The Systems Biology of Sudden Cardiac Death

描述(申请人提供)：心脏性猝死(SCD)仍然是西方世界的主要死因。据估计，美国每年约有10%-20%的死亡是由SCD引起的，大约5%的美国中年人口有明显的SCD易感性。在35岁及以上的成年人中，SCD的主要原因是冠状动脉疾病(约80%)和扩张型心肌病(~10%-15%)，风险随着年龄的增长而急剧增加。虽然植入式心脏转复除颤器(ICD)被证明在减少SCD的发生方面是有效的，但在大量患者中大规模部署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ICD患者可能永远不会需要ICD，而且到目前为止还没有有效的手段来识别SCD的高风险患者。我们的目标是从自上而下(全心光学标测、解剖重建和模拟)和自下而上(线粒体和细胞成像和建模)实现前所未有的结构和功能集成，以了解和模拟心肌细胞代谢和电生理过程之间的耦合如何在代谢应激条件下导致心律失常的风险。我们将其称为新陈代谢汇假说。集群项目1将测试这样的假设，即代谢汇可能是通过在完整灌流的豚鼠(GP)心脏中产生IKATP激活的局部区域而形成的，并将评估它们对心室传导和心律失常产生的影响。集群项目2将测试这样一种假设，即代谢应激的心肌特别容易在心力衰竭的情况下形成代谢下沉，导致心律失常。集群项目3将开发新的生物物理、代谢和解剖学上详细的电传导计算模型，并与集群项目1和2一起测试有关代谢和电生理功能之间的相互作用如何在代谢应激条件下导致心律失常的假说。代谢汇假说从来没有通过在心肌局部产生代谢解偶联的线粒体，以及测量对电传导和心律失常的影响来直接检验。衰竭心肌细胞是否对代谢振荡敏感，衰竭组织是否比正常组织更容易形成代谢槽，以及代谢槽是否形成衰竭心肌重入的底物，目前尚不清楚。该项目将检验这些假说，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.