Optimizing AF ablation by a novel optogenetics and computational approach

项目总结 心房颤动(房颤)是一种主要的公共卫生流行病，它损害生活质量，并与 中风、心力衰竭、痴呆症和死亡的风险。目前房颤的治疗策略是高度有效的 不够充分。旨在实现节律控制的抗心律失常药物疗效有限，可能会引发 室性心律失常，特别是在疾病的晚期；而针对心率控制的心律失常 只是部分缓解，因为他们专注于管理症状，而不是逆转心律失常本身。在……上面 另一方面，射频消融肺静脉是早期房颤治疗的基石， 高度有效地治疗通常由钙介导的触发因素引发的阵发性房颤发作 在这个离散的区域内。不幸的是，这种以解剖为目标的方法在更多的患者中效果差得多。 这种高度进展性疾病的晚期。事实上，持续性房颤的患者表现出显著的 潜在的心房肌病和广泛的心房结构和电重构。这反过来又提供了 涉及多个子波产生的复杂机制为房颤的持续提供了底物 与主动源(即驱动程序)和被动旁观者混在一起的重返大气层。 有效 旁观者 烧蚀 这种高风险的压倒一切的目标 能 提议 (RQA) 引导式 定量 在……里面 破坏性 文化 房颤 由肌磷脂(SLN)启动子。 世代 一代人， 交付的一个主要障碍是 消融L组在这种情况下，很难区分真正的房颤驾驶员和被动的房颤驾驶员 在任何给定的时间。这种复杂性要求使用试错方法来交付 病变总是会导致不必要的和不可逆转的心房心肌破坏。 高额奖励R21 在不永久破坏心房心肌的情况下，实现“烧伤学习”的范例。为了实现这个目标，我们 TO：1)利用递归量化分析伪实时识别激活的房颤驾驶员的位置 2)开发持续性房颤的计算模拟，并测试RQA的有效性。 在终止相同的房颤发作(不能在实验中实现)中与非引导组的比较；3)发展 功效参数，告知病变集合中哪些步骤是必需的，哪些是可有可无的 在房颤终止前改变房颤动力学；4)使用基于光遗传学的抑制方法，其中非 可擦除的房颤消融损伤组可以通过可定制的光导脉冲在Co. 心房样HiPSC-CMS和成纤维细胞的研究，以及5)在持续性小鼠遗传模型中测试UR方法 其中，使用以下方法实现上遗传学探针的心房选择性表达 成功完成这些概念验证研究后，L将获得 以及验证可翻译的方法，这将使该领域向下一步迈进一大步 针对晚期房颤患者的消融治疗，既有效又安全。 这个 该项目是开发下一代房颤消融策略 O O O一种新型的AAV矢量驱动 T

PROJECT SUMMARY Atrial fibrillation (AF) is a major public health epidemic that impairs quality of life and is associated with increased risk for stroke, heart failure, dementia, and death. Current therapeutic strategies for managing AF are highly inadequate. Anti-arrhythmic drugs aimed at achieving rhythm control have limited efficacy and can elicit ventricular pro-arrhythmia especially at advanced stages of the disease; whereas those directed at rate control are only partially palliative as they focus on managing symptoms rather than reversing the arrhythmia itself. On the other hand, radio-frequency ablation of the pulmonary veins, a corner stone of early AF management, is highly effective for treating paroxysmal episodes of AF thatare typically initiated by calcium-mediated triggers within this discrete region. Unfortunately, this anatomically-targeted approach is far less effective at more advanced stages of this highly progressive disease. Indeed, patients with persistent AF exhibit significant underlying atrial myopathy and widespread atrial structural and electrical remodeling. This, in turn, provides the substrate for the perpetuation of AF through complex mechanisms involving the genesis of multiple wavelet reentry with active sources (i.e. drivers) intermixed with passive bystanders. effective bystanders ablation overriding goal of this high-risk, can propose (RQA) guided quantitative in destructive cultures AF by a sarcolipin (SLN) promoter. generation generation, A major obstacle to the delivery of ablation l esion sets in this context is the difficulty of distinguishing bona-fide AF drivers from passive at any given time. This complexity mandates the use of a trial & error approach for the delivery of lesions which invariably leads to the unnecessary & irreversible destruction of atrial myocardium. high-reward R21 fulfill the `learn-by-burn' paradigm without permanently destroying atrial myocardium. Towards this goal, we to: 1) identify sites of active AF drivers in pseudo real-time using recurrence quantification analysis of local activation, 2) develop computational simulations of persistent AF and test the efficacy f RQA- vs unguided sets in terminating identical episodes of AF (not achievable experimentally); 3) develop efficacy parameters that inform which steps of a lesion set are required and which are dispensable altering AF dynamics prior to its termination; 4) use an inhibitory optogenetics based approach in which non- “erasable” AF ablation lesion sets can be delivered through customizable light-guided pulses in co- of atrial-like hiPSC-CMs and fibroblasts, and 5) test ur approach in a genetic murine model of persistent in which atrial-selective expression of the ptogenetics probe is achieved using Successful completion of these proof-of-concept studies wil l result in the and validation of translatable methods that will bring the field a major step closer owards next patient-specific ablation therapeutics for advanced AF that are both effective and safe. The project is to develop next generation AF ablation strategies that o o o a novel AAV vector driven t