Novel medical adjunctive therapy to catheter ablation for atrial fibrillation

项目摘要 心房颤动（AF）是最常见的心律失常，影响美国超过200万人， 预计到2050年，它将影响800万至1200万人。它负责每年超过60亿美元的医疗保健 在美国的支出。导管消融实现窦性心律是一种日益增长的治疗选择， 成功率高于抗肿瘤药物治疗。然而，导管消融术的成功率 次优对于持续性房颤患者，导管消融术的成功率甚至低于 阵发性房颤。星星房颤II随机多中心临床试验报告， 对于持续性房颤患者，一次手术后50%的心外膜脂肪组织（EAT）可能起作用， 在导管消融术后AF的进展、发展和复发中的独立作用。具体来说，左 心房（LA）EAT由于其邻近LA，可通过炎症，促纤维化， 和其他脂肪细胞因子。利拉鲁肽（一种胰高血糖素样肽-1类似物），一种有效治疗肥胖症的药物， 糖尿病，显著降低EAT。用导管稳定基底的组合医学方法 尚未对消融进行评价。因此，本项目的总体目标是评估 基质稳定作为持续性房颤患者接受导管消融术的后续治疗。我们 假设利拉鲁肽治疗将显著降低LAEAT并因此稳定（甚至 可能改善）AF基板。我们的具体目标是：1）评估LAEAT，EAT， 选择导管的持续性AF患者的心房大小/功能和炎症生物标志物 利拉鲁肽治疗引起的消融; 2）评价LAEAT与LA生物标志物的相关性。我们将 入选60例选择接受导管消融术的持续性房颤患者。消融前治疗将 包括：1）抗心律失常药物治疗和心脏复律（如果需要），以促进逆转电重构; 2)风险因素管理; 3）一半患者将随机接受利拉鲁肽治疗。预处理3个月后， 将使用基于窦肺静脉隔离的方法进行导管消融。主 终点为3个月时（消融术前）LAEAT的变化。基质评价将包括CT（EAT， LAEAT）、超声心动图（应变、EAT厚度）和入组时、消融前和一次消融时的生物标志物 年我们将通过长期事件记录，评估停用抗心律失常药物1年时无AF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将 帮助描绘可用于跟踪基质稳定治疗的参数。因此，这个开放标签 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种新方法至关重要，这种方法可以大大提高 AF患者的结局。

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.