A mechanistic role for cardiac myocyte apoptosis in heart failure

Declef Wencker, Madhulika Chandra, Khanh Nguyen, Wenfeng Miao, Stavros Garantziotis, Stephen M. Factor, Jamshid Shirani, Robert C. Armstrong, Richard N. Kitsis

Research output: Contribution to journalArticlepeer-review

657 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1497-1504
Number of pages8
JournalJournal of Clinical Investigation
Issue number10
StatePublished - May 2003

ASJC Scopus subject areas

  • General Medicine


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