: Abnormalities in ventricular repolarization contribute importantly to the pathogenesis of life-threatening arrhythmias. This research program seeks to improve our understanding of the prognostic significance of and the autonomic mechanisms underlying repolarization abnormalities in patients with LV dysfunction.T wave alternans (TWA) is a 2:1 fluctuation in the amplitude or shape of T wave that has been linked to the genesis of ventricular arrhythmias. We have previously demonstrated that TWA is associated with spontaneous arrhythmic events in patients undergoing an EP study. Two large prospective epidemiologic studies are proposed in this grant designed and powered to definitively test the hypotheses that TWA is associated with an increased risk of having an arrhythmic event in patients with LV dysfunction (1) who have not yet had an arrhythmic event, and (2) who present with syncope. These epidemiologic studies will be combined with mechanistic studies designed to characterize autonomic modulation of repolarization in patients with LV dysfunction. We previously demonstrated in healthy subjects that isoproterenol was associated with longer QT intervals and greater U wave amplitude at a given heart rate compared to atropine. A series of studies are proposed to explore how sympathetic-parasympathetic interactions modulate repolarization, and to distinguish two aspects of the effects of 13-blockers on repolarization: direct effects and long-term effects on autonomic balance. Taken together, these studies will establish a new set of methods for evaluating the autonomic modulation of repolarization in different disease states and in response to drugs. The support from this K24 will enable the applicant to devote a substantial amount of effort towards developing this research as part of a comprehensive program to mentor clinical investigators. This program will include an intensive clinical research experience, didactic courses, training in data presentation and grant writing. A Critical Review Committee of experts will advise and monitor the progress of the research fellows in the program. Columbia University and its affiliated medical center represent one of the largest referral centers anywhere for patients with both heart failure and arrhythmias, and have active training programs in Epidemiology and Biostatistics which will be invaluable to the applicant in accomplishing the Aims of this proposal and in training junior investigators in patient-oriented research.
