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Apoptosis and cardiomyopathy
J Narula1, F D Kolodgie, R Virmani
1MCP-Hahnemann University School of Medicine, Philadelphia, Pennsylvania, USA.
Insights
Apoptosis, a programmed cell death, occurs in adult heart muscle cells in heart failure. This cell death contributes to systolic dysfunction due to mitochondrial and protein loss.
Area of Science:
- Cardiology
- Cell Biology
- Pathology
Background:
- Apoptosis is genetically programmed cell death, distinct from necrosis.
- Terminally differentiated adult heart muscle cells were previously thought resistant to apoptosis.
- Heart failure is associated with ventricular dilatation and neurohormonal activation.
Purpose of the Study:
- To investigate the presence and mechanism of apoptosis in adult heart muscle cells in heart failure.
- To explore the relationship between apoptosis and systolic dysfunction in heart failure.
Main Methods:
- Histochemical analysis of endomyocardial biopsies from patients with dilated and ischemic cardiomyopathy.
- Examination of explanted hearts from patients with end-stage heart failure.
Main Results:
- Histochemical evidence confirmed apoptosis in adult heart muscle cells from failing hearts.
- Proposed mechanism involves upregulation of transcription factors, myocyte hypertrophy, and attempted cell cycle entry.
- Failed cell division leads to apoptosis, initiated by cytochrome c release and caspase activation.
- Caspase activation results in cytoplasmic protein fragmentation, but nuclear fragmentation is rare.
Conclusions:
- Apoptosis occurs in adult heart muscle cells during heart failure.
- The release of cytochrome c and loss of cytoplasmic proteins are hypothesized to cause systolic dysfunction.
Abstract:
Apoptosis is a form of cell death that has been described as distinct from necrotic cell death. It is believed to be genetically programmed and occurs as a physiologic process in various organ systems of body. Although it has been tacitly believed that apoptosis does not occur in the terminally differentiated adult heart muscle cells, studies in endomyocardial biopsies from patients with dilated and ischemic cardiomyopathy and in explanted hearts from patients with end-stage heart failure undergoing cardiac transplantation have demonstrated histochemical evidence of apoptosis. It has been proposed that ventricular dilatation and neurohormonal activation during heart failure lead to upregulation of transcription factors, induce myocyte hypertrophy, and prepare the cell for entry into the cell cycle. However, terminally differentiated myocytes cannot divide, and failing to divide they undergo apoptosis. Initiation of apoptosis is associated with activation of upstream cascade, including the release of cytochrome c from mitochondria to cytoplasm and the processing of proteolytic caspases. The activation of caspases leads to fragmentation of various cytoplasmic proteins, including contractile proteins. However, the nuclear fragmentation and condensation is completed only rarely. It is hypothesized that the release of cytochrome c from mitochondria and cytoplasmic protein loss in a living heart muscle cell should lead to systolic dysfunction.