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）的患病率在退伍军人群体中很高，并且这种疾病是 与许多心血管、神经认知和代谢异常有关。因此，OSA是一种主要的健康 关注退伍军人。在许多情况下，OSA的治疗不会导致显著改善 在结果测量中。这种不充分可能是由于连续治疗依从性降低所致。 气道正压通气（CPAP）或因为CPAP对结局指标的影响很小或不存在， 一些患者尽管坚持治疗。因此，直接影响共同体的创新疗法， 与OSA相关的发病率或增加CPAP依从性可能导致改善的结果措施。在 最近的资金周期，我们确定，每天重复暴露于轻度间歇性缺氧（MIH）， CPAP可改变自主神经系统活动，与CPAP相比可显著降低血压。 单独CPAP治疗。由于MIH与CPAP联用，因此MIH对血压的独立影响 没有建立。此外，还不确定这些结果是否会持续很长时间 周期（即数周至数月）。 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是 结合血压的降低，我们没有确定微血管功能的改变是否 很明显。微血管功能障碍与交感-迷走神经失衡一起可能不仅会产生后果， 用于外周血管阻力和血压，还用于肌肉灌注和代谢，从而 限制了OSA患者的运动表现并增加了疲劳性。因此，降低血压 MIH治疗后微血管功能的改善可能有助于改善运动 能力和反向表现疲劳的个人与OSA。 除了其对自主神经和心血管功能的潜在影响外，我们和其他人先前建立了 急性暴露于MIH会引发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，称为长期易化。但由于没有 CPAP我们已经表明，在睡眠之前或睡眠期间急性MIH导致呼吸暂停严重程度增加。 这可能是因为在低碳酸血症的情况下，不存在长时程易化的表现。 在睡眠期间，另一种可塑性形式（即渐进性可塑性）的启动可导致低碳酸血症 增强然而，可能的是，每天暴露于MIH的组合给药许多小时， 在睡眠期之前可以减轻导致上气道增加的渐进性增强的影响 稳定 独立于这种可能性，我们在前一个资助周期中表明，增加上气道稳定性 MIH治疗后，治疗性CPAP减少，依从性改善。 然而，CPAP依从性的改善也可能与两种刺激的唤醒阈值增加有关。 呼吸和非呼吸刺激。上述所有不确定因素将在本报告中予以解决。 提议

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.