(Verbatim from the application): Accurate prediction and prevention of ventricular tachyarrhythmias would have a major impact on the survival of approximately 300,000 persons/year in the US. Yet, the current status of the field is such that further efforts at identification, comprehension and application of novel approaches are warranted. Therefore, the goal of the proposed studies is to seek new directions for understanding the fundamental plasticity of myocardium such that we can deliberately induce therapeutically beneficial remodeling. Our general hypothesis is that we can remodel ion channels and gap junctions to prevent the occurrence of potentially lethal arrhythmias. Our approach focuses on the modulation of cardiac memory, a non-pathological form of remodeling that can be induced by ventricular pacing or arrhythmias and that is associated with altered repolarization, refractoriness and gap junctional density and distribution. Our protocols focus on integration of basic mechanism and clinical expression in pursuing three aims: to determine (1) the mechanisms underlying cardiac memory-induced regional ventricular alterations in repolarization and refractoriness in normal and arrhythmic infarcted hearts and the interaction with antiarrhythmic drugs; (2) the electrophysiological significance of the remodeling of gap junctions associated with cardiac memory in normal and infarcted, arrhythmic hearts; and (3) the ionic and molecular determinants of the electrophysiologic changes that characterize cardiac memory. The model is the chronically instrumented canine with or without infarction which undergoes 3 weeks of cardiac pacing to induce memory, and is studied in a clinical surrogate (the conscious dog) using electrocardiographic and vectorcardiographic techniques. We use cardiac mapping to determine ventricular activation and repolarization characteristics in the setting of memory with and without infarction, microelectrode techniques to determine the cellular mechanisms responsible for the changes seen in the intact animal studies, and biophysical and molecular techniques to understand accompanying sarcolemmal ion channel and gap junctional changes with the intent of identifying the subcellular mechanisms responsible for memory and its interaction with arrhythmias. Incorporated in the proposal as well are experiments aimed at understanding the mechanisms responsible for the unpredictability of antiarrhythmic drug actions, which may be a consequence of drug-memory interactions. The overall approach is both reductionist (asking questions about mechanism at the subcellular level) and integrative. We believe it will permit us to understand and to modulate memory and arrhythmias predictably and reproducibly in a clinical setting based on the mechanistic information derived.
Showing the most recent 10 out of 75 publications
