Apoptosis in Heart Failure Reversible

The contribution of cardiomyocyte apoptosis to cardiac pathologies such as myocardial infarction and terminal heart failure has been suggested on the basis of histochemical and biochemical demonstrations of apoptotic nuclear DNA fragmentation. However, these techniques have yielded highly different figures of apoptotic myocytes between different laboratories, sug-gesting that they are not without methodological pitfalls. Apoptotic “melt-ing rates” of myocardial tissue cannot be derived from DNA fragmentation histochemistry. Therefore, the debate on the relevance of myocyte apopto-sis is ongoing, although experimental studies with inhibitory interventions into the apoptotic program demonstrate its involvement in ischemia/reper-fusion associated myocyte losses and suggest its involvement in overload-induced heart failure. A unique feature of the apoptotic process in failing cardiomyocytes in the “postmitochondrial retardation” of the program: while cytochrome c release from the mitochondria, a critical step in the program, encompasses more than 50% the total myocardial cytochrome c and substantially activates further cytosolic steps of the program, biochem-ical signs of mucleolysis are still barely detectable and DNA fragmentation histochemistry only stains some 0.2% of the myocytes. It is proposed that this larte cytochrome c release impairs mitochondrial respiratory capacity, augments mitochondrial radical formation and activates caspase-mediated dergradation of cytosolic proteins involved in signaling and contraction.