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

> **NIH VA I01** · JOHN D DINGELL VA MEDICAL CENTER · 2024 · —

## Abstract

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 i...

## Key facts

- **NIH application ID:** 10878749
- **Project number:** 5I01CX000125-14
- **Recipient organization:** JOHN D DINGELL VA MEDICAL CENTER
- **Principal Investigator:** Jason H. Mateika
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878749

## Citation

> US National Institutes of Health, RePORTER application 10878749, Intermittent hypoxia-initiated plasticity in humans: A multi-pronged therapeutic approach to treat sleep apnea and overlapping co-morbidities. (5I01CX000125-14). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10878749. Licensed CC0.

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