Mechanisms of apoptosis in normal vs. hypertrophic cardiomyocytes. Cellular stresses such as hypoxia/reoxygenation trigger cardiomyocyte apoptosis via the mitochondrial death pathway. In cardiomyocytes from unstressed ‘normal’ hearts, release of cytochrome c leads to caspase activation and caspases contribute to the apoptotic process. AIF is also released, potentially by a Ca²⁺-dependent protease. AIF translocates to the nucleus where it promotes stage I DNA fragmentation (<50 kb fragments) via EndoG. In other cells, caspases activate nucleases to drive stage II DNA fragmentation (∼120 bp fragments). AIF may also stimulate the phospholipid scramblase Scrm-1 to promote externalization of phosphatidylserine (PtdSer) at the plasma membrane, a signal for cell recognition and engulfment. The study by Choudhury et al.³ indicates that apoptosis in hypertrophic cardiomyocytes is caspase independent and, although cytochrome c is released from mitochondria, there is no change in caspase activity in these cells. The shift to AIF-mediated, caspase-independent cell death in hypertophic cardiomyocytes highlights the need for further studies of cell death in the disease context.