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.

项目概要 阻塞性睡眠呼吸暂停 (OSA) 是一种常见疾病，会损害睡眠期间的稳定呼吸。 2 型糖尿病的危险因素，是全球残疾和心血管疾病的主要原因。 此外，OSA 还可诱发胰岛素抵抗、血管功能障碍和炎症——这些损害 最终导致糖尿病和动脉粥样硬化性心血管疾病的机制目前尚不清楚。 OSA 导致心脏代谢功能障碍尚不清楚。由于缺乏了解，因此无法确定。 确定哪些无症状患者需要治疗，或挽救那些无法治疗的患者的代谢健康 为了耐受持续气道正压通气 (CPAP) 治疗，已使用间歇性缺氧 (IH)。 模拟小鼠的 OSA 已被证明会导致血脂异常、血管僵硬和血糖升高。 此外，急性 IH 会增加血浆游离脂肪酸 (FFA) 和高血糖。 依赖的方式，并且这些作用可以通过药物或手术中断来消除 最近，也有研究表明 OSA 会增加夜间 FFA 和交感神经系统。 这些发现表明 OSA 是一种有效的药物。 脂肪组织脂肪分解和抑制葡萄糖清除的偶发原因，具有潜在的破坏性 累积的长期影响。 该项目的目标是了解：（目标 1）OSA 患者在进行 FFA 治疗时会出现血糖升高， （目标 2）通过什么机制回答这些问题将识别 OSA 易感患者， 并确定这些人的治疗目标 确定 OSA 的严重程度（通过测量）。 AHI 或睡眠期间增加的中位心率）与底物升高相关。 将在小鼠模型中评估性别和 AHI 对新陈代谢的独立和/或交互影响。 IH 的第二个目标是用普萘洛尔阻断 β 肾上腺素能来预防代谢功能障碍。 该项目旨在测试普萘洛尔与安慰剂在人类 OSA 中预防夜间睡眠障碍的功效 该提案将发现 OSA 促进代谢的机制。 功能障碍，识别易受这种病理生理学影响的患者，并介绍 β 的新用途 封锁治疗。