Defibrillation Mechanisms in Infarcted Hearts

描述（由申请人提供）：梗死心脏中高度异质的结构基质可能对除颤机制有重要贡献。然而，梗死结构和存活细胞电生理对休克后行为和除颤休克结果的作用从未被量化。本研究的总体目标是为心肌梗死条件下心室除颤的机制提供一个新的认识水平。我们假设，梗死心室易损上限和除颤阈值的增加是由以下原因造成的：1)梗死区虚电极极化的显著改变，源于肌细胞和肌成纤维细胞对电击的不同反应；2)梗死区休克后传播的复杂模式。包括通过边界凹陷区和富含成纤维细胞的疤痕传导的传播途径。为了验证这些假设，我们建议根据磁共振成像、免疫组织化学和电生理数据，建立详细的高分辨率3D解剖精确的双域模型：1)分离的梗死后兔心室楔形物，2)梗死后完整的兔心室（Specific Aim 1）。利用新的解剖精确模型，并结合梗死区域的微电极和光学记录，我们提出表征梗死愈合的离体兔心室制备中的虚拟电极极化和休克后传播模式（Specific Aim 2）。一旦研究了梗死区休克后的详细行为，我们建议使用梗死心室的真实模型结合全景光学映射实验，以确定易损上限和除颤阈值的变化，并阐明这些变化的机制（Specific Aim 3）。本应用中提出的结合紧密耦合的模拟/实验除颤方法，克服了当前实验技术无法解决在电击期间和之后仅限于心室壁深度的电行为的问题。通过该项目获得的关于除颤成功和失败的新见解有望最终导致心肌梗死患者除颤手术的理性而不是反复试验。本文提出的实验/模拟联合研究将阐明心肌梗死患者心室除颤的机制，从而解决除颤临床方面的核心问题。了解这些机制可能为优化除颤程序提供新的途径，或可能导致降低除颤阈值的新干预措施的发展。

DESCRIPTION (provided by applicant): 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.