The overall objective of our studies is to test two hypotheses. The first is that the response of delayed afterdepolarization-induced triggered rhythms to a combination of specific pacing techniques and pharmacologic agents will permit the differentiation of such rhythms from those resulting from """"""""normal"""""""" or """"""""abnormal"""""""" automaticity, or early afterdepolarizations. (These experiments will be done using standard microelectrode techniques to study disaggregated cardiac cells and isolated cardiac tissues.) Our second hypothesis is that the combination of pacing techniques and use of a matrix of pharmacologic agents (identified during the testing of hypothesis [1]) will enable us to differentiate triggered from reentrant and automatic arrhythmias in the in situ heart. Here, we will use standard electrophysiologic techniques and epicardial and endocardial mapping. We believe that the identification of mechanisms for arrhythmias not only is possible using the combination of electrophysiologic and pharmacologic techniques proposed, but that the improvement of our ability to understand and identify mechanism through this approach will be of benefit in the future design of antiarrhythmic drugs, as well as in the planning of antiarrhythmic therapy. To attain our objective we shall conduct electrophysiologic and pharmacologic studies in a series of systems of increasing complexity. The least complex model to be used from the point of view of arrhythmogenesis is the disaggregated cell. The response of arrhythmogenic mechanisms in such cells to pacing and to selected pharmacologic agents having different spectra of antiarrhythmic activity will be identified. The same approach will then be used in studies of isolated Purkinje, ventricular and coronary sinus fibers, and - finally - in intact animals. The method will involve developing """"""""rules"""""""" describing the behavior of delayed and of early afterdepolarization-induced triggered activity in response to pacing and to drugs; contrasting these to the """"""""rules"""""""" that describe the behavior of normal and abnormal automatic arrhythmias and of reentry; and then, having tested the specificity of these rules, applying them to the study of arrhythmias in the intact animal. This would provide a final test of the accuracy of the rules in the intact heart before their application to human studies. We believe that the combined use of electrophysiologic testing and a matrix of antiarrhythmic drugs and antibodies will satisfy our goals and will contribute in a useful way to the understanding and eventual treatment of arrhythmias in the clinic.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL028223-07
Application #
3339648
Study Section
Cardiovascular Study Section (CVA)
Project Start
1982-01-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Rosen, M R; Cohen, I S (2006) Molecular/genetic determinants of repolarization and their modification by environmental stress. J Intern Med 259:7-23
Binah, O; Rosen, M R (1992) Mechanisms of ventricular arrhythmias. Circulation 85:I25-31
Tseng, G N; Boyden, P A (1991) Different effects of intracellular Ca and protein kinase C on cardiac T and L Ca currents. Am J Physiol 261:H364-79
Molina-Viamonte, V; Anyukhovsky, E P; Rosen, M R (1991) An alpha-1-adrenergic receptor subtype is responsible for delayed afterdepolarizations and triggered activity during simulated ischemia and reperfusion of isolated canine Purkinje fibers. Circulation 84:1732-40
Anyukhovsky, E P; Rosen, M R (1991) Abnormal automatic rhythms in ischemic Purkinje fibers are modulated by a specific alpha 1-adrenergic receptor subtype. Circulation 83:2076-82
Viamonte, V A; Rosen, M R (1990) Premature escape beats induced by overdrive pacing in canine Purkinje fibers. Evidence for the role of normal automaticity as an underlying cellular mechanism. Circulation 82:234-43
Zaza, A; Kline, R P; Rosen, M R (1990) Effects of alpha-adrenergic stimulation on intracellular sodium activity and automaticity in canine Purkinje fibers. Circ Res 66:416-26
Zaza, A; Malfatto, G; Rosen, M R (1989) Electrophysiologic effects of ketanserin on canine Purkinje fibers, ventricular myocardium and the intact heart. J Pharmacol Exp Ther 250:397-405
Leichter, D; Danilo Jr, P; Boyden, P et al. (1988) A canine model of torsades de pointes. Pacing Clin Electrophysiol 11:2235-45
Rosen, M R (1988) Mechanisms for arrhythmias. Am J Cardiol 61:2A-8A

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