权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10676183
负责人：
FADI GABRIEL AKAR
金额：
$ 20.94万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10676183
关键词：
Ablation Active Sites Anatomy Animals Anti-Arrhythmia Agents Arrhythmia Atrial Fibrillation Biophysics Calcium Cardiac Myocytes Cessation of life Characteristics Coculture Techniques 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 Maps 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 Risk Source Testing Therapeutic Time Translating Translation Process Validation Ventricular adeno-associated viral vector 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

项目摘要

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

项目总结