There is now a growing body of clinical evidence that suggests a strong association between left ventricular dysfunction and sudden cardiac death in patients recovering from myocardial infarction. The mechanisms underlying this association remain to be determined. Alterations within the autonomic nervous system may represent one factor that links cardiac function to an increased mortality. Since ventricular dysfunction would tend to reduce stroke volume, an increased sympathetic and/or decreased parasympathetic activity may compensate for this fall in stroke volume by increasing heart rate and/or inotropic state to maintain a more normal cardiac output. These changes in autonomic activity would decrease refactory period and are, in fact, known to increase the vulnerability to ventricular fibrillation (VF). During preliminary experiments, it has been possible to develop an animal model in which VF could be reliably and reproducibly induced. This model combined anterior wall myocardial infarction with myocardial ischemia during exercise and its cessation. Approximately 60-70% of the animals so tested developed VF. Using this model, it is the purpose of this series of proposed experiments to investigate: a) the relationship between ventricular function and susceptibility to VF, and b) the contribution of the autonomic nervous system to sudden death. Furthermore, if the hypothesis linking ventricular function to sudden death is correct, then interventions that improve cardiac function should reduce the incidence of sudden death. This hypothesis will be tested using two approaches: endurance exercise training and cardiotonic drug therapy. The differences in ventricular function are probably subtle at rest but may become more pronounced when the heart is stressed. Submaximal exercise, alterations in afterload and myocardial ischemia at rest will be used as physiological relevant stressors. Ventricular function will be assessed using both regional and global indices of cardiac contractile function. Specifically, segment length contractility, stroke volume, and systolic ventricular pressure-volume relationships will be investigated. Diastolic properties of the heart will also be investigated. In a similar manner, autonomic activity will be indirectly assessed using pharmacological interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036336-03
Application #
3351274
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1986-07-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1990-06-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Billman, G E; McIlroy, B; Johnson, J D (1991) Elevated myocardial calcium and its role in sudden cardiac death. FASEB J 5:2586-92
Billman, G E (1990) Mechanisms responsible for the cardiotoxic effects of cocaine. FASEB J 4:2469-75
Billman, G E; McIlroy, B; Johnson, J D (1990) The role of elevated intracellular calcium in the susceptibility to ventricular fibrillation. Prog Clin Biol Res 327:755-63
Billman, G E (1990) Effect of carbachol and cyclic GMP on susceptibility to ventricular fibrillation. FASEB J 4:1668-73
Billman, G E; Dujardin, J P (1990) Dynamic changes in cardiac vagal tone as measured by time-series analysis. Am J Physiol 258:H896-902
Billman, G E; Randall, D C; Brown, D R et al. (1990) Hemodynamic and arrhythmogenic effects of aversive stress during myocardial ischemia. J Auton Nerv Syst 29:193-202
Billman, G E; Hoskins, R S (1989) Time-series analysis of heart rate variability during submaximal exercise. Evidence for reduced cardiac vagal tone in animals susceptible to ventricular fibrillation. Circulation 80:146-57
Collins, M N; Billman, G E (1989) Autonomic response to coronary occlusion in animals susceptible to ventricular fibrillation. Am J Physiol 257:H1886-94
Billman, G E; Hoskins, R S; Randall, D C et al. (1989) Selective vagal postganglionic innervation of the sinoatrial and atrioventricular nodes in the non-human primate. J Auton Nerv Syst 26:27-36
Billman, G E; Marsh, D H (1989) Effect of myocardial ischemia on hemodynamic response to carotid occlusion. Am J Physiol 256:H672-80

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