Mechanistic Determinants of Pacing-induced Cardiac Memory

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DESCRIPTION (provided by applicant): "Cardiac memory" refers to T wave changes during sinus rhythm or atrial pacing whose vectors track those of the QRS complexes during prior intervals of ventricular pacing or arrhythmia. The importance of cardiac memory is not only in its clinical impact with regard to cardiac pacing therapies and rhythm control but in its provision of a window for translating mechanisms that control repolarization from molecular determinant to human expression. Studying cardiac memory lets us follow activation-initiated repolarization changes recorded from the body surface ECG and VCG, through repolarization maps of the cardiac surface, action potentials in epicardium, midmyocardium and endocardium, the component gap junctions and ion channels that influence excitation and repolarization, and through the signaling molecules and gene transcription and its translation that appear mechanistically responsible for waveforms recorded on ECG and VCG. Every step in this translational sequence is considered in our research protocols, which are both reductionist (asking question regarding molecular mechanism) and integrative (synthesizing this information for the heart in situ). Of particular importance is that the T wave changes studied reflect a property of myocardial repolarization to remodel reversibly or irreversibly. And remodeling is a fundamental response of the heart to physiologic and pathologic stresses. To date, our research has emphasized long-term cardiac memory, induced by days- weeks of pacing and dependent-at least in part - on altered gene transcription for its occurrence and persistence. However, recent experiments have provided important leads impacting on our understanding of both short-term memory (induced by minutes-hours of pacing) and its transition to long-term memory. Hence the overall goal for our 5 year renewal application: is to understand mechanisms (a) initiating short-term cardiac memory, (b) determining the transition from short- to long-term memory and (c) determining maintenance and reversal of long-term memory. Our general hypotheses are that ventricular pacing alters myocardial stretch regionally to (a) initiate short-term memory via trafficking of ion channels and (b) initiate transcriptional changes whose downstream expression leads to long-term cardiac memory. We further hypothesize that (c) these changes are regional in their expression and can be modified or reversed. Studies will be performed in our intact canine model, in isolated cardiac tissues, in disaggregated myocytes and in a cell line. Although we use a variety of techniques from diverse disciplines, the research is electrophysiologically-driven. Rather than being reductionist, the approach attempts to synthesize information so that we can better comprehend and impact on a clinically important problem.