Cardiac β-adrenergic neuroeffector systems in acute myocardial dysfunction related to brain injury : evidence for catecholamine-mediated myocardial damage

• Published in: Circulation (New York, N.Y.) N.Y.), 1995-10, Vol.92 (8), p.2183-2189
• Main Authors: WHITE, M, WIECHMANN, R. J, FULLERTON, D, BRISTOW, M. R, RODEN, R. L, HAGAN, M. B, WOLLMERING, M. M, PORT, J. D, HAMMOND, E, ABRAHAM, W. T, WOLFEL, E. E, LINDENFELD, J
• Format: Article
• Language: English
• Subjects: Adenylyl Cyclases - metabolism; Adult; Biological and medical sciences; Brain Death - physiopathology; Cardiology. Vascular system; Case-Control Studies; Catecholamines - metabolism; Echocardiography; Female; GTP-Binding Proteins - metabolism; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Humans; Male; Medical sciences; Myocardial Contraction - physiology; Myocardium - metabolism; Myocardium - pathology; Receptors, Adrenergic, beta - physiology; Signal Transduction; Tissue Donors; Ventricular Dysfunction, Left - etiology; Ventricular Dysfunction, Left - physiopathology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.92.8.2183

Ten percent to 20% of potential cardiac donors with brain injury and no previous cardiac history have myocardial dysfunction. We assessed components of the beta-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. As measured by echocardiography, all DHD hearts exhibited a decreased shortening fraction (16 +/- 2%, mean +/- SEM). Although total and subpopulation beta-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. Compared with NF hearts, DHD hearts exhibit marked uncoupling of beta 1- and beta 2-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 beta-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.