(Circulation. 1995;92:2183-2189.)
© 1995 American Heart Association, Inc.
Articles |
Cardiac ß-Adrenergic Neuroeffector Systems in Acute Myocardial Dysfunction Related to Brain Injury
Evidence for Catecholamine-Mediated Myocardial Damage
From the Cardiology and Cardiothoracic Surgery Divisions, University of Colorado Health Sciences Center, Denver, and the University of Utah School of Medicine, Salt Lake City.
Correspondence to Michael R. Bristow, MD, Division of Cardiology, University of Colorado Health Sciences Center, B-139, 4200 E 9th Ave, Denver, CO 80262.
Background Ten percent to 20% of potential cardiac donors with brain injury and no previous cardiac history have myocardial dysfunction. We assessed components of the ß-receptor–G-protein–adenylyl cyclase complex as well as the contractile response in 10 explanted acutely failing human hearts (donor heart dysfunction [DHD]) and compared the results 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 ß-receptor densities measured by [125I]iodocyanopindolol (ICYP) were similar in the DHD and NF groups, DHD hearts exhibited a 30% decrease in maximum isoproterenol-stimulated adenylyl cyclase activity and a 50% decrease in the maximal response to zinterol. DHD hearts 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] versus 19.6±3.2 [NF] pmol cAMP · min-1 · mg-1, P<.05), but there was no significant decrease in adenylyl cyclase stimulation by Mn2+, a direct activator of adenylyl cyclase. Right ventricular trabeculae removed 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 between the two groups.
Conclusions Compared with NF hearts, DHD hearts exhibit marked uncoupling of ß1- and ß2-adrenergic receptors from adenylyl cyclase and contractile response stimulation as well as decreased intrinsic systolic function. Thus, acute myocardial dysfunction accompanying brain injury is characterized by marked alterations in ß-adrenergic signal transduction as well as changes in the contractile apparatus, and this profile is markedly different from what occurs in the chronically failing human heart.
Key Words: heart failure • catecholamines • receptors • adrenergic • beta • proteins
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