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(Circulation. 2001;104:2069.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Ventricular Dysfunction After Cardioplegic Arrest Is Improved After Myocardial Gene Transfer of a ß-Adrenergic Receptor Kinase Inhibitor

Hendrik T. Tevaearai, MD; Andrea D. Eckhart, PhD; Kyle F. Shotwell, BS; Katrina Wilson, BS; Walter J. Koch, PhD

From the Departments of Surgery (H.T.T., A.D.E., K.F.S., W.J.K.), Pharmacology and Cancer Biology (W.J.K.), and Medicine (K.W.) and the Howard Hughes Medical Institutes (K.W.), Duke University Medical Center, Durham, NC.

Correspondence to Walter J. Koch, PhD, Department of Surgery, Box 2606, MSRB Room 471, Duke University Medical Center, Durham, NC 27710. E-mail koch0002{at}mc.duke.edu

Background— Acute cardiac contractile dysfunction is common after cardiopulmonary bypass (CPB). A potential molecular mechanism is enhanced ß-adrenergic receptor kinase (ßARK1) activity, because ß-adrenergic receptor (ßAR) signaling is altered in cardiomyocytes after cardioplegia. Therefore, we examined whether adenovirus-mediated intracoronary delivery of a ßARK1 inhibitor (Adv-ßARKct) could prevent post-CPB dysfunction.

Methods and Results— Rabbits were randomized to receive 5x10¹¹ total viral particles of Adv-ßARKct or PBS. After 5 days, hearts were arrested with University of Wisconsin solution, excised, and stored at 4°C for 15 minutes or 4 hours before reperfusion on a Langendorff apparatus. Left ventricular (LV) function measured by end-diastolic pressure response to preload augmentation, contractility (LV dP/dt_max), and relaxation (LV dP/dt_min) was assessed by use of increasing doses of isoproterenol and compared with a control group of nonarrested hearts acutely perfused on the Langendorff apparatus. In the PBS-treated hearts, LV function decreased in a temporal manner and was significantly impaired compared with control hearts after 4 hours of cardioplegic arrest. LV function in Adv-ßARKct-treated hearts, however, was significantly enhanced compared with PBS treatment and was similar to control nonarrested hearts even after 4 hours of cardioplegia. Biochemically, several aspects of ßAR signaling were dysfunctional in PBS-treated hearts, whereas they were normalized in ßARKct-overexpressing hearts.

Conclusions— Myocardial gene transfer of Adv-ßARKct stabilizes ßAR signaling and prevents LV dysfunction induced by prolonged cardioplegic arrest. Thus, ßARK1 inhibition may represent a novel target in limiting depressed ventricular function after CPB.

Key Words: ischemia • reperfusion • cardiopulmonary bypass • gene therapy • signal transduction

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