Cardiac beta-adrenergic neuroeffector systems in acute myocardial dysfunction related to brain injury. Evidence for catecholamine-mediated myocardial damage.
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 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.


RESULTS
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.


CONCLUSIONS
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.
White
M
M
Division of Cardiology, University of Colorado Health Sciences Center, Denver 80262, USA.
Wiechmann
R J
RJ
Roden
R L
RL
Hagan
M B
MB
Wollmering
M M
MM
Port
J D
JD
Hammond
E
E
Abraham
W T
WT
Wolfel
E E
EE
Lindenfeld
J
J
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000328:Adult; D001926:Brain Death / Q000503:physiopathology*; D016022:Case-Control Studies; D002395:Catecholamines / Q000378:metabolism*; D004452:Echocardiography; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction; D014019:Tissue Donors; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000503:physiopathology
D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases