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: 8169368
• 负责人: Sanjiv M Narayan
• 金额: $ 3.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169368
• 关键词: Ablation; Action Potentials; Address; Affect; Algorithms; Anatomy; Animals; Arts; Atrial Fibrillation; Cicatrix; Complex; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Data; Data Collection; Development; Electric Countershock; Electrophysiology (science); Funding; Grant; Heart Atrium; Heart failure; Heterogeneity; Human; In Vitro; Individual; Institution; Link; Maps; Modeling; Morbidity - disease rate; Patients; Pharmaceutical Preparations; Phase; Population; Property; Pulmonary veins; Research; Research Personnel; 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; 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. 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 (一) 目标 心房颤动 (AF) 影响着美国 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可能延长生存期，但仍然很困难 (1)。消融方面的最新进展现在可以通过隔离肺静脉中的触发因素来治愈许多阵发性 AF 患者，这些患者的发作具有自限性 (12, 14)。不幸的是，消融很复杂，并且在大量持续性房颤患者中不太成功，其发作需要药物或心脏复律来终止（10）。在该组中，房颤在消融后复发的比例> 50%，需要多次消融并伴随发病率和死亡率 (5)。不幸的是，由于对人类如何以及在什么条件下发生房颤的了解不足，治疗受到限制。 人们越来越认识到结构异质性或动态组织特性可能引发纤维性颤动（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”）、在较大速率范围内减慢的传导速度 (CV) (36)）可能会导致 APD 交替。通过夸大复极色散，尤其是不一致的情况下 (33)，APD 交替可能是 AF 的直接机制。尽管 APD 交替蛋白尚未与动物或人类的 AF 联系起来，但我们在人类中获得了令人兴奋的初步数据，显示 APD 交替蛋白直接导致折返性 AF。作为 NBCR 的一个合作项目，这项研究将促进 Continuity 及其解剖学和电气模型以及患者特定建模算法的开发扩展，这些算法将允许与心房脉冲传导模型更好地集成。 我们的中心假设是，人类的心房颤动始于动作电位持续时间 (APD) 的交替，这反映了心房 APD 的急剧恢复和区域传导速度的广泛恢复，并解释了阵发性 AF 中肺静脉 (PV) 附近的 AF，但不能解释持续自动对焦。这项研究将 AF 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起来，以解决 3 个特定目标。 1. 确定心房动作电位持续时间 (APD) 的交替是否由陡峭的 APD 恢复或宽幅传导速度 (CV) 恢复引起，先于心房颤动发作。 我们将在电生理学研究中记录来自 64-128 个双心房篮柱的多部位单相动作电位 (MAP) 和 CV，无论有或没有药物调节，在计算机断层扫描引导下对阵发性和持续性 AF 患者进行心房重建。 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，来自数字心房解剖学参考的篮子图、等时分析和相位图。 我们还将确定这些部位是否位于阵发性 AF 患者的 PV 附近，而不是持续性 AF 患者。 3. 通过开发源自临床观察的电生理学的患者特异性计算模型，确定 AF 是否由心房不一致的 APD 交替引起。 我们将开发有限体积模型，其中结合了每位患者观察到的 CV 和 APD 恢复、心房形状和结构异质性，以将每位患者的模型与实际 AF 进行比较。