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

Background. Increased right ventricular (RV) afterload results in RV hypertrophy and dysfunction, as well as increased levels of intracellular beta -adrenergic receptor kinase (beta ARK1). We hypothesize that gene transfer of a,beta ARK1 inhibitor (beta ARKct) may improve RV performance, morbidity, and mortality early after pulmonary artery (PA) banding. Methods. Rabbits underwent PA banding 3 days after ri-ht coronary artery injection of an adenovirus containing the gene encoding the beta ARKct peptide (n = 14), beta -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 beta ARKct 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 beta ARKct improves survival and morbidity after PA banding. This represents a novel therapeutic modality for clinical situations involving increased RV afterload. (C) 2001 by The Society of Thoracic Surgeons.