Elucidating Mechanistic Relationships Between Atrial Ectopy, Atrial Remodeling and Atrial Fibrillation

阐明心房异位、心房重构和心房颤动之间的机制关系

• 批准号: 10641001
• 负责人: Edward Paul Gerstenfeld
• 金额: $ 80.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641001
• 关键词: Ablation; Affect; Age; American; Atrial Fibrillation; Atrial Premature Complexes; Benign; Calcium; Cardiac ablation; Cardiomyopathies; Case/Control Studies; Chronic; Clinic; Congestive Heart Failure; Coupled; Coupling; Data; Development; Early Intervention; Echocardiography; Electrophysiology (science); Fibrosis; Framingham Heart Study; Future; Health Care Costs; Heart Abnormalities; Heart Atrium; Heart failure; Histology; Holter Electrocardiography; Hour; Human; Individual; Laboratories; Lateral; Lead; Left; Left atrial structure; Link; Maintenance; Maps; Measurement; Mediating; Medical; Molecular; Molecular Profiling; Morbidity - disease rate; Myopathy; Palpitations; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pirfenidone; Prevention; Preventive therapy; Prospective, cohort study; Pulmonary veins; Quality of life; Recurrence; Research; Research Personnel; Risk; Series; Shortness of Breath; Source; Stress; Stroke; Symptoms; Testing; Time; Tissues; Ventricular; Ventricular Premature Complexes; Work; cardiovascular health; density; experience; experimental study; heart rhythm; hemodynamics; improved; lifestyle factors; mortality; novel; porcine model; prevent; transcriptome sequencing

Project Summary/Abstract The proposal seeks to establish a pathophysiologic link between premature atrial contractions (PACs) and atrial fibrillation (AF). It has been well established that patients with frequent PACs are more likely to develop incident AF. But whether PACs are causative, or an epiphenomenon, is unclear. We hypothesize that PACs from the pulmonary veins or lateral left atrium (LA) lead to more atrial dyssynchrony compared to PACs from other regions, and that this dyssynchrony leads to atrial structural remodeling (via increased wall stress) and fibrosis that serves to facilitate AF maintenance. Our preliminary data in a swine model of chronic PACs demonstrates that chronic PACs lead to atrial electrophysiologic (slow conduction) and structural (fibrosis) remodeling, which is more pronounced for dyssynchronous PACs from the lateral left atrium compared to synchronous PACs from the septum or controls without PACs. In our first Aim, we will explore in the swine model how differences in PAC coupling- interval and atrial rate affect the degree of atrial remodeling and whether PAC cessation leads to complete regression of remodeling. We will test whether an antifibrotic drug, pirfenidone, prevents adverse atrial structural and electrical remodeling in the presence of PACs. We will also assess which molecular changes precede the development of cardiomyopathy to determine the critical molecular pathways leading to PAC mediated atrial remodeling. In our second Aim, we will establish the importance of these findings in humans by performing a longitudinal case-control study of patients with a high burden of atrial ectopy to identify if chronic PAC-induced atrial dyssynchrony leads to echocardiographic atrial remodeling. We will determine whether patients with frequent PACs have more echocardiographic left atrial remodeling and AF over time compared to those without PACs. We will also determine whether specifically dyssynchronous PACs are more likely to lead to atrial remodeling and AF than synchronous PACs. The significance of the proposed work is that if frequent PACs are found to lead to remodeling that leads to the development of incident AF, early intervention in patients with frequent PACs, with medical therapy or catheter ablation, may prevent the later development of atrial remodeling and AF. Successful prevention of AF could mean that millions of individuals could avoid debilitating loss of quality of life and enormous healthcare costs.

项目摘要/摘要 该提案旨在建立早产心房（PAC）和心房之间的病理生理联系 纤颤（AF）。已经很好地确定，经常患有PAC的患者更有可能出现事件 AF。但是，尚不清楚PAC是病因还是epiphenomenon。我们假设来自 与其他地区的PAC相比 并且这种非同步导致心房结构重塑（通过增加的壁应力）和纤维化。 促进AF维护。我们在慢性PACS猪模型中的初步数据表明了慢性 PACS导致心房电生理（缓慢传导）和结构（纤维化）重塑，这更多 与隔膜同步PAC相比 或没有PAC的控件。在我们的第一个目标中，我们将在猪模型中探索PAC耦合的差异如何 间隔和心房率会影响心房重塑的程度，以及PAC戒断是否导致完成 重塑的回归。我们将测试一种抗纤维化药物，吡啶酮，可防止不良心房结构 和在PAC存在的情况下进行电重塑。我们还将评估哪些分子变化先于 心肌病的发展以确定导致PAC介导心房的关键分子途径 重塑。在我们的第二个目标中，我们将通过执行一个 纵向病例对照研究，对心房外部负担高的患者进行了研究，以识别慢性PAC诱导的 心房异步导致超声心动图心房重塑。我们将确定是否频繁 与没有PAC的PAC相比，PAC的超声心动图左心房重塑和AF随着时间的流逝。我们 还将确定特定的异步PAC是否更有可能导致心房重塑和AF 比同步PAC。拟议工作的重要性是，如果发现频繁的PAC导致 改建导致发生AF的发展，对PAC经常患者的早期干预，患有 医疗疗法或导管消融可能会阻止心房重塑和AF的后来发展。成功的 预防AF可能意味着数百万个人可以避免使生活质量丧失和巨大 医疗保健费用。

项目成果

Frequent Premature Atrial Contractions Lead to Adverse Atrial Remodeling and Atrial Fibrillation in a Swine Model.

在猪模型中，频繁的心房过早收缩会导致不良的心房重塑和心房颤动。

• DOI: 10.1161/circulationaha.123.065874
• 发表时间: 2024
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Higuchi,Satoshi;Voskoboinik,Aleksandr;Im,SungIl;Lee,Adam;Olgin,Jeffrey;Arbil,Ayla;Afzal,Junaid;Marcus,GregoryM;Stillson,Carol;Bibby,Dwight;Abraham,Theodore;Wilson,Emily;Gerstenfeld,EdwardP
• 通讯作者: Gerstenfeld,EdwardP

Atrial and ventricular cardiomyopathy associated with premature atrial contractions: Speckle-tracking echocardiography demonstrates reversibility following successful ablation.

• DOI: 10.1016/j.hrcr.2022.01.001
• 发表时间: 2022-04
• 期刊: HeartRhythm case reports
• 作者: Higuchi, Satoshi;Kim, Eun-Jeong;Gerstenfeld, Edward P;Bibby, Dwight;Schiller, Nelson B;Hsia, Henry H
• 通讯作者: Hsia, Henry H