ROLE OF B ADRENERGIC RECEPTOR ANTAGONISTS IN CARDIAC SURGERY PATIENTS

Duke University, Durham NC

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Abstract

We previously demonstrated that myocardial-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 AR signaling is reduced in adult humans after CPB, and 2) administration of chronic preoperative AR antagonists prevents 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 AR 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 AR 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 AR density. Differential activation along the AR 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 AR 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. Since patients with cardiac valve disease (CVD) frequently have congestive heart failure (CHF) and chronic myocardial beta-adrenergic receptor (BAR) desensitization, we next examined whether acute bAR dysfunction occurs during CPB in patients with CVD. After informed consent, 50 patients were enrolled. Right atrial biopsies were obtained at initiation and conclusion of CPB to assess BAR density and adenylyl cyclase (AC) activity. Plasma catecholamine concentrations increased 3-fold during CPB (p< 0.01). Although BAR density remained constant, isoproterenol-stimulated AC activity decreased significantly ( 30%; p<0.005). AC activity decreased 22% and 24% with direct G protein (NaF) or AC (manganese) activation, respectively. Patients with/without preoperative CHF exhibited similar degrees of acute myocardial BAR dysfunction during CPB. Acute myocardial BAR dysfunction occurs during CPB in patients with severe CVD requiring surgical correction, with/without pre-existing CHF. The primary underlying mechanism involves functional uncoupling of the BAR signal transduction pathway at the level of the AC moiety. This information should facilitate development of agents designed to prevent acute myocardial BAR dysfunction during CPB, potentially leading to improved outcome in this high-risk population. As a result of these initial studies, we are now examining mechanisms underlying CPB-induced BAR desensitization in humans. Phosphorylation kinases, G protein-coupling, and adenylyl cyclase isoforms are being examined. We are also performing an interventional trial to test the hypothesis that BAR antagonists protect patients from acute myocardial BAR desensitization during heart surgery with CPB.