Inflammatory Bowel Disease-Induced Inflammation Potentiates Atrial Fibrillation Risk

炎症性肠病引起的炎症会增加心房颤动的风险

• 批准号: 10606410
• 负责人: Andres F Pelaez
• 金额: $ 4.77万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606410
• 关键词: Acetylcholine; Action Potentials; Affect; Age; Agonist; Area; Arrhythmia; Atrial Fibrillation; Atrial Function; Atrophic; Attenuated; Autonomic nervous system; Carbachol; Cardiac Myocytes; Cardiovascular system; Cells; Chronic; Cicatrix; Colitis; Colon; Connexin 43; Connexins; Data; Development; Disease; Disease Progression; Disease remission; Dose; EKG P Wave; Electrocardiogram; Electrophysiology (science); Ensure; Event; Exhibits; Extravasation; Female; Fibrosis; Flare; Frequencies; Gastrointestinal tract structure; Genetic Predisposition to Disease; Goals; Heart; Heart Atrium; Heart Rate; Heterogeneity; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-6; Intestines; Length; Link; Mentorship; Messenger RNA; Modeling; Mucous Membrane; Mus; Muscarinic Acetylcholine Receptor; Muscarinic M2 Receptor; Muscarinics; Muscle Cells; Myopathy; Nerve; Patient risk; Patients; Perfusion; Persons; Rectum; Refractory; Research; Research Project Grants; Risk; Scientist; Signal Pathway; Signal Transduction; Sodium Channel; Structure; TNF gene; Testing; Time; Tissues; Training Technics; Ulcerative Colitis; Up-Regulation; Weight; Work; attenuation; cholinergic; comorbidity; dextran sulfate sodium induced colitis; gut dysbiosis; gut inflammation; gut microbiota; heart function; heart rate variability; high risk; in vivo; inflammatory marker; intestinal barrier; male; microbiota; microbiota metabolites; mouse model; preservation; rectal; response; success; systemic inflammatory response; tibia

PROJECT ABSTRACT Atrial fibrillation (AF) is the most common sustained arrhythmia that is estimated to affect over 40 million people worldwide. Increases in atrial electrophysiological (action potential duration dispersion, altered conduction velocity) and structural heterogeneity (fibrosis, scarring) can increase the risk for AF. The cause for AF is unknown, but a variety of factors such as genetic predisposition, age, cardiovascular co-morbidities, inflammatory diseases can increase its risk. Ulcerative colitis (UC), a subtype of inflammatory bowel disease, was recently shown to increase a patient’s risk for AF. UC is an intestinal inflammation within the colon and rectum of the gastrointestinal tract (GIT) that promotes gut dysbiosis. Patients with active colitis have a two-fold increased risk for AF, and even in remission exhibit changes in atrial excitation and contraction that show atrial remodeling. Yet, the mechanism with which UC increases the risk for AF remains undetermined and is the focus of my project. Preliminary data in a mouse model of active colitis show an attenuated vagal tone, increased sensitivity of the muscarinic acetylcholine receptor M2 (M2R) to cholinergic signaling, and prolonged atrial conduction. These changes are reversible during remission, but in the chronic colitis model are maintained along with a reduction in the heart/atrial weight, atrial myocyte size and electrophysiological and structural remodeling of the atria. Based on my pilot data I propose to test the overall hypothesis that UC-induced dysregulation of vagal nerve activity increases the risk for AF during UC disease progression. To test this hypothesis, I will use a mouse model of active and chronic colitis. Aim 1 will examine the mechanism by which the risk for atrial arrhythmic activity is increased during active colitis. In a mouse model of active colitis, I will determine if AF occurrence is a consequence of a dysregulation in vagal signaling, promoting electrophysiological heterogeneity. Aim 2 will determine the mechanism by which UC induces an exaggerated response of the heart to cholinergic signaling. I will examine if a UC-induced attenuated vagal tone promotes an upregulation of atrial cardiomyocyte M2R expression. Aim 3 will examine the mechanism by which the risk for atrial arrhythmic activity is increased during chronic colitis. In a mouse model of chronic colitis, I will determine if AF occurrence is a consequence of an increase in structural heterogeneity. The proposed work will elucidate a mechanism in which AF risk is increased during UC disease progression. Successful completion of the proposed research would provide an understanding of the interplay between the heart, GIT and ANS, and allow for a one possible mechanism of AF to be determined. The findings will lay the groundwork for the creation of a translational treatment for one of the diseases associated with UC. The research project will be guided by an exceptional team of sponsors that are well-suited to provide the proper training of the techniques needed to complete the research, mentorship, and to ensure short-term and long-term success of the trainee. The proposed work will also promote my ability to execute a scientific project and development as an independent scientist.

项目摘要 心房颤动（AF）是最常见的持续性心律失常，估计会影响超过4000万人 全世界。心房电生理学的增加（动作电位持续时间分散，导出改变 速度）和结构异质性（纤维化，疤痕）可以增加AF的风险。 AF的原因是 未知，但多种因素，例如遗传倾向，年龄，心血管合并症， 炎症性疾病可以增加其风险。溃疡性结肠炎（UC），炎症性肠病的亚型， 最近被证明会增加患者的AF风险。 UC是结肠内的肠道炎症， 胃肠道（GIT）的直肠促进肠道营养不良。活性结肠炎患者有两个倍 增加了AF的风险，甚至在缓解中也揭示了心房兴奋和收缩的变化，这表明房屋 重塑。然而，UC增加AF风险的机制仍然不确定，是重点 我的项目。活性结肠炎的小鼠模型中的初步数据显示迷走神经张力，增加 毒蕈碱乙酰胆碱受体M2（M2R）对胆碱能信号的敏感性，并延长心房 这些变化在缓解过程中是可逆的，但是在慢性结肠炎中沿着 随着心脏/截骨重量，心肌大小以及电生理和结构重塑的减少 中心。根据我的试点数据，我提出了测试加州大学诱导失调失调的总体假设 迷走神经活动会增加UC疾病进展过程中AF的风险。为了检验这个假设，我将使用 AIM 1将检查房屋风险的机制 活性结肠炎期间心律不齐的活性增加。在活性结肠炎的小鼠模型中，我将确定是否AF是否 发生是迷走神经传导失调的结果，促进电生理异质性。 AIM 2将确定UC诱导心脏对胆碱能的反应的机制 信号。我将检查UC引起的衰减迷走神经张力是否促进了心房心肌细胞的上调 M2R表达。 AIM 3将检查心房心律不齐活性风险的机制 在慢性结肠炎期间。在慢性结肠炎的小鼠模型中，我将确定发生AF是否发生 结构异质性的增加。拟议的工作将阐明AF风险的机制 UC疾病进展过程中的增加。成功完成拟议的研究将提供 了解心脏，git和ANS之间的相互作用，并允许一种可能的AF机制 要确定。这些发现将为创建一种转化处理奠定基础 与UC相关的疾病。该研究项目将由一个杰出的赞助商团队指导 非常适合提供完成研究，指导和 确保学员的短期和长期成功。拟议的工作还将促进我的能力 作为独立科学家执行科学项目和发展。