Mechanisms of Disease: apoptosis in heart failure-seeing hope in death

The loss of cardiomyocytes in failing or cardiomyopathic hearts is gradual and not accompanied by inflammation or major histomorphologic deformity. Apoptosis, therefore, seems to be the most logical mechanism of cell death. In this Review, Narula et al . discuss the role of apoptosis in systolic dysfunction and heart failure, and in the development of novel strategies for the management of heart failure. Apoptosis or programmed cell death is an evolutionarily conserved process of cell death, wherein cells die without provoking significant inflammatory response. There is convincing evidence that apoptosis contributes to the progression of heart failure. Apoptosis occurs through a cascade of subcellular events including cytochrome c release into the cytoplasm and activation of proteolytic caspases. Activated caspases lead to fragmentation of cytoplasmic proteins, including contractile apparatus, to a variable extent. It is proposed that the release of cytochrome c from mitochondria and contractile protein loss in living heart muscle cells contributes to systolic dysfunction. Interestingly, despite extensive changes in the cytoplasm, nuclear damage, which is the final event in apoptosis, is rather infrequent in the failing heart. Since the nucleus remains unaffected and the genetic blueprint intact in cells with interrupted apoptosis, these heart muscle cells might be amenable to cytoplasmic reconstitution. This process of ' apoptosis interruptus ' could allow development of novel strategies to reverse or attenuate heart failure. Key Points Heart failure is a major cardiovascular health problem worldwide Heart failure is characterized by inexorable progression of systolic dysfunction through the process of adverse cardiac remodeling even after the initial, causal injury has abated Understanding the pathophysiological substrates of cardiac remodeling can help in the development of novel strategies for prevention, arrest and reversal of the remodeling process Apoptosis plays a pivotal role in heart failure. Although the apoptotic cascade is initiated, it does not complete in heart failure (' apoptosis interruptus ') Interrupted apoptosis reconfirms that heart failure could often be a reversible disease state, and offers an attractive target for management