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

• 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
• 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

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

心房颤动（AF）是退伍军人中最常见的心律不齐的心律不齐，与 增加中风，心力衰竭和死亡的风险。受AF影响的美国人人数是 预计到2050年将增加约1600万。尽管有因果关系 最近建立了肥胖症和AF之间的基本病理生理机制和 它们对抗心律失常药物（AAD）疗法反应的影响尚不清楚。新兴证据 支持降低心脏Na+通道表达，作为一种潜在的促进机制。自从 阻塞心脏NA+通道（NAV1.5）的I类AADS通常用于治疗AF， 该提案的总体目标是阐明潜在的电生理学（EP）和分子 肥胖增加AF风险并调节对NA+通道阻滞剂的反应的机制 在饮食引起的肥胖（DIO）小鼠中。具体目标1将检验肥胖引起的AF的假设是 与DIO小鼠中氧化应激增加有关，这种作用部分由 调节心脏NA+通道。我们将测量房屋的生物标志物（4-羟基烯烯，4-HNE； 硝酸蛋白质，YNO2）和全身性（F2-异前体，ISOP）氧化应激，以及 将它们与精益控件进行比较。这个目标是基于我们以前的工作，表明SCN5A丧失 - 功能突变通过减少NAV1.5表达和电流（INA），飞行员数据来增加AF风险 表明DIO小鼠比瘦的控制更容易容易受AF，并且这种风险部分是由 NAV1.5的下调和增加的氧化应激。尽管最近取得了基于导管的进展 疗法，AADS继续通常用于治疗有症状的AF。但是，回应 个体患者的变化很大，膜活性药物与严重的毒性有关。 因此，主要的知识差距正在预测哪些AF患者最有可能对AAD反应。 我们的试点数据，在JBVA/UIC AF注册表中生成 对抗心律失常疗法的反应，但对Na+通道的反应与K+有不同的反应 通道阻止器AADS。这提出了要在特定目的2中测试的假设（Na+） 通道阻滞剂）在DIO小鼠中治疗AF中的AF中不如Sotalol（K+通道阻滞剂）。肥胖的老鼠会 经过快速的经食道心房起搏以诱导AF，然后用AADS敏锐或 长期以AF负担为主要结果。这个目标是基于我们的临床和动物数据 这表明氟卡因在肥胖患者和DIO小鼠中治疗AF的疗效降低 分别。我们的研究表明，肥胖介导的AF与氧化增加有关 应力，这部分是通过对心脏Na+通道的调节来介导的。具体的目标3将 定义肥胖来增加DIO小鼠AF风险的潜在分子机制：i） 识别ROS产生的来源和特定途径； ii）确定NAV1.5是否直接 由氧化应激增加的目标； iii）评估氧化应激如何影响表达 心脏NA+通道的活性。这个目标是基于我们早期的研究和试点数据 在用线粒体靶向抗氧化剂治疗的DIO小鼠中显示出AF负担的显着降低 （mitotempo）。拟议研究的直接影响将阐明潜在的EP和分子 肥胖会增加AF风险的机制；识别新型的氧化应激的心房生物标志物 这将转化为患者；发现用于治疗靶向的ROS产生的特定途径； 并检验了小鼠模型结果的假设可以转化为更好的抗心律失常 肥胖患者的治疗。 1