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Exogenous gene delivery to alter the function of the heart is a potential novel therapeutic strategy for treatment of cardiovascular diseases such as heart failure (HF).Before gene therapy approaches to alter cardiac function can be realized, efficient and reproducible in vivo gene techniques must be established to efficiently transfer transgenes globally to the myocardium. We have been testing the hypothesis that genetic manipulation of the myocardial [small beta, Greek]-adrenergic receptor ([small beta, Greek]-AR) system, which is impaired in HF, can enhance cardiac function. We have delivered adenoviral transgenes, including the human [small beta, Greek] (2-AR) (Adeno-[small beta, Greek]2 AR), to the myocardium of rabbits using an intracoronary approach. Catheter-mediated Adeno-[small beta, Greek]2 AR delivery produced diffuse multichamber myocardial expression, peaking 1 week after gene transfer. A total of 5 x 1011 viral particles of Adeno-[small beta, Greek]2 AR reproducibly produced 5- to 10-fold [small beta, Greek]-AR overexpression in the heart, which, at 7 and 21 days after delivery, resulted in increased in vivo hemodynamic function compared with control rabbits that received an empty adenovirus. Several physiological parameters, including dP/dtmax as a measure of contractility, were significantly enhanced basally and showed increased responsiveness to the [small beta, Greek]-agonist isoproterenol. Our results demonstrate that global myocardial in vivo gene delivery is possible and that genetic manipulation of [small beta, Greek]-AR density can result in enhanced cardiac performance. Thus, replacement of lost receptors seen in HF may represent novel inotropic therapy.J.Clin. Invest. 104:21-29 (1999).