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

Eros Leotta, Gerald Patejunas, Glenn Murphy, Joseph Szokol, Leslie McGregor, Jo Ann Carbray, Adam Hamawy, David Winchester, Neil Hackett, Ronald Crystal, Todd Rosengart

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Abstract

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 (AdCUVEGF121.1 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 AdCUVEGF121.1 animals (29% ± 14% vs 46% ± 8%, P = .02). The fractional area change recovered to baseline values within 7 days in the AdCUVEGF121.1 animals (62% ± 7%) but remained significantly impaired in the AdNull group compared with that in the AdCUVEGFI21.1 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 AdCUVEGF121.1 group in 5 of 6 segments. Fractional wall thickening returned to levels approximating prepacing values in all segments within 7 days in the AdCUVEGF121.1 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 AdCUVEGF121.1 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.

Original languageEnglish
Pages (from-to)1101-1113
Number of pages13
JournalJournal of Thoracic and Cardiovascular Surgery
Volume123
Issue number6
DOIs
Publication statusPublished - 1 Jun 2002
Externally publishedYes

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ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

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