Mechanical stretch and fibrillation dynamics in the left atrium

左心房的机械拉伸和颤动动力学

• 批准号: 7652416
• 负责人: Jerome Kalifa
• 金额: $ 26.6万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652416
• 关键词: Acute; Adult; Area; Arrhythmia; Atrial Fibrillation; Chronic; Complex; Congestive Heart Failure; Data; Dilatation - action; Dyes; Endoscopes; Evolution; Fibrosis; Frequencies; Heart; Heart Atrium; Heart failure; Lead; Left; Left atrial structure; Link; Location; Maintenance; Maps; Mechanics; Mitral Valve Insufficiency; Modeling; Myocardial; Natural regeneration; Nature; Optics; Patients; Pattern; Peptides; Play; Property; Pulmonary veins; Role; Ryanodine; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Secondary to; Sheep; Site; Source; Stretching; Surface; Techniques; Testing; Therapeutic; Time; Ventricular; Ventricular Dysfunction; interstitial; novel; pressure; research study

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.

描述（由申请人提供）：心房颤动（AF）是成人最常见的心律失常，与心房扩张相关，可急性或慢性。然而，心房扩张与房颤发生和/或维持之间的确切机制尚不清楚。最近的数据表明，左后心房（PLA）和肺静脉（PV）区域在阵发性和慢性心房颤动患者中有不同的作用。我们的总体目标是研究PLA的慢性结构重塑作为底物的作用，以控制急性和/或慢性心房拉伸对离体羊心脏AF维持的电生理机制的影响。此外，我们将研究PLA- pv区心肌牵张激活通道（SACs）是否专门参与急性或慢性牵张相关房颤发作的启动和维持。具体目的1是确定急性心房牵张条件下PLA区房颤驱动因子在延长房颤发作中的演变。我们将利用一个具有良好特征的兰根多夫灌注羊心脏急性心房拉伸模型和一种新型内窥镜耦合光学成像装置来可视化PLA心内膜表面和其他完整左心房部位的电活动。我们假设，如果心房内压力急剧增加，房颤源加速，变得更加稳定，并被限制在与PV交界处附近的PLA的有限区域内。在具体目标2中，我们将使用类似的测绘技术来研究二尖瓣反流（MR）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的增加，这些房颤源可能广泛分布于左心房。在具体目标3中，我们将利用一个过速诱发的慢性充血性心力衰竭（HF）模型来表征慢性拉伸和结构（广泛纤维化）重构的心房左房源的动力学。我们假设慢性扩张型心衰心房的广泛间质纤维化减少了房颤源的频率，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产生的波的纤颤传导的复杂性会增加。从我们提出的实验中获得的结果应该有助于促进对房颤扩张性心房机制的理解，并可能导致对患者的治疗改善。