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持续性心律失常，与 中风、心力衰竭和死亡的风险增加。受房颤影响的美国人数量为 预计到 2050 年将激增至约 1600 万。尽管存在因果关系 最近确定了肥胖和房颤之间的关系，其潜在的病理生理机制和 它们对抗心律失常药物（AAD）治疗反应的影响仍不清楚。新出现的证据 支持减少心脏 Na+ 通道表达作为一种潜在的贡献机制。自从 I 类 AAD 阻断心脏 Na+ 通道 (Nav1.5)，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）和分子生物学 肥胖增加 AF 风险并调节 Na+ 通道阻滞剂反应的机制 在饮食诱导的肥胖（DIO）小鼠中。具体目标 1 将检验以下假设：肥胖引起的 AF 是 与 DIO 小鼠氧化应激增加有关，这种作用部分是由 调节心脏 Na+ 通道。我们将测量心房的生物标志物（4-羟基壬烯醛，4-HNE； DIO 小鼠中的硝化蛋白（YNO2）和全身（F2-异前列腺素，IsoPs）氧化应激 将它们与精益控制进行比较。这一目标建立在我们之前的工作基础上，表明 SCN5A 丢失- 功能突变通过降低 Nav1.5 表达和电流 (INa) 增加 AF 风险，试验数据 结果表明，DIO 小鼠比瘦对照小鼠更容易发生 AF，这种风险部分是由 Nav1.5 下调并增加氧化应激。尽管基于导管的最新进展 治疗方法中，AAD 仍然常用于治疗症状性 AF。然而，回应 个体患者差异很大，膜活性药物与严重的毒性相关。 因此，一个主要的知识差距是预测哪些 AF 患者最有可能对 AAD 产生反应。 我们在 JBVA/UIC AF 登记处生成的试点数据不仅表明肥胖可以调节 对抗心律失常治疗有反应，但对 Na+ 通道与 K+ 通道的反应不同 通道阻断剂 AAD。这就提出了在具体目标 2 中要检验的假设：氟卡尼 (Na+ 通道阻滞剂）在治疗 DIO 小鼠 AF 方面不如索他洛尔（K+通道阻滞剂）。肥胖的老鼠会 接受快速经食管心房起搏诱发房颤，然后立即接受 AAD 治疗或 长期以房颤负担为主要结局。这一目标建立在我们的临床和动物数据的基础上 结果表明，氟卡尼治疗肥胖患者和 DIO 小鼠的 AF 疗效降低 分别。我们的研究表明，肥胖介导的房颤与氧化增加有关 压力，这部分是通过调节心脏 Na+ 通道介导的。具体目标 3 将 通过以下方式定义肥胖增加 DIO 小鼠 AF 风险的潜在分子机制： i) 确定 ROS 产生的来源和具体途径； ii) 判断 Nav1.5 是否直接 以氧化应激增加为目标； 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 使用线粒体靶向抗氧化剂治疗的 DIO 小鼠显示 AF 负担显着减轻 （水户TEMPO）。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；识别氧化应激的新型心房生物标志物 这将转化为患者；揭示用于治疗靶向的 ROS 产生的特定途径； 并检验小鼠模型的结果可以转化为更好的抗心律失常药物的假设 肥胖 AF 患者的治疗。 1