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 perfo...