Phenotyping Mechanistic Pathways for Adverse Health Outcomes in Sleep Apnea

睡眠呼吸暂停不良健康结果的表型机制途径

• 批准号: 10221778
• 负责人: Ali Azarbarzin
• 金额: $ 66.13万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10221778
• 关键词: Acute; Adherence; Adverse event; Affect; Apnea; Arousal; Attention; Biological Markers; Blood Pressure; Blood gas; Cardiovascular system; Caring; Clinical Trials; Confusion; Continuous Positive Airway Pressure; Data; Diagnosis; Disease; Drowsiness; Endothelium; Event; Excessive Daytime Sleepiness; Exhibits; Failure; Goals; Gold; Grant; Health; Health Benefit; Heart Rate; Heart failure; Hour; Hypoxemia; Hypoxia; Individual; Knowledge; Link; Measures; Mediating; Methods; Monitor; Neurocognitive; Neurocognitive Deficit; Nitrates; Nitric Oxide; Nitrites; Observational Study; Obstructive Sleep Apnea; Outcome; Oxidative Stress; Pathogenicity; Pathway interactions; Patient Selection; Patient-Focused Outcomes; Patients; Performance; Persons; Phenotype; Physiological; Plasma; Problem Solving; Prognostic Marker; Quality of life; Research; Risk; Severities; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Splint Device; Sympathetic Nervous System; Telephone; Testing; Therapeutic; Time; Vasodilation; Visit; Woman; Work; adverse outcome; airway obstruction; automobile accident; base; cardiometabolism; effective therapy; follow-up; high risk; improved; indexing; individualized medicine; men; mortality; novel; patient subsets; personalized medicine; prevent; response; vigilance

PROJECT SUMMARY/ABSTRACT Obstructive sleep apnea (OSA) is a highly prevalent disorder with adverse neurocognitive and cardio-metabolic outcomes. Continuous positive airway pressure (CPAP) is the gold standard therapeutic option to treat airway obstructions during sleep and thus, prevent its adverse cardiovascular and neurocognitive outcomes. Previous clinical trials, however, have largely failed to show a consistent impact of CPAP on these health outcomes. One of the main limitations of these trials is, we believe, inadequate characterization of OSA and its acute physiological consequences. By characterizing OSA based on the “apnea-hypopnea index (AHI)”, there is a potential risk of negative results. We surmise that, by better characterization of OSA-related physiological consequences during sleep, we will be able to identify individuals at high risk for these adverse outcomes and those who would benefit most from therapy. We have developed physiologically driven metrics to capture the precise burden of OSA-related hypoxemia (“hypoxic burden”), autonomic response (“heart rate burden”), and sleep fragmentation (“arousal burden”). Our preliminary data from large observational studies suggest that these metrics outperform conventional sleep study parameters. In Aim 1, we seek to demonstrate that OSA patients with high hypoxic burden will exhibit greater improvements, after 12 weeks of CPAP therapy, in endothelial function (flow-mediated vasodilation) and oxidative stress markers than those with a low hypoxic burden. In Aim 2, we will investigate how heart rate burden determines the reduction in 24-hour mean blood pressure after 12 weeks of CPAP treatment. Finally, in Aim 3, we will seek to demonstrate that OSA patients with larger degrees of sleep fragmentation, quantified by arousal burden, will respond more favorably to CPAP, in terms of improvement in daytime sleepiness and attention, than those with low arousal burden. While the primary analysis will be the change in these outcomes after 12 weeks of CPAP, we will also assess these outcomes at 4 weeks to examine their time course. A total of 158 men and women with apnea-hypopnea index ≥15 events/hour will receive CPAP for 12 weeks. Adherence to therapy will be carefully monitored and encouraged by regular phone calls and in-person visits. Adverse events will also be closely monitored and recorded. Overall, our proposal is expected to demonstrate that prognostic markers of OSA that more strongly link with health outcomes will not only improve the diagnosis of OSA, but also provide a physiological basis for identifying those individuals most responsive to CPAP therapy. These results will have key mechanistic implications for “individualized medicine” in OSA by focusing on subgroups of patients who would most benefit from CPAP therapy. This personalized medicine approach will provide the scientific knowledge needed to progress towards larger studies in selected patients. Such results are of major importance because they have great potential to improve the quality of life and health outcomes of patients with OSA.

项目概要/摘要 阻塞性睡眠呼吸暂停 (OSA) 是一种非常普遍的疾病，会损害神经认知和心脏代谢 持续气道正压通气 (CPAP) 是治疗气道的金标准治疗选择。 睡眠期间的阻塞，从而防止其不良的心血管和神经认知结果。 然而，临床试验基本上未能显示 CPAP 对这些健康结果的一致影响。 我们认为，这些试验的主要局限性之一是对 OSA 及其急性症状的描述不充分。 通过基于“呼吸暂停低通气指数 (AHI)”来表征 OSA，可以得出以下结论： 我们推测，通过更好地表征 OSA 相关的生理学，可能会带来负面结果的潜在风险。 睡眠期间的后果，我们将能够识别出这些不良后果的高风险个体， 那些将从治疗中受益最大的人，我们开发了生理驱动的指标来捕捉。 OSA 相关低氧血症的精确负担（“缺氧负担”）、自主反应（“心率负担”）和 睡眠碎片化（“觉醒负担”）。我们从大型观察研究中得到的初步数据表明，这些 指标优于传统的睡眠研究参数。 在目标 1 中，我们力图证明缺氧负担高的 OSA 患者将表现出更大的改善， CPAP 治疗 12 周后，内皮功能（血流介导的血管舒张）和氧化应激 在目标 2 中，我们将研究心率负担如何决定。 CPAP 治疗 12 周后 24 小时平均血压的降低 最后，在目标 3 中，我们将寻求。 证明睡眠碎片化程度较高（通过唤醒负担量化）的 OSA 患者将 在改善日间嗜睡和注意力方面，与接受 CPAP 治疗的人相比，他们对 CPAP 的反应更积极 虽然主要分析是 CPAP 12 周后这些结果的变化， 我们还将在 4 周时评估这些结果，以检查总共 158 名男性和女性的时间进程。 呼吸暂停低通气指数≥15 次/小时将接受 CPAP 治疗 12 周。 还将通过定期电话和亲自拜访来仔细监控和鼓励。 严密监控并记录。 总体而言，我们的建议预计将证明 OSA 的预后标志物与 健康结果不仅可以改善 OSA 的诊断，还可以为识别 OSA 提供生理基础 这些结果将对 CPAP 治疗最敏感的人产生关键的机制影响。 OSA 中的“个体化医疗”，重点关注最能从 CPAP 中受益的患者亚组 这种个性化的医学方法将提供取得进展所需的科学知识。 对选定患者进行更大规模的研究非常重要，因为它们具有巨大的潜力。 改善 OSA 患者的生活质量和健康结果。