Right ventricular gene therapy with a β-adrenergic receptor kinase inhibitor improves survival after pulmonary artery banding

Abstract

Background. Increased right ventricular (RV) afterload results in RV hypertrophy and dysfunction, as well as increased levels of intracellular β-adrenergic receptor kinase (βARK1). We hypothesize that gene transfer of a βARK1 inhibitor (βARKct) may improve RV performance, morbidity, and mortality early after pulmonary artery (PA) banding. Methods. Rabbits underwent PA banding 3 days after right coronary artery injection of an adenovirus containing the gene encoding the βARKct peptide ( n = 14), β-galactosidase ( n = 10), or an empty adenovirus ( n = 19). After banding, hemodynamic instability and maximal rate of increase in right ventricular pressure (RV dP/dt max) were documented. For 7 days after banding, animals were monitored for mortality, activity, and appetite. Results. When compared with controls, animals receiving the βARKct transgene showed improvement in survival at 7 days (92.8% ± 7% vs 48.3% ± 9%, p = 0.01), less lethargy, a trend toward greater RV dP/dt max (NS), and increased hemodynamic stability at the time of banding (78% vs 41%, p = 0.03). Conclusions. Selective RV expression of βARKct improves survival and morbidity after PA banding. This represents a novel therapeutic modality for clinical situations involving increased RV afterload.