Myocardial Adeno-Associated Virus Serotype 6–&bgr;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 &bgr;-adrenergic receptor (&bgr;AR) signaling and cardiac function. The peptide &bgr;ARKct, which can inhibit the activation of G protein–coupled receptor kinase 2 and improve &bgr;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 &bgr;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 &bgr;ARKct or green fluorescent protein as a control via AAV6-mediated direct intramyocardial injection. We also treated groups with concurrent administration of the &bgr;-blocker metoprolol. We found robust and long-term transgene expression in the left ventricle at least 12 weeks after delivery. &bgr;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 &bgr;AR signaling. Addition of metoprolol neither enhanced nor decreased &bgr;ARKct-mediated beneficial effects, although metoprolol alone, despite not improving contractility, prevented further deterioration of the left ventricle. Conclusions— Long-term cardiac AAV6-&bgr;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, &bgr;ARKct alone improves outcomes more than a &bgr;-blocker alone, whereas both treatments are compatible. These findings show that &bgr;ARKct gene therapy can be of long-term therapeutic value in HF.