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J Thorac Cardiovasc Surg 2003;125:1461-1469
© 2003 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Blocking the development of postischemic cardiomyopathy with viral gene transfer of the apoptosis repressor with caspase recruitment domain

From the Division of Cardiothoracic Surgery^a and Department of Physiology,^b University of Pennsylvania School of Medicine, Philadelphia, Pa, and the National Institute on Aging,^c National Institutes of Health, Baltimore, Md.

This work was supported by grants from the National Heart, Lung, and Blood Institute (HL07843 and HL59407).

Received for publication June 4, 2002. Revisions requested Aug 19, 2002; revisions received Sept 10, 2002. Accepted for publication Sept 24, 2002. Address for reprints: Timothy J. Gardner, MD, Professor and Chief, Division of Cardiothoracic Surgery, University of Pennsylvania School of Medicine, 6 Silverstein Pavilion, 3400 Spruce St, Philadelphia, PA 19104 (E-mail: gardnert{at}uphs.upenn.edu).

Objectives: Apoptosis caused by acute ischemia and subsequent ventricular remodeling is implicated as a mediator of heart failure. This study was designed to assess the efficacy of in vivo viral gene transfer of the antiapoptotic factor apoptosis repressor with caspase recruitment domain to block apoptosis and preserve ventricular geometry and function.
Methods: In a rabbit model of regional ischemia followed by reperfusion, an experimental group treated with adenovirus-apoptosis repressor with caspase recruitment domain was compared with empty vector adenovirus-null controls. Cardiac function was assessed by echocardiography and sonomicrometry of the border zone compared with the normal left ventricle. Animals were killed at 6 weeks with measurements of ventricular geometry and apoptosis.
Results: Animals with the apoptosis repressor with caspase recruitment domain (ARC group) maintained higher ejection fractions at 4 and 6 weeks, and sonomicrometry demonstrated greater protection of border zone fractional shortening at 6 weeks compared with the control group. The ARC group maintained superior preservation of left ventricular geometry with less ventricular dilation and wall thinning. Finally, there was reduced apoptosis in the rabbits treated with apoptosis repressor with caspase recruitment domain compared with the controls.
Conclusions: Gene transfer of apoptosis repressor with caspase recruitment domain preserves left ventricular function after ischemia. The benefit at 6 weeks is postulated to result from an apoptosis repressor with caspase recruitment domain-mediated reduction in apoptosis and ventricular remodeling. Adenovirus-apoptosis repressor with caspase recruitment domain administration offers a potential strategy after myocardial ischemia to protect the heart from late postischemic cardiomyopathy.

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