Van Eyk, Dunn - Proteomic and Genomic Analysis of Cardiovascular Disease - 2003 (522919), страница 18
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Recently, investigators have been studying inherited channelopathies in hopes of elucidating further the pathophysiology of heart failure. The cause of death in heartfailure is most likely to be sudden death resulting from cardiac arrhythmia. LongQT syndrome is associated with mutations in HERG and Kq family of genes andmyocytes in heart failure have shown action potential prolongation, representingpotassium channel downregulation, and repolarization abnormalities [7].
Newer3.2 Pathophysiology of Heart FailureFig. 3.1Pathogenesis of heart failure.concepts of heart failure pathophysiology are providing impetus for the development of more appropriate strategies in the management of heart failure. The useof drugs that act on the cardiac remodeling process (for example, antineuroendocrine agents or beta blockers) is one example of increased rationality in heart failure management. Such approaches may prevent the progression of failure, ratherthan, as in the past, to simply modify contractility and reduce symptoms [6].According to the cardiac “remodeling” hypothesis, cardiac hypertrophy andheart failure – at least in earlier stages – represent a classic example of homeostatic defense.
Overload, disease or injury to heart tissue, put in motion a set ofadaptive mechanisms to preserve the heart’s pumping capacity. Thus, factors suchas hypertensive pressure, infarction, inflammation, or genetic factors activatemechanisms of the adrenergic nervous system, the renin-angiotensin system andvarious mediators, including endothelin, cytokines, (tumor necrosis factors and interleukins), nitric oxide and oxidative stress. This activation in turn initiates theprogressive alterations called “remodeling”. Left ventricular remodeling has been47483 Heart Failure: A Genomics Approachdefined by the International Forum of Cardiac Remodeling as: “genome expression, molecular, cellular and interstitial changes that are manifested clinically aschanges in the size, shape and function of the heart after cardiac injury” [8].
Remodelling, at first adaptive, over time becomes maladaptive, and sustained cardiachypertrophy may culminate eventually in heart failure, salt and water retention,congestion, edema, low cardiac output, cardiac dysfunction and eventually death.Exactly how and at what point in the process adaptive hypertrophy becomes maladaptive heart failure is one of the challenges in heart failure research [9].The course of remodeling from initial event to altered phenotype is highly complex. The cascade of molecular, cellular and biochemical events driving the process are under active investigation. A basic working hypothesis has been proposed[8]. In this model, stress-induced changes in the myocyte, such as stretch, leads torelease of norepinephrine, angiotensin, endothelin and other factors.
A feedbackloop, or heart failure “treadmill” is set up whereby altered protein expression andmyocyte hypertrophy lead to a deterioration in cardiac function and then to increased neurohormonal stimulation and further deterioration. Aldosterone and cytokines may stimulate collagen synthesis fibrosis and remodeling of extracellularmatrix.At the level of the cell, left ventricular remodeling involves mainly the cardiomyocyte as the main player. Despite the diversity of stimuli that initate cardiac hypertrophy, the molecular responses of cardiomyocytes to hypertrophic signals aresimilar. The responses include myocyte hypertrophy and apoptosis, enhanced sarcomeric protein accumulation reorganization of myofibrillar structure, changes inthe extracellular matrix composition and functional abnormalities in excitationcontraction coupling.
Hypertrophic stimuli are accompanied by induction ofespression of immediate early genes, membrane type matrix metalloproteinases(MMP), which is increased in cardiomyopathy. Inhibition of MMP can attenuateleft ventricular dilation in heart failure and targeted deletion of MMP-9 alsoshowed limited ventricular enlargement and collagen accumulation after experimental myocardial induction in mice [10].
Kim et al. [11] demonstrated by overexpressing human MMP-1 in cardiac ventricles of mice that destruction of the collagen network in the myocardium caused cardiac hypertrophy and dysfunction.This animal model mimics human heart failure in that initially an adaptive response is seen followed by a progressive loss of function. Moreover this animalmodel provides direct evidence of the role of the extracellular matrix in the process of cardiac remodeling.At the gene level hypertrophic stimuli results in induction of immediate-earlygenes such as c-fos, c-myc, c-jun, and Egr1 and reprogramming of gene expression in the adult myocardium, such that genes encoding fetal protein isoformslike b-myosin heavy chain (MHC) and a-skeletal actin are up-regulated, whereasthe corresponding adult isoforms, a-MHC and a-cardiac actin, are down-regulated.The natriuretic peptides, atrial natriuretic peptide and brain natriuretic peptide,which decrease blood pressure by vasodilation and natriuresis, are also rapidly upregulated in the heart in response to hypertrophic signals.3.2 Pathophysiology of Heart FailureIn addition, myocardial remodeling as well involves the orchestration of a variety of mediators including circulating hormones (endocrine effect), hormones acting on neighboring cells of different types (paracrine effect), and those affectingthe cell of origin itself (autocrine effect).
These mediators include arginine vasopressin, natriuretic peptides, endothelin, peptide growth factors (e.g., transforming growth factor-b, platelet-derived growth factor), cytokines (e.g., interleukin-1 b,interleukin-6, tumor necrosis factor-a, leukemia inhibitory factor, cardiotrophin-1),and nitric oxide. Each and all of these mediators act on the failing heart thorougha complex web of signaling pathways [12].Increasing evidence suggests that enhanced production of reactive oxygen species together with accompanying oxidative stress has both functional and structural effects on remodeling. The myocardium is equipped with a variety of endogenous enzymatic and nonenzymatic antioxidant systems that are sufficient to metabolize oxygen free radicals generated during normal cellular activity.
In particulardismutation of superoxide anions by cytosolic copper/zinc and mitochondrialmanganese-containing superoxide dismutase (CuZnSOD and MnSOD, respectively) and the degradation of H2O2 by glutathione peroxidase (GPX) and catalaselimit the cytotoxic effect of reactive oxygen metabolites. Dieterich et al. demonstrated that no differences in gene expression of MnSOD, CuZnSOD and GPX exist between failing and nonfailing hearts, whereas catalase gene expression wasupregulated at both the mRNA and protein levels in failing hearts, possibly as acompensatory response [13].
Siwik et al. [14] showed that increased intracellularsuperoxide resulting from inhibition of CuZnSOD has profound effects on thecell growth, hypertrophic phenotype and apoptosis in neonatal rat cardiac myocytes in a graded manner. De Jong et al. [15] reported that xanthine oxidoreductase activity was elevated in failing but not in hypertrophic ventricles, suggestingits potential role in the induction of heart failure. Myocardial energetics has alsobeen shown to be altered in heart failure.
The hallmark of the change in myocardial metabolism in cardiac hypertrophy and the failing heart is a switch of thechief myocardial energy source from fatty acid B-oxidation to glycoysis resultingin down regulation of mitochondrial fatty acid oxidation cycle and medium chainacyl-coenzyme A dehydrogenase gene [16].As the heart remodels, it becomes larger, rounder, and its walls stiffen: grossphenotypic changes that may affect cardiac function.
Remodeling is regarded asan adverse sign in the progression to heart failure, and patients with major remodeling show worsening of function. Thus therapeutic efforts have been directedtowards slowing or reversing remodeling early in the course of heart failurethrough the use of such agents as angiotensin converting enzyme inhibitors andbeta blockers [8].49503 Heart Failure: A Genomics Approach3.3Genomic Approach to Heart FailureThe researcher involved in exploring the molecular pathophysiology of heart failure at the gene level faces a daunting challenge. Understanding heart failure involves working out the hundreds, if not thousands of genes, gene pathways, genegene and gene-protein interactions at every stage in the process that contribute tohypertrophy and eventual heart failure.
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