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.

项目简介：房颤(房颤)是最常见的持续性心律失常 到每年8万人死亡，影响到大约340万美国人，预计比 接下来的30到40年。终止房颤的主要电疗法是直流电复律，副作用显著 包括电穿孔和组织损伤，以及可能导致胃吸入的镇静风险 内容、肺炎等问题。射频消融治疗阵发性心脏病的成功率只有60%。 房颤，但持续性房颤不到30%。房颤的管理方法并不都是成功的，需要改进。 我们建议进一步研究、优化并使我们开发的低能量电疗法更接近临床 房颤抑制，低能量抗纤颤起搏(LEAP)。这包括在或附近传递5个电脉冲的序列 心律失常的主要频率来自两个场电极，而不是来自点源。我们已经证明了 Leap的成功率超过94%，而使用的复律能量不到10%。LEAP通过以下方式抑制房颤 在组织内的异质性处创建的虚拟电极，允许过驱动或欠驱动的房颤起搏。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 它是动物物种的一种，经过优化后可用于人类，并最终用于只需很小能量的治疗。 我们的体外光学标测(OM)实验和对完好的狗的体内研究证明了这一飞跃 以低至0.05J的能量扑灭房颤，比传统的复律少十倍以上。考虑到这些 令人鼓舞的结果是，我们计划采取一种综合的方法来优化这项技术，以便可能的临床应用。(1) 我们将开发快速最先进的房颤3D生理和结构准确的计算机模型，使用OM进行验证 来自狗、猪和移植的人类心脏的电压数据(来自埃默里医院的心脏移植计划) 以更好地理解和区分不同种类、结构和大小的心律失常。(2)我们将迭代地执行ex- 狗、猪和人心脏的活体房颤实验和计算机模拟以及狗和猪的活体房颤实验 为了测试我们的同步假设并使用它来优化电极配置、脉冲波形和脉冲定时 使用尽可能低的能量(低于疼痛阈值)抑制房颤，从而为发展铺平道路 植入性装置作为处理患者房颤的另一种方法。 这项研究的发现不仅将导致更多的新的和改进的心脏复律疗法 减少疼痛，但也将从根本上促进我们对房颤的机械理解 犬、猪和人在体朗多夫灌流光学标测和篮形导尿管的实验研究 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 将通过创建广泛的高时间/空间分辨率OM电压来增加可用于研究心律失常的资源 数据集和具有在网络上运行的准确的心房电生理和结构的近实时3D模拟平台- 浏览器环境，将通过专用网站向其他研究人员和一般公众提供。