Metabolic/Electrophysiological Model of the Heart under Ischemia/Reperfusion

描述(申请人提供)：心脏性猝死(SCD)通常归因于室颤，这是一种致命的心律失常，导致心脏不协调收缩。实验证明，心肌细胞在缺血再灌流条件下，其电兴奋性可被降低或消除。其机制涉及一系列的心肌细胞功能衰竭，在代谢应激条件下，活性氧(ROS)的产生增加，降低甚至消除心肌细胞的兴奋性。实验证据表明，心肌内这些不可兴奋的区域可以阻止电兴奋的传播。然而，代谢应激区的3D分布如何影响心脏的电生理行为仍不清楚。利用多尺度综合代谢和电生理的全心模型，为深入研究缺血再灌流条件下心律失常的发生机制提供了可能。这项研究的总体目标是研究整个心脏的代谢和电生理过程之间的耦合如何在缺血和再灌流下导致心律失常的风险。为了实现这一目标，我将从磁共振成像(MRI)和扩散张量磁共振成像(DTMRI)、电生理记录和线粒体代谢数据中开发和验证新的生物物理、代谢和解剖详细的豚鼠整个心脏电导计算模型。这些模型将被用来检验这样的假设，即代谢下沉(代谢诱导的不兴奋区域)促进再入，从而导致心律失常的产生。该模型克服了现有实验技术无法同时记录高空间和时间分辨率的心脏三维电活动和代谢活动的缺陷。从这项研究中获得的新见解有望最终导致识别ICD候选对象的选择标准的改进，以及对抗心律失常的新诊断和治疗程序的开发。这与NHLBI的任务有关，该任务旨在支持调查心脏病原因和治疗的基础研究。具体目的如下：1)利用MRI和DTMRI重建豚鼠心脏的几何形态、纤维结构和片层方向。结合成像数据、电生理记录和线粒体生物能量学数据，开发和验证电和代谢耦合的详细高分辨率豚鼠心脏三维计算模型。2)利用在特定目标下建立的计算模型1，探讨在缺血-再灌注条件下局部线粒体解偶联导致豚鼠心脏形成折返回路的机制。

DESCRIPTION (provided by applicant): Sudden Cardiac Death (SCD) is often attributed to ventricular fibrillation, a lethal arrhythmia that results in uncoordinated contraction of the heart. Experiments have demonstrated that the cardiac myocyte electrical excitability can be reduced or eliminated during conditions of ischemia and reperfusion. The mechanism involves a series of failures in myocyte function, in which increased production of reactive oxygen species (ROS) during conditions of metabolic stress reduces or even eliminates myocyte excitability. Experimental evidence has demonstrated that these inexcitable regions within the myocardium could block propagation of electrical excitation. However, how the 3D distribution of metabolically-stressed regions affects the electrophysiological behavior of the heart remains unknown. Utilizing multi-scale integrated metabolic and electrophysiological whole heart models could provide an opportunity to dissect the mechanisms for arrhythmia generation under the conditions of ischemia and reperfusion. The overall objective of this research is to address the ways in which coupling between metabolic and electrophysiological processes in the whole heart contribute to the risk of arrhythmia under ischemia and reperfusion. To achieve this objective, I will develop and validate, from magnetic resonance imaging (MRI) and diffusion-tensor magnetic resonance imaging (DTMRI), electrophysiological recordings, and mitochondrial metabolic data, novel biophysically-, metabolically- and anatomically-detailed computational models of electrical conduction in whole guinea pig hearts. These models will be used to test the hypothesis that the metabolic sinks (regions of metabolically- induced inexcitability) promote reentry and thus contribute to the generation of arrhythmia. The development of a validated realistic model of metabolic and electrophysiological processes under ischemia and reperfusion overcomes the inability of current experimental techniques to simultaneously record the 3D electrical and metabolic activity of the heart with high spatial and temporal resolution. The new insights gained from this study are expected to ultimately lead to improvement in the selection criteria for identifying ICD candidates, and in the development of novel diagnostic and therapeutic procedures for combating arrhythmias. This relates to the NHLBI mission to support basic research that investigates the causes and treatments of heart disease. The specific aims are as follows 1) Use MRI and DTMRI to reconstruct the geometry, fiber and sheet orientation of guinea pig hearts. Combine the imaging data, electrophysiological recordings, and mitochondrial bioenergetics data, to develop and validate electrically and metabolically coupled detailed high-resolution 3D computational models of guinea pig hearts. 2) Using the computational models developed under Specific Aim 1; investigate the mechanisms by which regional mitochondrial uncoupling under the conditions of ischemia- reperfusion results in the formation of reentrant circuits in the guinea pig heart.