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.
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