CARDIAC BETA-ADRENERGIC NEUROEFFECTOR SYSTEMS IN ACUTE MYOCARDIAL DYSFUNCTION RELATED TO BRAIN INJURY - EVIDENCE FOR CATECHOLAMINE-MEDIATEDMYOCARDIAL DAMAGE

Background Ten percent to 20% of potential cardiac donors with brain i njury and no previous cardiac history have myocardial dysfunction. We assessed components of the beta-receptor-G-protein-adenylyl cyclase co mplex as well as the contractile response in 10 explanted acutely fail ing human hearts (donor heart dysfunction [DHD]) and compared the resu lts with 13 age-matched nonfailing (NF) organ donor controls. Methods and Results As measured by echocardiography, all DHD hearts exhibited a decreased shortening fraction (16+/-2%, mean+/-SEM). Although total and subpopulation Preceptor densities measured by [I-125]iodocyanopind olol (ICYP) were similar in the DHD and NF groups, DHD hearts exhibite d a 30% decrease in maximum isoproterenol-stimulated adenylyl cyclase activity and a 50% decrease in the maximal response to zinterol. DHD h earts also exhibited decreases in adenylyl cyclase maximal stimulation by forskolin (211+/-25 [DHD] versus 295+/-23 [NF] pmol cAMP . min(-1) . mg(-1), P<.05) and 5'-guanylylimidodiphosphate (12.5+/-1.8 [DHD] ve rsus 19.6+/-3.2 [NF] pmol cAMP . min(-1) . mg(-1), P<.05), but there w as no significant decrease in adenylyl cyclase stimulation by Mn2+, a direct activator of adenylyl cyclase. Right ventricular trabeculae rem oved from DHD hearts exhibited a profound decrease in the contractile response to isoproterenol (8.7+/-1 [DHD] versus 22+/-2 [NF] mN, P<.001 ) as well as reduced calcium responses (7.2+/-1.6 [DHD] versus 14+/-3 [NF] mN, P=.03). Morphological examination of two hearts revealed some ultrastructural evidence suggestive of catecholamine-mediated injury, but there was no difference in tissue creatine kinase activity betwee n the two groups. Conclusions Compared with NF hearts, DHD hearts exhi bit marked uncoupling of beta(1)- and beta(2)-adrenergic receptors fro m adenylyl cyclase and contractile response stimulation as well as dec reased intrinsic systolic function. Thus, acute myocardial dysfunction accompanying brain injury is characterized by marked alterations in b eta-adrenergic signal transduction as well as changes in the contracti le apparatus, and this profile is markedly different from what occurs in the chronically failing human heart.