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Obesity-Mediated Atrial Fibrillation: Underlying Mechanisms and Responsiveness to Antiarrhythmic Therapy

肥胖介导的心房颤动：潜在机制和抗心律失常治疗的反应

基本信息

批准号：
10905978
负责人：
Dawood Darbar
金额：
--
依托单位：
JESSE BROWN VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10905978
关键词：
4 hydroxynonenal Acute Affect Aging American Animals Anti-Arrhythmia Agents Antioxidants Arrhythmia Atrial Fibrillation Biological Markers Cardiac Catheters Cessation of life Chronic Clinical Data Complex Data Down-Regulation Electrophysiology (science)Epidemic Esophagus F2-Isoprostanes Flecainide Functional disorder Genes Goals Heart Atrium Heart Block Heart failure Heterogeneity Human Inferior Knowledge Left Measures Mediating Membrane Metabolic syndrome Mitochondria Modeling Molecular Morbidity - disease rate Obese Mice Obesity Obesity Epidemic Oxidative Stress Oxidative Stress Induction Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Population Potassium Channel Predisposition Production Proteins Refractory Registries Risk Role Sotalol Source Testing Thinness Tissues Toxic effect Translating Veterans Work adverse drug reaction animal data channel blockers diet-induced obesity genetic variant in vivo imaging indium arsenide individual patient loss of function mutation mortality mouse model novel novel therapeutics obese patients primary outcome response stroke risk therapeutic target

项目摘要

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia in Veterans, is associated with increased risk for stroke, heart failure, and death. The number of Americans affected by AF is expected to surge to approximately 16 million by the year 2050. Although a causal relationship between obesity and AF was recently established, the underlying pathophysiological mechanisms and their impact on response to antiarrhythmic drug (AAD) therapy remain unclear. Emerging evidence supports reduced cardiac Na+ channel expression as one potential contributing mechanism. Since Class I AADs, which block the cardiac Na+ channel (Nav1.5), are commonly used to treat AF, the overarching goal of this proposal is to elucidate the underlying electrophysiologic (EP) and molecular mechanisms by which obesity increases risk of AF and modulates response to Na+ channel blockers in diet-induced obese (DIO) mice. Specific Aim 1 will test the hypothesis that obesity-induced AF is associated with increased oxidative stress in DIO mice and this effect is in part mediated by modulating the cardiac Na+ channel. We will measure biomarkers of atrial (4-hydroxynonenal, 4-HNE; nitrated proteins, YNO2) and systemic (F2-isoprostanes, IsoPs) oxidative stress in DIO mice and compare them with lean controls. This aim builds on our previous work showing that SCN5A loss-of- function mutations increase AF risk by reducing Nav1.5 expression and current (INa), pilot data showing that DIO mice are more prone to AF than lean controls and this risk is mediated in part by downregulation of Nav1.5 and increased oxidative stress. Despite recent advances in catheter-based therapies, AADs continue to be commonly used to treat symptomatic AF. However, response in an individual patient is highly variable and membrane-active drugs are associated with serious toxicities. Thus, a major knowledge gap is predicting which patients with AF are most likely to respond to AADs. Our pilot data, generated in the JBVA/UIC AF Registry, not only shows that obesity modulates response to antiarrhythmic therapy but that there is a differential response to Na+ channel versus K+ channel blocker AADs. This raises the hypothesis to be tested in Specific Aim 2 that flecainide (Na+ channel blocker) is inferior to sotalol (K+ channel blocker) in treating AF in DIO mice. Obese mice will undergo rapid transesophageal atrial pacing to induce AF and then be treated with AADs acutely or chronically with AF burden as the primary outcome. This aim builds on our clinical and animal data that shows reduced efficacy of flecainide in treatment of AF in obese patients and DIO mice respectively. Our studies have shown that obesity-mediated AF is associated with increased oxidative stress and this is mediated in part by modulation of the cardiac Na+ channel. Specific Aim 3 will define the underlying molecular mechanisms by which obesity increases risk of AF in DIO mice by: i) identifying the sources and specific pathways of ROS production; ii) determining if Nav1.5 is directly targeted by increased oxidative stress; and iii) evaluating how oxidative stress impacts the expression and activity of the cardiac Na+ channel. This aim builds on our earlier studies and pilot data where we show significant reduction in AF burden in DIO mice treated with a mitochondria-targeted antioxidant (MitoTEMPO). Direct impact of the proposed studies will elucidate the underlying EP and molecular mechanisms by which obesity increases risk of AF; identify novel atrial biomarkers of oxidative stress that will translate to patients; uncover specific pathways of ROS production for therapeutic targeting; and test the hypothesis that results from mouse models can be translated into better antiarrhythmic therapy in obese patients with AF. 1

房颤（AF）是退伍军人中最常见的持续性心律失常