Optimizing AF ablation by a novel optogenetics and computational approach

项目摘要 心房颤动（AF）是一种主要的公共卫生流行病，它损害生活质量，并与增加的 中风、心力衰竭、痴呆和死亡的风险。目前用于管理AF的治疗策略高度 不足旨在实现节律控制的抗心律失常药物疗效有限， 室性促心律失常，尤其是在疾病的晚期;而那些针对心率控制的 只是部分缓解，因为它们专注于管理症状，而不是逆转心律失常本身。对 另一方面，肺静脉的射频消融，早期房颤治疗的基石， 对治疗通常由钙介导触发物引发的阵发性房颤发作非常有效 在这个离散的区域内。不幸的是，这种解剖学靶向方法在更多的情况下效果要差得多。 这种高度进展性疾病的晚期。事实上，持续性房颤患者表现出显著的 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 通过涉及多重小波起源的复杂机制， 主动源（即驾驶员）与被动旁观者混合的再入。 有效 旁观者 消融 这一高风险的首要目标， 可以 提出 （RQA） 指导 定量 在 破坏性 文化 AF 通过肌磷脂（SLN）启动子。 一代 世代， 交付的一个主要障碍 在这种情况下，区分真正的AF驱动器和被动的AF驱动器是困难的 在任何特定的时间。这种复杂性要求使用试错法来交付 这些病变总是导致心房心肌不必要且不可逆的破坏。 高回报R21 实现“通过燃烧学习”范例，而不会永久性地破坏心房心肌。为了实现这一目标，我们 1）使用递归量化分析以伪实时方式识别活动AF驱动器的部位 2）开发持续性AF的计算模拟并测试RQA的有效性- 在终止相同的AF发作（实验无法实现）方面与无指导组相比; 3）开发 疗效参数，告知病变组的哪些步骤是必需的，哪些步骤是不必要的 在其终止之前改变AF动力学; 4）使用基于抑制性光遗传学的方法，其中非 “可擦除”AF消融损伤组可以通过定制的光导脉冲在共同提供， 心房样hiPSC-CM和成纤维细胞的遗传性小鼠模型中测试我们的方法，以及5）在持续性hiPSC-CM和成纤维细胞的遗传性小鼠模型中测试我们的方法。 其中使用以下方法实现胚胎发生学探针的心房选择性表达 成功完成这些概念验证研究将导致 以及可翻译方法的验证，这将使该领域朝着下一个方向迈出重要一步 有效且安全的晚期AF患者特异性消融治疗。 的 该项目旨在开发下一代AF消融策略， O O o一种新的AAV载体驱动的 不

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