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

项目总结：心房颤动（AF）是最常见的持续性心律失常： 每年有8万人死亡，影响大约340万美国人，预计将增加到1000万人。 未来30到40年。终止房颤的主要电疗法--直流电复律有明显的副作用 包括电穿孔和组织损伤，以及可能导致胃吸入的镇静风险 内容物、肺炎和其他问题。对于阵发性心脏病，射频消融的成功率仅高达60%。 房颤，但不到30%的持续性房颤。方法来管理房颤并不都是成功的，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， AF抑制，低能量抗纤颤起搏（LEAP）。这包括一系列5个电脉冲， 心律失常的主导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%，使用的能量不到心脏复律的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，这允许AF的加速或欠驱动起搏。 假设同步是AF通过LEAP终止的机制，因此可以应用于任何 动物物种，并优化用于人类，并最终用作需要非常小能量的治疗。 我们的离体光学标测（OM）实验和在完整犬中的体内研究表明，LEAP 以低至0.05 J的能量消除AF，比传统心脏复律低十倍以上。鉴于这些 我们计划采用一种综合的方法来优化这项技术，以便可能在临床上使用。（一） 我们将开发快速的最先进的AF的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（从埃默里医院的心脏移植项目获得） 以更好地理解和区分物种、结构和大小之间的心律失常。(2)我们将反复执行前- 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）进行AF抑制，从而为开发铺平道路 植入式设备作为治疗患者AF的另一种方法。 这项研究的发现不仅会导致新的和改进的心脏复律疗法， 减少疼痛，但也将从根本上推进我们对AF的机械理解， 活体Langendorff灌注狗、猪和人光学标测和篮状导管实验及其 生理学上精确的计算机模拟。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电压来增加心律失常研究的可用资源 数据集和近实时3D仿真平台，具有准确的心房电生理学和网络运行结构， 浏览器环境，将提供给其他研究人员和公众一般通过一个专门的网站。

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.