The purpose of this proposal is to determine the underlying mechanism and the treatment or prevention of acute myocardial beta-adrenergic receptor (betaAR) desensitization during cardiopulmonary bypass (CPB). Two hypotheses are to be tested, i.e., 1) acute myocardial betaAR sensitization during CPB is localized to the betaAR moiety and results from receptor phosphorylation and 2) intervention with intravenous metoprolol upon initiation of CPB will prevent myocardial betaAR desensitization during CPB. The hypotheses are the result of previous work by the PI who has reported that acute myocardial betaAR desensitization occurs within three hours of CPB. The PI now wishes to elucidate the mechanisms underlying betaAR desensitization by examining which kinases (GRK1-6, and PKA) are present in the human ventricle and atrium and then quantitate changes with CPB at the mRNA level using quantitative PCR and at the protein level using functional assays. The PI also proposes to perform an interventional trial designed to determine if prevention of intraoperative betaAR desensitization by administering IV metoprolol upon initiating cardiopulmonary bypass will prevent or limit postbypass myocardial dysfunction. The examination of the betaAR signal transduction pathway with and without metoprolol using atrial biopsies obtained before and after CPB include the analysis of betaAR number, subtype, functional coupling of receptors to G-proteins, and the determination of adenyl cyclase levels. Clinical outcomes to be assessed include changes in ejection fraction determined by transesophageal echo, level of post-CPB inotropic support, ICU hospital stay, and overall morbidity and mortality. It is anticipated that prevention of myocardial betaAR desensitization during cardiac surgery should lead to enhanced myocardial performance at the time of separation from CPB and use of fewer inotropic drugs.
