The System Biology of Sudden Cardiac Death

心脏性猝死的系统生物学

• 批准号: 7480250
• 负责人: Gordon Frank Tomaselli
• 金额: $ 33.24万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480250
• 关键词: Adult; Age; Arrhythmia; Cause of Death; Cavia; Computer Simulation; Condition; Coronary Arteriosclerosis; Coupling; Dilated Cardiomyopathy; Doctor of Medicine; Generations; Heart; Heart failure; Implantable Defibrillators; Instruction; Lead; Maps; Measures; Metabolic; Metabolic stress; Mitochondria; Modeling; Muscle Cells; Myocardium; Normal tissue morphology; Optics; Patients; Population; Predisposition; Process; Research; Risk; Stress; Structure; Systems Biology; Testing; Tissues; Universities; Ventricular; Western World; Work; cellular imaging; middle age; mortality; novel; reconstruction; simulation; sudden cardiac death

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.

描述（由申请人提供）：心脏猝死（SCD）仍然是西方世界的主要死亡原因。估计表明，美国SCD的所有年死亡率约为所有年死亡率的10-20％，大约5％的中年美国人口对SCD具有很大的倾向。 35岁及以上成人SCD的主要原因是冠状动脉疾病（CAD； 〜80％）和扩张的心肌病（约10-15％），随着年龄的增长，风险急剧增加。虽然事实证明，植入可植入的心脏逆变器除颤器（ICD）有效地减少SCD的发生，但在较大的患者人群中ICD的批发部署在经济上是不切实际的，并且忽略了大多数ICD患者可能永远不会需要它们的事实，并且尚无有效识别SCD患者的有效手段。从自上而下的（整个心脏光学映射，解剖学重建和模拟）以及从底部（线粒体和细胞成像和建模）中工作，我们的目的是实现结构和功能整合水平的前所未有的水平，以理解和模型的循环介绍，从而贡献了造型的级别和电子生理生理学过程中的趋势。代谢压力。我们将其称为代谢水槽假说。群集项目1将检验以下假设：代谢水槽可能是通过在完整的豚鼠（GP）心脏中产生IKATP激活的局部区域形成的，并将评估其对心室传导和心律不齐的影响的影响。群集项目2将检验以下假设：在心力衰竭的情况下，代谢压力的心肌特别容易形成导致心律不齐的代谢下水道。群集项目3将通过生物物理，代谢和解剖学上的电导传导的计算模型开发新颖的计算模型，并与群集项目1和2结合进行测试假设，介绍了在代谢压力条件下，代谢和电生理功能之间的相互作用的方式有助于产生ARRHYTHMIA的产生。代谢下水道假说从未通过在心肌局部区域产生线粒体的代谢解偶联并测量对心律失常的影响和产生心律不齐的影响。是否易于肌细胞易受代谢振荡的影响，是否或多或少易于或多或少容易形成代谢下水道，而不是正常组织，以及是否形成代谢下的水槽，是否构成了损坏心肌的底物。该项目将检验这些假设，结果对于我们对心律不齐的机制和治疗的理解将具有重要的重要性。