Optimizing AF ablation by a novel optogenetics and computational approach

通过新颖的光遗传学和计算方法优化 AF 消融

• 批准号: 10508937
• 负责人: FADI GABRIEL AKAR
• 金额: $ 25.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10508937
• 关键词: Ablation; Active Sites; Anatomy; Animals; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Biophysics; Calcium; Cardiac Myocytes; Cessation of life; Characteristics; Complex; Computer Simulation; Computers; Dementia; Disease; Electrophysiology (science); Epidemic; Exhibits; Female; Fibroblasts; Fibrosis; Frequencies; Funding; Future; Gene Transfer; Generations; Genes; Genetic; Goals; Heart Atrium; Heart failure; Hip region structure; Impairment; In Vitro; Learning; Lesion; Light; Measures; Mediating; Methods; Modeling; Mus; Myocardium; Myofibroblast; Myopathy; Optics; Patients; Physiologic pulse; Pre-Clinical Model; Progressive Disease; Property; Public Health; Pulmonary veins; Quality of life; Radiofrequency Interstitial Ablation; Recurrence; Resolution; Rewards; Source; Testing; Therapeutic; Time; Translating; Translation Process; Validation; Ventricular; adeno-associated viral vector; base; biophysical tools; efficacy testing; high reward; high risk; in silico; in vivo Model; individual patient; insight; male; meter; monolayer; mouse model; next generation; novel; optogenetics; palliative; promoter; sarcolipin; selective expression; stroke risk; symptom management; time use; transcription activator-like effector nucleases; virtual; virtual delivery

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

项目概要 心房颤动 (AF) 是一种严重的公共卫生流行病，会损害生活质量，并与增加死亡率有关。 中风、心力衰竭、痴呆和死亡的风险。目前治疗 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，并且可能引起 室性促心律失常，尤其是在疾病晚期；而那些针对速率控制的 只能部分缓解，因为它们专注于控制症状而不是逆转心律失常本身。在 另一方面，肺静脉射频消融是早期房颤治疗的基石， 对于治疗通常由钙介导的触发因素引发的阵发性房颤发作非常有效 在这个离散区域内。不幸的是，这种针对解剖学的方法在更多方面的效果要差得多。 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着的 潜在的心房肌病和广泛的心房结构和电重塑。这反过来又提供了 通过涉及多小波发生的复杂机制使 AF 永久存在的基质 再入时主动源（即驾驶员）与被动旁观者混合在一起。 有效的 旁观者 消融 这种高风险的首要目标， 能 提出 （风险质量保证） 引导的 定量的 在 破坏性的 文化 AF 由肌磷脂 (SLN) 启动子启动。 一代 一代， 交付的主要障碍 在这种情况下，消融病变组很难区分善意的 AF 驱动器和被动的 AF 驱动器。 在任何给定时间。这种复杂性要求使用试错方法来交付 病变总是会导致心房心肌不必要的和不可逆的破坏。 高回报R21 实现“边燃烧边学习”模式，而不永久破坏心房心肌。为了这个目标，我们 1) 使用重复量化分析伪实时识别活跃 AF 驱动因素的位点 局部激活，2）开发持续 AF 的计算模拟并测试 RQA 的功效 与无引导组在终止相同的 AF 发作方面相比（无法通过实验实现）； 3）开发 功效参数，告知病变组的哪些步骤是必需的，哪些是可有可无的 在终止之前改变 AF 动态； 4）使用基于抑制性光遗传学的方法，其中非 “可擦除”AF 消融病变组可以通过可定制的光导脉冲以共同的方式提供 心房样 hiPSC-CM 和成纤维细胞的研究，以及 5) 在持续性遗传小鼠模型中测试您的方法 其中光遗传学探针的心房选择性表达是通过使用实现的 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，这将使该领域下一步向前迈进一大步 针对晚期房颤的患者特异性消融疗法既有效又安全。 这 该项目旨在开发下一代房颤消融策略 哦 哦 o 新型 AAV 向量驱动 t