Mechanisms for Individual Differences in Hypertension in Obstructive Sleep
Condition: Sleep Apnea, Obstructive; Hypertension
MeSH terms: Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Hypertension
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Positive Airway Pressure
Intervention type(s): Device
Intervention description(s): Participants will use Positive Airway Pressure (PAP) treatment
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Adult subjects between the ages of 18 and 75 years of age with a diagnosis of untreated
        moderate to severe OSA as evidenced by an apnea/hypopnea index ≥ 15 events/hour who are
        about to be initiated on PAP treatment. We will make a conscious effort to recruit from all
        ethnic and social economic backgrounds.
      
Biospecimen description: 
      As a part of the research protocol, we intend to draw from each participant at baseline and
      following 4 months of PAP therapy. All samples will be processed according to the recommended
      procedures for the different analyses we intend to measure and stored at -80°C until
      analysis.
    
Keywords: Sleep Apnea; Hypertension; Positive Airway Pressure; Blood Pressure