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: 10706970
• 负责人: GIDEON KOREN
• 金额: $ 21.63万
• 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/10706970
• 关键词: Ablation; Adult; Affect; Age; Aging; Animal Model; Anti-Arrhythmia Agents; 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; Left atrial structure; Longevity; Maintenance; Maps; Mediating; Metalloproteases; Molecular; Molecular Profiling; Mus; Muscle Cells; Myofibroblast; Optics; Organ; Oryctolagus cuniculus; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; 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; 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; pharmacologic; 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.

老年人群中最常见的心律失常是心房颤动（AF）， 40岁以后的终生风险为25%。细胞衰老是一种应激反应，其特征在于 增殖能力的不可逆丧失，伴随着复杂的衰老相关分泌性 表型（SASP），可以对组织中的相邻细胞产生深远的影响。我们的研究计划是 基于以下前提：心房肌细胞（AM）和心房心脏成纤维细胞的细胞衰老 ACMFs在纤维化、炎症和肿瘤发生中起重要作用。总体假设 我们认为心房细胞衰老是心房衰老的重要组成部分， 具体来说，我们假设在老年人（和兔子）心房中， 衰老和衰老AM具有较低的致炎活性阈值，并且与衰老AM一起， ACMF导致纤维化和AF的触发。这项R21提案汇集了几位研究者， 非常不同的专业知识，以调查AF的机制，在老龄化的心脏，使用一种新的年龄适当的 大动物模型（兔）和从心脏和右心房附件获得的人样品。在 目的1 Koren小组将研究老年兔心房，与年轻心房比较，并将 AM和ACMF的分子和细胞分析的肿瘤发生。衰老将被操纵在 在Aim 1下使用药理学方法进行体内试验。离体心脏的光学标测将用于研究 胚胎发生在目标2中，该小组将研究人类心房以及获得的组织和AM 心脏直视手术时右心房的附件总之，我们设想，通过了解 控制细胞衰老的衰老机制，我们将能够减少纤维化和AF的发病率。