Intermittent Hypoxia-initiated Plasticity in Humans: A Multi-pronged Therapeutic Approach to Treat Sleep Apnea and Overlapping Co-morbidities

The prevalence of obstructive sleep apnea (OSA) is high in the United States and is a major health concern. This disorder is linked to numerous heart, blood vessel and nervous system abnormalities, along with increased tiredness while performing exercise likely because of a reduced blood supply to skeletal muscles. The gold standard treatment of OSA with continuous positive airway pressure (CPAP) in many cases does not lead to significant improvements in health outcomes because the recommended number of hours of treatment per night is often not achieved. Thus, development of novel treatments to eliminate apnea and lessen the occurrence of associated health conditions is important. The investigators will address this mandate by determining if repeated exposure to mild intermittent hypoxia (MIH) reduces heart and blood vessel dysfunction and tiredness/ fatigue experienced while exercise performance. The investigators propose that exposure to MIH has a multipart effect. MIH directly targets heart and blood vessel associated conditions, while simultaneously increasing upper airway stability and improving sleep quality. These modifications may serve to directly decrease breathing episodes and may also serve to improve usage of CPAP. Independent of its effect, MIH may serve as an adjunctive therapy which provides another path to reducing heart and blood vessel abnormalities that might ultimately result in improvements in exercise capacity and reverse performance fatigue in individuals with OSA.

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, the investigators 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 the investigators obtained some indirect evidence that modifications in autonomic nervous system activity were coupled to the reduction in blood pressure, the investigators 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, the investigators 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 the investigators 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, the investigators 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.

Eligibility Criteria:
Inclusion Criteria:

* Male or female of any race, 30-60 years of age with a BMI of less than 40 kg/m2 and a weight to hip ratio of less than 1.3in males and 1.2 in females along with pure or predominantly (i.e., comprised of both a central and obstructive component)OSA (AHI less than or equal to 100 events per hour and an average oxygen desaturation level of 85 % or greater).
* Participants will be newly diagnosed and not previously treated with CPAP.
* Participants will also be diagnosed with hypertension. Participants will either be untreated or will be treated unsuccessfully with a single prescribed medication for hypertension. Hypertension will be classified according to the American Heart Association 2018 criteria which includes an elevated systolic blood pressure in the range of 120-129 and a diastolic pressure less than 80 mmHg in addition to stage I and stage II hypertension defined by a systolic blood pressure greater than 130 mmHg and a diastolic pressure greater than 80 mmHg.
* Participants will also be included if they are pre-diabetic (HbA1C: 5.7 - 6.4 %; fasting blood glucose: 100 - 125 mg/dL) and have cholesterol levels ranging from 200-239 mg/dL.
* All participants will have normal lung function and a normal EKG with no or minimal alcohol consumption (\< 2 oz of alcohol/night).
* Females will be studied at similar points in their menstrual cycle.

Exclusion Criteria:

* Participants with baseline blood pressure greater than 160/110 will be excluded from participation.
* Participants on any medications, with the exception of a single prescribed medication for individuals with resistant hypertension.
* Participants with any other known disease (e.g. pulmonary hypertension).
* Participants using any sleep promoting supplements including melatonin.
* Night shift workers or participants who recently travelled across time zones.
* Pregnant females.