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A mechanistic role for cardiac myocyte apoptosis in heart failure
Detlef Wencker, … , Robert C. Armstrong, Richard N. Kitsis
Detlef Wencker, … , Robert C. Armstrong, Richard N. Kitsis
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1497-1504. https://doi.org/10.1172/JCI17664.
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Article Cardiology Article has an altmetric score of 25

A mechanistic role for cardiac myocyte apoptosis in heart failure

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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.

Authors

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

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Figure 4

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Abrogation of dilated cardiomyopathy by caspase inhibition. Vehicle or t...
Abrogation of dilated cardiomyopathy by caspase inhibition. Vehicle or the polycaspase inhibitor IDN 1965 (12.5 μg/h) was administered to line 7 transgenic mice by continuous subcutaneous infusion using osmotic minipumps (model 1002; ALZET Corp., Cupertino, California, USA), beginning at 3.5–4.0 weeks of age, when cardiac dimensions, function, and histology are normal, and continuing until sacrifice at 7.5–8.0 weeks of age, when these transgenic mice uniformly exhibit a severe dilated cardiomyopathy. At 7.5–8.0 weeks of age, echocardiography, TUNEL, and histological examination of cardiac tissue were performed. (a) Number of TUNEL-positive cardiac myocytes per 105 nuclei in vehicle- and IDN 1965–treated line 7 mice. *P < 0.03. (b) M-mode echocardiographic parameters from vehicle- and IDN 1965–treated line 7 mice. *P < 0.0003. (c) Coronal sections from vehicle- and IDN 1965–treated line 7 mice stained with H&E (bar, 1 mm), and sections from the indicated area of the left ventricular free wall stained with Masson’s trichrome (bar, 20 μm).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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