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

心外膜脂肪作为供体心脏中 VT/VF 动态局部调节因素的作用

• 批准号: 10160949
• 负责人: Kedar Kirtikumar Aras
• 金额: $ 9.91万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-07 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160949
• 关键词: Adipose tissue; Anatomy; Anti-Inflammatory Agents; Arrhythmia; Bioinformatics; Body mass index; Calcium; Cardiac; Catecholamines; Categories; Clinical; Coupling; Data; Development; Down-Regulation; Fatty acid glycerol esters; Future; Genetic Transcription; Healthcare Systems; Heart; Heart failure; Human; Hyperactivity; IL6 gene; Incidence; Inflammation; Inflammatory; Interleukin-6; Isoproterenol; Knowledge; Link; Mediating; Mediator of activation protein; Mentors; Molecular; Morbidity - disease rate; Obesity; Optics; Organ; Overweight; Paracrine Communication; Phase; Physiological; Play; Predisposition; Prevalence; Risk; Risk Factors; Role; Site; Stimulus; Tachyarrhythmias; Testing; Tissues; Toll-like receptors; Training; Up-Regulation; Ventricular; Ventricular Arrhythmia; Ventricular Fibrillation; Ventricular Premature Complexes; Ventricular Tachycardia; Western Blotting; adipocyte biology; adiponectin; base; calmodulin-dependent protein kinase II; cytokine; design; experimental study; insight; mortality; multimodality; next generation sequencing; novel marker; obesity treatment; paracrine; sudden cardiac death; transcriptome; transcriptome sequencing

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.

项目摘要： 在美国，心律不齐的心律不齐每年造成300,000次心脏死亡。这 这些心律不齐的机制在大多数情况下是心室心动过速（VT）和/或 心室纤颤（VF）。肥胖的不断增长也给 发病率和死亡率增加的医疗保健系统。重要的是，肥胖已经关联 心脏心律不齐，心脏死亡的风险增加与肥胖增加有关。 但是，肥胖可能导致心室心律不齐（VT/VF）的机制仍然存在 不完全理解。在此提案中，我计划使用多模式和多尺度方法 表征与持续肥胖相关的供体人心中的VT/VF。在指导阶段 这个项目，我将使用供体心来调查心外膜肥胖在促进VT/VF通过的作用 旁分泌信号传导，同时还接受了生物信息学和脂肪细胞生物学方面的专门培训。在 这个项目的独立阶段，我将使用供体心来研究心外膜肥胖的作用 产生心律失常触发器。下面概述的实验将提高我们对 VT/VF机制，还可以作为未来实验的概念证明 在临床环境中预测和治疗VT/VF漏洞的标记。