Heart Failure A Genomics Approach

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Choong Chin Liew 3.1

Overview of Heart Failure

Heart failure is a syndrome that occurs over time as the heart becomes less and less able to pump blood at a rate that is sufficient to meet the requirements of the body's organs, tissues and cells. For example, cardiomyopathies, which are disorders affecting the heart muscle, are a predominant cause of heart failure [1]. Heart failure may be right sided, left-sided, systolic or diastolic, or both. Clinically, systolic heart failure, an impairment of the right ventricle's ability to eject adequately during systole, is characterized by poor exercise tolerance and easy fatigability - characteristic effects of inadequate cardiac output and impaired tissue perfusion. Diastolic heart failure, the inability of the left ventricle to fill normally, is characterized by dyspnea, orthopnea, hepatomegaly, ascites, and edema, which result from elevated venous pressure. Clinical severity of heart failure varies from mild and asymptomatic to disabling to fatal without heart assist or heart transplant.

Congestive heart failure is rare in patients less than fifty; its prevalence increases to 5% for patients aged 50-70 and may be as high as 15% for patients aged over eighty. Heart failure is twice as common in black than in white populations and black patients tend to develop symptoms at a younger age [2]. Current drug therapies for heart failure include angiotensin-converting enzyme inhibitors, beta adrenergic blockers, diuretics and digoxin. However treatment success remains modest; patients with heart failure are often disabled, and survival is decreased. Having a diagnosis of heart failure increases the risk of death approximately four times, 5-year survival rates are 50% overall with median survival of 1.7-3.1 years in men and women, respectively. The likelihood of survival decreases with age and with more advanced heart failure [3].

A significant and increasing cause of morbidity and mortality, heart failure is becoming a major heath care burden. Over the past two decades the condition has increased by more than 150% and will continue to increase as the population ages and as death rates from acute myocardial infarction decline [2]. Currently, about 4 to 5 million people in the United States suffer from heart failure, resulting in the hospitalization of two million patients each year [4]. Approximately

Proteomic and Genomic Analysis of Cardiovascular Disease. Edited by Jennifer E. van Eyk, Michael J. Dunn

Copyright © 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30596-3

400,000 new cases of heart failure are diagnosed annually, and the cost of treatment is estimated at a low of US $10 billion annually [5], to as high as US $21 to $50 billion per year [2]. Life threatening heart failure unresponsive to drug therapy may require assistive devices, or heart transplant.

Clearly the burden of heart failure in ill health and mortality, its high cost and increasing prevalence are making it essential to develop new strategies for treating or preventing this common and debilitating disorder. Our understanding of heart failure is undergoing a paradigm shift as molecular, cellular and genetic research is developing new insights into the causes and progression of hypertrophy and heart failure. One result of this shift in thinking about heart failure is that drug therapies are beginning to be targeted to interfere in the progression of remodeling and improving contractility, rather than at symptom relief, as has been the approach in the past. Concurrent with advances at the molecular and cellular level, the genomics revolution is providing exciting new vistas of research to aid in further developing understanding of heart failure at the genomic level of genegene interactions and pathways. Although such research is in its infancy and practical genomics-based therapies remain in the far distant future, genomic research is beginning to provide new means to explore the extraordinary complexity of the genetic webs and pathways of this disease.

Pathophysiology of Heart Failure

A complex, multifactorial condition, heart failure occurs as a result of the interaction of environmental, physiological and genetic factors. In the United States, coronary artery disease and scarring from myocardial infarction are the most common factors leading to heart failure, followed by cardiomyopathy, and hypertension. Heart failure can also occur in patients with valvular heart disease or sustained arrhythmia, or it may be secondary to toxic agents such as alcohol, some chemotherapeutic drugs, or to pulmonary or systemic diseases. Regardless of the initial insult, however, heart failure is the final common pathway of almost any disease or injury that cause cardiac cell and tissue damage (Fig. 3.1).

Over the past twenty years our understanding of the pathophysiology of heart failure has undergone significant changes. The relatively simple hemodynamic model in which heart failure was regarded as a disorder of myocardial contractility has largely been superceded. Research efforts have reconceptualized the failing heart as much a condition of extracardiac neuroendocrine activation, cytokine release, and homeostatic mechanisms as it is a disorder of the heart proper [6]. Recently, investigators have been studying inherited channelopathies in hopes of elucidating further the pathophysiology of heart failure. The cause of death in heart failure is most likely to be sudden death resulting from cardiac arrhythmia. Long QT syndrome is associated with mutations in HERG and Kq family of genes and myocytes in heart failure have shown action potential prolongation, representing potassium channel downregulation, and repolarization abnormalities [7]. Newer

Inflamatory e.g. Viral myocarditis Sarcoidosis

Peripartum

Extramyocardial q j e.g. Coronary artery disease

O econaary Valvular heart disease e.g. Endocrine Rheumatologie Metabolic Amyloidosis

Congenital cardiac anomalies Hypertension cd

Cardiovascular Disease Mortality 2018

Fig. 3.1 Pathogenesis of heart failure.

(De-compensatory) Heart Failure

Fig. 3.1 Pathogenesis 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 use of drugs that act on the cardiac remodeling process (for example, antineuroendo-crine agents or beta blockers) is one example of increased rationality in heart failure management. Such approaches may prevent the progression of failure, rather than, as in the past, to simply modify contractility and reduce symptoms [6].

According to the cardiac "remodeling" hypothesis, cardiac hypertrophy and heart failure - at least in earlier stages - represent a classic example of homeo-static defense. Overload, disease or injury to heart tissue, put in motion a set of adaptive mechanisms to preserve the heart's pumping capacity. Thus, factors such as hypertensive pressure, infarction, inflammation, or genetic factors activate mechanisms of the adrenergic nervous system, the renin-angiotensin system and various mediators, including endothelin, cytokines, (tumor necrosis factors and in-terleukins), nitric oxide and oxidative stress. This activation in turn initiates the progressive alterations called "remodeling". Left ventricular remodeling has been defined by the International Forum of Cardiac Remodeling as: "genome expression, molecular, cellular and interstitial changes that are manifested clinically as changes in the size, shape and function of the heart after cardiac injury" [8]. Remodelling, at first adaptive, over time becomes maladaptive, and sustained cardiac hypertrophy 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 to release of norepinephrine, angiotensin, endothelin and other factors. A feedback loop, or heart failure "treadmill" is set up whereby altered protein expression and myocyte 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 extracellular matrix.

At the level of the cell, left ventricular remodeling involves mainly the cardio-myocyte as the main player. Despite the diversity of stimuli that initate cardiac hypertrophy, the molecular responses of cardiomyocytes to hypertrophic signals are similar. The responses include myocyte hypertrophy and apoptosis, enhanced sarcomeric protein accumulation reorganization of myofibrillar structure, changes in the extracellular matrix composition and functional abnormalities in excitation-contraction coupling. Hypertrophic stimuli are accompanied by induction of espression of immediate early genes, membrane type matrix metalloproteinases (MMP), which is increased in cardiomyopathy. Inhibition of MMP can attenuate left ventricular dilation in heart failure and targeted deletion of MMP-9 also showed limited ventricular enlargement and collagen accumulation after experimental myocardial induction in mice [10]. Kim et al. [11] demonstrated by overex-pressing 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 animal model 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-early genes 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 isoforms like ^-myosin heavy chain (MHC) and a-skeletal actin are up-regulated, whereas the 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 up-regulated in the heart in response to hypertrophic signals.

In 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 affecting the cell of origin itself (autocrine effect). These mediators include arginine vasopressin, natriuretic peptides, endothelin, peptide growth factors (e.g., transforming growth factor-/?, platelet-derived growth factor), cytokines (e.g., interleukin-1 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 thorough a 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 particular dismutation of superoxide anions by cytosolic copper/zinc and mitochondrial manganese-containing superoxide dismutase (CuZnSOD and MnSOD, respectively) and the degradation of H2O2 by glutathione peroxidase (GPX) and catalase limit 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 was upregulated at both the mRNA and protein levels in failing hearts, possibly as a compensatory response [13]. Siwik et al. [14] showed that increased intracellular superoxide resulting from inhibition of CuZnSOD has profound effects on the cell growth, hypertrophic phenotype and apoptosis in neonatal rat cardiac myo-cytes in a graded manner. De Jong et al. [15] reported that xanthine oxidoreduc-tase activity was elevated in failing but not in hypertrophic ventricles, suggesting its potential role in the induction of heart failure. Myocardial energetics has also been shown to be altered in heart failure. The hallmark of the change in myocar-dial metabolism in cardiac hypertrophy and the failing heart is a switch of the chief myocardial energy source from fatty acid B-oxidation to glycoysis resulting in down regulation of mitochondrial fatty acid oxidation cycle and medium chain acyl-coenzyme A dehydrogenase gene [16].

As the heart remodels, it becomes larger, rounder, and its walls stiffen: gross phenotypic changes that may affect cardiac function. Remodeling is regarded as an adverse sign in the progression to heart failure, and patients with major remodeling show worsening of function. Thus therapeutic efforts have been directed towards slowing or reversing remodeling early in the course of heart failure through the use of such agents as angiotensin converting enzyme inhibitors and beta blockers [8].

Genomic Approach to Heart Failure

The 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 to hypertrophy and eventual heart failure. The transition from compensated cardiac hypertrophy to decompensated heart failure is accompanied by marked changes in the expression of an array of genes in the heart. What is the marker for early myocardial decompensation and can we intervene in its progression? This discovery is the target for genomics-based studies (Fig. 3.2) [9].

Traditionally, the geneticists search for disease causing gene mutations was a lengthy and resource-consuming process. Genetics investigators searched for single mutated nucleotide(s) in the DNA sequence. This methodology, though highly fruitful for locating single gene mutations, is not adequate for elucidating the complexities of multi-gene based diseases such as heart failure in which multiple genes and gene clusters may be involved. As described above, multiple pathways are involved at different clinical stages and in different types of heart failure and several gene mutations or protein defects have been identified in cardiomyopathy.

The Human Genome Project and related projects have paved the way for future studies in genomics. In February 2001, completion was announced of the first map of the whole human genome, comprising more than 90% of the approximately 3 billion bases of the human genome [17, 18]. The Human Genome Project database will serve as an invaluable resource for identifying the complete structure of each gene, interindividual variations of gene structure related to biodiversity, the clustering of genes in each chromosome, and gene polymorphisms related to structure or function. Furthermore, we can exploit gene expression profiles and genome-wide linkage analyses to identify genes contributing to individual variations in disease risk, to develop more efficacious treatments by targeting novel genes or unidentified pathways, and to tailor individual responses to treatment on the basis of genetic constitution.

The technology of the Human Genome Project and the genomics revolution are beginning to transform our approach to such complex disorders as heart failure and cardiomyopathy by enabling investigators to look at the differential expression of hundreds of thousands of genes simultaneously, and to compare gene expression during disease development and over the course of disease progression [19]. The genomics approach by contrast to the single gene approach is a "holistic" technology that attempts to investigate the relationship between clusters of candidate genes expressed or active during the complex processes involved in disease [20, 21].

An important development of the Human Genome Project has been the application of EST methods of gene discovery. ESTs (Expressed Sequence Tags) are sequences derived from complementary DNA libraries, representing particular tissues or organs [22, 23]. Although ESTs are relatively short in sequence (hundreds a)

A 10,000 element cDNA array containing: over 3000 known, characterized genes over 7000 uncharacterized EST clusters e.g. Profiled DCM and HCM heart tissue

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