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.

老龄化人群中最常见的心律失常是心房颤动（AF），它带有估计的 40岁以后的终身风险为25％。细胞衰老是一种应力反应，其特征是 不可逆转的增殖能力丧失，伴随着复杂的衰老相关分泌 表型（SASP）可以对组织中的相邻细胞产生深远影响。我们的研究计划是 基于以下前提：心房心肌细胞（AMS）和心房成纤维细胞的细胞衰老 （ACMF）在纤维化，炎症和心律失常发生中起重要作用。总体假设 我们的建议是，心房细胞衰老是心房老化和增加的重要组成部分 AF的发病率。具体而言，我们假设在衰老的人（和兔）中庭中， 衰老和衰老AM具有较低的心律失常活动阈值，并且与衰老 ACMF会导致纤维化和AF的触发。该R21提案汇集了几位调查人员 使用新颖的年龄适中，以研究衰老心脏中AF的机制的非常不同的专业知识 大型动物模型（兔子）以及从外植的心脏和右心肢获得的人类样品。在 目标1与年轻的心房相比，科伦组将调查老化的兔子心房，并将其关联 心律失常，通过AM和ACMF的分子和细胞分析。衰老将被操纵 AIM1下使用药理方法的体内。心脏的光学映射将用于研究 心律失常。在AIM 2中，该小组将研究人类外养心房以及已获得的组织和AM 心脏手术期间的右心窝。总而言之，我们设想，通过了解 控制细胞衰老的老化机制，我们将能够降低纤维化和AF的发生率。