Apoptosis of Cardiomyocytes in Ventricular Remodeling After MI

Cardiomyocyte apoptosis has been demonstrated to occur months after acute MI, both in humans [113, 120, 136-138] and experimental animals [139-141]. Apoptotic rate was higher in the periinfarct region especially if persistent or recurrent ischemia was present, and lower in the remote myocardium, but still higher than in the control hearts. A gradual decrease of apoptotic rate over time has been reported, with end-stage ischemic heart failure having only a modest, but significant increase vs controls [120].

Ongoing apoptosis in the border zone and remote myocardium results in a reduction in cardiomyocyte number and might be therefore an important pathogenetic mechanism of ventricular remodeling after MI. Ventricular remodeling is characterized by progressive chamber dilatation, wall thinning, and systolic/diastolic dysfunction [142] beginning days after MI and persisting for weeks and months after the initial insult both at the site of MI and in the healthy myocardium [120, 143-146].

Apoptosis contributes to ventricular remodeling and heart failure not only through a reduction of the contractile cell mass, but probably also through another mechanism: activated caspases can cleave contractile proteins, such as actin, myosin, and troponin, leading to contractile dysfunction [1, 147]. It appears that all cardiomyocytes showing apoptotic changes do not die immediately; if the process of apoptosis is not complete in myocytes, it may differentially affect cytoplasmic proteins and nuclear substrates. Lack of nuclear fragmentation facilitates continuous loss of cytoplasmic proteins and may allow such cells to persist for prolonged periods in the myocardium, thus contributing to contractile failure in the surviving cells [42, 148, 149]. Consistently, caspase-3 activation is associated with a reduction in contractile performance of the left ventricle by destroying sarcomeric structure [150], and the degree of the myosin cleavage correlates with the contractile performance of the heart [151]. Moreover, caspase inhibition can reduce the occurrence of heart failure or impede its progression following MI by attenuating ventricular remodeling and protecting against myocardial protein cleavage [152-154].

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