Mechanistic Relationships Between Ethanol and Human Atrial Fibrillation

描述（由申请人提供）：乙醇是世界上最常用的药物。心房颤动（AF）是最常见的心律失常：目前影响数百万人 美国人，并负责大量的发病率和死亡率，估计每年的卫生保健费用超过65亿美元。小型观察性研究表明，乙醇可以触发急性发作的AF。大型，前瞻性，流行病学研究表明，乙醇的使用可能会导致新发AF。然而，无论是急性或慢性乙醇暴露和AF之间的潜在关联的机制仍然未知。调查这些因果机制很重要，原因有两个：首先，乙醇和AF之间因果关系的证据与超过1亿消费乙醇的美国人有关。考虑到乙醇是“心脏健康”的常见概念，证明乙醇具有促进AF的电生理和/或结构心脏效应将特别重要。其次，了解外部来源如何急性触发或慢性导致AF的发展将揭示AF的共同机制。目前还没有实验模型，其中人类AF可以被可靠地触发，也没有已知的方法来预防AF。因此，这项研究可以开辟一个新的领域，实验人类研究AF，最终导致新的治疗或临床策略，目标是负责AF的过程。在目标1中，我们将在接受侵入性消融术的阵发性房颤患者中进行一项静脉注射乙醇与安慰剂的随机试验，以确定乙醇的急性电生理效应在体内心肌上。我们将比较输注前后的房性早搏计数、不应期、传导速度、激动-恢复间期、恢复特性、对诱发AF的适应性。为了确保实验期间患者之间和患者内的血液乙醇浓度一致，我们将采用已建立的药代动力学模型来滴定，然后“钳位”，乙醇输注以维持通过系列呼吸测试确定的稳定的血液乙醇浓度。其机制将在利用光学映射的动物模型中进一步阐明。为了评估乙醇的慢性效应，目标2将涉及一系列乙醇评估和心脏超声心动图在心脏研究的二次分析，以确定是否乙醇诱导的左心房扩大是负责事件AF。慢性乙醇消耗的动物模型将被用来进一步阐明潜在的机制。在目标3中，我们将检查阵发性AF患者口服乙醇摄入量与AF发作之间的实时关联，阵发性AF患者佩戴自动记录心电图监测仪与透皮乙醇传感器配对，持续四周。将确定急性乙醇摄入与AF发作之间的关联强度以及乙醇相关发作之前的心律性质（包括心率、心率变异性和房性期前收缩计数）。

DESCRIPTION (provided by applicant): Ethanol is the most commonly consumed drug in the world. Atrial fibrillation (AF) is the most common arrhythmia: it currently affects several million Americans and is responsible for substantial morbidity and mortality with an estimated annual health care cost greater than 6.5 billion dollars. Small observational studies have suggested that ethanol can trigger acute episodes of AF. Large, prospective, epidemiological studies suggest that ethanol use may result in new-onset AF. However, the mechanisms underlying the potential association between either acute or chronic ethanol exposure and AF remain unknown. Investigating these causal mechanisms is important for two reasons: first, evidence of a causal association between ethanol and AF would be pertinent to the > 100 million Americans that consume ethanol. Given the common notion that ethanol is "heart healthy," demonstrating that ethanol has electrophysiological and/ or structural cardiac effects that promote AF would be particularly important. Second, understanding how an external source can acutely trigger or chronically lead to the development of AF would reveal common mechanisms underlying AF in general. There is currently no experimental model wherein human AF can be reliably triggered and no known method to prevent AF. This research could therefore open up a new field of experimental human research in AF that ultimately leads to novel therapies or clinical strategies targeting the processes responsible for AF. In Aim 1, we will perform a randomized trial of intravenous ethanol versus placebo in paroxysmal AF patients undergoing invasive ablation procedures to determine the acute electrophysiological effects of ethanol on in vivo myocardium. We will compare pre and post-infusion premature atrial contraction counts, refractory periods, conduction velocities, activation-recovery intervals, restitution properties, ad susceptibilities to induced AF. In order to assure a consistent blood ethanol concentration between patients and within-patients during the experiment, we will employ an established pharmacokinetic model to titrate and then "clamp" the ethanol infusion to maintain a steady blood ethanol concentration determined by serial breath tests. The mechanisms will be furthered elucidated in an animal model utilizing optical mapping. In order to assess the chronic effects of ethanol, Aim 2 will involve a secondary analysis of serial ethanol assessments and echocardiograms in the Framingham Heart Study to determine if ethanol-induced left atrial enlargement is responsible for incident AF. An animal model of chronic ethanol consumption will be used to further elucidate underlying mechanisms. In Aim 3, we will examine the real-time association between oral ethanol intake and AF episodes in paroxysmal AF patients wearing an automatically recording electrocardiographic monitor paired with a transdermal ethanol sensor for a four week period. The strength of the association between acute ethanol intake and AF episodes as well as the nature of the heart rhythm prior to ethanol-associated episodes (including heart rate, heart rate variability, and premature atrial contraction counts) will be determined.