Mechanisms for Individual Differences in Hypertension in Obstructive Sleep
Mechanisms for Individual Differences in Hypertension in Obstructive Sleep
Hypertension is a common consequence of obstructive sleep apnea (OSA). However, not all
 individuals with OSA have hypertension and there are major individual differences in blood
 pressure response to positive airway pressure treatment of OSA. This project is focused on
 determining the basis of these individual differences in blood pressure response to OSA and
 will evaluate the possible underlying reasons for these differences. The results will help
 clinicians to know whether or not to expect a reduction in blood pressure (BP) to OSA
 treatment in a given patient and thereby personalize patient management.
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), 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