Mechanistic Relationships Between Ethanol and Human Atrial Fibrillation

乙醇与人类心房颤动之间的机制关系

• 批准号: 9249436
• 负责人: GREGORY M MARCUS
• 金额: $ 55.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249436
• 关键词: Ablation; Action Potentials; Acute; Address; Affect; Alcohol consumption; Alcohols; American; Animal Experiments; Animal Model; Arrhythmia; Atrial Fibrillation; Atrial Premature Complexes; Blood; Blood Pressure; Breath Tests; Cardiac; Cardioscopes; Cardiovascular system; Case Series; Cessation of life; Cholesterol; Chronic; Clinical; Closure by clamp; Conflict (Psychology); Coronary heart disease; Coupled; Data; Development; Disease; Echocardiography; Electrophysiology (science); Ethanol; Etiology; Event; Evolution; Experimental Models; Framingham Heart Study; Guidelines; Health Care Costs; Heart; Heart Abnormalities; Heart Atrium; Heart Rate; Hospitalization; Human; Infusion procedures; Intravenous; Investigation; Lead; Left; Life; Measurable; Mechanics; Methods; Morbidity - disease rate; Myocardium; Nature; Observational Study; Optics; Oral; Patients; Perception; Pharmaceutical Preparations; Placebos; Plant Roots; Post-Menopausal Hormone Replacement Therapy; Predisposition; Prevention strategy; Primary Prevention; Procedures; Process; Property; Recommendation; Recovery; Refractory; Research; Risk; Smoking; Source; Stroke; Techniques; Technology; Time; alcohol effect; alcohol exposure; binge drinking; cardiovascular health; chronic alcohol ingestion; clinical investigation; clinical practice; data resource; epidemiology study; experimental study; heart rate variability; heart rhythm; in vivo; mortality; multidisciplinary; new therapeutic target; novel therapeutics; pharmacokinetic model; prevent; prospective; public health relevance; randomized trial; secondary analysis; sensor; success; time use; tool

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.

描述（由申请人提供）：乙醇是世界上最常消费的药物。心房颤动 (AF) 是最常见的心律失常：目前影响数百万人 美国人的发病率和死亡率很高，估计每年的医疗费用超过 65 亿美元。小型观察性研究表明，乙醇可引发房颤急性发作。大型前瞻性流行病学研究表明，使用乙醇可能导致新发房颤。然而，急性或慢性乙醇暴露与房颤之间潜在关联的机制仍不清楚。研究这些因果机制很重要，原因有两个：首先，乙醇和房颤之间因果关系的证据将与消耗乙醇的超过 1 亿美国人相关。鉴于乙醇是“心脏健康”的普遍观念，证明乙醇具有促进房颤的电生理和/或结构性心脏效应尤其重要。其次，了解外部来源如何急性触发或长期导致房颤的发展将揭示房颤的共同机制。目前还没有可以可靠触发人类房颤的实验模型，也没有已知的预防房颤的方法。因此，这项研究可能开辟 AF 人类实验研究的新领域，最终导致针对 AF 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 AF 患者中进行静脉注射乙醇与安慰剂的随机试验，以确定乙醇对体内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-恢复间隔、恢复特性以及诱发房颤的敏感性。为了确保实验期间患者之间和患者体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“夹紧”乙醇输注，以维持通过连续呼吸测试确定的稳定的血液乙醇浓度。该机制将在利用光学测绘的动物模型中进一步阐明。为了评估乙醇的慢性影响，目标 2 将涉及对 Framingham 心脏研究中的连续乙醇评估和超声心动图进行二次分析，以确定乙醇引起的左心房扩大是否是 AF 事件的原因。慢性乙醇消耗的动物模型将用于进一步阐明潜在机制。在目标 3 中，我们将检查阵发性 AF 患者佩戴自动记录心电图监测仪与经皮乙醇传感器配对四个星期后，口服乙醇摄入量与 AF 发作之间的实时关联。将确定急性乙醇摄入量与房颤发作之间的关联强度以及乙醇相关发作之前心律的性质（包括心率、心率变异性和房性早搏计数）。