© 2007 European Society of Cardiology
Promising aspects and caveats of studies on anti-apoptotic therapies in patients with heart failure
Section of Cardiothoracic Surgery, University of Nebraska Medical Center Omaha, NE, United States akhoynezhad{at}unmc.edu Tel.: +1 402 559 4424; fax: +1 402 559 6913.
Key Words: Heart failure • Apoptosis • Heart physiology • Cell signaling • Myocardial remodeling
Received November 3, 2006; The prevalence of heart failure is 1-2%, and it accounts for about 1-2% of total health-care budget in Europe [1]. Despite significant advances in medical and surgical treatment of heart failure this important challenge remains: During the last two decades, congestive heart failure has become an increasingly frequent reason for hospital admission and clearly represents a major health problem.
Within the past decade, there is accumulated evidence that apoptosis contributes significantly to the pathogenesis of heart failure. It is an important component of the remodeling process and the transition from adaptive myocardial condition to end-stage cardiac failure (Fig. 1). Apoptosis is executed by a family of ubiquitously expressed cysteine proteases termed caspases. Caspases are present in the cell as inactive pro-caspases that are activated in response to apoptotic stimuli. Two major molecular pathways in caspase activation are recognized in cardiocytes (Fig. 2). The death receptor pathway is best studied in the literature, but is thought to play only a secondary role in initiation of cardiomyocyte apoptosis [2]. Understanding of the attenuation and/or prevention of apoptotic pathways are important for physicians, because the therapeutic options are new frontiers of therapy for congestive heart failure [3]. In this issue of European Journal of Heart Failure, Ibe and co-authors elaborate upon an anti-apoptotic therapeutic intervention, which may offer potential treatment for patients with heart failure [4].
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1. Significance of cardiac apoptosis in patients with heart failure |
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Cardiocyte apoptosis is part of the phenotype of the failing heart, and has been detected in animal and human studies [5-8]. Apoptosis is a precisely orchestrated process that is hardwired into all metazoan cells. Apoptosis contributes to the development of congestive heart failure in at least two distinct ways. First, it reduces the number of contractile cardiocytes through a programmed cell death. The frequency of cardiocytes apoptosis in remote myocardium following human myocardial infarction, as well as in dilated cardiomyopathy, is 80/105 to 750/105 [5,9,10]. This low, but abnormal, rate of cardiocytes apoptosis represents a significant loss for adult human myocardium, since adult human cardiocytes have lost the replicative potential of neonatal cardiocytes. Finally, apoptosis of cardiac non-myocytes contributes significantly to the progressive nature of failing myocardium. Data from Takemura and co-workers supports the hypothesis that apoptosis of granulation cells is related to cardiac remodeling after myocardial infarction [11,12].
For the reasons mentioned above, the apoptotic signaling pathway in cardiocytes and non-cardiocytes is an important factor for transition from compensated to decompensated maladaptive growth in heart failure.
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2. Caveats in studies involving cardiocyte apoptosis |
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In order to critically review the current studies on apoptosis in failing myocardium, it is important to know that there are significant limitations of our current knowledge about cardiocyte apoptosis. It is unknown whether apoptosis is the primary event in pathological cardiac conditions or an epiphenomenon. Also, further investigation is needed to determine whether inhibition of apoptosis will delay disease progression in vivo and in translational human studies. It is conceivable that alternative forms of cell death and/or pathways to cell death may be activated once the mitochondrial or death-receptor pathway of cardiocyte apoptosis is therapeutically inhibited. Anti-apoptotic pharmaceutics have the highest potential to become clinically significant as a therapeutic option within the next decade. However, the safety and long-term consequences of these therapies are not adequately investigated; clinical integration of these strategies will require more studies. Such therapies may possibly lead to an alternative mode of cell death, such as necrosis or increased autoimmune and lymphoproliferative disorders. Also of concern is the inferiority of techniques used to detect cardiocyte apoptosis (Fig. 3). The positive predictive value of terminal deoxynucleotidyl-transferase mediated dUTP nick end-labeling (TUNEL), which is the most commonly used method to detect apoptosis, is less than appropriate. The heterogeneity of examined tissue samples can deteriorate the accuracy of DNA-laddering, because it cannot specify the cell type undergoing apoptosis in a tissue sample with multiple cell contents. The transience and brevity of apoptosis is another culprit for the low sensitivity rates of the diagnostic methods. Combination of two or more detection methods in the study population may increase the diagnostic accuracy. More accurate tools are needed for future studies, these are currently being developed.
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3. Anti-apoptotic strategies in the treatment of patients with heart failure |
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Prevention or attenuation of cardiocytes apoptosis is a very attractive and potentially efficient therapeutical goal in the treatment of patients with heart failure. Accumulating data will widen the spectrum of therapeutic strategies of the management of these patients. Elucidation of anti- and pro-apoptotic interventions will translate into new treatment options for heart failure.
Among a plethora of anti-apoptotic strategies, broad-spectrum caspase inhibitors represent a very attractive platform for novel treatment of heart failure. Such anti-apoptotic agents have been used successfully in a rodent model of acute myocardial infarction [13,14]. Armstrong and co-workers found that IDN-6734 reduces the size of myocardial infarction in rats, if the poly-caspase-inhibitor is given prior (47% reduction) or 1 h after (45% reduction) reperfusion of left anterior descending artery [14]. In another study, ZVAD.fmk decreased infarction size with improved hemodynamics, and attenuated apoptosis compared to control rats [13].
Experimental use of growth hormone and its relationship to soluble FAS system has been an attractive object for studies for several years [15]. In the current issue of European Journal of Heart Failure, Ibe and co-workers shed more light on this topic. The authors demonstrated increased cardiocyte apoptosis with larger left ventricular end-diastolic volumes, lower ejection fraction, and pronounced expression of soluble FAS receptor.
There are ubiquitous limitations, which affect the current study's results as well as the majority of other investigations involving cardiocyte apoptosis. However, there are specific limitations regarding the design of the experiments by Ibe et al. The investigators presumed that the apoptotic index in right ventricular biopsies would correlate with the one of left ventricle. This assumption may not be accurate in patients with different levels of left and right ventricular systolic or diastolic dysfunction, left-sided valvular pathologies, patients with pulmonary hypertension, etc. All these clinical scenarios cause increased volume or pressure overload in an isolated ventricle, causing increased cardiocyte apoptosis in the affected ventricle [3].
Ibe et al. were unable to demonstrate an effect of growth hormone injections on cardiocyte apoptosis probably due to some methodological restrictions [4]. However, there was a trend towards lower prevalence of cardiocyte apoptosis in patients treated with growth hormone. This failed to reach statistical significance due to a low number of patients. The underpowered study was further weakened by the short length and route of administration of the growth hormone therapy. Although the current study of Ibe and co-authors has its limitations, it offers important hemodynamic and echocardiographic data on patients treated with growth hormone. This translational research project provides an excellent motivation for larger studies on anti-apoptotic therapies in conditions associated with heart failure involving growth hormone therapy or possibly other anti-apoptotic agents.
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References |
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