Atrial Fibrillation in Aging Heart: Role of Senescent Atrial Cells

衰老心脏中的心房颤动：衰老心房细胞的作用

• 批准号: 10345318
• 负责人: GIDEON KOREN
• 金额: $ 26.05万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10345318
• 关键词: Ablation; Address; Adult; Affect; Age; Aging; Animal Model; Anti-Inflammatory Agents; Arrhythmia; Atrial Fibrillation; Biological Markers; Biopsy; Cardiac; Cardiac Surgery procedures; Cartoons; Cell Aging; Cell physiology; Cells; Characteristics; Clinical Trials; Complex; DNA Damage; Disease; Electrocardiogram; Fibroblasts; Fibrosis; Future; Gamma-H2AX; Genetic; Goals; Growth Factor; Health Benefit; Heart; Heart Atrium; Heterogeneity; Hospitalization; Human; Incidence; Inflammation; Inflammatory; Inflammatory Response; Investigation; Lead; Left atrial structure; Longevity; Maintenance; Maps; Mediating; Metalloproteases; Molecular; Molecular Profiling; Mus; Muscle Cells; Myofibroblast; Optics; Organ; Oryctolagus cuniculus; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Play; Population; Prevalence; Procedures; Process; Prognosis; Prospective Studies; Research; Research Personnel; Right atrial structure; Risk; Role; Sampling; Serum; Sinus; Somatic Cell; Stains; Stretching; Stroke; Telomere Shortening; Testing; Tissues; United States; Walking; age group; aged; aging population; auricular appendage; base; beta-Galactosidase; biological adaptation to stress; cell type; chemokine; cost; cytokine; cytotoxic; genotoxicity; in vivo; inflammatory marker; lifetime risk; mortality risk; mouse model; novel; novel therapeutics; prevent; senescence; stressor; transcriptome sequencing

The most common arrhythmia in the aging population is atrial fibrillation (AF), which carries an estimated lifetime risk of 25% after the age of 40 years. Cellular senescence is a stress response that is characterized by an irreversible loss of proliferative capacity, accompanied by a complex senescence-associated secretory phenotype (SASP) that can have profound effects on neighboring cells in the tissue. Our research plan is based on the following premises: Cellular senescence of atrial myocytes (AMs) and atrial cardiac fibroblasts (ACMFs) plays an important role in fibrosis, inflammation and arrhythmogenesis. The overarching hypothesis of our proposal is that atrial cell senescence is an important component of atrial aging and the increase incidence of AF. Specifically, we postulate that in the aging human (and rabbit) atrium, the interplay between aging and senescent AMs that have a lower threshold for arrhythmogenic activity and together with senescent ACMFs leads to fibrosis and the triggering of AF. This R21 proposal brings together several investigators with very different expertise to investigate mechanisms of AF in the aging heart, using a novel age-appropriate large animal model (rabbit), and human samples obtained from explanted hearts and right atrial appendage. In Aim 1 the Koren group will investigate the aging rabbit atria, as compared to the young atria, and correlate the arrhythmogenesis with molecular and cellular analysis of AMs and ACMFs. Senescence will be manipulated in vivo under Aim1 using pharmacologic approaches. Optical mapping of hearts ex vivo will be used to study arrhythmogenesis. In Aim 2 the group will study human explanted atria as well as tissue and AMs obtained from right atrial appendages during open heart surgery. In summary, we envision that by understanding the aging mechanisms that control cellular senescence we will be able to reduce fibrosis and the incidence of AF.

老年人口中最常见的心律失常是心房颤动(AF)，据估计 40岁以后终生风险为25%。细胞衰老是一种应激反应，其特征是 不可逆转的增殖能力丧失，伴有复杂的衰老相关分泌 表型(SASP)，可对组织中的邻近细胞产生深远影响。我们的研究计划是 基于以下前提：心房肌细胞(AM)和心房成纤维细胞的细胞衰老 (ACMFS)在纤维化、炎症和心律失常的发生中起重要作用。最重要的假设 我们的建议之一是，心房细胞衰老是心房衰老的重要组成部分，而 房颤的发生率。具体地说，我们假设在衰老的人(和兔)的心房中， 衰老和衰老的AM具有较低的致心律失常活动阈值，并伴有衰老 ACMFS导致纤维化和房颤的触发。这份R21提案将几名调查人员聚集在一起， 使用一种新的与年龄相适应的方法来研究老化心脏中房颤的机制 大动物模型(兔)，以及取自移植心脏和右心耳的人类样本。在……里面 目的1韩国研究小组将研究老龄兔的心房，并与年轻的心房进行比较。 AM和ACMFS的分子和细胞分析与心律失常的发生。衰老将被操控在 Aim1下的活体使用药理学方法。体外心脏光学标测将用于研究 心律失常。在目标2中，研究小组将研究人类移植的心房以及获得的组织和AM 在心内直视手术中从右心耳。总而言之，我们设想通过理解 控制细胞衰老的衰老机制，我们将能够减少纤维化和房颤的发生率。