Background—The upregulation of G protein–coupled receptor kinase 2 in failing myocardium appears to contribute to dysfunctional -adrenergic receptor (AR) signaling and cardiac function. The peptide ARKct, which can inhibit the activation of G protein–coupled receptor kinase 2 and improve 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 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 ARKct or green fluorescent protein as a control via AAV6-mediated direct intramyocardial injection. We also treated groups with concurrent administration of the -blocker metoprolol. We found robust and long-term transgene expression in the left ventricle at least 12 weeks after delivery. 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 AR signaling. Addition of metoprolol neither enhanced nor decreased ARKct-mediated beneficial effects, although metoprolol alone, despite not improving contractility, prevented further deterioration of the left ventricle.

Conclusions—Long-term cardiac AAV6-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, ARKct alone improves outcomes more than a -blocker alone, whereas both treatments are compatible. These findings show that ARKct gene therapy can be of long-term therapeutic value in HF.