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

房颤是退伍军人最常见的持续性心律失常，与 增加中风、心力衰竭和死亡的风险。受房颤影响的美国人人数为 预计到2050年将激增至约1600万。尽管一种因果关系 肥胖和房颤之间的关系是最近建立的，其潜在的病理生理机制和 它们对抗心律失常药物(AAD)治疗反应的影响尚不清楚。新出现的证据 支持减少心肌Na+通道的表达是一个潜在的作用机制。自.以来 I类AADs可阻断心脏Na+通道(NaV1.5)，通常用于治疗房颤、 这项建议的首要目标是阐明潜在的电生理(EP)和分子 肥胖增加房颤风险并调节对钠通道阻滞剂反应的机制 在饮食诱导肥胖(DIO)小鼠中。特定目标1将检验肥胖引起的房颤是 与DIO小鼠氧化应激增加有关，这种影响部分是通过 调节心脏钠离子通道。我们将测定心房的生物标志物(4-羟基壬烯醛，4-HNE； DIO小鼠体内硝化蛋白(YNO2)和全身性(F2-异前列烷，IsoP)氧化应激 将它们与精益控制进行比较。这个目标建立在我们之前的工作基础上，表明SCN5A损失- 功能突变通过减少NaV1.5的表达和电流(INA)，增加房颤的风险 显示DIO小鼠比瘦削对照组更容易发生房颤，这种风险部分是通过 NaV1.5的下调和氧化应激的增加。尽管最近基于导管的技术取得了进展 治疗上，AADS仍是治疗症状性房颤的常用药物。然而，在一个 患者个体的变化很大，膜活性药物与严重的毒性有关。 因此，一个主要的知识缺口是预测哪些房颤患者最有可能对AADS做出反应。 我们在JBVA/UIC房颤登记处生成的试点数据不仅表明肥胖对 对抗心律失常治疗的反应，但对Na+通道和K+通道的反应不同 通道阻滞剂AADS。这提出了要在特定目标2中测试的假设，即氟卡胺(Na+ 通道阻滞剂)治疗DIO小鼠房颤的效果不如索他洛尔(K+通道阻滞剂)。肥胖的老鼠会 经食道快速心房调搏诱发房颤，急性或急性应用AADS治疗 慢性以房颤负荷为主要结局。这个目标建立在我们的临床和动物数据基础上 这表明氟卡胺对肥胖患者和DIO小鼠的房颤治疗效果降低 分别进行了分析。我们的研究表明，肥胖导致的房颤与氧化增加有关 应激，这在一定程度上是通过调节心脏Na+通道来实现的。具体目标3将 确定肥胖增加DIO小鼠房颤风险的潜在分子机制：i) 确定ROS产生的来源和具体途径；ii)确定NaV1.5是否直接 以增加的氧化应激为靶点；以及iii)评估氧化应激如何影响表达 和心脏Na+通道的活性。这一目标建立在我们早期的研究和试点数据的基础上，我们 显示线粒体靶向抗氧化剂治疗DIO小鼠的房颤负荷显著降低 (MitoTEMPO)。拟议研究的直接影响将阐明潜在的EP和分子 肥胖增加房颤风险的机制；确定氧化应激的新的心房生物标记物 这将转化为患者；发现用于治疗靶向的ROS产生的特定途径； 并验证这样的假设，即小鼠模型的结果可以转化为更好的抗心律失常药物 肥胖型房颤患者的治疗。 1