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(Circulation. 2009;119:89-98.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Myocardial Adeno-Associated Virus Serotype 6–βARKct Gene Therapy Improves Cardiac Function and Normalizes the Neurohormonal Axis in Chronic Heart Failure

Giuseppe Rengo, MD; Anastasios Lymperopoulos, PhD; Carmela Zincarelli, MD; Maria Donniacuo, BS; Stephen Soltys, MS; Joseph E. Rabinowitz, PhD; Walter J. Koch, PhD

From the Center for Translational Medicine (G.R., A.L., C.Z., M.D., S.S., J.E.R., W.J.K.) and George Zallie and Family Laboratory for Cardiovascular Gene Therapy (G.R., A.L., M.D., W.J.K.), Department of Medicine, Thomas Jefferson University, Philadelphia, Pa.

Correspondence to Walter J. Koch, PhD, FAHA, Department of Medicine, Thomas Jefferson University, 1025 Walnut St, Room 317, Philadelphia, PA 19107. E-mail walter.koch{at}jefferson.edu

Received July 3, 2008; accepted October 17, 2008.

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

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

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Circulation 2009 119: 1-4. [Extract] [Full Text]