ROLE OF B ADRENERGIC RECEPTOR ANTAGONISTS IN CARDIAC SURGERY PATIENTS

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

We previously demonstrated that myocardial beta-adrenergic (bAR) function is reduced after cardiopulmonary bypass (CPB) in a canine model. Whether CPB results in similar effects on bAR function in adult humans during coronary artery bypass graft (CABG) surgery or valve surgery is not known. Therefore we initially tested two hypotheses in CABG patients: 1) myocardial bAR signaling is reduced in adult humans after CB, and 2) administration of chronic preoperative bAR antagonists percents this process. After informed consent, 52 patients undergoing aortocoronary surgery were enrolled. Atrial biopsies were obtained pre-CPB and immediately prior to discontinuation of CPB. Plasma catecholamine concentrations, myocardial bAR density, and functional responsiveness (basal, isoproterenol, zinterol, NaF, and Mn-stimulated adenylyl cyclase activity) were assessed. Catecholamine levels increased significantly during CPB (p<0.005). Myocardial bAR adenylyl cyclase coupling decreased during CPB as evidenced by 21% decrease in isoproterenol-stimulated adenylyl cyclase activity (750 [430] pmol cAMP/mg total protein/15 min Pre-CPB versus 540 [390] End-CPB, p=0.0062, median [interquartile range]) in spite of constant bAR density. Differential activation along the bAR signal transduction cascade localized the defect to the adenylyl cyclase moiety. Administration of chronic preoperative bAR antagonists did not prevent acute CPB-induced myocardial bAR dysfunction. These data demonstrate that myocardial adenylyl cyclase response to bAR agonists decreases acutely in adults during aortocoronary surgery requiring CPB, regardless of administration of chronic preoperative bAR antagonists. The mechanism underlying acute bAR dysfunction appears to be direct impairment of the adenylyl cyclase moiety. Similar fold increase in Mn-stimulated activity Pre- and End-CPB demonstrates preserved adenylyl cyclase catalytic activity, suggesting other mechanisms (e.g. decreased protein levels or altered isoform expression/function) may be responsible for decreased adenylyl cyclase function.