Myocyte apoptosis in heart failure

Human heart failure is preceded by a process termed cardiac remodeling in which heart chambers progressively enlarge and contractile function deteriorates. Programmed cell death (apoptosis) of cardiac muscle cells has been identified as an essential process in the progression to heart failure. The execution of the apoptotic program entails complex interactions between and execution of multiple molecular subprograms. Unlike necrosis, apoptosis is an orderly regulated process and, by inference, a logical therapeutic target if intervention occurs at an early stage. To identify potential therapeutic targets, it is imperative to have a full understanding of the apoptotic pathways that are functional in the cardiac muscle. Accordingly, the present review summarizes the apoptotic pathways operative in cardiac muscle and discusses therapeutic options related to apoptosis for the future treatment of human heart failure.     

Cell Death, Tissue Hypoxia and the Progression of Heart Failure

An important feature of heart failure is the progressive deterioration of left ventricular function that occurs in the absence of clinically apparent intercurrent adverse events. The mechanism or mechanisms responsible for this hemodynamic deterioration are not known. We and others have advanced the hypothesis that this hemodynamic deterioration results from progressive intrinsic contractile dysfunction of viable cardiomyocytes and/or from ongoing loss of cardiomyocytes. This review will focus on the concept of ongoing cardiac myocyte loss as a contributing factor to the progression of left ventricular dysfunction that characterizes the heart failure state. Specifically, the discussion will center on apoptosis or programmed cell death as a potential mediator of cardiomyocyte loss. In recent years, several studies have shown that constituent myocytes of failed explanted human hearts and hearts of animals with experimentally induced heart failure undergo apoptosis. Studies have also shown that cardiomyocyte apoptosis occurs following acute myocardial infarction, in the hypertrophied heart as well as in the aging heart; conditions frequently associated with the development of failure. While available data support the existence of myocyte apoptosis in the failing heart, lacking are studies which address the importance of myocyte apoptosis in the progression of LV dysfunction. As part of this discussion, we will address this issue and construct a case in support of a concept that the failing myocardium is subject to regional hypoxia, an abnormality that can potentially trigger cardiomyocyte apoptosis. If loss of cardiac myocytes through apoptosis can be shown to be an important contributor to the progression of heart failure, and if exact physiologic and molecular factors that trigger apoptosis in the heart can be identified, the stage will be set for the development of novel therapeutic modalities aimed at preventing, or at the very least retarding, the process of progressive ventricular dysfunction and the ultimate transition toward end-stage, intractable heart failure.     

Cardiomyocyte Apoptosis in Experimental Health Failure

Heart failure is characterized by progressive worsening of left ventricular (LV) function over time. The mechanism(s) responsible for this hemodynamic deterioration are not known. It is often assumed, but by no means established, that progressive LV dysfunction results largely from ongoing loss of functional cardiac units. If ongoing myocyte loss occurs during the course of evolving heart failure and can indeed account for the progressive deterioration of LV dysfunction, then the identification of factors responsible for this loss of muscle mass can potentially lead to novel therapeutic modalities aimed at preventing the transition toward intractable heart failure. Recent studies in experimental animals have shown that cardiac myocyte loss through apoptosis, or programmed cell death, occurs 1) following myocardial infarction, 2) in the presence of cardiac hypertrophy, 3) in the aging heart, and 4) in the setting of chronic heart failure. The observation of myocyte apoptosis in experimental animal models of heart failure has since been confirmed in the failed human heart. Considerable work has also been accomplished, and credible concepts advanced, in an attempt to uncover the physiological and molecular triggers of myocyte apoptosis in heart failure. While, at present, one can comfortably accept the existence of the phenomenon of myocyte apoptosis in the failing heart, two integral questions remain essentially unanswered. First, what pathophysiological factors(s), inherent to heart failure, trigger myocyte apoptosis? Second, how important is myocyte apoptosis in the progression of LV dysfunction and the transition to overt failure? The present article will summarize our current knowledge of myocyte apoptosis based largely on data available from animal models of myocardial infarction, hypertrophy, and failure.     

Cardiomyopathy of aging in the mammalian heart is characterized by myocardial hypertrophy, fibrosis and a predisposition towards cardiomyocyte apoptosis and autophagy

Aging is associated with an increased incidence of heart failure, but the existence of an age-related cardiomyopathy remains controversial. Differences in strain, age and technique of measuring cardiac function differ between experiments, confounding the interpretation of these studies. Additionally, the structural and genetic profile at the onset of heart failure has not been extensively studied. We therefore performed serial echocardiography, which allows repeated assessment of left ventricular (LV) function, on a cohort of the same mice every 3 months as they aged and demonstrated that LV systolic dysfunction becomes apparent at 18 months of age. These aging animals had left ventricular hypertrophy and fibrosis, but did not have inducible ventricular tachyarrhythmias. Gene expression profiling of left ventricular tissue demonstrated 40 differentially expressed probesets and 36 differentially expressed gene ontology terms, largely related to inflammation and immunity. At this early stage of cardiac dysfunction, we observed increased cardiomyocyte expression of the pro-apoptotic activated caspase-3, but no actual increase in apoptosis. The aging hearts also have higher levels of anti-apoptotic and autophagic factors, which may have rendered protection from apoptosis. In conclusion, we describe the functional, structural and genetic changes in murine hearts as they first develop cardiomyopathy of aging.     

慢性心力衰竭合并肾功能不全住院患者270例临床分析

目的探讨慢性心力衰竭住院患者肾功能不全发生率及与心功能的关系。方法收集慢性心力衰竭患者资料,应用改良的简化肾脏病饮食研究方程评估患者的肾功能,计算慢性心力衰竭住院患者肾功能不全发生率,采用有序分组数据的线性检验来检验患者肾功能与心功能的关系。结果慢性心力衰竭患者肾功能不全发生率为31．5％,NYHA心功能分级与。肾小球滤过率水平之间存在相关关系且为线性相关。结论慢性心力衰竭患者肾功能不全发生率较高;慢性心力衰竭患者NYHA心功能分级愈高,患者肾功能愈差。     

A synopsis of research in cardiac apoptosis and its application to congestive heart failure

Cardiac apoptosis diminishes the contractile mass, which leads to heart failure. Apoptosis of cardiac non-myocytes also contributes to maladaptive remodeling and the transition to decompensated congestive heart failure. New antiapoptotic interventions and medications will be available within the next decade. The aim of this study is to provide a critical synopsis of research projects on cardiocyte apoptosis that have implications for current and future practice and to identify methods to prevent or attenuate apoptosis in patients who have poor ventricular function. A retrospective literature review reveals a great many important publications. However, very few investigators discuss the clinical ramifications of cardiocyte apoptosis, nor do they address the clinician who sees poor ventricular contractility daily. Most studies are still investigational and involve antiapoptotic agents such as broad-spectrum caspase inhibitors, antioxidants, calcium channel blockers, insulin-like growth-factor 1, and poly(adenosine diphosphate ribose) synthetase inhibitors. some options have already been incorporated into the clinical practices of cardiologists and cardiac surgeons: repairing or replacing diseased or damaged valves before ventricular function deteriorates; reducing afterload with medication or intra-aortic balloon pulsation in patients who display acute increases in afterload; decreasing catecholamine-induced cardiotoxicity in hemodynamically compromised patients, by using beta-blockers and phosphodiesterase inhibitors; and inserting intra-aortic balloon pumps or ventricular assist devices early in cases of failing myocardium. Coronary revascularization early in myocardial infarction is effective antiapoptotic therapy. Other therapeutic targets are cardiopulmonary bypass and aortic cross-clamping, both of which require reductions in associated myocardial apoptosis.     

Apoptosis in heart failure and the senescent heart

The progressive loss of cardiac myocytes by apoptotic cell death has been discussed as an important pathogenic component in the failing myocardium as well in the aging heart. The degree to which apoptosis contributes to myocyte loss in these conditions, however, is a controversial issue. This review focuses on the regulation of apoptosis, evidence implicating apoptosis as a mechanism for the progression and development of heart failure, the role of apoptotic death in senescent cardiac dysfunction, as well as on the problems of detection of apoptosis.     

Studies of Prevention, Treatment and Mechanisms of Heart Failure in the Aging Spontaneously Hypertensive Rat

The spontaneously hypertensive rat (SHR) is an animal model of genetic hypertension which develops heart failure with aging, similar to man. The consistent pattern of a long period of stable hypertrophy followed by a transition to failure provides a useful model to study mechanisms of heart failure with aging and test treatments at differing phases of the disease process. The transition from compensated hypertrophy to failure is accompanied by changes in cardiac function which are associated with altered active and passive mechanical properties of myocardial tissue; these events define the physiologic basis for cardiac decompensation. In examining the mechanism for myocardial tissue dysfunction, studies have demonstrated a central role for neurohormonal activation, and specifically the renin-angiotensin-aldosterone system. Pharmacologic attenuation of this system at differing points in the course of the process suggests that prevention but not reversal of myocardial tissue dysfunction is possible. The roles of the extracellular matrix, apoptosis, intracellular calcium, beta-adrenergic stimulation, microtubules, and oxygen supply-demand relationships in ultimately mediating myocardial tissue dysfunction are reviewed. Studies suggest that while considerable progress has been made in understanding and treating the transition to failure, our current state of knowledge is limited in scope and we are not yet able to define specific mechanisms responsible for tissue dysfunction. It will be necessary to integrate information on the roles of newly discovered, and as yet undiscovered, genes and pathways to provide a clearer understanding of maladaptive remodeling seen with heart failure. Understanding the mechanism for tissue dysfunction is likely to result in more effective treatments for the prevention and reversal of heart failure with aging. It is anticipated that the SHR model will assist us in reaching these important goals.     

Treatment of heart failure with beta-blockers. Mechanisms and results

Sympathetic activation is a significant predictor of a poor prognosis in heart failure. Excessive stimulation with norepinephrine produces apoptosis, tachycardia and arrhythmias thereby leading to progression of left ventricular dysfunction and worsening of outcome. #-Blockers reduce morbidity and improve cardiac function. They have been shown to improve survival (MERIT-HF, CIBIS II and US-Carvedilol Trials). A careful uptitration of dosages is achievable with a low rate of side effects. The mechanisms of #-blocker effects in heart failure are cardiac protection from ş-adrenoceptor overstimulation, antiarrhythmic effects, reduction in heart rate and positive energetic effects or a combination thereof.     

Pathophysiology and therapy of heart failure, new insights and developments. Part I.

During the last decades heart failure has become a syndrome of major concern. Despite a decline in the occurrence of coronary artery disease and improved treatment of systemic hypertension, its primary aetiologic factors, the incidence of heart failure has been ever increasing. It is estimated that in the U.S.A. and most of western Europe approximately 1% of the population suffers from congestive heart failure. Its importance is directly related to its very adverse prognosis with an annual mortality rate as high as 50-60% in the advanced stages of failure. Although treatment with certain vasodilators or converting enzyme inhibitors may improve survival to some extent, the remaining mortality rate still remains high. As it is also extremely difficult to improve the clinical well-being of heart failure patients, emphasis is now on the early phase of failure and in particular on the preceding stage of asymptomatic ventricular dysfunction. Recent animal and human data indicate the significance of myocardial hypertrophy as a first step towards progressive myocardial muscle dysfunction superimposed on the initial cardiac event which leads to asymptomatic ventricular dysfunction. Moreover, there is evidence that neurohumoral activation occurs before heart failure has developed. Although available data only relate to circulating neurohormones, early alterations in local paracrine or autocrine acting systems may well be at issue. Also, whereas heart failure is generally considered a cardiac disorder, there is accumulating evidence that peripheral systems such as the skeletal musculature and the kidney are markedly involved. Changes in peripheral tissue function are not necessarily related to a reduction in cardiac pump function and tissue perfusion, but may be intrinsic of nature. Thus, significant abnormalities in skeletal muscle oxidative metabolism occur which are not secondary to regional flow disturbances. The recognition of cardiac and peripheral changes before or during the early phases of heart failure are likely to alter the current strategies in the treatment of this syndrome.     

Role of heart rate reduction in the prevention of experimental heart failure: comparison between If-channel blockade and β-receptor blockade

To investigate whether heart rate reduction via I(f)-channel blockade and β-receptor blockade prevents left ventricular (LV) dysfunction, we studied ivabradine and metoprolol in angiotensin II-induced heart failure. Cardiac dysfunction in C57BL/6J mice was induced by implantation of osmotic pumps for continuous subcutaneous dosing of angiotensin II (1.8 mg/kg per day SC) over a period of 3 weeks. Ivabradine (10 mg/kg per day) and metoprolol (90 mg/kg per day), which resulted in similar heart rate reduction, or placebo treatments were simultaneously started with infusion of angiotensin II. After 3 weeks, LV function was estimated by conductance catheter technique, cardiac remodeling assessed by estimation of cardiac hypertrophy, fibrosis, and inflammatory stress response by immunohistochemistry or PCR, respectively. Compared with controls, angiotensin II infusion resulted in hypertension in impaired systolic (LV contractility, stroke volume, end systolic elastance, afterload, index of arterial-ventricular coupling, and cardiac output; P<0.05) and diastolic (LV relaxation, LV end diastolic pressure, τ, and stiffness constant β; P<0.05) LV function. This was associated with a significant increase in cardiac hypertrophy and fibrosis. Increased cardiac stress was also indicated by an increase in cardiac inflammation and apoptosis. Both ivabradine and metoprolol led to a similar reduction in heart rate. Metoprolol also reduced systolic blood pressure. Ivabradine led to a significant improvement in systolic and diastolic LV function (P<0.05). This was associated with less cardiac hypertrophy, fibrosis, inflammation, and cardiac apoptosis (P<0.05). Metoprolol treatment did not prevent the reduction in cardiac function and adverse remodeling, despite a reduction of the inflammatory stress response. Behind heart rate reduction, additional beneficial cardiac effects contribute to heart failure prevention with I(f)-channel inhibition.     

Drosophila as a model to study cardiac aging

With age, cardiac performance declines progressively and the risk of heart disease, a primary cause of mortality, rises dramatically. As the elderly population continues to increase, it is critical to gain a better understanding of the genetic influences and modulatory factors that impact cardiac aging. In an attempt to determine the relevance and utility of the Drosophila heart in unraveling the genetic mechanisms underlying cardiac aging, a variety of heart performance assays have recently been developed to quantify Drosophila heart performance that permit the use of the fruit fly to investigate the heart's decline with age. As for the human heart, Drosophila heart function also deteriorates with age. Notably, with progressive age the incidence of cardiac arrhythmias, myofibrillar disorganization and susceptibility to heart dysfunction and failure all increase significantly. We review here the evidence for an involvement of the insulin-TOR pathway, the K_ATP channel subunit dSur, the KCNQ potassium channel, as well as Dystrophin and Myosin in fly cardiac aging, and discuss the utility of the Drosophila heart model for cardiac aging studies.     

Biomarkers

Epidemiologic, clinical, and basic research has identified several antecedent conditions that predispose individuals to heart failure and its predecessor, asymptomatic left ventricular remodeling and dysfunction (stage B heart failure). Many biochemical markers have been described that characterize the remodeling process and the development of cardiac dysfunction. Although natriuretic peptides and cardiac troponin are currently used in the context of diagnosis, risk stratification, and management of stage C and D heart failure, many other biomarkers provide insights into the underlying pathophysiology of left ventricular dysfunction, suggesting new directions for fundamental research or the development of new therapies.     

PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function

Oxidative stress is caused by an imbalance between reactive oxygen species (ROS) production and the ability of an organism to eliminate these toxic intermediates. Mutations in PTEN-inducible kinase 1 (PINK1) link mitochondrial dysfunction, increased sensitivity to ROS, and apoptosis in Parkinson's disease. Whereas PINK1 has been linked to the regulation of oxidative stress, the exact mechanism by which this occurs has remained elusive. Oxidative stress with associated mitochondrial dysfunction leads to cardiac dysfunction and heart failure (HF). We hypothesized that loss of PINK1 in the heart would have deleterious consequences on mitochondrial function. Here, we observed that PINK1 protein levels are markedly reduced in end-stage human HF. We also report that PINK1 localizes exclusively to the mitochondria. PINK1(-/-) mice develop left ventricular dysfunction and evidence of pathological cardiac hypertrophy as early as 2 mo of age. Of note, PINK1(-/-) mice have greater levels of oxidative stress and impaired mitochondrial function. There were also higher degrees of fibrosis, cardiomyocyte apoptosis, and a reciprocal reduction in capillary density associated with this baseline cardiac phenotype. Collectively, our in vivo data demonstrate that PINK1 activity is crucial for postnatal myocardial development, through its role in maintaining mitochondrial function, and redox homeostasis in cardiomyocytes. In conclusion, PINK1 possesses a distinct, nonredundant function in the surveillance and maintenance of cardiac tissue homeostasis.     

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy with a median survival of less than 8 months and a 5-year survival of <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying this deadly form of heart disease remain unclear. Although interstitial amyloid fibril deposition of Ig light chain proteins is a major cause of cardiac dysfunction in AL cardiac amyloidosis, we have previously shown that amyloid precursor proteins directly impair cardiac function at the cellular and isolated organ levels, independent of fibril formation. In this study, we report that amyloidogenic light chain (AL-LC) proteins provoke oxidative stress, cellular dysfunction, and apoptosis in isolated adult cardiomyocytes through activation of p38 mitogen-activated protein kinase (MAPK). AL-LC–induced p38 activation was found to be independent of the upstream MAPK kinase, MKK3/6, and instead depends upon transforming growth factor-β-activated protein kinase-1 binding protein-1 (TAB1)-mediated p38α MAPK autophosphorylation. Treatment of cardiomyocytes with SB203580, a selective p38 MAPK inhibitor, significantly attenuated AL-LC–induced oxidative stress, cellular dysfunction, and apoptosis. Our data provide a unique mechanistic insight into the pathogenesis of AL-LC cardiac toxicity and suggest that TAB1-mediated p38α MAPK autophosphorylation may serve as an important event leading to cardiac dysfunction and subsequent heart failure.     

Apoptosis and congestive heart failure

Congestive heart failure (CHF) is the final clinical manifestation of a variety of cardiac (myopathies), coronary (atherosclerosis), and systemic diseases (diabetes, hypertension). Regardless of the origin of the cardiac insult, left ventricular dysfunction resulting in decreased cardiac output elicits a series of adaptational processes that attempt to compensate for some of the decrement in myocardial function. One of the key manifestations of these compensatory processes is cardiac hypertrophy, which is characterized by a marked increase in myocyte size and an increase in contractile proteins. The benefits resulting from these compensatory adaptational mechanisms, however, are only transient, and within a period of months to years, the changes induced in the myocardium fail to sustain cardiac output at a level that is sufficient to meet the demands of the body; subsequently, physical performance is impaired. Typically, progressive dilation and thinning of the left ventricle occur along with progression of CHF. The mechanisms responsible for the thinning of ventricular tissue and loss of left ventricular mass are poorly understood; traditionally, such loss has been attributed to tissue necrosis based on the morphologic observation of dead cardiac myocytes. Very recently, there have been data suggesting that apoptosis, a form of programmed cell death (PCD), occurs in the heart and may be responsible, at least in part, for the progression of CHF and the chronic loss of left ventricular function and mass. Evidence for a role of apoptosis/PCD in the progression of heart failure has been obtained from a variety of observations, including in vitro studies of cardiac myocytes in culture, experimental animal models of cardiac injury, and cardiac tissue obtained from patients with CHF. Thus, apoptosis/PCD may be a critical mechanism involved in the progressive loss of cardiac myocytes, which ultimately results in end-stage heart failure. In this brief review, the evidence for apoptosis/PCD in cardiac myocytes is presented and its potential role in the progression of CHF is analyzed. In particular, the genomic basis for apoptosis in cardiac myocytes is explored, and its relevance to the identification of novel targets for future pharmacological interventions is discussed. (Trends Cardiovasc Med 1997;7:249-255). ? 1997, Elsevier Science Inc.     

Diagnosis and assessment in heart failure

Heart failure is a common and growing problem. Its optimal and effective management and the evaluation of new therapies require assessment of underlying etiology, type of cardiac dysfunction, severity, prognosis, and response to therapy. Unfortunately, the lack of a universally agreed definition of heart failure and uniform criteria make an accurate and complete diagnosis of heart failure difficult. Currently, a wide range of investigations and assessments is available, including assessment of symptoms, exercise performance, and cardiac function. In particular, left ventricular (LV) ejection fraction (EF) is widely used and a good marker of the severity of LV dysfunction and prognosis. It is now being recognized that the early identification and treatment of patients with asymptomatic LV dysfunction may prevent subsequent progression to symptomatic heart failure. Recently, attention has focused on the neurohormonal activation that occurs early in heart failure, and especially increasing evidence suggests that plasma levels of neurohormones and brain natriuretic peptides, may be useful biochemical markers in the diagnosis and assessment of heart failure at an early stage. Further evaluation of this neurohormonal activation and treatments directed towards it may provide considerable benefits in improving patient morbidity and mortality. (c)1999 by CHF, Inc.     

Who cares for the patient with heart failure?

Heart failure is a progressive and often fatal clinical syndrome caused by cardiac dysfunction. Therapeutic advances in both acute and chronic heart failure care have resulted in the ability to partially or completely reverse cardiac dysfunction, with accompanying reductions in attributable morbidity, mortality, and cost. In order to examine who is best suited to provide care for the patient with heart failure, we must recognize that treatment options vary in relationship to the stage of the disorder. Use of a contemporary heart failure classification scheme facilitates stratification of primary and secondary prevention and tertiary care options.