Mechanistic Relationships Between Ethanol and Human Atrial Fibrillation

描述(申请人提供)：乙醇是世界上最常用的药物。房颤(房颤)是最常见的心律失常：目前影响着数百万人 据估计，每年的医疗保健费用超过65亿美元，导致大量的发病率和死亡率。小型观察性研究表明，乙醇可以引发急性房颤发作。大规模的前瞻性流行病学研究表明，使用乙醇可能会导致新发的房颤。然而，急性或慢性酒精暴露与房颤之间潜在关联的潜在机制仍不清楚。研究这些因果机制很重要，原因有两个：第一，乙醇和房颤之间存在因果关系的证据与消费乙醇的1亿美国人有关。鉴于乙醇“有益心脏健康”的普遍概念，证明乙醇具有促进房颤的电生理和/或结构性心脏效应将特别重要。其次，了解外部来源如何强烈地触发或慢性地导致房颤的发生，将揭示房颤的共同机制。目前还没有可靠地触发人体房颤的实验模型，也没有已知的预防房颤的方法。因此，这项研究可能开辟房颤人体实验研究的新领域，最终导致针对房颤相关过程的新疗法或临床策略。在目标1中，我们将在接受侵入性消融手术的阵发性房颤患者中进行静脉注射乙醇和安慰剂的随机试验，以确定乙醇对活体心肌的急性电生理影响。我们将比较输注前后的房性早搏计数、不应期、传导速度、激活-恢复间期、恢复特性、诱发房颤的易感性。为了确保在实验期间患者和患者体内的血液乙醇浓度保持一致，我们将使用已建立的药代动力学模型来滴定乙醇输注，然后“夹住”乙醇输注，以保持通过连续呼气测试确定的稳定的血液乙醇浓度。这些机制将在利用光学测绘的动物模型中进一步阐明。为了评估酒精的慢性影响，AIM 2将在弗雷明翰心脏研究中对一系列酒精评估和超声心动图进行二次分析，以确定酒精导致的左房扩大是否与房颤事件有关。慢性酒精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，我们将检验在四周期间佩戴自动记录心电监护仪和透皮酒精传感器的阵发性房颤患者的口服酒精摄入和房颤发作之间的实时关联。将确定急性酒精摄入与房颤发作之间的关联强度以及酒精相关发作(包括心率、心率变异性和房性早搏计数)之前心律的性质。

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.