ATRIAL FIBRILLATION AND ALTERNANS OF ACTION POTENTIAL DURATION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 （一） 目标 心房纤颤（AF）影响美国220万人，并且是一种主要的 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，但仍然困难（1）。消融术的最新进展使其 有可能治愈许多阵发性房颤患者，其发作是自限性的， 隔离肺静脉中的触发器（12，14）。不幸的是，消融是复杂的， 在大量持续性房颤人群中不太成功，其发作需要药物或 心脏复律终止（10）。在该组中，房颤消融后复发率> 50%，需要 多次消融伴随发病率和死亡率（5）。不幸的是，心理治疗 由于对AF如何以及在何种条件下在人类中发生的理解不足而受限。 越来越多的人认识到，结构异质性或动态组织特性 可以引发纤维化（33）。动物、体外和计算机研究表明， 动作电位时程（APD）中的每隔一拍振荡（交替）， 心室颤动（33）。从机制上讲，组织异质性，如疤痕，或动力学 例如APD的陡峭恢复（即，“速率响应”）、减慢APD的传导速度（CV 对于宽范围的速率（36），可能导致APD交替。通过夸大复极 如果APD交替是AF的一个直接机制，那么APD交替可能是AF的一个直接机制。 尽管APD交替还没有与动物或人类的AF联系起来，但我们有令人兴奋的发现。 人类的初步数据显示APD交替直接导致折返性AF。 NBCR的合作项目，这项研究将促进扩展到发展 连续性及其解剖和电气模型以及患者特定建模 算法，将允许更大的整合与模型的脉冲传导， 心房 我们的中心假设是人类的心房颤动是由交替性作用引起的 电位时程（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，并解释了阵发性肺静脉（PV）附近的AF AF但不是持续性AF。本研究结合了AF患者的复杂数据收集 采用独特的最先进的患者特异性计算建模进行消融，以解决3 具体目标。 1. 为了确定是否交替心房动作电位时程（APD），导致 陡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， 在电生理研究中，64-128个双心房篮状电极，有和没有药理学 调制，在阵发性和 持续性房颤患者。 2. 确定房颤的第一次搏动是否伴随传导阻滞和折返。 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图 解剖、等时线分析和相位图。 我们还将确定这些地点是否 阵发性房颤但非持续性房颤患者的肺静脉附近。 3. 为了确定房颤是否由心房不一致的APD交替引起， 从临床观察到的电生理学导出的患者特异性计算模型。 我们将开发有限体积模型，将观察到的CV和APD恢复， 每例患者的心房形状和结构异质性，以比较模型与实际AF 在每一个病人。

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.