Intracoronary Adenovirus-Mediated Delivery and Overexpression of the β 2 -Adrenergic Receptor in the Heart

Abstract

Background —Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of β 2 -adrenergic receptors (β 2 ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human β 2 AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery. Methods and Results —Rabbits underwent percutaneous subselective catheterization of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-βGal) or the β 2 AR (Adeno-β 2 AR). Ventricular function was assessed before catheterization and 3 to 6 days after gene delivery. Both left circumflex– and right coronary artery–mediated delivery of Adeno-β 2 AR resulted in ≈10-fold overexpression in a chamber-specific manner. Delivery of Adeno-βGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of β 2 ARs in the LV improved global LV contractility, as measured by dP/dt max , at baseline and in response to isoproterenol at both 3 and 6 days after gene delivery. Conclusions —Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the β 2 AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.