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J Thorac Cardiovasc Surg 2002;123:1101-1113
© 2002 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CSP)

Gene therapy with adenovirus-mediated myocardial transfer of vascular endothelial growth factor 121 improves cardiac performance in a pacing model of congestive heart failure

From Evanston Northwestern Healthcare,^a Evanston, Ill, and the Institute of Genetic Medicine,^b Weill Medical College of Cornell University, New York, NY.

This work was supported in part by grants from the Jeffry M. and Barbara Picower Foundation, Palm Beach, Fla; National Institutes of Health grants RO1 HL 57318 and RO1 HL6698-01; Evanston Northwestern Healthcare Research Institute, Evanston, Ill; and GenVec, Inc, Gaithersburg, Md.

Presented in part at the Seventy-third Annual Meeting of the American Heart Association, November 2000, New Orleans, La.

Received for publication June 18, 2001. Revisions requested Aug 2, 2001; revisions received Aug 20, 2001. Accepted for publication Oct 2, 2001. Address for reprints: Todd K. Rosengart, MD, Evanston Hospital, Division of Cardiothoracic Surgery, Burch 100, 2650 Ridge Ave, Evanston, IL 60201 (E-mail: trosengart{at}enh.org).

Background: Myocardial ischemia is the most common cause of congestive heart failure. Angiogenic therapy has recently been demonstrated to enhance myocardial perfusion in the ischemic setting. We therefore hypothesized that administration of adenovirus encoding for vascular endothelial growth factor could be used to enhance myocardial function in a pacing-induced model of heart failure.
Methods: Yorkshire swine underwent a left thoracotomy with placement of a ventricular epicardial pacing system. Animals received adenovirus coding either for the 121-amino-acid isoform of vascular endothelial growth factor (Ad_CUVEGF121.1 group, n = 8) or a null vector coding for no genes (AdNull group, n = 8). The adenovirus was administered in the left ventricular free wall as 10 transepicardial injections of 100 µL each (total dose of 10¹¹ particle units). After a 1-week recovery period, animals were paced at a rate of 230 beats/min for 7 days to induce heart failure. Transthoracic echocardiographic and sonomicrometric measurements were performed before pacing (baseline), on termination of pacing (day 0), and then weekly for 3 weeks.
Results: The fractional area change was significantly decreased in AdNull animals at day 0 after pacing compared with the Ad_CUVEGF121.1 animals (29% ± 14% vs 46% ± 8%, P = .02). The fractional area change recovered to baseline values within 7 days in the Ad_CUVEGF121.1 animals (62% ± 7%) but remained significantly impaired in the AdNull group compared with that in the Ad_CUVEGF121.1 animals up to day 21 (P = .04). Similarly, fractional wall thickening demonstrated a decrease at day 0 after pacing that was greater (P < .05) in the AdNull group compared with that in the Ad_CUVEGF121.1 group in 5 of 6 segments. Fractional wall thickening returned to levels approximating prepacing values in all segments within 7 days in the Ad_CUVEGF121.1 group but remained significantly impaired compared with prepacing fractional wall thickening (P < .05) in the AdNull group in 5 of 6 segments up to day 21 after pacing. Segmental shortening, as measured by sonomicrometry, also was significantly decreased at day 7 in the AdNull group compared with that in the Ad_CUVEGF121.1 group (10% ± 4% vs 16% ± 3%, P = .004) and remained significantly impaired (P < .05) in the AdNull group at day 14 and 21 when compared with baseline values.
Conclusion: Preservation of cardiac performance and a more rapid recovery of myocardial function can be achieved in a model of pacing-induced cardiomyopathy with adenovirus-mediated administration of vascular endothelial growth factor compared with that seen in a null virus control group. These data suggest that angiogenic therapy may be useful clinically in treating cardiomyopathy.

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