cardiovascular-agents and Inflammation

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

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

Acute heart failure (AHF) is a complex, heterogeneous, clinical syndrome with high morbidity and mortality, incurring significant health care costs. Patients transition from home to the emergency department, the hospital, and home again and require decisions surrounding diagnosis, treatment, and prognosis at each step of the way. The purpose of this review is to examine the epidemiology, etiology, and classifications of AHF and specifically focus on practical information relevant to the clinician. We examine the mechanisms of decompensation relevant to clinical presentations-including precipitating factors, neuroendocrine interactions, and inflammation-along with how consideration of these factors may help select therapies for an individual patient. The prevalence and significance of end-organ manifestations such as renal, gastrointestinal, respiratory, and neurologic manifestations are discussed. We also highlight how the development of renal dysfunction relates to the choice of a variety of diuretics that may be useful in specific circumstances and review guideline-directed medical therapy. We discuss the practical use (and pitfalls) of a variety of evidence-based clinical scoring criteria available to risk stratify patients with AHF. Finally, evidence-based management of AHF is discussed, including both pharmacologic and nonpharmacologic therapies, including the lack of evidence for using old and new vasodilators and the recent evidence regarding initiation of newer therapies in hospital. Overall, we suggest that clinicians consider implementing the newer data in AHF and subject existing practice patterns and treatments to the same rigour as new therapies.

Topics: Acute Disease; Algorithms; Cardiac Rehabilitation; Cardiovascular Agents; Cognitive Dysfunction; Diagnostic Techniques, Cardiovascular; Diuretics; Evidence-Based Medicine; Gastrointestinal Diseases; Heart Failure; Humans; Inflammation; Kidney Diseases; Noninvasive Ventilation; Renin-Angiotensin System; Severity of Illness Index; Sleep Apnea Syndromes; Sympathetic Nervous System

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

The findings of randomized trials of neurohormonal modulation have been neutral in heart failure with preserved ejection fraction and consistently positive in heart failure with reduced ejection. Left ventricular remodeling promotes the development and progression of heart failure with preserved and reduced ejection fraction. However, different stimuli mediate left ventricular remodeling that is commonly concentric in heart failure with preserved ejection fraction and eccentric in heart failure with reduced ejection. The stimuli that promote concentric left ventricular remodeling may account for the neutral findings of neuhormonal modulation in heart failure with preserved ejection fraction. Low-grade systemic inflammation-induced microvascular endothelial dysfunction is currently the leading hypothesis behind the development and progression of heart failure with preserved ejection fraction. The hypothesis provided the rationale for several randomized controlled trials that have led to neutral findings. The trials and their limitations are reviewed.

Topics: Animals; Cardiovascular Agents; Comorbidity; Heart Disease Risk Factors; Heart Failure; Heart Ventricles; Humans; Inflammation; Inflammation Mediators; Recovery of Function; Risk Assessment; Signal Transduction; Stroke Volume; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

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

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

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

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

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

The prevalence of heart failure (HF) with preserved ejection fraction (HFpEF) is higher than that of HF with reduced/midrange ejection fraction (HFrEF/HFmrEF). However, no evidence-based guidelines for managing HFpEF have been generated. The current body of knowledge indicates that fibrosis and inflammation are important components of the cardiac remodeling process in HFpEF. In addition, macrophages potentially play an important role in pro-inflammatory and profibrotic processes in HFpEF patients, whereas HFpEF comorbidities could be a driving force for systemic microvascular inflammation and endothelial dysfunction. Under such circumstances, macrophages reportedly contribute to inflammation and fibrosis through 3 phases namely, inflammation, repair, and resolution. Signal transduction pathway-targeted therapies using animal experiments have generated important discoveries and breakthroughs for understanding the underlying mechanisms of HFpEF. However, only a handful of studies have reported promising results using human trials. Further investigations are therefore needed to elucidate the exact mechanisms underlying HFpEF and immune-pathogenesis of cardiac fibrosis.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Comorbidity; Fibrosis; Heart Failure; Humans; Inflammation; Inflammation Mediators; Macrophages; Molecular Targeted Therapy; Myocardium; Signal Transduction; Stroke Volume; Ventricular Function, Left

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

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

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

Atrial fibrillation (AF) is the most common type of arrhythmia in the general population with a prevalence that reaches one third of patients with arterial hypertension. Several risk factors frequently associated with hypertension predispose the myocardium to AF by inducing atrial inflammation and fibrosis and altering atrial electrical and mechanical characteristics. AF influences the quality of life of hypertensive patients since it increases incidence of stroke and other thromboembolic events, and mortality. Polyunsaturated fatty acids of the ω-3 family (ω-3 PUFA) have been demonstrated to be beneficial in cardiovascular disease prevention by reducing plasma lipids and blood pressure levels and decreasing the risk of sudden death. These fatty acids can act as potent anti-inflammatory and anti-arrhythmic agents. Many studies have investigated a possible preventive effect of ω-3 PUFA on incident AF reporting contradictory results. This article overviews the evidence currently available on this important topic and provides some conclusive remarks on the possibility that these fatty acids could be beneficial in hypertensive patients.

Topics: Atrial Fibrillation; Cardiovascular Agents; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Fibrosis; Humans; Hypertension; Incidence; Inflammation; Quality of Life; Risk Factors

Nanoparticles promise to advance strategies to treat vascular disease. Since being harnessed by the cancer field to deliver safer and more effective chemotherapeutics, nanoparticles have been translated into applications for cardiovascular disease. Systemic exposure and drug-drug interactions remain a concern for nearly all cardiovascular therapies, including statins, antithrombotic, and thrombolytic agents. Moreover, off-target effects and poor bioavailability have limited the development of completely new approaches to treat vascular disease. Through the rational design of nanoparticles, nano-based delivery systems enable more efficient delivery of a drug to its therapeutic target or even directly to the diseased site, overcoming biological barriers and enhancing a drug's therapeutic index. In addition, advances in molecular imaging have led to the development of theranostic nanoparticles that may simultaneously act as carriers of both therapeutic and imaging payloads. The following is a summary of nanoparticle therapy for atherosclerosis, thrombosis, and restenosis and an overview of recent major advances in the targeted treatment of vascular disease.

Topics: Animals; Cardiovascular Agents; Chemotaxis, Leukocyte; Cholesterol; Drug Carriers; Drug Evaluation, Preclinical; Forecasting; Humans; Inflammation; Macrophages; Mice; Nanoparticles; Neointima; Neovascularization, Pathologic; Plaque, Atherosclerotic; RNA Interference; RNA, Small Interfering; Thrombosis; Vascular Diseases

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

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

The NLRP3 inflammasome is an intracellular, multimeric protein complex that initiates a potent inflammatory response to danger signals. After acute myocardial infarction, NLRP3 inflammasome-dependent inflammation promotes adverse left ventricular remodeling and recurrent atherosclerotic events. Selective and nonselective inhibitors of the NLRP3 inflammasome or its downstream effectors (interleukin-1β and interleukin-18) may prevent adverse left ventricular remodeling and recurrent atherosclerotic events. In this review, we highlight strategies to inhibit NLRP3 inflammasome activity and their potential roles in the management of acute myocardial infarction.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Humans; Inflammasomes; Inflammation; Inflammation Mediators; Molecular Targeted Therapy; Myocardial Infarction; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction

An accumulating body of evidence indicates that NLRP3 inflammasome plays a crucial role in the pathophysiology of cardiovascular diseases, including atherosclerosis and acute myocardial infarction (MI). NLRP3 inflammasome is a multimeric protein complex that leads to activation of caspase-1, which further induces maturation of interleukin (IL)-1β and IL-18. Activated caspase-1 also induces a particular form of cell death called pyroptosis by the cleavage of gasdermin D. Our and other groups have shown that inhibition of the NLRP3 inflammasome attenuates the inflammatory response and ameliorates myocardial dysfunction and remodeling in animal models of acute MI. Interestingly, investigations have suggested that NLRP3 inflammasome has cell-specific roles in different cell types, such as inflammatory cells, cardiomyocytes, cardiac fibroblasts, and vascular endothelial cells, after acute MI. Moreover, the recent CANTOS trial showed that inhibition of IL-1β was efficacious in secondary prevention for cardiovascular events in patients with previous MI. These findings suggest that NLRP3 inflammasome may be a potential target for the prevention and therapy of MI. This review summarizes recent knowledge on NLRP3 inflammasome and focuses on its cell-specific roles in acute MI.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cytokines; Endothelial Cells; Fibroblasts; Humans; Inflammasomes; Inflammation; Inflammation Mediators; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Signal Transduction

Acute myocardial infarction (AMI) is associated with the induction of a sterile inflammatory response that leads to further injury. The NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a macromolecular structure responsible for the inflammatory response to injury or infection. NLRP3 can sense intracellular danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is primed and triggered by locally released damage-associated molecular patterns and amplifies the inflammatory response and cell death through caspase-1 activation. Here, we examine the scientific evidence supporting a role for NLRP3 in AMI and the available strategies to inhibit the effects of the inflammasome. Our focus is on the beneficial effects seen in experimental models of AMI in preclinical animal models and the initial results of clinical trials.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cytokines; Humans; Inflammasomes; Inflammation; Inflammation Mediators; Myocardial Infarction; Myocardium; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Signal Transduction

In the vascular system, the endothelial surface layer (ESL) as the inner surface of blood vessels affects mechanotransduction, vascular permeability, rheology, thrombogenesis, and leukocyte adhesion. It creates barriers between endothelial cells and blood and neighbouring cells. The glycocalyx, composed of glycoconjugates and proteoglycans, is an integral component of the ESL and a key element in inter- and intracellular communication and tissue homeostasis. In pathophysiological conditions (atherosclerosis, infection, ischemia/reperfusion injury, diabetes, trauma and acute lung injury) glycocalyx-degrading factors, i.e. reactive oxygen and nitrogen species, matrix metalloproteinases, heparanase and sialidases, damage the ESL, thereby impairing endothelial functions. This leads to increased capillary permeability, leucocyte-endothelium interactions, thrombosis and vascular inflammation, the latter further driving glycocalyx destruction. The present review highlights current knowledge on the vasculoprotective role of the ESL, with specific emphasis on its remodelling in inflammatory vascular diseases and discusses its potential as a novel therapeutic target to treat vascular pathologies.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Endothelial Cells; Glycocalyx; Humans; Inflammation; Inflammation Mediators; Signal Transduction; Vascular Diseases; Vascular Remodeling

The morbidity of myocarditis demonstrates an upward tendency by years, is commonly defined as the inflammation of myocytes and is caused by multiple factors. With the development of the molecular biological technique, great breakthroughs in the diagnosis and understanding of pathophysiological mechanisms of myocarditis have recently been achieved. Several questions remain unresolved, however, including standard treatment approaches to myocarditis, which remain controversial and ambiguous. Heart rate, as an independent risk factor, has been shown to be related to cardiac disease. Recent studies also show that the autonomic nervous system is involved in immunomodulatory myocarditis processes. Heart rate reduction treatment is recommended in myocarditis based on a number of animal experiments and clinical trials. It is possible that heart rate-lowering treatments can help to attenuate the inflammatory response and myocyte injury and reverse ventricular remodeling. However, how to execute the protective effects of heart rate reduction on myocarditis is still not clear. In this review, we discuss the pathogenesis and pathophysiological process of viral myocarditis and propose heart rate lowering as a therapeutic target for myocarditis, especially in light of the third-generation β-blockade carvedilol and funny channel blocker ivabradine. We also highlight some additional beneficial effects of such heart rate reduction agents, including anti-inflammatory, antioxidation, anti-nitrosative stress, anti-fibrosis and antiapoptosis properties.

Topics: Adrenergic beta-Antagonists; Animals; Cardiovascular Agents; Carvedilol; Heart Rate; Humans; Inflammation; Ivabradine; Myocarditis

Heart failure (HF) is a clinical syndrome of diverse etiologies and can be associated with preserved, reduced, or mid-range ejection fraction (EF). In the community, heart failure with preserved ejection fraction (HFpEF) is emerging as the most common form of HF. There remains considerable uncertainty regarding its pathogenesis, diagnosis, and optimal therapeutic approach. Hypotheses have been advanced to explain the underlying pathophysiology responsible for HFpEF, but to date, no specific therapy based on these hypotheses has been proven to improve outcomes in HFpEF. We provide a clinically focused review of the epidemiology, clinical presentation, diagnostic approach, pathophysiology, and treatment of HFpEF.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Dyspnea; Exercise Tolerance; Heart Failure; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Incidence; Inflammation; Ivabradine; Mineralocorticoid Receptor Antagonists; Mortality; Nitrates; Phosphodiesterase 4 Inhibitors; Risk Factors; Stroke Volume

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

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

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

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

Acetylsalicylic acid (aspirin) is a prototypic cyclooxygenase (COX) inhibitor. It was synthesized serendipitously from a natural compound, i.e., salicylic acid, with known analgesic activity. This chemical modification, obtained for the first time in an industrial environment in 1897, endowed aspirin with the unique capacity of acetylating and inactivating permanently COX-isozymes. Traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) were developed to mimic the pharmacological effects of aspirin, using aspirin-sensitive experimental models of pain and inflammation as the template for screening new chemical entities. Among the tNSAIDs, some were endowed with moderate COX- selectivity (e.g., diclofenac), but no studies of sufficient size and duration were performed to show any clinically relevant difference between different members of the class. Similarly, no serious attempts were made to unravel the mechanisms involved in the shared therapeutic and toxic effects of tNSAIDs until the discovery of COX-2. This led to characterizing their main therapeutic effects as being COX-2-dependent and their gastrointestinal (GI) toxicity as being COX-1-dependent, and provided a rationale for developing a new class of selective COX-2 inhibitors, the coxibs. This review will discuss the clinical pharmacology of tNSAIDs and coxibs, and the clinical read-outs of COX-isozyme inhibition. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance."

Topics: Animals; Anticarcinogenic Agents; Cardiovascular Agents; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Gastrointestinal Diseases; Heart Diseases; Humans; Inflammation; Isoenzymes; Molecular Structure; Neoplasms; Risk Factors; Signal Transduction; Structure-Activity Relationship

Statins are known to prevent heart failure (HF). However, it is unclear whether statins as class or type (lipophilic or hydrophilic) improve outcomes of established HF.. The current meta-analysis was performed to compare the treatment effects of lipophilic and hydrophilic statins on inflammation and cardiac function in HF. Outcomes were indicators of cardiac function [changes in left ventricular ejection fraction (LVEF) and B-type natriuretic peptide (BNP)] and inflammation [changes in highly sensitive C-reactive protein (hsCRP) and interluekin-6 (IL-6)].. We conducted a search of PubMed, EMBASE, and the Cochrane databases until December 31, 2014 for randomized control trials (RCTs) of statin versus placebo in patients with HF. RCTs with their respective extracted information were dichotomized into statin type evaluated and analyzed separately. Outcomes were pooled with random effect approach, producing standardized mean differences (SMD) for each statin type. Using these pooled estimates, we performed adjusted indirect comparisons for each outcome.. Data from 6214 patients from 19 trials were analyzed. Lipophilic statin was superior to hydrophilic statin treatment regarding follow-up LVEF (SMD, 4.54; 95% CI, 4.16-4.91; P < 0.001), BNP (SMD, -1.60; 95% CI, -2.56 to -0.65; P < 0.001), hsCRP (SMD, -1.13; 95% CI, -1.54 to -0.72; P < 0.001), and IL-6 (SMD, -3.75; 95% CI, -4.77 to -0.72; P < 0.001) in HF.. Lipophilic statin produces greater treatment effects on cardiac function and inflammation compared with hydrophilic statin in patients with HF. Until data from adequately powered head-to-head trial of the statin types are available, our meta-analysis brings clinicians and researchers a step closer to the quest on which statin--lipophilic or hydrophilic--is associated with better outcomes in HF.

Topics: Anti-Inflammatory Agents; Biomarkers; Cardiovascular Agents; Heart Failure; Humans; Hydrophobic and Hydrophilic Interactions; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Randomized Controlled Trials as Topic; Stroke Volume; Treatment Outcome; Ventricular Function, Left

In addition to their role as xenobiotic metabolizing enzymes, cytochrome P450 (CYP) epoxygenases actively contribute to the metabolism of endogenous substances such as arachidonic acid. Epoxyeicosatrienoic acids (EETs) are epoxide derivative of arachidonic acid. CYP2C8/9 and CYP2J2 are the main epoxygenases expressed in human tissues including endothelial cells which are the chief sources of EET formation in human body. Once formed, EETs are primarily metabolized to their less biologically active metabolites, dihydroxyeicosatrienoic acids, by soluble epoxy hydrolase (sEH) enzyme. EETs possess a wide range of established protective effects on human cardiovascular system of which vasodilatory, angiogenic and anti-inflammatory actions have been more extensively described. On the other hand, inflammation has shown to decrease the expression and activity of CYP enzyme, including epoxygenases. Given the fact that CYP epoxygenase-derive EETs exhibit potent cardiovascular protective effects, including anti-inflammation, and that inflammation suppress CYP activation and EET formation, it would make sense to speculate that under inflammatory conditions there exists an inflammation-epoxygenase-EET-inflammation vicious cycle in which the inflammation-induced downregulation of CYP epoxygenases causes a decrease in the EET production. Insufficient EET synthesis would, in turn, lead to an ineffective EET-mediated anti-inflammatory effect, leading to an augmentation of systemic and regional inflammatory responses and further downregulation of CYP epoxygenase activity/EET production. This cycle, if any, might help to better understanding of pathophysiology of chronic cardiovascular diseases and also could be an emerging target for further pharmacological therapy of disorders in which increased inflammatory responses are known to occur.

Topics: Animals; Arachidonic Acid; Cardiovascular Agents; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Humans; Inflammation

Heart failure is a growing global epidemic that involves in its pathophysiology a proinflammatory state. Since the first description of elevated cytokine levels in this setting, there has been increasing interest in understanding the role of these molecules in left-ventricular remodeling and function. Over the years, intense research on the 'cytokine theory' of heart failure has allowed evaluation of the role of inflammatory biomarkers not only as pathogenetic mediators, but also as potential tools in the diagnosis and risk stratification of heart failure patients. Whereas current evidence does not support the use of inflammatory biomarkers for the diagnosis of heart failure, the assessment of their levels and the connection between their changes and changes in clinical status and prognosis has been well validated. At present, the utility of anti-inflammatory therapies in heart failure is still debated, since trials of anti-inflammatory agents in this setting have pointed out controversial results. On the contrary, established treatments of heart failure, including β-blockers, renin-angiotensin system antagonists, and aldosterone-receptor blockers seem able to act by modulating cytokine expression, suggesting a new role for these molecules in guiding heart failure therapy. Therefore, the binomial topic of heart failure and inflammation still has a number of fields not completely explored: our aim is to update current knowledge and future perspectives.

Topics: Anti-Inflammatory Agents; Biomarkers; Cardiovascular Agents; Heart Failure; Humans; Inflammation; Inflammation Mediators

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

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

Cardiovascular disease is the leading determinant of mortality and morbidity in women. Functional foods are attracting interest as potential regulators of the susceptibility to disease. Supported by epidemiological evidence, chocolate has emerged as a possible modulator of cardiovascular risk. Chocolate, or cocoa as the natural source, contains flavanols, a subclass of flavonoids. The latter years have witnessed an increasing number of experimental and clinical studies that suggest a protective effect of chocolate against atherogenesis. Oxidative stress, inflammation, and endothelial function define three biological mechanisms that have shown sensitivity to chocolate. Moreover, the consumption of chocolate has been involved in the protective modulation of blood pressure, the lipid profile, the activation of platelets, and the sensitivity to insulin. Dark chocolate seems more protective than milk or white chocolate. Despite this array of benefits, there is a lack of well designed clinical studies demonstrating cardiovascular benefit of chocolate. The high caloric content of chocolate, particularly of some less pure forms, imposes caution before recommending uncontrolled consumption.

Topics: Animals; Cacao; Cardiovascular Agents; Cardiovascular Diseases; Endothelium, Vascular; Flavonols; Functional Food; Humans; Inflammation; Insulin; Lipids; Phytotherapy; Plant Preparations; Platelet Activation

The therapeutic areas of infectious diseases and oncology have benefited from abundant scaffold diversity in natural products, able to interact with many specific targets within the cell and indeed for many years have been source or inspiration for the majority of FDA approved drugs. The present review describes natural products (NPs), semi-synthetic NPs and NP-derived compounds that have undergone clinical evaluation or registration from 2005 to 2010 by disease area i.e. infectious (bacterial, fungal, parasitic and viral), immunological, cardiovascular, neurological, inflammatory and related diseases and oncology.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Biological Products; Cardiovascular Agents; Cardiovascular Diseases; Communicable Diseases; Drug Discovery; Humans; Inflammation; Metabolic Diseases; Neoplasms; Nervous System Diseases; Plant Extracts; Plants, Medicinal

Statins possess several pleiotropic effects and have been shown in vitro and in vivo to inhibit the expression of inflammatory mediators and downregulate molecules involved in extracellular matrix (ECM) degradation. Recent observational studies in humans suggest that statins may have a role in abdominal aortic aneurysm (AAA) prevention or may even inhibit aneurysm expansion. In this review, we summarize the effects of statins on the vessel wall of aneurysmal aortas and currently available data concerning their inhibitory effects on aneurysm progression.

Topics: Animals; Aortic Aneurysm, Abdominal; Atorvastatin; Blood Vessels; Cardiovascular Agents; Disease Progression; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Matrix Metalloproteinases; Models, Animal; Pyrroles; Risk Assessment; Simvastatin

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

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

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

Morbidity of patients with cardiac syndrome X (typical anginal-like chest pain and normal coronary arteriogram) is high with continuing episodes of chest pain and frequent hospital readmissions. Management of this syndrome represents a major challenge for the treating physician. Conventional therapies with antianginal agents such as nitrates, calcium channel antagonists, classic beta-adrenoceptor blockers and nicorandil have been tried, with variable success. However, this might be related to a failure to target the underlying pathophysiology and, clearly, more effective therapies are needed. Supporting evidence for the important role of endothelial dysfunction and oxidative stress in the pathogenesis of cardiac syndrome X has come from the recent observation that basal superoxide production predicts future cardiovascular events in this patient group. This review will discuss the pathophysiology, current medical management and potential new pharmacological treatment for patients with cardiac syndrome X which target endothelial dysfunction and oxidative stress. What's already known about this topic? Morbidity of patients with cardiac syndrome X is high. The important role of endothelial dysfunction and oxidative stress in the pathogenesis of cardiac syndrome X. What does this article add? This review will discuss the pathophysiology, current medical management and potential new pharmacological treatment for patients with cardiac syndrome X which target endothelial dysfunction and oxidative stress.

Topics: Animals; Antioxidants; Cardiovascular Agents; Cognitive Behavioral Therapy; Endothelium, Vascular; Estrogen Replacement Therapy; Estrogens; Exercise; Humans; Inflammation; Insulin Resistance; Microcirculation; Microvascular Angina; Myocardial Ischemia; Oxidative Stress; Treatment Outcome

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

New treatment options have improved the prognosis of patients with pulmonary arterial hypertension. However, drugs such as prostanoids, PDE5 inhibitors and endothelin receptor antagonists mainly act as vasodilating agents. Recently, it has become clear that pulmonary arterial hypertension is an inflammatory and vasoproliferative disease. Therefore new anti-inflammatory and antiproliferative treatments are needed. This review will focus on the pathogenesis of inflammation and vasoproliferation in pulmonary hypertension. In addition, an overview on possible new antiinflammatory and antiproliferative drugs in pulmonary hypertension (e.g. Rho-kinase inhibitors, imatinib mesylate. HMG-CoA reductase inhibitors) will be given along with recent patents.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cell Proliferation; Endothelial Cells; Endothelium, Vascular; Enzyme Inhibitors; Humans; Hypertension, Pulmonary; Inflammation; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle

Systolic heart failure is a feed-forward phenomenon with devastating consequences. Impaired cardiac function is the initiating event, but central nervous system mechanisms activated by persistent altered neural and humoral signals from the periphery play an important sustaining role. Animals with experimentally induced heart failure have neurochemical abnormalities in the brain that, when manipulated, profoundly affect sympathetic drive, volume regulation, and cardiac remodeling--critical determinants of outcome. This brief review explores recent studies that provide a strong rationale for the development of pharmaceutical agents that target central nervous system abnormalities in heart failure.

Topics: Aldosterone; Angiotensins; Animals; Blood-Brain Barrier; Brain; Cardiovascular Agents; Cell Communication; Cytokines; Drug Carriers; Drug Design; Heart Failure, Systolic; Humans; Inflammation; Sympathetic Nervous System

Chronic cardiopulmonary disease typically induces and maintains (over)activation of several phylogenetically old adaptational and defensive mechanisms. Activation was usually needed for a limited period during acute danger or injury. In chronic disease conditions, however, those mechanisms are kept activated for longer periods. Eventually, irreversible damage is done and this contributes to impaired function and worse prognosis in a variety of chronic disease. Landmark trials in chronic heart failure have provided robust evidence for prognostic benefit for neurohormonal antagonists. Retrospective and epidemiological data for their beneficial effect in chronic obstructive pulmonary disease begin to accumulate and new fields (e.g. cancer and stroke) could be pending in the future.

Topics: Cachexia; Cardiovascular Agents; Clinical Trials as Topic; Comorbidity; Heart Failure; Humans; Inflammation; Neurotransmitter Agents; Pulmonary Disease, Chronic Obstructive; Renin-Angiotensin System; Risk Factors; Stroke

In this review we discuss the role of pigment epithelium-derived factor (PEDF) as a possible new target molecule to therapeutically influence cardiovascular disease. PEDF is a multifunctional, pleiotropic protein with antiangiogenic, antitumorigenic, antioxidant, anti-inflammatory, antithrombotic, neurotrophic and neuroprotective properties. First identified in retinal pigment epithelium cells, it is expressed in various tissues throughout the body such as the eye, liver and adipose tissue. Recently PEDF has also been characterized in the heart. PEDF has been suggested to have a protective role in atherosclerosis, the main cause of coronary heart disease, myocardial infarction and heart failure due to its anti-inflammatory, antioxidant and antithrombotic effects in the vessel wall and platelets. Additionally PEDF has strong antiangiogenic effects by inducing apoptosis in endothelial cells and by regulating the expression of other angiogenic factors. Therefore blocking of PEDF locally for example in ischemic tissue in the heart might favour angiogenesis, induce neovascularization and lead to increased perfusion of the injured tissue. On the other hand, local overexpression of PEDF restricted to atherosclerotic lesions might block angiogenesis, inflammation and thrombosis at these sites and thus counteract destabilization and rupture of the lesion otherwise caused by inflammatory activation and excessive angiogenesis and inhibit subsequent thrombus formation.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Eye Proteins; Humans; Inflammation; Neovascularization, Pathologic; Nerve Growth Factors; Serpins

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

Heme oxygenase-1, an enzyme degrading heme to carbon monoxide, iron, and biliverdin, has been recognized as playing a crucial role in cellular defense against stressful conditions, not only related to heme release. HO-1 protects endothelial cells from apoptosis, is involved in blood-vessel relaxation regulating vascular tone, attenuates inflammatory response in the vessel wall, and participates in blood-vessel formation by means of angiogenesis and vasculogenesis. The latter functions link HO-1 not only to cardiovascular ischemia but also to many other conditions that, like development, wound healing, or cancer, are dependent on neovascularization. The aim of this comprehensive review is to address the mechanisms of HO-1 regulation and function in cardiovascular physiology and pathology and to demonstrate some possible applications of the vast knowledge generated so far. Recent data provide powerful evidence for the involvement of HO-1 in the therapeutic effect of drugs used in cardiovascular diseases. Novel studies open the possibilities of application of HO-1 for gene and cell therapy. Therefore, research in forthcoming years should help to elucidate both the real role of HO-1 in the effect of drugs and the clinical feasibility of HO-1-based cell and gene therapy, creating the effective therapeutic avenues for this refined antioxidant system.

Topics: Animals; Apoptosis; Biliverdine; Carbon Monoxide; Cardiovascular Agents; Cardiovascular Diseases; Child; Diabetes Complications; Endothelium, Vascular; Enzyme Induction; Female; Genetic Therapy; Heme; Heme Oxygenase-1; Humans; Inflammation; Iron; Male; Mice; Mice, Knockout; Neovascularization, Physiologic; Rabbits; Rats; Vasomotor System

Insulin resistance, cardiometabolic syndrome, and hypertension are common health problems with significant consequences for individuals and society. The pathogenesis of these disorders is complex and not fully understood. In this article we review the current knowledge about the effects of lifestyle modification and pharmacologic antihypertensive agents on insulin resistance and hypertension.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Agents; Endothelium, Vascular; Humans; Hypertension; Inflammation; Insulin Resistance; Life Style; Mineralocorticoid Receptor Antagonists; Obesity; Renin; Renin-Angiotensin System

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

Atrial fibrillation occurs and maintains itself in the context of a morphologically and functionally altered atrial substrate that can be induced by stressors such as underlying diseases (cardiac or noncardiac) or aging. The resultant structural remodeling is a slow process that progressively affects myocytes and the myocardial interstitium, and takes place from as early as the first days of atrial tachyarrhythmia. The left atrium, and particularly its posterior wall, is the location where remodeling is concentrated to the greatest extent. The mechanisms that underlie the remodeling process in atrial fibrillation have not yet been completely elucidated, although experimental and clinical investigations have indicated a number of signaling systems, inflammation, oxidative stress, atrial stretching and ischemia as factors involved in the cascade of events that leads to atrial fibrillation. The aim of this Review is to provide a comprehensive overview of the morphological changes that characterize the fibrillating atrial myocardium at histological and ultrastructural levels, and the established and hypothetical pathogenetic mechanisms involved in structural remodeling. This article also highlights the emerging therapies being developed to prevent progression of atrial fibrillation.

Topics: Animals; Atrial Fibrillation; Atrial Function; Cardiovascular Agents; Catheter Ablation; Cell Death; Connexins; Disease Models, Animal; Disease Progression; Fibrosis; Heart Atria; Humans; Inflammation; Myocardial Ischemia; Myocardium; Oxidative Stress; Risk Factors; Tachycardia, Supraventricular; Treatment Outcome

Systemic sclerosis (SSc) is a complex and heterogeneous chronic illness characterized by substantial patient to patient variability in clinical manifestations, internal organ involvement, and outcome. Genetic factors contribute to disease susceptibility, but environmental influences also play a significant role. The pathogenesis of SSc encompasses vascular, immunological, and fibrotic processes, which contribute to clinical manifestations and morbidity and must be addressed in the treatment plan. Although vascular interventions appear to reduce the frequency and severity of complications, such as scleroderma renal crisis and pulmonary hypertension, current therapies generally target the immune component of SSc in a non-selective fashion and have largely failed as diseases-modifying interventions. Newer insights into the mechanisms underlying autoimmunity, vascular injury and destruction, and particularly tissue fibrosis provide novel potential targets for therapy. Transforming growth factor-ss is a ubiquitous cytokine that appears to contribute to fibroblast activation, collagen overproduction, and pathological tissue fibrosis. Neutralizing antibodies and small molecules that block TGF-beta activation or function are effective in shutting down TGF-beta signaling and selectively inhibit the progression of fibrosis and may be entering clinical trials for the treatment of SSc.

Topics: Blood Vessels; Cardiovascular Agents; Fibrosis; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Inflammation; Kidney Diseases; Lung Diseases, Interstitial; Raynaud Disease; Scleroderma, Systemic; Skin; Transforming Growth Factor beta; Treatment Outcome

Healing after myocardial infarction (MI) is a well-orchestrated time-dependent process that involves inflammation, tissue repair with extracellular collagen matrix (ECCM) deposition and scar formation, and remodeling of myocardial structure, matrix, vasculature, and function. Rapid early ECCM degradation followed by slow ECCM replacement and maturation during post-MI healing results in a prolonged window of enhanced vulnerability to adverse remodeling. Decreased ECCM results in adverse ventricular remodeling, dysfunction, and rupture. Inflammation, a critical factor in normal healing, if impaired results in adverse remodeling and rupture. Several therapeutic drugs prescribed after MI exert pleiotropic effects that suppress ECCM and inflammation during healing and may have good, bad, or ugly consequences. This article reviews the potential impact of pleiotropic effects of some prototypic cardiac drugs such as renin-angiotensin-aldosterone system (RAAS) inhibitors, statins, and thrombolytics during healing post-ST-segment-elevation MI (STEMI), with special focus on inflammation, ECCM and remodeling, and implications in the elderly.

Topics: Aging; Animals; Cardiovascular Agents; Collagen; Extracellular Matrix; Humans; Inflammation; Myocardial Infarction; Ventricular Remodeling; Wound Healing

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

The slow progression over decades of coronary atheroma is often compensated for by arterial remodeling and collateral circulation. Coronary artery disease is therefore often asymptomatic. Sudden rupture of unstable atheromatous plaque always leads to endocoronary thrombus formation. The magnitude and the time frame of this endovascular thrombotic process determine the severity of its clinical consequences: no symptoms, exercise angina, unstable angina, acute transmural myocardial infarction, or sudden death. Two amply validated treatments have the potential to decrease both the probability and the severity of plaque rupture: statins and platelet inhibitors, which are both indicated in all cases of coronary disease. The other therapeutic tools - anti-ischemic drugs, ACE inhibitors, angioplasty, and coronary bypass - are widely used in the management of coronary disease, but their indications should be tailored to each individual clinical situation.

Topics: Cardiovascular Agents; Coronary Disease; Coronary Thrombosis; Disease Progression; Humans; Inflammation; Myocardial Revascularization; Risk Factors; Rupture

Over the last 3 decades, our ability to mechanically dilate obstructive coronary arterial stenoses has fundamentally altered our approach to managing patients with coronary artery disease (CAD). The result has been a swing from an initial pharmacologic approach to anatomically driven revascularization. An accumulation of clinical evidence provides strong support for such intervention in acute coronary syndromes (ACS). In stable CAD, dilative therapy was believed to be superior based on the assumption that high-risk coronary anatomy or myocardial ischemia increases the risk of future death and myocardial infarction. However, there have been major advances in our understanding of the pathophysiology of ACS and the recognition of the significance of predisposing non-flow-limiting coronary stenoses prone to rupture, as well as increasing insight into plaque and patient vulnerability. This improved understanding of the disease has led to the more aggressive use of appropriately targeted pharmacologic agents and an evolution in what constitutes optimal medical therapy (OMT). Data from recent studies, such as the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, support the concept that in patients with stable CAD, OMT alone in this day and age compares favorably with a therapeutic strategy combining OMT with mechanical intervention. Thus, the treatment pendulum may be swinging back to the understanding that "best practice" today requires the judicious use of interventional and medical therapies in the appropriate patient population.

Topics: Acute Coronary Syndrome; Angina, Unstable; Angioplasty, Balloon, Coronary; Benchmarking; Cardiovascular Agents; Chronic Disease; Coronary Disease; Disease Progression; Endothelium, Vascular; Humans; Inflammation; Myocardial Revascularization; Oxidative Stress; Risk Factors; Xanthophylls

Despite extensive research and novel treatments, chronic heart failure (CHF) remains a cause of high morbidity and mortality. Mounting evidence suggested that immune activation and inflammation play critical roles in the pathogenesis of CHF. In this review, we examine the current evidence regarding this contemporary pathophysiological mechanism, and evaluate the effects of conventional and novel cardiovascular drugs, such as calcium sensitisers and statins, on the immune and inflammatory mediator's network. Although therapies, which specifically antagonise tumour necrosis factor-alpha have not demonstrated considerable benefit in patients with CHF, there is an increasing evidence to suggest greater value from non-specific anti-inflammatory approaches, including: pentoxifylline, intravenous immunoglobulin, immune modulation therapy, growth hormones, physical training and nutrition regulation. Several innovative therapeutic targets, such as peroxisome proliferator-activated receptor gamma activators, Rho-kinase, p38 mitogen-activated protein kinase, nuclear transcription factor NF-kappaB, recovering or augmenting parasympathetic tone, cardiac resynchronisation therapy, macrophage inhibitors and chemokine receptor antagonists, are briefly discussed in this review. While we have recently demonstrated the potential merits of combining low-dose methotrexate with conventional therapy, through extensively modulating the activated immune and inflammatory mediator's network, there is a need for further rigorous research of this complex network, especially involving current promising therapies which modulate this system. Such evidence has the potential to revolutionise changes for the management of this disorder. Based on the 'heterogeneity' of immune activation and inflammation among different CHF populations, an 'optimised combination treatment' may offer exciting benefits for individual therapy in the future.

Topics: Anti-Inflammatory Agents; Cardiovascular Agents; Heart Failure; Humans; Inflammation; Inflammation Mediators; Tumor Necrosis Factor-alpha

Interest in intranasal (IN) administration as a non-invasive route for drug delivery continues to grow rapidly. The nasal mucosa offers numerous benefits as a target issue for drug delivery, such as a large surface area for delivery, rapid drug onset, potential for central nervous system delivery, and no first-pass metabolism. A wide variety of therapeutic compounds can be delivered IN, including relatively large molecules such as peptides and proteins, particularly in the presence of permeation enhancers. The current review provides an in-depth discussion of therapeutic aspects of IN delivery including consideration of the intended indication, regimen, and patient population, as well as physicochemical properties of the drug itself. Case examples are provided to illustrate the utility of IN dosing. It is anticipated that the present review will prove useful for formulation scientists considering IN delivery as a delivery route.

Topics: Administration, Intranasal; Analgesics; Antiemetics; Cardiovascular Agents; Carrier Proteins; Central Nervous System; Chemistry, Pharmaceutical; Cholinesterase Inhibitors; Drug Administration Schedule; Drug Compounding; Drug Stability; Humans; Hydrophobic and Hydrophilic Interactions; Hypnotics and Sedatives; Inflammation; Molecular Weight; Nasal Mucosa; Solubility; Vaccines

The aim of this chapter is to present and identify potential pharmacological targets in endothelial cell-monocyte interactions leading to vascular syndrome and involving inflammation, coagulation, vascular remodelling and thrombosis. Increasing evidence is indicating that endothelial cells play a key role in atherothombosis by their capacity to attract, bind and allow the extravasation of monocytes to sites of inflammation. Surface expression and/or activation of constituent cell adhesion molecules (for e.g. P-selectin, E-selectin, ICAM-1, and VCAM-1) on endothelial cells together with chemokines such as CXCL8 (IL-8), Platelet-activating factor (PAF), CCL2 and CCL5 (Table 1) allow the rolling, adhesion and extravasation of monocytes. This review focuses on pharmacological targets implicated in endothelial cells interactions with monocytes/macrophages in vascular disease states and on cutting edge genomic tools for the identification and characterization of such targets.

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Communication; Chemokines; Endothelial Cells; Genomics; Humans; Inflammation; Intercellular Adhesion Molecule-1; Macrophages; Membrane Glycoproteins; Monocytes; P-Selectin; Platelet Activating Factor; Platelet Endothelial Cell Adhesion Molecule-1; Signal Transduction; Vascular Cell Adhesion Molecule-1

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

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

In vitro and ex vivo interactions of betaadrenoceptor blocking drugs, antihistamines and chloroquine with blood platelets and polymorphonuclear leukocytes resulted in different alterations of regulatory functions of these blood cells. Inhibition of platelet aggregation, arachidonate regulatory pathway, 5-hydroxytryptamine transportation, removal of platelet membrane receptors, inhibition of second messenger pathways at subcellular level and suppression of phagocytosis are indicative of nonreceptor rather than specific receptor interactions. Binding of drugs with biomembranes is reversible depending on the ionic charge of the molecule and hydrophobicity of the bilayer, partition coefficient, pH and pKa of the amphiphilic molecules and other physico-chemical properties of amphiphilic drugs. Alterations in the drug molecule structure alters the drug-phospholipid binding profile. Any change in the metabolism of membrane phospholipids directly or indirectly influences one or more of the important components of the phospholipid-signalling pathway. In addition to changes in phospholipase A, C and D activities, protein kinase C, calmodulin-phosphodiesterase, Ca2+,Mg2+-ATPase, Na+,K+-ATPase and other messengers were found to be changed in cells and tissue after cationic amphiphilic drug (CAD) administration. Although not much has been understood of the mechanism by which some CAD affect immune functions, there are good reasons to suggest that these effects might occur. CADs share sufficient similarities in their structure even though they come from diverse pharmacological classes. CADs affect ion transport, immune functions, tumour growth, serotonin metabolism and several other functions in the body. Extensive therapeutic use and associated side effects have generated a great deal of interest in understanding the nonreceptor interactions with CADs.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Blood Platelets; Cardiovascular Agents; Chloroquine; Histamine H1 Antagonists; Humans; Inflammation; Leukocytes; Reperfusion Injury; Thromboembolism

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

Persistent inflammation, involving increased levels of inflammatory cytokines, seems to play a pathogenic role in chronic heart failure (HF) by influencing heart contractility, inducing hypertrophy and promoting apoptosis, contributing to myocardial remodeling. While several stimuli may be operating such as heat shock proteins, microbial antigens and oxidative stress, it seems that the inflammatory response to these stimuli may represent a common final pathogenic pathway in HF regardless of the initial event. Traditional cardiovascular drugs appear to have little influence on the cytokine network, and immunomodulatory therapy has emerged as a possible new treatment modality in HF. Several animal studies and also some clinical studies have suggested that downregulation of inflammation may improve cardiac performance. However, the results from the placebo-controlled anti-tumor necrosis factor studies suggest no improvement or even adverse effects of such therapy. Although somewhat disappointing, these negative results do not necessarily argue against the 'cytokine hypothesis'. These studies just underscore the challenges in developing treatment modalities that can modulate the cytokine network in HF patients resulting in beneficial net effects. Further research will have to identify more precisely the most important actors in the immunopathogenesis of chronic HF in order to develop more specific immunomodulating agents for this disorder.

Topics: Animals; Apoptosis; Cardiomegaly; Cardiovascular Agents; Chronic Disease; Clinical Trials as Topic; Cytokines; Down-Regulation; Heart Failure; Humans; Immunologic Factors; Inflammation; Myocardial Contraction; Treatment Outcome; Ventricular Remodeling

Topics: Acarbose; Animals; Cardiovascular Agents; Diabetes Mellitus; Diabetic Angiopathies; Endothelium, Vascular; Humans; Hypoglycemic Agents; Inflammation; Insulin Resistance; Metformin; Obesity; Oxidative Stress; Sulfonylurea Compounds; Thiazolidinediones

The patient with chronic kidney disease and coronary artery disease (CAD) presents special challenges. This report reviews the scope of the challenge, the hostile internal milieu predisposing to CAD and cardiac events, management issues, unresolved dilemmas, and the need for randomized trials to allow for evidence-based treatment.

Topics: Angioplasty, Balloon, Coronary; Biomarkers; Cardiovascular Agents; Coronary Artery Bypass; Coronary Artery Disease; Creatinine; Diabetes Complications; Diagnosis, Differential; Drug Administration Schedule; Humans; Hyperhomocysteinemia; Hyperlipidemias; Hypertension; Inflammation; Kidney Failure, Chronic; Mass Screening; Oxidative Stress; Predictive Value of Tests; Prevalence; Reproducibility of Results; Risk Factors; Treatment Failure; United States

Topics: Arteriosclerosis; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Hypoglycemic Agents; Inflammation; Insulin Resistance

Inflammation is a reaction to primary injury of various kinds, such as infection and trauma, which has both beneficial and detrimental effects. Inflammation has been associated with major diseases of the heart and vessels. Research has focused not only on ischaemia but also on post-ischaemic reperfusion, which is known to activate and amplify the inflammatory response. Although reperfusion should always be attempted in the clinical environment, it has been shown experimentally that it can cause some cardiac damage, in addition to that caused by ischaemia. Therefore, it is reasonable to attempt to increase the benefit obtainable with reperfusion by modulating inflammatory processes triggered by reperfusion itself. In this field, different potential therapeutic targets have been identified and interventions have been tested over the last 30 years. With the exception of adenosine, which probably does not act merely through inhibition of the inflammatory response, no other compounds have yet proven successful in clinical trials. Active research is ongoing. Broadening the approach from the heart to the cardiovascular system, promising data is emerging on cardiovascular protection conferred by statins in patients with coronary heart disease (CHD) and high levels of C-reactive protein (CRP), a systemic marker of inflammation. Similarly, results of trials aimed at preventing cardiovascular events by eradicating chronic infections will be among the first to directly test whether such therapies will decrease risks of cardiovascular disease.

Topics: Adenosine; Animals; Bacterial Infections; Cardiovascular Agents; Complement System Proteins; Cytokines; Enzyme Inhibitors; Heart Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Matrix Metalloproteinase Inhibitors; Neutrophils; Reactive Oxygen Species

Each horse with laminitis is presented to the veterinarian at a different stage in progression of the condition and with varying severity. The pathogenic timing is often unknown and is difficult to determine. Because timing and severity are related to both the lesion's severity and responsiveness to treatment, these factors are critical to treatment selection and success. It is erroneous to assume that each horse with laminitis should receive each treatment. It is therefore important to ascertain as logically and objectively as possible the pathophysiological stage of development of each horse when it is examined. Therapeutic failure may result from inappropriate interpretation of the clinical signs and pathophysiologic condition of the patient in order to coordinate a treatment regimen.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Cardiovascular Agents; Foot Diseases; Hoof and Claw; Horse Diseases; Horses; Inflammation

Micro-organisms continue to provide an important source of chemical diversity for the discovery of compounds with new biological activities. Microbial metabolites discovered recently using assays to detect compounds with potential pharmacological utility are surveyed and found to represent an extensive range of structural types produced by a wide variety of organisms. Assays used for screening samples produced by microbial processes must be robust, sensitive and specific and able to operate above a background of potential interferences from a number of sources. Discovery assays currently in use fall into three main categories cell-based, receptor-ligand interaction and enzyme inhibition assays. Trends in the use of these assays and new developments in assay technology applicable to the screening of microbial samples are examined with particular reference to the high throughput screening environment. For microbial screening to be a competitive route to new drug leads, the disciplines involved must be engineered into a seamlessly integrated process to deliver novel compounds with the required biological properties rapidly.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Cardiovascular Agents; Cardiovascular Diseases; Chemistry, Pharmaceutical; Drug Evaluation, Preclinical; Guinea Pigs; Humans; Industrial Microbiology; Inflammation; Neoplasms, Experimental; Neovascularization, Pathologic; Nerve Growth Factors; Platelet Aggregation Inhibitors; Rats; Receptors, Drug

Detoxifying and blood-activating Chinese medicine granule formula, which includes 15 g of Polygonum cuspidatum Sieb. et Zucc. (Polygonum cuspidatum) and 10 g of Crataegus pinnatifida Bunge (Hawthorn), can relieve the symptoms and serve as supplementary treatment for unstable angina.. This study aimed to explore the role of detoxifying and blood-activating formulae in the treatment of unstable angina and the potential mechanism involved.. A total of 144 participants with unstable angina were randomly divided into experimental and control groups. Both groups were treated with standardized Western medicine; the experimental group was additionally treated with detoxifying and blood-activating Chinese medicine granules, which included 15 g of P. cuspidatum and 10 g of C. pinnatifida for 4 weeks. The primary endpoint was the frequency of weekly angina pectoris attacks before and after treatment. The secondary endpoints, also observed before and after treatment, included blood glucose, blood lipids, high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10, and adiponectin levels, as well as the ratio of pro/anti-inflammatory factors and evaluation scales of symptoms and syndromes in Chinese and Western medicine.. In both experimental and control groups, the frequency of weekly angina pectoris attacks was lower after treatment (P < 0.01), but with no significant intergroup difference (P = 0.10). After intervention, the hs-CRP, TNF-α, and IL-6 levels decreased, while the IL-10 and adiponectin levels significantly increased in the experimental group (P < 0.05 or 0.01). The ratios of the inflammatory factors significantly decreased after treatment, particularly in the experimental group (P < 0.01). Symptoms and syndromes were also ameliorated in the experimental group (P < 0.01), showing a significant difference from the control group (P < 0.01).. Detoxifying and blood-activating formulae can reduce the frequency and relieve symptoms of unstable angina, and this mechanism may be related to a regulation of the balance of pro- and anti-inflammatory factors.

Topics: Aged; Aged, 80 and over; Angina, Unstable; Cardiovascular Agents; Crataegus; Cytokines; Drugs, Chinese Herbal; Fallopia japonica; Female; Gene Expression Regulation; Humans; Inflammation; Male; Middle Aged; Phytotherapy

To investigate the clinical effectiveness of pioglitazone in the combination treatment of patients with asthma concurrent with coronary heart disease (CHD).. Fifty patients aged 40-75 years with asthma concurrent with CHD were examined. External respiratory function (ERF), electrocardiograms, blood pressure (BP), and anthropometric measurements were assessed in all the patients. Blood and urine laboratory values and high-sensitivity C-reactive protein (hs-CRP) concentrations were estimated; endothelial function was determined measuring endothelium-dependent and endothelium-independent vasodilation (EDVD and EIVD). The patients were randomized into a comparison group receiving only standard therapy and a study group taking pioglitazone as part of combination therapy for 3 months.. At the randomization stage prior to pioglitazone combination therapy, the patient groups did not statistically significantly differ in basic clinical and anamnestic data. Three-month standard therapy resulted in stabilization of ERF and endothelial function. During the treatment, there were increases in the frequency of asthma symptoms and the duration of angina attacks, however, there was a decline in hs-CRP levels (p<0.001). Incorporation of pioglitazone into the standard treatment regimen of patients with asthma concurrent with CHD improved clinical disease control, decreased the degree of bronchial obstruction and the frequency of angina pain and asthma attacks using nitroglycerin and salbutamol, lowered systolic and diastolic blood pressure, improved EDVD (increases in the maximum linear velocity of blood flow after a test for reactive hyperemia (RH), index of reactivity (IR), and A% brachial artery (BA) diameter) and EIVD (increases in IR and A% BA diameter), and reduced systemic inflammation from hs-CRP values (p<0.001) and hypercholesterolemia from total cholesterol levels (p<0.02).. The incorporation of pioglitazone in the combination therapy of patients with asthma concurrent with CHD improves the clinical course of the diseases and increases their control, reduces systemic inflammation, and improves endothelial functional activity.. Цель исследования. Изучить особенности клинической эффективности пиоглитазона в комплексной терапии больных, страдающих бронхиальной астмой (БА) в сочетании с ишемической болезнью сердца (ИБС). Материалы и методы. Обследовали 50 пациентов с БА в сочетании с ИБС в возрасте 40-75 лет. У всех оценивали функцию внешнего дыхания (ФВД), электрокардиограмму, артериальное давление (АД) и антропометрические показатели. Проводили оценку лабораторных показателей крови и мочи, определяли концентрацию высокочувствительного С-реактивного белка (вч-СРБ), функцию эндотелия с измерением зависимой и независимой от эндотелия вазодилатации (ЗЭВД и НЗЭВД). Пациентов рандомизировали на группу сравнения, которая получала только стандартную терапию, и основную группу, в которой в составе комплексной терапии больные получали пиоглитазон в течение 3 мес. Результаты. Группы пациентов на этапе рандомизации до включения в комплексную терапию пиоглитазона статистически значимо не различались по основным клиническим и анамнестическим данным. Стандартная 3-месячная терапия приводила к стабилизации показателей ФВД и функции эндотелия. В процессе лечения увеличились частота симптомов БА, длительность ангинозных приступов, однако отмечалось снижение уровня вч-СРБ (p<0,001). Включение пиоглитазона в стандартную терапию больных БА в сочетании с ИБС приводило к улучшению клинического контроля над заболеваниями, уменьшению степени обструкции бронхов, снижению частоты ангинозных болей и приступов БА с применением нитроглицерина и сальбутамола, систолического и диастолического АД, улучшению показателей ЗЭВД (увеличению показателей максимальной линейной скорости кровотока после пробы с реактивной гиперемией - РГ, индекса реактивности - ИР, Δ% диаметра плечевой артерии - ПА) и НЗЭВД (увеличению ИР и Δ% диаметра ПА), снижению уровня системного воспаления по показателю вч-СРБ (p<0,001) и гиперхолестеринемии по показателю общего холестерина (p<0,02). Заключение. Включение пиоглитазона в комплексную терапию пациентов с БА в сочетании с ИБС улучшает клиническое течение заболеваний и повышает контроль над их течением, снижает уровень системного воспаления и улучшает функциональную активность эндотелия.

Topics: Asthma; Cardiovascular Agents; Coronary Disease; Drug Monitoring; Drug Therapy, Combination; Endothelium, Vascular; Female; Heart Function Tests; Humans; Inflammation; Male; Middle Aged; Pioglitazone; Respiratory Function Tests; Thiazolidinediones; Treatment Outcome

Late-acquired stent malapposition (LASM) is a common finding after sirolimus-eluting stent (SES) implantation and may be the cause for late stent thrombosis. Inflammation may play a pivotal role in LASM just as it plays in stent restenosis. We have therefore investigated seven polymorphisms involved in inflammatory processes, related in previous reports to restenosis, on the risk of LASM in SES patients. Patients with ST-elevation myocardial infarction who underwent SES implantation and had intravascular ultrasonography (IVUS) data available for both immediate post-intervention and 9-month follow-up were included in the present study. In total, 104 patients from the MISSION! Intervention Study were genotyped for the caspase-1 5352 G/A, eotaxin 1382 A/G, CD14 260 A/G, colony stimulating factor 2 1943 C/T, IL10 -1117 C/T, IL10 4251 C/T, and the tumor necrosis factor alpha 1211 C/T polymorphisms. LASM occurred in 26/104 (25%) of patients. We found a significantly higher risk for LASM in patients carrying the caspase-1 (CASP1) 5352 A allele (RR = 2.32; 95% CI 1.22-4.42). In addition, mean neointimal growth was significantly lower in patients carrying this LASM risk allele (1.6 vs. 4.1%, p = 0.014). The other six polymorphisms related to inflammation were not significantly related to the risk of LASM. In conclusion, carriers of the 5352 A allele in the caspase-1 gene are at increased risk of developing LASM after SES implantation. If this is confirmed in larger studies, then screening for this polymorphism in patients undergoing percutaneous coronary interventions could eventually help cardiologists to better select between commercially available stents.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Caspase 1; Chi-Square Distribution; Drug-Eluting Stents; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Inflammation; Inflammation Mediators; Male; Middle Aged; Myocardial Infarction; Netherlands; Prospective Studies; Risk Assessment; Risk Factors; Sirolimus; Time Factors; Treatment Outcome; Ultrasonography, Interventional

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

There are several reports of the use of adenosine as a cardioprotective agent during cardiac surgery. Adenosine treatment might affect neutrophils and inflammatory mediators. The present prospective randomized study was designed to investigate the effect of adenosine pretreatment on myocardial recovery and inflammatory response in patients undergoing elective coronary artery bypass surgery.. A prospective, randomized, controlled study.. Operative unit and ICU in a university hospital in Finland.. Thirty male patients undergoing primary, elective coronary revascularization.. Patients in the adenosine group received a 7-min infusion of adenosine (total, 650 microg/kg) before the initiation of cardiopulmonary bypass.. Postoperative creatine kinase (CK)-MB release and hemodynamics were recorded. Perioperative leukocyte and cytokine release were measured.. Adenosine pretreatment resulted in less CK-MB release and an improved postbypass cardiac index. Similar leukocyte counts and cytokine responses were seen in both groups perioperatively. Neutrophil counts were similar between the groups before and after myocardial ischemia when measured simultaneously in arterial and coronary sinus blood.. The present results support the hypothesis that adenosine pretreatment is cardioprotective in humans, but the present dose failed to regulate the inflammatory responses after coronary artery bypass grafting.

Topics: Adenosine; Aged; Cardiovascular Agents; Coronary Artery Bypass; Cytokines; Heart; Hemodynamics; Humans; Inflammation; Leukocyte Count; Male; Middle Aged; Myocardial Reperfusion Injury; Prospective Studies

Fully absorbable polymeric scaffolds, as a potential alternative to permanent metallic stents, are entering the clinical field. The aim of this study is to assess the in vivo biocompatibility of a novel Sirolimus-eluting (SIR) absorbable scaffold based on poly(L-lactide) (PLLA) and poly(4-hydroxybutyrate) (P4HB) for interventional application.. Absorbable PLLA/P4HB scaffolds either loaded with SIR coating or unloaded scaffolds were implanted interventionally into common carotid arteries of 14 female. Bare metal stents (BMS) served as control. Peroral dual anti-platelet therapy was administered throughout the study. Stented common carotid arteries segments were explanted after 4 weeks, and assessed histomorphometrically.. The absorbable scaffolds showed a decreased residual lumen area and higher stenosis after 4 weeks (PLLA/P4HB: 6.56 ± 0.41 mm² and 37.56 ± 4.67%; SIR-PLLA/P4HB: 6.90 ± 0.58 mm² and 35.60 ± 3.15%) as compared to BMS (15.29 ± 1.86 mm² and 7.65 ± 2.27%). Incorporation of SIR reduced the significantly higher inflammation of unloaded scaffolds however not to a level compared to bare metal stent (PLLA/P4HB: 1.20 ± 0.19; SIR-PLLA/P4HB: 0.96 ± 0.24; BMS: 0.54 ± 0.12). In contrast, the BMS showed a slightly elevated vascular injury score (0.74 ± 0.15), as compared to the PLLA/P4HB (0.54 ± 0.20) and the SIR-PLLA/P4HB (0.48 ± 0.15) groups.. In this preclinical model, the new absorbable polymeric (SIR-) scaffolds showed similar technical feasability and safety for vascular application as the permanent metal stents. The higher inflammatory propensity of the polymeric scaffolds was slightly reduced by SIR-coating. A smaller strut thickness of the polymeric scaffolds might have been a positive effect on tissue ingrowth between the struts and needs to be addressed in future work on the stent design.

Topics: Absorbable Implants; Angioplasty, Balloon; Animals; Cardiovascular Agents; Carotid Artery, Common; Carotid Stenosis; Inflammation; Materials Testing; Models, Animal; Polyesters; Prosthesis Design; Sirolimus; Sus scrofa; Time Factors

Myocardial infarction (MI) is a serious heart health problem in the world with a high mortality rate. Our study is mainly aimed at validating the antioxidative stress and antiapoptotic effects of escin in a H. H9c2 cells were divided into control group, H. We found that the level of reactive oxygen species (ROS) in the H. These results indicated that escin inhibits H

Topics: Apoptosis; Cardiovascular Agents; Cells, Cultured; Escin; Humans; Hydrogen Peroxide; Inflammation; Myocytes, Cardiac; NF-kappaB-Inducing Kinase; Oxidants; Oxidative Stress; Protein Serine-Threonine Kinases; Signal Transduction

Cardiorenal syndrome (CRS) remains the leading cause of death in hospitalized patients for all disease entities. Sacubitril/Valsartan (Sac/Val) therapy has been proved to improve prognostic outcome in patients with heart failure or chronic kidney disease. This study tested the hypothesis that combined levosimendan and Sac/Val was superior to just one therapy on protecting the heart and kidney against simultaneous heart and kidney ischemia (I) (for 50-min)-reperfusion (R) (for 7-days) (i.e., double IR) injury (defined as CRS).. Adult-male Spraque-Dawley rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (double IR), group 3 [double IR+levosimendan (10 mg/kg by intra-peritoneum administration at 30 min/followed by days 1-5 once daily after IR procedure)], group 4 [double IR+Sac/Val (10 mg/kg, orally at 30 min/followed by days 1-5 twice daily after IR procedure)], and group 5 (double IR+Sac/Val+levosimendan). By day 7 after double-IR, the left-ventricular-ejection fraction (LVEF)/left-ventricular-fraction-shortening (LVFS) were highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3/4, but they showed no difference between groups 3/4, whereas the circulatory heart-failure (brain-natriuretic peptide)/proinflammatory (suppression of tumorigenicity-2) biomarkers, blood-urea-nitrogen/creatinine and ratio of urine protein to creatinine (all p < 0.0001) exhibited an opposite pattern of LVEF among the groups. The protein expressions of inflammatory (tumor necrosis factor-α/interleukin-1ß/matrix metalloproteinase-9)/oxidative-stress (NOX-1/NOX-2/NOX-4)/apoptotic (mitochondrial-Bax/caspase-3/poly-(ADP-ribose)-polymerase)/fibrotic (Smad3/transforming growth factor-ß)/mitochondrial-damaged (cytosolic-cytochrome-C)/myocardial-hypertrophic (ß-MHC) biomarkers in LV myocardium exhibited an opposite pattern of LVEF among the groups (all p < 0.0001). The cellular expressions of inflammatory (CD68)/DNA-damaged (γ-H2AX) biomarkers and infarct/fibrotic areas in LV myocardium and kidney displayed an opposite pattern of LVEF among the groups (all p < 0.0001).. Combined levosimendan and Sac/Val was superior to merely one therapy on protecting the heart and kidney as well as preserving their functions against double IR injury.

Topics: Aminobutyrates; Animals; Apoptosis; Biphenyl Compounds; Cardio-Renal Syndrome; Cardiovascular Agents; Drug Combinations; Fibrosis; Humans; Inflammation; Kidney; Male; Myocardium; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Simendan; Stroke Volume; Valsartan; Ventricular Function, Left

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Topics: Acute Coronary Syndrome; Animals; C-Reactive Protein; Cardiovascular Agents; Coronary Artery Disease; Endothelial Cells; Humans; Inflammation; Mice; Ranolazine; Sodium; Sodium Channel Blockers

Diabetes is a serious global health concern which severely affected public health as well as socio-economic growth worldwide. Scutellarin (SCU), a bioactive flavonoid, is known for its efficacious action against a range of ailments including cardiovascular problems. The present study was conducted to find out possible protective effect and its associated mechanisms of SCU on experimental type 2 diabetes-induced cardiac injury.. Type 2 diabetes was induced by treating animals with high fat diet for 4 weeks and a single intraperitoneal dose (35 mg/kg body weight) of streptozotocin and diabetic animals received SCU (10 or 20 mg/kg/day) for 6 weeks.. Scutellarin attenuated type 2 diabetes-induced hyperglycemia, bodyweight loss, hyperlipidaemia, cardiac functional damage with histopathological alterations and fibrosis. Scutellarin treatment to type 2 diabetic mice ameliorated oxidative stress, inflammatory status and apoptosis in heart. Furthermore, the underlying mechanisms for such mitigation of oxidative stress, inflammation and apoptosis in heart involved modulation of Nrf2/Keap1 pathway, TLR4/MyD88/NF-κB mediated inflammatory pathway and intrinsic (mitochondrial) apoptosis pathway, respectively.. The current findings suggest that SCU is effective in protecting type 2 diabetes-induced cardiac injury by attenuating oxidative stress and inflammatory responses and apoptosis, and it is also worth considering the efficacious potential of SCU to treat diabetic cardiomyopathy patients.

Topics: Animals; Apigenin; Apoptosis; Biomarkers; Blood Glucose; Body Weight; Cardiovascular Agents; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dose-Response Relationship, Drug; Gene Expression Regulation; Glucuronates; Heart Diseases; Inflammation; Lipids; Male; Mice; Oxidative Stress; RNA, Messenger

Zilver PTX nitinol self-expanding drug-eluting stent with paclitaxel coating is effective for treatment of superficial femoral artery (SFA) disease. However, as with any stent, it induces a measure of vascular inflammatory response. The current clinical trial (NCT02734836) aimed to assess vascular patency, remodeling, and inflammatory markers with intravascular optical coherence tomography (OCT) in patients with SFA disease treated with Zilver PTX stents.. Serial OCT examinations were performed in 13 patients at baseline and 12-month follow-up. Variables evaluated included neointimal area, luminal narrowing, thrombus area, stent expansion as well as measures of inflammation including, peri-strut low-intensity area (PLIA), macrophage arc, neovascularization, stent strut apposition and coverage.. Percentage of malapposed struts decreased from 10.3 ± 7.9% post-intervention to 1.1 ± 2.2% at 12-month follow-up, but one patient showed late-acquired stent malapposition (LASM). The percent of uncovered struts at follow-up was 3.0 ± 4.5%. Average expansion of stent cross-sectional area from baseline to follow-up was 35 ± 19%. The average neointimal area was 7.8 ± 3.8 mm. At 12-month follow-up, OCT analysis of Zilver PTX stent shows outward remodeling and minimal neointimal growth, but evidence of inflammation including PLIA, neovessels, thrombus and macrophages.. Thirteen patients with PAD had paclitaxel-coated stents implanted in their SFAs and were then imaged with OCT at baseline and 12-month follow-up. OCT proxy metrics of inflammation were quantified.

Topics: Aged; Aged, 80 and over; Alloys; Angioplasty, Balloon; Cardiovascular Agents; Drug-Eluting Stents; Female; Femoral Artery; Humans; Inflammation; Male; Middle Aged; Neointima; Paclitaxel; Peripheral Arterial Disease; Predictive Value of Tests; Prospective Studies; Prosthesis Design; Risk Factors; Self Expandable Metallic Stents; Time Factors; Tomography, Optical Coherence; Treatment Outcome; Vascular Patency; Vascular Remodeling

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Inflammasomes; Inflammation; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction

Recently, attention has been focused on the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the mechanism of and as a treatment target for neuropathic and inflammatory pain. Ivabradine, a blocker of HCN channels, was demonstrated to have an effect on neuropathic pain in an animal model. Therefore, in the present study, we evaluated the effect of ivabradine on inflammatory pain, and under the hypothesis that ivabradine can directly influence inflammatory responses, we investigated its effect in in vivo and in vitro studies.. After approval from our institution, we studied male Sprague-Dawley rats aged 8 weeks. Peripheral inflammation was induced by the subcutaneous injection of carrageenan into the hindpaw of rats. The paw-withdrawal threshold (pain threshold) was evaluated by applying mechanical stimulation to the injected site with von Frey filaments. Ivabradine was subcutaneously injected, combined with carrageenan, and its effect on the pain threshold was evaluated. In addition, we evaluated the effects of ivabradine on the accumulation of leukocytes and TNF-alpha expression in the injected area of rats. Furthermore, we investigated the effects of ivabradine on LPS-stimulated production of TNF-alpha in incubated mouse macrophage-like cells.. The addition of ivabradine to carrageenan increased the pain threshold lowered by carrageenan injection. Both lamotrigine and forskolin, activators of HCN channels, significantly reversed the inhibitory effect of ivabradine on the pain threshold. Ivabradine inhibited the carrageenan-induced accumulation of leukocytes and TNF-alpha expression in the injected area. Furthermore, ivabradine significantly inhibited LPS-stimulated production of TNF-alpha in the incubated cells.. The results of the present study demonstrated that locally injected ivabradine is effective against carrageenan-induced inflammatory pain via HCN channels. Its effect was considered to involve not only an action on peripheral nerves but also an anti-inflammatory effect.

Topics: Animals; Cardiovascular Agents; Carrageenan; Gene Expression Regulation; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Inflammation; Ivabradine; Male; Pain; Potassium Channels; Rats; Rats, Sprague-Dawley

Successful resuscitation from cardiac arrest results in a post-cardiac arrest syndrome, which can evolve in the days to weeks after return of sustained circulation. The components of post-cardiac arrest syndrome are brain injury, myocardial dysfunction, systemic ischemia/reperfusion response, and persistent precipitating pathophysiology. Pediatric post-cardiac arrest care focuses on anticipating, identifying, and treating this complex physiology to improve survival and neurological outcomes. This scientific statement on post-cardiac arrest care is the result of a consensus process that included pediatric and adult emergency medicine, critical care, cardiac critical care, cardiology, neurology, and nursing specialists who analyzed the past 20 years of pediatric cardiac arrest, adult cardiac arrest, and pediatric critical illness peer-reviewed published literature. The statement summarizes the epidemiology, pathophysiology, management, and prognostication after return of sustained circulation after cardiac arrest, and it provides consensus on the current evidence supporting elements of pediatric post-cardiac arrest care.

Topics: Acute Kidney Injury; Adrenal Insufficiency; Anticonvulsants; Brain Damage, Chronic; Cardiomyopathies; Cardiopulmonary Resuscitation; Cardiovascular Agents; Child; Combined Modality Therapy; Fluid Therapy; Glucose Metabolism Disorders; Heart Arrest; Humans; Hypnotics and Sedatives; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infections; Inflammation; Monitoring, Physiologic; Multiple Organ Failure; Neuromuscular Blocking Agents; Oxygen Inhalation Therapy; Prognosis; Reperfusion Injury; Respiratory Therapy; Time Factors

Neutrophils have both detrimental and beneficial effects in myocardial infarction (MI), but little is known about the underlying pathways. S100A8/A9 is a pro-inflammatory alarmin abundantly expressed in neutrophils that is rapidly released in the myocardium and circulation after myocardial ischaemia. We investigated the role of S100A8/A9 in the innate immune response to MI.. In 524 patients with acute coronary syndrome (ACS), we found that high plasma S100A8/A9 at the time of the acute event was associated with lower left ventricular ejection fraction (EF) at 1-year and increased hospitalization for heart failure (HF) during follow-up. In wild-type C57BL/6 mice with MI induced by permanent coronary artery ligation, treatment with the S100A9 blocker ABR-238901 during the inflammatory phase of the immune response inhibited haematopoietic stem cell proliferation and myeloid cell egression from the bone marrow. The treatment reduced the numbers of neutrophils and monocytes/macrophages in the myocardium, promoted an anti-inflammatory environment, and significantly improved cardiac function compared with MI controls. To mimic the clinical scenario, we further confirmed the effects of the treatment in a mouse model of ischaemia/reperfusion. Compared with untreated mice, 3-day ABR-238901 treatment significantly improved left ventricular EF (48% vs. 35%, P = 0.002) and cardiac output (15.7 vs. 11.1 mL/min, P = 0.002) by Day 21 post-MI.. Short-term S100A9 blockade inhibits inflammation and improves cardiac function in murine models of MI. As an excessive S100A8/A9 release is linked to incident HF, S100A9 blockade might represent a feasible strategy to improve prognosis in ACS patients.

Topics: Animals; Calgranulin A; Calgranulin B; Cardiovascular Agents; Disease Models, Animal; Inflammation; Mice; Mice, Inbred C57BL; Myeloid Cells; Myocardial Infarction; Myocardium

Topics: Animals; Anti-Inflammatory Agents; Cardiology; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diffusion of Innovation; Hematopoiesis; Humans; Inflammation; Inflammation Mediators; Interleukin-1beta

Inflammation and oxidative stress play a crucial role in the development of diabetic cardiomyopathy (DCM). We previously had synthesized an Aza resveratrol-chalcone derivative 6b, of which effectively suppressing lipopolysaccharide (LPS)-induced inflammatory response in macrophages. This study aimed to investigate the potential protective effect of 6b on DCM and underlying mechanism. In H9c2 myocardial cells, 6b potently decreased high glucose (HG)-induced cell fibrosis, hypertrophy and apoptosis, alleviating inflammatory response and oxidant stress. In STZ-induced type 1 diabetic mice (STZ-DM1), orally administration with 6b for 16 weeks significantly attenuated cardiac hypertrophy, apoptosis and fibrosis. The expression of inflammatory cytokines and oxidative stress biomarkers was also suppressed by 6b distinctly, without affecting blood glucose and body weight. The anti-inflammatory and antioxidative activities of 6b were mechanistic associated with nuclear factor-kappa B (NF-κB) nucleus entry blockage and Nrf2 activation both in vitro and in vivo. The results indicated that 6b can be a promising cardioprotective agent in treatment of DCM via inhibiting inflammation and alleviating oxidative stress. This study also validated the important role of NF-κB and Nrf2 taken in the pathogenesis of DCM, which could be therapeutic targets for diabetic comorbidities.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apoptosis; Cardiovascular Agents; Cell Line; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Gene Expression Regulation; Glucose; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Rats; Resveratrol; Signal Transduction; Streptozocin

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Gene Expression Regulation; Humans; Inflammation; Protein Biosynthesis; RNA Stability

Emerging evidences indicate that heat-shock protein 90 (HSP90) is associated with atherogenesis. However, the effect of HSP90 on plaque stability is largely unknown. In this study, we explored the role of HSP90 in plaque development and its regulatory mechanisms on vasculature.. Heat-shock protein90-overexpression lentivirus (Lenti-HSP90) was used to transfect apoE. As a result, HSP90 gene overexpression led to reduction in en face plaque area and increase in unstable plaque with heavier accumulation of lipids. Concomitantly, more macrophages, less smooth muscle cells, and collagen were generated, suggesting aggravated inflammation. However, inhibition of HSP90 with 17-AAG, a HSP90-inhibitor, induced opposing effects. Moreover, HSP90 upregulated plaque MMP-8, which might be the underlying mechanism of the change in plaque vulnerability index. Further, the translocation of NF-κB was promoted by HSP90, while inhibition of NF-κB significantly reduced MMP-8 production, which is upregulated by HSP90.. These findings suggested that HSP90 governs plaque development and vulnerability, as well as inflammation, at least in part via MMP-8 and NF-κB signaling pathways.

Topics: Animals; Apolipoproteins E; Benzoquinones; Cardiovascular Agents; Carotid Arteries; Carotid Artery Diseases; Disease Models, Animal; Gene Expression Regulation; Genetic Vectors; HSP90 Heat-Shock Proteins; Inflammation; Inflammation Mediators; Lactams, Macrocyclic; Lentivirus; Male; Matrix Metalloproteinase 8; Mice; Mice, Knockout; NF-kappa B; Plaque, Atherosclerotic; RAW 264.7 Cells; Signal Transduction; Transduction, Genetic; Transfection

The study included 62 patients with uncomplicated primary and secondary infectious endocarditis admitted to S.PBotkin city hospital from 2011 to 2014. The emphasis is laid on diagnostic significance of dynamic measurements of the levels of C-reactive protein, tumour necrosis factor and highly sensitive troponin-1 for the evaluation of activity of the infectious/toxic process, severity of the disease, and detection of complications. The study revealed the relationship of the enhanced level of troponin-1 with changes of inflammation markers, morphofunctional characteristics of myocardium, and circulatory failure. Morphologicl study demonstrated inflammatory and dystrophic changes in myocardium, focal and diffuse cardiofibrosis suggesting development of non-coronarogenic myocardial lesions that play an important role in the progress of cardiac failure associated with infectious endocarditis.

Topics: Adult; Anti-Bacterial Agents; Biomarkers; C-Reactive Protein; Cardiovascular Agents; Echocardiography; Endocarditis; Female; Heart Failure; Humans; Inflammation; Male; Middle Aged; Myocardium; Outcome Assessment, Health Care; Severity of Illness Index; Statistics as Topic; Troponin I; Tumor Necrosis Factor-alpha

We report an autopsy case of a coronary aneurysm with massive adventitial inflammation post-percutaneous coronary intervention with sirolimus-eluting stent (SES) insertion in the left circumflex (LCX) coronary artery for ischemic heart disease 3 years prior to death. The internal elastic membrane was disrupted opposite the site of the eccentric LCX plaque due to injury during stenting, and the adventitia showed massive inflammatory cell infiltration, mainly consisting of eosinophils. The LCX showed aneurysmal dilatation with inflammatory cell infiltration. Inappropriate SES implantation attracted chronic inflammation. Chronic inflammation can lead to the development of coronary artery aneurysms.

Topics: Aged, 80 and over; Autopsy; Cardiovascular Agents; Coronary Aneurysm; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Drug-Eluting Stents; Everolimus; Fatal Outcome; Female; Heart Injuries; Humans; Inflammation; Percutaneous Coronary Intervention; Prosthesis Design; Treatment Outcome; Ultrasonography, Interventional; Vascular System Injuries

This study sought to evaluate whether the permanent fluoropolymer-coated Xience Xpedition everolimus-eluting stent (Xience-EES) exhibits lower acute thrombogenicity compared with contemporary drug-eluting stents (DES) with biodegradable polymer coatings in an acute swine shunt model.. Previous pre-clinical and clinical experience suggests that several factors may influence the predisposition for acute thrombus formation of polymer-coated DES, including stent design and the polymer coating technology. It remains unclear whether relevant differences exist with respect to acute thrombogenicity, particularly between current commercial stent designs using permanent polymers and those using biodegradable polymers.. An ex vivo carotid to jugular arteriovenous porcine shunt model involving a test circuit of 3 in-line stents, was used to test acute thrombogenicity, where Xience-EES (n = 24) was compared with 4 CE-marked DES with biodegradable polymer coatings (BioMatrix Flex, Synergy, Nobori, and Orsiro [n = 6 each]). After 1 h of circulation, platelet aggregation in whole mount stents was evaluated by confocal microscopy with immunofluorescent staining against dual platelet markers (CD61/CD42b) along with scanning electron microscopy.. Xience-EES showed the least percentage of thrombus-occupied area as compared with the biodegradable polymer-coated DES, with a significant difference compared with BioMatrix Flex and Synergy (mean differences: [BioMatrix Flex: 15.54, 95% confidence interval [CI]: 11.34 to 19.75, p < 0.001; Synergy: 8.64, 95% CI: 4.43 to 12.84, p < 0.001; Nobori: 4.22, 95% CI: -0.06 to 8.49, p = 0.055; Orsiro: 2.95, 95% CI: -1.26 to 7.15, p = 0.286). The number of cell nuclei on strut surfaces was also the least in Xience-EES, with a significant difference relative to BioMatrix Flex, Nobori, and Orsiro (mean ratios: BioMatrix Flex: 4.73, 95% CI: 2.46 to 9.08, p < 0.001; Synergy: 1.44, 95% CI: 0.75 to 2.76, p = 0.51; Nobori: 5.97, 95% CI: 3.11 to 11.44, p < 0.001; Orsiro: 5.16, 95% CI: 2.69 to 9.91, p < 0.001).. Xience-EES's overall design confers acute thromboresistance relative to contemporary DES with biodegradable coatings, with less platelet aggregation versus BioMatrix Flex and Synergy, and less inflammatory cell attachment versus BioMatrix Flex, Nobori, and Orsiro, in an ex vivo swine shunt model, which lends support to reported clinical findings of lower early stent thrombosis.

Topics: Acute Disease; Animals; Blood Coagulation; Cardiovascular Agents; Coated Materials, Biocompatible; Drug-Eluting Stents; Endovascular Procedures; Everolimus; Inflammation; Materials Testing; Microscopy, Confocal; Microscopy, Electron, Scanning; Models, Animal; Platelet Aggregation; Polymers; Prosthesis Design; Swine; Thrombosis; Time Factors

This study investigates the therapeutic potential of intracoronary tacrolimus against acute myocardial infarction (AMI) in minipigs with serial cardiac magnetic resonance (CMR) and changes at histological and protein levels. Twelve minipigs subjected to permanent left anterior descending artery ligation were randomized as tac-treated group (n=6, with intracoronary tacrolimus treatment) and controls (n=6). CMR with cine and late gadolinium enhancement (LGE) studies were performed on postoperative days 2, 5, and 21. There were no significant differences in left ventricular function (LVF), contractility, and LGE between the two groups on day 2. On day 5, the tac-treated group showed a significantly higher ejection fraction, smaller infarct, and lower day-5/day-2 infarct ratio than controls. On day 21, the controls demonstrated further deterioration of LVF and infarct. Contrastingly, the tac-treated animals demonstrated preservation of LVF, contractility, significantly smaller infarct, and lower day-21/day-2 infarct ratios compared with those on day 5 and controls. The in vivo CMR results were correlated with in vitro findings on histology, immunostaining, and Western blotting which revealed significantly less fibrosis, higher vascularities, less CD68+ and CD40+ inflammatory cells, lower expressions of inflammatory (MMP-9, NF-κB, and TNF-α), and apoptotic (Bax, Caspase-3, c-PARP) biomarkers, respectively, in tac-treated AMI minipigs than controls.

Topics: Animals; Apoptosis; Biomarkers; Cardiac Imaging Techniques; Cardiovascular Agents; Heart Ventricles; Immunohistochemistry; Inflammation; Magnetic Resonance Imaging, Cine; Male; Myocardial Infarction; Swine; Swine, Miniature; Tacrolimus; Ventricular Function, Left

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

The present study is aimed to investigate the effect of Gualou Xiebai Decoction (GXD) ethanol extract on myocardial fibrosis and clarify the possible mechanism.. Rats with ligated left anterior descending coronary artery were treated with GXD ethanol extract (1.14 g/kg, 2.27 g/kg, 4.53 g/kg) daily via gavage for 4 weeks. Histopathological changes and collagen distribution were evaluated by haematoxylin and eosin and Masson staining. The mRNA levels of Collagen I and Collagen III were detected by real-time PCR. The expressions of TGF-β1, TGFβ receptor (TGFβR)I, TGFβRII, P-Smad2/3 and Smad7 were determined by Western blot.. GXD treatment was significantly reduced the heart weight/body weight ratio (P < 0.05) as well as the left ventricle weight/body weight ratio (P < 0.05). It also significantly alleviated the degree of inflammation, decreased myocardial collagen volume fraction (P < 0.05 ∼ 0.01), together with markedly prevented the upregulations of Collagen I and Collagen III (P < 0.05 ∼ 0.01). Moreover, GXD downregulated expressions of TGF-β1, TGFβRI, TGFβRII, Smad2/3 whereas improved Smad7 expression in the myocardial fibrosis rats.. GXD ameliorates myocardial fibrosis induced by cardiac infarction with ligated left anterior descending coronary artery, the mechanism maybe involve in inhibiting the TGF-β1 signalling pathway.

Topics: Allium; Animals; Cardiovascular Agents; Collagen; Drugs, Chinese Herbal; Fibrosis; Heart Ventricles; Inflammation; Male; Myocardial Infarction; Myocardium; Organ Size; Phytotherapy; Rats; Rats, Wistar; Signal Transduction; Smad Proteins; Smad2 Protein; Smad3 Protein; Smad7 Protein; Transforming Growth Factor beta1; Trichosanthes

Because systemic inflammation after coronary intervention places patients at increased risk of subsequent cardiac events, we aimed to compare clinical outcomes and chronic serum inflammation markers of paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES) in hemodialysis patients. Paclitaxel-eluting stents and SES were implanted in 36 patients with 46 lesions, and 32 patients with 40 lesions, respectively. In addition to 1-year major adverse cardiac event (MACE) rates, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), neopterin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) were also compared before and 9 months after percutaneous coronary intervention (PCI). The incidence of MACE was significantly lower in the PES group than in the SES group (11.1 vs. 25.0 %, respectively, P = 0.042), mainly due to the reduction of target lesion revascularization in the PES group (6.5 vs. 17.5 %, P = 0.003). The logarithm of hs-CRP as well as IL-6 decreased significantly 9 months post-PCI compared with pre-PCI in the PES group (hs-CRP: 3.65 ± 0.35 vs. 2.91 ± 0.48, P = 0.007; IL-6: 6.73 ± 3.66 vs. 2.61 ± 2.29, P = 0.017) but not in the SES group (hs-CRP: 3.33 ± 0.29 vs. 3.42 ± 0.27, P not significant; IL-6: 6.08 ± 4.97 vs. 5.66 ± 4.29, P not significant). However, neopterin, ICAM-1, and VCAM-1 remained unchanged both pre-PCI and 9 months post-PCI in both groups. Moreover, MACE were less frequent in patients with decreased hs-CRP levels 9 months post-PCI compared with patients without decreased hs-CRP levels (P = 0.002) in all patients. Paclitaxel-eluting stents appear to be more effective than SES in reducing MACE rates, especially target lesion revascularization, and may be able to stabilize local inflammatory changes of target lesions specifically in patients on hemodialysis. Thus PES, which inhibit in-stent restenosis and cardiac events in hemodialysis patients, may play an important role in suppression of chronic inflammatory response in target lesions as compared with SES. Chronic continuous inflammation plays an important role after implantation of both types of stent with regard to in-stent restenosis in patients on hemodialysis.

Topics: Aged; Biomarkers; C-Reactive Protein; Cardiovascular Agents; Chi-Square Distribution; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Humans; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Middle Aged; Paclitaxel; Percutaneous Coronary Intervention; Prosthesis Design; Renal Dialysis; Risk Factors; Sirolimus; Time Factors; Treatment Outcome; Vascular Cell Adhesion Molecule-1

The aim of this study was to assess the efficacy of stent-based delivery of succinobucol alone and in combination with rapamycin in a porcine coronary model.. Current drugs and polymers used to coat coronary stents remain suboptimal in terms of long term efficacy and safety. Succinobucol is a novel derivative of probucol with improved antioxidant and anti-inflammatory properties.. Polymer-free Yukon stents were coated with 1% succinobucol (SucES), 2% rapamycin (RES), or 1% succinobucol plus 2% rapamycin solutions (SucRES) and compared with a bare metal stent (BMS).. The in vivo release profile of SucES indicated drug release up to 28 days (60% drug released at 7 days); 41 stents (BMS, n = 11; SucES, n =10; RES, n = 10; SucRES, n = 10) were implanted in the coronary arteries of 17 pigs. After 28 days, mean neointimal thickness was 0.31 ± 0.14 mm for BMS, 0.51 ± 0.14 mm for SucES, 0.19 ± 0.11 mm for RES, and 0.36 ± 0.17 mm for SucRES (P < 0.05 for SucES vs. BMS). SucES increased inflammation and fibrin deposition compared with BMS (P < 0.05), whereas RES reduced inflammation compared with BMS (P < 0.05).. In this model, stent-based delivery of 1% succinobucol using a polymer-free stent platform increased neointimal formation and inflammation following coronary stenting.

Topics: Animals; Cardiovascular Agents; Cattle; Cell Survival; Cells, Cultured; Coronary Vessels; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Eluting Stents; Endothelial Cells; Fibrin; Inflammation; Male; Metals; Models, Animal; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Percutaneous Coronary Intervention; Probucol; Prosthesis Design; Sirolimus; Swine

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

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 current study sought to examine inflammation at the stented segments of Nobori (Terumo Corporation, Tokyo, Japan) and Cypher (Cordis, Miami, Florida) drug-eluting stents (DES), as well as free radical production and endothelial function of the adjacent nonstented segments in a pig coronary model.. Nobori is a novel DES, incorporating a biolimus A9-eluting biodegradable polymer coated only on the abluminal surface of the stent. These unique features may favorably affect inflammation and endothelial function, as compared to the currently marketed DES. Presently, pre-clinical data on direct comparison of the various generations of DES are not available.. A total of 18 DES were implanted in pig coronary arteries and subsequently explanted at 1 month. Stented segments were assessed by angiography and histology. Ex vivo vasomotor function and superoxide production in segments proximal and distal to the stent were determined. The vasoconstriction, endothelial-dependent relaxation, and endothelial-independent relaxation of proximal and distal nonstented segments were measured.. Histological evaluation revealed lower inflammatory response with Nobori than with Cypher DES. There is trend for lower angiographic percentage diameter stenosis in Nobori versus Cypher groups (p = 0.054). There was increased endothelium-dependent relaxation, decreased endothelin-1-mediated contraction, and less superoxide production in the vessel segments proximal and distal to Nobori versus Cypher stents.. Our data show significantly lower inflammatory response in the stented segments, and rapid recovery of endothelial function of peristent segments in the Nobori group compared with Cypher DES group at 1 month in porcine coronary artery model.

Topics: Angioplasty, Balloon, Coronary; Animals; Cardiovascular Agents; Coronary Angiography; Coronary Restenosis; Coronary Vessels; Dose-Response Relationship, Drug; Drug-Eluting Stents; Endothelium, Vascular; Inflammation; Japan; Models, Animal; Prosthesis Design; Recovery of Function; Sirolimus; Superoxides; Sus scrofa; Time Factors; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

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

The time-dependent changes in endothelial and healing properties of coronary arteries implanted with a biodegradable polymer-based biolimus A9-eluting stent (BioPol-BES) have not been investigated. We evaluated the short-term and the long-term in vivo response of BioPol-BES, as compared to a permanent polymer-based sirolimus-eluting stent (PermPol-SES), and a bare metal stent (BMS).. Overlapping stents were placed in 33 swine (n=11 for BES, SES, and BMS, respectively) for two and four weeks and single stents in 30 miniature pigs (n=18 for BES, n=9 for SES, n=3 for BMS) for three, nine and 15-month evaluations. The vessel patency, arterial healing and endothelialisation were assessed by angiography, histopathology and scanning electron microscopy. At four weeks, the endothelialisation at overlapping stent regions was greater with BioPol-BES (87.8±3.7%) and BMSs (98.0±0.4%) than with PermPol-SES (66.4±3.2%). The inflammation score in vessels implanted with single BioPol-BES increased slightly from three to 15 months (0.00±0.00 to 0.28±0.14), while this increase was more pronounced with PermPol-SES (0.11±0.07 to 1.56±0.68). Compared to BMS moderate lymphocyte infiltration was seen with BioPol-BES, and marked granulomatous formation with PermPol-SES.. The level of endothelial coverage in BioPol-BES was comparable to BMS at four weeks, with no significant increase of inflammatory reaction up to 15 months.

Topics: Angioplasty, Balloon; Animals; Cardiovascular Agents; Coronary Angiography; Coronary Vessels; Drug-Eluting Stents; Endothelial Cells; Granuloma; Inflammation; Lactic Acid; Lymphocytes; Metals; Microscopy, Electron, Scanning; Models, Animal; Polyesters; Polymers; Prosthesis Design; Sirolimus; Swine; Swine, Miniature; Time Factors; Ultrasonography; Vascular Patency; Wound Healing

Topics: Angioplasty, Balloon, Coronary; Animals; Cardiovascular Agents; Coated Materials, Biocompatible; Coronary Angiography; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Drug-Eluting Stents; Female; Inflammation; Prosthesis Design; Prosthesis Failure; Swine; Swine, Miniature

Cocaine use is associated with increased cardiovascular mortality and can promote acute coronary syndrome (ACS). Use of beta-blockers is controversial in patients who use cocaine, and the safety and efficacy of these medications in ACS in patients actively using cocaine is unknown. We enrolled 90 patients with ACS and positive urine drug screen for cocaine. Patients received standard ACS therapy plus either labetalol (n = 60) or diltiazem (n = 30). Blood pressure and heart rate were measured at baseline and 48 hours. Levels of serum CD40 ligand, interleukin (IL)-6, and choline at baseline and 48 hours were determined. There were no baseline differences in hemodynamics or serum levels of inflammatory markers between the labetalol and diltiazem groups. Both groups experienced a significant and equivalent decrease in BP and HR at 48 hours compared with baseline. At 48 hours of treatment, there were significant decreases of 17% in CD40 ligand (P < .005) and 16% in IL-6 (P < .005) but no change in choline in the diltiazem group. Furthermore, in the labetalol group, there were significant differences of 30% in CD40 ligand (P < .005 time and group comparison), 22% in IL-6 (P < .005 time and group comparison), and 18% in choline (P < .005 time and group comparison). There were no adverse events during hospitalization in any patients who received labetalol. In conclusion, labetalol appears to be safe in cocaine-associated ACS. Furthermore, labetalol provides a beneficial hemodynamic response and, in comparison to diltiazem, potentiates an anti-inflammatory vascular response in this setting.

Topics: Acute Coronary Syndrome; Adrenergic alpha-Antagonists; Adult; Aged; Biomarkers; Cardiovascular Agents; CD40 Ligand; Cocaine-Related Disorders; Diltiazem; Female; Georgia; Hemodynamics; Humans; Inflammation; Interleukin-6; Labetalol; Male; Middle Aged; Treatment Outcome

Nitric oxide (NO) homeostasis maintained by neuronal/endothelial nitric oxide (NO) synthase (n/eNOS) contributes to regulate cardiac function under physiological conditions. At the early stages of ischaemia, NO homeostasis is disturbed due to Ca2+-dependent e/nNOS activation. In endothelial cells, successive drop in NO concentration may occur due to both uncoupling of eNOS and/or successive inhibition of nNOS catalytic activity mediated by arachidonic acid-induced tyrosine phosphorylation of this enzyme. The reduced NO bioavailability triggers nuclear factor (NF)-kB activation followed by the induction of inducible NOS (iNOS) expression. In cardiomyocytes ischaemia also triggers the induction of iNOS expression during reperfusion. The massive amounts of NO which are subsequently produced following iNOS induction may exert on cardiomyocytes and the other cell types of cells of the heart, such as endothelial and smooth muscle cells, macrophages and neutrophils, opposing effects, either beneficial or toxic. The balance between these two double-faced actions may contribute to the final clinical outcomes, determining the degree of functional adaptation of the heart to ischaemia/reperfusion injury. In the light of this new vision on the critical role played by the cross-talk between n/eNOS and iNOS as well as the non enzymatic NO production by nitrite, we have reason to believe that new pharmacological measurements or experimental interventions, such as ischaemic preconditioning, aimed at counteracting the drop in NO levels beyond the normal range of NO homeostasis during early reperfusion can represent an efficient strategy to reduce the extent of functional impairment and cardiac damage in the heart exposed to ischaemia/reperfusion injury.

Topics: Animals; Cardiovascular Agents; Homeostasis; Humans; Inflammation; Inflammation Mediators; Ischemic Preconditioning, Myocardial; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Signal Transduction

Paclitaxel is an antiproliferative agent in drug-eluting stents with largely unknown tissue interaction. Toxicity might result from overdosage and/or accumulation. Part 1 of this two-step study investigated how paclitaxel uptake depends on dose density, coronary drug transfer kinetics, and elution efficacy.. With cobalt chromium stents and Polyzene-F nanoscale coating, low, intermediate, and high paclitaxel dose densities (25 microg, 50 microg, and 150 microg per stent) were investigated in porcine right coronary arteries (RCAs). Coronary and myocardial tissue concentration measurements and determination of on-stent paclitaxel and plasma concentrations were performed at 2, 8, 24, and 72 hours.. For all stents, uptake was similar at all time intervals (paclitaxel RCA concentration range, 1,610-33,300 ng). Low- and intermediate-dose stents showed similar RCA concentrations, but those for high-dose stents were three times greater. Residual on-stent paclitaxel concentration was not time-dependent, at 33.3% on low-, 30.6% on intermediate-, and 17.4% on high-dose stents. Paclitaxel was measurable in only the plasma immediately after stent placement, with a linear dose relationship and a timely regression: measurements in high-dose stents were 0.0454-0.656 ng/mL at 1 minute and 0.0329-0.0879 ng/mL at 5 minutes. Untreated control samples of the left coronary artery showed a linear dose-dependent concentration (12.6 ng/g, 21.2 ng/g, and 85.2 ng/g).. Overall coronary paclitaxel uptake is fairly independent from the baseline overall dose density and, hence, depends on immediate binding mechanisms of the arterial wall. This is supported by the fact that, regardless of the applied dose density, the kinetics of paclitaxel uptake did not follow an exposure time pattern.

Topics: Angioplasty, Balloon, Coronary; Animals; Biological Availability; Cardiovascular Agents; Chromium Alloys; Coated Materials, Biocompatible; Coronary Vessels; Dose-Response Relationship, Drug; Drug-Eluting Stents; Female; Inflammation; Models, Animal; Myocardium; Paclitaxel; Polymers; Prosthesis Design; Swine; Swine, Miniature; Tissue Distribution

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

Atherosclerosis, restenosis, and posttransplant graft atherosclerosis are characterized by endothelial damage, infiltration of inflammatory cells, and proliferation of smooth muscle cells. The CXCR3-activating chemokines interferon-gamma inducible protein 10 (IP10) and MIG (monokine induced by interferon-gamma) have been implicated in vascular repair and remodeling. The underlying molecular mechanisms, however, remain elusive. Here, we show that wire-mediated arterial injury induced local and systemic expression of IP10 and MIG, resulting in enhanced recruitment of CXCR3(+) leukocytes and hematopoietic progenitor cells. This was accompanied by profound activation of mammalian target of rapamycin complex (mTORC)1, increased reactive oxygen species production, apoptosis, and intimal hyperplasia. Genetic and pharmacological inactivation of CXCR3 signaling not only suppressed recruitment of inflammatory cells but also abolished mTORC1 activation, reduced reactive oxygen species generation, and blocked apoptosis of vascular cells, resulting in significant reduction of intimal hyperplasia in vivo. In vitro, stimulation of T cells with IP10 directly activated mTORC1 and induced generation of reactive oxygen species and apoptosis in an mTORC1-dependent manner. These results strongly indicate that CXCR3-dependent activation of mTORC1 directly links stimulation of the Th1 immune system with the proliferative response of intimal cells in vascular remodeling.

Topics: Animals; Apoptosis; Cardiovascular Agents; Carrier Proteins; Cell Proliferation; Chemokine CXCL10; Chemokine CXCL9; Chemotaxis; Disease Models, Animal; Everolimus; Femoral Artery; Hematopoietic Stem Cells; Humans; Hyperplasia; Inflammation; Jurkat Cells; Mice; Mice, Inbred BALB C; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor); Reactive Oxygen Species; Receptors, CXCR3; Signal Transduction; Sirolimus; Th1 Cells; Time Factors; TOR Serine-Threonine Kinases

Long lesions and complex vessel anatomy frequently require the use of overlapping stents to treat a lesion. The purpose of this study was to evaluate the long-term effects of overlapping the Axxess Biolimus A9 eluting stent (BES) with two of the most commonly used, commercially available drug eluting stents. These stents were compared to BxVelocity bare metal (BMS) stents in a porcine coronary stent-injury model.. Nineteen juvenile farm swine, 25-35 kg in weight, 3-6 months in age were utilised. Each animal received an Axxess stent to their coronary artery as permitted by the individual animal's anatomy. A second stent, either a Cypher, sirolimus eluting stent (SES) or, a Taxus, paclitaxel eluting stent (PES), or a BxVelocity bare metal stent (BMS) were implanted in an overlapped fashion. The animals were then followed for either 28 or 180 days as specified by a randomisation scheme. At the end of each follow-up period, they were euthenised, and the vessels containing the overlapping stents were harvested, processed into histological sections, and analysed. Compared to bare metal stents, overlapped segments using DES exhibited delayed vascular healing compared to both the proximal and distal non-overlap sites at each of the follow-up time point. Overall, in the non-overlap stent segments, SES induced significantly more inflammation and neointimal hyperplasia compared to PES and BMS.. In this study of BMS and two different types of DES overlapped with the Axxess Biolimus A9 eluting stent, we found that while there was a delay in the degree of vascular healing with DES compared to BMS, the specific type of DES that was overlapped with BES did not affect the behaviour of the overlap zone in terms of most of the histomorphometric measures at 28 or 180 days. This was true whether the stent was drug eluting or bare metal. More inflammation with delayed healing was seen in the SES compared to PES and BMS.

Topics: Angioplasty, Balloon, Coronary; Animals; Cardiovascular Agents; Cell Proliferation; Coronary Angiography; Coronary Vessels; Drug-Eluting Stents; Hyperplasia; Inflammation; Models, Animal; Nickel; Paclitaxel; Platelet Aggregation Inhibitors; Prosthesis Design; Sirolimus; Stents; Swine; Time Factors; Titanium; Wound Healing

We compared local vessel healing and inflammatory responses associated with nonoverlapping sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES).. Sirolimus and paclitaxel may have different effects on vascular healing. In the present study, we analyzed the local histologic effects of drug-eluting stents (DES).. We placed 43 stents (22 PES and 21 SES) in 16 Yucatan minipigs. Stents were randomly assigned and placed in the left anterior descending, circumflex, or right coronary arteries (one stent per artery), covering a region previously injured by balloon angioplasty.. Histopathologic analysis showed that the distribution of injury scores was similar between the two stent groups, reflecting the homogeneity of coronary injury secondary to balloon overstretch. Electron microscopy showed complete endothelialization in most cases. Incomplete endothelialization was present in 12.5% of PES and almost 20% of SES at 30 days. In the PES group, moderate to severe inflammation was found in eight arteries, whereas only one vessel had moderate inflammation in the SES group. Severe inflammation was observed significantly more often in the PES than in the sirolimus group (P = 0.006). With the PES group, stent struts overlying side branches had a significantly higher frequency of poor endothelialization scores than did stent struts that did not overlay side branches (P = 0.006).. In this preclinical study in a pig model of in-stent restenosis, implantation of nonoverlapping DES was associated with local inflammatory reactions and decreased endothelial repair. Impaired endothelialization was visualized in the struts overlying side branches.

Topics: Angioplasty, Balloon, Coronary; Animals; Cardiovascular Agents; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Drug-Eluting Stents; Inflammation; Paclitaxel; Platelet Endothelial Cell Adhesion Molecule-1; Platelet-Derived Growth Factor; Sirolimus; Swine; Swine, Miniature; Time Factors; Vascular Endothelial Growth Factor A; Wound Healing

High-sensitivity C-reactive protein (hsCRP) levels can predict cardiovascular events among apparently healthy individuals and patients with coronary artery disease (CAD). However, hsCRP levels vary among ethnic populations. We previously reported hsCRP levels in Japanese to be much lower than in Western populations. We investigated the prognostic value of hsCRP levels in Japanese patients with stable CAD. The hsCRP levels were measured in 373 Japanese patients who underwent elective coronary angiography and thereafter decided to receive only medical treatment. Patients were followed up for 2.9+/-1.5 years for major cardiovascular events (death, myocardial infarction, unstable angina, stroke, aortic disease, peripheral arterial disease, or heart failure). The median hsCRP level was 0.70 mg/l. During the follow-up, cardiovascular events occurred in 53 (14%) of the 373 patients. Compared with 320 patients without events, 53 with events had higher hsCRP levels (median 1.06 vs. 0.67 mg/l, P<0.05). To clarify the association between hsCRP levels and cardiovascular events, the 373 study patients were divided into tertiles according to hsCRP levels: lower (<0.4 mg/l), middle (0.4-1.2mg/l), and higher (>1.2mg/l). The Kaplan-Meier analysis demonstrated a significant difference in the event-free survival rate between higher vs. middle or lower tertiles (P<0.05). In multivariate Cox regression analysis, the hsCRP level of >1.0mg/l was an independent predictor for cardiovascular events (hazard ratio, 2.0; 95%CI, 1.1-3.4; P<0.05). Thus, in Japanese patients with stable CAD who received only medical treatment, higher hsCRP levels, even >1.0mg/l, were found to be associated with a significantly increased risk for further cardiovascular events.

Topics: Aged; Asian People; Biomarkers; C-Reactive Protein; Cardiovascular Agents; Cohort Studies; Coronary Angiography; Coronary Disease; Disease Progression; Disease-Free Survival; Female; Humans; Inflammation; Inflammation Mediators; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Predictive Value of Tests; Proportional Hazards Models; Risk Assessment; Time Factors; Treatment Outcome; Up-Regulation

In part 1 of the present study, the authors demonstrated that coronary paclitaxel uptake from drug eluting stents (DESs) was not dependent on exposure time and dose. In this second part, the effect of the different paclitaxel dose densities on long-term biologic behavior was evaluated.. In 40 minipigs, (with 4- and 12-week follow-up), identical stents with the same three paclitaxel dose densities as in part 1 were implanted in the right coronary artery. Minipigs implanted with Polyzene-F nanocoated stents served as the control group. Quantitative angiography measuring average luminal diameter (from three in-stent reference points), minimal luminal diameter (from the point of maximum in-stent stenosis), average late loss, maximum late loss, and binary stenosis rate was performed, as was microscopy to determine neointimal thickening, injury score, and inflammation.. All three DESs were associated with a high average late loss, binary stenosis rate, and neointimal thickening, without significant differences. Drug-free stents had significantly less late in-stent stenosis: there was an average late loss of 0.3 mm +/- 0.3 in drug-free stents versus 0.8 mm +/- 0.2 in intermediate-dose stents and 1.5 mm +/- 0.6 in high-dose stents (P = .04). DES-associated inflammation was high in all DESs and six times higher as in the drug-free stents (Kornowski scores of 0.2 +/- 0.1 in drug-free stents, 1.3 +/- 0.9 in low-dose stents, 1.7 +/- 0.8 in intermediate-dose stents, and 1.3 +/- 1.0 in high-dose stents; P = .04). It worsened with time in all DESs, as did late in-stent stenosis.. The extensive and long-term retention of paclitaxel even in a low-dose formulation, at least according to the present labeling of DESs, might be associated with negative long-term results with regard to inflammation and late in-stent stenosis.

Topics: Angioplasty, Balloon, Coronary; Animals; Cardiovascular Agents; Coated Materials, Biocompatible; Coronary Angiography; Coronary Restenosis; Coronary Vessels; Dose-Response Relationship, Drug; Drug-Eluting Stents; Female; Inflammation; Models, Animal; Paclitaxel; Prosthesis Design; Prosthesis Failure; Swine; Swine, Miniature; Time Factors

Topics: Anti-Inflammatory Agents; Biomarkers; C-Reactive Protein; Cardiovascular Agents; Coronary Disease; Humans; Incidence; Inflammation; Practice Guidelines as Topic; Risk Assessment; Risk Factors; Time Factors; Up-Regulation

Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Glycation End Products, Advanced; Humans; Hypoglycemic Agents; Inflammation; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Signal Transduction; Tumor Necrosis Factor-alpha

Although Bell's palsy is the most common acute facial paralysis, the cause of it is still unknown. This made the treatment for it remain very limited. Many methods are simply symptomatic treatment. Up to now we have known that Bell's palsy is related to viral infection and the pathomechanism of Bell's palsy involves inflammatory oedema and entrapment neuropathy in the narrow bony facial canal. So treatment plans for Bell's palsy mainly focus on antiviral therapy, relieving inflammatory oedema and accelerating facial nerve recovery. Sodium beta-aescin is derived from horse chestnut and its major constituent is aescigenin which has been approved by China national drug standard. The pharmacologic action of sodium beta-aescin is to relieve tissue oedema, recover vasopermeability and eliminate pressure caused by oedema. Nowadays sodium beta-aescin has been widely used clinically for encephaledema or tumefaction caused by trauma or operation. It also can be used for treating disease of digestive system and increasing intravenous tension and improving microcirculation. Although many papers had been published on the anti-edema effects of sodium beta-aescin, little was known about the effects in treating oedema complicated by Bell's palsy.

Topics: Bell Palsy; Cardiovascular Agents; Chemistry, Pharmaceutical; Drug Design; Edema; Escin; Facial Paralysis; Humans; Inflammation; Ischemia; Models, Biological; Models, Theoretical; Pharmaceutical Preparations; Sodium

We compared the healing and inflammatory responses of polymer-free bare-metal stents (BMS), polymer-free sirolimus-eluting stents (SES) and polymer-free sirolimus-eluting stents plus estradiol (SES+ED) to Cypher drug-eluting stents (CDES) in a rabbit model of overlapping stent placement.. Inflammatory responses to polymers and delayed healing remain important safety issues associated with CDES. Whether nonpolymeric stents that elute sirolimus or sirolimus and estradiol provoke less inflammation and heal better is unknown.. Twenty-eight rabbits received 2 overlapping stents in each iliac artery: SES, SES+ED, BMS, or CDES, and vessels were harvested at 28 days for histology and scanning electron microscopy.. Although similar at nonoverlapping segments, neointimal thickness within the overlap site of CDES was significantly less than in SES, SES+ED, and BMS (0.07 +/- 0.04 mm vs. 0.16 +/- 0.03 mm, 0.14 +/- 0.03 mm, and 0.15 +/- 0.03 mm, p < 0.0001). Endothelialization was greater in SES, SES+ED, and BMS compared with CDES in nonoverlapping sections (80.0 +/- 5.0% vs. 95.3 +/- 5.0%, 97.5 +/- 2.5%, and 96.7 +/- 3.8%; p = 0.0028) and overlapping sections (85.8 +/- 2.9% vs. 90.8 +/- 6.3%, 89.2 +/- 6.3%, and 48.3 +/- 2.9%; p < 0.0001). The number of luminal eosinophils was also less in overlapping sections of SES, SES+ED, and BMS versus CDES but was similar in nonoverlapping sections.. Polymer-free stents coated with SES or SES+ED result in less robust neointimal suppression but markedly improved arterial healing compared with CDES in the rabbit model.

Topics: Angioplasty, Balloon; Animals; Cardiovascular Agents; Cytokines; Drug-Eluting Stents; Fibrinolytic Agents; Iliac Artery; Inflammation; Intercellular Signaling Peptides and Proteins; Metals; Microscopy, Electron, Scanning; Models, Animal; Organ Culture Techniques; Polymers; Prosthesis Design; Rabbits; Sirolimus; Stents; Wound Healing

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

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

Topics: Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus; Dyslipidemias; Europe; Female; Genetic Predisposition to Disease; Guideline Adherence; Health Promotion; Heart Rate; Humans; Hypertension; Hypoglycemic Agents; Hypolipidemic Agents; Inflammation; Kidney Diseases; Life Style; Lipids; Male; Metabolic Syndrome; Motor Activity; Nutritional Physiological Phenomena; Obesity; Overweight; Primary Prevention; Risk Assessment; Risk Factors; Sex Factors; Smoking; Smoking Cessation; Stress, Psychological; Treatment Outcome

Topics: Blood Pressure; Cardiovascular Agents; Cardiovascular Diseases; Diabetes Mellitus; Dyslipidemias; Female; Genetic Predisposition to Disease; Guideline Adherence; Health Promotion; Heart Rate; Humans; Hypertension; Hypoglycemic Agents; Hypolipidemic Agents; Inflammation; Kidney Diseases; Life Style; Lipids; Male; Metabolic Syndrome; Motor Activity; Nutritional Physiological Phenomena; Obesity; Overweight; Primary Prevention; Risk Assessment; Risk Factors; Sex Factors; Smoking; Smoking Cessation; Stress, Psychological; Treatment Outcome

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

In older patients who are known to be at greater risk for atrial fibrillation, we aimed to determine whether patients who develop atrial fibrillation-flutter (AF) after major thoracic surgery have an exaggerated white blood cell (WBC) count in response to surgical stress compared with those who do not develop AF.. Using a prospective database, 272 patients 60 years or older who were in sinus rhythm before surgery and had elective lobectomy, pneumonectomy, or esophagectomy were studied. Patients did not receive perioperative medications to prevent AF. Clinical characteristics and preoperative 12-lead electrocardiogram were examined and WBC counts were recorded for patients prior to and for up to five days after surgery.. Atrial fibrillation-flutter was observed in 74 of 272 (27%) patients a median of 3 days after surgery. The increase in WBC count from preoperative to postoperative day 1 and age were jointly significant predictors of AF by multiple logistic regression (area under the receiver operating characteristic curve = 0.69). Using this model, a twofold increase in WBC from presurgery to postoperative day 1 corresponded to a 3.3-fold increase in the odds of developing AF (95% confidence interval [CI] 2.0 to 8.3) and for each 10 year increase in age, a 1.8-fold increase in risk of AF (95% CI 1.1 to 2.8) was seen.. Increments in WBC were greater in patients with AF and coincided with the peak onset of AF. These prospective data support an important role for stress-mediated autonomic mechanisms in the pathogenesis of AF after major thoracic surgery. We aim to examine further whether WBC elevations on postoperative day one can help further risk stratify patients younger than 60 years or those with the highest risk who could benefit from one or more AF prevention strategies.

Topics: Age Factors; Aged; Anti-Inflammatory Agents; Atrial Fibrillation; Atrial Flutter; Autonomic Nervous System; Cardiovascular Agents; Disease Susceptibility; Esophagectomy; Female; Humans; Inflammation; Leukocyte Count; Leukocytosis; Male; Middle Aged; Odds Ratio; Pneumonectomy; Postoperative Complications; Postoperative Period; Prospective Studies; Risk Factors; Stress, Physiological

Decrease of fibrinolytic potential is considered to be a risk factor for arterial thrombosis. The recently described thrombin-activatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis by cleaving of the C-terminal lysine residues from fibrin, thereby inhibiting tPA mediated plasminogen activation. The role of plasma TAFI antigen (Ag) levels and gene polymorphisms in arterial thrombosis is still not elucidated. In this prospective study, the association between plasma TAFI Ag levels and the TAFI gene polymorphisms, Ala147Thr, Thr325Ile and -438A/G, with refractory unstable angina pectoris (UAP) was determined. The study population consisted of 209 patients with UAP of whom 76 were refractory and 133 non-refractory to medical treatment. In the same study population the contribution of these polymorphisms to plasma TAFI Ag levels was determined. Plasma TAFI Ag levels were significantly higher in non-refractory patients compared to refractory patients (geometric mean 114.4 and 105.6 U/dl respectively, p=0.042). Plasma TAFI Ag levels in the lowest quartile resulted in a 2.6 fold (95% confidence interval 1.2-5.9) increased risk for refractory UAP compared to plasma TAFI Ag levels in the upper quartile. The three studied TAFI polymorphisms had an independent and additive effect on plasma TAFI Ag levels. However, no significant association between the individual TAFI polymorphisms and refractiveness was observed. In conclusion, in this study population plasma TAFI Ag levels are significantly correlated with refractiveness in patients with UAP. Furthermore, all three polymorphisms contribute independently to plasma TAFI Ag levels, but not to refractiveness.

Topics: Aged; Alleles; Angina, Unstable; Biomarkers; Carboxypeptidase B2; Cardiovascular Agents; Drug Resistance; Exons; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Hemostasis; Humans; Inflammation; Male; Middle Aged; Polymorphism, Genetic; Prospective Studies; Risk Factors; Treatment Outcome

The cardio-protective effects of neutrophil depletion or inhibition of neutrophil activation early in the course of myocardial reperfusion has been established. Whether these treatments would be effective during extended periods of reperfusion has not been ascertained. Open-chest anesthetized dogs were subjected to left circumflex artery (LCX) occlusion for 90 minutes followed by 72 hours of reperfusion. Dogs were randomized into one of four groups: 1) control; 2) Ilo-2 (iloprost 100 ng/kg/min administered via the left atrium beginning 10 minutes after LCX occlusion and continuing 2 hours into reperfusion); 3) Ilo-48 (iloprost 100 ng/kg/min administered as above until 1 hour after reperfusion then 25 ng/kg/min for 48 hours of reperfusion; or 4) antibody (neutrophil antibody administered before occlusion and 1/2 hourly for 2 hours of reperfusion and then every 24 hours). Myocardial infarct size, as a percentage of the area at risk assessed after 72 hours of reperfusion, was significantly smaller in the antibody-treated group (32.1 +/- 5.0% mean +/- SEM) or Ilo-48 (22.6 +/- 4.0%) treatment group compared with control (48.7 +/- 5.6%) or Ilo-2 (57.6 +/- 5.2%) groups. Regional myocardial blood flow studies demonstrated that all groups developed similar degrees of ischemia. The iloprost-treated groups had lower mean arterial blood pressures during occlusion and reperfusion than groups 1 and 4 (p less than 0.05). Circulating neutrophil counts were increased in groups 1 and 2 at 24 and 48 hours after reperfusion compared to groups 3 and 4 (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cardiovascular Agents; Cell Count; Coronary Circulation; Coronary Disease; Dogs; Epoprostenol; Hemodynamics; Iloprost; Inflammation; Male; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Neutrophils; Peroxidase; Time Factors

Topics: Anti-Inflammatory Agents; Cardiovascular Agents; Flavonoids; Inflammation; Vitamins; Water

Topics: Cardiovascular Agents; Chloramphenicol; Humans; Inflammation; Muscle Relaxants, Central; Quinine; Respiratory System; Respiratory Tract Diseases

Topics: Cardiovascular Agents; Flavones; Flavonoids; Inflammation