Defibrillation Mechanisms in Infarcted Hearts

描述（由申请人提供）：梗死心脏中的高度异质性结构基质可能对除颤机制有重大贡献。然而，梗死结构和存活细胞电生理学对电击后行为和除颤电击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的心室除颤机制提供一个新的理解水平。我们假设，梗死心室中易损性上限和除颤阈值的增加是由于1）梗死区域中虚拟电极极化的显著改变，这源于肌细胞和肌成纤维细胞对电击的不同反应，以及2）梗死区域中电击后传播的复杂模式，包括通过凹陷的边缘区区域的传播路径和通过富含成纤维细胞的瘢痕的传导。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，开发详细的高分辨率3D解剖学准确的bidomain模型：1）具有愈合梗死的孤立兔心室楔样制备物，2）具有愈合梗死的完整兔心室（特定目的1）。使用新的解剖学精确模型的孤立的准备，并结合微电极和光学记录从梗死区域，我们提出的特点虚拟电极极化和休克后传播模式在孤立的兔心室准备愈合梗死（具体目标2）。一旦研究了梗塞区的详细电击后行为，我们建议使用梗塞心室的真实模型结合全景光学标测实验，以确定易损性上限和除颤阈值的变化，并阐明导致这些变化的机制（具体目标3）。如在本申请中提出的，用于除颤的组合的紧密耦合的模拟/实验方法克服了当前实验技术在电击期间和之后不能解析限于心室壁深度的电行为的缺陷。通过本项目获得的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程序的合理而非试错进步。拟议的实验/模拟相结合的研究将阐明心肌梗死心脏心室除颤的机制，从而解决心脏除颤的临床方面的核心问题。这些机制的知识可以提出新的途径，以优化除颤程序或可能导致新的干预措施，降低除颤阈值的发展。

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.