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J Am Coll Cardiol, 2003; 41:761-764, doi:10.1016/S0735-1097(02)02958-3
© 2003 by the American College of Cardiology Foundation
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EDITORIAL COMMENT

Myocyte apoptosis: programming ventricular remodeling*

Kartik Mani, MBBS* and Richard N. Kitsis, MD, FACC*,*

* Departments of Medicine (Molecular Cardiology) and Cell Biology, Albert Einstein College of Medicine, Bronx, New York USA

* Reprint requests and correspondence: Dr. Richard N. Kitsis, Departments of Medicine (Molecular Cardiology) and Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
kitsis{at}aecom.yu.edu

Of the more than 1 million Americans who suffer recognized myocardial infarctions (MIs) annually, about 300,000 die in the first year, and a similar number fall victim to crippling heart failure (HF) (1). Although advances in revascularization and HF therapies have somewhat blunted its devastating impact, this modern-day scourge remains an important clinical challenge. Heart failure following MI can result from the acute loss of myocytes in the infarct zone, but more often is precipitated by the delayed and progressive pathologic remodeling of the ventricle. In this issue of the Journal, Abbate et al. (2) examine the relationship between apoptotic death of cardiac myocytes in the infarcted and noninfarcted regions, and the subsequent development of HF in patients with recent MI.

Current understanding of the pathophysiology of MI has been modified to incorporate observations that myocytes die by apoptosis, as well as necrosis (3,4). Apoptosis is a suicide process that is hardwired into all metazoan cells. The death machinery can be activated by signals originating outside (for example, deficiencies of nutrients/oxygen/survival factors, reactive oxygen species, stretch, ultraviolet radiation, drugs) or inside (such as cell cycle perturbations, deoxyribonucleic acid damage) the cell. The executioners of apoptosis are a family of cysteine proteases called caspases that cleave proteins following aspartic acid residues (5). Synthesized as largely inert proenzymes, caspases themselves are activated by proteolytic cleavage and reassembly of subunits into an active holoenzyme. Caspases then cut multiple cellular proteins to bring about the orderly demise of the cell. Caspase activation is regulated by two central death pathways. One involves the activation of cell surface death receptors by death ligands (6); in the other, the mitochondrial release of apoptotic activators, such as cytochrome c, is the critical event (7). Both of these central death pathways, and interconnections between them, have been shown to mediate apoptosis in cardiac myocytes (8–10).

Work in rodent models of myocardial infarction indicates that most cell death in the first 2 to 4 h following coronary occlusion occurs by apoptosis (3,8,11,12). Necrosis becomes more prominent between 6 and 24 h (3). Cell death in the infarct zone is large in magnitude (5,000/105 to 30,000/105 or 5% to 30% of the myocytes in the heart) but short in duration (mostly complete in <24 h) (Table 1) (8,12–14). Left ventricular remodeling begins within hours to days and continues for months (15,16). Initially, remodeling may involve side-to-side slippage of myocytes, resulting in infarct expansion. Later, in response to volume overload and neurohumoral signals, the noninfarcted remote myocardium undergoes hypertrophy, which initially helps to decrease wall stress. Ultimately, however, the left ventricle dilates, its walls thin, and contractile function deteriorates.


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  		Table 1 Previous Work Demonstrating Apoptosis in Myocardial Infarction and Heart Failure

 
Although the precise cellular and molecular bases of these complex remodeling events are not known, myocyte apoptosis in the noninfarcted remote myocardium appears to be involved. In contrast to the high-frequency, short-lived burst of cell death that occurs during the first 24 h in the infarct zone, myocyte apoptosis in the remote myocardium is infrequent (10/105 to 100/105 in rodent studies [11,14,17]; 200/105 to 750/105 in human studies [13,18–20]) and can persist for months. For reference, hearts from normal rodents and humans exhibit a baseline frequency of apoptosis of 1/105 to 10/105 (8,11–13,18,20,21). Does the low, but abnormal, rate of myocyte apoptosis in the remote myocardium contribute substantially to myocyte loss? To answer this question, one needs to know the time required for a myocyte to undergo apoptosis during myocardial infarction in vivo. This is not known, and on the basis of studies with cultured cells including adult cardiac myocytes, could range from 1 to 24 h (22–24). If we arbitrarily take 12 h as the time required for myocyte apoptosis to occur in vivo and 500/105 as the apoptotic frequency in the remote myocardium, then approximately 1% of the myocytes in the remote myocardium would be lost per day. Although some of this cell loss may be mitigated by replacements derived from stem cell populations, the impact of this myocyte death could be considerable and is consistent with the 10- to 62-day time course of demise of the patients studied by Abbate et al. (2). We emphasize that these kinds of calculations are at best gross approximations because of assumptions concerning the time required for myocyte apoptosis to take place in vivo.

It is interesting to note that the frequency of myocyte apoptosis in the remote myocardium following human myocardial infarction (200/105 to 750/105) is very similar to that observed in three independent human studies of end-stage dilated cardiomyopathy (80/105 to 250/105) (18,20,21). This is in keeping with the notion that, regardless of inciting etiology, low but abnormal rates of myocyte apoptosis play a role in the transition to heart failure. The sufficiency of these low rates of myocyte apoptosis to induce HF has been demonstrated in a transgenic mouse model of low-level caspase-8 activation in which apoptotic rates of only 23/105 are adequate to induce a lethal dilated cardiomyopathy over several months (25). If this rate of apoptosis is sufficient to create a dilated cardiomyopathy de novo, it is reasonable to posit that even less myocyte loss in the remote myocardium may be required to precipitate failure in hearts that have previously suffered a large infarction.

Studies in which myocyte apoptosis has been inhibited by various genetic and pharmacologic means have demonstrated decreases in infarct size, left ventricular dilation, contractile dysfunction, and, in some cases, mortality in various rodent models of ischemia-reperfusion (10,26–30) and HF (25,31,32). These results establish that apoptosis plays an important role in the pathogenesis of heart disease in these rodent models and suggest that inhibition of myocyte death may provide a target for new therapies. Further work will be needed to test the extent to which these results can be extrapolated to the human syndromes.

In this issue of the Journal, Abbate et al. (2) address the important question of the role of myocyte apoptosis in the genesis of left ventricular dilation and thinning of noninfarcted remote myocardium following human MI. Their approach was to identify clinical and pathophysiologic correlates of accelerated myocyte apoptosis (2) in a postmortem study. The population consists of 14 patients dying from atraumatic causes 10 to 62 days following MI with a persistently occluded infarct-related artery. Most were men in their seventies, had large (>30%) transmural infarcts, clinical evidence of congestive heart failure, and a short median survival of 16 days following the infarction. Of the 14 patients, 8 had multivessel coronary disease and 7 had suffered a prior infarction >6 months earlier. Only one patient was diabetic. As per the authors, none of the patients had clinical or pathologic evidence of reinfarction. The major conclusions were: 1) the apoptotic rate in the remote myocardium correlated strongly with thinning of this region; 2) the apoptotic rate in the infarct area correlated strongly with left ventricular dilation; and 3) apoptotic rates in the infarct zone and remote myocardium both correlated with symptomatic evidence of heart failure. These findings are novel in that they directly correlate specific features of postinfarct remodeling with apoptotic rates.

One aspect of the data that is at variance with previous work is the apoptotic rate reported for the infarct zone 10 to 62 days following the acute event (approximate mean of 18% or 18,000/105). The authors suggest that this high rate may reflect selection bias for exceptionally sick patients. It seems unlikely, however, that these rates of apoptosis could be sustained for so prolonged a period. Whether they reflect an ischemic event immediately before death or perhaps medications such as inotropes is unclear. Alternatively, the massive loss of total nuclei in the infarct zone from the initial infarction may have artifactually elevated the percentages by decreasing the denominator (8).

This study provides new information beyond that available in previous human studies (13,19,33,34). The direct correlation of apoptotic rates in the infarct and remote myocardium with left ventricular chamber size and wall thickness, respectively, suggest that myocyte apoptosis plays an important role in both aspects of remodeling. This information may help provide a baseline for future studies of anti-apoptosis therapies in humans.


   Footnotes
 
Dr. Kitsis is funded by grants from the National Institutes of Health (RO1 HL60665 and RO1 HL61550). He is also the Charles and Tamara Krasne Faculty Scholar in Cardiovascular Research of the Albert Einstein College of Medicine, the recipient of the Monique Weill-Caulier Career Scientist Award, and a collaborator with Idun Pharmaceuticals, Aventis Inc., and Millennium Pharmaceuticals.

* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. Back


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