Apoptosis of cardiac myocytes has been described in a variety of cardiovascular diseases, including heart failure, ischemia without or with reperfusion, atherosclerosis, myocarditis, transplant rejection and arrhythmogenic disorders. The loss of cardiac myocytes in the heart means that these cells are lost forever. Therefore, apoptosis of cardiac myocytes at a low frequency will result in a gradual loss of functional cardiac myocytes and may, over years, lead to a substantial loss of pump function of the heart. Apoptosis may be an important process contributing to the progress of heart failure (Bing, 1994).
Myocyte cell death during ischemia and reperfusion
Until 10 years ago, necrosis was considered to be the only, or at least the main, mechanism of myocyte death after myocardial infarction. Cell death was secondary to energy deficit, cytoplasmic proteins were released and there was an inflammatory reaction by infiltrating macrophages, which preceded scar formation. Lately, however, experimental studies have shown that myocytes undergo cell death by necrosis as well as apoptosis during ischemia and reperfusion. Whether apoptosis is triggered during ischemia or during reperfusion is still controversial. In the 1990’s evidence grew that apoptosis precedes necrosis and constitutes the prevailing form of myocyte death. Apoptosis of cardiac myocytes appears to be the major form of initial myocardial damage produced by occlusion of a major epicardial coronary artery. Necrotic cardiac myocyte death mostly followed apoptosis and contributed to the progressive loss of cells in the infarcted region of the wall (Bardales et al., 1996; Kajstura et al., 1996). Recent evidence indicates that apoptosis is primarily expressed during reperfusion (Fliss and Gattinger, 1996; Gottlieb et al., 1994; Zhao et al., 2000) and that necrosis rapidly develops after ischemia, progressing from subendocardial to subepicardial regions
of the left ventricular wall. Without reperfusion necrosis reaches its full transmural extent after 6-7 hours of ischemia (Rochitte et al., 1998; Zhao et al., 2000). However, infarct size may be determined not only by the duration of ischemia but also by pathological events occurring during reperfusion. Necrosis appears to be a dynamic pathologic process that continues over at least 24 hours of reperfusion after a fixed period of ischemia (Rochitte et al., 1998). In contrast to the extent of necrosis, which peaked at 24 hours of reperfusion the appearance of apoptotic cells in the peri-necrotic area progressively increased up to 72 hours of reperfusion (Zhao and Vinten-Johansen, 2002).
It is not clear yet whether apoptosis precedes or is followed by necrosis, or whether both mechanisms of cell death occur simultaneously by separate pathways. The data suggest that necrosis and apoptosis occur simultaneously during reperfusion, with necrosis developing relatively rapid, during the early phase of reperfusion and apoptosis following during the late phase of reperfusion. However some studies suggest a crossover of apoptosis to necrosis (Umansky et al., 1997; Umansky and Tomei, 1997). Other investigators have shown that infarct size in an in vivo rat model is reduced by inhibiting apoptosis in the acute stage (Vakeva et al., 1998; Yue et al., 1998).
Myocyte cell death after myocardial infarction
In patients with a history of myocardial infarction heart failure may develop in the absence of ongoing ischemia or recurrent infarction. Loss of contractile function in this group of patients is attributed to post-infarction LV remodelling. Three regions are evident in the infarcted heart: infarcted myocardium which is unperfused and akinetic; borderzone myocardium, which is perfused and hypokinetic, and the so- called remote myocardium, which is well perfused and has preserved contractility. Immediately after infarction the extent of borderzone myocardium may be small, and function may be impaired only moderately. However, in time the area of dysfunctional myocardium may become enlarged leading to progressive impairment of function (Jackson et al., 2002). Although the exact cause of the progressive reduction in contractility of uninfarcted borderzone myocardium is not established yet, increased stress and the resulting strain may fundamentally alter the borderzone myocardium. Experimental studies have demonstrated that expanding regional infarction can initiate a myopathic process that spreads beyond the immediate peri-infarct region and may involve the entire ventricle (Jackson et al., 2002). Apoptotic myocytes are found in the borderzone myocardium (Jackson
et al., 2002) suggesting that non-ischemic myocyte loss due to stretch-induced apoptosis produces global ventricular dysfunctioning.
Myocyte cell death in failing hearts
Evidence is growing that myocyte cellular degeneration is one of the most prominent phenomena in failing human myocardium. Myocytes die by multiple mechanisms in the failing human heart: apoptosis, oncosis and autophagic cell death (Narula et al., 1996; Olivetti et al., 1997; Kostin et al., 2003). Although there is no doubt that apoptosis plays an important role in cardiac diseases, the importance of apoptosis still has to be clarified. The problem of quantification of apoptotic cells has not been completely solved because of the following three reasons: methodological (overinterpretation of results, no differentiation between myocytes and non-myocytes), experimental (global or regional acute ischemia, chronic conditions such as heart failure or hibernating myocardium), and interpretation (unknown time period for the completion of apoptosis). This problem is reflected in the large differences in incidence of apoptosis reported (Elsasser et al., 2001; Freude et al., 1998).
Coronary artery disease is the etiologic factor in 68% of the patients with heart failure (Gheorghiade and Bonow, 1998), indicating that two third of the cases suffers from myocardial ischemia. Ischemia and heart failure associated neurohumoral activation of the heart by the sympathetic nervous system and the renin-angiotensin system create environmental stresses to the heart which are exaggerated by progressive stretch of the ventricular walls.