The highly heterogeneous structural substrate in the infarcted heart can have a major contribution to the mechanisms of defibrillation. However, the role of infarct structure and surviving cell electrophysiology on post-shock behavior and the outcome of the defibrillation shock have never been quantified. The overall objective of this research is to provide a new level of understanding of the mechanisms for ventricular defibrillation under the conditions of myocardial infarction. We hypothesize that increases in the upper limit of vulnerability and defibrillation threshold in the infarcted ventricles result from 1) dramatically altered virtual electrode polarization in the infarcted region, stemming from the different responses of myocytes and myofibroblasts to the shock, and 2) the convoluted pattern of post-shock propagation in the region of infarction, involving propagation pathways through depressed border zone regions and conduction through the fibroblast-rich scar. To test the hypotheses, we propose to develop, from magnetic resonance imaging, immunohistochemical, and electrophysiological data, detailed high-resolution 3D anatomically-accurate bidomain models of 1) isolated rabbit ventricular wedge-like preparations with healed infarction, and 2) intact rabbit ventricles with healed infarction (Specific Aim 1). Using the new anatomical-accurate model of the isolated preparation, and in combination with microelectrode and optical recordings from the region of infarct, we propose to characterize virtual electrode polarization and post-shock propagation patterns in the isolated rabbit ventricular preparation with healed infarction (Specific Aim 2). Once the detailed post-shock behavior of the infarct zone is investigated, we propose to use the realistic model of the infarcted ventricles in combination with panoramic optical mapping experiments, to determine the changes in the upper limit of vulnerability and defibrillation threshold and to elucidate the mechanisms responsible for these changes (Specific Aim 3). The combined tightly-coupled simulation/experimental approach to defibrillation, as proposed in this application, overcomes the inability of current experimental techniques to resolve electrical behavior confined to the depth of the ventricular wall during and after the shock. The new insights into the success and failure of defibrillation to be obtained by this project are expected to ultimately lead to rational rather than trial-and-error advancements in defibrillation procedure in patients with myocardial infarction. The proposed combined experimental/simulation research will elucidate the mechanisms for ventricular defibrillation in hearts with myocardial infarction, and will thus address a problem central to the clinical aspect of defibrillation. Knowledge of these mechanisms could suggest new routes to optimizing defibrillation procedure or could lead to the development of novel interventions that lower defibrillation threshold. ? ? ?
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