Pilot Study of Beta Adrenergic Blockade to Prevent Metabolic Consequences of Sleep Apnea

β 肾上腺素能阻滞剂预防睡眠呼吸暂停代谢后果的初步研究

• 批准号: 9372432
• 负责人: Jonathan C. Jun
• 金额: $ 8.18万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9372432
• 关键词: Acute; Adipose tissue; Adrenal Glands; Adrenergic Agents; Adrenergic beta-Antagonists; Affect; Atherosclerosis; Blood Vessels; Breathing; Cardiovascular Diseases; Cholesterol; Chronic; Classification; Clinical; Clinical Research; Continuous Positive Airway Pressure; Data; Denervation; Diabetes Mellitus; Diagnosis; Disease; Dose; Double-Blind Method; Dyslipidemias; Exposure to; Fatty Acids; Female; Functional disorder; Funding; Gender; Glucose; Glucose Intolerance; Goals; Health; Heart Rate; Heart failure; Human; Hyperglycemia; Hyperlipidemia; Hypertension; Hypoxemia; Hypoxia; Impairment; Individual; Inflammation; Insulin Resistance; Interruption; Intervention; Knowledge; Lead; Link; Lipolysis; Measures; Mediating; Metabolic; Metabolic syndrome; Metabolism; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Obstructive Sleep Apnea; Operative Surgical Procedures; Outcome; Oxygen; Patients; Pharmacology; Pilot Projects; Placebo Control; Placebos; Plasma; Prevalence; Propranolol; Randomized; Research; Risk Factors; Severities; Signal Transduction; Sleep; Sleep Apnea Syndromes; Sympathetic Nervous System; Testing; Triglycerides; United States; Vascular Diseases; Withdrawal; Woman; cardiovascular risk factor; clinical application; diabetes risk; disability; disorder risk; efficacy testing; endothelial dysfunction; evidence base; experimental study; hemodynamics; male; men; mouse model; novel; oral glucose tolerance; prevent; secondary outcome; stressor

PROJECT SUMMARY Obstructive sleep apnea (OSA) is a common disorder that impairs stable breathing during sleep. OSA is a risk factor for type 2 diabetes, a leading cause of worldwide disability and cardiovascular disease. Furthermore, OSA can induce insulin resistance, vascular dysfunction, and inflammation – insults that ultimately lead to diabetes and atherosclerotic cardiovascular disease. Currently, the mechanism by which OSA causes cardiometabolic dysfunction is not known. This lack of knowledge makes it impossible to determine which asymptomatic patients require treatment, or to salvage the metabolic health of those unable to tolerate continuous positive airway pressure (CPAP) therapy. Intermittent hypoxia (IH) has been used to simulate a OSA in mice. Chronic IH has been shown to cause dyslipidemia, vascular stiffness, and glucose intolerance. Moreover, acute IH increased plasma free fatty acids (FFA) and hyperglycemia in a dose- dependent manner, and these effects were abolished by pharmacologic or surgical interruption of the sympathetic nervous system. Recently, it has also been shown that OSA increases nocturnal FFA and glucose levels and causes insulin resistance during sleep. These findings demonstrate that OSA is a potent episodic cause of adipose tissue lipolysis and inhibited glucose clearance, with potentially devastating cumulative long-term impacts. The goal of this project is to understand: (Aim 1) in which OSA patients do FFA and glucose elevations occur, and (Aim 2) by what mechanism? Answers to these questions will identify susceptible patients with OSA, and identify treatment targets for these individuals. It is hypothesized that severity of OSA (as measured by AHI or by increased median heart rate during sleep) correlates with substrate elevations. Additionally, independent and/or interactive effects of gender and AHI on metabolism will be assessed. In a mouse model of IH, beta adrenergic blockade with propranolol prevented metabolic dysfunction. Thus, the second aim of this project is to test the efficacy of propranolol versus placebo in human OSA for preventing nocturnal substrate elevations. This proposal will discover mechanisms by which OSA contributes to metabolic dysfunction, identify patients susceptible to this pathophysiology, and introduce the novel use of beta blockade for therapy.

项目摘要 阻塞性睡眠呼吸暂停（OSA）是一种常见疾病，会损害睡眠期间稳定的呼吸。 OSA是一个 2型糖尿病的危险因素，这是全球残疾和心血管疾病的主要原因。 此外，OSA可以诱导胰岛素抵抗，血管功能障碍和炎症 - 侮辱 最终导致糖尿病和动脉粥样硬化心血管疾病。目前，该机制 OSA导致心脏代谢功能障碍尚不清楚。缺乏知识使得不可能 确定哪些不对称患者需要治疗，或挽救无法治疗的患者 耐受持续的阳性气道压力（CPAP）治疗。间歇性缺氧（IH）已习惯 模拟小鼠中的OSA。已显示慢性IH引起血脂异常，血管僵硬和葡萄糖 intlerance。此外，急性IH增加了血浆无脂肪酸（FFA）和剂量中的高血糖 依赖方式，这些作用被药理或手术中断废除了 交感神经系统。最近，还显示OSA增加了夜间FFA和 葡萄糖水平并在睡眠期间引起胰岛素抵抗。这些发现表明OSA是有效的 脂肪组织脂解和抑制葡萄糖清除率的发作性原因，潜在的毁灭性 累积长期影响。 该项目的目的是了解：（ AIM 1）OSA患者进行FFA和葡萄糖升高的情况， （AIM 2）通过什么机制？这些问题的答案将确定患有OSA的敏感患者， 并确定这些人的治疗目标。假设OSA的严重程度（如 AHI或通过增加睡眠期间心率的增加）与底物高度相关。此外， 将评估性别和AHI对代谢的独立和/或交互作用。在鼠标模型中 在IH的情况下，β肾上腺封闭式阻塞和普萘洛尔预防了代谢功能障碍。那是第二个目标 该项目是为了测试人OSA中普萘洛尔与安慰剂的效率，以防止夜间活动 底物高程。该提议将发现OSA对代谢贡献的机制 功能障碍，识别患者敏感这种病理生理学的患者，并引入了β的新颖使用 治疗块。