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: 10441000
• 负责人: Flavio H Fenton
• 金额: $ 7.24万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441000
• 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不齐：它有助于 每年80,000人死亡，影响约340万美国人，预计将增加到1000万 接下来的30至40年。终止AF的主要电疗法DC心脏version具有显着的副作用 除了镇静的风险外，包括电穿孔和组织损伤，这可能导致胃抽吸 内容，肺炎和其他问题。阵发的射频消融率仅高达60％ AF，但持久性AF的不到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，优化并使我们开发的低能电疗法更接近诊所 AF抑制，低能反振动起搏（LEAP）。这是由在或附近传递的5次电脉冲的火车组成 心律不齐的主要频率来自两个场电极，而不是从点源。我们已经表明 LEAP的成功率超过94％，使用心脏扭转能量的10％。 LEP抑制AF 在组织内部的异质性产生的虚拟电极，该电极允许AF的超速驱动或降低起搏。我们 假设同步是通过飞跃终止AF的机制，因此可以应用于任何 动物物种并被优化以用于人类，并最终用作需要非常小能量的治疗方法。 我们的前视光学映射（OM）实验和完整犬的体内研究表明了Leap 用低至0.05 J的能量扑灭AF，比常规心脏version抗性少了十倍以上。鉴于这些 令人鼓舞的结果，我们计划采用一种综合方法来优化该技术以供临床使用。 （1） 我们将开发使用OM验证的AF的快速状态3D生理和结构精确的计算机模型 来自狗，猪和外植的人心的电压数据（从埃默里医院的心脏移植程序获得） 更好地理解和区分物种，结构和大小之间的心律不齐。 （2）我们将迭代执行 狗，人类心脏和计算机模拟中的体内AF实验以及狗和猪的体内AF实验 为了测试我们的同步假设，并使用它来优化电极配置，脉冲波形和脉冲正时 对于使用最低能量的AF抑制（低于疼痛阈值），从而为发展铺平了道路 可植入的设备作为患者管理AF的另一种方法。 这项研究的发现不仅会导致更大的新的和改进的心疗疗法 减轻疼痛 Vivo Langendorff灌注狗，猪和人类光学映射以及篮子导管实验及其 生理上精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 将通过创建大量的高时间/空间分辨率OM电压来增强心律不齐的可用资源 数据集和一个近实时的3D仿真平台，具有准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用网站提供给其他研究人员和公众。