Cardiovascular & Haematological Disorders - Drug Targets - Volume 10, Issue 4, 2010

This special issue contains a clustering of articles pertaining to the inflammatory aspects of cardiovascular disease. Over the last several decades, various aspects of cardiac pathology have demonstrated an inflammatory basis. This is especially true of atherosclerotic heart disease, where our understanding has evolved from a bland role for lipids to a very profoundly inflammatory state characterized by expression of various inflammatory genes, transcription factors and biochemical mediators. Endothelial dysfunction and inflammatory pathology are seen in such diverse states as diabetic cardiovascular disease and the metabolic syndrome to arrhythmias such as atrial fibrillation. In this series of manuscripts, Dr. Negi and Anand discuss the epidemiology of cardiovascular disease and the role of risk factors in the pathogenesis of coronary artery disease. This is followed by a discussion of the paradigm shift in our understanding of atherogenesis and the evolving role of T cell-derived cytokines, chemokines, various inflammatory cells and endothelium in pathogenesis. The paradigm shift in heart disease and a historical perspective of our understanding of inflammation biology are emphasized. Drs. Finch and Joseph review the role of an important mediator, homocysteine, in cardiovascular remodeling, inflammation and oxidative stress seen in heart failure and other cardiac disease states. Drs. Agrawal, Hammond and Singh discuss the evolving and pivotal role of C reactive protein in cardiovascular pathology and its interaction with lipoproteins. Dr. Kelly Smith reviews the atheroprotective effects of exercise and the possible mechanisms mediating this process, such as modulation of endothelial, mononuclear and adipocyte function. Finally Drs. Negi, Sovari and Dudley provide insights into the role of inflammation, oxidative stress and neurohumoral pathways that lead to the common arrhythmia, atrial fibrillation. A dissection of the role of inflammatory pathways and proteins in the pathogenesis of various cardiovascular disease states can lead to potential targets for novel tailored therapies in the future. Better understanding of the proinflammatory roles of smoking, hypertension, oxidant diets and stress and the balancing effect of exercise and stress-reduction strategies may also help in development of better preventive strategies. In this regard, the enhanced development of specific biomarkers that serve as excellent surrogates of vascular inflammation will further the field and allow other translational studies to be conducted. It is hoped that this initial series of articles will summarize the importance of the inflammatory paradigm in heart disease and open the area for further research into an essential aspect of these disease states.

C-reactive protein (CRP) is secreted by hepatocytes as a pentameric molecule made up of identical monomers, circulates in the plasma as pentamers, and localizes in atherosclerotic lesions. In some cases, localized CRP was detected by using monoclonal antibodies that did not react with native pentameric CRP but were specific for isolated monomeric CRP. It has been reported that, once CRP is bound to certain ligands, the pentameric structure of CRP is altered so that it can dissociate into monomers. Accordingly, the monomeric CRP found in atherosclerotic lesions may be a stationary, ligand-bound, by-product of a ligand-binding function of CRP. CRP binds to modified forms of low-density lipoprotein (LDL). The binding of CRP to oxidized LDL requires acidic pH conditions; the binding at physiological pH is controversial. The binding of CRP to enzymatically-modified LDL occurs at physiological pH; however, the binding is enhanced at acidic pH. Using enzymatically-modified LDL, CRP has been shown to prevent the formation of enzymatically-modified LDL-loaded macrophage foam cells. CRP is neither pro-atherogenic nor atheroprotective in ApoE-/- and ApoB100/100Ldlr -/- murine models of atherosclerosis, except in one study where CRP was found to be slightly atheroprotective in ApoB100/100Ldlr -/- mice. The reasons for the ineffectiveness of human CRP in murine models of atherosclerosis are not defined. It is possible that an inflammatory environment, such as those characterized by acidic pH, is needed for efficient interaction between CRP and atherogenic LDL during the development of atherosclerosis and to observe the possible atheroprotective function of CRP in animal models.

Chronic heart failure is a major public health problem causing considerable morbidity and mortality. Recent studies have shown that an elevated plasma level of homocysteine is a strong independent risk factor for heart failure, in addition to atherosclerotic disease. Preclinical studies have demonstrated that induced hyperhomocysteinemia acts via multiple pathogenic mechanisms, including inflammation and oxidative stress, to promote adverse cardiac remodeling and failure. However, clinical studies have not conclusively shown a causative relation between hyperhomocysteinemia and cardiovascular disease. This article will review current data concerning homocysteine and its pathogenic relationship to heart failure.

Atherosclerotic vascular disease is a major cause of morbidity and mortality throughout the world. The clinical manifestations include coronary artery disease and myocardial infarction, cerebrovascular disease, renovascular disease and peripheral vascular disease. Initially considered a bland occlusive disease mediated to a great extent by lipids, atherosclerosis can now be considered an inflammatory disease, in its own right. This has led to a paradigm shift in disease management. We have come a long way since the time of Celsus, Galen, Virchow, Rokitansky and others when the components of the inflammatory cascade were first described. The development of mouse knock out models, improved molecular approaches to studying atheromatous blood vessels and development of sophisticated imaging and biomarker studies have enhanced our understanding of the molecular pathways in atherosclerosis. This brief review will attempt to weave together the historical, biochemical, immunological and molecular developments that have led to our current understanding of a deadly but treatable and potentially preventable disease.

Atherosclerotic coronary heart disease (CHD) is a major health problem worldwide. Epidemiological studies have identified the role of several modifiable and non-modifiable risk factors in the pathogenesis of CHD. Aggressive risk modification has led to a significant improvement in the morbidity and mortality from CHD. However, there is a growing need to identify better modalities of risk prediction in CHD. Many of these newer risk markers, currently under evaluation, are based on the newer concept that atherosclerosis is more than merely a problem of lipid imbalance. There has been a recent shift in the paradigm towards inflammation and oxidative stress as the key drivers in the pathophysiology of atherosclerosis and its complications. Further understanding of this complex interplay of lipid and inflammatory factors is likely to pave way to a better understanding of this disease and its myriad complications.

Atrial fibrillation (AF) remains the most commonly encountered sustained arrhythmia in clinical practice and contributes to increased morbidity and mortality. Management of AF poses a challenge due to the refractory nature of the arrhythmia and the associated thromboembolic complications. Recent studies have implicated both systemic and local cardiac inflammation in the development as well as persistence of AF. This has been validated by the occurrence of high levels of systemic markers of inflammation in patients with post operative as well as chronic AF. High levels of markers of oxidative stress have also been found in patients with persistent AF when compared with controls, indicating a role of systemic reactive oxidative species in the perpetuation of this arrhythmia. The renin angiotensin system (RAS) is believed to be upregulated in AF and may contribute to the pathogenesis of AF by producing a state of cardiac or systemic oxidative stress and /or inflammation. In this review, we aim to discuss the emerging evidence linking inflammation, and oxidative stress with AF.

Cardiovascular disease is the main cause of death in the United States. Although it is recognized that moderate intensity long-term exercise can decrease the chances of dying from cardiovascular disease by favorably modifying risk factors such as hypertension, obesity, hyperlipidemia, and insulin resistance, physical activity also enhances longevity by mechanisms independent of these risk factors. This review briefly summarizes what is known about the inflammatory nature of atherosclerosis and how long-term aerobic exercise can reduce the atherogenic activity of endothelial cells, blood mononuclear cells, and adipose tissue.

The beneficial effects of restoration of coronary flow in patients with acute myocardial infarction may be hampered by inadequate tissue perfusion. Among other factors, it is likely that platelets contribute substantially to this phenomenon. Platelets may compromise blood flow at the microvascular level by forming a part of microemboli, by adhering to reperfused, capillary or venular endothelium or to attached leukocytes, by releasing substances producing vasoconstriction, or through toxic effects. Patients with acute coronary syndromes have an increased number of circulating activated platelets, and this systemic platelet activation has been related to the presence and extent of myocardial necrosis. The mechanisms of platelet deposition to reperfused microvessels are not fully understood, but likely involve the interaction between adhesion molecules such as selectins or glycoproteins expressed on these cells upon activation and their ligands on the surface of endothelial cells or polymorphonuclear leukocytes. While these interactions are potentially important therapeutic targets in acute myocardial infarction, reducing platelet deposition and increasing myocardial salvage by direct effects on the microvasculature is still challenging with the existing armamentarium of antiplatelet agents. This review summarizes the current knowledge on the mechanisms of platelet-mediated myocardial damage after reperfusion and the effects of pharmacological interventions aimed to reduce microvascular platelet deposition and platelet-mediated myocardial injury.

Nitric oxide (NO) plays an important role in states of erythrocyte dysfunction, including sickle cell disease (SCD), malaria, and banked blood preservation. By understanding the role of nitric oxide in these conditions, which are accompanied by hemolysis, vasoocclusion, and erythrocyte dysfunction, new therapeutic targets may be identified to treat complications of these disease states. Furthermore, the role of the erythrocyte in the controlled release of NO in hypoxic tissues is of particular interest, and two theories are discussed regarding this mechanism. In this article, the role of nitric oxide in erythrocyte function, sickle cell anemia, malaria, and damage to banked blood is reviewed, and the use of NO targeted therapies for erythrocyte disease states is discussed.

Cardiovascular diseases (CVDs) such as atherosclerosis, hypertension and diabetes, are major global health problems and one of the leading causes of death. Thrombosis associated with multiple CVDs such as atherosclerosis and diabetes further increase morbidity by causing myocardial infarction or stroke. The members of Protein Kinase C (PKC) family are serine threonine kinases, abundantly expressed in cells that maintain cardiovascular health. Studies done using pharmacological tools that block wide range of PKCs or specific PKC isoforms and PKC gene knockout animals revealed that these enzymes regulate critical functional responses in cardiovascular cells. Interestingly, PKC isotype activity is context specific and PKC isotypes may have opposing functional roles depending on cell type and cellular environment (eg., cardiomyocytes, platelets). Furthermore, precise structural differences that occur amongst these isoforms have lead to development of compounds that inhibit or activate specific PKC isoforms. Thus, it is feasible to enhance the protective effects of a PKC isoform, while minimizing the damage caused by other members of PKC family. In this review, we summarize the role of each of these PKC isoforms in various cardiovascular diseases. In addition, we detail the specific PKC isoform modulators, their mechanism of action and ability to treat cardiovascular diseases, as evaluated in animal models or human subjects.