# Project 02:  Mechanisms for Individual Differences in Hypertension in Obstructive Sleep Apnea

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $308,975

## Abstract

ABSTRACT
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 3 months of
therapy: oxidative stress, as assessed by urinary isoprostanes, urinary norepinephrine, renin activity, levels of
aldosterone and endothelin-1, endothelial function, 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 norepinephrine at baseline and greater falls with therapy. Animal studies
show that the key enzyme mediating oxidative stress in OSA is NADPH oxidase, 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 r...

## Key facts

- **NIH application ID:** 9978113
- **Project number:** 5P01HL094307-10
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** SAMUEL T. KUNA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $308,975
- **Award type:** 5
- **Project period:** — → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978113

## Citation

> US National Institutes of Health, RePORTER application 9978113, Project 02:  Mechanisms for Individual Differences in Hypertension in Obstructive Sleep Apnea (5P01HL094307-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9978113. Licensed CC0.

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