Integrative Experimental and Multiscale High Resolution ModeIntegrative Experimental and Multiscale High Resolution Modling of Atrial Arrhythmias to Optimize Low Energy Anti-fibrillation Pacing (LEAP)

综合实验和多尺度高分辨率模式房性心律失常的综合实验和多尺度高分辨率建模以优化低能量抗颤起搏 (LEAP)

• 批准号: 9920773
• 负责人: Flavio H Fenton
• 金额: $ 37.42万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920773
• 关键词: 3-Dimensional; Ablation; Acute; Adopted; Affect; American; Anatomy; Animals; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Canis familiaris; Cardiac ablation; Catheters; Cell model; Cessation of life; Chronic; Clinic; Clinical; Clinical Data; Complex; Computer Models; Computer Simulation; Data; Data Set; Defibrillators; Development; Devices; Disease; Electric Countershock; Electrocardiogram; Electrodes; Electrophysiology (science); Electroporation; Environment; Family suidae; Fiber; Frequencies; Generations; Heart; Heart Atrium; Heart Transplantation; Heart failure; Heterogeneity; Hospitals; Hour; Human; In Situ; Internet; Lead; Left atrial structure; Life; Location; Measures; Methods; Modeling; Morphology; Muscle; Optics; Pain; Pain Threshold; Pathology; Patients; Pattern; Physiologic pulse; Physiological; Pneumonia; Population; Preparation; Property; Protocols documentation; Radiofrequency Interstitial Ablation; Research; Research Personnel; Resolution; Resources; Right atrial structure; Risk; Running; Sedation procedure; Signal Transduction; Source; Stomach Content; Stroke; Structure; Tachycardia; Technology; Testing; Time; Tissues; Training; United States; Validation; animal tissue; base; cardiovascular risk factor; clinically translatable; design; disabling symptom; effective therapy; electric field; experience; experimental study; heart rhythm; implantable device; improved; in silico; in vivo; microCT; programs; response; side effect; simulation; spatiotemporal; success; virtual; voltage; web site

PROJECT SUMMARY: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia: it contributes to 80,000 deaths annually and affects approximately 3.4 million Americans, with a projected increase to 10 million over the next 30 to 40 years. The primary electrical therapy for termination of AF, DC cardioversion, has significant side effects including electroporation and tissue damage, in addition to risks from sedation that can result in aspiration of stomach contents, pneumonia, and other problems. Radiofrequency ablation has a success rate of only up to 60% for paroxysmal AF, but less than 30% for persistent AF. Approaches to manage AF are not all successful and improvements are needed. We propose to further study, optimize and bring closer to the clinic our developed low-energy electrical therapy for AF suppression, low-energy antifibrillation pacing (LEAP). This consists of a train of 5 electrical pulses delivered at or near the dominant frequency of the arrhythmia from two field electrodes, rather than from a point source. We have shown that LEAP has a success rate of more than 94% and uses less than 10% the energy of cardioversion. LEAP suppresses AF by virtual electrodes created at heterogeneities within the tissue, which permits overdrive or underdrive pacing of AF. We hypothesize that synchronization is the mechanism by which AF is terminated via LEAP and thus, can be applied to any animal species and be optimized to be used in humans and eventually to be used as treatment requiring very small energies. Our ex-vivo optical mapping (OM) experiments and in-vivo studies in intact dogs have demonstrated that LEAP extinguishes AF with energies as low as 0.05 J, more than ten times less than conventional cardioversion. Given these encouraging results, we plan to adopt an integrative approach to optimizing this technology for possible clinical use. (1) We will develop fast-state-of-the-art 3D physiological and structural accurate computer models of AF, validated using OM voltage data from dogs, pigs and explanted human hearts (obtained from the heart transplant program at Emory Hospital) to better understand and distinguish arrhythmias between species, structures and sizes. (2) We will iteratively perform ex- vivo AF experiments in dog, pigs and human hearts and computers simulations and in-vivo AF experiments in dogs and pigs to test our synchronization hypothesis and use it to optimize electrode configurations, pulse waveforms and pulse timing for AF suppression using the lowest energies possible (below the pain threshold), Thereby paving the way for development of implantable devices as another methods for managing AF in patients. The findings from this research will not only lead to new and improved cardioversion therapies with greater reductions in pain, but also will fundamentally advance our mechanistic understanding of AF from the combined ex vivo Langendorff perfused dog, pig and human optical mapping and basket catheter experiments and their physiologically accurate computer simulation counterparts. An additional important impact from this study, is that we will enhance resources available for the study of arrhythmias by creating extensive high time/space resolution OM voltage data sets and a near-real-time 3D simulation platform with accurate atrial electrophysiology and structures running in a web- browser environment that will be made available to other researchers and the public in general via a dedicated website.

项目摘要：心房颤动 (AF) 是最常见的持续性心律失常：它有助于 每年有 80,000 人死亡，影响约 340 万美国人，预计在此期间将增加到 1,000 万 未来30到40年。终止房颤的主要电疗法、直流电复律具有显着的副作用 包括电穿孔和组织损伤，以及可能导致胃误吸的镇静风险 内容、肺炎和其他问题。射频消融治疗阵发性的成功率只有60% AF，但持续性 AF 低于 30%。管理 AF 的方法并非全部成功，需要改进。 我们建议进一步研究、优化我们开发的低能量电疗法并使其更接近临床。 房颤抑制、低能量抗颤起搏 (LEAP)。这由一串 5 个电脉冲组成，在或接近 心律失常的主频率来自两个场电极，而不是来自点源。我们已经证明 LEAP 的成功率超过 94%，并且使用心脏复律能量不到 10%。 LEAP 通过以下方式抑制 AF 在组织内的异质性处创建虚拟电极，允许 AF 的超速或欠速起搏。我们 假设同步是通过 LEAP 终止 AF 的机制，因此可以应用于任何 动物物种，并经过优化以用于人类，并最终用作需要非常小的能量的治疗。 我们对完整狗的离体光学测绘 (OM) 实验和体内研究表明，LEAP 消除 AF 的能量低至 0.05 J，比传统心脏复律低十倍以上。鉴于这些 令人鼓舞的结果，我们计划采用综合方法来优化这项技术，以供可能的临床使用。 (1) 我们将开发快速、最先进的 3D 生理和结构精确的 AF 计算机模型，并使用 OM 进行验证 来自狗、猪和移植人类心脏的电压数据（从埃默里医院的心脏移植项目获得） 更好地理解和区分物种、结构和大小之间的心律失常。 (2) 我们将迭代地执行前 狗、猪和人类心脏的体内 AF 实验以及狗和猪的计算机模拟和体内 AF 实验 测试我们的同步假设并用它来优化电极配置、脉冲波形和脉冲定时 使用尽可能最低的能量（低于疼痛阈值）抑制房颤，从而为发展铺平道路 植入式设备作为治疗患者房颤的另一种方法。 这项研究的结果不仅会带来新的和改进的心脏复律疗法， 减轻疼痛，同时也将从根本上增进我们对 AF 机制的理解。 Vivo Langendorff灌注狗、猪和人类光学测绘和篮式导管实验及其 生理上准确的计算机模拟对应物。这项研究的另一个重要影响是，我们 将通过创建广泛的高时间/空间分辨率 OM 电压来增强可用于心律失常研究的资源 数据集和近实时 3D 模拟平台，具有精确的心房电生理学和在网络中运行的结构 浏览器环境将通过专门的网站向其他研究人员和公众提供。