¹Department of Surgery, Duke University Medical Center, Durham, NC, USA

²Department of Medicine, Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA

Correspondence to: WJ Koch, Department of Surgery, Duke University Medical Center, Room 472, MSRB, Research Drive, Durham, NC 27710, USA

Gene transfer to modify donor heart function during transplantation has significant therapeutic implications. Recent studies by our laboratory in transgenic mice have shown that overexpression of ₂-adrenergic receptors (₂-ARs) leads to significantly enhanced cardiac function. Thus, we investigated the functional consequences of adenovirus-mediated gene transfer of the human ₂-AR in a rat heterotopic heart transplant model. Donor hearts received 1 ml of solution containing 1 ´ 10¹⁰ p.f.u. of adenovirus encoding the ₂-AR or an empty adenovirus as a control. Five days after transplantation, basal left ventricular (LV) pressure was measured using an isolated, isovolumic heart perfusion apparatus. A subset of hearts was stimulated with the ₂-AR agonist, zinterol. Treatment with the ₂-AR virus resulted in global myocardial gene transfer with a six-fold increase in mean -AR density which corresponded to a significant increase in basal contractility (LV + dP/dt_max, control: 3152.1 ± 286 versus ₂-AR, 6250.6* ± 432.5 mmHg/s; n = 10, *P < 0.02). ₂-AR overexpressing hearts also had higher contractility after zinterol administration compared with control hearts. Our results indicate that myocardial function of the transplanted heart can be enhanced by the adenovirus-mediated delivery of ₂-ARs. Thus, genetic manipulation may offer a novel therapeutic strategy to improve donor heart function in the post- operative setting.

gene therapy; -adrenergic receptor; cardiac function; transplantation; adenovirus