Intracoronary adenovirus-mediated delivery and overexpression of the beta(2)-adrenergic receptor in the heart - Prospects for molecular ventricular assistance

Background-Genetic modulation of ventricular function may offer a novel the rapeutic strategy for patients with congestive heart failure. Myocardial ov erexpression of beta(2)-adrenergic receptors (beta(2)ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormaliti es found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovi rus containing the human beta(2)AR cDNA to ventricular myocardium via cathe ter-mediated subselective intracoronary delivery. Methods and Results-Rabbits underwent percutaneous subselective catheteriza tion of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-beta Gal) or the beta( 2)AR (Adeno-beta(2)AR). Ventricular function was assessed before catheteriz ation and 3 to 6 days after gene delivery. Both left circumflex- and right coronary artery-mediated delivery of Adeno-beta(2)AR resulted in approximat e to 10-fold overexpression in a chamber-specific manner. Delivery of Adeno -beta Gal did not alter in vivo left ventricular (LV) systolic function, wh ereas overexpression of beta(2)ARs in the LV improved global LV contractili ty, 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 po tentially therapeutic transgene is feasible, and acute global LV function c an be enhanced by LV-specific overexpression of the beta(2)AR. Thus, geneti c modulation to enhance the function of the heart may represent a novel the rapeutic strategy for congestive heart failure and can be viewed as molecul ar ventricular assistance.