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J Thorac Cardiovasc Surg 2003;125:998-1006
© 2003 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Multigene adenoviral therapy for the attenuation of ischemia-reperfusion injury after preservation for cardiac transplantation

Haitham J. Abunasra, FRCSa, Ryszard T. Smolenski, MD, PhDa,b, John Yap, FRCSa, Mary Sheppard, MD, FRCPatha, Timothy O'Brien, MD, PhDc, Magdi H. Yacoub, FRSa

From the Heart Science Centre, Imperial College at Harefield Hospital, Harefield, United Kingdom,a Department of Biochemistry, Medical University of Gdansk, Poland,b and the Division of Endocrinology, Mayo Clinic, Rochester, Minn.c

Supported by the British Heart Foundation (PG 99/173).

Received for publication Feb 25, 2002. Revisions requested May 31, 2002; revisions received July 30, 2002. Accepted for publication Aug 6, 2002. Address for reprints: Professor Sir Magdi H. Yacoub, Heart Science Centre, Imperial College School of Medicine at Harefield Hospital, Harefield, Middlesex, UB9 6JH, United Kingdom (E-mail: m.yacoub{at}ic.ac.uk).

Objective: The protective effect of adenovirus-mediated ex vivo multigene transfer with superoxide dismutase, a free radical scavenger, and nitric oxide, a vasodilator with anti-inflammatory properties, was examined in the rat heart during experimental ischemia-reperfusion mimicking preservation for cardiac transplantation.
Methods: Donor rat hearts (n = 6 per group) were perfused with solution containing adenoviral vector carrying genes for ß-galactosidase (group A), endothelial nitric oxide synthase (group B), manganese superoxide dismutase (group C), or both endothelial nitric oxide synthase and manganese superoxide dismutase (group D). Hearts were then implanted heterotopically into the abdomens of recipient rats. Four days later, transplanted hearts were collected, connected to a Langendorff perfusion apparatus, and subjected to 6 hours of ischemia followed by 1 hour of reperfusion. Cardiac function was evaluated with an intraventricular balloon at the beginning of Langendorff perfusion and after ischemia-reperfusion.
Results: Effective gene transfection was confirmed with X-gal staining in group A hearts. Positive immunoreactivity for endothelial nitric oxide synthase, manganese superoxide dismutase, or both was present predominantly in cardiomyocytes in group B, C, and D hearts. Percentage recovery of preischemic left ventricular developed pressure was 62.1% ± 7.36% in group A; recoveries were increased to 79.6% ± 6.4%, 86.8% ± 9.1%, and 79.4% ± 6.2% in groups B, C, and D, respectively.
Conclusion: These results indicate that adenoviral gene transfer of manganese superoxide dismutase and endothelial nitric oxide synthase can attenuate myocardial ischemia-reperfusion injury, with the former providing the most significant protection. Combined overexpression of manganese superoxide dismutase and endothelial nitric oxide synthase did not enhance myocardial recovery any further.


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