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(Circulation. 2002;106:I-212.)
© 2002 American Heart Association, Inc.

Thoracic Transplantation and Mechanical Support for Congestive Heart Failure

Viral Gene Transfer of the Antiapoptotic Factor Bcl-2 Protects Against Chronic Postischemic Heart Failure

Subhasis Chatterjee, MD; Allan S. Stewart, MD; Lawrence T. Bish, BA; Vasant Jayasankar, MD; Elizabeth M. Kim, BS; Timothy Pirolli; Jeffrey Burdick, BS; Y. Joseph Woo, MD; Timothy J. Gardner, MD; H. Lee Sweeney, PhD

From the Division of Cardiothoracic Surgery (S.C., A.S.S., V.J., J.B., J.W., T.J.G.) and the Department of Physiology (L.T.B., E.M.K., T.P., H.L.S.), University of Pennsylvania School of Medicine, Philadelphia, Pa.

Correspondence to Timothy J. Gardner, MD, 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

Abstract

Background Apoptosis secondary to acute ischemia and chronic remodeling is implicated as a mediator of heart failure. This study was designed to assess the effect of in vivo viral gene transfer of the anti-apoptotic factor Bcl-2 to block apoptosis and preserve ventricular geometry and function.

Methods and Results In a rabbit model of regional ischemia followed by reperfusion, an experimental group treated with adeno-Bcl-2 was compared with a control group receiving empty vector adeno-null. Function was assessed by echocardiography, and sonomicrometry of the border zone was compared with the normal left ventricle (LV). Animals were killed at 6 weeks, and an additional group was killed after 3 days to see whether virus administration conferred an immediate effect. Animals that were administered Bcl-2 maintained higher ejection fractions at 2, 4, and 6 weeks compared with controls. Sonomicrocrystals demonstrated greater protection of border zone fractional shortening at 6 weeks. The Bcl-2 group had superior preservation of LV geometry with less ventricular dilatation and wall thinning. There was also reduced apoptosis compared with the controls. Finally, in the animals killed at 3 days, no functional difference was observed between the Bcl-2 and control groups.

Conclusions Gene transfer of Bcl-2 preserves LV function after ischemia despite the absence of an observed acute protective effect. The benefit at 6 weeks is postulated to result from a Bcl-2–mediated reduction in apoptosis and ventricular remodeling. Adeno–Bcl-2 administration offers a potential strategy to protect the heart from late postischemic heart failure.

Key Words: apoptosis • gene therapy • heart failure • myocardial infarction • remodeling