ATRIAL FIBRILLATION AND ALTERNANS OF ACTION POTENTIAL DURATION

心房颤动和动作电位持续时间的交替

• 批准号: 8362804
• 负责人: Andrew D. McCulloch
• 金额: $ 3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362804
• 关键词: Ablation; Action Potentials; Address; Affect; Algorithms; Anatomy; Animals; Atrial Fibrillation; Biomedical Computing; Cicatrix; Complex; Computer Simulation; Data; Data Collection; Development; Electric Countershock; Electrophysiology (science); Funding; Grant; Heart Atrium; Heart failure; Heterogeneity; Human; In Vitro; Individual; Link; Maps; Modeling; Morbidity - disease rate; National Center for Research Resources; Patients; Pharmaceutical Preparations; Phase; Population; Principal Investigator; Property; Pulmonary veins; Research; Research Infrastructure; Resources; Shapes; Sinus; Site; Source; Stroke; Structure; Symptoms; Tissues; United States; United States National Institutes of Health; Ventricular Fibrillation; X-Ray Computed Tomography; computer studies; cost; digital; man; mortality; reconstruction; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. (A) OBJECTIVES Atrial fibrillation (AF) affects 2.2 million individuals in the United States, and is a major cause of stroke, heart failure and mortality (8). Maintaining sinus rhythm reduces symptoms and may prolong survival, yet remains difficult (1). Recent advances in ablation now make it possible to cure many patients with paroxysmal AF, whose episodes are self-limiting, by isolating triggers in the pulmonary veins (12, 14). Unfortunately, ablation is complex, and less successful in the large population with persistent AF, whose episodes require drugs or cardioversion to terminate (10). In this group, AF recurs post-ablation in > 50 %, requiring multiple ablations with attendant morbidity and mortality (5). Unfortunately, therapy is limited by a poor understanding of how, and under what conditions, AF occurs in humans. It is increasingly appreciated that structural heterogeneities or dynamic tissue properties may initiate fibrillation (33). Animal, in vitro and computational studies have shown that every-other-beat oscillations (alternans) in action potential duration (APD), may initiate ventricular fibrillation (33). Mechanistically, tissue heterogeneities such as scar, or dynamics such as steep restitution (i.e. "rate-response") of APD, conduction velocity (CV) that slows for a broad range of rates (36), may cause APD alternans. By exaggerating repolarization dispersion, particularly if discordant (33), APD alternans may be a direct mechanism for AF. Although APD alternans has yet to be linked with AF in animals or man, we have exciting preliminary data in humans showing APD alternans leading directly to reentrant AF. As a collaborative project of the NBCR this research will promote extensions to the development of Continuity and its anatomic and electrical models and patient-specific modeling algorithms that will permit greater integration with models of impulse conduction in the atria. Our central hypothesis is that Atrial Fibrillation in humans initiates from Alternans of Action Potential Duration (APD), that reflects steep restitution of atrial APD and broad restitution of regional conduction velocity, and explains AF near the pulmonary veins (PV) in paroxysmal AF but not persistent AF. This study marries sophisticated data collection in patients at AF ablation with unique state-of-the-art patient-specific computational modeling to address 3 Specific Aims. 1. To determine whether alternans of atrial action potential duration (APD), resulting from steep APD restitution or broad conduction velocity (CV) restitution, precedes the onset of Atrial Fibrillation. We will record multi-site monophasic action potentials (MAP) and CV from 64-128 bi-atrial basket poles at electrophysiologic study, with and without pharmacologic modulation, in atrial reconstructions guided by computed tomography in paroxysmal and persistent AF patients. 2. To determine whether the first beats of AF follow conduction block and reentry. We will use patient-specific structure-function data, from basket maps referenced to digital atrial anatomy, isochronal analysis and phase mapping. We will also determine if these sites lie near PVs in patients with paroxysmal AF but not persistent AF. 3. To determine whether AF is caused by atrial discordant APD alternans, by developing patient-specific computational models derived from clinically observed electrophysiology. We will develop finite-volume models that incorporate observed CV and APD restitution, atrial shape and structural heterogeneities for each patient, to compare modeled to actual AF in each patient.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 (一) 目标 心房颤动 (AF) 影响着美国 220 万人，是一种主要疾病 中风、心力衰竭和死亡的原因 (8)。维持窦性心律可减轻症状 并可能延长生存期，但仍然很困难 (1)。消融方面的最新进展现已使其成为可能 有可能治愈许多阵发性房颤患者，其发作具有自限性， 隔离肺静脉中的触发因素 (12, 14)。不幸的是，消融是复杂的，并且 在大量患有持续性房颤的人群中效果较差，其发作需要药物或 心脏复律终止(10)。在该组中，AF 消融后复发率 > 50%，需要 多次消融会导致发病率和死亡率 (5)。不幸的是，治疗是 由于对人类如何以及在什么条件下发生 AF 知之甚少，因此受到限制。 人们越来越认识到结构异质性或动态组织特性 可能引发颤动 (33)。动物、体外和计算研究表明 动作电位持续时间 (APD) 中的每隔一次心跳振荡 (alternans) 可能会引发 心室颤动 (33)。从机制上讲，组织异质性，例如疤痕或动力学 例如 APD 的陡峭恢复（即“速率响应”）、减慢的传导速度 (CV) 对于大范围的速率 (36)，可能会导致 APD 交替。通过夸大复极化 分散，特别是如果不一致 (33)，APD 交替可能是 AF 的直接机制。 尽管 APD alternans 尚未与动物或人类的 AF 联系起来，但我们有令人兴奋的发现 人类初步数​​据显示 APD 交替直接导致折返性房颤。作为一个 NBCR 的合作项目这项研究将促进开发的扩展 连续性及其解剖学和电气模型以及患者特定建模 算法将允许与脉冲传导模型更好地集成 心房。 我们的中心假设是，人类的心房颤动是由行动交替引发的 潜在持续时间 (APD)，反映心房 APD 的急剧恢复和心房 APD 的广泛恢复 区域传导速度，并解释阵发性肺静脉 (PV) 附近的 AF AF，但不是持续性 AF。这项研究结合了 AF 患者的复杂数据收集 使用独特的、最先进的针对患者的特定计算模型进行消融，以解决 3 具体目标。 1. 确定心房动作电位持续时间 (APD) 的交替是否由 陡峭的 APD 恢复或宽传导速度 (CV) 恢复，先于 心房颤动。 我们将记录多位点单相动作电位 (MAP) 和 CV 电生理学研究中的 64-128 个双心房篮杆，有或没有药理学 调制，在计算机断层扫描引导的心房重建中阵发性和 持续性房颤患者。 2.判断房颤的首搏是否遵循传导阻滞和折返。 我们将 使用患者特定的结构功能数据，来自参考数字心房的篮子图 解剖学、等时分析和相图。 我们还将确定这些网站是否撒谎 阵发性 AF 患者的 PV 附近，但持续性 AF 患者则不然。 3. 确定 AF 是否由心房不协调的 APD 交替引起，通过开发 来自临床观察的电生理学的患者特定计算模型。 我们将开发包含观察到的 CV 和 APD 恢复的有限体积模型， 每个患者的心房形状和结构异质性，以将模型与实际 AF 进行比较 在每个病人身上。