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...