In vivo ventricular gene delivery of a β-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction

Abstract

Background - Genetic manipulation to reverse molecular abnormalities associated with dysfunctional myocardium may provide novel treatment. This study aimed to determine the feasibility and functional consequences of in vivo β-adrenergic receptor kinase (βARK1) inhibition in a model of chronic left ventricular (LV) dysfunction after myocardial infarction (MI). Methods and Results - Rabbits underwent ligation of the left circumflex (LCx) marginal artery and implantation of sonomicrometric crystals. Baseline cardiac physiology was studied 3 weeks after MI; 5×1011 viral particles of adenovirus was percutaneously delivered through the LCx. Animals received transgenes encoding a peptide inhibitor of βARK1 (Adeno-βARKct) or an empty virus (EV) as control. One week after gene delivery, global LV and regional systolic function were measured again to assess gene treatment. Adeno-βARKct delivery to the failing heart through the LCx resulted in chamber-specific expression of the βARKct. Baseline in vivo LV systolic performance was improved in Adeno-βARKct-treated animals compared with their individual pre-gene delivery values and compared with EV-treated rabbits. Total β-AR density and βARK1 levels were unchanged between treatment groups; however, β-AR-stimulated adenylyl cyclase activity in the LV was significantly higher in Adeno-βARKct-treated rabbits compared with EV-treated animals. Conclusions - In vivo delivery of Adeno-βARKct is feasible in the infarcted/failing heart by coronary catheterization; expression of βARKct results in marked reversal of ventricular dysfunction. Thus, inhibition of βARK1 provides a novel treatment strategy for improving the cardiac performance of the post-MI heart.