Mechanisms for Individual Differences in Hypertension in Obstructive Sleep

We seek to assess the clinical determinants and molecular/genetic mechanisms underlying known
individual differences in BP response to obstructive sleep apnea (OSA). This will result in a
more personalized approach to BP management of OSA patients. Hypertension is a common
consequence of OSA. Animal studies with cyclical intermittent hypoxia indicate that oxidative
stress is likely the major mechanism, but cardiovascular response to arousals may also play a
role. However, not all individuals with OSA have hypertension. Moreover, recent meta-analyses
of treatment trials of OSA show major individual differences in BP response. The largest drop
in BP with positive airway pressure (PAP) therapy for OSA is in patients with resistant
hypertension taking three or more BP medications. This project is focused on determining the
basis of these individual differences in BP response to OSA and PAP treatment. For Aim 1, we
will assemble four groups of OSA subjects with: 1) no hypertension; 2) controlled
hypertension on medications and/or lifestyle modifications; 3) uncontrolled hyper-tension
despite one or two anti-hypertensive medications; and 4) resistant hypertension. We will
assess reductions in BP with PAP therapy with mean nocturnal (sleep) arterial BP being the
primary end-point. The prediction is that group 4 will show the largest fall in BP, even
after controlling for relevant covariates, group 3 the next biggest fall, while groups 1 and
2 will show minimal BP changes. Both intent to treat and per protocol analyses, i.e.,
analyzing only those subjects who had PAP adherence of ≥ 4 hours/day and are adherent to
medication, will be conducted. All subjects will have the following measured before and after
4 months of therapy: urinary isoprostanes and plasma levels of norepinephrine, renin
activity, aldosterone, oxidized LDL, endothelin-1, and inflammatory biomarkers. In Aim 2, we
hypothesize that those individuals with higher BP at baseline and the greatest BP response to
PAP therapy will have higher levels of urinary isoprostanes and plasma norepinephrine at
baseline and greater falls with therapy. Animal studies show that the key enzyme mediating
oxidative stress in OSA is nicotinamide adenine dinucleotide phosphate-oxidase (NADPH)
oxidase (NOX), in particular NOX2. Thus, NADPH oxidase activity will also be assessed.
Individuals with the largest falls in BP on PAP therapy are hypothesized to have the highest
activity of this enzyme at baseline. There are known genetic variants of this enzyme that
affect its structure/activity. Thus, individual differences could be the result of genetic
variants. To address this, we will employ in-depth sequencing and evaluate variants in 7 key
genes regulating NOX2 structure/activity. Gene variants identified will be related to BP
responses and to NADPH oxidase activity. In Aim 3, the role of arousals in the BP response to
OSA will be assessed using a novel measurement of heart rate response to arousal. We
hypothesize that the heart rate response to arousal will be related to the BP and molecular
outcomes of Aims 1 and 2. Finally, given the complex relationship between OSA and BP, Aim 4
will utilize structural equation modeling to assess the relative impact of the various
biological pathways.

Inclusion Criteria:

- Age between 18 and 75 years

- Apnea-Hypopnea Index (AHI) ≥ 15 events/hr on diagnostic polysomnography(PSG)

- No previous history of surgical treatment of OSA, and no medical treatment of OSA
within the past 6 months

- Adherence to prescribed anti-hypertensive medications as assessed by an average
adherence between Visits 1-2 of at least 0.85

- Arm circumference less than 50 cm

Exclusion Criteria:

- Unable or unwilling to provide informed consent

- No telephone access or inability to return for follow-up

- Diagnosis of another sleep disorder in addition to OSA (e.g., periodic limb movement
disorder [greater than 5 limb movements associated with arousal/hr of sleep], central
sleep apnea [greater than 50% of apneas are central apneas], obesity hypoventilation
syndrome, narcolepsy)

- Positive urine drug screen for any of the following: amphetamines, cocaine, opiates,
barbiturates, benzodiazepines, phencyclidine (PCP), tetrahydrocannabinol (THC),
alcohol (ETOH), methadone (Visit 1)

- Requiring oxygen, bi-level positive airway pressure, or adaptive servo-ventilation for
treatment of OSA

- Oxygen saturation < 87% for a period of 2 minutes during resting wakefulness during
home sleep testing (HST) or PSG (Visit 2)

- Severe and inadequately controlled arterial hypertension (SBP greater than 180 mm Hg;
diastolic BP greater than 110 mm Hg on 2 of 3 spot measurements on Visit 1)

- Participants with 24-hr SBP ≥ 140 mm Hg who are not on BP medications and participants
on 4 or more BP medications with a 24-hr SBP < 135 mm Hg (Visit 2)

- A clinically unstable medical condition as defined by a change in medications in the
previous month, including anti-hypertensive medications, or a new medical diagnosis in
the previous 2 months (e.g., myocardial infarction, chronic heart failure, unstable
angina, active infection, thyroid disease, depression or psychosis, cirrhosis,
surgery, or cancer)

- Shift workers, individuals who regularly experience jet lag, or have irregular work
schedules by history over the last 3 months

- Women who are pregnant or sexually active and of child-bearing age not using a form of
contraceptive

- Routine consumption of > 2 alcoholic beverages/day Excessive use of caffeine (greater
than 10 cups/day)

- Inability to communicate verbally or less than a 5th grade reading level