A mechanistic role for cardiac myocyte apoptosis in heart failure

TLDR

Heart failure is a common, lethal disease whose pathogenesis remains poorly understood, although recent studies have detected low levels of myocyte apoptosis in failing human hearts. The study aimed to determine whether this apoptosis is incidental, protective, or a causal contributor to heart failure. Transgenic mice with minimal myocardial apoptosis developed lethal dilated cardiomyopathy, while inhibiting apoptosis prevented cardiac dilation and dysfunction, providing the first direct evidence that myocyte apoptosis drives heart failure and pointing to potential therapeutic strategies.

Abstract

Heart failure is a common, lethal condition whose pathogenesis is poorly understood. Recent studies have identified low levels of myocyte apoptosis (80–250 myocytes per 105 nuclei) in failing human hearts. It remains unclear, however, whether this cell death is a coincidental finding, a protective process, or a causal component in pathogenesis. Using transgenic mice that express a conditionally active caspase exclusively in the myocardium, we demonstrate that very low levels of myocyte apoptosis (23 myocytes per 105 nuclei, compared with 1.5 myocytes per 105 nuclei in controls) are sufficient to cause a lethal, dilated cardiomyopathy. Interestingly, these levels are four- to tenfold lower than those observed in failing human hearts. Conversely, inhibition of cardiac myocyte death in this murine model largely prevents the development of cardiac dilation and contractile dysfunction, the hallmarks of heart failure. To our knowledge, these data provide the first direct evidence that myocyte apoptosis may be a causal mechanism of heart failure, and they suggest that inhibition of this cell death process may constitute the basis for novel therapies.