This Mentored Patient-Oriented Research Career Development Award application focuses on a program of research designed to study the intracardiac mechanisms underlying T-wave alternans (TWA) of the electrocardiogram in individuals with prior myocardial infarcts and depressed cardiac systolic function in order to improve its computation and therefore its ability to predict those who are at risk for ventricular tachycardia (VT) or fibrillation (VF). This work will build on the applicant?s prior research and training in clinical cardiology and invasive electro-physiology, as well as in basic science, computer science and numerical methods. The proposed research will test the hypothesis that programmed ventricular stimulation in patients with ischemic heart disease and left ventricular dysfunction induces proarrhythmic nonuniformities in ventricular repolarization, and results in redistribution of TWA late in the T-wave, and TWA phase reversal, that are detectable by novel analyses of the ECG. There are two specific aims: 1) To establish that an increased magnitude of TWA late in the T-wave and TWA phase reversal parallel changes in the endocardial dispersion of ventricular repolarization measured, using monophasic action potentials, during progressive programmed ventricular stimulation leading to the induction of VT/VF. 2) To prospectively test, in patients with ischemic heart disease and left ventricular dysfunction, the performance of a new index of myocardial electrical instability, derived from the data calibrating TWA late magnitude and phase to the dispersion of monophasic action potential duration obtained in the research performed to fulfill Specific Aim 1, in predicting the incidence of spontaneous VT/VF. The applicant will perform this work under the supervision and guidance of his Mentor, and with guidance from a Scientific Advisory Committee comprising experts in basic and clinical electrophysiology, in the interpretation of monophasic action potentials, in numeric modeling and signal processing, in statistics and in clinical research. This structured approach will ensure the successful completion of this project and, in this way, the development of the applicant into an independent clinician-investigator.
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