffening of the blood vessels. The pathogenesis is complex and mediated by adhesion molecules, inflammatory cells, and smooth muscle cells. Statins have been the major drugs in treating hypercholesterolemia for the past two decades despite little efficacy. There is an urgent need for new drugs that can replace statins or combined with statins. The preclinical studies evaluating atherosclerosis require an ideal animal model which resembles the disease condition, but there is no single animal model which mimics the disease. The animal models used are rabbits, rats, mice, hamsters, mini pigs, etc. Each animal model has its own advantages and disadvantages. The method of induction of atherosclerosis includes diet, chemical induction, mechanically induced injuries, and genetically manipulated animal models. This review mainly focuses on the various animal models, method of induction, the advantages, disadvantages, and the current perspectives with regard to preclinical studies on atherosclerosis.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Cricetinae; Disease Models, Animal; Disease Progression; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice; Rabbits; Rats; Swine

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

Leptin has received much attention since its cloning in 1994. Initially, leptin research centered on satiety, energy balance and sympathetic activation. However, hyperleptinemia has since been identified as an independent risk factor for various cardiovascular pathologies including atherosclerotic coronary artery disease. Over the last decade, multiple studies have implicated leptin as an important mediator in endothelial dysfunction and neointimal hyperplasia, both key steps in the evolution of atherosclerotic vascular changes. Additionally, more recent evidence indicates that paracrine leptin release from perivascular adipose tissue (PVAT) has deleterious effects on the underlying endothelium and vascular smooth muscle cells (SMC), including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, SMC proliferation and the role of PVAT-derived leptin with an emphasis on the coronary circulation and discussions of currently proposed molecular mechanisms of PVAT-mediated coronary endothelial dysfunction and neointimal hyperplasia.

Topics: Adipose Tissue; Animals; Atherosclerosis; Cardiovascular Agents; Down-Regulation; Endothelium, Vascular; Humans; Hyperplasia; Leptin; Models, Cardiovascular; Molecular Targeted Therapy; Systemic Vasculitis; Tunica Intima; Up-Regulation

Atherosclerosis is considered to be a chronic inflammatory disease of the arterial wall. Atherogenesis is accompanied by local production and release of inflammatory mediators, for which the macrophage is a major source. The proinflammatory cytokine, interferon (IFN)-γ derived from T cells, is expressed at high levels in atherosclerotic lesions. IFN-γ is the classic macrophage-activating factor, vital for both innate and adaptive immunity. It primes macrophages to produce chemokines and cytotoxic molecules and induces expression of genes that regulate lipid uptake. IFN-γ is a key trigger for the formation and release of reactive oxygen species. IFN-γ has important effects on endothelial cells, promoting expression of adhesion molecules. Atherogenic effects of IFN-γ have been shown in murine models where exogenous administration enhances atherosclerotic lesion formation while knockout of IFN-γ or its receptor reduces lesion size. IFN-γ signaling is largely mediated by a Janus kinase (JAK) to signal transduction and activator of transcription (STAT)1 cytosolic factor pathway. A clear understanding of IFN-γ effects on atherogenesis should enable development of novel targeted interventions for clinical use in the prevention and treatment of atherosclerosis. This review will discuss the actions of the cytokine IFN-γ and its complex effects on cells involved in atherosclerosis.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Drug Design; Humans; Inflammation Mediators; Interferon-gamma; Molecular Targeted Therapy; Signal Transduction

Leukotrienes are biologically active lipid mediators of inflammation involved in atherogenesis. Obstructive sleep apnoea (OSA) patients exhibit early atherosclerosis and activation of the leukotriene pathway. In OSA patients, the production of leukotrienes is increased in relation to OSA severity and in vitro exposure of immune cells to intermittent hypoxia increases leukotriene pathway transcription. Moreover, the leukotriene transcriptional pathway is associated with early vascular remodelling. Lastly, obesity is a major confounding factor for leukotriene activation in OSA. The aim of this review was to focus on the intricate network of leukotrienes, chronic intermittent hypoxia, and atherosclerosis, with an emphasis on the role of leukotrienes in the early atherosclerosis observed in OSA patients.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Confounding Factors, Epidemiologic; Gene Expression Regulation; Humans; Hypoxia; Inflammation Mediators; Leukotrienes; Obesity; Risk Factors; Signal Transduction; Sleep Apnea, Obstructive; Transcription, Genetic

Topics: Atherosclerosis; Cardiovascular Agents; Decision Making; Humans; Primary Prevention; Time Factors

Modern cardiology was born early in the twentieth century. Here I list and review what I believe to be the ten most important advances in the twentieth century in this field. They are as follows: electrocardiography, cholesterol-induced atherosclerosis, cardiac catheterization, cardiovascular surgery, coronary angiography and percutaneous coronary angioplasty, the coronary care unit, the development of new cardiovascular drugs, preventive cardiology, cardiac imaging, and implanted cardiac pacemakers/defibrillators.

Topics: Animals; Atherosclerosis; Biomedical Research; Cardiac Catheterization; Cardiac Surgical Procedures; Cardiology; Cardiovascular Agents; Cholesterol; Coronary Angiography; Coronary Care Units; Echocardiography; Electrocardiography; History, 20th Century; History, 21st Century; Humans; Percutaneous Coronary Intervention; Preventive Health Services

The aim of the study was to compare the efficacy of revascularization versus medical therapy in patients with atherosclerotic renal artery stenosis (ARAS). ARAS is the most common cause of secondary hypertension and is associated with several complications, such as renal failure, coronary artery disease, cardiac destabilization, and stroke. Medical therapy is the cornerstone for management of ARAS; however, numerous trials have compared medical therapy with revascularization in the form of percutaneous renal artery angioplasty (PTRA) or percutaneous renal artery angioplasty with stent placement (PTRAS). Medline (PubMed and Ovid SP), Embase, Cochrane Central Register of Controlled Clinical Trials (CENTRAL), and Cochrane Database of Systematic Review (CDSR) were searched till present (November 2013) to identify clinical trials where medical therapy was compared with revascularization (PTRA or PTRAS). We performed a meta-analysis using a random effects model. The heterogeneity was assessed using I2 values. The initial database search identified 540 studies and 7 randomized controlled trials, and 2,139 patients were included in the final analysis. Angioplasty with or without stenting was not superior to medical therapy with respect to any outcome. The incidence of nonfatal myocardial infarction was 6.74% in both the stenting and medical therapy group (odds ratio=0.998, 95% confidence interval 0.698 to 1.427, p=0.992), and incidence of renal events in stenting population was found to be 19.58% versus 20.53% in medical therapy (odds ratio=0.945, 95% confidence interval 0.755 to 1.182, p=0.620). In conclusion, PTRA or PTRAS does not improve outcomes compared with medical therapy in patients with ARAS. Future studies should investigate to identify patient subgroups that may benefit from such an intervention.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Global Health; Humans; Morbidity; Renal Artery Obstruction; Treatment Outcome; Vascular Surgical Procedures

Topics: Animals; Arteries; Atherosclerosis; Cardiovascular Agents; Humans; Macrophages; Signal Transduction

Options for modification of lipoprotein metabolism and, thus, for reduction of atherothrombotic complication have widened over recent years. Apart from the development of novel approaches new pharmacological formulations of common lipid lowering drugs have been prepared- e.g. statin-containing nanoparticles, fibrate nanoparticles with a much higher bioavailability etc. Even the oldest lipid lowering agents - resins - have not been forgotten due to its once again discovered positive impact of these agents on glucose homeostasis while optimally complementing the action of statins. Clinical trials of therapies targeting HDL particle metabolism are being in progress despite we have not gathered any unambiguous evidence of positive effect of the CETP inhibitors or apoA1 mime-tics on the progression of atherosclerosis. Brand new approaches in the treatment of dyslipidemia including MTTP and PCSK9 inhibition or therapies utilizing anti-sense technologies rapidly accumulate evidence from clinical studies. We have already learned about their lipid-modifying efficacy particularly in patients with familial hypercholesterolemia, however, data from other patients´ populations can be expected quite soon.

Topics: Acute Coronary Syndrome; Atherosclerosis; Cardiovascular Agents; Carrier Proteins; Clinical Trials as Topic; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Proprotein Convertase 9; Proprotein Convertases; Serine Endopeptidases

The chronic inflammatory nature of atherosclerosis is nowadays widely accepted. Dendritic cells (DCs) are likely to play a crucial role in directing innate and adaptive immunity against altered (self-)antigens, such as oxidized low density lipoproteins (oxLDL). DCs are found in early lesions and their numbers become even higher when the lesion progresses. DCs are most abundant in areas of neovascularization where they are often found near T cells. All stages from precursors to fully mature DCs are present in human plaques. Treatment of atherosclerosis is currently based on reducing risk factors, e.g. by use of statins and beta-blockers. Some of these pharmacological agents also show anti-inflammatory properties and consequently can affect DC function. Yet, many patients remain at risk for acute coronary events, and new therapies to treat atherosclerosis are needed. One therapeutic strategy is based on isolation of patient's DCs that are then pulsed with appropriate antigen(s) ex vivo, e.g. (immunogenic components of) oxLDL or total extract of atherosclerotic plaque tissue, and returned to the blood stream. Other approaches to ensure immune protection include generation of tolerogenic DCs, or using DCs to deplete detrimental Th1 or Th17 cells. However, the future lies in direct targeting of DCs by manipulating functions of different DC subsets. Therefore, it would be useful to isolate plaque-resident DCs to be able to identify unique antigen(s) on their surface. The challenge is to selectively identify regulatory molecules and novel therapies to inhibit DC migration and function during atherogenesis, without affecting normal DC function under physiological conditions.

Topics: Adaptive Immunity; Animals; Atherosclerosis; Cardiovascular Agents; Cholesterol; Dendritic Cells; Humans; Immunity, Innate; Vaccination

Atherosclerosis is a progressive multifaceted inflammatory disease affecting large- and medium-sized arteries. Typical feature of this disease is the formation and build-up of atherosclerotic plaques characterized by vascular extracellular matrix degradation and remodeling. Many studies have documented degradation of native elastin, the main extracellular matrix protein responsible for resilience and elasticity of arteries, by local release of elastases, leading to the production of elastin-derived peptides (EDP). These peptides have been proposed to actively participate in the progression of the disease by accelerating different biological processes, such as LDL oxidation and calcification of the vascular wall. These pathophysiological effects are mediated by the binding of EDP on a peculiar heterotrimeric receptor named elastin receptor complex (ERC). In this article, we review the contribution of elastin in biological processes involved in atherosclerosis progression from its initial elastase-driven degradation to its ultimate cellular effects. Finally, we discuss the ERC and its derived signaling pathways as promising therapeutic targets.

Topics: Animals; Arteries; Atherosclerosis; Cardiovascular Agents; Disease Progression; Elastin; Humans; Molecular Targeted Therapy; Pancreatic Elastase; Peptide Fragments; Plaque, Atherosclerotic; Receptors, Cell Surface; Signal Transduction

Atherosclerosis is the major cause of mortality in the developed countries. Although presently known risk factors have some predictive value for the disease, a major part of the variability in this process remains unexplained. It is extremely important to find new approaches for better understanding of the disease and for treating it. Exploration of the sphingolipid metabolism is one of these approaches. Sphingolipids are a large class of lipids with structural and signaling functions. Recent researches indicated that these lipids play important roles in the development of atherosclerosis. In this chapter, we summarized the major findings in the field.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Drug Design; Humans; Lysophospholipids; Molecular Targeted Therapy; Signal Transduction; Sphingolipids; Sphingomyelins; Sphingosine

We comment on the associations between epicardial adiposity and cardiovascular disease (CVD) and associated risk factors. The effects of lifestyle measures and CVD drugs on cardiac adipose tissue are also discussed.. Epicardial adipose tissue exerts cardioprotective properties; however, in cases of pathological enlargement, epicardial fat can lead to myocardial inflammation and dysfunction as well as left ventricular hypertrophy and coronary artery disease (CAD) due to paracrine actions that include increased production of reactive oxygen species, atherogenic and inflammatory cytokines. Cardiac adiposity is associated with CAD, obesity, type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease, and chronic kidney disease, as well as with CVD risk factors such as lipids, hypertension, obesity markers, and carotid atherosclerosis.. Due to its anatomical and functional proximity to the coronary circulation, epicardial adipose tissue may represent an even more direct CVD risk marker than central adiposity. Lifestyle measures and certain drugs may affect its thickness, although there are limited data currently available. The clinical implications of epicardial fat in daily practice remain to be established in future studies.

Topics: Adiposity; Animals; Atherosclerosis; Cardiovascular Agents; Coronary Artery Disease; Humans; Risk Factors; Risk Reduction Behavior

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

Stenosed segments of arteries significantly alter the blood flow known from healthy vessels. In particular, the wall shear stress at critically stenosed arteries is at least an order of magnitude higher than in healthy situations. This alteration represents a change in physical force and might be used as a trigger signal for drug delivery. Mechano-sensitive drug delivery systems that preferentially release their payload under increased shear stress are discussed. Therefore, besides biological or chemical markers, physical triggers are a further principle approach for targeted drug delivery. We hypothesize that such a physical trigger is much more powerful to release drugs for vasodilation, plaque stabilization, or clot lysis at stenosed arteries than any known biological or chemical ones.

Topics: Animals; Atherosclerosis; Biomechanical Phenomena; Cardiovascular Agents; Constriction, Pathologic; Drug Carriers; Drug Delivery Systems; Hemodynamics; Humans; Mechanotransduction, Cellular; Models, Cardiovascular; Nanoparticles; Regional Blood Flow; Stress, Mechanical

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

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

Macrophages can be found in all stages of atherosclerosis and are major contributors of atherosclerotic plaque development, progression and destabilization. Continuous recruitment of monocytes drives this chronic inflammatory disease, which can be intervened by several strategies: reducing the inflammatory stimulus by lowering circulating lipids and promoting cholesterol efflux from plaque, direct and indirect targeting of adhesion molecules and chemokines involved in monocyte adhesion and transmigration and inducing macrophage death in atherosclerotic plaques in combination with anti-inflammatory drugs. This review discusses the outlined strategies to deplete macrophages from atherosclerotic plaques to promote plaque stabilization.

Topics: Animals; Anti-Inflammatory Agents; Arteries; Atherosclerosis; Biological Transport; Cardiovascular Agents; Chemotaxis; Cholesterol Ester Transfer Proteins; Cholesterol, LDL; Enzyme Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Lipoproteins, HDL; Macrophage Activation; Macrophages; Plaque, Atherosclerotic

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

The prevalence of gallstones disease in Western countries is 10 - 15%. Gallstones can be one of two types - cholesterol or pigment - with cholesterol gallstones representing nearly the 80% of the total. Cholesterol and pigment gallstones have different predisposing factors: cholesterol gallstones are related to supersaturated bile in cholesterol, whereas black pigment gallstones are related to hyperbilirubinbilia factors (hemolysis, etc.); these are necessary, but not sufficient, factors to produce gallstones in vivo. Gall bladder mucosa factors (gall bladder secretion of mucin, local bile stasis and production of endogenous biliary β-glucuronidase) may coexist with the aforementioned factors and facilitate gallstone nucleation and growth. The gold-standard treatment for symptomatic gallstones is laparoscopic cholecystectomy. Several studies have reported a significant reduction in the onset of symptomatic gallstones disease in patients undergoing chronic therapy with statins, which can reduce bile cholesterol saturation. Aspirin, which has been shown to reduce the local production of gall bladder mucins (mucosal or parietal factors of gallstone formation) in animal experimental models, does not appear to reduce the risk of symptomatic gallstones disease when tested alone. The new horizon of oral therapy for the prevention of symptomatic gallstone disease needs to evaluate the long-term effect of statins and chronic aspirin administration in patients with dyslipidemia and/or atherosclerosis.

Topics: Administration, Oral; Animals; Aspirin; Atherosclerosis; Cardiovascular Agents; Cholecystolithiasis; Cholesterol; Dyslipidemias; Gallbladder; Gallstones; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Risk Assessment; Risk Factors; Treatment Outcome

Morbidities related to atherosclerosis, such as acute coronary syndromes (ACS) including unstable angina and myocardial infarction, remain leading causes of mortality. Unstable plaques are inflamed and infiltrated with macrophages and T lymphocytes. Activated dendritic cells interact with T cells, yielding predominantly Th1 responses involving interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α), while the role of interleukin 17 (IL-17) is questionable. The expansion of CD28nullCD4 or CD8 T cells as well as pattern recognition receptors activation (especially Toll-like receptors; TLR2 and TLR4) is characteristic for unstable plaque. Inflammation modifies platelet and fibrin clot characteristics, which are critical for ACS. Understanding of the inflammatory mechanisms of atherothrombosis, bridging inflammation, oxidative stress and immune regulation, will allow for the detection of subjects at risk, through the use of novel biomarkers and imaging techniques including intravascular ultrasound, molecular targeting, magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). Moreover, understanding the specific inflammatory pathways of plaque rupture and atherothrombosis may allow for immunomodulation of ACS. Statins and anti-platelet drugs are anti-inflammatory, but importance of immune events in ACS warrants the introduction of novel, specific treatments directed either on cytokines, TLRs or inflammasomes. While the prime time for the introduction of immunologically inspired diagnostic tests and treatments for atherosclerosis have not come yet, we are closer than ever before to finally being able to benefit from this vast body of experimental and clinical evidence. This paper provides a comprehensive review of the role of the immune system and inflammation in ACS.

Topics: Acute Coronary Syndrome; Animals; Anti-Inflammatory Agents; Atherosclerosis; Autoimmune Diseases; Bacterial Infections; Cardiovascular Agents; Cytokines; Dendritic Cells; Diagnostic Imaging; Disease Models, Animal; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammasomes; Inflammation; Macrophages; Mast Cells; Matrix Metalloproteinases; Molecular Targeted Therapy; Myocardial Reperfusion Injury; Oxidative Stress; Plaque, Atherosclerotic; Platelet Aggregation Inhibitors; Receptors, Pattern Recognition; Rupture, Spontaneous; T-Lymphocyte Subsets; Thrombophilia

Smoking is a major risk factor for the development of atherosclerosis, stroke and myocardial infarction. Cigarette smoke consists of a complex mixture of about 4000 compounds. Out of these, polycyclic hydrocarbons, tobacco-specific nitrosamines, oxidizing agents and carbon monoxide have been implicated in the development of atherosclerosis. Recent studies have shown that nicotine (the addictive component of cigarettes) binds to high affinity cell-surface receptors and accelerates the atherogenic process. These receptors are called nicotinic acetylcholine receptors (nAChRs) and are expressed ubiquitously in almost all cells existing in the blood vessels. The present review summarizes the pro-atherogenic effects of nAChR ligands such as nicotine and tobacco nitrosamines. The contribution of different nAChR subunits in plaque growth, progression and neovascularization are discussed in detail. The signaling pathways underlying the actions of the nAChRs ligands in blood vessels are also described. Finally, the feasibility of nAChR ligands as therapeutic targets for atherosclerosis is summarized. We believe that the information presented in this review is relevant for atherosclerosis patients who are active smokers, exposed to environmental tobacco smoke or use nicotine patches or gums for smoking cessation.

Topics: Animals; Atherosclerosis; Blood Vessels; Cardiovascular Agents; Drug Design; Humans; Ligands; Nicotine; Nicotinic Agonists; Nitrosamines; Receptors, Nicotinic; Risk Factors; Signal Transduction; Smoking; Smoking Prevention; Tobacco Use Cessation Devices

Topics: Animals; Atherosclerosis; Biomarkers; Cardiovascular Agents; Diabetes Complications; Dyslipidemias; Early Diagnosis; Fibrinolytic Agents; Global Health; Health Behavior; Health Care Costs; Homocysteine; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperhomocysteinemia; Hypertension; Magnetic Resonance Imaging; Medication Adherence; Plaque, Atherosclerotic; Risk Factors; Risk Reduction Behavior; Stents; Thrombosis; United States

The G protein-coupled receptor TGR5 is a key player of the bile acid signaling network, and its activation has been proved to increase the glycemic control, to enhance energy expenditure and to exert anti-inflammatory actions. Accordingly, TGR5 ligands have emerged in drug discovery and preclinical appraisals as promising agents for the treatment of liver diseases, metabolic syndrome and related disorders.. Recent advances in the field of TGR5 modulators are reviewed, with a particular attention on patent applications and peer-reviewed publications in the past 6 years.. Activation of TGR5 showed to protect mice from diabesity and insulin resistance, to improve liver functions, as well as to attenuate the development of atherosclerosis. However, although the efficacy of TGR5 agonists in mice is encouraging, further studies are needed to determine their potential in humans and to evaluate carefully the balance between the therapeutic benefits and adverse effects associated with the target. The development of new TGR5 selective ligands to support studies in animal models will surely facilitate the understanding of the complexity of TGR5 signaling network.

Topics: Animals; Atherosclerosis; Blood Glucose; Cardiovascular Agents; Diabetes Mellitus; Drug Design; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Ligands; Molecular Structure; Patents as Topic; Protein Conformation; Receptors, G-Protein-Coupled; Structure-Activity Relationship

Matrix metalloproteinases (MMPs) have a pivotal role in the natural history of atherosclerosis and its cardiovascular consequences. Non-selective MMP inhibition with doxycycline appears as a potential strategy to reduce the residual risk observed in patients already at intensive lipid lowering strategies. However, specific MMPs have different and even contradicting roles in the natural history of atherosclerosis, rendering broad spectrum MMP inhibition an important yet somewhat simplistic approach towards residual risk reduction in coronary atherosclerosis. Overall, the balance of non-selective MMP inhibition might shift to the favorable side in particular settings such as in acute coronary syndromes, where in addition to its potential plaque stabilization properties, doxycycline shows promise in preventing ischemia-reperfusion injury and left ventricular remodeling. Nevertheless, to date, most animal models used do not represent advanced coronary atherosclerosis seen in humans, and large and well-designed clinical studies are lacking. We discuss the available evidence and recent patents supporting the role of doxycycline in atherosclerosis.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Doxycycline; Evidence-Based Medicine; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Patents as Topic; Protease Inhibitors; Signal Transduction; Translational Research, Biomedical; Treatment Outcome

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

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

Conjugated linoleic acids (CLAs) are biologically highly active lipid compounds that have attracted great scientific interest due to their ability to cause either inhibition of atherosclerotic plaque development or even regression of pre-established atherosclerotic plaques in mice, hamsters and rabbits. The underlying mechanisms of action, however, are only poorly understood. Since cell culture experiments are appropriate to gain insight into the mechanisms of action of a compound, the present review summarizes data from cell culture studies about the metabolism and the actions of CLAs on atherosclerosis-related events in endothelial cells (ECs) and smooth muscle cells (SMCs), which are important cells contributing to atherosclerotic lesion development. Based on these studies, it can be concluded that CLAs exert several beneficial actions including inhibition of inflammatory and vasoactive mediator release from ECs and SMCs, which may help explain the anti-atherogenic effect of CLAs observed in vivo. The observation that significant levels of CLA metabolites, which have been reported to have significant biological activities, are well detectable in ECs and SMCs indicates that the anti-atherogenic effects observed with CLAs are presumably mediated not only by CLAs themselves but also by their metabolites.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Cardiovascular Agents; Cells, Cultured; Dietary Fats, Unsaturated; Endothelial Cells; Humans; Linoleic Acids, Conjugated; Myocytes, Smooth Muscle

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

Heart disease remains the leading cause of mortality in the United States despite recent reductions in the death rate. Complications of coronary artery disease and its sequelae are the most common mechanism of demise. There have been great advances in the prevention and treatment of acute myocardial infarction, and the literature is replete with articles on attempted localization of so-called vulnerable plaques and vulnerable or high-risk patients to find either that high-risk plaque or that individual before the event. Unfortunately, the search for the so-called vulnerable plaque is hampered by the lack of both natural history studies and proven local or regional therapies for these otherwise asymptomatic plaques. Although emphasis on the vulnerable or high-risk patient is appropriate, identifying these individuals in primary prevention is difficult. This article highlights insights into the pathophysiology of vulnerable plaque and presents a perspective on current treatments, improved risk stratification, and potential technologic advances that might affect future diagnosis and management.

Topics: Atherosclerosis; Cardiovascular Agents; Coronary Angiography; Coronary Artery Disease; Disease Progression; Drug Therapy, Combination; Female; Humans; Male; Myocardial Infarction; Prognosis; Risk Assessment; Severity of Illness Index; Survival Rate

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

Endovascular treatment for atherosclerotic renal artery stenosis (ARAS) was first performed >30 years ago and its use has increased rapidly since then. However, only recently have large randomized trials rigorously evaluated its clinical benefit.. We systematically reviewed the controlled studies on primary stenting for atherosclerotic renal artery stenosis. Studies were included if they compared the outcome of stenting with other treatments, or the outcome associated with different stent characteristics or stenting methods.. Stenting is preferred over angioplasty alone and over surgery when revascularization is indicated for ostial ARAS, except in cases of coexistent aortic disease indicating surgery. Randomized controlled trials showed no significant benefit and substantial risk of renal artery stenting over medication alone in patients with atherosclerotic ARAS without a compelling indication. Improvements in the procedure, such as with distal embolic protection devices and coated stents, are not associated with better clinical outcomes after stent placement for ARAS.. Recent evidence shows that impaired renal function associated with ARAS is more stable over time than previously observed. Optimal medical treatment should be the preferred option for most patients with ARAS. Only low-level evidence supports compelling indications for revascularization in ARAS, including rapidly progressive hypertension or renal failure and flash pulmonary edema.

Topics: Angioplasty; Atherosclerosis; Cardiovascular Agents; Evidence-Based Medicine; Humans; Patient Selection; Renal Artery Obstruction; Risk Assessment; Severity of Illness Index; Stents; Treatment Outcome; Vascular Surgical Procedures

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

First discovered as orphan receptors, liver X receptors (LXRs) were subsequently identified as the nuclear receptor target of the cholesterol metabolites, oxysterols. There are 2 LXR receptors encoded by distinct genes: LXRalpha is most highly expressed in the liver, adipose, kidney, adrenal tissues, and macrophages and LXRbeta is ubiquitously expressed. Despite differential tissue distribution, these isoforms have 78% homology in their ligand-binding domain and appear to respond to the same endogenous ligands. Work over the past 10 years has shown that the LXR pathway regulates lipid metabolism and inflammation via both the induction and repression of target genes. Given the importance of cholesterol regulation and inflammation in the development of cardiovascular disease, it is not surprising that activation of the LXR pathway attenuates various mechanisms underlying atherosclerotic plaque development. In this brief review, we will discuss the impact of the LXR pathway on both cholesterol metabolism and atherosclerosis.

Topics: Animals; Atherosclerosis; Biological Transport; Cardiovascular Agents; Cholesterol; Endothelial Cells; Humans; Inflammation Mediators; Ligands; Liver X Receptors; Macrophages; Muscle, Smooth, Vascular; Orphan Nuclear Receptors; Signal Transduction

Nutraceuticals are potentially healthful foods that play a role in maintaining human well being, enhancing health and preventing, or even treating, specific diseases. More than for any other diseases, cardiovascular diseases occur in association with risk factors that are amenable to prevention or treatment by nutraceutical interventions. Several ingredients marketed for use in dietary supplements address such risk factors. The ability of nutraceuticals to favorably influence cardiovascular risk factors and atherosclerotic vascular disease should be recognized as an enormous opportunity for the prevention or treatment of this common condition. In this review, we attempt at summarizing some of the recent research findings on omega-3-polyunsaturated fatty acids and antioxidant polyphenols that have beneficial cardiovascular effects to update the practicing clinicians on the potential benefits of nutraceuticals in this area.

Topics: Atherosclerosis; Cardiovascular Agents; Diet, Mediterranean; Dietary Supplements; Fatty Acids, Omega-3; Flavonoids; Functional Food; Humans; Phenols; Polyphenols; Treatment Outcome

The high prevalence of obesity, atherosclerosis, and cardiovascular disease (CVD) is largely attributable to the contemporary lifestyle that is often sedentary and includes a diet high in saturated fats and sugars and low ingestion polyunsaturated fatty acids (PUFAs), fruit, vegetables, and fiber. Epidemiological studies have confirmed a strong association between fat intake, especially saturated- and transfatty acids, plasma cholesterol levels, and rate of coronary heart disease (CHD) mortality. In counterpart, beneficial cardiovascular effects have been reported in populations consuming the "healthy" Mediterranean-type diet. Indeed, many nutrients and phytochemicals in fruits, vegetables, and wine, including fiber, vitamins, minerals, antioxidants, have shown to be independently or jointly responsible for the apparent reduction in CVD risk. Therefore, in patients with overt CVD, efforts have focused on combining both drug treatments and nutrition interventions. Undoubtedly, the advances in the knowledge of both the disease processes and healthy dietary components have provided new avenues to develop pharmaceutical and/or dietary strategies to halt the development of vascular disease. In this regard, within the last years, pioneering nutritional strategies, such as nutraceuticals, have been developed aimed at reducing the main atherosclerotic risk factors and promoting cardiovascular health. Furthermore, a growing body of clinical evidence has demonstrated positive cardiovascular effects associated with dietary fibers, cholesterol-lowering natural agents, olive oil, omega-3 PUFAs, antioxidants, and polyphenols intake. Moreover, monounsaturated fatty acids intake has shown to modulate the expression of key atherosclerotic-related genes. Yet, in the case of antioxidants, some large clinical trials have failed to confirm such atheroprotective effects. Furthermore, there might be interactions between these natural food supplements and cardiovascular medications that cannot be overlooked. Hence, there is a need for a better understanding and more scientific evidence of the relative contribution of major nutraceutical constituents to the inhibition of the progression of atherosclerosis and its clinical consequences.

Topics: Atherosclerosis; Cardiovascular Agents; Clinical Trials as Topic; Diet; Dietary Supplements; Evidence-Based Medicine; Functional Food; Humans; Risk Factors; Treatment Outcome

Prospective randomized clinical trials that support operative correction of atherosclerotic renovascular disease or catheter-based intervention compared with optimal medical management are lacking. Despite various limitations in study design, each of the five randomized trials reported to date had demonstrated no apparent benefit for renal artery intervention compared with medical management. Three ongoing randomized trials promise to provide additional data and the results of these latter studies will likely dictate future reimbursement through the Centers for Medicare and Medicaid Services.

Topics: Angioplasty; Atherosclerosis; Cardiovascular Agents; Evidence-Based Medicine; Humans; Prospective Studies; Randomized Controlled Trials as Topic; Renal Artery Obstruction; Research Design; Treatment Outcome; Vascular Surgical Procedures

The management of atherosclerotic renal artery stenosis is controversial. Although it may appear intuitive that restoring normal blood flow to the kidney(s) is the treatment of choice, there are no data showing an obvious advantage of interventional therapy compared with medical therapy. In this article, we discuss the most recent advances in the treatment of atherosclerotic renal artery stenosis with a focus on randomized studies comparing medical treatment with angioplasty/stenting, particularly in patients with underlying renal dysfunction. The available data are still of limited quality but provide support against indiscriminate use of interventions, as these treatments appear no better than best medical treatment that focuses on blood pressure control, use of blockers of the renin-angiotensin system, and aggressive cardiovascular risk management.

Topics: Angioplasty, Balloon; Angiotensin Receptor Antagonists; Atherosclerosis; Cardiovascular Agents; Humans; Renal Artery Obstruction; Renal Insufficiency; Stents

Atherosclerosis and its clinical manifestations (i.e. myocardial infarction, stroke) are major causes of mortality and morbidity in Western countries. Endothelial dysfunction is considered the first step in the cascade leading up to coronary events. Increasing evidence suggests that direct inhibition of thromboxane A2/prostaglandin (TP)-receptors may not only have anti-platelet effects but also impact endothelial dysfunction as well as inflammatory component of atherosclerosis. While TP-receptor involvement in platelet function has received the greatest attention, more recent findings support the critical role of TP-receptor in other pathophysiological aspects of atherothrombosis. Prostanoids (i.e. TxA2, F2-isoprostanes, prostaglandins endoperoxides PGG2/PGH2) are known to promote the initiation and progression of atherosclerosis, not only via platelet activation, but through leukocyte-endothelial interactions and vasoconstriction. Dysfunctional endothelium, characterised by increased COX-activity, releases prostanoids that promote endothelial exposure to adhesion molecules and induce smooth muscle cell contraction. Plaque macrophages synthesise PGH2/PGG2 via COX-2; these potent prostanoids can trigger platelet activation and aggregation despite COX-1 inhibition by aspirin. TP-receptor inhibition has been reported to exert anti-atherosclerotic effects in pre-clinical model of disease. Reduction of plaque burden was associated with plaque stabilisation documented by the reduction in the content of macrophages, apoptotic cells, MMPs and endothelin-1, and the increase in smooth muscle cells content. TP-receptor blockade might have an anti-atherosclerotic and plaque stabilisation effect. The possibility of combining anti-platelet activity with an anti-atherosclerotic effect via selective TP-receptor inhibitors could have important implications especially in clinical conditions associated with increased production of prostanoids, such as diabetes.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Endothelial Cells; Humans; Muscle, Smooth, Vascular; Platelet Aggregation Inhibitors; Receptors, Prostaglandin; Receptors, Thromboxane A2, Prostaglandin H2; Signal Transduction; Thrombosis

Endothelial lipase (EL) is a phospholipase that belongs to the lipoprotein lipase (LPL) family, which includes LPL and hepatic lipase (HL). Similar to LPL and HL, EL regulates lipoprotein metabolism, mainly high-density lipoprotein (HDL) metabolism and HDL cholesterol (HDL-C) levels in humans and mice. Existing data strongly suggest that inhibition of EL in humans would be expected to increase the HDL-C level. However, it has not been definitively established whether the effect of EL activity on HDL-C levels translates into effects on reverse cholesterol transport or atherosclerosis. The available data regarding the impact of EL expression and activity on HDL metabolism, reverse cholesterol transport, and atherosclerosis are reviewed.

Topics: Animals; Atherosclerosis; Biological Transport; Cardiovascular Agents; Cholesterol; Endothelium, Vascular; Enzyme Inhibitors; Humans; Lipase; Lipoproteins, HDL; Mice; Polymorphism, Single Nucleotide

Chronic inflammation is a pathogenic feature of atherosclerosis and cardiovascular disease mediated by substances including angiotensin II, proinflammatory cytokines, and free fatty acids. This promotes generation of reactive oxygen species in vascular endothelial cells and smooth muscle cells, which mediate injury through several mechanisms. Reciprocal relationships between endothelial dysfunction and insulin resistance as well as cross-talk between hyperlipidaemia and the renin-angiotensin-aldosterone system (RAAS) at multiple levels contribute importantly to a variety of risk factors. Therefore, combination therapy that simultaneously addresses multiple mechanisms for the pathogenesis of atherosclerosis is an attractive emerging concept for slowing progression of atherosclerosis. Combined therapy with statins, peroxisome proliferator-activated receptors, and RAAS blockade demonstrates additive beneficial effects on endothelial dysfunction and insulin resistance when compared with monotherapies in patients with cardiovascular risk factors due to both distinct and interrelated mechanisms. These additive beneficial effects of combined therapies are consistent with laboratory and recent clinical studies. Thus, combination therapy may be an important paradigm for treating and slowing progression of atherosclerosis, coronary heart disease, and co-morbid metabolic disorders characterized by endothelial dysfunction and insulin resistance.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Atherosclerosis; Calcium Channel Blockers; Cardiovascular Agents; Drug Therapy, Combination; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Insulin Resistance; NADPH Oxidases; Oxidative Stress; Peroxisome Proliferator-Activated Receptors; Reactive Oxygen Species; Renin-Angiotensin System; Treatment Outcome; Vitamin E

Surrogate markers have recently come under scrutiny since a few of the considered most reliable intermediate endpoints (LDL-c, HDL-c and HbA(1c)) have failed to predict clinical benefit following pharmacological intervention in the causal pathway. However, it follows that comprehending the pathophysiological complexity of atherosclerotic vascular disease, no single surrogate is likely to be omniscient in the translation of benefit or harm of a certain therapy. Especially surrogates that are assessed in the circulation merely reflect a part of the complex multipathway disease. Such markers do not have the ability to monitor potential side effects of interventions or assess the activation of unknown pro-atherogenic pathways. Contrary to such soluble endpoints, vascular imaging data can provide information on atherosclerosis as a continuous variable, since the disease process of the vascular wall itself is assessed. Understanding this continuity from the earliest stages through to the vascular complications is essential, as the arterial wall reflects the net effect of either known or yet to be discovered hereditary as well as environmental factors. In this review we will focus on challenges and pitfalls using plasma biomarkers as surrogate endpoints for the assessment of cardiovascular drug efficacy. Subsequently, we will focus on vascular imaging modalities as tools to investigate atherosclerosis.

Topics: Atherosclerosis; Biomarkers; Brachial Artery; Cardiovascular Agents; Carotid Arteries; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials as Topic; Coronary Vessels; Glycated Hemoglobin; Humans; Magnetic Resonance Imaging; Regional Blood Flow; Research Design; Tunica Intima; Ultrasonography; Vasodilation

Atherosclerosis is the leading cause of death worldwide. To date, the use of statins to lower LDL levels has been the major intervention used to delay or halt disease progression. These drugs have an incomplete impact on plaque burden and risk, however, as evidenced by the substantial rates of myocardial infarctions that occur in large-scale clinical trials of statins. Thus, it is hoped that by understanding the factors that lead to plaque regression, better approaches to treating atherosclerosis may be developed. A transplantation-based mouse model of atherosclerosis regression has been developed by allowing plaques to form in a model of human atherosclerosis, the apoE-deficient mouse, and then placing these plaques into recipient mice with a normolipidemic plasma environment. Under these conditions, the depletion of foam cells occurs. Interestingly, the disappearance of foam cells was primarily due to migration in a CCR7-dependent manner to regional and systemic lymph nodes after 3 days in the normolipidemic (regression) environment. Further studies using this transplant model demonstrated that liver X receptor and HDL are other factors likely to be involved in plaque regression. In conclusion, through the use of this transplant model, the process of uncovering the pathways regulating atherosclerosis regression has begun, which will ultimately lead to the identification of new therapeutic targets.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Cardiovascular Agents; Cell Movement; Disease Models, Animal; DNA-Binding Proteins; Drug Discovery; Foam Cells; Gene Expression Profiling; Humans; Lipoproteins, HDL; Liver X Receptors; Mice; Mice, Knockout; Orphan Nuclear Receptors; Receptors, CCR7; Receptors, Cytoplasmic and Nuclear

Understanding of the pathophysiology of atherogenesis has evolved substantially during the last few decades. Atherosclerosis was once identified as a lipid-storage disease, but is now recognized as a subacute inflammatory condition of the vessel wall, characterized by infiltration of macrophages and T cells, which interact with one another and with cells of the arterial wall. The pathological mechanisms of obesity recapitulate many features of the inflammatory processes at work in atherosclerosis. Our current appreciation of the similarities between obesity and atherosclerosis has already fostered innovations for the diagnosis, prognosis, and prevention of these two conditions.

Topics: Adipocytes; Animals; Anti-Inflammatory Agents; Apoptosis; Atherosclerosis; Cardiovascular Agents; Humans; Immunity, Innate; Immunologic Factors; Inflammation; Inflammation Mediators; Insulin Resistance; Lipid Metabolism; Macrophages; Obesity; Prognosis; Risk Assessment; Risk Factors; Rupture; T-Lymphocytes

Inflammatory pathways have been implicated in the initiation and progression of cardiovascular diseases. Accelerated atherosclerosis has been described in patients with chronic inflammatory diseases, particularly rheumatoid arthritis, disproportionate to individuals' detectable traditional vascular risk factors. This finding suggests that other pathways associated with inflammation might account for increased vascular risk in such diseases. Highly specific biologic agents can precisely block the activity of cytokines generated during inflammatory cascades; the effects of these inflammatory moieties on vascular physiology and overall risk of cardiovascular events has been directly evaluated. This review summarizes key epidemiologic, physiologic and model data, which together suggest that tumor necrosis factor, a pivotal cytokine in the inflammatory cascade, is directly involved in vascular pathophysiology and that its inhibition might confer an overall advantage to the recipient. Moreover, such data obtained in chronic inflammatory diseases likely have relevance to primary atherosclerosis.

Topics: Animals; Anti-Inflammatory Agents; Arteries; Arthritis, Rheumatoid; Atherosclerosis; Cardiovascular Agents; Chronic Disease; Elasticity; Endothelium, Vascular; Heart Failure; Humans; Inflammation; Inflammation Mediators; Insulin Resistance; Lipid Metabolism; Obesity; Registries; Risk Assessment; Risk Factors; Signal Transduction; Treatment Outcome; Tumor Necrosis Factor-alpha

The metabolic syndrome of vascular risk is threatening large numbers of ever-younger people. To date, the syndrome has been chiefly viewed as a potential risk marker that confers a heightened probability of developing type 2 diabetes and occlusive atherothrombotic disease of large- and medium-sized arteries. Accumulating evidence suggests that the components of the metabolic syndrome may also adversely affect the microvasculature through several inter-related mechanisms. These include the following observations: classic risk factors for macrovascular disease such as high blood pressure and dyslipidaemia also accelerate microvascular complications of diabetes, lesser disturbances of glucose metabolism (i.e. impaired glucose tolerance) may be associated with some forms of microvascular dysfunction, non-glucose intermediary metabolites may promote renovascular hypertension thereby damaging the microvasculature, and insulin resistance appears to be directly associated with microvascular dysfunction. In turn, microvascular complications such as nephropathy and autonomic neuropathy may promote the development and progression of atherosclerosis. We argue that the vascular implications of the metabolic syndrome should be broadened to include the microvasculature. The hypothesis that vascular events can be prevented, or at least deferred, through earlier therapeutic intervention in pre-diabetic subjects with glucose intolerance is amenable to testing in clinical trials.

Topics: Anti-Obesity Agents; Antihypertensive Agents; Atherosclerosis; Cardiovascular Agents; Disease Progression; Glucose Intolerance; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Metabolic Syndrome; Microcirculation; Prediabetic State; Risk Assessment; Risk Factors; Signal Transduction; Vascular Diseases

Atherosclerotic renovascular disease (aRVD) is an increasingly recognized cause of severe hypertension and declining kidney function. Patients with aRVD have been demonstrated to have an increased risk of adverse cardiovascular events compared with patients without aRVD. For these reasons, >45,000 renal artery revascularization procedures are performed annually, with significant growth observed in the number of procedures performed each year. The efficacy of contemporary revascularization therapies in the treatment of aRVD is unproven and controversial, with no level I data to support current practices. Lower-level data suggest that kidney function improvement is a key indicator of subsequent improved survival free of adverse cardiovascular events and dialysis, and that observed improvements of hypertension confer, at best, limited benefit. This review focuses on existing data on the management of aRVD, including data from completed and ongoing randomized clinical trials. This review also examines other existing data regarding aRVD that may guide current treatment and future research efforts into this significant clinical and public health problem until widely accepted level I evidence emerges.

Topics: Angioplasty; Atherosclerosis; Cardiovascular Agents; Disease Progression; Evidence-Based Medicine; Humans; Hypertension, Renovascular; Kidney; Patient Selection; Randomized Controlled Trials as Topic; Renal Artery Obstruction; Renal Dialysis; Stents; Treatment Outcome; Vascular Surgical Procedures

Atherosclerosis is a chronic and progressive inflammatory vascular disease that is characterized by a complex interplay between some components of the bloodstream and the arterial wall. The lipid derivatives eicosanoids have been identified as important mediators that contribute to mechanisms of atherogenesis. Prostaglandins and thromboxane A2 are members of the eicosanoid family synthesized from arachidonic acid by the combined action of cyclooxygenases and prostaglandins and thromboxane A2 synthase. Thromboxane A2, a potent platelet activator and vasoconstrictor and prostacyclin, a platelet inhibitor and vasodilator, are the most important in the development of cardiovascular diseases. Several pro-atherogenic biological effects have also been attributed to isoprostanes, a class of eicosanoid isomers formed via a free radical-mediated oxidation of fatty acids esterified in membrane phospholipids. Both groups of lipids manifest their biological activities by binding to specific receptors in target cells. In this article, we will describe the biological roles of prostacyclin, thromboxane A2 and isoprostanes in atherogenesis and discuss the latest pharmacological studies assessing the therapeutic effects of drugs that specifically target their biosynthesis and/or biological activities on vascular inflammation and atherosclerotic lesion development.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Cyclooxygenase Inhibitors; Drug Delivery Systems; Eicosanoids; Epoprostenol; Humans; Inflammation; Isoprostanes; Thromboxane A2

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 present article reviews the use of flow-mediated dilatation in clinical cardiovascular research. Its value as a surrogate tool for development of antiatherosclerotic drugs and noninvasive assessment of cardiovascular risk is also discussed.. Atherosclerosis remains the leading cause of cardiovascular morbidity and mortality. Development of new drugs is required to target both the evolution of this disease and its clinical consequences. Noninvasive measures of arterial function and structure have been widely used as intermediate phenotypes in clinical trials. Numerous studies have demonstrated the interplay between vascular risk factors and endothelial function as assessed by flow-mediated dilatation in children and adults. Additionally, a number of studies have documented the prognostic value of the method.. Detection of early arterial changes can prove particularly useful in clinical research for the development of antiatherosclerotic drugs. They permit identification of vascular toxicity as well as characterization of the safety and risk profile of a new cardiovascular treatment modality on vascular health. This approach is likely to prove cost-effective before embarking on large longitudinal studies to assess cardiovascular morbidity and mortality.

Topics: Atherosclerosis; Blood Flow Velocity; Cardiovascular Agents; Clinical Trials as Topic; Endothelium, Vascular; Humans; Regional Blood Flow; Treatment Outcome; Vasodilation

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

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 author describes some of the numerous domains regarding the new topic called "Vascular endothelial dysfunction, oxidative stress". The endothelium is responsible for the constancy and integrity of the milieu interieur by producing various substances. Endothelial dysfunction occurs when there is imbalance between vasodilators and vasoconstrictors, growth factors and their inhibitors, proinflammatory and antiinflammatory agents, prothrombotic and fibrinolytic activities. The reason for this imbalance may be response to vascular endothelial or intimal injury caused by mechanical, physical, chemical, microbiological, immunologic, genetic damage or any of their combination. Endothelial dysfunction occurring on the huge inner surface of the vessels (the endothelium) is responsible for the triggering of atherosclerosis, which is a chronic vascular disease. All the risk factors of vascular pathology are leading to chronic (cardio)vascular diseases by causing endothelial dysfunction. Decreased endogenous antioxidative capacity leads to oxidative stress by free radical reactions of physiological oxidative metabolic processes, ending as the ultimate reason for endothelial dysfunction induced by risk factors. The therapeutic and preventive effects of causal antioxidant treatments having intracellular and mitochondrial effects (statins, angiotensin-converting-enzyme inhibitors, angiotensin-receptor-blockers, acetylsalicylic acid, and third generation beta-blockers) should be emphasized. It is also important to underline the physiological-pathophysiological-therapeutic consubstantiality and systemic nature of human vasculature and to emphasize the preventive-therapeutic significance of the vascular consequence cascade. And finally, there has been large process in the assessment of oxidative stress and consecutive endothelial dysfunction which revolutionized our clinical point of view.

Topics: Atherosclerosis; Cardiovascular Agents; Endothelium, Vascular; Humans; Hungary; Journalism, Medical; Oxidative Stress; Periodicals as Topic; Risk Factors

Our understanding of the events that occur within atherosclerotic plaques has improved dramatically over the last 2 decades, particularly with regard to the role of plaque destabilisation and the onset of clinical ischaemic syndromes. Many potential targets have been identified for therapeutic intervention aimed at disease prevention, plaque stabilisation and regression. Furthermore, many potential biomarkers of vascular disease have generated interest in terms of monitoring disease activity and the effect of therapeutic agents. However, despite much scientific promise with in vitro cell and animal models, there has been much less success in modulation of these processes in clinical practice. This review will highlight the local and systemic factors associated with disease progression and acute plaque destabilisation, the current role of therapeutic agents and the potential for targeted plaque modification.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Atherosclerosis; Biomarkers; Blood Coagulation; C-Reactive Protein; Cardiovascular Agents; Cytokines; Disease Progression; Hematologic Agents; Homocysteine; Humans; Hypolipidemic Agents; Inflammation; Intercellular Signaling Peptides and Proteins; Lipid Metabolism; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Protease Inhibitors; Signal Transduction

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

Soluble guanylyl cyclase (sGC) is one of the key enzymes of the nitric-oxide (NO)/cyclic 3',5'-guanosine monophosphate (cGMP) pathway. Located in virtually all mammalian cells, it controls the vessel tone, smooth muscle cell growth, platelet aggregation, and leukocyte adhesion. In vivo sGC activity is mainly regulated by NO which in turn is released from L-arginine by nitric oxide synthases. One of the main diseases of the cardiovascular system, endothelial dysfunction, leads to a diminished NO synthesis and thus increases vessel tone as well as the risk of thrombosis. The predominant therapeutic approach to this condition is a NO replacement therapy, as exemplified by organic nitrates, molsidomin, and other NO releasing substances. Recent advances in drug discovery provided a variety of other approaches to activate sGC, which may help to circumvent both the tolerance problem and some non-specific actions associated with NO donor drugs. Substances like BAY 41-2272 stimulate sGC in a heme-dependent fashion and synergize with NO, allowing to enhance the effects both of endogenous NO and of exogenous NO donors. On the other hand, heme-independent activators like BAY 58-2667 allow to activate sGC even if it is rendered unresponsive to NO due to oxidative stress or heme loss. Furthermore, a few substances have been described as specific inhibitors of sGC that allow to alleviate the effects of excess NO production as seen in shock. This review discusses the cardiovascular effects of heme-dependent and heme-independent activators as well as of inhibitors of sGC.

Topics: Animals; Atherosclerosis; Carbon Monoxide; Cardiovascular Agents; Cyclic GMP; Guanylate Cyclase; Humans; Hypertension; Hypertension, Pulmonary; Nitric Oxide; Nitric Oxide Donors; Signal Transduction

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

In various cardiac diseases, thrombembolism constitutes a major risk, and in these patients clinically silent microembolic signals (MES) are detectable within the transcranial Doppler frequency spectrum (TCD) of the major brain arteries. MES are already an accepted surrogate parameter of the future risk of stroke in patients with carotid artery stenosis. The aim of this review is to summarize and evaluate the data about occurence and clinical impact of MES in patients with chronic cardiac diseases and to clarify whether cardiogenic MES can serve as a surrogate parameter of the heart's future thrombembolic risk as well.. We performed a systematic MEDLINE search and reviewed the currently available literature about chronic cardiac diseases and atheroaortic plaques leading to MES apart from cardiosurgical procedures.. The cardiac conditions producing MES are heterogenous and therefore the prevalence of MES is highly variable. The data in patients with acute or after myocardial infarction, endocarditis, patent foramen ovale, mitral valve prolapse, dilatative cardiomyopathy and intracardiac thrombus is promising but only small patient cohorts have been investigated by means of TCD in these categories. MES in atrial fibrillation, or derived from atheroaortic plaques, have been investigated more intensively, but again larger cohorts need to be explored to draw firm conclusions. In all cardiac diseases there is a lack of large prospective studies allowing to reliably correlating MES with clinical events. Compared to carotid artery disease, the current knowledge about the impact of cardiogenic MES on the patient's risk is sparse. This should encourage the clinical research in this promising field.

Topics: Aortic Diseases; Atherosclerosis; Cardiovascular Agents; Chronic Disease; Heart Diseases; Humans; Intracranial Embolism; Risk Factors; Ultrasonography, Doppler, Transcranial

Molecular imaging biomarkers are playing an increasingly important role in efforts to increase the probability of success of drug candidates by helping to validate novel drug targets in support of proof-of-concept testing early in the drug discovery and development process. By facilitating better and faster decision-making, molecule and mechanism-based failures can be identified and eliminated from a research portfolio early in development thereby focusing research efforts on the best drug candidates and therapeutic hypotheses. Molecular imaging can be used to improve the cost-effectiveness of studying unprecedented mechanisms, decrease cycle time, and improve drug pipeline quality.

Topics: Animals; Antineoplastic Agents; Atherosclerosis; Biomarkers, Pharmacological; Cardiovascular Agents; Central Nervous System Agents; Diagnostic Imaging; Drug Design; Humans; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Neoplasms; Optics and Photonics; Patient Selection; Positron-Emission Tomography; Technology, Pharmaceutical; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography

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

Looking back at animal and clinical studies published since the 1920s, the notion of rapid regression and stabilization of atherosclerosis in humans has evolved from a fanciful goal to one that might be achievable pharmacologically, even for advanced plaques. Our review of this literature indicates that successful regression of atherosclerosis generally requires robust measures to improve plasma lipoprotein profiles. Examples of such measures include extensive lowering of plasma concentrations of atherogenic apolipoprotein B (apoB)-lipoproteins and enhancement of 'reverse' lipid transport from atheromata into the liver, either alone or in combination. Possible mechanisms responsible for lesion shrinkage include decreased retention of apoB-lipoproteins within the arterial wall, efflux of cholesterol and other toxic lipids from plaques, emigration of foam cells out of the arterial wall, and influx of healthy phagocytes that remove necrotic debris and other components of the plaque. Unfortunately, the clinical agents currently available cause less dramatic changes in plasma lipoprotein levels, and, thereby, fail to stop most cardiovascular events. Hence, there is a clear need for testing of new agents expected to facilitate atherosclerosis regression. Additional mechanistic insights will allow further progress.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Diet, Fat-Restricted; Disease Models, Animal; Gene Transfer Techniques; Genetic Therapy; Humans; Lipid Metabolism; Mice; Primates; Rabbits; Remission Induction; Swine; Treatment Outcome

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

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

Autophagy is a catabolic pathway for bulk destruction of long-lived proteins and organelles via lysosomes. Basal autophagy represents a reparative, life-sustaining process, but unrestrained autophagic activity promotes cell death. A growing body of evidence suggests that autophagy occurs in advanced atherosclerotic plaques. Vascular smooth muscle cells, macrophages, or endothelial cells treated in vitro with proatherogenic stimuli reveal certain features typical of autophagy, such as LC3 processing, formation of myelin figures, and extensive vacuolization. However, despite the increasing interest in autophagy, its role in atherosclerosis remains poorly understood. Most likely, autophagy safeguards plaque cells against cellular distress, in particular oxidative injury, by degrading the damaged intracellular material. In this way, autophagy is antiapoptotic and contributes to cellular recovery in an adverse environment. Because atherosclerosis is an inflammatory disorder of the arterial intima, pharmacologic approaches have recently been developed to stabilize vulnerable, rupture-prone lesions through selective induction of macrophage autophagic death.

Topics: Apoptosis; Atherosclerosis; Autophagy; Cardiovascular Agents; Endothelial Cells; Humans; Macrophages; Membrane Proteins; Microtubule-Associated Proteins; Oxidative Stress; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; TOR Serine-Threonine Kinases

L-Arginine is the substrate of endothelial nitric oxide synthase (eNOS) and the main precursor of nitric oxide (NO) in the vascular endothelium. L-Arginine improves endothelial function in patients with hypercholesterolemia, hypertension and smokers, while its role in diabetes remains unclear. Oral supplementation of L-arginine leads to a significant improvement of endothelium-dependent forearm vasodilation in hypercholesterolemic patients, while intravenous infusion of L-arginine improves endothelial function in healthy smokers. L-Arginine has anti-hypertensive properties, although its effects on endothelial function in hypertensive patients needs further evaluation. In conclusion, L-arginine administration may be useful in patients with premature atherosclerosis.

Topics: Age Factors; Arginine; Atherosclerosis; Cardiovascular Agents; Diabetes Mellitus; Endothelium, Vascular; Female; Humans; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Time Factors; Vasodilation

It is generally accepted that the increased cardiovascular morbidity and mortality in hypertension are related to target organ damage. Classically, the target organs are heart, brain, and kidneys. This brief report examines whether high arterial pressure may also affect other organs, such as aorta and large arteries. An attempt was also made to elucidate the relationship between disorders of the aorta and large arteries and other cardiovascular risk factors to the pathophysiology and treatment of patients with hypertension and its severe comorbid disease, atherosclerosis.

Topics: Arteries; Atherosclerosis; Blood Pressure; Cardiovascular Agents; Humans; Hypertension; Risk Factors; Vascular Resistance

Cardiovascular disease (CVD) remains one of the leading causes of morbidity and mortality in the developed world, and there is a clear need to develop novel therapeutic strategies to reduce cardiovascular risk further than is currently possible. Traditionally, the effectiveness of new cardiovascular drugs has been evaluated in clinical trials using cardiovascular outcomes as endpoints. However, such trials require large numbers of patients followed over long periods of time. Clinical trials using surrogate markers for CVD may be shorter in duration and involve fewer participants. Measurement of atherosclerotic progression is an ideal surrogate marker as it is predictive of future cardiovascular events. The "gold standard" for detecting and defining the severity, extent, and rate of atherosclerotic progression has been quantitative coronary angiography. However, this technique has fundamental limitations. More recently, measurement of carotid intima-media thickness using B-mode ultrasound and measurement of atheroma volume using intravascular ultrasound have emerged as more accurate techniques for detecting atherosclerotic progression. Both of these techniques have potential utility as surrogate endpoints in place of cardiovascular outcomes in clinical trials. Their use might facilitate the more rapid development of novel, safe, and effective therapies.

Topics: Atherosclerosis; Biomarkers; Cardiovascular Agents; Carotid Arteries; Coronary Angiography; Forecasting; Humans; Reproducibility of Results; Treatment Outcome; Ultrasonography

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

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

Caveolae are 50-100 nm cell surface plasma membrane invaginations that are highly enriched in cholesterol and sphingolipids and are characterized by the protein marker caveolin-1. Caveolin-1 is highly expressed in terminally differentiated cells. Among these cells, endothelial cells, smooth muscle cells, and macrophages have all been shown to play key roles in the development of vascular disease. Atherosclerosis and neointimal formation are two major processes that have been associated with arterial occlusion. In both cases, caveolin-1 has been shown to play an important role. However, depending on the cell type and the metabolic pathways regulated by this protein, caveolin-1 may positively or negatively influence the development of vascular disease. Both of these aspects will be discussed in this review.

Topics: Animals; Arteries; Atherosclerosis; Cardiovascular Agents; Caveolae; Caveolin 1; Endothelium, Vascular; Humans; Macrophages; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Thrombosis

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

Imaging of the arterial wall yields validated surrogate markers that can provide an early indication with regards to efficacy of novel cardiovascular drugs. This paper attempts to address the use of atherosclerosis imaging as a benchmarking tool for a well informed decision whether to proceed to large morbidity and mortality studies in the assessment of a novel therapeutic strategy.. Imaging of the artery wall can be used to evaluate individual cardiovascular risk and has additive value over conventional risk scores as it directly addresses the disease process. In controlled clinical trials, vascular imaging has shown that the efficacy of lipid-modifying pharmacotherapy can be evaluated in both high and low-risk populations and that the findings parallel outcomes of clinical studies with similar interventions.. Arterial imaging may provide the first glimpse of the efficacy or failure of a novel strategy to combat atherosclerosis. These findings suggest that vascular imaging could be employed to probe whether or not a large morbidity and mortality endpoint study should be the next step in a clinical development program.

Topics: Anticholesteremic Agents; Atherosclerosis; Biomarkers, Pharmacological; Cardiovascular Agents; Diagnostic Imaging; Drug Design; Humans

Inflammation contributes to the formation and progression of atherosclerosis and the therapeutic potential of some anti-inflammatory drugs has been evaluated for possible antiatherosclerotic effects. This review will briefly describe the mechanisms underlying the inflammation-atherosclerosis connection, the effect of various anti-inflammatory therapies on atherosclerotic disease and a sampling of the potential targets and agents under evaluation.. Some agents with anti-inflammatory properties appear to have beneficial effects on atherosclerosis or subsequent risk for cardiovascular events, while others have been disappointing. The anti-inflammatory actions of statins have been linked retrospectively with their favorable effects on atherosclerosis progression and clinical outcomes. The cardiovascular safety of COX-2 inhibitors is being assessed prospectively in patients with atherosclerosis. Potential new therapeutic agents targeting other inflammatory mechanisms and oxidative stress are being evaluated in animal models and clinical trials.. Due to the contributory inflammatory pathways in atherosclerosis, the properties of existing and novel anti-inflammatory agents are being carefully and actively evaluated in cardiovascular disease. Advances in our understanding of both atherosclerosis and the inflammatory contributors may play an important role in future strategies to decrease the incidence of atherosclerotic cardiovascular disease.

Topics: Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Humans; Inflammation; Lipoproteins; Monocytes

Smoking should be stopped and hypertension, diabetes mellitus, dyslipidemia, and hypothyroidism treated in patients with peripheral arterial disease (PAD) of the lower extremities. Statins decrease the incidence of intermittent claudication and improve exercise duration until the onset of intermittent claudication in persons with PAD and hypercholesterolemia. Antiplatelet drugs such as aspirin or clopidogrel, especially clopidogrel, angiotensin-converting enzyme inhibitors, and statins should be given to all persons with PAD. Beta blockers should be given if coronary artery disease is present. Exercise rehabilitation programs and cilostazol increase exercise time until intermittent claudication develops. Chelation therapy should be avoided. Indications for lower extremity percutaneous transluminal angioplasty or bypass surgery are (1) incapacitating claudication in persons interfering with work or lifestyle, (2) limb salvage in persons with limb-threatening ischemia as manifested by rest pain, nonhealing ulcers, and/or infection or gangrene, and (3) vasculogenic impotence.

Topics: Angioplasty, Balloon; Atherosclerosis; Cardiovascular Agents; Exercise; Humans; Intermittent Claudication; Lower Extremity; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Prevalence; Risk Factors; Smoking Cessation; Stents; Vascular Surgical Procedures

Anti-oxidised low-density lipoprotein (anti-oxLDL) antibodies are a heterogeneous group of autoantibodies including both pathogenic and protective subsets. Whereas in most studies the levels of anti-oxLDL antibodies were associated with enhanced atherosclerosis as evaluated by different methods, immunization with oxLDL leads to elevated levels of anti-oxLDL and protection against atherosclerosis. Anti-oxLDL can also be used for immunomodulation of atherosclerosis (i.e. possible therapeutic use of intravenous immunoglobulin, oral tolerance). More specific autoantibodies out of total anti-oxLDL should be selected, for instance, anti-oxLDL/beta-2-glycoprotein I complex, hence defining the fine-tuning of anti-oxLDL antibodies might detect which autoantibodies are pathogenic and which can be used therapeutically.

Topics: Animals; Atherosclerosis; Autoantibodies; Cardiovascular Agents; Epitope Mapping; Humans; Immune Tolerance; Immunoglobulins, Intravenous; Immunotherapy; Lipoproteins, LDL; Thrombosis

Cardiovascular diseases, the clinical paradigm of atherosclerosis, are the primary cause of mortality in developed countries. The origin of the atheromatous lesion is multifactorial, as it is the therapeutic approach to its prevention and clinical complications. The initial symptoms of ischemia in a vascular bed are usually evident when the atherosclerotic process is very advanced, being indicative of a diffuse disease and of an elevated future risk for ischemic events in other vascular territories. We perform this review in this clinical scenario, highlighting the preventive and therapeutic aspects of demonstrated clinical efficacy, with no detail of those treatments with benefit insufficiently proven.

Topics: Angina Pectoris; Anticoagulants; Atherosclerosis; Brain Ischemia; Cardiovascular Agents; Combined Modality Therapy; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myocardial Infarction; Myocardial Ischemia; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Risk Factors

Accumulation of inflammatory cells identifies atherosclerotic plaque at risk for rupture. Typically, activated immune cells occupy the rupture-prone areas of the atherosclerotic lesion. These cells are an appealing therapeutic target for novel strategies of plaque stabilization. Biologic consequences of plaque inflammation ultimately depend not only on the cellular players populating the lesion but also on triggers of immune activation originating from within the plaque or arriving from the circulation, and immune effector mechanisms that mediate cellular damage and plaque destabilization. Recent studies have provided insights into particular immune mechanisms in the atherosclerotic plaque that contribute to plaque vulnerability. This knowledge provides the basis for potential immunomodulatory therapies in cardiovascular disease. These therapeutic approaches can be classified as (1) immunomodulatory effects of existing therapies, (2) therapies targeting inflammatory triggers, and (3) agents inhibiting specific immune mechanisms.

Topics: Anti-Bacterial Agents; Atherosclerosis; Autoantigens; Bacterial Vaccines; Cardiovascular Agents; Heat-Shock Proteins; Humans; Immunity, Cellular; Immunity, Innate; Immunologic Factors; Immunotherapy; Inflammation; Lipoproteins, LDL; Viral Vaccines

Peroxisome proliferator-activated receptors (PPARs) alpha (alpha), beta/delta (beta/delta), and gamma (gamma) are members of the nuclear receptor superfamily, which also includes the estrogen, androgen, and glucocorticoid receptors. Recent evidence suggests that PPARs regulate genes involved in lipid metabolism, glucose homeostasis, and inflammation in various tissues; however, the mechanisms involved are not completely understood. Anti-diabetic drugs, called glitazones, can selectively activate PPARgamma, and hypolipidemic drugs, called fibrates, can weakly activate PPARalpha. Both classes of drugs can decrease insulin resistance and dyslipidemias, which also makes them attractive for treating the metabolic syndrome. The metabolic syndrome exhibits a constellation of risk factors for atherosclerosis that include obesity, insulin resistance, dyslipidemias, and hypertension. Interestingly, all three PPARs are present in macrophages and can therefore have a profound effect on several disease processes, including atherosclerosis. Macrophages are key players in atherosclerotic lesion development. Currently, the first line of defense in reducing the risk of atherosclerosis is aimed at lowering low-density lipoproteins (LDL) and raising high-density lipoproteins (HDL), but a large percentage of patients on statins still succumb to coronary artery disease. However, with the development of drugs selectively activating PPARs, a new arsenal of drugs specifically targeting to the macrophage/foam cell may potentially have a profound impact on how we treat cardiovascular disease.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Humans; Macrophages; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Aneurysm; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortic Rupture; Atherosclerosis; Cardiovascular Agents; Combined Modality Therapy; Comorbidity; Diagnostic Imaging; Evidence-Based Medicine; Female; Femoral Artery; Humans; Iliac Artery; Intestines; Ischemia; Leg; Male; Mesenteric Arteries; Middle Aged; Peripheral Vascular Diseases; Popliteal Artery; Prevalence; Randomized Controlled Trials as Topic; Renal Artery; Risk Factors; Risk Reduction Behavior; Treatment Outcome; Vascular Surgical Procedures

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 background use of a number of established therapies presents a key challenge for the development of novel anti-atherosclerotic agents: how to predict potential efficacy before the completion of long-term trials with endpoints such as mortality. This challenge has stimulated the search to develop intermediate measures of efficacy. Recent advances now allow intravascular ultrasound (IVUS) to provide an accurate assessment of atheroma accumulation within the arterial wall. Here we describe how IVUS can be applied to the serial assessment of atheroma burden in response to treatment with a range of anti-atherosclerotic strategies, which has resulted in its emergence as a key technology in the evaluation and approval of novel drugs.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Clinical Trials as Topic; Disease Progression; Drug Design; Humans; Ultrasonography, Interventional

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

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

More than 70% of patients with Type 2 diabetes mellitus (T2DM) die because of cardiovascular diseases. Current therapeutic strategies are based on separate treatment of insulin resistance and dyslipidaemia. Development of drugs with multimodal activities should improve management of the global cardiovascular risk of T2DM patients and result in better patient compliance. New therapeutic strategies are aimed at targeting the entire spectrum of dysfunctioning organs, cells and regulatory pathways implicated in the pathogenesis of T2DM, dyslipidaemia and atherosclerosis. PPAR family members play major roles in the regulation of lipid metabolism, glucose homeostasis and inflammatory processes, making these transcription factors ideal targets for therapeutic strategies against these diseases. This review discusses why PPARs and development of novel selective PPAR modulators, dual and pan PPAR agonists constitute promising approaches for the treatment of diabetes, dyslipidaemia and atherosclerosis.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Combined Modality Therapy; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Peroxisome Proliferator-Activated Receptors

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

Endothelium is not a mere monolayer of cells separating flowing blood and vascular wall, but plays a key role in maintenance of vascular homeostasis. Nitric oxide is the principal mediator of endothelial function; it is a potent vasodilator, it inhibits platelet aggregation, vascular smooth muscle cell migration and proliferation, and monocytes adhesion. Cardiovascular risk factors promote development of endothelial dysfunction, characterized by impairment of endothelium-dependent vasodilation (EDV) and by pro-coagulant/pro-inflammatory endothelial activities. The assessment of EDV is a common parameter for testing endothelial function. EDV in the coronary arteries is angiographically evaluated by measurement of the vessel response to endothelial agonists, such as acetylcholine. A non-invasive technique for the detection of EDV employs the ultrasound evaluation of flow-mediated dilation (FMD) of the brachial artery following reactive hyperemia. A close relation between FMD and coronary vasomotor response to acetylcholine has been demonstrated. Endothelial dysfunction in the coronary circulation may precede development of angiographically evident coronary atherosclerosis; endothelial dysfunction has been also associated with a higher prevalence of coronary artery disease and resulted predictive of future cardiovascular events; recently, it has been associated with a higher risk of restenosis after coronary stent implantation. Endothelial dysfunction is actually considered a reversible phenomenon; drug therapies with ACE-inhibitors, angiotensin receptor blockers, statins, antioxidants agents have shown a beneficial effect on endothelial function.

Topics: Atherosclerosis; Cardiovascular Agents; Coronary Artery Disease; Coronary Vessels; Endothelium, Vascular; Humans; Nitric Oxide; Risk Factors; Vasodilation

Although the features of diabetic cardiomyopathy, atherosclerosis, and nephropathy have been clinically characterized, the pathogenesis and the mechanisms underlying the abnormalities in the diabetic heart and kidney are not fully understood. During the past several years, in an attempt to discover interventions for diabetes-related complications, researchers have refocused their attention from the hemodynamic aspects of the disease to the biochemical interactions of glucose and proteins. Diabetes is a disorder of chronic hyperglycemia, and glucose participates in diabetic complications such as atherosclerosis, cardiac dysfunction, and nephropathy. Chronic hyperglycemia accelerates the reaction between glucose and proteins and leads to the formation of advanced glycation end products (AGE), which form irreversible cross-links with many macromolecules such as collagen. In diabetes, these AGE accumulate in tissues at an accelerated rate. The development of the novel compound dimethyl-3-phenacylthiazolium chloride (alagebrium chloride), which chemically breaks AGE cross-links, led to several preclinical animal studies that showed an attenuation or reversal of disease processes of the heart and kidney. In diabetes, AGE not only structurally stiffen structural collagen backbones but also act as agonists to AGE receptors (RAGE) on various cell types, which stimulate the release of profibrotic growth factors, promote collagen deposition, increase inflammation, and ultimately lead to tissue fibrosis. In the heart, large vessels, and kidney, these reactions produce diastolic dysfunction, atherosclerosis, and renal fibrosis. Administration of the cross-link breaker alagebrium chloride in these diabetic animals attenuates these pathologic phenomena, restoring functionality to the heart, vasculature, and kidney.

Topics: Animals; Atherosclerosis; Blood Glucose; Cardiomyopathies; Cardiovascular Agents; Diabetic Angiopathies; Diabetic Nephropathies; Fibrosis; Glycation End Products, Advanced; Humans; Myocardium; Thiazoles

Topics: Aesculus; Arteriosclerosis; Atherosclerosis; Biomedical Research; Cardiovascular Agents; Fagaceae; Flavonoids; Humans; Rutin

Microvascular dysfunction is known to play a key role in patients with angina and nonobstructive coronary artery disease. We investigated the impact of ranolazine among patients with angina and nonobstructive coronary artery disease.. In this randomized, double-blinded, placebo-controlled pilot trial, 26 patients with angina once weekly or more, abnormal stress test, and nonobstructive coronary artery disease (<50% stenosis by angiography and fractional flow reserve >0.80) were randomized 1:1 to ranolazine or placebo for 12 weeks. Primary end point was ΔSeattle Angina Questionnaire (SAQ) angina frequency score. Baseline and 3 months follow-up SAQ, Duke Activity Status Index scores along with invasive fractional flow reserve, coronary flow reserve (CFR), hyperemic myocardial resistance, and cardiopulmonary exercise testing measurements were performed.. Ranolazine did not demonstrate improvement in SAQ angina frequency score, invasive microvascular function, or peak metabolic equivalent compared with placebo at 3 months. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02147067.

Topics: Atherosclerosis; Cardiovascular Agents; Double-Blind Method; Fractional Flow Reserve, Myocardial; Humans; Myocardial Ischemia; Pilot Projects; Ranolazine; Treatment Outcome

Ischaemia in different arterial territories before acute myocardial infarction (AMI) may influence post-AMI outcomes. No studies have evaluated prospectively collected information on ischaemia and its effect on short- and long-term coronary mortality. The objective of this study was to compare patients with and without prospectively measured ischaemic presentations before AMI in terms of infarct characteristics and coronary mortality.. As part of the CALIBER programme, we linked data from primary care, hospital admissions, the national acute coronary syndrome registry and cause-specific mortality to identify patients with first AMI (n = 16,439). We analysed time from AMI to coronary mortality (n = 5283 deaths) using Cox regression (median 2.6 years follow-up), comparing patients with and without recent ischaemic presentations. Patients with ischaemic presentations in the 90 days before AMI experienced lower coronary mortality in the first 7 days after AMI compared with those with no prior ischaemic presentations, after adjusting for age, sex, smoking, diabetes, blood pressure and cardiovascular medications [HR: 0.64 (95% CI: 0.57-0.73) P < 0.001], but subsequent mortality was higher [HR: 1.42 (1.13-1.77) P = 0.001]. Patients with ischaemic presentations closer in time to AMI had the lowest seven day mortality (P-trend = 0.001).. In the first large prospective study of ischaemic presentations prior to AMI, we have shown that those occurring closest to AMI are associated with lower short-term coronary mortality following AMI, which could represent a natural ischaemic preconditioning effect, observed in a clinical setting.. Clinicaltrials.gov identifier NCT01604486.

Topics: Aged; Aged, 80 and over; Angina Pectoris; Atherosclerosis; Cardiovascular Agents; Cerebrovascular Disorders; Electronic Health Records; Female; Follow-Up Studies; Humans; Ischemia; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Prognosis; Prospective Studies; Risk Factors

Topics: Adult; Atherosclerosis; Cardiovascular Agents; Carnitine; Diet; Female; HEK293 Cells; Humans; Male; Methylamines; Methylhydrazines; Organic Cation Transport Proteins; Seafood; Solute Carrier Family 22 Member 5

Recruitment and retention of participants are critical to the success of a randomised controlled trial. Gaining the views of potential trial participants who decline to enter a trial and of trial participants who stop the trial treatment is important and can help to improve study processes. Limited research on these issues has been conducted on healthy individuals recruited for prevention trials in the community.. Semi-structured interviews with people who were eligible but had declined to participate in the Aspirin for Asymptomatic Atherosclerosis (AAA) trial (N = 11), and AAA trial participants who had stopped taking the trial medication (N = 11). A focus group with further participants who had stopped taking the trial medication (N = 6). (Total participants N = 28).. Explanations for declining to participate could be divided into two groups: the first group were characterised by a lack of necessity to participate and a tendency to prioritise other largely mundane problems. The second group's concern was with a high level of perceived risk from participating.Explanations for stopping trial medication fell into four categories: side effects attributed to the trial medication; starting on aspirin or medication contraindicating to aspirin; experiencing an outcome event, and changing one's mind.. These results indicate that when planning trials (especially in preventive medicine) particular attention should be given to designing appropriate recruitment materials and processes that fully inform potential recruits of the risks and benefits of participation.. ISRCTN66587262.

Topics: Aged; Aspirin; Asymptomatic Diseases; Atherosclerosis; Cardiovascular Agents; Female; Focus Groups; Health Behavior; Health Knowledge, Attitudes, Practice; Humans; Interviews as Topic; Male; Middle Aged; Motivation; Patient Dropouts; Patient Education as Topic; Patient Selection; Primary Prevention; Qualitative Research; Risk Assessment; United Kingdom

To evaluate the safety and effectiveness of the Zilver vascular stent in the treatment of de novo or restenotic lesions in the external and common iliac arteries.. Regardless of the results of an initial percutaneous transluminal angioplasty (PTA), 151 consecutive patients were implanted with Zilver vascular stents (Cook, Bloomington, Ind) in up to two stenotic (< or =10 cm) or occluded (< or =5 cm) atherosclerotic lesions of the external or common iliac arteries. The primary endpoint was the rate of major adverse events within 9 months after the procedure. Major adverse events were defined as death, myocardial infarction, target lesion revascularization, and limb loss. Secondary endpoints included acute procedural success, 30-day clinical success, 9-month patency rate, 9-month functional status (on the basis of the validated Walking Impairment Questionnaire), and ankle-brachial index (ABI).. of 1-, 6-, and 9-month follow-up are reported. Results The 9-month device and/or procedural-related major adverse event rate (adjudicated by an independent clinical events committee) was 2.7%. The all-cause major adverse event rate was 7.5%. Both rates were substantially below the prespecified objective performance criterion of 16%. The acute procedure success rate and 30-day clinical success rate were 98.0% and 94.0%, respectively. The 9-month patency rate, measured with duplex ultrasonography, was 92.9%. Significant improvement in the ABI and walking distance and walking speed scores, relative to preprocedural values, was seen at 1 month and was maintained through 9-month follow-up.. The Zilver vascular stent is safe and effective as an adjunct to PTA in the treatment of symptomatic disease of the iliac arteries.

Topics: Aged; Amputation, Surgical; Angioplasty, Balloon; Ankle; Arterial Occlusive Diseases; Atherosclerosis; Blood Pressure; Brachial Artery; Cardiovascular Agents; Female; Humans; Iliac Artery; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Prosthesis Design; Radiography; Recovery of Function; Recurrence; Risk Assessment; Stents; Surveys and Questionnaires; Time Factors; Treatment Outcome; United States; Vascular Patency; Walking

Depressive symptoms have been associated with increased risk of coronary artery disease and poor prognosis among patients with existing coronary artery disease, but whether depressive symptoms specifically influence atherosclerotic progression among such patients is uncertain.. The Post-CABG Trial randomized patients with a history of coronary bypass graft surgery to either an aggressive or a moderate lipid-lowering strategy and to either warfarin or placebo. Coronary angiography was conducted at enrollment and after a median follow-up of 4.2 years. Depressive symptoms were assessed at enrollment with the Centers for Epidemiologic Studies Depression scale (CES-D) in 1319 patients with 2496 grafts. In models that adjusted for age, gender, race, treatment assignment, and years since coronary bypass graft surgery, a CES-D score > or =16 was positively associated with risk of substantial graft disease progression (OR 1.50, 95% CI 1.08 to 2.10, P=0.02) and marginally associated with a 0.11-mm (95% CI -0.22 to 0.01 mm, P=0.07) decrease in minimum lumen diameter, but not with risk of graft occlusion (P=0.30). Additional adjustment for past medical history, blood pressure, and renal function did not materially alter these results. This association was virtually absent among participants randomly assigned to aggressive lipid-lowering therapy.. These findings suggest that depressive symptoms are associated with a higher risk of atherosclerotic progression among patients with saphenous vein grafts and that aggressive lipid lowering can minimize this increased risk. Whether depressive symptoms increase progression in other types of coronary atherosclerosis and whether aggressive lipid lowering attenuates such progression will require additional study.

Topics: Adult; Aged; Aged, 80 and over; Atherosclerosis; Cardiovascular Agents; Coronary Artery Bypass; Coronary Artery Disease; Depression; Disease Progression; Female; Humans; Male; Middle Aged; Prospective Studies; Risk Factors

The influence of optimal medical treatment (OMT) with or without additional percutaneous transluminal angioplasty (PTA) on vascular inflammation in peripheral arterial occlusive disease (PAD) patients was investigated. Patients with intermittent claudication (IC) and angiographically verified PAD were randomized to OMT (n = 28) or OMT + PTA (n = 28) and followed for 12 months. Ankle-brachial index (ABI), treadmill walking distances (WD), visual analogue scale (VAS), and blood sampling for the determination of selected soluble biomarkers were undertaken at baseline and after 3 and 12 months. After both 3 and 12 months, ABI, WD and VAS were highly significantly improved in favour of OMT + PTA (p < 0.05 for all). Significant improvements were recorded in both groups in serum lipids (p < 0.01 for all), except for triglycerides, and in the inflammatory markers P-selectin, interleukin-6, interleukin-10, monocyte chemoattractant protein-1 and fibrinogen (p < 0.05 for all). There were, however, no differences in the changes from baseline between the groups in any variable. Intervention with OMT alone or in combination with PTA did not differ with regard to the effects on serum lipids and markers of inflammation in our population of PAD patients. The combined treatment was, however, better for the treadmill walking distance.

Topics: Aged; Angioplasty, Balloon; Ankle; Atherosclerosis; Biomarkers; Blood Pressure; Brachial Artery; Cardiovascular Agents; Combined Modality Therapy; Female; Finland; Humans; Inflammation; Intermittent Claudication; Male; Middle Aged; Pain Measurement; Peripheral Vascular Diseases; Prospective Studies; Recovery of Function; Severity of Illness Index; Time Factors; Treatment Outcome; Walking

Topics: Adipokines; Atherosclerosis; Cardiovascular Agents; Carotid Intima-Media Thickness; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Male; Nicotinamide Phosphoribosyltransferase; Plaque, Atherosclerotic; Resistin; Risk Factors

Interventional therapies such as drug-eluting stents (DES) and drug-coated balloons (DCB) have significantly improved the clinical outcomes of patients with coronary occlusions in recent years. Despite this marked improvement, ischemic cardiovascular disease remains the most common cause of death worldwide. To address this, research efforts are focused on improving the safety and efficacy of the next generation of these devices. However, current experimental methods are unable to account for the influence of atherosclerotic lesions on drug uptake and retention. Therefore, in this study, we used an integrated approach utilizing both in vitro and in silico methods to assess the performance of DCB therapy. This approach was validated against existing in vivo results before being used to numerically estimate the effect of the atheroma. A bolus release of sirolimus was observed with our coating matrix. This, coupled with the rapid saturation of specific and non-specific binding sites observed in our study, indicated that increasing the therapeutic dose coated onto the balloons might not necessarily result in greater uptake and/or retention. Additionally, our findings alluded to an optimal exposure time, dependent on the coating matrix, for the DCBs to be expanded against the vessel. Moreover, our findings suggest that a biphasic drug release profile might be beneficial for establishing and maintaining the saturation of bindings sites within severely occluded vessels. Ultimately, we have demonstrated that computational methods may be capable of assessing the efficacy of DCB therapy as well as predict the influence of atherosclerotic lesions on said efficacy.

Topics: Angioplasty, Balloon, Coronary; Atherosclerosis; Cardiovascular Agents; Computer Simulation; Coronary Occlusion; Coronary Restenosis; Coronary Vessels; Dose-Response Relationship, Drug; Drug Liberation; Drug-Eluting Stents; Humans; Models, Cardiovascular; Sirolimus; Treatment Outcome

In the present paper, the magnetic drug targeting using drug coated Fe. The governing equations of continuity, momentum and volume fraction were solved by taking into account the effects of kelvin force and magnetophoresis. Finite volume method is used for discretization of unsteady two-phase flow equations.. In low magnetic numbers, the most important phenomenon is the gradual formation of drug droplet on the location of the wire. The drug drop holds the drug near the target tissue for a long time and has a positive role in the MDT as a source of drug over time. Also, in high magnetic numbers, the amount of drug in the tissue is also high at the time of the formation of the droplet. However, the number of vortices formed in the flow increases, and this leads to get the target further away from the tissue. Two main phenomena of drug droplet formation and vortices generation were observed as positive and negative factors in MDT, respectively. The results showed that in a specific magnetic number, the MDT function could be optimal. If the wire is located in the upstream region of the stenosis, it will have a small positive effect on the concentration of the drug in the target tissue.

Topics: Atherosclerosis; Cardiovascular Agents; Computer Simulation; Constriction, Pathologic; Drug Carriers; Drug Delivery Systems; Humans; Magnetic Fields; Magnetics; Magnetite Nanoparticles; Nanoparticles; Numerical Analysis, Computer-Assisted; Time Factors

Recently, 12 randomized clinical trials (RCTs) have demonstrated the efficacy of novel therapies for mainly secondary prevention of atherosclerotic cardiovascular disease. However, given the potential overlapping eligibility of the RCTs, along with the cost of the new therapies, there are uncertainty and questions about implementing these RCT findings in real-world clinical practice.. To determine the eligibility and preventive potential for these new preventive therapies in a contemporary population.. This population-based contemporary cohort study included 6292 patients with known ischemic heart disease (IHD) and 2277 with a previous myocardial infarction (MI) enrolled between November 2003 and February 2015. Analyses were performed in the Copenhagen General Population Study with a mean (SD) of 7.7 (3.5) years of follow-up. The data were analyzed between January and October 2019.. We determined the drug eligibility and evidence-based potential for preventing major cardiovascular events of the 12 cardiovascular drugs tested in the following recent RCTs: IMPROVE-IT, PEGASUS, EMPA-REG, LEADER, SUSTAIN-6, FOURIER, CANVAS, REVEAL, CANTOS, COMPASS, ODYSSEY-OUTCOMES, and REDUCE-IT. The analyses were performed in patients with known IHD or with a previous MI at baseline.. Of 6292 participants, 3861 (61%) were men and the mean (interquartile range) age was 69 (62-76) years. In patients with IHD or MI at baseline, eligibility for 1 or more new medications was 80% (n = 5036) and 99% (n = 2273), respectively, by meeting RCT enrollment criteria. Dividing the new therapies into 4 drug classes (lipid-modifying, antithrombotic, anti-inflammatory, and antidiabetic drugs), 2594 and 1834 patients with IHD or MI (41% and 81%, respectively) were eligible for 2 or more drug classes simultaneously. The 5-year estimated percentage of major cardiovascular events that could be prevented for each new therapy was 1% to 20% in patients with IHD or MI at baseline.. Most patients with known IHD or previous MI are eligible for additional new secondary prevention therapies. This raises questions for the cardiovascular community and health care authorities about access to these potentially expensive therapies, including strategies for prioritizing their use.

Topics: Aged; Atherosclerosis; Cardiovascular Agents; Cohort Studies; Evidence-Based Pharmacy Practice; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Secondary Prevention

Atherosclerosis is the process that underlies heart attack and stroke. A characteristic feature of the atherosclerotic plaque is the accumulation of apoptotic cells in the necrotic core. Prophagocytic antibody-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells; however, these therapies can cause off-target clearance of healthy tissues, which leads to toxicities such as anaemia. Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of the antiphagocytic CD47-SIRPα signalling axis. We demonstrate that these single-walled carbon nanotubes accumulate within the atherosclerotic plaque, reactivate lesional phagocytosis and reduce the plaque burden in atheroprone apolipoprotein-E-deficient mice without compromising safety, and thereby overcome a key translational barrier for this class of drugs. Single-cell RNA sequencing analysis reveals that prophagocytic single-walled carbon nanotubes decrease the expression of inflammatory genes linked to cytokine and chemokine pathways in lesional macrophages, which demonstrates the potential of 'Trojan horse' nanoparticles to prevent atherosclerotic cardiovascular disease.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; CD47 Antigen; Disease Models, Animal; Female; Macrophages; Male; Mice, Transgenic; Nanomedicine; Nanotubes, Carbon; Phagocytosis; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Receptors, Immunologic; Signal Transduction

Dyslipidemia-induced atherosclerosis, which has a risk of high morbidity and mortality, can be alleviated by metabolic activation associated with mitochondrial function. The effect of dichloroacetate (DCA), a general pyruvate dehydrogenase kinase (PDK) inhibitor, on in vivo energy expenditure in ApoE

Topics: Adipose Tissue, Brown; AMP-Activated Protein Kinases; Animals; Apolipoproteins E; Atherosclerosis; Cardiovascular Agents; Dichloroacetic Acid; Diet, Western; Dyslipidemias; Energy Metabolism; Enzyme Inhibitors; Fibroblast Growth Factors; Gene Expression Regulation; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Mitochondria; Obesity; Oxygen Consumption; Plaque, Atherosclerotic; PPAR alpha; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; RNA, Messenger; Signal Transduction; Uncoupling Protein 1

Topics: Animals; Antioxidants; Atherosclerosis; Bone Marrow Cells; Cardiovascular Agents; Cell Survival; Cells, Cultured; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Endothelial Cells; Male; Mice; Ophiopogon; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry

Drug-eluting stent (DES) strut fracture (SF) is associated with higher incidence of In-stent restenosis (ISR)-return of blockage in a diseased artery post stenting-than seen with bare metal stents (BMS). We hypothesize that concomitance of drug and SF leads to greater neointimal response.. Controlled release of therapeutic agents, such as sirolimus and its analogs, or paclitaxel from has reduced tissue based DES failure modes compared to BMS. ISR is dramatically reduced and yet the implications of mechanical device failure is magnified.. Bilateral Xience Everolimus-eluting stents (EES) were implanted in 20 New Zealand White rabbits on normal (n = 7) or high fat (HF)/high cholesterol (HC) (n = 13) diets. Implanted stents were intact or mechanically fractured. Everolimus concentration was as packaged or pre-eluted. After 21 days, stented vessels were explanted, resin embedded, MicroCT scanned, and analyzed histomorphometrically.. Fractured EES were associated with significant (P < 0.05) increases in arterial stenosis and neointimal formation and lower lumen-to-artery area ratios compared to intact EES. Hyperlipidemic animals receiving pre-eluted EES revealed no significant difference between intact and fracture groups.. SF increases intimal hyperplasia, post EES implant, and worse with more advanced disease. Pre-eluted groups, reflective of BMS, did not show significant differences, suggesting a synergistic effect of everolimus and mechanical injury, potentially explaining the lack of SF reports for BMS. Here, we report that ISR has a higher incidence with SF in EES, the clinical implication is that patients with SF after DES implantation merit careful follow-up.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Cholesterol, Dietary; Diet, High-Fat; Disease Models, Animal; Drug-Eluting Stents; Endovascular Procedures; Everolimus; Hyperplasia; Iliac Artery; Neointima; Prosthesis Design; Prosthesis Failure; Rabbits; Time Factors

Inhibition of the mechanistic target of rapamycin (mTOR) is a promising approach to halt atherogenesis in different animal models. This study evaluated whether the mTOR inhibitor everolimus can stabilize pre-existing plaques, prevent cardiovascular complications and improve survival in a mouse model of advanced atherosclerosis.. Everolimus enhances features of plaque stability and counters cardiovascular complications in ApoE

Topics: Animals; Antigens, Ly; Atherosclerosis; Brain; Cardiovascular Agents; Carotid Artery Diseases; Carotid Artery, Common; Diet, Western; Disease Models, Animal; Disease Progression; Everolimus; Female; Fibrillin-1; Heart; Hypoxia, Brain; Macrophages; Mice, Knockout, ApoE; Monocytes; Motor Activity; Myocardial Contraction; Neovascularization, Pathologic; Plaque, Atherosclerotic; Protein Kinase Inhibitors; TOR Serine-Threonine Kinases

Drug toxicity is a common and even serious problem in the gastrointestinal tract that is thought to be caused by a broad spectrum of agents. Although withdrawal of the causative agent would cure the disease knowledge is scarce and mostly derives from case reports and series.. To investigate potential triggers of drug-induced colitis (DiC).. We conducted a retrospective, observational case control study. Patients were assigned to DiC or one of two age- and gender-matched control groups (non-inflammatory controls and inflammatory colitis of another cause) based on histopathological findings. Histopathology was reassessed in a subset of patients (28 DiC with atherosclerosis, DiC without atherosclerosis and ischaemic colitis each) for validation purposes. Medical history was collected from the electronic database and patient records. Statistical analysis included chi-squared test,. Drug-induced colitis was detected in 211 endoscopically sampled biopsy specimens of the colon mucosa (7% of all screened colonoscopic biopsy samples); a total of 633 patients were included equally matched throughout the three groups (291 males, mean age: 62.1 ± 16.1 years). In the univariate analysis, DiC was associated with diuretics, dihydropyridines, glycosides, ASS, platelet aggregation inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), statins and fibrates, and with atherosclerosis, particularly coronary heart disease, and hyperlipoproteinaemia. Echocardiographic parameters did not show substantial differences. In the multivariate analysis only fibrates [odds ratio (OR) = 9.1], NSAIDs (OR = 6.7) and atherosclerosis (OR = 2.1) proved to be associated with DiC. Both DiC reassessment groups presented milder inflammation than ischaemic colitis. The DiC patients with atherosclerosis exhibited histological features from both DiC without atherosclerosis and ischaemic colitis.. Several drugs indicated for the treatment of cardiovascular and related diseases are associated with DiC. Atherosclerosis and microcirculatory disturbances seem to play an important pathogenetic role.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Biopsy; Cardiovascular Agents; Case-Control Studies; Colitis; Colon; Colonoscopy; Comorbidity; Female; Humans; Intestinal Mucosa; Male; Microcirculation; Middle Aged; Retrospective Studies; Risk Factors

Topics: Atherosclerosis; Cardiovascular Agents; Humans; Vascular Stiffness

Dronedarone is a multichannel-blocking antiarrhythmic drug for the treatment of atrial fibrillation. Observational data hypothesized a cardioprotective effect. In an in vitro endothelial cell-platelet model, we evaluated the molecular atheroprotective effects of dronedarone.. Following a 24-h incubation of human umbilical vein endothelial cells (HUVECs) with dronedarone (concentration 50, 100, and 150 ng/mL), they were then stimulated for 1 h with lipopolysaccharide (LPS) and were subsequently incubated in direct contact with thrombin-activated platelets. After incubation, the expression of CD40L and CD62P on platelets, and the expression of ICAM-1, VCAM-1, urokinase-type plasminogen activator receptor (uPAR), and membrane type 1 matrix metalloproteinase (MT1-MMP) on endothelial cells were measured by flow cytometry.. Preincubation with 150 ng/mL of dronedarone reduced the expression of uPAR on endothelial cells after proinflammatory stimulation with LPS and also by direct endothelial contact with activated platelets (p = 0.0038). In contrast, the expression of CD40L and CD62P on platelets after proinflammatory stimulation with thrombin was significantly increased through direct preincubation with 50/100/150 ng/mL of dronedarone. However, dronedarone had no effects on the expression of MT1-MMP and ICAM-1 in HUVECs.. In this in vitro analysis, dronedarone directly increased platelet activation but showed significant direct effects on endothelial cells and indirect effects on platelets on selected markers of atherosclerosis.

Topics: Atherosclerosis; Blood Platelets; Cardiovascular Agents; CD40 Ligand; Cells, Cultured; Cytoprotection; Dronedarone; Human Umbilical Vein Endothelial Cells; Humans; Lipopolysaccharides; P-Selectin; Platelet Activation; Receptors, Urokinase Plasminogen Activator; Signal Transduction

In previous studies, it was demonstrated that lipid core nanoparticles (LDE) resemble the low-density lipoprotein structure and carrying the antiproliferative agent paclitaxel (PTX) strongly reduced atherosclerosis lesions induced in rabbits by cholesterol feeding. Currently, the aim was to verify whether combining LDE-PTX treatment with methotrexate (MTX) associated with LDE (LDE-MTX) could accelerate the atherosclerosis regression attained with single LDE-PTX treatment, after withdrawing the cholesterol feeding. Thirty-eight rabbits were fed 1% cholesterol chow for 8 weeks. Six of these rabbits were then euthanized for analyses of the aorta (controls). In the remaining rabbits, cholesterol feeding was withdrawn, and those 32 animals were allocated to 3 groups submitted to different 8-week intravenous treatments, all once/week: LDE-PTX (n = 10; 4 mg/kg), LDE-PTX + LDE-MTX (n = 11; 4 mg/kg), and LDE-alone (n = 11). Rabbits were then euthanized and aortas were excised for morphometric, immunohistochemical, and gene expression analyses. After cholesterol feeding withdrawal, in comparison with LDE-alone group, both LDE-PTX and LDE-PTX + LDE-MTX treatments had the ability to increase the regression of plaque areas: -49% in LDE-PTX and -59% for LDE-PTX + LDE-MTX. However, only LDE-PTX + LDE-MTX treatment elicited reduction in the intima area, estimated in -57%. Macrophage presence in aortic lesions was reduced 48% by LDE-PTX and 43% by LDE-PTX + LDE-MTX treatment. Matrix metalloproteinase 9 was reduced by either LDE-PTX (74%) or LDE-PTX + LDE-MTX (78%). Tumor necrosis factor α gene expression was reduced 65% by LDE-PTX and 79% by LDE-PTX + LDE-MTX. In conclusion, treatment with LDE-PTX indeed accelerated plaque reduction after cholesterol feeding; LDE-PTX + LDE-MTX further increased this effect, without any observed toxicity. These results pave the way for the use of combined chemotherapy to achieve stronger effects on aggravated, highly inflamed atherosclerotic lesions.

Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; Cardiovascular Agents; Cholesterol, Dietary; Cytokines; Disease Models, Animal; Drug Compounding; Drug Therapy, Combination; Inflammation Mediators; Lipids; Liposomes; Male; Matrix Metalloproteinase 9; Methotrexate; Nanoparticles; Paclitaxel; Plaque, Atherosclerotic; Rabbits

Atherosclerosis (AS) is mainly responsible for cardiovascular diseases. The present study investigated whether Lipingshu capsule (LPS), whose ingredients are present in health food stores, has beneficial effect on AS.. ApoE. LPS reduces atherosclerotic lesions and thus alleviates AS by lipid profile modulation and inflammation inhibition.

Topics: Animals; Anti-Inflammatory Agents; Aorta; Apolipoproteins E; Atherosclerosis; Capsules; Cardiovascular Agents; Chemokine CCL5; Cholesterol, HDL; Cholesterol, LDL; Cytokines; Diet, High-Fat; Disease Models, Animal; Drugs, Chinese Herbal; Humans; Lipoproteins, LDL; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Plant Extracts; Plaque, Atherosclerotic; Treatment Outcome; Triglycerides; Tumor Necrosis Factor-alpha

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Disease Models, Animal; Heart Rate; Hemodynamics; Ivabradine; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Plaque, Atherosclerotic; Stress, Mechanical

Atherosclerotic cardiovascular disease (ASCVD) causes most deaths in the United States and accounts for the highest healthcare spending. The association between the modifiable risk factors (MRFs) of ASCVD and pharmaceutical expenditures are largely unknown.. We examined the association between MRFs and pharmaceutical expenditures among adults with ASCVD using the 2012 and 2013 Medical Expenditure Panel Survey. A 2-part model was used while accounting for the survey's complex design to obtain nationally representative results. All costs were adjusted to 2013 US dollars using the gross domestic product deflator. The annual total pharmaceutical expenditure among those with ASCVD was $71.6 billion, 33% of which was for medications for cardiovascular disease and 14% medications for diabetes mellitus. The adjusted relationship between MRFs and pharmaceutical expenditures showed significant marginal increase in average annual pharmaceutical expenditure associated with inadequate physical activity ($519 [95% confidence interval (CI), $12-918;. Worsening MRFs were proportionally associated with higher annual pharmaceutical expenditures among patients with established ASCVD regardless of non-ASCVD comorbidity. In-depth studies of the roles played by other factors in this association can help reduce medication-related expenditures among ASCVD patients.

Topics: Adult; Aged; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Diabetes Mellitus; Drug Costs; Health Expenditures; Health Surveys; Humans; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Socioeconomic Factors; Survival Rate; United States

Topics: Angiotensin Receptor Antagonists; Angiotensins; Atherosclerosis; Cardiovascular Agents; Emphysema; Humans; Pulmonary Disease, Chronic Obstructive; Tomography

Topics: Angiotensin Receptor Antagonists; Angiotensins; Atherosclerosis; Cardiovascular Agents; Emphysema; Humans; Pulmonary Disease, Chronic Obstructive; Tomography

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Clinical Trials as Topic; Humans; Immunity, Innate; Inflammation Mediators; Lipid Metabolism; Molecular Targeted Therapy; Plaque, Atherosclerotic; Signal Transduction

Apple polyphenol contains abundant procyanidins, which have been associated with an anti-atherosclerosis and cholesterol-lowering effect. The aim of this study was to investigate whether apple procyanidins (APCs) feature therapeutic efficacy in terms of regressing atherosclerosis and whether this efficacy is due to mechanisms other than a cholesterol-lowering effect.. After eight weeks on an atherogenic diet, rabbits were given a normal diet for another eight weeks to normalize the increased serum lipids level. The rabbits in the baseline group were sacrificed at this stage. The control group was subsequently fed a normal diet for eight weeks, while the APCs group was administrated 50 mg/kg/day of APCs in addition to the normal diet. Serum lipids and aortic intimal-medial thickness (IMT) were serially examined, and the resected aorta was examined histologically and through molecular biology.. Aortic IMT on ultrasonography and the lipid accumulation area examined using Sudan IV staining were significantly reduced in the APCs group as compared to the control group. Serum lipid profiles were not different between the groups. Immunohistochemistry showed significantly decreased staining of an oxidative stress marker and significantly increased staining of ATP-binding cassette subfamily A member 1 (ABCA1) in the APCs group. Western blotting and RT-PCR also showed increased expression of ABCA1 mRNA and its protein in the APCs group.. This study revealed that APCs administration causes a regression of atherosclerosis. APCs might hold promise as an anti-atherosclerotic agent.

Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; ATP Binding Cassette Transporter 1; Biflavonoids; Cardiovascular Agents; Catechin; Cholesterol; Disease Models, Animal; Fruit; Lipoproteins, LDL; Male; Malus; Oxidative Stress; Phytotherapy; Plants, Medicinal; Plaque, Atherosclerotic; Proanthocyanidins; Reactive Oxygen Species; RNA, Messenger; Scavenger Receptors, Class E; Time Factors; Up-Regulation

Buchang NaoXinTong (NXT), a Chinese medicine, has been widely used to treat patients with coronary heart disease in China. However, the underlying mechanisms need more elucidations. In this study, we investigated if NXT can inhibit the progression of the established lesions while stabilizing plaques. Apolipoprotein E deficient (apoE(-/-)) mice in 3 groups received following treatment: group 1 was fed a high-fat diet (HFD) for 18 weeks; group 2 was prefed HFD for 12 weeks followed by HFD containing NXT for additional 6 weeks; group 3 was prefed HFD for 8 weeks followed by HFD containing NXT for additional 10 weeks. After treatment, serum and aorta samples were collected and determined lipid profiles, lesions, collagen content, mineralization, and macrophage accumulation in aortic root, respectively. NXT had slight effect on serum lipid profiles but significantly reduced progression of the advanced lesions. In aortic wall, NXT increased smooth muscle cell/collagen content in lesion cap while reducing buried fibrous caps, mineralization, and macrophage accumulation within lesions, which suggests that NXT can stabilize plaques. In addition, NXT increased expression of smooth muscle 22α mRNA while inhibiting expression of matrix metalloproteinase-2 and tumor necrosis factor α mRNA in aortas. Our study demonstrates that NXT can reduce advanced atherosclerosis and enhance the plaque stability in apoE(-/-) mice.

Topics: Actins; Animals; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Biomarkers; Cardiovascular Agents; Diet, High-Fat; Disease Models, Animal; Drugs, Chinese Herbal; Fibrosis; Gene Expression Regulation; Genetic Predisposition to Disease; Lipids; Macrophages; Male; Matrix Metalloproteinase 2; Mice, Knockout; Phenotype; Phytotherapy; Plants, Medicinal; Plaque, Atherosclerotic; RNA, Messenger; Rupture, Spontaneous; Time Factors; Tumor Necrosis Factor-alpha

Aortic mural thrombi in a normal (non-aneurysmal or minimally atherosclerotic) vessel are an uncommon condition. They are usually located in the descending aorta and, less frequently, in the aortic arch or in the abdominal aorta. The typical clinical presentation is the appearance of symptoms/signs of peripheral arterial embolization, such as lower limb or visceral ischaemia, but these can also be accidentally found in asymptomatic patients. We report the case of a 40-year old man with untreated hypertension and dyslipidaemia admitted to hospital for atypical chest pain associated with an elevation in high-sensitivity troponin T with normal creatine kinase isoenzime MB creatine kinase isoenzyme. Elektrocardiogram (EKG) and transthoracic echocardiography were non-diagnostic; in order to exclude an aortic dissection, a gated chest computed tomography was performed and showed an aortic thrombus on a minimally atherosclerotic wall. Then, a transoesophageal echocardiography confirmed an aortic floating thrombus (7 × 4 mm). Cardiac surgeons advised against surgery and therapy with antiplatelet, low molecular weight heparin, β-blocker, antihypertensive and lipid-lowering drugs was initiated. A complete resolution of the thrombus was observed at the 12-day tomographic control.

Topics: Adult; Aorta, Thoracic; Aortic Diseases; Aortography; Asymptomatic Diseases; Atherosclerosis; Cardiovascular Agents; Echocardiography, Transesophageal; Humans; Male; Plaque, Atherosclerotic; Thrombosis; Tomography, X-Ray Computed; Treatment Outcome

Atherosclerotic renal artery stenosis (ARAS) can reduce renal blood flow, tissue oxygenation, and GFR. In this study, we sought to examine associations between renal hemodynamics and tissue oxygenation with single-kidney function, pressor hormones, and inflammatory biomarkers in patients with unilateral ARAS undergoing medical therapy alone or stent revascularization.. Nonrandomized inpatient studies were performed in patients with unilateral ARAS (>60% occlusion) before and 3 months after revascularization (n=10) or medical therapy (n=20) or patients with essential hypertension (n=32) under identical conditions. The primary study outcome was change in single-kidney GFR. Individual kidney hemodynamics and volume were measured using multidetector computed tomography. Tissue oxygenation (using R(2)* as a measure of deoxyhemoglobin) was determined by blood oxygen level-dependent magnetic resonance imaging at 3 T. Renal vein neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattractant protein-1 (MCP-1), and plasma renin activity were measured.. Total GFR did not change over 3 months in either group, but the stenotic kidney (STK) GFR rose over time in the stent compared with the medical group (+2.2[-1.8 to 10.5] versus -5.3[-7.3 to -0.3] ml/min; P=0.03). Contralateral kidney (CLK) GFR declined in the stent group (43.6±19.7 to 36.6±19.5 ml/min; P=0.03). Fractional tissue hypoxia fell in the STK (fraction R(2)* >30/s: 22.1%±20% versus 14.9%±18.3%; P<0.01) after stenting. Renal vein biomarkers correlated with the degree of hypoxia in the STK: NGAL(r=0.3; P=0.01) and MCP-1(r=0.3; P=0.02; more so after stenting). Renal vein NGAL was inversely related to renal blood flow in the STK (r=-0.65; P<0.001). Biomarkers were highly correlated between STK and CLK, NGAL (r=0.94; P<0.001), and MCP-1 (r=0.96; P<0.001).. These results showed changes over time in single-kidney GFR that were not evident in parameters of total GFR. Furthermore, they delineate the relationship of measurable tissue hypoxia within the STK and markers of inflammation in human ARAS. Renal vein NGAL and MCP-1 indicated persistent interactions between the ischemic kidney and both CLK and systemic levels of inflammatory cytokines.

Topics: Aged; Atherosclerosis; Biomarkers; Cardiovascular Agents; Cell Hypoxia; Chemokine CCL2; Endovascular Procedures; Female; Glomerular Filtration Rate; Humans; Inflammation Mediators; Kidney; Lipocalin-2; Magnetic Resonance Imaging; Male; Middle Aged; Multidetector Computed Tomography; Oxygen; Recovery of Function; Renal Artery Obstruction; Renal Circulation; Renin; Stents; Time Factors; Treatment Outcome

Inflammatory monocytes/macrophages produce various proteinases, including matrix metalloproteinases, and degradation of the extracellular matrix by these activated proteinases weakens the mechanical strength of atherosclerotic plaques, which results in a rupture of the plaque. Peroxisome proliferator-activated receptor-γ induces a polarity shift of monocytes/macrophages toward less inflammatory phenotypes and has the potential to prevent atherosclerotic plaque ruptures. Therefore, we hypothesized that nanoparticle-mediated targeted delivery of the peroxisome proliferator-activated receptor-γ agonist pioglitazone into circulating monocytes could effectively inhibit plaque ruptures in a mouse model.. We prepared bioabsorbable poly(lactic-co-glycolic-acid) nanoparticles containing pioglitazone (pioglitazone-NPs). Intravenously administered poly(lactic-co-glycolic-acid) nanoparticles incorporated with fluorescein isothiocyanate were found in circulating monocytes and aortic macrophages by flow cytometric analysis. Weekly intravenous administration of pioglitazone-NPs (7 mg/kg per week) for 4 weeks decreased buried fibrous caps, a surrogate marker of plaque rupture, in the brachiocephalic arteries of ApoE(-/-) mice fed a high-fat diet and infused with angiotensin II. In contrast, administration of control-NPs or an equivalent dose of oral pioglitazone treatment produced no effects. Pioglitazone-NPs inhibited the activity of matrix metalloproteinases and cathepsins in the brachiocephalic arteries. Pioglitazone-NPs regulated inflammatory cytokine expression and also suppressed the expression of extracellular matrix metalloproteinase inducer in bone marrow-derived macrophages.. Nanoparticle-mediated delivery of pioglitazone inhibited macrophage activation and atherosclerotic plaque ruptures in hyperlipidemic ApoE(-/-) mice. These results demonstrate a promising strategy with a favorable safety profile to prevent atherosclerotic plaque ruptures.

Topics: Administration, Intravenous; Angiotensin II; Animals; Apolipoproteins E; Atherosclerosis; Brachiocephalic Trunk; Cardiovascular Agents; Cathepsins; Cell Differentiation; Cells, Cultured; Chemistry, Pharmaceutical; Cytokines; Diet, High-Fat; Disease Models, Animal; Disease Progression; Drug Carriers; Inflammation Mediators; Lactic Acid; Macrophages, Peritoneal; Male; Matrix Metalloproteinases; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Nanoparticles; Phenotype; Pioglitazone; Plaque, Atherosclerotic; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rupture, Spontaneous; Thiazolidinediones

Drug-eluting coronary stents reduce restenosis rate and late lumen loss compared with bare-metal stents; however, drug-eluting coronary stents may delay vascular healing and increase late stent thrombosis. The peroxisome proliferator-activated receptor-delta (PPARδ) exhibits actions that could favorably influence outcomes after drug-eluting coronary stents placement.. Here, we report that PPARδ ligand-coated stents strongly reduce the development of neointima and luminal narrowing in a rabbit model of experimental atherosclerosis. Inhibition of inflammatory gene expression and vascular smooth muscle cell (VSMC) proliferation and migration, prevention of thrombocyte activation and aggregation, and proproliferative effects on endothelial cells were identified as key mechanisms for the prevention of restenosis. Using normal and PPARδ-depleted VSMCs, we show that the observed effects of PPARδ ligand GW0742 on VSMCs and thrombocytes are PPARδ receptor dependent. PPARδ ligand treatment induces expression of pyruvate dehydrogenase kinase isozyme 4 and downregulates the glucose transporter 1 in VSMCs, thus impairing the ability of VSMCs to provide the increased energy demands required for growth factor-stimulated proliferation and migration.. In contrast to commonly used drugs for stent coating, PPARδ ligands not only inhibit inflammatory response and proliferation of VSMCs but also prevent thrombocyte activation and support vessel re-endothelialization. Thus, pharmacological PPARδ activation could be a promising novel strategy to improve drug-eluting coronary stents outcomes.

Topics: Angioplasty, Balloon; Animals; Aorta; Aortic Diseases; Atherosclerosis; Blood Platelets; Cardiovascular Agents; Carotid Artery Injuries; Cell Movement; Cell Proliferation; Cells, Cultured; Coronary Artery Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drug-Eluting Stents; Energy Metabolism; Glucose Transporter Type 1; Human Umbilical Vein Endothelial Cells; Humans; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Platelet Activation; PPAR delta; Protein Serine-Threonine Kinases; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Rats; Rats, Sprague-Dawley; Re-Epithelialization; Recurrence; Signal Transduction; Steroids; Thrombosis; Time Factors; Transfection

Traditional fermented cheese whey (TFCW), containing probiotics, has been used both as a dairy food with ethnic flavor and a medicine for cardiovascular disease, especially regulating blood lipid among Kazakh. We therefore investigated anti-atherosclerotic effects of TFCW in atherosclerotic rabbits and identified lactic acid bacteria (LAB) and yeasts in TFCW.. Atherosclerotic rabbits were induced by administration of atherosclerotic diet for 12 weeks and divided randomly into three groups and treated for 4 weeks with Simvastatin (20 mg/kg) or TFCW (25 mg/kg) and (50 mg/kg). In addition, a normal control group and an atherosclerotic group were used for comparison. All drugs were intragastrical administered once daily 10 mL/kg for 4 weeks. Body weight (BW), lipid profiles, C-reactive protein (CRP), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) were tested and theromatous plaques and the number of foam cells and infiltrating fibroblast cells in the thoracic aorta endothelium was evaluated by hematoxylin and eosin stainin. LAB and yeasts were isolated and purified by conventional techniques and identified using morphological and biochemical properties as well as gene sequences analysis.. After 4 weeks of treatment, high and low dose TFCW decreased serum TC, TG, LDLC, CRP, VCAM-1 and ICAM-1 (P < 0.05) compared to atherosclerotic group, and increased HDL-C (P < 0.05) compared to normal controls. Histological analysis showed TFCW reduced VCAM-1 expression and formation of atheromatous plaques on the aortic endothelium of atherosclerotic rabbits.. Seven classes of LBA from two different genera including Lactobacillus brevis, Lactobacillus kefianofaciens, Lactobacillus helveticus, Lactobacillus Casei, Lactobacillus plantarum, Lactobacillus kefiri and Lactococcus lactic as well as 2 classes of yeasts from two different genera including Saccharomyces unisporus and Issatchenkia orientalis were isolated and identified from TFCW. In summary, TFCW, containing 7 classes of LBA and 2 classes of yeasts, has significant anti-atherosclerotic potential in atherosclerotic rabbits and may modulate lipid metabolism and protect aorta in the atherosclerotic condition, which might be related to various probiotics acting through reducing the CRP, VCAM-1 and ICAM-1 levels and protecting the aortic endothelium.

Topics: Animals; Aorta; Atherosclerosis; Body Weight; C-Reactive Protein; Cardiovascular Agents; Cheese; Lipids; Male; Probiotics; Rabbits; Vascular Cell Adhesion Molecule-1; Whey

A study of the chemical constituents from the Australian Sponge

Topics: Animals; Atherosclerosis; Australia; Cardiovascular Agents; Cell Line, Tumor; Hep G2 Cells; Humans; Porifera; Sesquiterpenes; Xanthones

Topics: Angioplasty; Atherosclerosis; Cardiovascular Agents; Humans; Patient Selection; Renal Artery Obstruction; Risk Factors; Stents; Treatment Outcome

Blood vessel endothelial dysfunction induced by oxidized low-density lipoprotein (ox-LDL) has been implicated in the pathogenesis of atherosclerosis and vasculopathy. The ox-LDL-elicited reactive oxygen species (ROS) release has been assumed to serve a critical function in endothelial damage. Myricitrin (from Myrica cerifera) is a natural antioxidant that has strong anti-oxidative, anti-inflammatory, and anti-nociceptive activities. However, the protective effect of myricitrin on ROS-induced endothelial cell injury and its related molecular mechanisms have never been investigated. This study demonstrates that myricitrin can inhibit ox-LDL-induced endothelial apoptosis and prevent plaque formation at an early stage in an atherosclerotic mouse model. The administration of myricitrin in vivo decreases the thickness of the vascular wall in the aortic arch of ApoE-/- mice. In vitro study shows that ox-LDL-induced human umbilical vein endothelial cell apoptosis can be reduced upon receiving myricitrin pre-treatment. Treatment with myricitrin significantly attenuated ox-LDL-induced endothelial cell apoptosis by inhibiting LOX-1 expression and by increasing the activation of the STAT3 and PI3K/Akt/eNOS signaling pathways. At the same time, our result demonstrates that myricitrin treatment optimizes the balance of pro/anti-apoptosis proteins, including Bax, Bad, XIAP, cIAP-2, and survivin. Our study suggests that myricitrin treatment can effectively protect cells from ox-LDL-induced endothelial cell apoptosis, which results in reduced atherosclerotic plaque formation. This result indicates that myricitrin can be used as a drug candidate for the treatment of cardiovascular diseases.

Topics: Animals; Aortic Diseases; Apolipoproteins E; Apoptosis; Apoptosis Regulatory Proteins; Atherosclerosis; Biopsy; Cardiovascular Agents; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Flavonoids; Human Umbilical Vein Endothelial Cells; Humans; Lipoproteins, LDL; Male; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinase; Plaque, Atherosclerotic; Proto-Oncogene Proteins c-akt; Scavenger Receptors, Class E; Signal Transduction; STAT3 Transcription Factor; Time Factors; X-Ray Microtomography

Topics: Atherosclerosis; Cardiovascular Agents; Cholesterol, LDL; Consensus Development Conferences as Topic; Europe; Humans; Hypolipidemic Agents; Life Style; Lipoprotein(a); Molecular Targeted Therapy; Oligonucleotides, Antisense; Practice Guidelines as Topic; Precision Medicine; Proprotein Convertase 9; Proprotein Convertases; Radionuclide Imaging; Risk Factors; Scotland; Sedentary Behavior; Serine Endopeptidases; Smoking; Societies, Medical

Explore the relation between body mass index (BMI) and cardiovascular disease, and the influence of optimal medical therapy (OMT) on this relationship.. Patients from the REACH cohort, an international, prospective cohort of patients with or at high risk of atherosclerosis with documentation of potential confounders, including treatments and risk factors, were followed up to 4 years (n = 54 285). Patients were categorized according to baseline BMI (ranging from underweight to Grade III obesity). Optimal medical therapy was defined as the use of the four cardioprotective medication classes (statins, ACE inhibitors/angiotensin II receptor blockers, β-blockers, and antiplatelet agents). The main outcomes were all-cause mortality, cardiovascular (CV) mortality, and CV events. In primary and secondary prevention, a reverse J-shaped curve best described the relationship between BMI categories and the incidence of the various outcomes. In secondary prevention, the highest adjusted risks were observed for underweight patients (1.97, P < 0.01, and 1.29, P = 0.03, for CV mortality and CV events) and the lowest HRs were observed, respectively, in Grade II and Grade III obese patients (0.73, P < 0.01 and 0.80, P < 0.01). The proportion of patients on OMT increased with BMI from 10.1 to 36% (P < 0.001). The apparent CV protection conferred by obesity persisted in patients receiving OMT.. An obesity paradox was observed in both primary and secondary CV prevention patients. The intensity of use of evidence-based preventive medications does not account for the paradoxical CV protection associated with obesity. At extremes of BMI, further interventions beyond OMT may be needed to reduce CV risk.

Topics: Age Distribution; Aged; Atherosclerosis; Body Mass Index; Cardiovascular Agents; Cardiovascular Diseases; Evidence-Based Medicine; Female; Global Health; Humans; Male; Middle Aged; Obesity, Metabolically Benign; Prospective Studies; Risk Factors; Thrombosis; Treatment Outcome

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Humans; Renal Artery Obstruction; Vascular Surgical Procedures

The aim of the study was to evaluate the effect of the nutritional supplements Pycnogenol and TECA (total triterpenic fraction of Centella Asiatica) on atherosclerosis progression in low-risk asymptomatic subjects with carotid or femoral non-stenosing plaques.. This was an observational pilot substudy of the San Valentino epidemiological cardiovascular study. The study included 1363 subjects aged 45-60 without any conventional risk factors who had non stenosing atherosclerotic plaques (<50%) in at least one carotid or common femoral bifurcation, allocated into 6 groups: Group 1 (CONTROLS): management was based on education, exercise, diet and lifestyle changes. This same management plan was used in all groups; Group 2 Pycnogenol 50 mg/day; Group 3 Pycnogenol 100 mg/day; Group 4 Aspirin 100 mg/day or Ticlopidine 250 mg/day if intolerant to aspirin; Group 5 Aspirin 100 mg/day and Pycnogenol 100 mg/day; Group 6 Pycnogenol 100 mg/day plus TECA (total triterpenic fraction of Centella Asiatica) 100 mg/day. There was a six monthly follow-up up to 30 months. Plaque progression was assessed using the ultrasonic arterial score based on the arterial wall morphology and the number of plaques that progressed from the non-stenotic to the stenotic group. A secondary endpoint was to evaluate the changes in oxidative stress at baseline and at 30 months.. The ultrasonic score increased significantly in groups 1, 2 and 4 but not in groups 3, 5 and 6 suggesting a beneficial effect of Pycnogenol 100 mg. The percentage of plaques that progressed from class IV to class V was 8.4% in group 2, 5.3% in group 3, 4% in group 5 and 1.1% in group 6 (P<0.0001) compared with 16.6% in group 4 (aspirin) and 21.3% in the control group suggesting a beneficial effect of Pycnogenol. The lowest rate of progression was in group 6 (Pycnogenol plus TECA). At 30 months, the oxidative stress in all the Pycnogenol groups was less than in the control group. The oxidative stress was lower in the Pycnogenol 100 mg group than the Pycnogenol 50 mg group (P<0.0001). In the combined group of Pycnogenol and TECA the oxidative stress was less than the Pycnogenol alone (P<0.001).. Pycnogenol and the combination of Pycnogenol+TECA appear to reduce the progression of subclinical arterial lesions in low-risk asymptomatic subjects. The reduction in plaque progression was associated with a reduction in oxidative stress. The results justify a large randomized controlled study to demonstrate the efficacy of the combined Pycnogenol and TECA prophylactic therapy in subclinical atherosclerosis.

Topics: Asymptomatic Diseases; Atherosclerosis; Cardiovascular Agents; Carotid Artery Diseases; Carotid Intima-Media Thickness; Centella; Dietary Supplements; Disease Progression; Drug Therapy, Combination; Female; Femoral Artery; Flavonoids; Humans; Italy; Male; Middle Aged; Oxidative Stress; Phytotherapy; Pilot Projects; Plant Extracts; Plants, Medicinal; Plaque, Atherosclerotic; Platelet Aggregation Inhibitors; Time Factors; Treatment Outcome; Triterpenes

Atherosclerosis is a chronic inflammatory disease, which is associated with increased expression of adhesion molecules and monocyte recruitment into the arterial wall. This study evaluated whether hexane extracts from the edible part (DB-H1) or bark region (DB-H2) of Dioscorea. batatas Decne have anti-atherosclerotic properties in vivo and in vitro experiments. We also identified bioactive components in the hexane extracts. Thirty-six apolipoprotein E (ApoE(-/-) ) mice and 12 control (C57BL/6J) mice were given a Western-type diet for 11 or 21 wk. To examine the effects of yam extracts on lesion development, ApoE(-/-) mice were orally administered DB-H1 or DB-H2 for the duration of the study (200 mg/kg b.w./day, 3 times per wk). Both DB-H1 and DB-H2 significantly reduced the total atherosclerotic lesion area in the aortic root. In addition, plasma concentrations of total cholesterol, oxidized-low-density lipoprotein, and c-reactive protein were decreased by administration of DB-H1 and DB-H2. Consistent with the in vivo observations, DB-H1 and DB-H2 inhibited tumor necrosis factor (TNF)-α-induced vascular cell adhesion molecule-1 expression and adhesion of THP-1 monocytes to TNF-α-activated vascular smooth muscle cells. It was also found that treatment with DB-H1 or DB-H2 resulted in the inhibition nitric oxide (NO) and reactive oxygen species production and iNOS expression in macrophages. Thus, DB-H1 and DB-H2 seem to influence atherosclerosis by affecting the production of inflammatory mediators in vivo. Our results suggest that yam extracts have the potential to be used in the prevention of atherosclerosis.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; C-Reactive Protein; Cardiovascular Agents; Dioscorea; In Vitro Techniques; Inflammation Mediators; Linoleic Acids; Lipoproteins, LDL; Macrophages; Male; Mice; Mice, Inbred C57BL; Monocytes; Muscle, Smooth, Vascular; Phytotherapy; Plant Extracts; Reactive Oxygen Species; Sitosterols; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Topics: Angina Pectoris; Atherosclerosis; Blood Specimen Collection; Cardiovascular Agents; Coronary Angiography; Edetic Acid; Humans; Mean Platelet Volume; Metabolic Syndrome; Thromboxane A2

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in developed and developing countries. Despite decades of effort, unhealthy lifestyle habits and ASCVD risk factor levels remain high and are increasing in many population groups. A new approach to ASCVD prevention is needed. Multiple lines of evidence from animal and human studies suggest that atherosclerosis regression and normalization of vessel function can occur when low-density lipoprotein cholesterol (LDL-C) lowering occurs early in the course of atherosclerosis or when very aggressive LDL-C lowering occurs somewhat later. We propose a new paradigm focused on curing atherosclerosis early in the course of the disease. An approach that resets the vascular aging clock composed of initial regression therapy followed by periodic retreatment to suppress atherosclerosis development may be possible, with the ultimate goal of preventing subsequent ASCVD events. Proof-of-concept studies are needed to determine: 1) the optimal age and/or extent of atherosclerosis for intervention and LDL-C-lowering therapy; 2) the intensity and duration of therapy for inducing atherosclerosis regression; and 3) documenting the normalization of vascular function. Ultimately, this new paradigm will need to be evaluated in ASCVD outcomes trials.

Topics: Atherosclerosis; Cardiovascular Agents; Decision Making; Humans; Primary Prevention

We aimed to identify factors easily collected at admission in patients with transient ischemic attack (TIA) that were associated with early recurrence, so as to guide clinicians' decision-making about hospitalization in routine practice. From September 2011 to January 2013, all TIA patients who were referred to the University Hospital of Dijon, France, were identified. Vascular risk factors and clinical information were collected. The etiology of the TIA was defined according to the results of complementary examinations performed at admission as follows: large artery atherosclerosis (LAA-TIA) TIA, TIA due to atrial fibrillation (AF-TIA), other causes, and undetermined TIA. Logistic regression analyses were performed to identify factors associated with any recurrence at 48 hours (stroke or TIA). Among the 312 TIA patients, the etiology was LAA-TIA in 33 patients (10.6%), AF-TIA in 57 (18.3%), other causes in 23 (7.3%), and undetermined in 199 (63.8%). Early recurrence rates were 12.1% in patients with LAA-TIA, 5.3% in patients with AF-TIA, 4.3% in patients with another cause of TIA, and 1.0% in patients with undetermined TIA. In multivariable analysis, the LAA etiology was independently associated with early recurrence (odds ratio [OR]: 12.03; 95% confidence interval [CI]: 1.84-78.48, p=0.009). A non-significant trend was also observed for AF-TIA (OR: 3.82; 95% CI: 0.40-36.62, p=0.25) and other causes (OR: 3.73; 95% CI: 0.30-46.26, p=0.31). A simple initial assessment of TIA patients in the emergency room would be helpful in targeting those with a high risk of early recurrence and who therefore need to be hospitalized.

Topics: Aged; Aged, 80 and over; Atherosclerosis; Atrial Fibrillation; Cardiovascular Agents; Coronary Disease; Diabetes Mellitus; Diagnostic Imaging; Emergencies; Female; France; Humans; Hypercholesterolemia; Hypertension; Ischemic Attack, Transient; Length of Stay; Male; Middle Aged; Patient Admission; Recurrence; Risk Factors; Smoking

Topics: Acute Disease; Age Factors; Aneurysm, False; Aorta, Abdominal; Aorta, Thoracic; Aortic Diseases; Aortic Dissection; Aortic Valve; Atherosclerosis; Bicuspid Aortic Valve Disease; Cardiovascular Agents; Clinical Laboratory Techniques; Diagnostic Imaging; Early Diagnosis; Endovascular Procedures; Female; Genetic Diseases, Inborn; Heart Defects, Congenital; Heart Valve Diseases; Hematoma; Humans; Long-Term Care; Male; Neoplasms, Vascular Tissue; Physical Examination; Risk Factors; Vascular Calcification; Vascular Stiffness; Vascular Surgical Procedures

Topics: Atherosclerosis; Cardiovascular Agents; Decision Making; Humans; Primary Prevention

Topics: Atherosclerosis; Cardiovascular Agents; Decision Making; Humans; Primary Prevention

Topics: Atherosclerosis; Cardiovascular Agents; Decision Making; Humans; Primary Prevention

Clinical studies show that metformin attenuates all‐cause mortality and myocardial infarction compared with other medications for type 2 diabetes, even at similar glycemic levels. However, there is paucity of data in the euglycemic state on the vasculoprotective effects of metformin. The objectives of this study are to evaluate the effects of metformin on ameliorating atherosclerosis.. Using ApoE−/− C57BL/6J mice, we found that metformin attenuates atherosclerosis and vascular senescence in mice fed a high‐fat diet and prevents the upregulation of angiotensin II type 1 receptor by a high‐fat diet in the aortas of mice. Thus, considering the known deleterious effects of angiotensin II mediated by angiotensin II type 1 receptor, the vascular benefits of metformin may be mediated, at least in part, by angiotensin II type 1 receptor downregulation. Moreover, we found that metformin can cause weight loss without hypoglycemia. We also found that metformin increases the antioxidant superoxide dismutase‐1.. Pleiotropic effects of metformin ameliorate atherosclerosis and vascular senescence.

Topics: Animals; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Blood Glucose; Cardiovascular Agents; Cellular Senescence; Disease Models, Animal; Hypoglycemic Agents; Male; Metformin; Mice, Inbred C57BL; Mice, Knockout; Receptor, Angiotensin, Type 1; Superoxide Dismutase; Superoxide Dismutase-1; Weight Loss

To evaluate the effect of the novel angiotensin receptor blocker Fimasartan on the development of atherosclerosis and plaque stabilization in an animal model.. Twenty-four rabbits received an aortic balloon injury from 30 cm to a level just above the aortic valve to the iliac bifurcation using 3 Fr Fogarty catheters on third day of the experiment, followed by a 1% cholesterol diet for 8 weeks. The rabbits were randomized to receive placebo or 3 or 6 mg · kg⁻¹ · d⁻¹ Fimasartan. The study was double blinded. The rabbits started receiving their medications 2 days before the aortic balloon injury and treatment continued. Atherosclerosis burden was determined by calculating the intima-media ratio of the infrarenal portion of the aorta because the bulk of the atherosclerotic burden was limited to the infrarenal region. The frequency of plaque disruption with thrombosis and the proportions of the plaques that were occupied by macrophages, smooth muscle cells, and collagen were determined.. Relative to the placebo group, the Fimasartan-treated rabbits had less atherosclerosis [intima-media ratio (mean ± SEM) of 1.14 ± 0.21 vs. 1.51 ± 0.26, P = 0.005], fewer disrupted plaques with thrombi (3 of 16 vs. 5 of 8, P = 0.047), lower proportion of macrophages (17.5% ± 2.5% vs. 26% ± 3.5%, P = 0.03), higher proportion of smooth muscle cells (43.5% ± 8.3% vs. 11.9% ± 2.1%, P = 0.001), and higher proportion of collagen (34.3% ± 6.4% vs. 19.7% ± 2.1%, P = 0.02).. These results show that the newly developed angiotensin receptor blocker, Fimasartan, attenuated atherosclerosis progression and reduced macrophage accumulation in the rabbit aortic plaques.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Aorta, Abdominal; Atherosclerosis; Biphenyl Compounds; Cardiovascular Agents; Collagen; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Macrophages; Myocytes, Smooth Muscle; Plaque, Atherosclerotic; Pyrimidines; Rabbits; Random Allocation; Tetrazoles; Tunica Intima; Tunica Media

Sphingosine 1-phosphate (S1P) partly accounts for antiatherogenic properties of high-density lipoproteins. We previously demonstrated that FTY720, a synthetic S1P analog targeting all S1P receptors but S1P receptor type 2, inhibits murine atherosclerosis. Here, we addressed the identity of S1P receptor mediating atheroprotective effects of S1P.. Low-density lipoprotein receptor-deficient mice on cholesterol-rich diet were given selective S1P receptor type 1 agonist KRP-203 (3.0 mg/kg per day; 6 and 16 weeks). KRP-203 substantially reduced atherosclerotic lesion formation without affecting plasma lipid concentrations. However, KRP-203 induced lymphopenia, reduced total (CD4(+), CD8(+)) and activated (CD69(+)/CD8(+), CD69(+)/CD4(+)) T cells in peripheral lymphoid organs, and interfered with lymphocyte function, as evidenced by decreased T-cell proliferation and interleukin-2 and interferon-γ production in activated splenocytes. Cyto- and chemokine (tumor necrosis factor-α, regulated and normal T cell expressed and secreted) levels in plasma and aortas were reduced by KRP-203 administration. Moreover, macrophages from KRP-203-treated mice showed reduced expression of activation marker MCH-II and poly(I:C)-elicited production of tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6. In vitro studies demonstrated that KRP-203 reduced tumor necrosis factor-α, interleukin-6, and interferon-γ-induced protein-10 production; IκB and signal transducer and activator of transcription-1 phosphorylation; and nuclear factor κB and signal transducer and activator of transcription-1 activation in poly(I:C)-, lipopolysaccharide-, or interferon-γ-stimulated bone marrow macrophages, respectively.. Present results demonstrate that activation of S1P signaling pathways inhibit atherosclerosis by modulating lymphocyte and macrophage function and suggest that S1P receptor type 1 at least partially mediates antiatherogenic effects of S1P.

Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; Biomarkers; Cardiovascular Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dendritic Cells; Disease Models, Animal; Endothelial Cells; Humans; Inflammation; Inflammation Mediators; Lipids; Lymphocyte Activation; Lymphopenia; Macrophage Activation; Macrophages; Mice; Mice, Knockout; Receptors, LDL; Receptors, Lysosphingolipid; Signal Transduction; Sulfhydryl Compounds; U937 Cells

We report an unusual case of a patient whose whole cerebral circulation was supported by poor vicariate collaterals and a severely atherosclerotic right vertebral artery, with no brain perfusion abnormalities. Our belief is that despite the brain imaging and the absence of symptoms, because of his critical vascular disease and the paucity of data from large randomised clinical trials on vertebra-basilar revascularisation, the case required an extremely cautious approach regarding any kind of revascularisation. An accurate imaging analysis together with clinical features allowed us to decide on a strategy based on optimal medical therapy and careful clinical monitoring.

Topics: Atherosclerosis; Cardiovascular Agents; Carotid Stenosis; Cerebrovascular Circulation; Collateral Circulation; Drug Therapy, Combination; Humans; Magnetic Resonance Angiography; Male; Middle Aged; Perfusion Imaging; Predictive Value of Tests; Subclavian Steal Syndrome; Treatment Outcome; Vertebrobasilar Insufficiency

Oxidized lipoproteins stimulate autophagy in advanced atherosclerotic plaques. However, the mechanisms underlying autophagy induction and the role of autophagy in atherogenesis remain to be determined. This study was designed to investigate the mechanisms by which 7-ketocholesterol (7-KC), a major component of oxidized lipoproteins, induces autophagy. This study was also designed to determine the effect of autophagy induction on apoptosis, a central event in the development of atherosclerosis. Exposure of human aortic smooth muscle cells to 7-KC increased autophagic flux. Autophagy induction was suppressed by treating the cells with either a reactive oxygen species scavenger or an antioxidant. Administration of 7-KC concomitantly up-regulated Nox4 expression, increased intracellular hydrogen peroxide levels, and inhibited autophagy-related gene 4B activity. Catalase overexpression to remove hydrogen peroxide or Nox4 knockdown with siRNA reduced intracellular hydrogen peroxide levels, restored autophagy-related gene 4B activity, and consequently attenuated 7-KC-induced autophagy. Moreover, inhibition of autophagy aggravated both endoplasmic reticulum (ER) stress and cell death in response to 7-KC. In contrast, up-regulation of autophagic activity by rapamycin had opposite effects. Finally, activation of autophagy by chronic rapamycin treatment attenuated ER stress, apoptosis, and atherosclerosis in apolipoprotein E knockout (ApoE(-/-)) mouse aortas. In conclusion, we demonstrate that up-regulation of autophagy is a cellular protective response that attenuates 7-KC-induced cell death in human aortic smooth muscle cells.

Topics: Animals; Aorta; Apoptosis; Atherosclerosis; Autophagy; Autophagy-Related Proteins; Cardiovascular Agents; Cell Death; Cells, Cultured; Cysteine Endopeptidases; Enzyme Inhibitors; Free Radical Scavengers; Humans; Hydrogen Peroxide; Ketocholesterols; Male; Mice; Microtubule-Associated Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NADPH Oxidase 4; NADPH Oxidases; Reactive Oxygen Species; Sirolimus; Up-Regulation

We have successfully synthesized (-)-epigallocatechin-3-gallate (EGCG) encapsulated nanostructured lipid carriers (NLCE) and chitosan-coated NLCE (CSNLCE) using natural lipids, surfactant, chitosan, and EGCG. Nanoencapsulation dramatically improved EGCG stability. CSNLCE significantly increased EGCG content in THP-1-derived macrophages compared with nonencapsulated EGCG. As compared to 10 μM nonencapsulated EGCG, both NLCE and CSNLCE at the same concentration significantly decreased macrophage cholesteryl ester content. NLCE and CSNLCE significantly decreased mRNA levels and protein secretion of monocyte chemoattractant protein-1 (MCP-1) levels in macrophages, respectively. These data suggest that nanoencapsulated EGCG may have a potential to inhibit atherosclerotic lesion development through decreasing macrophage cholesterol content and MCP-1 expression.

Topics: Atherosclerosis; Camellia sinensis; Cardiovascular Agents; Catechin; Cell Line; Chemokine CCL2; Cholesterol; Drug Compounding; Drug Stability; Humans; Macrophages; Nanoparticles; Plant Extracts

Topics: Acute Coronary Syndrome; Aged, 80 and over; Aortic Diseases; Atherosclerosis; Calcinosis; Cardiovascular Agents; Colitis, Ischemic; Dietary Supplements; Humans; Hyperparathyroidism, Secondary; Hypertension; Hypotension; Kidney Failure, Chronic; Male; Myocardial Ischemia; Nephrosclerosis; Obesity; Parenteral Nutrition; Pneumatosis Cystoides Intestinalis; Renal Dialysis; Splanchnic Circulation

To evaluate differences in strut coverage, inflammation and endothelialization between two second-generation polymer-based drug-eluting stents (DES) in an atherosclerotic rabbit double-injury iliac artery model at 28 days follow-up.. Rabbits with induced atheroma received bilateral iliac artery stents: everolimus-eluting stent (Xience V EES; Abbott Vascular), zotarolimus-eluting stent (Resolute ZES; Medtronic CardioVascular), or bare-metal stent (BMS; MultiLink Vision; Abbott Vascular). After 28 days, total neointimal coverage examined by scanning electron microscopy was >98% for all three stent types. Neointimal thickness above stent struts was decreased by 50% in Xience V EES (0.06 ± 0.01 mm; P = 0.00001) compared with BMS (0.15 ± 0.03 mm) and Resolute ZES (0.12 ± 0.04 mm). Luminal area was largest for Xience V EES (3.79 ± 0.33 mm(2) ; P = 0.0003 for Xience V EES vs. BMS), followed by Resolute ZES (3.46 ± 0.45 mm(2) ; P = 0.083 for Resolute ZES vs. BMS) and BMS (3.07 ± 0.53 mm(2) ). Percentage area stenosis was smallest for Xience V EES (17.23 ± 3.64%; P = 0.00001), while BMS (30.25 ± 7.48%) and Resolute ZES (30.79 ± 7.15%) did not differ. Endothelial monolayer regrowth was significantly lower in Resolute ZES (65 ± 13%) versus BMS (79 ± 11%; P = 0.004). There was no difference between Xience V EES (74 ± 10%) and BMS. Xience V EES was further associated with a lower number of inflammatory cells surrounding the stent struts (7 ± 2 per strut) in comparison to Resolute ZES (15 ± 6; P = 0.0001) and BMS (17 ± 9; P = 0.0005).. In this atherosclerotic rabbit model, Xience V EES suppressed neointimal thickening better, with normal endothelial regrowth as compared with BMS, and less strut-induced inflammation.

Topics: Angioplasty, Balloon; Animals; Atherosclerosis; Cardiovascular Agents; Cell Proliferation; Disease Models, Animal; Drug-Eluting Stents; Endothelial Cells; Everolimus; Iliac Artery; Inflammation; Male; Neointima; Prosthesis Design; Rabbits; Radiography; Sirolimus; Time Factors; Vascular System Injuries

Nanoparticle processing is implicated in enhancing bioactive or nutritional compound release from raw foods. The aim of the present study was to evaluate whether different particle processing might affect the lipid-lowering activity of Dioscorea pseudojaponica (DP) and to investigate whether DP could be a potential functional food for prevention of atherogenesis. Its possible molecular mechanisms were also evaluated.. The results indicated that 50 mesh-size DP (50 mesh DP) particles exhibited stronger effects than nanoscale DP (nano DP) particles in terms of lowering the level of serum cholesterol as well as reducing the extent of fatty liver and aortic fatty streak. Moreover, both DP particle types, particularly 50 mesh DP, significantly activated AMPK (5'-adenosine monophosphate-activated protein kinase) and deactivated ACC (acetyl-CoA carboxylase), as demonstrated by the increased levels of both enzymes in their phosphorylated form. Coincidently, high-performance liquid chromatography (HPLC) analysis showed a higher content (P < 0.01) of dioscin, a known lipid-lowering compound, in 50 mesh DP than in nano DP.. These results suggest that improper processing conditions will lead to the decomposition of bioactive components in yam. They also demonstrate for the first time that the lipid-lowering mechanisms of DP may occur through the AMPK-ACC pathway.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Anticholesteremic Agents; Aorta; Atherosclerosis; Cardiovascular Agents; Cholesterol, Dietary; Diet; Dioscorea; Diosgenin; Disease Models, Animal; Fatty Liver; Food Handling; Functional Food; Hypercholesterolemia; Liver; Male; Nanoparticles; Particle Size; Plant Preparations; Plant Tubers; Rabbits

Although Virtual Histology intravascular ultrasound (VH-IVUS) is increasingly used in clinical research, the reproducibility of plaque composition remains unexplored in significant coronary artery and stented lesions. The purpose of this study was to assess the reproducibility of necrotic core and calcium content in atherosclerotic coronary lesions that were treated with a bioresorbable everolimus-eluting vascular scaffold (BVS) using a new measurement method (Shin's method) by VH-IVUS. Eight patients treated with a BVS (Abbott Vascular, Santa Clara, CA, USA) were analyzed with serial VH-IVUS assessments, i.e., pre- and post-stenting, and at 6 months and 2 years follow-up. A total of 32 coronary segments were imaged to evaluate the reproducibility of volumetric VH-IVUS measurements. In Shin's method, contours are drawn around the IVUS catheter (instead of the lumen) and vessel. Overall, in the imaged coronary segment, for necrotic core and dense calcium volumes, the relative intra-observer differences were 0.30 ± 0.22, 0.19 ± 0.16% for observer 1 and 0.45 ± 0.41, 0.36 ± 0.47% for observer 2, respectively. The inter-observer relative differences of necrotic core and dense calcium volumes were 0.51 ± 0.79 and 0.56 ± 1.01%, respectively. The present study demonstrates a good reproducibility for both, intra-observer and inter-observer measurements using Shin's method. This method is suitable for the measurement of necrotic core and dense calcium using VH-IVUS in longitudinal studies, especially studies on bioresorbable scaffolds, because the degradation process will be fully captured independently of the location of the struts and their greyscale appearance.

Topics: Absorbable Implants; Angioplasty, Balloon, Coronary; Atherosclerosis; Cardiovascular Agents; Cohort Studies; Coronary Artery Disease; Coronary Vessels; Drug-Eluting Stents; Everolimus; Female; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Necrosis; Observer Variation; Prosthesis Design; Reproducibility of Results; Sirolimus; Treatment Outcome; Ultrasonography, Interventional; Vascular Calcification

Recent studies indicate that regulatory T cells (Tregs) attenuate murine atherosclerosis. Since interleukin (IL)-2 induces Tregs proliferation, we tested the impact of L19-IL2, a fusion antibody specific to extra-domain B of fibronectin (ED-B) containing an active human IL-2 molecule, in experimental atherosclerosis.. L19-IL2 or appropriate controls were given intravenously to 6 month old Western diet-fed apoE(-/-) mice on day 1, 3, and 5. Human IL-2 was detected on day 7 within atherosclerotic plaques of L19-IL2-treated mice, and magnetic resonance imaging of the plaques showed a significant adventitial gadolinium enhancement on day 7 and 13, suggesting microvascular leakage as a result of the pharmacodynamic activity of L19-IL2. Treatment with L19-IL2 significantly reduced the size of pre-established atherosclerotic plaques at the thoracic aorta (Sudan III stained area) and in the aortic root area (microscopic, morphometric analysis) on day 7 as compared to controls (L19, D1.3-IL2, NaCl) as well as compared to baseline (day 0). Tregs markers Foxp3 and CTLA4 were highly increased in plaques after L19-IL2 treatment compared to controls (p<0.01), whereas the macrophage marker Mac3 was significantly reduced (p<0.03). Co-treatment with IL-2-receptor blocking antibody PC61 abrogated L19-IL2-induced plaque reduction compared with IgG control (p<0.03).. L19-IL2 delivers functional IL-2 to pre-established atherosclerotic plaques of WD-fed apoE(-/-) mice resulting in significant plaque size reduction mediated by local Tregs.

Topics: Animals; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Cardiovascular Agents; Cell Proliferation; Diet, High-Fat; Disease Models, Animal; Humans; Injections, Intravenous; Lipids; Macrophages; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Knockout; Recombinant Fusion Proteins; T-Lymphocytes, Regulatory; Time Factors

To evaluate the effect of a polymer-free Biolimus A9-eluting stent [BioFreedom (BF)], compared with that of a biodegradable polymer-based Biolimus A9-eluting stent [BioMatrix Flex (BMF)] and a bare metal stent (BMS) in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries.. Rabbits were fed with 1% cholesterol diet (n = 14) for 14 days, both iliac arteries were balloon denuded and radiated, and then rabbits were switched to 0.15% cholesterol diet. After 4 weeks, BF (n = 8), BMF (n = 8), and BMS (n = 8) were deployed in denuded and radiated areas. Four weeks later animals were euthanized, arterial segments were processed for morphometry.. The neointimal area in vessels implanted with BF stents was significantly less than that seen in vessels implanted with BMS (0.90 mm(2) ± 0.14 vs. 1.29 mm(2) ± 0.23, P <0.01). Percent fibrin and fibrin score were higher with BMF stents compared to BMS (P <0.03 and <0.04) and giant cell number was significantly higher with both BMF and BF stents (P < 0.01 for both). Percent endothelialization was significantly higher and % uncovered struts were lower with BMS compared to either BMF or BF stents (P < 0.05 for both).. This study demonstrates that compared to BMS, BF stents significantly decreased neointimal hyperplasia.

Topics: Absorbable Implants; Angioplasty, Balloon; Animals; Atherosclerosis; Cardiovascular Agents; Constriction, Pathologic; Disease Models, Animal; Drug-Eluting Stents; Fibrin; Hypercholesterolemia; Hyperplasia; Iliac Artery; Inflammation; Male; Metals; Neointima; Plaque, Atherosclerotic; Polymers; Prosthesis Design; Rabbits; Sirolimus; Stents; Time Factors

Topics: Atherosclerosis; Autoantibodies; Biomarkers; Cardiovascular Agents; Clinical Trials as Topic; Humans; Inflammation; Myocardial Infarction

The expression of bone morphogenetic proteins (BMPs) is enhanced in human atherosclerotic and calcific vascular lesions. Although genetic gain- and loss-of-function experiments in mice have supported a causal role of BMP signaling in atherosclerosis and vascular calcification, it remains uncertain whether BMP signaling might be targeted pharmacologically to ameliorate both of these processes.. We tested the impact of pharmacological BMP inhibition on atherosclerosis and calcification in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice fed a high-fat diet developed abundant vascular calcification within 20 weeks. Prolonged treatment of LDLR-/- mice with the small molecule BMP inhibitor LDN-193189 was well-tolerated and potently inhibited development of atheroma, as well as associated vascular inflammation, osteogenic activity, and calcification. Administration of recombinant BMP antagonist ALK3-Fc replicated the antiatherosclerotic and anti-inflammatory effects of LDN-193189. Treatment of human aortic endothelial cells with LDN-193189 or ALK3-Fc abrogated the production of reactive oxygen species induced by oxidized LDL, a known early event in atherogenesis. Unexpectedly, treatment of mice with LDN-193189 lowered LDL serum cholesterol by 35% and markedly decreased hepatosteatosis without inhibiting HMG-CoA reductase activity. Treatment with BMP2 increased, whereas LDN-193189 or ALK3-Fc inhibited apolipoprotein B100 secretion in HepG2 cells, suggesting that BMP signaling contributes to the regulation of cholesterol biosynthesis.. These results definitively implicate BMP signaling in atherosclerosis and calcification, while uncovering a previously unidentified role for BMP signaling in LDL cholesterol metabolism. BMP inhibition may be helpful in the treatment of atherosclerosis and associated vascular calcification.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Atherosclerosis; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Proteins; Cardiovascular Agents; Cholesterol, LDL; Diet, High-Fat; Disease Models, Animal; Endothelial Cells; Fatty Liver; Female; Hep G2 Cells; Humans; Lipoproteins, LDL; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Pyrazoles; Pyrimidines; Reactive Oxygen Species; Receptors, LDL; Recombinant Fusion Proteins; Signal Transduction; Time Factors; Vascular Calcification

This study evaluated the effect of prostaglandin E1 (PGE1) on the stability of atherosclerotic plaque. A vulnerable plaque model was established in rabbits, using balloon injury combined with a high-cholesterol diet. The rabbits were distributed into a control group, a low-dose PGE1 treatment group, a moderate-dose PGE1 treatment group, a high-dose PGE1 treatment group, and a simvastatin treatment group, with treatments lasting for 4 weeks. At week 13 (at the end of the experiments), atherosclerotic plaque was triggered by injection of Russell's viper venom (Chinese) and histamine. Serological, pathological, immunohistochemical, and gene-expression studies were subsequently performed. PGE1 treatment did not alter serum lipid levels; however, PGE1 dose-dependently increased the thickness of the fibrous caps, and decreased the plaque vulnerability index. The plaque contents of macrophage- and the mRNA levels of monocyte-chemotactic protein-1, matrix metalloproteinase-1, and matrix metalloproteinase-9 were markedly reduced in all of the PGE1 treatment groups, with the high-dose of PGE1 being more effective than the simvastatin treatment. These findings suggest that PGE1 dose-dependently enhances the stability of atherosclerotic plaque. The high-dose of PGE1 presented more protection in terms of inhibiting macrophage accumulation and inflammatory expression in plaque. Our findings suggest a novel drug for the treatment of atherosclerosis.

Topics: Alprostadil; Angioplasty, Balloon; Animals; Anti-Inflammatory Agents; Aorta, Abdominal; Aortic Diseases; Atherosclerosis; Cardiovascular Agents; Chemokine CCL2; Cholesterol, Dietary; Cytokines; Daboia; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Down-Regulation; Fibrosis; Histamine; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation Mediators; Lipid Metabolism; Macrophages; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 9; Plaque, Atherosclerotic; Rabbits; RNA, Messenger; Simvastatin; Viper Venoms

To present the 5-year angiographic and clinical results of a retrospective registry assessing the performance of sirolimus-eluting stents (SES) in the treatment of infrapopliteal atherosclerotic disease.. From 2004 to 2009, 158 patients (95 men; mean age 71.9 years) with chronic lower limb ischemia (Rutherford categories 3-6) underwent primary SES placement in focal infrapopliteal lesions. The angiographic endpoint was patency, defined as freedom from in-stent stenosis (ISS) >50%. Clinical endpoints were death, amputation, and bypass surgery. Results were correlated with patient and lesion characteristics and cumulative outcomes were assessed with Kaplan-Meier analysis.. Technical success was achieved in all cases. The primary patency rates were 97.0% after 6 months, 87.0% after 12 months, and 83.8% at 60 months. In-stent stenosis was predominantly observed in the first year after stent placement. Female gender was associated with a higher rate of ISS. During clinical follow-up of 144 (91%) patients over a mean 31.1±20.3 months, there were 27 (18.8%) deaths, 4 (2.8%) amputations, and no bypass surgery. Clinical status improved in 92% of the patients with critical limb ischemia (CLI) and 77% of the patients suffering from claudication (p=0.022).. Treatment of focal infrapopliteal lesions with SES showed encouraging long-term angiographic results in this registry. Clinical improvement was evident, but more pronounced in CLI patients than in patients suffering from claudication. Further studies are needed to evaluate the potential clinical benefit of SES as compared to balloon angioplasty or bare metal stents in the treatment of infrapopliteal lesions.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Angioplasty, Balloon; Atherosclerosis; Cardiovascular Agents; Chi-Square Distribution; Chronic Disease; Constriction, Pathologic; Drug-Eluting Stents; Female; Germany; Humans; Ischemia; Kaplan-Meier Estimate; Lower Extremity; Male; Middle Aged; Popliteal Artery; Proportional Hazards Models; Prosthesis Design; Radiography; Registries; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Time Factors; Treatment Outcome; Vascular Patency; Vascular Surgical Procedures

Topics: Angioplasty, Balloon; Atherosclerosis; Cardiovascular Agents; Drug-Eluting Stents; Female; Humans; Ischemia; Lower Extremity; Male; Popliteal Artery; Sirolimus

Dao-Tan decoction (DTD) is a Chinese herb prescription used to treat atherosclerosis or dizziness for centuries. Previous study shows that DTD could inhibit intercellular adhesion molecule-1 (ICAM-1) expression induced by tumor necrosis factor-α (TNF-α). However, its mechanism has never been clearly described.. To examine the hypothesis that DTD might inhibit TNF-α-induced ICAM-1 expression through regulating the mitogen-activated protein kinase (MAPK) pathways, involving Jun N-terminal kinase (JNK) and p38.. The rats were orally administrated with DTD for 3 days (2.3 g/kg per day), then the serum was collected. Human umbilical vein endothelial cells (HUVECs) were cultured and stimulated by TNF-α with or without DTD serum. The expression of ICAM-1 mRNA was examined by reverse transcription-polymerase chain reaction and the expression of p38 and JNK was examined by Western blot analysis.. DTD serum significantly inhibits TNF-α-induced ICAM-1 expression by 17-41% on HUVECs. TNF-α-induced JNK and p38 activations, which were involved in ICAM-1 expression, were significantly inhibited with DTD serum treatment by 10-50% on HUVEC.. Based on the theory of traditional Chinese medicine (TCM), pathogenesis of atherosclerosis is caused by "blood" and "phlegm" attached on blood vessels. DTD has a function of "dissolving phlegm", thus it is chosen for the treatment of atherosclerosis. This study demonstrated that DTD could inhibit the expression of ICAM-1, by significantly preventing the activation of JNK and p38, which are important factors of atherosclerosis. Therefore, the present study indicates the pharmacological basis for treatment of atherosclerosis with DTD.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Cells, Cultured; Down-Regulation; Drugs, Chinese Herbal; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Signaling System; p38 Mitogen-Activated Protein Kinases; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Serum; Tumor Necrosis Factor-alpha

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Humans; Inflammation

Aim of the study was investigation of influence of diabetes mellitus (DM) on rate of detection of multifocal atherosclerosis (MFA) in patients with ischemic heart disease (IHD) at examination before coronary artery bypass grafting (CABG). We retrospectively analyzed 2411 hospital forms of patients with IHD subjected to CABG. DM was found in 317 patients (group 1). Control group (n=350) comprised patients of comparable sex and age without DM. Clinico-anamnestic data, parameters of coronary angiography, ultrasound and angiographic study of the aorta, brachiocephalic and peripheral arterial beds were compared between these groups. Patients with diabetes compared with patients of the control group more frequently had increased thickness of intima media complex (92 and 77%, respectively; p=0.0001). Simultaneous involvement of 2 or more arterial beds were detected in 46.1% of patients with DM and in 33.1% of control patients. Involvement of only one (coronary) arterial basin was more frequent in patients without DM (p=0.0001). Multifactorial analysis showed that independent effect on detection of MFA produced intima media thickness, presence of DM and history of acute disturbance of brain circulation. Thus among patients with IHD MFA before CABG was found in 46.1% of patients with DM and 33.1% of similar sex and age patients without DM. Patients with DM require focused examination for detection of manifestations of MFA and conduct of necessary curative and preventive interventions.

Topics: Aged; Angiography; Atherosclerosis; Cardiovascular Agents; Carotid Intima-Media Thickness; Coronary Artery Bypass; Coronary Artery Disease; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Preventive Medicine; Risk Assessment; Risk Factors; Russia; Severity of Illness Index; Ultrasonography, Doppler, Color; Vascular Patency

Obesity is a risk factor for atherosclerosis, a polyvascular process associated with reduced survival. In nonvascular surgery populations, a paradox between body mass index (BMI) and survival is described. This paradox includes reduced survival in underweight patients, whereas overweight and obese patients have a survival benefit. No clear explanation for this paradox has been given. Therefore, we evaluated the presence of the obesity paradox in vascular surgery patients and the influence of polyvascular disease on the obesity paradox.. In this retrospective study, 2933 consecutive patients were classified according to their preoperative BMI (kg/m(2)) and screened for polyvascular disease and cardiovascular risk factors before surgery. In addition, medication use at the time of discharge was noted. Outcome was all-cause mortality during a median follow-up of 6.0 years (interquartile range, 2-9 years).. BMI (kg/m(2)) groups included 68 (2.3%) underweight (BMI <18.5), 1379 (47.0%) normal (BMI 18.5-24.9, reference), 1175 (40.0%) overweight (BMI 25-29.9), and 311 (10.7%) obese (BMI ≥ 30) patients. No direct interaction between BMI, polyvascular disease, and long-term outcome was observed. Underweight was an independent predictor of mortality (hazard ratio, 1.65; 95% confidence interval, 1.22-2.22). In contrast, overweight protected for all-cause mortality (hazard ratio, 0.79; 95% confidence interval, 0.700-0.89). Cardioprotective medication usage in underweight patients was the lowest (P < .001), although treatment targets for risk factors were equally achieved within all treated groups.. Overweight patients referred for vascular surgery were characterized by an increased incidence of polyvascular disease and required more extensive medical treatment for cardiovascular risk factors at discharge. Long-term follow-up showed a paradox of reduced mortality in overweight patients.

Topics: Aged; Atherosclerosis; Body Mass Index; Cardiovascular Agents; Chi-Square Distribution; Female; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Netherlands; Obesity; Prevalence; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Risk Factors; Thinness; Time Factors; Treatment Outcome; Vascular Surgical Procedures

Vascular protective effects of Ginkgo biloba extract (GBE) may involve both antioxidant-related and anti-inflammatory mechanisms. GBE was recently suggested as a heme oxygenase (HO)-1 inducer. The role of HO-1 in anti-atherogenesis and related vascular protective effects of GBE awaited further clarification.. Tumor necrosis factor (TNF)-α was used to stimulate adhesiveness of human aortic endothelial cells (HAECs) to monocytes, an in vitro sign simulating atherogenesis. Pretreatment with GBE reduced TNF-α-stimulated endothelial adhesiveness, which could be attenuated by HO-1 inhibitors ZnPP IX or SnPP IX. GBE increased HO-1 expression and enzyme activity in HAECs. Pretreatment with MAP kinase inhibitor SB203580 significantly reduced GBE-induced HO-1 expression. Furthermore, GBE activated the translocation of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2), and increased its binding to the antioxidant response element (ARE) of the HO-1 gene. Pretreatment with PEG-SOD or other antioxidant reagents did not alter GBE-induced endothelial HO-1 expression. In vivo study also showed that GBE treatment could reduce leukocyte adherence to injury arteries, and enhance HO-1 expression in circulating monocytes and in arteries after wire injury, suggesting the in vivo induction of HO-1 by GBE.. GBE could inhibit cytokine-induced endothelial adhesiveness by inducing HO-1 expression via the activation of p38 and Nrf-2 pathways, a mechanism in which oxidative stress is not directly involved. GBE might exert its anti-atherogenesis and vascular protective effects by inducing vascular HO-1 expression.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Atherosclerosis; Binding Sites; Cardiovascular Agents; Cell Adhesion; Coculture Techniques; Disease Models, Animal; Endothelial Cells; Enzyme Activation; Enzyme Inhibitors; Ginkgo biloba; Heme Oxygenase-1; Humans; Membrane Proteins; Mice; Monocytes; NF-E2-Related Factor 2; Nitric Oxide Synthase Type III; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Plant Extracts; Protein Transport; RNA Interference; RNA, Messenger; Time Factors; Transfection; Tumor Necrosis Factor-alpha; U937 Cells; Vascular Cell Adhesion Molecule-1; Vascular System Injuries

The Impact of Nicorandil in Angina (IONA) trial demonstrated that the use of nicorandil, an anti-anginal drug, reduced future cardiovascular events in patients with stable angina. We hypothesized that nicorandil has beneficial effects on coronary arterial plaque characteristics and atherosclerogenesis.. Preintervention intravascular ultrasound-virtual histology was performed prospectively in 65 consecutive patients with stable angina pectoris. There were no differences in coronary risk factors between the nicorandil (n = 16) and non-nicorandil (n = 49) groups. However, the nicorandil group demonstrated a larger %fibrous tissue (68 ± 10 vs. 62 ± 11%, P = 0.049) and a smaller %necrotic core tissue (11 ± 7 vs. 16 ± 10%, P = 0.049) compared with the non-nicorandil group. Multiple regression analysis showed that %necrotic core tissue (P = 0.045) was negatively and %fibrous tissue (P = 0.026) was positively associated with the use of nicorandil independent of statin use. We also analyzed the effect of nicorandil on atherosclerotic lesion formation in a mouse model of atherosclerosis. Lipid profiles were unaffected, but the area of atherosclerotic lesion and plaque necrosis were significantly reduced following 8-week nicorandil treatment in ApoE-deficient mice fed an atherogenic diet. Nicorandil significantly reduced the expression levels of endoplasmic reticulum stress markers, C/EBP homologous protein (CHOP) and glucose regulated protein/BiP (GRP78) in atherosclerotic lesions. Nicorandil significantly attenuated tunicamycin-induced CHOP upregulation in cultured THP-1 macrophages.. Nicorandil exerts its anti-atherogenic effect by mechanisms different from those of statins. Long-term nicorandil treatment is a potentially suitable second-line prevention therapy for patients with coronary artery disease.

Topics: Administration, Oral; Aged; Aged, 80 and over; Angina Pectoris; Animals; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Cardiovascular Agents; Cells, Cultured; Chi-Square Distribution; Coronary Artery Disease; Cytokines; Disease Models, Animal; Drug Administration Schedule; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Endothelial Cells; Fibrosis; Humans; Inflammation Mediators; Japan; Lipids; Logistic Models; Macrophages; Male; Mice; Mice, Knockout; Middle Aged; Molecular Chaperones; Necrosis; Nicorandil; Odds Ratio; Retrospective Studies; Time Factors; Treatment Outcome; Ultrasonography, Interventional

Sesamol, a phenolic component of lignans, has been previously shown to reduce lipopolysaccharide-induced oxidative stress and upregulate phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase pathways. In the present study, we synthesized a modified form of sesamol (INV-403) to enhance its properties and assessed its effects on atherosclerosis.. Watanabe heritable hyperlipidemic rabbits were fed with high-cholesterol chow for 6 weeks and then randomized to receive high-cholesterol diet either alone or combined with INV-403 (20 mg/kg per day) for 12 weeks. Serial MRI analysis demonstrated that INV-403 rapidly reduced atherosclerotic plaques (within 6 weeks), with confirmatory morphological analysis at 12 weeks posttreatment revealing reduced atherosclerosis paralleled by reduction in lipid and inflammatory cell content. Consistent with its effect on atherosclerosis, INV-403 improved vascular function (decreased constriction to angiotensin II and increased relaxation to acetylcholine), reduced systemic and plaque oxidative stress, and inhibited nuclear factor-κB activation via effects on nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation with coordinate reduction in key endothelial adhesion molecules. In vitro experiments in cultured endothelial cells revealed effects of INV-403 in reducing IκBα phosphorylation via inhibition of IκB kinase 2 (IKK2).. INV-403 is a novel modified lignan derivative that potently inhibits atherosclerosis progression via its effects on IKK2 and nuclear factor-κB signaling.

Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; Benzodioxoles; Cardiovascular Agents; Cattle; Cell Adhesion Molecules; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Gene Expression Regulation; Hyperlipidemias; I-kappa B Kinase; I-kappa B Proteins; Magnetic Resonance Imaging; Male; NF-kappa B; NF-KappaB Inhibitor alpha; Oxidative Stress; Phenols; Phosphorylation; Rabbits; Time Factors; Transfection; Vasoconstriction; Vasodilation

The peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone has been suggested to exert cardiovascular protection through the improvement of lipid metabolism, anti-inflammation, anti-proliferation etc. However, whether renin-angiotensin system (RAS) is involved in the vascular protective effects of PPARγ agonists is not fully understood. The present study aimed to investigate the effects of the renin-angiotensin system in vascular protection mediated by PPARγ agonists.. To investigate the actions of the renin-angiotensin system in vascular protection mediated by activation of PPARγ in vivo and in vitro.. Rats were fed a regular diet (n = 8), a cholesterol-rich diet plus methylthiouracil (80 mg/Kg/day, n = 10), a cholesterol-rich diet plus methylthiouracil and rosiglitazone (4 mg/kg/day, n = 10). The rosiglitazone treatment was started from one month after the start of cholesterol-rich diet plus methylthiouracil, and lasted five months. Cultured vascular smooth muscle cells (VSMCs) were pretreated with 1 μmol/L angiotensin II (ANG II) for 6 h and randomly divided into the control group; the ANG II group (1 μmol/L ANG II); the groups respectively treated with different concentration rosiglitazone (20, 30, 50) μmol/L for 12 h; the groups treated with 30 μmol/L rosiglitazone for (6, 12, 24) h. Morphology changes of the aortic tissues were observed by hematoxylin and eosin stain. The VSMC growth was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Angiotensin II and expression of angiotensin receptors were determined by radioimmunoassay, reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry.. After 6 months, lipid deposition, VSMC proliferation and migration toward intima were observed in aortic tissues in the rats on a cholesterol-rich diet plus methylthiouracil, while these pathological changes induced by the cholesterol-rich diet were significantly suppressed by rosiglitazone. In addition, VSMC proliferation induced by ANG II was markedly inhibited by rosiglitazone. Rosiglitazone markedly down-regulated expression of angiotensin type 1 receptor (AT1R) and up-regulated expression of angiotensin type 2 receptor (AT2R) in the aortic tissues and ANG II-treated VSMCs.. The present study demonstrated that PPARγ agonist rosiglitazone suppressed ANG II-induced VSMC proliferation in vitro and early atherosclerotic formation evoked by cholesterol-rich diet in vivo. These vasculoprotective effects of rosiglitazone were mediated at least partially by reduction in local tissue ANG II concentration, down-regulation of AT1R expression and up-regulation of AT2R expression both at the mRNA and protein levels.

Topics: Angiotensin II; Animals; Aortic Diseases; Atherosclerosis; Blotting, Western; Cardiovascular Agents; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Hypercholesterolemia; Immunohistochemistry; Lipids; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; PPAR gamma; Radioimmunoassay; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Rosiglitazone; Thiazolidinediones; Time Factors

Topics: Atherosclerosis; Body Mass Index; Cardiovascular Agents; Humans; Incidence; Obesity; Prevalence; Risk Assessment; Risk Factors; Thinness; Time Factors; Treatment Outcome; Vascular Surgical Procedures

Plasma concentrations of high-density lipoprotein (HDL)-cholesterol correlate inversely with the incidence of myocardial infarction in humans. We investigated the effect of treatment with human apolipoprotein A-I (apoA-I), the principal protein of HDL, on plaque disruption in an animal model.. Seventy apolipoprotein E knockout mice were induced to develop atherosclerotic lesions in the brachiocephalic artery by feeding a high-fat diet for 9 weeks. Mice then received twice-weekly treatment with human apoA-I (8 mg/kg) or vehicle, for 2 weeks. The incidence of acute plaque disruption was reduced by 65% in mice receiving apoA-I (P < 0.01). Plaques in treated mice had a more stable phenotype, with an increase in smooth muscle cell (SMC): macrophage ratio (P = 0.05), principally the consequence of an increase in the number of SMC in plaques. In the fibrous cap, there were reductions in matrix metalloproteinase-13 (-69%, P < 0.0001) and S100A4, a marker of SMC de-differentiation (-60%, P < 0.0001). These results indicate that 2 weeks of treatment with small amounts of human apoA-I produces more stable plaques in a mouse model.. Treatment with apoA-I has the potential to stabilize plaques and prevent plaque rupture in humans.

Topics: Animals; Apolipoprotein A-I; Apolipoproteins E; Atherosclerosis; Brachiocephalic Trunk; Cardiovascular Agents; Cell Dedifferentiation; Cholesterol, HDL; Collagen; Disease Models, Animal; Fibrosis; Humans; Inflammation Mediators; Macrophages; Male; Matrix Metalloproteinase 13; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Plaque, Atherosclerotic; Rupture, Spontaneous; S100 Calcium-Binding Protein A4; S100 Proteins

Diabetic retinopathy is a microvascular complication of diabetes mellitus whose prevalence is closely related to the presence of nephropathy and hypertension. The aim was to study clinical and pharmacological factors that are associated with an increased need for laser photocoagulation in patients with diabetic nephropathy and retinopathy.. Cross sectional study of 63 patients followed in the Diabetic Nephropathy consultation. Patients were divided into 2 groups according to whether or not previously have received photocoagulation. In each subgroup were studied demographic variables, anthropometric, laboratory, cardiovascular risk factors and treatment received by each patient for the control of hypertension, diabetes and others diseases.. We observed that the group had received photocoagulation had more years of diabetes evolution, more history of cardiovascular disease and a lower creatinine clearance. Similarly, the percentage of patients treated with carvedilol was significantly higher in the subgroup who had not received photocoagulation while the percentage of patients treated with beta-blockers was significantly higher in the subgroup that received photocoagulation; no significant differences was observed in the degree of control blood pressure.. Clinical and pharmacological factors related to the requirements of laser photocoagulation were years of diabetes evolution, history of cardiovascular disease, the stage of kidney disease and the treatment with beta-blockers.

Topics: Aged; Antihypertensive Agents; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Humans; Hyperlipidemias; Hypertension; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Laser Coagulation; Male; Middle Aged; Recurrence; Risk Factors; Smoking

Topics: Animals; Apolipoprotein A-I; Atherosclerosis; Brachiocephalic Trunk; Cardiovascular Agents; Humans; Male; Plaque, Atherosclerotic

Because both endothelin-1 (ET-1) and angiotensin II (AngII) are independent mediators of arterial remodeling, we sought to determine the role of ET receptor inhibition in AngII-accelerated atherosclerosis and aortic aneurysm formation. We administered saline or AngII and/or bosentan, an endothelin receptor antagonist (ERA) for 7, 14, or 28 days to 6-week- and 6-month-old apolipoprotein E-knockout mice. AngII treatment increased aortic atherosclerosis, which was reduced by ERA. ET-1 immunostaining was localized to macrophage-rich regions in aneurysmal vessels. ERA did not prevent AngII-induced aneurysm formation but instead may have increased aneurysm incidence. In AngII-treated animals with aneurysms, ERA had a profound effect on the non-aneurysmal thoracic aorta via increasing wall thickness, collagen/elastin ratio, wall stiffness, and viscous responses. These observations were confirmed in acute in vitro collagen sheet production models in which ERA inhibited AngII's dose-dependent effect on collagen type 1 α 1 (COL1A1) gene transcription. However, chronic treatment reduced matrix metalloproteinase 2 mRNA expression but enhanced COL3A1, tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-2 mRNA expressions. These data confirm a role for the ET system in AngII-accelerated atherosclerosis but suggest that ERA therapy is not protective against the formation of AngII-induced aneurysms and can paradoxically stimulate a chronic arterial matrix remodeling response.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Aorta; Aortic Aneurysm; Apolipoproteins E; Atherosclerosis; Biomechanical Phenomena; Bosentan; Cardiovascular Agents; Cell Adhesion; Collagen; Down-Regulation; Endothelin-1; Integrin beta1; Interferon-gamma; Mice; Mice, Knockout; Stress, Physiological; Sulfonamides; Vasoconstrictor Agents

Accelerated atherosclerosis is a major diabetic complication initiated by the enhanced recruitment of monocytes into the vasculature. In this study, we examined the therapeutic potential of the phytonutrients ursolic acid (UA) and resveratrol (RES) in preventing monocyte recruitment and accelerated atherosclerosis.. Dietary supplementation with either RES or UA (0.2%) protected against accelerated atherosclerosis induced by streptozotocin in high-fat diet-fed LDL receptor-deficient mice. However, mice that received dietary UA for 11 weeks were significantly better protected and showed a 53% reduction in lesion formation while mice fed a RES-supplemented diet showed only a 31% reduction in lesion size. Importantly, UA was also significantly more effective in preventing the appearance of proinflammatory GR-1(high) monocytes induced by these diabetic conditions and reducing monocyte recruitment into MCP-1-loaded Matrigel plugs implanted into these diabetic mice. Oxidatively stressed THP-1 monocytes mimicked the behavior of blood monocytes in diabetic mice and showed enhanced responsiveness to monocyte chemoattractant protein-1 (MCP-1) without changing MCP-1 receptor (CCR2) surface expression. Pretreatment of THP-1 monocytes with RES or UA (0.3-10μM) for 15h resulted in the dose-dependent inhibition of H(2)O(2)-accelerated chemotaxis in response to MCP-1, but with an IC(50) of 0.4μM, UA was 2.7-fold more potent than RES.. Dietary UA is a potent inhibitor of monocyte dysfunction and accelerated atherosclerosis induced by diabetes. These studies identify ursolic acid as a potential therapeutic agent for the treatment of diabetic complications, including accelerated atherosclerosis, and provide a novel mechanism for the anti-atherogenic properties of ursolic acid.

Topics: Animals; Aortic Diseases; Atherosclerosis; Cardiovascular Agents; Cell Line; Chemokine CCL2; Chemotaxis, Leukocyte; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Dose-Response Relationship, Drug; Female; Humans; Hyperlipidemias; Kidney; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Oxidative Stress; Receptors, CCR2; Receptors, LDL; Resveratrol; Stilbenes; Time Factors; Triterpenes; Ursolic Acid

Topics: Atherosclerosis; Cardiovascular Agents; Disease Progression; Endovascular Procedures; Evidence-Based Medicine; Humans; Hypertension; Patient Selection; Randomized Controlled Trials as Topic; Renal Artery Obstruction; Renal Insufficiency; Risk Assessment; Risk Factors; Stents; Treatment Outcome; Vascular Surgical Procedures

The role of and indications for interventions for renal artery stenosis have long been a hot topic of debate. Despite numerous reports and studies over the years, there remain many unanswered questions. Among them are: Who should be intervened upon? What should be the objectives of intervention? What is the optimal mode of intervention? More recently, several randomized studies have attempted to answer some of these basic questions, but unfortunately have left many unanswered questions. In the following debate, the authors consider the existing literature and attempt to convince us that the majority, or the minority, of patients with renal artery stenoses should be intervened upon.

Topics: Atherosclerosis; Cardiovascular Agents; Disease Progression; Endovascular Procedures; Evidence-Based Medicine; Humans; Patient Selection; Randomized Controlled Trials as Topic; Renal Artery Obstruction; Risk Assessment; Risk Factors; Stents; Treatment Outcome

Successful drug development has been hampered by a limited understanding of how to translate laboratory-based biological discoveries into safe and effective medicines. We have developed a generic method for predicting the effects of drugs on biological processes. Information derived from the chemical structure and experimental omics data from short-term efficacy studies are combined to predict the possible protein targets and cellular pathways affected by drugs.. Validation of the method with anti-atherosclerotic compounds (fenofibrate, rosuvastatin, LXR activator T0901317) demonstrated a great conformity between the computationally predicted effects and the wet-lab biochemical effects. Comparative genome-wide pathway mapping revealed that the biological drug effects were realized largely via different pathways and mechanisms. In line with the predictions, the drugs showed differential effects on inflammatory pathways (downstream of PDGF, VEGF, IFNγ, TGFβ, IL1β, TNFα, LPS), transcriptional regulators (NFκB, C/EBP, STAT3, AP-1) and enzymes (PKCδ, AKT, PLA2), and they quenched different aspects of the inflammatory signaling cascade. Fenofibrate, the compound predicted to be most efficacious in inhibiting early processes of atherosclerosis, had the strongest effect on early lesion development.. Our approach provides mechanistic rationales for the differential and common effects of drugs and may help to better understand the origins of drug actions and the design of combination therapies.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Drug Design; Fenofibrate; Fluorobenzenes; Gene Expression Regulation; Humans; Hydrocarbons, Fluorinated; Mice; Microarray Analysis; Models, Biological; Pyrimidines; Regulatory Elements, Transcriptional; Rosuvastatin Calcium; Structure-Activity Relationship; Sulfonamides; Systems Biology

Apolipoprotein A-I (apoA-I) exerts many potentially anti-atherogenic properties and is therefore attractive for prevention and therapy of coronary heart disease. Since induction of apoA-I production by small molecules has turned out as difficult, application of exogenous apoA-I is pursued as an alternative therapeutic option. To counteract fast renal filtration of apoA-I, a trimeric high-molecular weight variant of apoA-I (TripA) was produced by recombinant technology. We compared TripA and apoA-I for important properties in reverse cholesterol transport. Reconstituted high-density lipoproteins (rHDL) containing TripA or apoA-I together with palmitoyl-2-oleyl-phosphatidylcholine (POPC) differed slightly by size. Compared to apoA-I, TripA activated lecithin:cholesterol acyltransferase (LCAT) with similar maximal velocity but concentration leading to half maximal velocity was slightly reduced (K(m)=2.1±0.3μg/mL vs. 0.59±0.06μg/mL). Both in the lipid-free form and as part of rHDL, TripA elicited cholesterol efflux from THP1-derived macrophages with similar kinetic parameters and response to liver-X-receptor activation as apoA-I. Lipid-free TripA is bound and transported by aortic endothelial cells through mechanisms which are competed by apoA-I and TripA and inhibited by knock-down of ATP-binding cassette transporter (ABC) A1. Pre-formed TripA/POPC particles were bound and transported by endothelial cells through mechanisms which are competed by excess native HDL as well as reconstituted HDL containing either apoA-I or TripA and which involve ABCG1 and scavenger receptor B1 (SR-BI). In conclusion, apoA-I and TripA show similar in vitro properties which are important for reverse cholesterol transport. These findings are important for further development of TripA as an anti-atherosclerotic drug.

Topics: Animals; Aorta; Apolipoprotein A-I; Atherosclerosis; ATP-Binding Cassette Transporters; Cardiovascular Agents; Cattle; Coronary Disease; Endothelial Cells; Gene Silencing; Humans; Kinetics; Lipoproteins, HDL; Phosphatidylcholine-Sterol O-Acyltransferase; Phosphatidylcholines; Protein Binding; Protein Transport; Recombinant Proteins; RNA, Small Interfering

Topics: Animals; Aortic Diseases; Apoptosis; Atherosclerosis; Cardiovascular Agents; Caspases; Diabetes Mellitus, Experimental; Diabetic Angiopathies; DNA Damage; Female; Human Umbilical Vein Endothelial Cells; Humans; Male; Mitochondria; Monocytes; Plaque, Atherosclerotic; Triterpenes; Tumor Suppressor Protein p53; Ursolic Acid

Around 16% of all patients who present with atheromatous renovascular disease (ARVD) in the United States undergo revascularization. Historically, patients with advanced chronic kidney disease (CKD) have been considered least likely to show improvement in renal functional terms, or survival. We aimed to investigate whether differences in outcomes after revascularization compared to medical management might be observed in ARVD patients if stratified by their CKD classes.. Two prospective cohorts, a UK center with a traditionally conservative approach, and a German center who undertook a proactive revascularization approach, were compared. An improvement in renal function was defined as > 20% renal improvement at one year's follow-up. To improve validity and comparability, revascularized patients in the UK center were also used within analyses,. 347 (UK conservative group), 89 (UK revascularized group), and 472 (German center) patients were included in the analysis. When subdivided by CKD stage, patient ages between the two centers were comparable. Improvements in renal function were observed in twice as many patients who underwent revascularization as compared to medical treatment, particularly in the latter CKD stages, 15.2 (German revascularization) vs. 0% in CKD 1-2, 12.2 (UK), and 32.8 (German) revascularization vs. 14.1% in CKD3, and 53.1 and 53.8 vs. 28.3 in patients with CKD 4-5. The improvements in eGFR were 10.2 (16) and 8.1 (12.5) ml/min/year in the German and UK revascularized groups, respectively, vs. -0.05 (6.8) ml/min/year in the medical cohort in CKD 4-5. Improvements in blood pressure control were noted at 1 year overall and within each CKD category. Multivariate analysis revealed that revascularization independently reduced the risk of death by 45% in all patients combined (RR 0.55, P = 0.013).. Although this study has significant methodological limitations, it does shows that percutaneous renal revascularization can improve renal function in advanced CKD (stages 4-5), and that this can provide a survival advantage in prospective analysis.

Topics: Adult; Aged; Aged, 80 and over; Angioplasty, Balloon; Atherosclerosis; Cardiovascular Agents; Chronic Disease; Databases as Topic; Female; Germany; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Logistic Models; Male; Middle Aged; Odds Ratio; Prospective Studies; Recovery of Function; Renal Artery Obstruction; Risk Assessment; Risk Factors; Severity of Illness Index; Stents; Time Factors; Treatment Outcome; United Kingdom

This study aimed to find the effects of heparin on atherosclerosis and the production of matrix metalloproteinase (MMP)-2 in low-density lipoprotein receptor-deficient (LDLr(-/-)) mice.. Sixteen 7-week-old LDLr(-/-) mice were randomized to receive sterile water or heparin. The levels of total cholesterol, high-density lipoprotein cholesterol, triglyceride and homocysteine were measured. Mean lesions area was calculated as the total atherosclerotic lesions area and expressed as a percentage of total luminal surface area. The lesions area was measured blindly by the same person using computer-assisted image analysis. The expression and localization of the MMP-2 was examined by immunohistochemistry.. All mice exhibited atherosclerotic lesions in the aortic sinus and aortic surface. Total cholesterol was decreased, while high-density lipoprotein cholesterol was increased in heparin compared with that in control group (P=0.001 and 0.002). Triglyceride was not significantly different between the two groups (P=0.92). The amount of atherosclerotic lesions in the aortic surface was 40.5% lower in heparin group than that in the control group (P<0.001). The mean area of atherosclerotic lesions in the aortic sinus was also less in the heparin group than that in the control group. Coincidently, the expression of MMP-2 in the atherosclerotic lesions in the heparin group was 49.3% lower than that in the control group (P<0.001).. Heparin can inhibit the production of MMP-2 in the atherosclerotic lesions and improve the atherosclerotic lesions in LDLr(-/-) mice.

Topics: Animals; Aorta; Atherosclerosis; Biomarkers; Body Weight; Cardiovascular Agents; Cholesterol; Cholesterol, HDL; Disease Models, Animal; Eating; Heparin; Homocysteine; Immunohistochemistry; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, LDL; Triglycerides

Topics: Angioplasty, Balloon; Atherosclerosis; Cardiovascular Agents; Chronic Disease; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Recovery of Function; Renal Artery Obstruction; Risk Assessment; Risk Factors; Severity of Illness Index; Stents; Time Factors; Treatment Outcome

The American Heart Association (AHA) Scientific Sessions 2009 meeting held in Orlando, FL, USA included topics covering new treatments for cardiovascular disease. This conference report highlights selected presentations on stem cell treatments for ischemia, treatments for hypertension and atherosclerosis, and LDL-lowering compounds.

Topics: Anticholesteremic Agents; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Cholesterol, LDL; Humans; Hypertension; Myocardial Ischemia; Stem Cell Transplantation

The purpose of this study was to ascertain the impact of obesity on the cost of disease management in people with or at high risk of atherothrombotic disease from a governmental perspective using a bottom-up approach to cost estimation. In addition, the aim was also to explore the causes of any differences found.. The health-care costs of obesity were estimated from 2819 participants recruited into the nationwide Australian REACH Registry with established atherothrombotic disease or at least three risk factors for atherothrombosis. Enrollment was in 2004, through primary care general practices. Information was collected on the use of cardiovascular drugs, hospitalizations and ambulatory care services. 'Bottom-up' costing was undertaken by assigning unit costs to each health-care item, based on Australian Government-reimbursed figures 2006-2007. Linear-mixed models were used to estimate associations between direct medical costs and body mass index (BMI) categories.. Annual pharmaceutical costs per person increased with increasing BMI category, even after adjusting for gender, age, living place, formal education, smoking status, hypertension and diabetes. Adjusted annual pharmaceutical costs of overweight and obese participants were higher ($7 (P=0.004) and $144 (<0.001), respectively) than those of the normal weight participants. This was due to participants in higher BMI categories receiving more pharmaceuticals than normal weight participants. There was no significant change across the BMI categories in annual ambulatory care costs and annual hospital costs.. In these participants with or at high risk of atherothrombotic disease, annual pharmaceutical costs were greater in participants of higher BMI category, but there was not such a gradient in the annual hospital or ambulatory care costs. The greater cardiovascular pharmaceutical costs for participants of higher BMI categories remained even after adjusting for a range of demographic factors and comorbidities. Our results suggest that these costs are explained by the higher number of drugs used among people with atherothrombotic disease. Further investigation is needed to understand the reasons for this level of drug use.

Topics: Aged; Atherosclerosis; Australia; Body Mass Index; Cardiovascular Agents; Female; Health Care Costs; Humans; Male; Obesity; Prospective Studies; Registries

Apolipoprotein (apoA)-I mimetic peptides are a promising type of anti-atherosclerosis therapy, but how the structural features of these peptides relate to the multiple antiatherogenic functions of HDL is poorly understood.. To establish structure/function relationships of apoA-I mimetic peptides with their antiatherogenic functions.. Twenty-two bihelical apoA-I mimetic peptides were investigated in vitro for the capacity and specificity of cholesterol efflux, inhibition of inflammatory response of monocytes and endothelial cells, and inhibition of low-density lipoprotein (LDL) oxidation. It was found that mean hydrophobicity, charge, size of hydrophobic face, and angle of the link between the helices are the major factors determining the efficiency and specificity of cholesterol efflux. The peptide with optimal parameters was more effective and specific toward cholesterol efflux than human apoA-I. Charge and size of hydrophobic face were also the major factors affecting antiinflammatory properties, and the presence of cysteine and histidine residues was the main factor determining antioxidant properties. There was no significant correlation between capacities of the peptides to support individual functions; each function had its own optimal set of features.. None of the peptides was equally effective in all the antiatherogenic functions tested, suggesting that different functions of HDL may have different mechanisms and different structural requirements. The results do suggest, however, that rationalizing the design of apoA-I mimetic peptides may improve their therapeutic value and may lead to a better understanding of mechanisms of various antiatherogenic functions of HDL.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apolipoprotein A-I; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Biological Transport; Cardiovascular Agents; Cell Line; Cholesterol; Drug Design; Endothelial Cells; Humans; Hydrophobic and Hydrophilic Interactions; Inflammation Mediators; Lipoproteins, LDL; Mice; Molecular Mimicry; Monocytes; Peptides; Protein Conformation; Structure-Activity Relationship; Surface Properties

Nifedipine, an L-type calcium channel blocker, protects against the progression of atherosclerosis. We investigated the molecular basis of the antiatherosclerotic effect of nifedipine in macrophages and apolipoprotein E-deficient mice.. In macrophages, nifedipine increased peroxisome proliferator-activated receptor-gamma (PPARgamma) activity without increasing PPARgamma-binding activity. Amlodipine, another L-type calcium channel blocker, and 1,2-bis-(o-aminophenoxy)-ethane-N,N,-N',N'-tetraacetic acid tetraacetoxy-methyl ester (BAPTA-AM), a calcium chelator, decreased PPARgamma activity, suggesting that nifedipine does not activate PPARgamma via calcium channel blocker activity. Inactivation of extracellular signal-regulated kinase 1/2 suppressed PPARgamma2-Ser112 phosphorylation and induced PPARgamma activation. Nifedipine suppressed extracellular signal-regulated kinase 1/2 activation and PPARgamma2-Ser112 phosphorylation, and mutating PPARgamma2-Ser112 to Ala abrogated nifedipine-mediated PPARgamma activation. These results suggested that nifedipine inhibited extracellular signal-regulated kinase 1/2 activity and PPARgamma2-Ser112 phosphorylation, leading to PPARgamma activation. Nifedipine inhibited lipopolysaccharide-induced monocyte chemoattractant protein-1 expression and induced ATP-binding cassette transporter A1 mRNA expression, and these effects were abrogated by small interfering RNA for PPARgamma. Furthermore, in apolipoprotein E-deficient mice, nifedipine treatment decreased atherosclerotic lesion size, phosphorylation of PPARgamma2-Ser112 and extracellular signal-regulated kinase 1/2, and monocyte chemoattractant protein-1 mRNA expression and increased ATP-binding cassette transporter A1 expression in the aorta.. Nifedipine unlike amlodipine inhibits PPARgamma-Ser phosphorylation and activates PPARgamma to suppress monocyte chemoattractant protein-1 expression and induce ATP-binding cassette transporter A1 expression in macrophages. These effects may induce antiatherogenic effects in hypertensive patients.

Topics: Amlodipine; Animals; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Calcium Channel Blockers; Cardiovascular Agents; Cells, Cultured; Chelating Agents; Chemokine CCL2; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Egtazic Acid; Enzyme Activation; Flavonoids; Humans; Lipopolysaccharides; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C3H; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mutation; Nifedipine; Phosphorylation; PPAR gamma; Protein Kinase Inhibitors; RNA Interference; RNA, Messenger; Time Factors; Transfection

Topics: Aged; Ankle Brachial Index; Aspirin; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Evidence-Based Medicine; Female; Hemorrhage; Humans; Male; Middle Aged; Primary Prevention; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Scotland; Time Factors; Treatment Outcome

Topics: Atherosclerosis; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Humans; Hypoglycemic Agents; Nitric Oxide

Atherogenic lipids and chronic inflammation drive the development of cardiovascular disorders such as atherosclerosis. Many cardiovascular drugs target the liver which is involved in the formation of lipid and inflammatory risk factors. With robust systems biology tools and comprehensive bioinformatical packages becoming available and affordable, the effect of novel treatment strategies can be analyzed more comprehensively and with higher sensitivity. For example, beneficial as well as adverse effects of drugs can already be detected on the gene and metabolite level, and prior to their macroscopic manifestation. This chapter describes a systems approach for a prototype CV drug with established beneficial and adverse effects. All relevant steps, for example, experimental design, tissue collection and high quality RNA preparation, bioinformatical analysis of functional processes, and pathways (targeted and untargeted) are addressed.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Female; Gene Regulatory Networks; Humans; Hydrocarbons, Fluorinated; Inflammation; Liver X Receptors; Mice; Orphan Nuclear Receptors; RNA; Software; Statistics as Topic; Sulfonamides; Systems Biology

To examine whether danshensu could protect vascular endothelia in a rat model of hyperhomocysteinemia.. The model was established by feeding rats with a methionine-rich diet (1 g·kg⁻¹·d⁻¹) for 3 months. Immediately following the discontinuation of methionine-rich diet, rats were treated with danshensu (67.5 mg·kg⁻¹·d⁻¹, po) or saline for 3 additional months. One group of rats receiving vitamin mixture (folic acid, vitamin B12 and vitamin B6) was included as a positive control. One group of rats not exposed to methionine-rich diet was also included as a blank control. The expression of tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) protein in the descending aorta was examined using immunohistochemistry and Western blot. Homocysteine and blood concentration of endothelin and nitric oxide (NO) was also examined.. Methionine-rich diet resulted in accumulation of "foam cells", up-regulated expression of TNF-alpha and ICAM-1 in the descending aorta, and significantly increased serum homocysteine. Plasma endothelin concentration was significantly increased; NO was decreased. Danshensu treatment, either simultaneous to methionine-rich diet or afterwards, attenuated the above mentioned changes.. Chronic treatment with danshensu could prevent/attenuate the formation of atherosclerosis. Potential mechanisms include inhibited expression of representative proinflammatory cytokines and adhesion molecules in arterial endothelia. Changes in homocysteine and circulating molecules that control vascular contraction/relaxation via endothelial cells (eg, endothelin and NO) were also implicated.

Topics: Animals; Aorta, Thoracic; Atherosclerosis; Cardiovascular Agents; Diet; Disease Models, Animal; Endothelins; Endothelium, Vascular; Female; Hyperhomocysteinemia; Intercellular Adhesion Molecule-1; Lactates; Male; Methionine; Nitric Oxide; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

DCs (dendritic cells) are present in atherosclerotic lesions leading to vascular inflammation, and the number of vascular DCs increases during atherosclerosis. Previously, we have shown that the levels of circulating DCPs (DC precursors) are reduced in acute coronary syndromes through vascular recruitment. In the present study, we have investigated whether DCP levels are also reduced in stable CAD (coronary artery disease). The levels of circulating mDCPs (myeloid DCPs), pDCPs (plasmacytoid DCPs) and tDCP (total DCPs) were investigated using flow cytometry in 290 patients with suspected stable CAD. A coronary angiogram was used to evaluate a CAD score for each patient as follows: (i) CAD excluded (n=57); (ii) early CAD (n=63); (iii) moderate CAD (n=85); and (iv) advanced CAD (n=85). Compared with controls, patients with advanced stable CAD had lower HDL (high-density lipoprotein)-cholesterol (P=0.03) and higher creatinine (P=0.003). In advanced CAD, a significant decrease in circulating mDCPs, pDCPs and tDCPs was observed (each P<0.001). A significant inverse correlation was observed between the CAD score and mDCPs, pDCPs or tDCPs (each P<0.001). Patients who required percutaneous coronary intervention or coronary artery bypass grafting had less circulating mDCPs, pDCPs and tDCPs than controls (each P<0.001). Multiple stepwise logistic regression analysis suggested mDCPs, pDCPs and tDCPs as independent predictors of CAD. In conclusion, we have shown that patients with stable CAD have significantly lower levels of circulating DCPs than healthy individuals. Their decrease appears to be an independent predictor of the presence of, and subsequent therapeutic procedure in, stable CAD.

Topics: Aged; Atherosclerosis; Biomarkers; C-Reactive Protein; Cardiovascular Agents; Cell Count; Cholesterol, HDL; Coronary Angiography; Coronary Artery Disease; Dendritic Cells; Disease Progression; Female; Humans; Male; Middle Aged; Risk Factors; Severity of Illness Index; Stem Cells

Atherosclerosis begins in childhood with fatty streaks, which progress seamlessly to fibrous plaques in adulthood. These plaques, in turn, might rupture and cause thrombotic arterial occlusion and ischemic damage to vital organs. The earliest stages and progression of atherosclerosis in youth are influenced by the same major established risk factors for this condition in adults-dyslipidemia, hypertension, smoking, obesity, and diabetes mellitus. Controlling these risk factors at any age is beneficial, but the earlier primary prevention begins, the better the result. As recommended by the American Academy of Pediatrics, pediatricians should support both control and prevention of these risk factors in children via lifestyle modification. Drug treatment can be used to supplement lifestyle modification in the few cases of children with genetic dyslipidemias who do not respond to diet changes. Ultimately, however, effective prevention of adult disease requires a massive cultural change.

Topics: Adolescent; Adult; Atherosclerosis; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Complications; Disease Progression; Dyslipidemias; Humans; Hypertension; Pediatrics; Physician's Role; Practice Guidelines as Topic; Primary Prevention; Risk Factors; Risk Reduction Behavior; Smoking; Societies, Medical; United States; Young Adult

We explored the effect of hydrogen sulfide (H(2)S) on atherosclerotic progression, particularly on intracellular adhesion molecule-1 (ICAM-1) in apolipoprotein-E knockout (apoE(-/-)) mice and human umbilical vein endothelial cells (HUVECs).. ApoE(-/-) mice were treated with sodium hydrosulfide (NaHS) or DL-propargylglycine (PPG); HUVECs were pretreated with NaHS. Compared with control mice, apoE(-/-) mice showed decreased plasma H(2)S level and aortic H(2)S production but increased plasma ICAM-1 and aortic ICAM-1 protein and mRNA. Compared with apoE(-/-) mice, apoE(-/-)+NaHS mice showed increased plasma H(2)S level, but decreased size of atherosclerotic plaque and plasma and aortic ICAM-1 levels, whereas apoE(-/-)+PPG mice showed decreased plasma H(2)S level but enlarged plaque size and increased plasma and aortic ICAM-1 levels. NaHS suppressed ICAM-1 expression in tumor necrosis factor (TNF)-alpha-treated HUVECs. NaHS inhibited IkappaB degradation and NF-kappaB nuclear translocation in HUVECs treated with TNF-alpha.. The vascular CSE/H(2)S pathway was disturbed in apoE(-/-) mice. H(2)S exerted an antiatherogenic effect and inhibited ICAM-1 expression in apoE(-/-) mice. H(2)S inhibited ICAM-1 expression in TNF-alpha-induced HUVECs via the NF-kappaB pathway.

Topics: Active Transport, Cell Nucleus; Alkynes; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Body Weight; Cardiovascular Agents; Cells, Cultured; Cystathionine gamma-Lyase; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Enzyme Inhibitors; Foam Cells; Glycine; Humans; Hydrogen Sulfide; I-kappa B Proteins; Intercellular Adhesion Molecule-1; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; NF-kappa B; RNA, Messenger; Sulfides; Tumor Necrosis Factor-alpha

The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that functions as an endogenous sensor for bile acids and regulates cholesterol and fatty acid metabolism. The effect of FXR activation on aortic plaque formation was assessed by feeding apolipoprotein E-deficient (ApoE-/-) mice with the synthetic FXR ligand INT-747, a cheno-deoxycholic acid derivative, at doses of 3 and 10 mg x kg(-1) x day(-1), or with rosiglitazone, a peroxisome proliferator-activated receptor-gamma ligand, at the dose of 10 mg x kg(-1) x day(-1) for 12 wk. Administration of INT-747 reduced formation of aortic plaque area by 95% (P < 0.01), and a similar antiplaque activity was exerted by administration of rosiglitazone. INT-747 administration to ApoE-/- mice reduced aortic expression of IL-1beta, IL-6, and CD11b mRNA, while it upregulated the expression of FXR and its target gene, the small heterodimer partner (SHP). FXR activation reduced the liver expression of sterol regulatory element binding protein 1c, resulting in reduced triglyceride and cholesterol content in the liver and amelioration of hyperlipidemia. FXR expression, mRNA and protein, was detected in human macrophages and macrophage cell lines. FXR activation by natural and synthetic ligands in these cell types attenuated IL-1beta, IL-6, and TNF-alpha gene induction in response to Toll-like receptor 4 activation by LPS. Using spleen monocytes from wild-type and FXR-/- mice, we demonstrated that FXR gene ablation exacerbates IL-6 and TNF-alpha generation by LPS-stimulated macrophages. FXR was also able to reduce cholesterol uptake on macrophages by regulation of CD36 and ABCA1 expression. We found that FXR and SHP are expressed in the aorta and macrophages and that FXR ligands might have utility in prevention and treatment of atherosclerotic lesions.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Cardiovascular Agents; CD11b Antigen; CD36 Antigens; Chenodeoxycholic Acid; Disease Models, Animal; DNA-Binding Proteins; Female; Humans; Hyperlipidemias; Interleukin-1beta; Interleukin-6; Ligands; Lipids; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; PPAR gamma; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Rosiglitazone; Sterol Regulatory Element Binding Protein 1; Thiazolidinediones; Toll-Like Receptor 4; Transcription Factors; Tumor Necrosis Factor-alpha

Topics: Animals; Aorta; Atherosclerosis; Cardiovascular Agents; Cystathionine gamma-Lyase; Endothelial Cells; Humans; Hydrogen Sulfide; Intercellular Adhesion Molecule-1; Muscle, Smooth, Vascular; Sulfides

Urotensin II (UII) and its receptor UT are upregulated in the pathological setting of various cardiovascular diseases including atherosclerosis. However, their exact role in atherosclerosis remains to be determined. In the present study we used four strains of mice; wild-type (WT), UT(+) (a transgenic strain expressing human UT driven by the alpha-smooth muscle-specific, SM22, promoter), ApoE knockout (ko), and UT(+)/ApoE ko. All animals were fed high fat diet for 12 weeks. Western blot analysis revealed a significant increase in aortic UT expression in UT(+) relative to WT mice (P<0.05). Aortas of ApoE ko mice expressed comparable UT protein level to that of UT(+). Immunohistochemistry revealed the presence of strong expression of UT and UII proteins in the atheroma of UT(+), ApoE ko and UT(+)/ApoE ko mice, particularly in foam cells. Serum cholesterol and triglyceride levels were significantly increased in ApoE ko and in UT(+)/ApoE ko but not in UT(+) mice when compared to WT mice (P<0.0001). Analysis of aortas showed a significant increase in atherosclerotic lesion in the UT(+), ApoE ko and UT(+)/ApoE ko compared to WT mice (P<0.05). Oral administration of the UT receptor antagonist SB-657510A (30 microg/Kg/day gavage) for 10 weeks in a group of ApoE ko mice fed on high fat diet resulted in a significant reduction of lesion (P<0.001). SB-657510A also significantly reduced ACAT-1 protein expression in the atherosclerotic lesion of ApoE ko mice (P<0.05). The present findings demonstrate an important role for UT in the pathogenesis of atherosclerosis. The use of UT receptor antagonists may provide a beneficial tool in the management of this debilitating disease process.

Topics: Acetyl-CoA C-Acetyltransferase; Animals; Aorta; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Blotting, Western; Cardiovascular Agents; Cholesterol, Dietary; Disease Models, Animal; Foam Cells; Humans; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microfilament Proteins; Muscle Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Promoter Regions, Genetic; Receptors, G-Protein-Coupled; Sulfonamides; Triglycerides; Urotensins

Mildronate, an inhibitor of L-carnitine biosynthesis and transport, is used in clinics as a modulator of cellular energy metabolism and is a cardioprotective drug. L-Carnitine is a pivotal molecule in fatty acid oxidation pathways and its regulation in vasculature might be a promising approach for antiatherosclerotic treatment. This study was performed to evaluate the effects of mildronate treatment on the progression of atherosclerosis and the content of L-carnitine in the vascular wall.. ApoE/LDLR(-/-) mice received mildronate at doses of 30 and 100 mg/kg for 4 months. Lipid profile was measured in plasma and atherosclerotic lesions were analyzed in whole aorta and aortic sinus. L-Carnitine concentration was assessed in rat aortic tissues after 2 weeks of treatment with mildronate at a dose of 100 mg/kg.. The chronic treatment with mildronate at a dose of 100 mg/kg significantly reduced the size of atherosclerotic plaques in the aortic roots and in the whole aorta, and slightly decreased the free cholesterol level. In addition, mildronate treatment decreased L-carnitine concentration in rat aortic tissues.. Long-term mildronate treatment decreases L-carnitine content in aortic tissues and attenuates the development of atherosclerosis in apoE/LDLR(-/-) mice.

Topics: Animals; Aorta; Atherosclerosis; Betaine; Cardiovascular Agents; Carnitine; Energy Metabolism; Female; Lipids; Male; Methylhydrazines; Mice; Mice, Knockout; Rats; Rats, Wistar

Growth hormone-releasing peptides (GHRPs) as CD36 selective ligands feature potent anti-atherosclerotic activity that is associated with an upregulation of the peroxisome proliferator-activated receptor gamma (PPARgamma)-liver X receptor alpha (LXRalpha)-ATP-binding cassette (ABC) transporter pathway. However, the mechanism involved in PPARgamma activation in response to CD36 signalling has yet to be determined. Therefore, the present study aims to elucidate the upstream molecular mechanisms through which EP 80317, a selective CD36 ligand, promotes lipid efflux from macrophages through PPARgamma activation.. [3H]-Cholesterol- and [3H]-methylcholine chloride-labelled murine macrophages treated with EP 80317 showed a significant increase in cholesterol and phospholipid efflux to both apolipoprotein A-I and high-density lipoprotein in a CD36-dependent manner. Lipid efflux was associated with enhanced activation of PPARgamma. The signalling pathway by which this CD36 ligand promoted lipid efflux involved an increase in intracellular 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) levels induced by extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent cyclooxygenase-2 (COX-2) expression, leading to PPARgamma activation. In agreement, EP 80317-mediated cholesterol efflux was abrogated by inhibitors of PPARgamma, ERK1/2, and COX-2 as well as ABC transporter inhibitors, whereas a p38 mitogen-activated protein kinase inhibitor had no effect.. These findings suggest a central role for the prostanoid 15d-PGJ2 in PPARgamma activation and the upregulation of the ABC transporter pathway in response to CD36 activation by synthetic GHRPs analogues. The resulting enhanced cholesterol efflux might explain, at least in part, the atheroprotective effect of selective CD36 ligands.

Topics: Animals; Apolipoprotein A-I; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Biological Transport; Cardiovascular Agents; CD36 Antigens; Cell Line; Cholesterol; Cyclooxygenase 2; Disease Models, Animal; Lipoproteins; Lipoproteins, HDL; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Oligopeptides; Phospholipids; PPAR gamma; Prostaglandin D2; Signal Transduction; Time Factors

The aim of present study was to evaluate antioxidant property of Glycyrrhiza glabra root extracts using in vitro models. The dose-dependent aqueous and ethanolic extracts demonstrated the scavenging activity against nitric oxide (concentration that caused 50% inhibition of nitric oxide radicals [IC(50)]=72 and 62.1 microg/ml, respectively), superoxide (IC(50)=64.2 and 38.4 microg/ml, respectively), hydroxyl (IC(50)=81.9 and 63 microg/ml, respectively), DPPH (IC(50)=43.6 and 28.3 microg/ml, respectively) and ABTS(*+) (IC(50)=77.3 and 57.2 microg/ml, respectively) radicals. Further, both extracts showed strong reducing power and iron-chelating capacities. In the Fe(2+)/ascorbate system, both extracts were found to inhibit mitochondrial fraction lipid peroxidation. In copper-catalyzed human serum and low-density lipoprotein oxidation models, both extracts significantly (P<0.05) lengthened the lag phase along with a decline in the oxidation rate, conjugated dienes, lipid hydroperoxides and thiobarbituric acid reactive substance formation. In conclusion, ethanolic extract of G. glabra possess considerable antioxidant activity and protective effect against the human lipoprotein oxidative system.

Topics: Antioxidants; Atherosclerosis; Cardiovascular Agents; Chelating Agents; Copper; Dose-Response Relationship, Drug; Free Radical Scavengers; Glycyrrhiza; Inhibitory Concentration 50; Iron; Lipid Peroxidation; Lipoproteins, LDL; Mitochondria; Oxidation-Reduction; Plant Extracts; Plant Roots; Thiobarbituric Acid Reactive Substances

5-Lipoxygenase activating protein (FLAP) has been implicated in a number of different pathophysiological conditions owing to its involvement in leukotriene synthesis. Development of FLAP inhibitors has attracted considerable attention in recent years owing to genetic data supporting their potential as a valid pharmacological approach in prevention or treatment of atherosclerotic disease.. Since 2005, among other companies, Merck applied for several FLAP inhibitor patents. Patent WO 2008/030369 is the most recent and discloses novel molecules that act as potent inhibitors of FLAP. These compounds are claimed to be useful in the treatment of atherosclerosis, asthma, symptoms of allergic rhinitis and chronic obstructive pulmonary disease either in monotherapy or in combination with established treatments for the above-mentioned disorders. Although data for the potency of representative molecules from the current patent are reported, it is difficult to compare these compounds with previously described compounds.. Two FLAP inhibitors are already in clinical development for the treatment of respiratory and atherosclerotic disease by other pharmaceutical companies. Based on the in vitro activities of representative tested compounds from this patent, it is probable that these agents could be of therapeutic value but further preclinical studies are needed to evaluate their therapeutic potential and safety before clinical development.

Topics: 5-Lipoxygenase-Activating Proteins; Aniline Compounds; Animals; Asthma; Atherosclerosis; Cardiovascular Agents; Carrier Proteins; Humans; Membrane Proteins; Molecular Structure; Patents as Topic; Pyridines; Respiratory System Agents; Structure-Activity Relationship

Rho kinases have been shown to be involved in the pathogenesis of atherosclerosis. This study examined the effects of fasudil, a specific Rho kinase inhibitor, on plaque development and progression in atherosclerotic mice. Sixty apolipoprotein E-knockout (apoE-KO) mice were fed a high-fat diet. Mice started to receive fasudil at the same time as fat feeding (early treatment), or after 12 weeks of fat feeding (delayed treatment). In each administrative schedule, mice were divided into three groups: low dose fasudil group (30 mg/kg/day), high dose fasudil group (100mg/kg/day) and control group (tap water) (n=10, respectively). Plaque size was determined by using ultrasound biomicroscopy (UBM) and histological examinations. Brachiocephalic artery UBM analysis showed that in early treatment, both doses of fasudil significantly reduced lesion size compared with the controls (P<0.05). In delayed-fasudil treatment, plaque area was reduced by 54% (P<0.05) after 12 weeks of treatment at a high dose of fasudil (100mg/kg/day). The UBM findings were confirmed by histological studies at the corresponding arterial sites. The beneficial effect was also observed in the left common carotid arteries that delayed-fasudil treatment reduced the plaque size in a dose-dependent manner. The arterial intima-medial thickness (IMT) and maximal flow velocity of both arteries were lower in fasudil-treated group (100mg/kg/day) in comparison with the control mice. Furthermore, fasudil treatment (100mg/kg/day) reduced the macrophage accumulation in atherosclerotic lesions. However, fasudil had no effects on blood pressure and plasma lipid concentrations in both studies. In conclusion, our studies showed that blocking Rho kinase reduced both the early development and later progression of atherosclerotic plaques in apoE-KO mice by using a novel micro-ultrasound approach.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Apolipoproteins E; Atherosclerosis; Blood Pressure; Brachiocephalic Trunk; Cardiovascular Agents; Carotid Artery Diseases; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Immunohistochemistry; Lipids; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Acoustic; Protein Kinase Inhibitors; rho-Associated Kinases; Time Factors

Topics: Animals; Atherosclerosis; Biological Transport; Cardiovascular Agents; CD36 Antigens; Cholesterol; Cyclooxygenase 2; Growth Hormone-Releasing Hormone; Humans; Macrophages, Peritoneal; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Oligopeptides; Phospholipids; PPAR gamma; Prostaglandin D2; Signal Transduction

Australia's Pharmaceutical Benefits Scheme supports the use of effective drugs for the prevention and control of cardiovascular risk factors. However, there are little data available describing per person costs of medication in primary prevention and secondary prevention in the community. We aim to understand annual expenditure on cardiovascular medicines according to the level and extent of cardiovascular disease, using participants enrolled in the Reduction of Atherothrombosis for Continued Health (REACH) registry. 2873 participants were recruited into the REACH registry through 273 Australian general practices. Cardiovascular medicines review was undertaken at baseline. Average weighted costs of medications were estimated using government-reimbursed prices. Annual costs were stratified by disease extent and location. The annual mean cost of pharmaceuticals per person was 1307 AU dollars. The average reported medicine use per person across all states and participants groups varied significantly. Participants with cerebrovascular or peripheral arterial disease were prescribed less cardiovascular medication than those with coronary artery disease (CAD) (mean number of drugs 3.5 vs. 4.5, P < 0.0001) and (3.6 vs. 4.5, P < 0.0001), while those with risk factor alone had the same medication use as those with CAD (mean number 4.5). Medication use was lower in Western Australia in comparison to eastern States. Participants with existing cerebrovascular disease and peripheral vascular disease receive less preventive therapy than those with CAD or even risk factors alone. This observation is consistent across all mainland states. Given the evidence of the effectiveness and cost-effectiveness of treating all types of vascular diseases, the present study suggests that there is scope to improve the treatment of these high-risk participants in Australia.

Topics: Aged; Antihypertensive Agents; Atherosclerosis; Australia; Body Mass Index; Cardiovascular Agents; Cardiovascular Diseases; Employment; Female; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Male; Middle Aged; Platelet Aggregation Inhibitors; Registries; Risk Factors; Rural Population; Socioeconomic Factors; Suburban Population; Urban Population

Topics: Aged; Atherosclerosis; Cardiovascular Agents; Female; Humans; Male; Medication Adherence; Treatment Outcome

The European Society of Cardiology Annual Congress, held in Barcelona, included topics covering new therapeutic developments in the field of cardiovascular disease. This conference report highlights selected presentations on the development and progression of atherosclerosis, imaging techniques for treating atherosclerosis and clinical trials of treatments for cardiovascular disease. Investigational drugs discussed include ticagrelor (AstraZeneca AG).

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Disease Progression; Drug Delivery Systems; Drug Design; Drugs, Investigational; Humans

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Aortic Diseases; Aortic Rupture; Atherosclerosis; Biomarkers; Cardiovascular Agents; Complementary Therapies; Disease Progression; Drugs, Chinese Herbal; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation Mediators; Lipids; Simvastatin

Topics: Anti-Inflammatory Agents; Atherosclerosis; Blood Circulation; Cardiovascular Agents; China; Drugs, Chinese Herbal; Humans; Medicine, Chinese Traditional

A strong negative correlation between polyphenols consumption and coronary heart disease has been extensively documented. These results prompted investigations on the mechanisms responsible for polyphenols effects in cardiovascular disease. The aim of this work was to investigate in apoE KO mice the effect of P183/1 (a mixture of cathechin, caffeic acid and resveratrol) on atherosclerosis and gene expression patterns in the vascular wall. ApoE KO mice were fed a diet supplemented with P183/1, 40 and 160 mg/kg body weight/day for 8 weeks. The supplementation with the high dose of P183/1 significantly reduced the presence of atherosclerotic plaque by 40 and 36% in the aortic sinus and in the ascending aorta, respectively. This reduction was associated with a reduced expression of markers for macrophages, lymphocytes (both Th1 and Th2) and of MCP-1, MIP-1alpha, MIP-1beta, CCR1, CCR2 and ET1 in the vascular wall. In conclusion, P183/1 supplementation significantly decreases atherosclerosis in ApoE KO mice by affecting inflammatory cells recruitment and expression of pro-inflammatory chemokines in the vascular wall.

Topics: Animals; Anti-Inflammatory Agents; Aorta; Apolipoproteins E; Atherosclerosis; Caffeic Acids; Cardiovascular Agents; Catechin; Cytokines; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Gene Expression; Mice; Mice, Knockout; Receptors, Chemokine; RNA, Messenger; Stilbenes

Sirolimus is a potent immunosuppressive agent and has an anti-atherosclerotic effect through its anti-proliferative property. The present study was undertaken to investigate the effect of sirolimus on intracellular cholesterol homeostasis in human vascular smooth muscle cells (VSMCs) in the presence of inflammatory cytokine IL-1 beta. We explored the effect of sirolimus on the lipid accumulation of VSMCs in the presence of IL-1 beta, using Oil Red O staining and quantitative measurement of intracellular cholesterol. The effect of sirolimus on the gene and protein expression of lipoprotein receptors and ATP binding cassettes (ABCA1 and ABCG1) was examined by real-time PCR and Western blotting, respectively. Furthermore, the effect of sirolimus on cholesterol efflux from VSMCs in the presence or absence of IL-1 beta was also investigated using [(3)H] cholesterol efflux. Finally, we examined the effect of sirolimus on the production of inflammatory cytokines in VSMCs using ELISA. Sirolimus reduced intracellular lipid accumulation in VSMCs mediated by IL-1 beta possibly due to the reduction of expression of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) receptors. Sirolimus increased cholesterol efflux from VSMCs and overrode the suppression of cholesterol efflux induced by IL-1 beta. Sirolimus also increased ABCA1 and ABCG1 genes expression, even in the presence of IL-1 beta. We further confirmed that sirolimus inhibited mRNA and protein expression of inflammatory cytokines IL-6, tumor necrosis factor-alpha, IL-8, and monocyte chemoattractant protein-1. Inhibition of lipid uptake together with increasing cholesterol efflux and the inhibition of inflammatory cytokines are all important aspects of the anti-atherosclerotic effects of sirolimus on VSMCs.

Topics: Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Azo Compounds; Cardiovascular Agents; Cells, Cultured; Cholesterol; Coloring Agents; Coronary Vessels; Cytokines; Dose-Response Relationship, Drug; Gene Expression; Homeostasis; Humans; Inflammation; Interleukin-1beta; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Receptors, LDL; RNA, Messenger; Sirolimus; Staining and Labeling

The pharmacologic treatment of the cardiovascular comorbidities in patients with peripheral arterial disease (PAD) can have a profound effect on the outcomes of these patients. Guidelines for the treatment of hypertension, hyperlipidemia, diabetes, and tobacco use have been published by the American Heart Association and American College of Cardiology (AHA/ACC). Patients with PAD are often under-treated for these conditions. We sought to evaluate the adherence to these established guidelines in all new patients presenting with PAD to a vascular surgery clinic and delineate the opportunity for vascular surgeon involvement in these treatments. Consecutive new patients with symptomatic, objectively proven PAD (ankle-brachial index < 0.9) were evaluated in a vascular surgery clinic by a staff vascular surgeon. PAD risk factors, pre-visit medications, and prior cardiovascular interventions were recorded. Patients were stratified whether they were receiving appropriate preventive pharmacotherapy and whether they were meeting AHA/ACC goals. In patients without prior cardiovascular history, screening for these conditions was performed. One hundred sixty-seven new patients were evaluated over a 1-year period. Objectively diagnosed PAD included intermittent claudication in 115 (69%) and critical limb ischemia in 52 (31%) patients. Average age was 67.8 years, and 73 patients (44%) were current smokers. At initial evaluation, only 115 (69%) patients reported antiplatelet use. Patients with a recorded diagnosis of hypertension met clinical guidelines in 39 instances (71%). Eighteen patients (20%) with diabetes mellitus had poor glycemic control (Hgb-A1C > 7.0%). Seventeen (19%) of 88 patients with a history of hyperlipidemia were not adequately treated. Vascular surgeon medical interventions resulted in 31% of patients being started on antiplatelet therapy, 29% of hypertension therapies were modified, 19% of established lipid therapy was modified, and lipid therapy was initiated in 20%. A new diagnosis of hypertension was made in 10 cases (6%) and hyperlipidemia in 13 cases (7%). Despite clear guidelines for the medical community regarding cardiovascular prevention, a large percentage of patients with symptomatic PAD presenting to the vascular surgery clinic are not receiving appropriate therapy for their comorbidities or are not meeting the established goals. Vascular surgeons have an important role in promoting vascular health through the systemic prevention of isch

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Atherosclerosis; California; Cardiovascular Agents; Drug Utilization; Female; Guideline Adherence; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Male; Patient Compliance; Peripheral Vascular Diseases; Physician's Role; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Practice Patterns, Physicians'; Registries; Retrospective Studies; Risk Factors; Smoking; Smoking Cessation; Specialties, Surgical; Vascular Surgical Procedures

Inflammation contributes importantly to all stages of atherosclerosis, including the onset of acute thrombotic complications. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. Moreover, statins have been shown to possess several pleiotropic properties independent of cholesterol lowering in experimental settings. Based on these premises, we investigated the anti-inflammatory and anti-atherothrombotic properties of rosuvastatin in vivo, testing its effect on cholesterol and monocyte accumulation, and on adhesion molecules and tissue factor (TF) expression. ApoE-deficient female mice were fed a cholesterol-rich diet containing rosuvastatin (0, 1, 2 or 10 mg kg(-1)d(-1)) for 12 weeks. Treatment with rosuvastatin did not significantly affect either body weight gain or plasma total cholesterol (C) and triglyceride levels. However, rosuvastatin treatment dose-dependently reduced ICAM-1 expression in the aortic valves (V) (up to 40% inhibition, p<0.05) and in the proximal segment of the ascending aorta (AA) (-50%, p<0.001). Similarly, rosuvastatin inhibited VCAM-1 expression in the V (-40%) and in the AA (-35%, p<0.05). Moreover, there was a reduced accumulation of macrophages in the V in a dose-dependent and statistically significant manner (-45%, p<0.01). These anti-inflammatory effects were reflected in a reduction of cholesterol deposition in the entire aorta, both in the free and in the esterified form. Finally, the expression of tissue factor, the most potent pro-thrombogenic agent, was consistently reduced in AA by rosuvastatin treatment (-71%, p<0.001). Altogether, these data demonstrate that rosuvastatin has anti-inflammatory and anti-atherothrombotic activities in apoE-deficient mice that could translate in a beneficial effect on atherogenesis.

Topics: Animals; Anti-Inflammatory Agents; Aorta; Aortic Valve; Apolipoproteins E; Atherosclerosis; Cardiovascular Agents; Cholesterol; Cholesterol, Dietary; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fluorobenzenes; Intercellular Adhesion Molecule-1; Macrophages; Mice; Mice, Knockout; Pyrimidines; Rosuvastatin Calcium; Sulfonamides; Thromboplastin; Time Factors; Vascular Cell Adhesion Molecule-1

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Disease Progression; Drug Design; Humans; Inflammation

Evidence has been provided that red wine possesses antiatherogenic activities in virtue of its content in polyphenols (flavonoids and non-flavonoids substances). Here, some red wines (Negroamaro, Primitivo and Lambrusco) were tested for their ability to trigger nitric oxide (NO) production from human healthy peripheral blood mononuclear cells (PBMC). Negroamaro was the strongest inducer of NO from PBMC and deprivation of polyphenols did not influence its NO generation capacity. This fact supports the involvement of polyphenols in the NO production even in the absence of alcohol, which also per se does not exert any significant activity. These results are also corroborated by the evidence that PBMC inducible-nitric oxide synthase expression occurred by the effect of samples containing polyphenols but this expression was very weak when polyphenols were removed from the whole Negroamaro. In synthesis, flavonoids and resveratrol, major constituents of red wine, once absorbed at intestinal level, enter circulation and trigger monocytes for NO production. To the best of our knowledge, this is the first demonstration of a direct effect of red wine on monocytes for NO release to occur. On the other hand, also the macrophage contingent from gut-associated lymphoid tissue can contribute to NO generation, besides the aliquot produced by endothelial cells, as previously demonstrated by various authors. Taken together, these results support the concept that moderate intake of red wine can prevent atherosclerosis via production of NO, a potent vasodilator of terminal vessels.

Topics: Alcohol Drinking; Atherosclerosis; Cardiovascular Agents; Dose-Response Relationship, Drug; Ethanol; Flavonoids; Humans; Leukocytes, Mononuclear; Lipopolysaccharides; Nitric Oxide; Nitric Oxide Synthase Type II; Phenols; Polyphenols; Up-Regulation; Wine

There have been increasing evidences that atherosclerosis is not the result of diabetes mellitus, but that both type 2 diabetes mellitus and atherosclerosis may share common pathogenesis, as Stern proposed as 'common soil' hypothesis in 1995. There are several candidates for 'common soil', such as insulin resistance, vascular inflammation and endothelial dysfunction. Recently many of clinical studies have indicated that some drugs can prevent or delay the development of cardiovascular diseases (CVD). Furthermore, many studies have suggested that some classes of drugs may prevent the development of type 2 diabetes. It is to be noted that most of the drugs may have both actions, i.e., to prevent development of new diabetes and to prevent CVD. Furthermore, they are reported to inhibit inflammation or endothelial dysfunction. Taken together, it is hypothesized that the drug which may have antiatherogenetic action may also have antidiabetic action, and vice versa. This hypothesis may provide the new insights into perspectives of drug development both to prevent type 2 diabetes and to prevent CVD.

Topics: Atherosclerosis; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelium, Vascular; Humans; Hypoglycemic Agents; Inflammation; Models, Biological

Uday Saxena was appointed Chief Scientific Officer at Dr Reddy's Laboratories in 2000. In this role he provides the leadership and general strategy for the company's drug discovery research into metabolic disorders, cardiovascular disorders, inflammation, cancer and anti-infectives. He is also a member of the company's Senior Management Council. He gained his PhD at the Memorial University of Newfoundland, his thesis covering biochemical and functional characterisation of rat C-reactive protein with respect to lipid, lipoprotein metabolism, atherosclerosis and inflammation. On completing his postdoctoral fellowship at Colombia University, he went onto work on various drug discovery projects as Senior Scientist and Principal Research Scientist at Parke-Davis Warner-Lambert and as Director and Vice-President for preclinical research at AtheroGenics, Inc., before undertaking his current position. Uday Saxena has written over 50 peer-reviewed articles and invited reviews. He is currently on the Editorial Board of two international drug discovery-related journals including Expert Opinion on Therapeutic Targets.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Drug Delivery Systems; Humans

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Atherosclerosis; Cardiovascular Agents; Coronary Artery Disease; Diabetes Mellitus; Dyslipidemias; Health Behavior; Hematologic Agents; Humans; Hypertension; Hypolipidemic Agents; Influenza Vaccines; Mineralocorticoid Receptor Antagonists; Motor Activity; Obesity; Smoking Cessation

Cardiovascular biomarker research efforts have resulted in the identification of new risk factors and novel drug targets, as well as the establishment of treatment guidelines. Government agencies, academic research institutions, diagnostic industries, and pharmaceutical companies all recognize the importance of biomarkers in advancing therapies to improve public health. In drug development, biomarkers are used to evaluate early signals of efficacy and safety, to select dose, and to identify the target population. The United States Food and Drug Administration has relied on biomarkers to support clinical applications in many therapeutic fields, including cardiovascular disease. The appropriate application of cardiovascular biomarkers requires an understanding of disease natural history, the mechanism of the intervention, and the characteristics and limitations of the biomarker. Channels of communication among researcher, developer, and regulator must remain open to maximize the success of future biomarker efforts. In 2003, 2004, and 2005, an international panel of cardiovascular biomarker experts convened at the "Cardiovascular Biomarker and Surrogate Endpoints Symposia" held in Bethesda, Md, to discuss the use of biomarkers in the development of improved cardiovascular diagnostics and therapeutics. The information presented in the present report summarizes the authors' perspective distilled from these proceedings.

Topics: Atherosclerosis; Biomarkers; Cardiovascular Agents; Cardiovascular Diseases; Diagnostic Imaging; Drug Approval; Drug-Related Side Effects and Adverse Reactions; Endpoint Determination; Humans; Risk Factors; United States

Earlier studies evaluating long-term survival in type A acute aortic dissection (TA-AAD) have been restricted to a small number of patients in single center experiences. We used data from a contemporary, multi-center international registry of TA-AAD patients to better understand factors associated with long-term survival.. We examined 303 consecutive patients with TA-AAD enrolled in the International Registry of Acute Aortic Dissection (IRAD) between 1996 and 2003. We included patients who were discharged alive and had documented clinical follow-up data. Kaplan-Meier survival curves were constructed to depict cumulative survival in patients from date of hospital discharge. Stepwise Cox proportional hazards analysis was performed to identify independent predictors of follow-up mortality. We found that 273 (90.1%) patients had been managed surgically and 30 (9.9%) were managed medically. Patients who were dead at follow-up were more likely to be older (63.9 versus 58.4 years, P=0.007) and to have had previous cardiac surgery (23.9% versus 10.6%, P=0.01). Survival for patients treated with surgery was 96.1%+/-2.4% and 90.5%+/-3.9% at 1 and 3 years versus 88.6%+/-12.2% and 68.7%+/-19.8% without surgery (mean follow-up overall, 2.8 years, log rank P=0.009). Multivariate analysis identified a history of atherosclerosis (relative risk (RR), 2.17; 95% confidence interval [CI], 1.08 to 4.37; P=0.03) and previous cardiac surgery (RR, 2.54; 95% CI, 1.16 to 5.57; P=0.02) as significant, independent predictors of follow-up mortality.. Contemporary 1- and 3-year survival in patients with TA-AAD treated surgically are excellent. Independent predictors of survival during the follow-up period do not appear to be influenced by in-hospital risks but rather preexisting comorbidities.

Topics: Acute Disease; Age Factors; Aged; Antihypertensive Agents; Aortic Aneurysm; Aortic Dissection; Atherosclerosis; Cardiac Surgical Procedures; Cardiovascular Agents; Case Management; Comorbidity; Europe; Female; Follow-Up Studies; Humans; Hypertension; Japan; Life Tables; Male; Middle Aged; Mortality; Patient Discharge; Postoperative Complications; Proportional Hazards Models; Registries; Risk Factors; Survival Analysis; Treatment Outcome; United States

The clinical profiles and outcomes of patients treated surgically for acute type B aortic dissection (ABAD) are often reported for those in small series or for those cared for at a single institution over a long time period, during which a continuous evolution in techniques has occurred. Accordingly, we sought to evaluate the clinical features and surgical results of patients enrolled in the International Registry of Acute Aortic Dissection by identifying primary factors that influenced surgical outcome and estimating average surgical mortality for ABAD in the current era.. A comprehensive analysis of 290 clinical variables and their relation to surgical outcomes for 82 patients who required surgery for ABAD (from a population of 1256 patients; mean+/-SD age, 60.6+/-15.0 years; 82.9% male) and who were enrolled in the International Registry of Acute Aortic Dissection was performed. The overall in-hospital mortality was 29.3%. Factors associated with increased surgical mortality based on univariate analysis were preoperative coma or altered consciousness, partial thrombosis of the false lumen, evidence of periaortic hematoma on diagnostic imaging, descending aortic diameter >6 cm, right ventricle dysfunction at surgery, and shorter time from the onset of symptoms to surgery. Factors associated with favorable outcomes included radiating pain, normotension at surgery (systolic blood pressure 100 to 149 mm Hg), and reduced hypothermic circulatory arrest time. The 2 independent predictors of surgical mortality were age >70 years (odds ratio, 4.32; 95% confidence interval, 1.30 to 14.34) and preoperative shock/hypotension (odds ratio, 6.05; 95% confidence interval, 1.12 to 32.49).. The present study provides insights into current-day clinical profiles and surgical outcomes of ABAD. Knowledge about different preoperative clinical conditions may help surgeons in making treatment decisions among these high-risk patients.

Topics: Acute Disease; Aged; Anastomosis, Surgical; Antihypertensive Agents; Aortic Aneurysm, Thoracic; Aortic Dissection; Aortic Rupture; Atherosclerosis; Blood Vessel Prosthesis Implantation; Cardiovascular Agents; Comorbidity; Disease Susceptibility; Europe; Female; Follow-Up Studies; Heart Diseases; Hemodynamics; Hospital Mortality; Humans; Hypertension; Japan; Male; Marfan Syndrome; Middle Aged; Paraplegia; Postoperative Complications; Registries; Spinal Cord Ischemia; Stents; Survival Analysis; Treatment Outcome; United States

Topics: Arteriosclerosis; Atherosclerosis; Cardiovascular Agents; Drug Therapy; Flavonoids; Research

Topics: Arteriosclerosis; Atherosclerosis; Cardiovascular Agents; Humans; Intestines; Muscle Relaxants, Central; Parasympatholytics