ATRIAL FIBRILLATION AND ALTERNANS OF ACTION POTENTIAL DURATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 （一） 目标 房颤（AF）影响美国220万人，是中风、心力衰竭和死亡的主要原因（8）。维持窦性心律可减轻症状并延长生存期，但仍很困难（1）。消融术的最新进展使得通过隔离肺静脉中的触发点，治愈许多发作自限性阵发性房颤患者成为可能（12，14）。不幸的是，消融是复杂的，并且在患有持续性AF的大量人群中不太成功，其发作需要药物或心脏复律来终止（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，治疗受到对人类AF如何以及在何种条件下发生的理解不足的限制。 越来越多的人认识到，结构异质性或动态组织特性可能引发纤维化（33）。动物、体外和计算研究表明，动作电位时程（APD）中的每隔一拍振荡（交替）可能引发心室颤动（33）。从机制上讲，组织异质性（如疤痕）或动力学（如APD的急剧恢复（即“速率响应”））、传导速度（CV）在宽范围速率下减慢（36）可能导致APD交替。通过夸大复极离散，特别是如果不一致（33），APD交替可能是AF的直接机制。尽管APD交替尚未与动物或人类的AF相关，我们有令人兴奋的人类初步数据显示APD交替直接导致折返性AF。作为NBCR的一个合作项目，这项研究将促进连续性及其解剖和电模型发展的扩展以及允许与心房中的脉冲传导模型更大集成的患者特定建模算法。 我们的中心假设是，人类的房颤始于动作电位时程交替（APD），这反映了心房APD的急剧恢复和局部传导速度的广泛恢复，并解释了阵发性房颤中肺静脉（PV）附近的房颤，而不是持续性房颤。本研究将房颤消融患者的复杂数据收集与独特的最先进患者-具体的计算模型，以解决3个具体目标。 1. 确定心房动作电位时程（APD）的交替（由APD急剧恢复或传导速度（CV）广泛恢复引起）是否先于房颤发作。 我们将在电生理研究中记录64-128个双心房篮状电极的多部位单相动作电位（MAP）和CV，在阵发性和持续性AF患者的计算机断层扫描引导下进行心房重建时进行和不进行药物调制。 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，来自参考数字心房解剖结构的篮图、等时分析和相位标测。 我们还将确定这些部位是否位于阵发性房颤但非持续性房颤患者的肺静脉附近。 3. 通过开发源自临床观察到的电生理学的患者特异性计算模型，确定房颤是否由心房不一致APD交替引起。 我们将开发有限体积模型，该模型将观察到的CV和APD恢复、心房形状和结构异质性纳入每例患者，以比较每例患者的模型与实际AF。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. (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.