Metabolic/Electrophysiological Model of the Heart under Ischemia/Reperfusion

描述（由申请人提供）：心源性猝死（SCD）通常归因于心室颤动，这是一种致命的心律失常，导致心脏收缩不协调。实验证明，在缺血和再灌注条件下，心肌细胞电兴奋性可以降低或消除。该机制涉及肌细胞功能的一系列失败，其中在代谢应激条件下活性氧（ROS）的产生增加降低甚至消除肌细胞兴奋性。实验证据表明，心肌内的这些不可兴奋区域可以阻断电兴奋的传播。然而，代谢应激区域的3D分布如何影响心脏的电生理行为仍然是未知的。利用多尺度集成的代谢和电生理全心脏模型可以提供一个机会，解剖缺血和再灌注条件下心律失常的产生机制。这项研究的总体目标是解决的方式，在整个心脏的代谢和电生理过程之间的耦合有助于缺血和再灌注心律失常的风险。为了实现这一目标，我将开发和验证，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，新的生物，代谢和解剖学详细的计算模型的电传导在整个豚鼠心脏。这些模型将用于检验代谢汇（代谢诱导的不兴奋性区域）促进折返并因此促成心律失常产生的假设。缺血和再灌注下代谢和电生理过程的经验证的现实模型的发展克服了目前的实验技术无法同时记录具有高空间和时间分辨率的心脏的3D电和代谢活动。从这项研究中获得的新见解有望最终导致改善识别ICD候选人的选择标准，并开发新的诊断和治疗程序来对抗心律失常。这与NHLBI的使命有关，即支持调查心脏病病因和治疗方法的基础研究。具体目的如下：1）利用MRI和DTMRI重建豚鼠心脏的几何结构、纤维和片层取向。结合联合收割机的成像数据，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豚鼠心脏的详细的高分辨率三维计算模型。2)使用根据特定目标1开发的计算模型;研究缺血-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.