The Systems Biology of Sudden Cardiac Death

描述（由申请人提供）：心源性猝死（SCD）仍然是西方世界的主要死因。据估计，美国每年约有10-20%的死亡率是由SCD引起的，大约5%的中年美国人口有SCD的显著易感性。35岁及以上成人SCD的主要原因是冠状动脉疾病（CAD; ~ 80%）和扩张型心肌病（~10-15%），风险随着年龄的增长而急剧增加。虽然植入式心律转复除颤器（ICD）已被证明可有效降低SCD的发生率，但在大量患者人群中大规模部署ICD在经济上是不切实际的，并且忽略了这样一个事实，即大多数植入ICD的患者可能永远不需要ICD，而且目前还没有有效的方法来识别SCD风险最高的患者。从上到下（全心脏光学标测、解剖重建和模拟）和自下而上（线粒体和细胞成像和建模），我们的目标是达到前所未有的结构和功能的整合水平，以便理解和模拟在以下条件下，肌细胞中代谢和电生理过程之间的耦合导致心律失常风险的方式：代谢应激我们称之为代谢汇假说。群集项目1将检验代谢汇可能通过在完整灌注的豚鼠（GP）心脏中产生IKATP激活的局部区域而形成的假设，并将评估其对心室传导和心律失常产生的影响。群集项目2将检验代谢应激心肌特别容易形成代谢汇导致心力衰竭背景下心律失常的假设。集群项目3将开发新的生物药理学，代谢和解剖学详细的电传导计算模型，并与集群项目1和2，测试假设的方式，其中代谢和电生理功能之间的相互作用有助于代谢应激条件下产生心律失常。代谢汇假说从未通过在心肌局部区域产生线粒体的代谢解偶联和测量对电传导和心律失常产生的影响来直接检验。衰竭的心肌细胞是否易受代谢振荡的影响，衰竭的组织是否比正常组织更易或更不容易形成代谢汇，以及代谢汇是否形成衰竭心肌中折返的基质尚不清楚。本项目将测试这些假设，其结果将对我们理解心律失常的机制和治疗具有重要意义。

DESCRIPTION (provided by applicant): Sudden Cardiac Death (SCD) remains a leading cause of death in the western world. Estimates suggest that roughly 10-20% of all annual mortality in the U.S. results from SCD and that approximately 5% of the middle-aged U.S. population has a significant predisposition to SCD. The major causes of SCD in adults age 35 and older are coronary artery disease (CAD; ~ 80%) and dilated cardiomyopathy (~10-15%), with risk increasing dramatically with age. While implantable cardioverter defibrillators (ICDs) are proving to be effective in reducing the occurrence of SCD, wholesale deployment of ICDs in large patient populations is impractical economically and ignores the facts that the majority of patients with ICDs are likely never to require them and that there are as yet no effective means for identifying patients at highest risk for SCD. Working both from the top-down (whole heart optical mapping, anatomical reconstruction and simulation) and from the bottom up (mitochondrial and cellular imaging and modeling), our aim is to achieve an unprecedented level of integration of structure and function in order to understand and model the ways in which coupling between metabolic and electrophysiological processes in the myocyte contribute to risk of cardiac arrhythmias under conditions of metabolic stress. We refer to this as the metabolic sink hypothesis. Cluster Project 1 will test the hypothesis that metabolic sinks may be formed by producing local regions of IKATP activation in the intact-perfused guinea pig (GP) heart and will assess their impact on ventricular conduction and arrhythmia generation. Cluster Project 2 will test the hypothesis that metabolically stressed myocardium is particularly susceptible to formation of metabolic sinks leading to arrhythmia in the setting of heart failure. Cluster Project 3 will develop novel biophysically, metabolically and anatomically detailed computational models of electrical conduction and, in conjunction with Cluster Projects 1 & 2, test hypotheses regarding the ways in which the interplay between metabolic and electrophysiological function contributes to generation of arrhythmias under conditions of metabolic stress. The metabolic sink hypothesis has never been tested directly by producing metabolic uncoupling of mitochondria in local regions of myocardium and measuring effects on electrical conduction and generation of arrhythmias. Whether or not failing myocytes are susceptible to metabolic oscillations, whether or not failing tissue is more or less susceptible to formation of metabolic sinks than is normal tissue, and whether or not metabolic sinks form a substrate for reentry in failing myocardium is unknown. This project will test these hypotheses and the results will have major importance for our understanding of the mechanisms and treatment of arrhythmias.