Intermittent hypoxia-initiated plasticity in humans: A multi-pronged therapeutic approach to treat sleep apnea and overlapping co-morbidities.

摘要 阻塞性睡眠呼吸暂停(OSA)在退伍军人中的患病率很高，这种疾病是 与许多心血管、神经认知和代谢异常有关。因此，阻塞性睡眠呼吸暂停综合征是一种主要的健康 退伍军人群体的担忧。在许多情况下，阻塞性睡眠呼吸暂停综合征的治疗并没有带来显著的改善 在结果衡量方面。这种不足可能是治疗依从性降低的结果 气道正压(CPAP)或因为CPAP对预后指标的影响很小或没有 一些患者尽管有足够的依从性。因此，直接影响合作的创新疗法-- 与阻塞性睡眠呼吸暂停相关的疾病或增加CPAP依从性可能会导致结果测量的改善。在 在最近的资金周期中，我们建立了每天重复暴露于轻度间歇性低氧(MIH)加上 CPAP改变自主神经系统活动并显著降低血压 单用CPAP治疗。由于MIH与CPAP相耦合，MIH对血压的独立作用 还没有建立起来。此外，目前还不能确定这些结果是否会持续很长时间。 周期(即周到月)。 尽管我们获得了一些间接证据表明，自主神经系统活动的改变 再加上血压的降低，我们没有确定微血管功能的改变是否 很明显。微血管功能障碍和交感-迷走神经失衡不仅可能导致后果 用于外周血管阻力和血压，也用于肌肉灌流和代谢，从而 限制阻塞性睡眠呼吸暂停患者的运动能力和增加疲劳性。因此，血压的降低 MIH治疗后微血管功能的改善可能有助于改善运动 阻塞性睡眠呼吸暂停患者的能力和反向操作疲劳。 除了对自主神经和心血管功能的潜在影响外，我们和其他人之前已经建立了 急性暴露于MIH会引起人类上呼吸道肌肉活动的持续增加。这 持续增加是呼吸可塑性的一种形式，称为长期促进。然而，在没有 我们已经证明，睡眠前或睡眠中的急性MIH会导致呼吸暂停严重程度的增加。 这可能是因为在出现低碳酸血症时缺乏长期促进作用的表现。 睡眠期间，通过启动另一种形式的可塑性，即所谓的渐进性，可以诱发低碳酸血症 增强功能。然而，有可能每天接触MIH的时间长达数小时 睡眠前可减轻渐进性增加导致上呼吸道增加的影响 稳定性。 不考虑这种可能性，我们在之前的资金周期中表明，增加了上呼吸道的稳定性 在接受MIH治疗后，治疗性CPAP的减少和依从性的改善是相关联的。 然而，改善对CPAP的遵守也可能与提高两者的觉醒阈值有关 呼吸性和非呼吸性刺激。上述所有不确定性都将在目前得到解决 求婚。

Abstract The prevalence of obstructive sleep apnea (OSA) is high in the Veteran population and this disorder is linked to numerous cardiovascular, neurocognitive and metabolic abnormalities. Thus, OSA is a major health concern in the Veteran population. Treatment of OSA in many cases does not lead to significant improvements in outcome measures. This inadequacy may be a consequence of reduced treatment adherence with continuous positive airway pressure (CPAP) or because the effect of CPAP on outcome measures is small or absent in some patients despite adequate adherence. Consequently, innovative therapies that directly impact co- morbidities linked to OSA or that increase CPAP adherence could lead to improved outcome measures. In the recent funding cycle, we established that repeated daily exposure to mild intermittent hypoxia (MIH) coupled with CPAP modifies autonomic nervous system activity and dramatically decreases blood pressure compared to CPAP treatment alone. Because MIH was coupled with CPAP, the independent effect of MIH on blood pressure was not established. Moreover, it was not established if these outcomes were sustained for a prolonged time period (i.e. weeks to months). Although we obtained some indirect evidence that modifications in autonomic nervous system activity were coupled to the reduction in blood pressure, we did not establish if modifications in microvascular function were evident. Microvascular dysfunction together with sympatho-vagal imbalance may have consequences not only for peripheral vascular resistance and blood pressure but also for muscle perfusion and metabolism, thereby limiting exercise performance and increasing fatigability in patients with OSA. Thus, reductions in blood pressure and improvement in microvascular function following treatment with MIH might serve to improve exercise capacity and reverse performance fatigue in individuals with OSA. Besides its potential effect on autonomic and cardiovascular function, we and others previously established that acute exposure to MIH initiates sustained increases in upper airway muscle activity in humans. This sustained increase is a form of respiratory plasticity known as long-term facilitation. However, in the absence of CPAP we have shown that acute MIH immediately prior to or during sleep leads to increases in apnea severity. This might occur because the manifestation of long-term facilitation is absent in the presence of hypocapnia. Hypocapnia can be induced during sleep by the initiation of another form of plasticity known as progressive augmentation. However, it is possible that the combination of daily exposure to MIH administered many hours before the sleep period may mitigate the effects of progressive augmentation leading to increased upper airway stability. Independent of this possibility, we showed in the previous funding cycle that increased upper airway stability following treatment with MIH was coupled to a reduction in therapeutic CPAP and improved adherence. However, improved adherence to CPAP might also be linked to an increase in the arousal threshold to both respiratory and non-respiratory stimuli. All the uncertainties outlined above will be addressed in the present proposal.