Cardiac Autonomic Activation In Atrial Fibrillation Triggers And Substrate

心房颤动的心脏自主激活触发因素和基质

• 批准号: 10636441
• 负责人: Francisco Altamirano
• 金额: $ 80.3万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636441
• 关键词: Ablation; Acute; Adult; Affect; Afferent Neurons; Animal Model; Animals; Apnea; Arrhythmia; Atrial Fibrillation; Atrial Function; Automobile Driving; Autonomic nervous system; Basic Science; Blood; Blood Circulation; Blood Vessels; Blood specimen; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiac ablation; Chronic; Chronic Disease; Clinical Sciences; Clinical Trials; Clinical assessments; Coculture Techniques; Congestive Heart Failure; Coronary Circulation; Coronary sinus structure; Data; Dementia; Development; Diagnostic; Economic Burden; Electrophysiology (science); Engineering; Epidemic; FDA approved; Ganglia; Gene Expression; Genomics; Goals; Guidelines; Healthcare; Heart; Heart Atrium; Heart failure; Human; Innovative Therapy; Knowledge; Longevity; Maintenance; Measures; Mediating; Methods; MicroRNAs; Molecular; Morbidity - disease rate; Myocardial; Nerve; Neurons; Output; Pathogenesis; Patients; Peptide Initiation Factors; Play; Positioning Attribute; Predisposition; Prevalence; Prevention strategy; Procedures; Recurrence; Refractory; Reporting; Research; Research Priority; Risk; Risk Factors; Role; Route; Sampling; Sleep Apnea Syndromes; Substance P; Syncope; System; Technology; Testing; Therapeutic; Tissues; United States National Institutes of Health; Veins; antagonist; canine model; cardiac tissue engineering; care burden; diagnostic tool; effective therapy; human pluripotent stem cell; improved; induced pluripotent stem cell; innovation; insight; mortality; neural; neuroregulation; novel; paracrine; peripheral blood; prevent; response; sensory system; stroke risk; targeted treatment; temporal measurement; treatment strategy

PROJECT SUMMARY/ABSTRACT Atrial fibrillation (AF) is the most common sustained adult arrhythmia, associated with an increased risk of stroke, heart failure and dementia. With increased longevity in chronic diseases, the prevalence of AF – currently estimated at 46 million worldwide – is dramatically rising. Catheter ablation – tissue destruction – is the most effective therapy but is fraught with procedural risks and suboptimal efficacy. The cardiac autonomic system (CANS) is known to be involved in the pathogenesis of AF, but no specific diagnostic or therapeutic approaches have evolved from this. Our long-term goal is to devise neuromodulatory AF treatment and preventive strategies and fill the knowledge gap on the mechanisms by which CANS neuronal and humoral paracrine output modulate atrial function in humans. We break through existing technical barriers that limited our understanding of intrinsic cardiac ganglia, capitalizing on the vein of Marshall as a vascular route to sample its electrophysiology and humoral responses, collecting atrial coronary circulation blood, and recording nerve activity from the ganglionated plexi (GP). Our extensive preliminary data in patients shows that apnea increases GP activity measured using novel percutaneous technology in AF patients undergoing ablation procedures. Remarkably, we found that Substance P (SP) collected from the coronary sinus is elevated compared to undetectable levels in peripheral blood of AF patients suggesting that GP activation via secreted SP may play a role in AF substrates. In large animal models, we have found that specific ablation of GP sensory neurons blunts the pro-fibrillatory response to apnea and that a crescendo GP response occurs after repeated consecutive apneas. Our data in human pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCM) shows that chronic SP treatment affects cardiomyocyte electrophysiology and modifies gene expression of miR-21 targets. These exciting observations, innovative methods, and unique clinical and basic science expertise position our team to develop this project successfully. We propose the central hypothesis that CANS produces a substrate for AF through neural (nerve firing) and humoral effects (secretome), in which SP – released by GP sensory neurons – plays a major role in increasing susceptibility to AF through direct electrophysiological and genomic effects in atrial cardiomyocytes. The central hypothesis will be tested by pursuing studies 1) in humans with paroxysmal and persistent AF aiming to measure nerve activity and secretome of intrinsic ganglia through the vein of Marshall during ablation procedures, 2) in canine models of acute and persistent AF to determine whether ablation of GP or SP antagonism ameliorates AF, 3) in hiPSC-aCM and engineered atrial tissues to elucidate SP actions. The proposed research is significant because it is expected to provide a mechanistic understanding of the relationship between CANS and sleep apnea for the continued development of effective therapies against AF. Ultimately, such knowledge can offer new opportunities to develop innovative therapies to treat AF.

项目总结/摘要 心房颤动（AF）是最常见的持续性成人心律失常，与卒中风险增加相关， 心力衰竭和痴呆随着慢性病患者寿命的延长，AF的患病率-目前 估计全球有4600万人-正在急剧上升。导管消融-组织破坏-是最 有效的治疗，但充满了手术风险和次优疗效。心脏自主神经系统 已知CANS参与AF的发病机制，但尚无特异性诊断或治疗方法 都是从这个进化而来的。我们的长期目标是设计神经调节性房颤治疗和预防策略 填补了CANS神经元和体液旁分泌输出调节机制的知识空白 人类的心房功能我们突破了现有的技术障碍，限制了我们对内在的理解。 心脏神经节，利用马歇尔静脉作为血管路线对其电生理学进行采样， 体液反应，收集心房冠状动脉循环血液，并记录神经活动， 神经节丛（GP）。我们在患者中的大量初步数据显示，呼吸暂停增加GP活性 在接受消融术的房颤患者中使用新型经皮技术进行测量。值得注意的是， 我们发现，从冠状窦收集的P物质（SP）与检测不到的水平相比有所升高， 提示通过分泌的SP激活GP可能在AF底物中起作用。 在大型动物模型中，我们发现特异性消融GP感觉神经元可使促炎性神经元钝化， GP反应在呼吸暂停后逐渐增强，并且在重复连续呼吸暂停后发生GP反应逐渐增强。我们的数据 人多能干细胞衍生的心房心肌细胞（hiPSC-aCM）显示，长期SP治疗影响 心肌细胞电生理学和修饰miR-21靶基因表达。这些令人兴奋的观察， 创新的方法和独特的临床和基础科学专业知识使我们的团队能够开发这个项目 成功地我们提出了中心假设，即CANS通过神经元产生AF的底物， （神经放电）和体液效应（分泌组），其中SP-由GP感觉神经元释放-发挥作用。 在通过直接电生理和基因组效应增加房颤易感性中的主要作用， 心房心肌细胞中心假设将通过以下研究进行验证：1）在患有阵发性 持续性房颤，旨在通过马歇尔静脉测量神经活动和内神经节分泌物 在消融术过程中，2）在急性和持续性AF的犬模型中，以确定是否消融GP 或SP拮抗作用改善AF，3）在hiPSC-aCM和工程化心房组织中阐明SP作用。的 拟议的研究是重要的，因为它有望提供一个机制的理解的关系， CANS和睡眠呼吸暂停之间的关系，以继续开发有效的AF治疗方法。最终， 这些知识可以为开发治疗AF的创新疗法提供新的机会。