Abstract 2888: Uncoupling of Myocardial Beta-Adrenergic Receptor Signaling During CABG
Cardiopulmonary bypass (CPB) and cardioplegic arrest (CA) can lead to impaired ventricular function after cardiac surgery. This can result in a greater need for inotropic support and increased morbidity and mortality. Our objective is to determine if there is significant uncoupling of cardiac β-adrenergic receptors (β-AR) during CABG and to define the mechanism for impaired signaling through this pathway which is critical in regulating cardiac function. Fifty patients who underwent elective CABG with CPB and CA were enrolled. All patients had a LIMA to LAD graft and a total of 2–5 bypass grafts. Myocardial β-AR signaling was assessed in right atrial biopsies obtained before CPB and just prior to weaning from CPB before initiating any inotropic support. There was no operative mortality. All patients with an EF of < 25% (n=14) required at least one inotrope to wean from CPB. All patients had significantly impaired myocardial β-AR signaling after CABG as measured by basal and isoproterenol-stimulated adenylyl cyclase (AC) activity in sarcolemmal membrane preparations (n=50 pre- and post-CABG, P< 0.02). There was no change in β-AR density pre-and post-CABG. There was no difference in protein expression of the G proteins Gαs and Gαi. There was, however, a 2-fold increase in G protein-coupled receptor kinase-2 (GRK2) activity post-CABG (P< 0.03) as measured by rhodopsin phosphorylation. GRK2 is a serine-threonine kinase which phosphorylates and uncouples agonist-occupied β-AR and is important in regulating cardiac function in vivo. In addition, there was a 3.4-fold increase in GRK2 activity post-CABG in patients with an EF of < 25% (n=14, P< 0.02) and this correlated with the greater need for inotropic support to wean from CPB in this subset of patients. Myocardial β-AR signaling is impaired following CABG. The primary mechanism appears to be an increase in GRK2 activity, likely resulting from increased circulating and local catecholamine levels associated with CPB and CA. This is more significant in patients with low EF who had an increased need for inotropic support to wean from CPB. Inhibition of cardiac GRK2 activity may represent a novel strategy to improve outcomes in high-risk patients undergoing CABG.