Atrial Remodeling and Susceptibility to Fibrillation

心房重塑和颤动的易感性

• 批准号: 10619520
• 负责人: Thao P. Nguyen
• 金额: $ 43.04万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10619520
• 关键词: Accounting; Action Potentials; Address; Aging; Animal Model; Arrhythmia; Atherosclerosis; Atrial Fibrillation; Behavior; Cardiac Myocytes; Cell Lineage; Cell Separation; Cells; Clinical; Clinical Research; Closure by clamp; Communication; Complex; Computational Biology; Coupling; Data; Dementia; Deposition; Development; Electrophysiology (science); Elements; Epidemic; Etiology; Evolution; Fibroblasts; Fibrosis; Functional disorder; Future; Gap Junctions; Gene Expression; Genetic Transcription; Genomics; Goals; Health Care Costs; Heart Atrium; Heart failure; High Prevalence; Human; Hypertension; Intervention; Knowledge; Laboratories; Link; Maintenance; Mathematics; Mission; Modeling; Morbidity - disease rate; Muscle Cells; Myofibroblast; Natural History; Obesity; Oryctolagus cuniculus; Pathway interactions; Patients; Pattern; Phase; Pre-Clinical Model; Predisposition; Prevalence; Prevention strategy; Preventive; Preventive therapy; Process; Public Health; Rattus; Reproducibility; RiboTag; Risk; Risk Factors; Role; Source; Stress; Stroke; Testing; Therapeutic; Tissues; United States National Institutes of Health; Ventricular; Work; clinically relevant; design; disability; epidemiology study; innovation; interdisciplinary approach; lifetime risk; mortality; myocardial injury; novel; patch clamp; pre-clinical; public health relevance; response; single-cell RNA sequencing; synergism; transcriptome; virtual

PROJECT SUMMARY Long before the onset of permanent AF, AF risk factors promote fibrotic remodeling with ensuing progressive atriomyopathy. After the onset of permanent AF, electrical remodeling and transcriptional remodeling have occurred. Mechanisms underlying how these three remodeling processes relate to one another and to the evolution of AF from susceptibility in the clinical phase to permanence in the clinical phase are unknown. If the critical gap of knowledge regarding the cellular determinants of preclinical electrical remodeling is not elucidated, golden opportunities for intervention with risk-modifying and preventive therapies provided by the long preclinical phase of AF will remain missed. The long-term goal is to discover a novel preventive strategy for permanent AF. The overall objective in this application is to determine whether myocyte electrical remodeling is the final common pathway in preclinical atriomyopathy that increases the vulnerability of atrial myocytes to arrhythmia triggers and consequently of the fibrotic atrial tissue to AF. The central hypothesis is that whereas fibrosis initiates the preclinical phase of AF susceptibility, subsequent electrical remodeling is critical to transition from the preclinical to clinical phase of AF permanence. This hypothesis is formulated based on compelling preliminary data from the applicant's six novel robust and clinically relevant rat and rabbit models of AF susceptibility and permanence. An integrative multidisciplinary approach that incorporates technical innovations in electrophysiology, genomics, and computational biology will be used to test a novel, transformative mechanistic concept. Two aims are proposed to define how myofibroblast- and myocyte-centric mechanisms work independently and in synergy with stress to contribute to AF development and maintenance. Specifically, each aim is designed to determine whether preclinical electrical remodeling of atrial myocytes is caused by myocyte-myofibroblast electrical communication (Aim 1) and/or (2) remodeling of the gene expression of critical myocyte ionic currents (Aim 2). Both mechanisms will be investigated in the absence and presence with stress synergy. The proposal is significant because it will identify potential targets for early risk-modifying intervention in the preclinical phase. The study is conceptually innovative because we introduce six novel robust animal models of AF susceptibility and permanence and advance the novel mechanistic concept of atrial AP ventricularization as a driver for the transformation of AF from susceptibility to permanence. The study is also technically innovative because it will generate the first RiboTag rat model, the first single cell transcriptomic profiling using 10x Genomics for cardiomyocytes, and the first dynamic clamp application in atrial tissue.

项目摘要 在永久性AF发作之前，AF危险因素在随后的进步中促进纤维化重塑 心房病。永久AF发作后，电重塑和转录重塑具有 发生。这三个重塑过程与彼此之间以及与 AF从临床阶段的易感性从临床阶段的永久性的演变尚不清楚。如果是 关于临床前电重塑的细胞决定因素的知识的关键差距未阐明，而是 长期临床前提供的风险改造和预防疗法的黄金机会 AF的阶段将仍然错过。长期的目标是发现一种新型的预防策略。 本应用的总体目的是确定心肌电气重塑是否是最终常见 临床前术中的途径增加了心肌对心律不齐的触发因素的脆弱性和 因此，纤维化心房组织到AF。中心假设是纤维化启动 AF敏感性的临床前阶段，随后的电重塑对于从临床前的过渡至关重要 到AF持续性的临床阶段。该假设是根据引人入胜的初步数据提出的 申请人的六个新型鲁棒和临床相关的大鼠以及AF敏感性和持久性的兔子模型。 一种综合多学科方法，结合了电生理学，基因组学的技术创新， 计算生物学将用于测试一种新颖的变革性机械概念。两个目标是 提议定义肌纤维细胞和以心肌细胞为中心的机制如何独立起作用，并与 压力为AF开发和维护做出贡献。具体而言，每个目标旨在确定 心肌细胞的临床前电重塑是否是由肌细胞肌纤维细胞电气引起的 通信（AIM 1）和/或（2）重塑临界肌细胞离子电流的基因表达（AIM 2）。 在不存在应力协同作用的情况下，将研究两种机制。该提议是 意义重大，因为它将确定临床前阶段早期风险改良干预的潜在目标。 该研究在概念上具有创新性 永久性并推进了房屋AP心室的新型机械概念，作为驱动程序的驱动力 AF从易感性转变为持久性。这项研究在技术上也是创新的，因为它将 生成第一个Ribotag大鼠模型，这是使用10倍基因组学的第一个单细胞转录组学分析 心肌细胞，以及在心房组织中的第一个动态夹具。

项目成果

Revisiting Antiarrhythmic Drug Therapy for Atrial Fibrillation: Reviewing Lessons Learned and Redefining Therapeutic Paradigms.

• DOI: 10.3389/fphar.2020.581837
• 发表时间: 2020
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Geng M;Lin A;Nguyen TP
• 通讯作者: Nguyen TP

Adult zebrafish ventricular electrical gradients as tissue mechanisms of ECG patterns under baseline vs. oxidative stress.

成年斑马鱼心室电梯度作为基线与氧化应激下心电图模式的组织机制。

• DOI: 10.1093/cvr/cvaa238
• 发表时间: 2021
• 期刊: Cardiovascular research
• 影响因子: 10.8
• 作者: Zhao,Yali;James,NicholasA;Beshay,AshrafR;Chang,EileenE;Lin,Andrew;Bashar,Faiza;Wassily,Abram;Nguyen,Binh;Nguyen,ThaoP
• 通讯作者: Nguyen,ThaoP

Constructing Adult Zebrafish Einthoven's Triangle to Define Electrical Heart Axes.

• DOI: 10.3389/fphys.2021.708938
• 发表时间: 2021
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Zhao Y;Chen C;Yun M;Issa T;Lin A;Nguyen TP
• 通讯作者: Nguyen TP

Proarrhythmic Electrical Remodeling by Noncardiomyocytes at Interfaces With Cardiomyocytes Under Oxidative Stress.

• DOI: 10.3389/fphys.2020.622613
• 发表时间: 2020
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Zhao Y;Iyer S;Tavanaei M;Nguyen NT;Lin A;Nguyen TP
• 通讯作者: Nguyen TP