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

Nature Clinical Practice Cardiovascular Medicine volume 3, pages 681–688 (2006)Cite this article

Abstract

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

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Figure 1: Apoptosis in human myocardium.
Figure 2: The cascade of apoptosis in cardiomyocytes.
Figure 3: Release of cytochrome c from mitochondria into cytoplasm as evidence of apoptosis in heart failure.
Figure 4: Activation of caspase-3 by extramitochondrial cytochrome c.
Figure 5: Evidence that apoptosis does not complete in heart failure even after the release of cytochrome c and activation of caspase-3.
Figure 6: Left ventricular myocardial sections from an ischemic cardiomyopathic heart explanted during transplantation demonstrating that the activated apoptotic cascade invokes a protective response by upregulation of antiapoptotic factors.
Figure 7: Resolution of mediators of apoptosis after left ventricular assist device implantation.

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Author information

Authors and Affiliations

  1. the Professor of Medicine, Chief of the Division of Cardiology,

    Jagat Narula

  2. Associate Dean for Research at the University of California, Irvine, CA

    Jagat Narula

  3. research scientist and directs the molecular cardiology laboratory at the University of California School of Medicine, Irvine, CA

    Nezam Haider

  4. Professor of Pathology at the Policlinico San Matteo, Pavia, Italy

    Eloisa Arbustini

  5. University of Minnesota School of Medicine,

    Y Chandrashekhar

  6. VA Medical Center, Minneapolis, MN, USA

    Y Chandrashekhar

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  1. Jagat Narula
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  2. Nezam Haider
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  3. Eloisa Arbustini
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  4. Y Chandrashekhar
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Corresponding author

Correspondence to Jagat Narula.

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The authors declare no competing financial interests.

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Narula, J., Haider, N., Arbustini, E. et al. Mechanisms of Disease: apoptosis in heart failure—seeing hope in death. Nat Rev Cardiol 3, 681–688 (2006). https://doi.org/10.1038/ncpcardio0710

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  • DOI: https://doi.org/10.1038/ncpcardio0710

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