ATRIAL FIBRILLATION AND ALTERNANS OF ACTION POTENTIAL DURATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 (A)目标 在美国，房颤影响着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可能延长生存期，但仍很困难(1)。消融的最新进展使得通过隔离肺静脉中的触发因素来治愈许多阵发性房颤患者成为可能，这些患者的发作是自限的(12，14)。不幸的是，消融是复杂的，在大量持续性房颤患者中消融不太成功，他们的发作需要药物或复律来终止(10)。在这组患者中，消融后房颤复发率为50%，需要多次消融并伴有发病率和死亡率(5)。不幸的是，治疗受到对房颤如何发生以及在什么情况下发生在人类身上的糟糕理解的限制。 人们越来越认识到，结构的异质性或动态的组织属性可能会引发纤颤(33)。动物、体外和计算机研究表明，动作电位时程的每隔一拍振荡(Alternans)可能引发室颤(33)。从机制上讲，组织的不均一性，如疤痕，或动力学，如动作电位的陡峭恢复(即“速率-反应”)，传导速度(CV)在很大的速率范围内减慢(36)，都可能导致动作电位交替。通过夸大复极离散度，特别是在不协调的情况下(33)，动作电位交替可能是房颤的直接机制。尽管在动物或人类中，交替动作与房颤有关，但我们有令人兴奋的人类初步数据显示，动作电位交替直接导致折返性心房颤动。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学模型以及患者特定建模算法的扩展，使其能够与心房内的脉冲传导模型更好地集成。 我们的中心假设是，人类的心房颤动起源于动作电位时程的交替，它反映了心房动作电位时程的陡峭恢复和局部传导速度的广泛恢复，并解释了发作性房颤中肺静脉附近的房颤，而不是持续性房颤。这项研究将房颤消融患者的复杂数据收集与独特的最先进的患者特定计算模型结合在一起，以解决三个特定目标。 1.探讨陡度动作电位时程恢复或宽传导速度恢复引起的心房动作电位时程交替是否先于心房颤动的发生。在CT引导下对阵发性和持续性房颤患者进行心房重建的电生理研究中，我们将记录-128型双房篮电极的多部位单相动作电位(MAP)和变异系数(CV)。 2.确定房颤第一次搏动是否跟随传导阻滞和折返。我们将使用患者特定的结构-功能数据，从参考数字心房解剖的篮图、等时分析和时相映射。我们还将确定这些部位是否位于阵发性房颤患者的室间隔附近，但不是持续性房颤患者。 3.通过根据临床观察的电生理学建立患者特有的计算模型，以确定房颤是否是由房室不协调的动作电位交替引起的。我们将开发有限体积模型，将观察到的每个患者的CV和APD恢复、心房形状和结构异质性纳入其中，以与每个患者的实际房颤进行比较。

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.