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

项目总结/摘要 该提案旨在建立房性期前收缩（PAC）和心房颤动之间的病理生理学联系。 纤维性颤动（AF）。已经确定频繁PAC的患者更有可能发生事件 AF.但是，PAC是否是病因，还是一种附带现象，尚不清楚。我们假设， 肺静脉或侧左心房（LA）与来自其它区域的PAC相比导致更多的心房不同步， 并且这种不同步导致心房结构重构（通过增加壁应力）和纤维化， 以便于AF维护。我们在慢性PAC猪模型中的初步数据表明，慢性PAC PAC导致心房电生理（慢传导）和结构（纤维化）重构，这是更多的 与来自间隔的同步PAC相比，来自左心房外侧的不同步PAC明显 或者没有PAC的对照。在我们的第一个目标中，我们将在猪模型中探索PAC偶联的差异- 间隔和心房率影响心房重构的程度，以及PAC停止是否导致完全的 重塑的回归。我们将测试抗纤维化药物吡非尼酮是否可以预防不良心房结构， 和电重构的影响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介导的心房颤动的关键分子途径 重塑在我们的第二个目标中，我们将通过执行一个 对心房异位负荷高的患者进行纵向病例对照研究，以确定慢性PAC诱导的 心房不同步导致超声心动图心房重构。我们将确定患者是否经常 与无PAC的患者相比，PAC患者随时间推移的超声心动图左心房重构和AF更多。我们 还将确定是否特别不同步的PAC更可能导致心房重构和AF 比同步PAC更好拟议工作的意义在于，如果发现频繁的PAC会导致 导致AF事件发生的重构，频繁PAC患者的早期干预， 药物治疗或导管消融可以预防心房重构和AF的后期发展。 预防AF可能意味着数百万人可以避免生活质量的衰弱损失， 医疗费用。

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.