Novel medical adjunctive therapy to catheter ablation for atrial fibrillation

项目摘要 房颤是最常见的心律失常，在美国有200多万人患有 预计到2050年，它将影响800万至1200万人。它负责每年60亿美元的医疗保健 在美国的支出。导管消融以实现窦性心律是一种日益增长的治疗选择，因为它 与抗心律失常药物治疗相比，成功率更高。然而，导管消融的成功率是 不太理想。对于持续性房颤患者，导管消融的成功率甚至比那些患有房颤的患者更低 阵发性房颤。STAR房颤II随机多中心临床试验报告平均无房颤 对于持续性房颤患者，一次手术后50%。心外膜脂肪组织(EAT)可能在 在导管消融后房颤的进展、发展和复发中的独立作用。具体地说，向左 心房(LA)EAT由于与LA毗邻，可能通过炎症、纤维化和纤维化直接影响LA底物， 和其他脂肪细胞因子。利拉鲁肽(一种胰升糖素样肽-1类似物)，一种治疗肥胖和 糖尿病，显著减少进食量。用导管固定底物的一种联合医学方法 还没有对消融进行评估。因此，本项目的总体目标是评估 在接受导管消融的持续性房颤患者中，基质稳定化作为辅助治疗。我们 假设利拉鲁肽治疗将显著减少LaEat，从而稳定(甚至 也许改善)AF基板。我们的具体目标是：1)评估Laeat、Eat、 选择导管的持续性房颤患者的心房大小/功能和炎症生物标志物 利拉鲁肽治疗的消融；2)评估LAEAT与LA生物标志物的相关性。我们会 纳入60名选择接受导管消融的持续性房颤患者。消融前治疗将 包括：1)抗心律失常药物治疗和复律(如果需要)，以促进逆电重构； 2)危险因素管理；3)随机一半接受利拉鲁肽治疗。治疗前治疗3个月后， 导管消融将采用基于肺静脉窦隔离的方法。初级阶段 治疗终点为术后3个月(消融前)LAEAT改变。基质评估将包括CT(EAT， LAEAT)、超声心动图(张力、EAT厚度)和生物标记物在登记、消融前和一次 年。我们将在长期事件记录的抗心律失常药物停药一年后评估摆脱房颤的情况 监测和比较基线Laeat。评估广泛的成像和血液生物标志物阵列将 帮助描述可用于跟踪底物稳定治疗的参数。因此，这个开放的标签 利拉鲁肽联合导管消融治疗房颤的临床研究将提供基础数据 对于进一步测试和验证这一新方法至关重要，这一方法可以显著改进 房颤患者的预后。

Project Summary Atrial fibrillation (AF) is the most common arrhythmia affecting well over 2 million people in the US with projections that it will affect 8-12 million people by 2050. It is responsible for >$6 billion in annual health care expenditures in the US. Catheter ablation to achieve sinus rhythm is a growing therapeutic option due to its greater success rate compared to antiarrhythmic drug therapy. Yet, success rates for catheter ablation are suboptimal. For patients with persistent AF, catheter ablation has even lower success rates than for those with paroxysmal AF. The STAR AF II randomized multicenter clinical trial reported an average freedom from AF after one procedure of 50% for patients with persistent AF. Epicardial adipose tissue (EAT) may play an independent role in the progression, development and recurrence of AF after catheter ablation. Specifically, left atrial (LA) EAT due to its contiguity to the LA may directly influence LA substrate via inflammatory, profibrotic, and other adipocytokines. Liraglutide (a glucagon like peptide-1 analog), an effective therapy for obesity and diabetes, markedly reduces EAT. A combined medical approach for substrate stabilization with catheter ablation has not been evaluated. Thus, the overall goal of this project is to assess the novel approach of substrate stabilization as adjunctive therapy in patients with persistent AF undergoing catheter ablation. We hypothesize that Liraglutide treatment will significantly reduce LAEAT and consequently stabilize (and even perhaps ameliorate) AF substrate. Our specific aims are to: 1) Assess for serial changes in LAEAT, EAT, atrial size/function and biomarkers of inflammation in patients with persistent AF who opt for catheter ablation due to Liraglutide treatment; 2) Evaluate the correlation of LAEAT to LA biomarkers. We will enroll 60 patients with persistent AF who have elected to undergo catheter ablation. Pre-ablation therapy will include: 1) antiarrhythmic drug therapy and cardioversion (if needed) to promote reverse electrical remodeling; 2) Risk factor management; 3) Half will be randomized to receive Liraglutide. After pre-treatment for 3 months, catheter ablation will be performed using an antral pulmonary vein isolation based approach. The primary endpoint will be change in LAEAT at 3 months (prior to ablation). Substrate evaluation will include CT (EAT, LAEAT), echocardiography (strain, EAT thickness), and biomarkers at enrollment, pre-ablation, and at one year. We will assess freedom from AF at one year off antiarrhythmic drugs documented by long-term event monitoring and compare baseline LAEAT. Evaluating the broad array of imaging and blood biomarkers will help delineate parameters that can be used to track substrate stabilization therapy. Thus, this open label clinical study of Liraglutide in combination with catheter ablation for AF will provide foundational data that will be critical for the further testing and validation of this novel approach, one that could substantially improve outcomes for patients with AF.