Myocardial Adeno-Associated Virus Serotype 6-Beta Arkct Gene Therapy Improves Cardiac Function And Normalizes The Neurohormonal Axis In Chronic Heart Failure

Background-The upregulation of G protein-coupled receptor kinase 2 in failing myocardium appears to contribute to dysfunctional beta-adrenergic receptor (beta AR) signaling and cardiac function. The peptide beta ARKct, which can inhibit the activation of G protein-coupled receptor kinase 2 and improve beta AR signaling, has been shown in transgenic models and short-term gene transfer experiments to rescue heart failure (HF). This study was designed to evaluate long-term beta ARKct expression in HF with the use of stable myocardial gene delivery with adeno-associated virus serotype 6 (AAV6).Methods and Results-In HF rats, we delivered beta ARKct or green fluorescent protein as a control via AAV6-mediated direct intramyocardial injection. We also treated groups with concurrent administration of the beta-blocker metoprolol. We found robust and long-term transgene expression in the left ventricle at least 12 weeks after delivery. beta ARKct significantly improved cardiac contractility and reversed left ventricular remodeling, which was accompanied by a normalization of the neurohormonal (catecholamines and aldosterone) status of the chronic HF animals, including normalization of cardiac beta AR signaling. Addition of metoprolol neither enhanced nor decreased beta ARKct-mediated beneficial effects, although metoprolol alone, despite not improving contractility, prevented further deterioration of the left ventricle.Conclusions-Long-term cardiac AAV6-beta ARKct gene therapy in HF results in sustained improvement of global cardiac function and reversal of remodeling at least in part as a result of a normalization of the neurohormonal signaling axis. In addition, beta ARKct alone improves outcomes more than a beta-blocker alone, whereas both treatments are compatible. These findings show that beta ARKct gene therapy can be of long-term therapeutic value in HF. (Circulation. 2009; 119: 89-98.)