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(Circulation. 2004;109:1590-1593.)
© 2004 American Heart Association, Inc.

Brief Rapid Communication

Targeted ß-Adrenergic Receptor Kinase (ßARK1) Inhibition by Gene Transfer in Failing Human Hearts

Matthew L. Williams, MD^*; Jonathan A. Hata, MD^*; Jacob Schroder, MD; Edward Rampersaud, MD; Jason Petrofski, MD; Andre Jakoi, BS; Carmelo A. Milano, MD; Walter J. Koch, PhD

From the Department of Surgery, Duke University Medical Center (M.L.W., J.A.H., J.S., E.R., J.P., A.J., C.A.M., W.J.K.), Durham, NC; Department of Surgery, Massachusetts General Hospital (M.L.W.), Boston, Mass; and Center for Translational Medicine (W.J.K.), Thomas Jefferson University, Philadelphia, Pa.

Correspondence to Walter J. Koch, PhD, FAHA, Director, Center for Translational Medicine, Jefferson Medical College, 1025 Walnut St, Room 410, Philadelphia, PA 19107. E-mail walter.koch{at}jefferson.edu

Received December 16, 2003; revision received February 12, 2004; accepted February 18, 2004.

Background— Failing human myocardium is characterized by an attenuated contractile response to ß-adrenergic receptor (ßAR) stimulation due to changes in this signaling cascade, including increased expression and activity of the ß-adrenergic receptor kinase (ßARK1). This leads to desensitization and downregulation of ßARs. Previously, expression of a peptide inhibitor of ßARK1 (ßARKct) has proven beneficial in several animal models of heart failure (HF).

Methods and Results— To test the hypothesis that inhibition of ßARK1 could improve ß-adrenergic signaling and contractile function in failing human myocytes, the ßARKct was expressed via adenovirus-mediated (AdßARKct) gene transfer in ventricular myocytes isolated from hearts explanted from 10 patients with end-stage HF undergoing cardiac transplantation. AdßARKct also contained the marker gene, green fluorescent protein, and successful gene transfer was confirmed via fluorescence and immunoblotting. Compared with uninfected failing myocytes (control), the velocities of both contraction and relaxation in the AdßARKct-treated cells were increased in response to the ß-agonist isoproterenol (contraction: 57.5±6.6% versus 37.0±4.2% shortening per second, P<0.05; relaxation: 43.8±5.5% versus 27.5±3.9% lengthening per second, P<0.05). Fractional shortening was similarly enhanced (12.2±1.2% versus 8.0±0.9%, P<0.05). Finally, adenylyl cyclase activity in response to isoproterenol was also increased in AdßARKct-treated myocytes.

Conclusions— These results demonstrate that as in animal models of HF, expression of the ßARKct can improve contractile function and ß-adrenergic responsiveness in failing human myocytes. Thus, ßARK1 inhibition may represent a therapeutic strategy for human HF.

Key Words: myocytes • heart failure • gene therapy

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