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: 7484207
• 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/7484207
• 关键词: Acute; Adult; Area; Arrhythmia; Atrial Fibrillation; Chronic; Complex; Condition; 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; Numbers; Optics; Pathological Dilatation; Patients; Pattern; Peptides; Play; Property; Pulmonary veins; Rate; Role; Ryanodine; Ryanodine Receptor Calcium Release Channel; Secondary to; Sheep; Site; Source; Stretching; Surface; Techniques; Testing; Therapeutic; Time; Ventricular; Ventricular Dysfunction; Week; 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.

说明(申请人提供)：房颤(房颤)是成人最常见的心律失常，与急性或慢性的心房扩张有关。然而，心房扩张与房颤的启动和/或维持有关的确切机制尚不清楚。最近的数据表明，在阵发性房颤患者和慢性房颤患者中，左房后区和肺静脉区起着不同的作用。我们的总体目标是研究作为控制急性和/或慢性心房牵张对绵羊心脏房颤维持的电生理机制影响的底物--解放军的慢性结构重塑的作用。此外，我们还将研究解放军-PV区的心肌牵张激活通道(SAs)是否特定地参与了急性或慢性牵张相关房颤发作的启动和维持。具体目标1是确定在急性心房牵拉条件下，解放军房颤驾驶员在延长房颤发作期间的演变。我们将利用一种具有良好特征的急性心房牵张的朗宁多夫灌流羊心模型和一种新型的内窥镜耦合光学标测装置来可视化解放军和其他完整的左房部位的心内膜表面的电活动。我们假设，如果房内压急剧增加，房颤源会加速，变得更稳定，并被限制在与肺静脉交界处附近的有限区域内。在特定目标2中，我们将使用类似的标测技术在二尖瓣返流(MR)绵羊心脏模型中研究慢性心房扩张的影响。我们推测，慢性心房扩张继发的心房重构导致潜在房颤源的数量增加，这些房颤源可能广泛分布于整个左房。在具体目标3中，我们将利用心动过速诱导的慢性充血性心力衰竭(HF)模型来表征慢性拉伸和结构性(广泛纤维化)重构的心房的左房来源的动力学特征。我们假设慢性扩张的心衰心房广泛的间质纤维化减少了房颤源的频率，有助于房颤源在解放军的稳定。然而，由于在HF中触发活动的倾向增加，我们预计从这种来源出现的波的纤颤传导的复杂性会增加。我们提出的实验结果将有助于促进对扩张的心房中房颤机制的理解，并可能导致患者的治疗改进。