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 该提案寻求在房性早搏和房性早搏之间建立一种病理生理联系。 房颤(AF)。众所周知，频繁发生PAC的患者更有可能发生突发事件 自动对焦。但PAC是因果现象，还是附带现象，目前尚不清楚。我们假设PAC来自 与其他区域的PAC相比，肺静脉或左侧心房(LA)导致更多的心房不同步性， 这种不同步性导致心房结构重构(通过增加的壁应力)和纤维化 以方便房颤的维护。我们在猪慢性PAC模型中的初步数据表明，慢性PAC PAC导致心房电生理(传导缓慢)和结构(纤维化)重构，这更多的是 与来自间隔的同步性PAC相比，左心房外侧的同步性PAC明显 或者没有PAC的控制。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- 间期和房率影响心房重构的程度以及PAC是否停止导致完全重构 重塑的消退。我们将测试抗纤维化药物吡非尼酮是否能预防不良的心房结构。 以及在PAC存在的情况下进行电气重塑。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介导的心房的关键分子通路 改建。在我们的第二个目标中，我们将通过执行一项 心房异位高负荷患者的纵向病例对照研究，以确定慢性PAC是否诱发 心房不同步性导致超声心动图心房重构。我们将确定患者是否经常患有 与无PAC组相比，PAC组随时间推移有更多的超声心动图左房重构和房颤。我们 也将确定是否特定的不同步PAC更有可能导致心房重构和房颤 而不是同步PAC。拟议工作的意义在于，如果发现频繁的PAC导致 导致偶发性房颤发生的重构，对频繁PAC患者的早期干预， 药物治疗或导管消融，可防止心房重构和房颤的后期发展。成功 房颤的预防可能意味着数百万人可以避免虚弱的生活质量损失和巨大的 医疗保健成本。

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