Defibrillation Mechanisms in Infarcted Hearts

描述(申请人提供)：梗死心脏中高度不均匀的结构底物对除颤机制有重要贡献。然而，梗死结构和存活细胞电生理学对休克后行为和除颤休克结局的作用从未被量化。本研究的总体目标是对心肌梗死条件下的室性除颤机制有一个新的认识。我们假设，梗死脑室易损性上限和除颤阈值的增加是由于1)梗死区虚拟电极极化的显著改变，源于心肌细胞和肌成纤维细胞对休克的不同反应，以及2)梗死区休克后传播的曲折模式，涉及通过凹陷的边缘区域的传播路径和通过富含成纤维细胞的疤痕的传导。为了验证这些假设，我们建议从磁共振成像、免疫组织化学和电生理学数据中建立详细的高分辨率3D解剖准确的兔脑室模型：1)愈合的梗塞的分离的兔脑室楔形标本，2)愈合的梗塞完整的兔脑室(特定目标1)。利用新的精确解剖模型，结合脑梗死区的微电极和光学记录，我们提出了在愈合的兔脑室梗塞中的虚拟电极极化和休克后传播模式的特征(特定目标2)。一旦研究了梗死区详细的休克后行为，我们建议使用梗死脑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(特定目标3)。在本申请中提出的结合紧密耦合的模拟/实验方法来除颤，克服了目前的实验技术无法解决在电击期间和之后限于室壁深度的电行为的问题。该项目对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理性进步，而不是反复尝试。拟议的实验/模拟联合研究将阐明心肌梗死患者心脏除颤的机制，从而解决除颤临床方面的核心问题。对这些机制的了解可能会为优化除颤程序提供新的途径，或者可能导致降低除颤阈值的新干预措施的开发。

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.