The treatment of ischemic and non-ischemic cardiac arrhythmias depends largely on empiricism. In part this is because electrocardiographic diagnosis relies as much on an understanding of phenomenology as on the actual mechanisms that underlie arrhythmias. This, in turn, reflects the fact that there are major gaps in our understanding of the mechanisms that induce arrhythmias in cardiac cells and their expression in the intact heart. The proposed research is directed at two areas that relate to these problems: the mechanisms underlying normal and abnormal impulse initiation, and the role of autonomic modulation in the expression of arrhythmias. We intend to concentrate on alpha adrenergic modulation of arrhythmias - especially in ischemia; and on developing means for discriminating among arrhythmogenic mechanisms to benefit clinical diagnosis and treatment. Two major hypotheses will be tested: (1) The alpha adrenergic receptor-effector system contributes importantly to abnormal impulse initiation during ischemia and reperfusion; (2) By using pacing protocols and a matrix of cardioactive drugs we can identify the mechanisms underlying arrhythmias, understand their manifestations in the intact heart, and treat them. Fifteen specific aims and subhypotheses are proposed. All relate to the identification of normal and abnormal automaticity and of early and delayed afterdepolarizations and resultant triggered activity. For hypothesis (1) the contributions of a adrenergic stimulation (and the consideration of beta and muscarinic interactions) are considered. For hypothesis (2) the use of pacing and cardioactive drugs to differentiate among mechanisms are considered. The experiments incorporate techniques that permit us to study mechanisms at the levels of the cell and channel, of isolated tissues, of biochemical modulators, and of intact animals. Moreover, there is application of a matrix of cardioactive drugs and pacing that has shown promise in diagnosis at the level of the intact heart. Through this combined approach, using basic and clinical electrophysiologic techniques, together with biochemical and biophysical methods, we believe we shall improve our understanding of mechanism and our application of this understanding to diagnosis, prevention and therapy of arrhythmias.
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