Role of epicardial adiposity as a local mediator of VT/VF dynamics in donor human hearts

项目总结： 在美国，每年有30万人因室性快速性心律失常而猝死。这个 大多数病例中这些心律失常的机制是室性心动过速(VT)和/或 室颤(VF)。不断增长的肥胖率也给我们带来了沉重的负担 卫生保健系统的发病率和死亡率都在增加。重要的是，肥胖与 与肥胖增加相关的心脏性猝死风险增加的心律失常。 然而，肥胖导致室性心律失常(VT/VF)的机制仍然存在 不完全理解。在这份提案中，我计划使用多模式和多规模的方法来 描述与持续性肥胖有关的供者心脏VT/VF的特征。在指导阶段 在这个项目中，我将使用供体心脏来研究心外膜肥胖症在促进VT/VF中的作用 旁分泌信号，同时还接受生物信息学和脂肪细胞生物学的专门培训。在 在这个项目的独立阶段，我将使用供体心脏来研究心外膜肥胖症在 产生致心律失常的触发器。下面概述的实验将增进我们对 VT/VF机制，也可作为未来实验的概念验证，旨在开发新的 在临床环境中预测和治疗室速/室颤易损性的标志物。

Project Summary: Ventricular tachyarrhythmias are responsible for 300,000 sudden cardiac deaths a year in the US. The mechanisms underlying these arrhythmias in the majority of cases are ventricular tachycardia (VT) and/or ventricular fibrillation (VF). The ever-increasing prevalence of obesity also poses a significant burden on the health care system with increased morbidity and mortality. Importantly, obesity has been associated with cardiac arrhythmias with increased risk of sudden cardiac death linked to increased adiposity. However, the mechanisms by which obesity could result in ventricular arrhythmias (VT/VF) remain incompletely understood. In this proposal, I plan to use a multimodal and multiscale approach to characterize VT/VF in donor human hearts associated with sustained obesity. In the mentored phase of this project, I will use donor hearts to investigate the role of epicardial adiposity in promoting VT/VF via paracrine signaling, while also getting specialized training in bioinformatics and adipocyte biology. In the independent phase of this project, I will use donor hearts to investigate the role of epicardial adiposity in generating arrhythmogenic triggers. The experiments outlined below will advance our understanding of VT/VF mechanisms and also serve as proof-of-concept for future experiments designed to develop new markers to predict and treat VT/VF vulnerability in a clinical setting.