Sleep Apnea Endophenotypes: One Size Does Not Fit All

项目摘要 OSA的定义是上呼吸道反复收缩，这一过程会导致一过性低氧血症和 从睡眠中唤醒，与各种心血管、代谢和神经认知有关 后果。阻塞性睡眠呼吸暂停综合征是最常见的呼吸系统疾病，大约10%的中年男性和 美国的女性和全球高达10亿的女性。尽管持续气道正压(PAP)是一种 有效的治疗方法并不总是耐受性好，依从性也不是很理想。OSA越来越多地 被认为是一种多因素障碍，可能由于不同的原因发生在不同的人身上，不仅是因为 解剖学倾向(上呼吸道的塌陷性)，但也与低觉醒阈值(唤醒)有关 上呼吸道扩张肌功能障碍和呼吸控制不稳定。通过细心 测量这些潜在因素和阻塞性睡眠呼吸暂停综合征的症状，这项建议旨在 了解阻塞性睡眠呼吸暂停综合征的不同机制-内型-如何导致不同的症状或 后果--表型。这些不同的表型从没有明显症状到 在方向盘上睡着，经历心脏新陈代谢的后果。此外，解决 潜在的原因可能有助于个体化治疗，预测对PAP的依从性，并了解 长期的PAP治疗将会或不会改善症状。临床实践中的一个主要挑战是 了解特定症状是否由阻塞性睡眠呼吸暂停综合症引起，以及这些症状是否会随着 治疗。此外，我们目前正在努力寻找OSA的替代疗法，这可能取决于 潜在的机制。同样，我们目前不知道哪些患者应该进行临床试验，因为似乎 例如，不太可能所有的OSA患者都能从PAP治疗中获得心血管益处，因为并不是所有的患者都有 心脏病。我们的目标是1)了解阻塞性睡眠呼吸暂停综合征的潜在原因或内型对 阻塞性睡眠呼吸暂停综合征患者的症状，2)阐明内型如何预测对非阻塞性睡眠呼吸暂停综合征的反应 CPAP疗法，如氧气或镇静催眠药，以及3)定义潜在的内型(机制) 调节阻塞性睡眠呼吸暂停综合征治疗过程中的表型变化(疾病的临床表现)。最终我们希望 我们的努力将推动OSA领域的发展，并有助于减轻痛苦或减轻/预防疾病负担。

Project Summary OSA is defined by repetitive collapse of the upper airway, a process which leads to transient hypoxemia and arousals from sleep, and is associated with various cardiovascular, metabolic, and neurocognitive consequences. OSA is the most common respiratory disorder, affecting roughly 10% of middle aged men and women in the USA and up to 1 billion globally. Although continuous positive airway pressure (PAP) is an efficacious therapy, it is not always well tolerated and adherence is less than ideal. OSA is increasingly recognized as a multifactorial disorder that can occur in different people for different reasons, not only due to anatomical predisposition (collapsibility of the upper airway), but also related to low arousal threshold (wake up too easily), dysfunction in upper airway dilator muscles and instability in ventilatory control. Through careful measurement of these underlying factors and the symptoms experienced in OSA, this proposal seeks to understand how different mechanisms underlying OSA – endotypes – lead to different symptoms or consequences – phenotypes. These different phenotypes range from having no appreciable symptoms, to falling asleep at the wheel, to experiencing cardiometabolic consequences. Additionally, addressing the underlying cause might be useful to personalize therapy, to predict adherence to PAP, and to understand which symptoms will or will not improve with long term PAP therapy. A major challenge in clinical practice is understanding whether particular symptoms are due to OSA, and whether these symptoms will improve with treatment. Moreover, we are currently struggling to find alternative therapies for OSA which will likely depend on underlying mechanism. Similarly, we do not currently know which patients to put into clinical trials since it seems unlikely that, e.g., all OSA patients will have cardiovascular benefits to PAP therapy since not all are at risk of heart disease. Our goals are 1) To understand the contribution of the underlying cause, or endotype, of OSA to the symptoms experienced by people with OSA, 2) To elucidate how the endotype predicts response to non CPAP therapies, such as oxygen or sedative hypnotics, and 3) To define how underlying endotype (mechanism) mediates changes in phenotype (clinical manifestations of disease) with treatment of OSA. Ultimately we hope that our efforts will advance the OSA field and help to alleviate suffering or reduce/prevent disease burden.