Mechanical stretch and fibrillation dynamics in the left atrium

描述（由申请人提供）：房颤（AF）是成人中最常见的心律失常，与心房扩张相关，可能是急性或慢性的。然而，心房扩张与房颤发生和/或维持的确切机制尚不清楚。最近的数据表明，左心房后壁（PLA）和肺静脉（PV）区域在心房扩张的阵发性与慢性AF患者中发挥不同的作用。我们的总体目标是研究PLA的慢性结构重构作为控制急性和/或慢性心房牵张对离体绵羊心脏AF维持的电生理机制的影响的底物的作用。此外，我们将研究PLA-PV区域中的心肌牵张激活通道（SAC）是否专门参与AF急性或慢性牵张相关发作的启动和维持。具体目标1是确定在急性心房牵张条件下PLA处AF驱动器在长期AF发作中的演变。我们将利用一个特征良好的Langendorff灌注羊心脏模型的急性心房牵张和一个新的内窥镜耦合光学映射设置可视化的电活动的endoorbital表面的PLA和其他完整的左心房网站。我们假设，如果心房内压力急剧增加，AF源加速，变得更加稳定，并局限于PLA与PV交界处附近的有限区域。在特定目标2中，我们将使用类似的标测技术研究二尖瓣返流（MR）绵羊心脏模型中慢性心房扩张的影响。我们假设继发于慢性心房扩张的心房重构导致潜在房颤源数量增加，可能广泛分布于左心房。在特定目标3中，我们将利用心率过速诱导的慢性充血性心力衰竭（HF）模型来表征长期伸展和结构（广泛纤维化）重塑心房中左心房源的动态特征。我们假设慢性扩张的HF心房中广泛的间质纤维化降低了AF源的频率，有助于其在PLA处的稳定。然而，由于HF中触发活动的倾向增加，我们预计从这些来源出现的波的解释性传导的复杂性增加。从我们提出的实验中获得的结果应该有助于促进对扩张心房中AF机制的理解，并可能导致患者治疗的改善。

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common arrhythmia in adults and is associated with atrial dilatation which may be acute or chronic. However, the precise mechanisms linking atrial distension to AF initiation and/or maintenance are unknown. Recent data suggest that the posterior left atrium (PLA) and the pulmonary veins (PV) region play different roles in paroxysmal vs. chronic AF patients who have dilated atria. Our general objective is to investigate the role of chronic structural remodeling of the PLA as a substrate controlling the effects of acute and/or chronic atrial stretch on the electrophysiological mechanisms of AF maintenance in isolated sheep hearts. In addition, we will investigate whether myocardial stretch-activated channels (SACs) in the PLA-PV region are specifically involved in the initiation and maintenance of acute or chronic stretch- related episodes of AF. Specific Aim 1 is to determine the evolution of AF drivers at the PLA over prolonged AF episodes under conditions of acute atrial stretch. We will utilize a well-characterized Langendorff-perfused sheep heart model of acute atrial stretch and a novel endoscope-coupled optical mapping set-up to visualize the electrical activity on the endocardial surface of the PLA and other intact left atrial sites. We hypothesize that, if intra-atrial pressure is acutely increased, AF sources accelerate, become more stable and are confined to a limited area of the PLA near a junction with a PV. In Specific Aim 2, we will use a similar mapping technique to investigate the effects of chronic atrial dilatation in a mitral regurgitation (MR) sheep heart model. We postulate that atrial remodeling secondary to chronic atrial dilatation leads to an increase in the number of potential AF sources, which may be widely distributed across the left atrium. In Specific Aim 3, we will utilize a model of tachypacing-induced chronic congestive heart failure (HF) to characterize the dynamics of left atrial sources in chronically stretched and structurally (extensive fibrosis) remodeled atria. We hypothesize that the extensive interstitial fibrosis in chronically dilated HF atria reduces the frequency of AF sources, contributes to their stabilization at the PLA. However, because of an increased propensity of triggered activity in HF, we expect an increase of the complexity of fibrillatory conduction of waves emerging from such sources. The results obtained from our proposed experiments should help advance the understanding of the mechanisms of AF in the dilated atria and could lead to therapeutic improvements for patients.