Obstructive Sleep Apnea (OSA) and Metabolic Syndrome: Role of Oxidative Stress

The metabolic syndrome has been defined as insulin resistance, central obesity, systemic
hypertension and dyslipidemia and is associated with increased cardiovascular (CV) risk.
Obstructive Sleep Apnea-Hypopnea (OSAH) is also associated with increased CV risk and
insulin resistance. Since OSAH is associated with oxidative stress and pro-inflammatory
processes, both of which are associated with insulin resistance, it follows that oxidative
stress and inflammation may mediate the linkage between OSAH, insulin resistance and
ultimately, the metabolic syndrome.

The overall goal of this research is to test the hypothesis that oxidative stress and
inflammation link OSAH to insulin resistance as well as other CV risk-promoting conditions
reflecting the metabolic syndrome (e.g. hyperlipidemia). We will specifically test if the
individual sleep consequences of OSAH, including sleep fragmentation and intermittent sleep
hypoxia, promote oxidative stress and inflammation which in turn promote insulin resistance
and other features of the metabolic syndrome.

Aim 1a: To determine the effect of sleep fragmentation on oxidative stress and inflammation
and features of the metabolic syndrome including insulin resistance, dyslipidemia, obesity,
and hypertension.

Aim 1b: To assess the interaction between pre-existing metabolic syndrome and the overweight
condition without metabolic syndrome, with regard to the effects of sleep fragmentation on
the study variables, we will contrast the effect of experimentally-induced sleep
fragmentation in non-OSAH/overweight individuals with the metabolic syndrome,
non-OSAH/overweight individuals without metabolic syndrome and a control group of
non-OSAH/normal weight without metabolic syndrome.

Aim: 2: To evaluate the effect of intermittent sleep hypoxia on oxidative stress and
inflammation and explore the relationships between these two processes and insulin
resistance, lipid profile, heart period variability and plasma cortisol.

Aim: 3: Using microarray data from peripheral monocytes, we will explore if specific gene
expression patterns after the study conditions are associated with alterations consistent
with metabolic syndrome.

Aim: 4: This exploratory aim is to collect preliminary data regarding the correlation among
genetic variations (polymorphisms), gene expression patterns (microarray) and resultant
protein production (proteomics). These data will be used for hypothesis development.

Inclusion Criteria:

- Nonsmoker for at least 6 months

- No history of movement disorder during sleep, or circadian rhythm disorder

- No excessive daytime sleepiness

- No history of chronic insomnia, mood or affective disorders or other psychiatric
disorders

- Participants maintain a regular sleep-wake pattern with an estimated sleep time
between 6.5 and 10 hours per night

- Ability and willingness to avoid meat with its juice (gravy), cured or smoked foods
and green leafy vegetables, fruit and fruit juices, food products or vitamin
supplements containing vitamin C and E supplements for at least 1 day prior to and
during the study periods

- Consumption of less than 1 alcoholic beverage per day

- Ability to understand the study and sign the informed consent

- Not currently pregnant

- Live within 45 miles of the study site

- No uncontrolled hypertension (blood pressure greater than 150/100)

- Willingness to avoid caffeinated beverages and food during the study protocol period

Participants With Sleep Apnea:

- Diagnosis of severe Obstructive Sleep Apnea and Hypopnea (OSAH) (RDI greater than 25)
and initiation of positive airway pressure therapy more than 1 month before
enrollment

- Must have had an adequate clinical titration of positive airway pressure therapy

- On positive airway pressure for at least 1 month with adherence of more than 5 hours
of use per day with no history of snoring, no excessive daytime sleepiness and no
reported observed apnea episodes on positive airway pressure

- Willing to sleep with and without positive airway pressure therapy as required by the
study protocol

Exclusion Criteria:

- History or physical examination evidence of active coronary artery disease, heart
failure, cardiomyopathy, syncope, potentially life-threatening arrhythmia, stroke,
transient ischemic attack, neurologic impairment, renal, hepatic or thyroid disease
(unless on stable thyroid replacement medication); history of diabetes mellitus;
history of cancer within the past 10 years (other than basal cell carcinoma), venous
thrombosis, or collagen-vascular disease or other condition that the investigators
believe may be exacerbated by participation in the stud

- History of awakening with angina pectoris

- Currently taking medication for mood or affective disorders or that affect heme
metabolism, autonomic nervous system or sleep architecture, or prescribed nitrates or
corticosteroids

- Physician-diagnosed Alzheimer's or non-Alzheimer's dementia

- Previous surgery for sleep apnea

- Hematocrit less than 32

- Use of a hearing aid in one or both ears

- History of a bleeding disorder, abnormal bleeding, or known adverse reaction to
heparin

- Inability to obtain venous blood or a low likelihood of obtaining venous access as
required in this protocol

- History of migraine of a nature, frequency, and severity that, in the investigators'
judgement, may be precipitated by participation in the protocol

- Presence of a potentially life-threatening dysrhythmia on the clinical diagnostic PSG

- History of motor vehicle accident due to falling asleep; not currently employed as a
driver in the transportation industry or an airplane pilot

- Lipid-lowering agents for participants without a history of sleep apnea

- Individuals on positive airway pressure therapy for sleep apnea must not have lost
more than 10 pounds of weight since starting this treatment