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

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Abstract
Background Acute cardiac contractile dysfunction is common after cardiopulmonary bypass (CPB). A potential molecular mechanism is enhanced β-adrenergic receptor kinase (βARK1) activity, because β-adrenergic receptor (βAR) signaling is altered in cardiomyocytes after cardioplegia. Therefore, we examined whether adenovirus-mediated intracoronary delivery of a βARK1 inhibitor (Adv-βARKct) could prevent post-CPB dysfunction. Methods and Results Rabbits were randomized to receive 5×10 11 total viral particles of Adv-βARKct 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-βARKct-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 βAR signaling were dysfunctional in PBS-treated hearts, whereas they were normalized in βARKct-overexpressing hearts. Conclusions Myocardial gene transfer of Adv-βARKct stabilizes βAR signaling and prevents LV dysfunction induced by prolonged cardioplegic arrest. Thus, βARK1 inhibition may represent a novel target in limiting depressed ventricular function after CPB.

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