Vein of Marshall as a therapeutic agent in the treatment of atrial fibrillation

描述（由申请人提供）：本项目的广泛、长期目标是探索马歇尔静脉（VOM）乙醇输注在治疗房颤（AF）中的潜在作用。AF是成人中最常见的持续性心律失常，影响超过250万美国人，并与中风和死亡率的显著增加相关。房颤导管消融术包括肺静脉窦隔离（PVAI），是治疗房颤的最有效治疗策略，约80%的患者可实现正常心律。PVAI的机制基础、最佳导管技术和并发症风险的重要详情不完整或存在争议。VOM是冠状窦的左心房静脉分支，其是左上级腔静脉的胚胎残余，并且包含与AF的发生有关的重要交感神经和副交感神经。起源于VOM的异常异位搏动已被证明会引发AF。VOM位于LA中的位置，该位置通常是PVAI中的目标组织的一部分，并且可能难以消融通常由于其厚度（横向脊）。值得注意的是，它也位于冠状窦和左肺静脉之间，这是一个通常消融以避免左心房扑动的区域。它也可以靠近左心房和食管之间的接触点。一种新的技术，逆行插管的VOM的开发和验证在狗和人。一旦插管，乙醇输注可实现快速组织消融，无附带损伤风险。潜在优势包括：促进AF的交感神经和副交感神经支配的消融、AF的VOM触发器的消融、从其心外膜侧消融侧脊以及从右侧手术快速组织消融。我们建议研究这种技术的机制基础的细节，并建立其在人类房颤治疗中的作用。具体目标#1是在犬中确定VOM乙醇输注的电生理学效应。我们假设，VOM乙醇灌注导致显著的直接和间接的电生理变化，影响其维持AF的能力。直接影响将包括一个新的乙醇消融不可兴奋的LA区。间接效应包括消除VOM所携带的迷走神经和交感神经影响。将进行实验来描述这些影响。具体目标#2是确定VOM乙醇输注作为人类房颤导管消融术的有用辅助手段的作用。将在接受常规AF导管消融的患者中测试VOM乙醇输注的可行性、安全性、消融效果和手术影响。一旦确定了可行性和安全性，我们将在一项随机临床试验中评估连续VOM乙醇输注在原发性房颤导管消融术中的价值，以及在既往PVAI后复发性房颤病例中的价值。 公共卫生相关性：房颤是一个严重的健康问题，可导致中风并增加死亡率。导管消融在其治疗中有效，但可以改进。我们已经开发出一种新技术，该技术在机械上是合理的，并且可以改善AF的基于导管的治疗。

DESCRIPTION (provided by applicant): The broad, long-term objective of this project is to explore the potential role of ethanol infusion in the vein of Marshall (VOM) in the treatment of atrial fibrillation (AF). AF is the most common sustained rhythm disorder in adults, affects more than 2.5 million Americans, and is associated with significant increases in stroke and mortality. Catheter ablation of AF, consists of pulmonary vein antral isolation (PVAI) and is the most powerful therapeutic strategy to treat AF, achieving normal rhythm in ~80% of patients. Important details of the mechanistic basis of PVAI, the optimal catheter technique, and the risk of complications are incomplete or controversial. The VOM is a left atrial vein branch of the coronary sinus that is the embryonic remnant of the left superior vena cava, and contains important sympathetic and parasympathetic nerves that have been implicated in the genesis of AF. Abnormal ectopic beats originating from the VOM have been shown to initiate AF. The VOM lies in a location in the LA that is normally part of the targeted tissue in PVAI and can be difficult to ablate conventionally due to its thickness (lateral ridge). Of note, it is also between the coronary sinus and the left pulmonary veins, an area commonly ablated to avoid left atrial flutter. It can also run close to the point of contact between the left atrium and the esophagus. A new technique to retrogradely cannulate the VOM was developed and validated in dogs and humans. Once cannulated, ethanol infusion achieves rapid tissue ablation without risk of collateral damage. The potential advantages include: ablation of sympathetic and parasympathetic innervation that promotes AF, ablation of VOM triggers for AF, ablation the lateral ridge from its epicardial side, and rapid tissue ablation from a right-sided procedure. We propose to study details of the mechanistic basis of this technique and to establish its role in the treatment of AF in humans. Specific aim #1 is to establish in dogs the electrophysiological effects of VOM ethanol infusion. We hypothesize that VOM ethanol infusion leads to marked direct and indirect electrophysiological changes in the LA that affect its ability to sustain AF. Direct effects would include of a new ethanol- ablated unexcitable LA area. Indirect effects would include abolition of vagal and sympathetic influences carried by the VOM. Experiments will be performed to delineate these effects. Specific aim #2 is to establish the role of VOM ethanol infusion as a useful adjunct to catheter ablation of AF in humans. Feasibility, safety, ablative effects and procedural impact of VOM ethanol infusion will be tested in patients subjected to conventional AF catheter ablation. Once the feasibility and safety are established, we will assess, in a randomized clinical trial, the value of adjunctive VOM ethanol infusion in de novo AF catheter ablation with PVAI, and in cases of recurrent AF after previous PVAI. PUBLIC HEALTH RELEVANCE: Atrial fibrillation is a significant health problem that causes stroke and increases death rates. Catheter ablation works in its treatment but can be improved. We have developed a new technique that is mechanistically sound and may improve catheter-based treatment of AF.