Mechanistic Relationships Between Ethanol and Human Atrial Fibrillation

乙醇与人类心房颤动之间的机制关系

基本信息

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
项目类别：
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

项目摘要

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）：乙醇是世界上最常见的药物。心房颤动（AF）是最常见的心律失常：目前影响数百万美国人，负责大量的发病率和死亡率，估计每年的医疗保健费用超过65亿美元。小型观察性研究表明，乙醇可以触发AF的急性发作。大型，前瞻性的流行病学研究表明，使用乙醇可能会导致新的AF。但是，急性或慢性乙醇暴露与AF之间潜在关联的基础机制尚不清楚。研究这些因果机制的重要性很重要：首先，乙醇与AF之间因果关系与食用乙醇的> 1亿美国人有关的证据。考虑到乙醇是“心脏健康”的普遍观念，表明乙醇具有促进AF的电生理和/或结构性心脏作用，这一点尤其重要。其次，了解外部来源如何急剧触发或长期导致AF的发展将揭示一般AF的共同机制。当前没有实验模型可以可靠地触发人AF，也没有预防AF的已知方法。因此，这项研究可以为AF中的一个新的实验性研究领域开放，最终导致针对负责AF的过程的新型疗法或临床策略。在AIM 1中，我们将在接受侵入性消融手术的阵发性AF患者中对静脉注射乙醇与安慰剂进行随机试验，以确定乙醇对体内心肌的急性电生理作用。我们将比较输注前和后早产的心房收缩计数，难治性周期，传导速度，激活恢复间隔，恢复性质，AD敏感性诱导的AF。为了确保在实验过程中确保患者和患者之间的血液乙醇浓度一致，我们将采用既定的药代动力学模型来滴定，然后“夹住”乙醇输注以维持由串行呼气测试确定的稳定的血液乙醇浓度。该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作用，AIM 2将涉及Framingham心脏研究中的连续乙醇评估和超声心动图的次要分析，以确定乙醇诱导的左心房增大是否导致AF发生AF。慢性乙醇消耗的动物模型将用于进一步阐明基本机制。在AIM 3中，我们将检查口服乙醇摄入量与AF发作之间的实时关联，该患者穿着自动记录的心电图监测仪，并在四个星期内与透皮乙醇传感器配对。将确定急性乙醇摄入与AF发作之间的关联以及在与乙醇相关发作之前（包括心率，心率变异性和过早心房收缩计数）之前的心律的性质。