There is considerable evidence that the malignant ventricular arrhythmias which occur weeks or months following myocardial infarction are usually due to reentry. Our long term goal is to understand the cellular mechanisms of the slow discontinuous conduction which supports reentry. Recent clinical trials emphasize the need for new approaches to drug therapy. The following specific aims are directed to this goal. FIRST to determine the role of modulation of cell-to-cell electrotonic coupling in arrhythmogenesis nad antiarrhythmic action. SECOND, to determine the effect of transient ischemia on conduction in normal myocardium and on conduction in pre-existing infarcted myocardium. THIRD, to evaluate the role of refractoriness in changes in arrhythmogeneicity induced by agents which modify cell coupling. Multi-site simultaneous electrograms will be recorded from ventricular myocardium and from the infarcted region that has undergone occlusion and reperfusion of the left anterior descending coronary artery three to four weeks prior to study. Body surface potentials will be signal averaged to analyze late potentials and programmed ventricular extrastimulation employed to measure refractoriness and test susceptibility to arrhythmias. Heptanol, which decreases cell coupling, and angiotensin II which increases cell coupling, will be introduced into the coronary circulation to determine their effects on conduction, the appearance of late potentials and susceptibility to arrhythmias. Parallel experiments in vitro on normal and infarcted epicardial tissues will evaluate the effects of these agents on anisotropy. Direct effects of these agents on gap junctional function will be evaluated using current and voltage clamps in isolated ventricular myocyte pairs. Similar experiments measuring conduction, late potentials, inducibility of arrhythmias will evaluate the effects of ischemia superimposed on pre- existing infarction. These studies correlated at three levels of experimentation (isolated myocytes, tissue preparation and in situ) will produce new basic information that is not only important in terms of understanding the basic electrophysiology of conduction but will also provide the experimental basis and theoretical rationale for designing new modes of antiarrhythmic therapy based on the manipulation of cell coupling; current antiarrhythmic agents are designed to alter membrane properties.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL033593-08
Application #
3345630
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1984-12-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Callans, D J; Moore, E N; Spear, J F (1996) Effect of coronary perfusion of heptanol on conduction and ventricular arrhythmias in infarcted canine myocardium. J Cardiovasc Electrophysiol 7:1159-71
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Callans, D J; Kieval, R S; Hook, B G et al. (1992) Effect of coronary perfusion of heptanol or potassium on conduction and ventricular arrhythmias. Am J Physiol 263:H1382-9
Kieval, R S; Spear, J F; Moore, E N (1992) Gap junctional conductance in ventricular myocyte pairs isolated from postischemic rabbit myocardium. Circ Res 71:127-36
Kadish, A; Balke, C W; Levine, J F et al. (1989) Activation patterns in healed experimental myocardial infarction. Circ Res 65:1698-709
Levine, J H; Moore, E N; Kadish, A H et al. (1988) Mechanisms of depressed conduction from long-term amiodarone therapy in canine myocardium. Circulation 78:684-91
Moore, E N; Spear, J F (1988) Electrophysiologic studies on ventricular tachyarrhythmias in a chronic canine infarct model. J Electrocardiol 21 Suppl:S64-7
Levine, J H; Merillat, J C; Stern, M et al. (1987) The cellular electrophysiologic changes induced by ablation: comparison between argon laser photoablation and high-energy electrical ablation. Circulation 76:217-25
Levine, J H; Moore, E N; Weisman, H F et al. (1987) Depression of action potential characteristics and a decreased space constant are present in postischemic, reperfused myocardium. J Clin Invest 79:107-16

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