Understanding the role of mitochondrial dysfunction in cardiac arrhythmias using a novel 3D panoramic optical mapping system

使用新型 3D 全景光学测绘系统了解线粒体功能障碍在心律失常中的作用

基本信息

批准号：
10394805
负责人：
Elaine Y Wan
金额：
$ 40.5万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10394805
关键词：
3-Dimensional Action Potentials Address Aging Anatomy Animal Model Area Arrhythmia Atrial Fibrillation Atrial Flutter Atrial Tachycardia Attenuated Cardiac Cardiac Myocytes Cations Clinical Complex DNA Sequence Alteration Dependovirus Detection Diabetes Mellitus Electrophysiology (science)Excision Fibrosis Gene Transfer Genes Goals Health Heart Heart Atrium Heart failure Heterogeneity Human Hypertension Image Individual Lead Light Mediating Methodology Mitochondria Modeling Modification Morbidity - disease rate Multimodal Imaging Mus Mutation Myocardial Infarction Optics Oxidative Stress Pathway interactions Pattern Physiologic pulse Process Proteins Reactive Oxygen Species Reporter Research Resolution Risk Factors Role Rotation Sinus Stroke System Testing Transgenic Mice Transgenic Organisms Variant Ventricular Ventricular Arrhythmia Ventricular Fibrillation Ventricular Tachycardia aging population catalase effective therapy experimental study grasp imaging system innovation mitochondrial dysfunction mortality mouse model novel optogenetics preservation prevent sudden cardiac death treatment strategy

项目摘要

ABSTRACT Cardiac arrhythmias are a major cause of morbidity and mortality, and are increasingly prevalent due to an aging population with diabetes, heart failure and hypertension. Atrial fibrillation (AF) and ventricular fibrillation (VF), are chaotic arrhythmias, whereas, atrial tachycardia (AT), atrial flutter (AFL) and ventricular tachycardia (VT) are more organized, focal or macro-reentrant arrhythmias. Our grasp of the specific mechanisms that allow for the cardiac substrate to harbor organized and/or chaotic rhythms is incomplete. Causative factors of arrhythmias include fibrosis, increased late Na+ current and increased reactive oxidative stress (ROS) causing augmented mitophagy, which is a process of eliminating defective mitochondria to maintain the overall health of the mitochondrial pool. Our methodological breakthrough is to use 3D panoramic anatomical and optical mapping, in conjunction with mitophagy detection to characterize the interplay amongst electrical activation, substrate heterogeneity due to fibrosis and mitophagy, and action potential duration (APD) heterogeneity. Our proposed concept is that larger or greater number of areas of fibrosis, APD heterogeneity and/or mitophagy will allow for more chaotic atrial or ventricular arrhythmias. By individually disrupting these pathways and defining the consequences on arrhythmogenesis, we will determine how these three processes are co-regulated or functionally inter-dependent. We crossed mice with a reporter Keima protein which detects mitophagy, together with two lines of transgenic mice with spontaneous and sustained AF, AFL, AT, VT and VF due to mutations in the human cardiac NaV1.5 channel gene SCN5A. This project presents an integrated experimental approach using (1) multi-modality imaging of whole hearts of murine models of Na+ overload with AF, AFL, AT, VT and VF or myocardial infarction induced VT/VF to understand the mechanisms of organized and chaotic atrial and ventricular arrhythmogenesis, (2) AAV delivery of mitochondrial catalase to reverse increased mitophagy after myocardial infarction and (3) optogenetics via AAV delivery of channelrhodopsin-2 into whole murine hearts and use of focused light stimulation to trigger, prevent and terminate atrial and ventricular arrhythmias. The proposed experiments are highly significant and innovative in that co-registered 3D panoramic imaging will allow us to dissect the mechanisms that drive organized and chaotic cardiac arrhythmias, which may lead to new and effective treatment strategies of cardiac arrhythmias.

抽象的心律失常是发病和死亡的主要原因，并且由于老龄化而日益普遍患有糖尿病、心力衰竭和高血压的人群。心房颤动（AF）和心室颤动（VF）是混乱性心律失常，而房性心动过速 (AT)、心房扑动 (AFL) 和室性心动过速 (VT) 更有组织性、局灶性或宏观折返性心律失常。我们对具体机制的掌握容纳有组织和/或混乱节律的心脏基质是不完整的。心律失常的致病因素包括纤维化、晚期 Na+ 电流增加和反应性氧化应激 (ROS) 增加，导致增强线粒体自噬，是消除有缺陷的线粒体以维持线粒体整体健康的过程线粒体池。我们的方法论突破是使用 3D 全景解剖和光学测绘，结合线粒体自噬检测来表征电激活、底物之间的相互作用由于纤维化和线粒体自噬导致的异质性，以及动作电位持续时间（APD）异质性。我们提出的概念是更大或更多数量的纤维化区域、APD异质性和/或线粒体自噬将允许更混乱的房性或室性心律失常。通过单独破坏这些途径并定义对心律失常发生的影响，我们将确定这三个过程如何共同调节或功能上相互依赖。我们将小鼠与检测线粒体自噬的报告基因 Keima 蛋白进行杂交两系转基因小鼠由于基因突变而患有自发性和持续性 AF、AFL、AT、VT 和 VF 人类心脏 NaV1.5 通道基因 SCN5A。该项目提出了一种综合实验方法使用 (1) 具有 AF、AFL、AT、VT 和 VF 的 Na+ 超载小鼠模型的全心脏多模态成像或心肌梗死引起的 VT/VF 了解有组织和混乱的心房和心房的机制室性心律失常发生，（2）AAV 递送线粒体过氧化氢酶以逆转后增加的线粒体自噬心肌梗死和（3）通过 AAV 将视紫红质通道蛋白 2 递送至整个小鼠心脏的光遗传学使用聚焦光刺激来触发、预防和终止房性和室性心律失常。拟议的实验非常重要且具有创新性，因为共同配准的 3D 全景成像将使我们能够剖析驱动有组织和混乱的心律失常的机制，这可能会导致新的和心律失常的有效治疗策略。