Phenotyping Mechanistic Pathways for Adverse Health Outcomes in Sleep Apnea

项目总结/摘要 阻塞性睡眠呼吸暂停（OSA）是一种高度流行的神经认知和心血管代谢障碍 结果。持续气道正压通气（CPAP）是治疗气道疾病的金标准治疗选择， 睡眠期间的障碍，从而防止其不利的心血管和神经认知结果。先前 然而，临床试验在很大程度上未能显示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阻塞性睡眠呼吸暂停及其急性发作的特征描述不足。 生理后果。通过基于"呼吸暂停低通气指数（AHI）"表征OSA， 潜在的负面结果风险。我们推测，通过更好地描述OSA相关的生理学特征， 我们将能够识别出这些不良后果的高风险个体， 最能从治疗中获益的人我们已经开发了生理驱动的指标，以捕捉 OSA相关低氧血症（"低氧负荷"）、自主神经反应（"心率负荷"）的精确负荷，以及 睡眠碎片化（“唤醒负担”）。我们从大型观察性研究中获得的初步数据表明， 指标优于常规睡眠研究参数。 在目标1中，我们试图证明具有高低氧负荷的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 与低氧负荷低的人相比，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小时平均血压降低。最后，在目标3中，我们寻求 为了证明具有较大程度睡眠碎片的OSA患者，通过唤醒负担量化， 在改善日间嗜睡和注意力方面，CPAP的反应比那些 低唤醒负担。虽然主要分析将是CPAP治疗12周后这些结局的变化， 我们还将在4周时评估这些结果，以检查其时间进程。共有158名男女 呼吸暂停低通气指数≥ 15次事件/小时的患者将接受CPAP治疗12周。坚持治疗将是 通过定期电话和亲自访问进行仔细监测和鼓励。不良事件也将 密切监测和记录。 总的来说，我们的建议有望证明，OSA的预后标志物，更密切地联系在一起， 健康结果不仅可以改善OSA的诊断，还可以为识别OSA提供生理学基础。 对CPAP治疗反应最好的人。这些结果将具有关键的机械影响， 通过关注最能从CPAP中获益的患者亚组，在OSA中实施"个体化用药" 疗法这种个性化的医学方法将提供所需的科学知识， 在选定的患者中进行的大型研究。这些结果非常重要，因为它们具有巨大的潜力， 改善OSA患者的生活质量和健康状况。

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.