The dogma over the past 3 decades, particularly in the field of sleep medicine, has been
that intermittent hypoxia (IH) is a detrimental stimulus that leads to a number of
co-morbidities including autonomic (e.g. increased sympathetic nervous system activity),
cardiovascular (e.g. hypertension, atherosclerosis, arterial fibrillation), cognitive
(e.g. loss of gray matter, neural injury and impaired neural function coupled to
sleepiness) and metabolic dysfunction (dyslipidemia, hyperglycemia, insulin resistance).
This belief was based principally on animal studies that employed protocols that were for
the most part severe in nature in regards to length and/or intensity of the hypoxic
stimulus. However, the elimination of IH in humans with sleep apnea using continuous
positive airway pressure (CPAP) has often been ineffective in mitigating the above
mentioned co-morbidities. The lack of compliance with CPAP, length of treatment with CPAP
(i.e. short durations), and the possibility that IH or other hallmarks of sleep apnea are
not the primary mechanism response for the listed co-morbidities, are possible reasons
for the absence of improvement in humans.
In contrast to the findings outlined in the previous paragraph, work completed over a
similar time frame indicates that some forms of IH may be beneficial in nature. Many
studies using a variety of protocols and species, including humans, established that
exposure to mild IH initiates sustained increases in the activity of motoneurons, nerves
and muscles that contribute to the enhancement of ventilation and the maintenance of
upper airway patency. This sustained increase has been termed long-term facilitation
(LTF) and this phenomenon has been the focus of PI's research program for two decades.
Long-term facilitation is the principle form of respiratory plasticity that we documented
in healthy humans, and in humans with obstructive sleep apnea (OSA) and spinal cord
injury (SCI). The initiation of this phenomenon is mediated by a number of
neuromodulators (e.g. serotonin, adenosine, noradrenaline) that trigger components of at
least two cellular pathways, deemed the Q and S pathways, which mediate the phenomenon.
Besides the initiation of LTF, studies in rats and humans have provided compelling
evidence that mild IH might be cardiovascular (e.g. angiogenesis, reductions in blood
pressure, reductions in infarct size), neurocognitive (e.g. brain neurogenesis, reduced
oxidative stress and inflammation) and metabolically (e.g. decreased cholesterol,
decreased low density and very low lipoprotein, increased high density lipoproteins and
reduced hyperglycemia) protective. Many reviews over the past decade, including reviews
from PI's laboratory have addressed the underlying physiological cellular mechanisms and
the translation to whole animals and humans. Briefly, mild IH may lead to moderate
increases in reactive oxygen species. These moderate levels of reactive oxygen species
activate transcription factors (e.g. hypoxia-inducible factor 1α, nuclear factor
erythroid-derived 2-like 2, GATA binding protein 4) that lead to the induction of many
cytoprotective proteins. These proteins serve, for example, to reduce oxidative stress
(e.g. superoxide dismutase, glutathione, thioredoxin), inflammation (e.g. inducible
nitric oxide synthase), apoptosis (e.g. B-cell lymphoma 2), and promote vasodilation
(e.g. heme oxygenase 1) and the formation of blood vessels (e.g. vascular endothelial
growth factor). These modifications that ultimately manifest in improved cardiovascular,
autonomic and neurocognitive outcomes indicate that beneficial responses can be initiated
by IH in a dose dependent fashion without accompanying maladaptive responses. Despite
this recognition, the beneficial responses to IH in humans with sleep apnea have not been
fully delineated.
Besides these potential beneficial effects it has been established that daily repeated
exposure to IH promotes other forms of motor plasticity. Indeed, IH promotes recovery of
limb motor function in both rats and humans. Initial studies in humans with SCI revealed
that electromyography of the gastrocnemius muscle coupled with measures of ankle torque
significantly increased following exposure to brief episodes of IH in humans with SCI. In
a subsequent study, exposure to 15 to 90 s episodes of hypoxia each day over 5
consecutive days significantly improved walking speed and duration in 10 meter and 6
minute walking tests in humans with an incomplete SCI. Interestingly, the effect of daily
exposure to IH on walking speed was enhanced when combined with 30 minutes of walking
each day, which led the authors to conclude that the combined therapies promote greater
functional benefits in individuals with incomplete SCI. Thus, daily repeated exposure to
IH could have significant therapeutic effects on limb motor function in individuals with
SCI accompanied by sleep apnea. Likewise, exposure to this stimulus could promote LTF of
upper airway muscle activity leading to reduced therapeutic pressures, improved
compliance and enhanced outcome measures as outlined. These possibilities coupled with
the direct effects that IH has on those co-morbidities linked to sleep apnea indicates
that IH may be effective in mitigating those issues linked to both respiratory and limb
motor dysfunction in individuals with sleep apnea and spinal cord injury.
Based on the findings outlined in the previous paragraphs the working hypothesis for the
present proposal is that exposure to mild IH leads to LTF of upper airway muscle activity
that manifests in increased stability of the upper airway, which could ultimately reduce
the CPAP required to treat OSA. As previously reported, a reduction in the therapeutic
pressure necessary for the maintenance of airway patency leads to improved comfort and
ultimately treatment compliance, which is approximately 40 % amongst users. Indeed, the
preliminary data shows that following acute exposure to IH during sleep, and repeated
daily exposure to IH during wakefulness, the therapeutic pressure required for the
maintenance of upper airway patency was significantly reduced during sleep. The reduced
therapeutic pressure was also coupled to a reduction in upper airway resistance and the
critical closing pressure. These modifications ultimately led to increased CPAP
compliance. The numerous co-morbidities listed in the initial paragraph, which have been
linked to hallmarks of sleep apnea (e.g. sleep fragmentation and severe IH), could be
significantly improved by increased compliance to CPAP. In addition, as outlined above,
IH may directly impact on a variety of co-morbidities associated with sleep apnea
independent of CPAP compliance. Collectively, exposure to IH could impact on
comorbidities linked to sleep apnea both directly and via improved therapeutic compliance
to CPAP.
Aim 1: We will determine if mild IH can serve as an adjunct therapy coupled to CPAP to
mitigate associated co-morbidities via its direct effects on a variety of autonomic,
cardiovascular, neurocognitive and metabolic measures and indirectly by improving CPAP
compliance in able bodied individuals with OSA and hypertension. Our primary outcome
variable is blood pressure measured during quiet wakefulness over the 24 hour period.
Secondary outcomes include blood pressure measured during sleep over 24 hours, along with
the measurement of beat to beat blood pressure, autonomic nervous system activity, blood
biomarkers and neurocognitive tests. Additional secondary outcomes include measures of
upper airway collapsibility, therapeutic pressure and adherence.
Aim 2: We will employ spinal cord injured participants with OSA and hypertension to
determine if mild IH can be coupled with CPAP to mitigate cardiovascular, metabolic and
neurocognitive co-morbidities directly, and indirectly by improving CPAP compliance. We
will also examine if the mitigation of cardiovascular, metabolic and neurocognitive
co-morbidities is accompanied by recovery of respiratory motor function during
wakefulness and sleep, and motor limb function during wakefulness following repeated
daily exposure to mild IH in these individuals.