Basis of sex-specific therapeutic responses to obstructive sleep apnea: Oxidative stress, inflammation, and vascular function

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Project Summary The absolute number of cardiovascular-associated deaths in women exceed those in men. Key modifiable risk factors for cardiovascular disease (CVD) rise as women age, when CVD prevalence becomes higher compared with same-age men. The relatively abrupt, age-related reduction in estrogen — which had previously served as a major antioxidant defense system—may be why. Compared with men (in whom greater early-life, ongoing oxidative stress may serve as a compensatory adaptation as they age), women’s vascular systems may be more vulnerable to this sharp rise in acute oxidative stress. One highly prevalent source of oxidative stress is obstructive sleep apnea (OSA), which is associated with incident hypertension, CVD, and diabetes. OSA’s intermittent hypoxemia and recurrent arousals cause deleterious health effects via oxidative stress, which triggers inflammation-related decreases in nitric oxide bioavailability. Thus, oxidative stress is considered a key intermediary through which OSA promotes vascular dysfunction. Even without OSA, middle-aged and older women have worse vascular function than do age-matched men. Critically, OSA prevalence also rises sharply as women age, suggesting sex-based pathophysiology. Our team’s preliminary data suggest sex-specific differences in oxidative stress and vascular dysfunction in middle-aged and older women with OSA, as evidenced by higher post-sleep nitrate levels and worse endothelial dysfunction compared with men; however, only women have improved glycemic measures after three months of positive airway pressure (PAP) therapy. This may indicate a sex-specific treatment effect on oxidative stress. Although it is the first line OSA treatment, a marked number of OSA patients do not meet minimum PAP therapy adherence requirements. Thus, N-acetylcysteine, a readily available, safe antioxidant may be a valuable, adjunct therapy for patients with OSA. To address these significant issues, we will study women and men (aged 50–75 years) with moderate-to-severe OSA and minimal, well-controlled comorbidities. Our primary objectives are to identify sex-specific differences in: a) the effects of OSA on overnight oxidative stress and inflammatory biomarkers; b) vascular function; and c) effects of PAP therapy plus N-acetylcysteine or placebo. Our overarching hypotheses are: 1) OSA differentially contributes to adverse cardiovascular consequences in middle-aged and older women compared with age-matched men via increased oxidative stress; 2) Women’s greater benefit from PAP therapy is due to their larger decline in overnight oxidative stress; and 3) Adjunctive therapy with a novel supplement helps prevent CVD morbidity from OSA. Given the staggering public health burden of CVD, targeting a treatable risk factor such as OSA in women presents a critical opportunity to markedly improve health in an enormous, vulnerable population. Mitigating OSA-induced oxidative stress with an accessible supplement—N-acetylcysteine—will be especially valuable for those who struggle with PAP use or have only partial improvement in oxidative stress with PAP therapy.