Mechanisms of Sex-specific responses to obstructive sleep apnea Therapies (MoST) - Project Summary Obstructive sleep apnea (OSA) — a chronic disorder characterized by intermittent hypoxemia and recurrent arousal — deleteriously affects health via oxidative stress, which in turn triggers inflammation and decreases nitric oxide bioavailability. Accordingly, oxidative stress is a key intermediary through which OSA erodes vascular function. Across young- to late-adulthood, men experience a steady, linear increase in cardiovascular disease (CVD). In contrast, the relatively abrupt loss of estrogen—a powerful antioxidant defense system—with menopause appears to heighten women’s modifiable CVD risk factors, CVD prevalence, and cardiovascular- associated deaths, all of which are higher compared with same-age men. Notably, OSA prevalence also rises sharply after menopause, approaching that of men. Concurrently, in postmenopausal women the vasculature becomes vulnerable to sharp rises in acute oxidative stress, possibly explaining their increased OSA-based sequelae. In particular, the critical, endogenous glutathione (GSH)-based antioxidant defense system is diminished in both OSA and in women ages 50–55, corresponding with menopause onset. Given that OSA is a modifiable CVD risk factor but adherence to first-line OSA therapy (i.e., positive airway pressure [PAP] therapy), is known to be difficult and inadequate, identifying safe alternative therapies for OSA is critical. N-acetylcysteine (NAC) is a readily available, safe, precursor antioxidant that boosts the intracellular GSH pool. NAC is a prime candidate for mitigating moderate-to-severe OSA-associated oxidative stress and resultant CVD given the profile of oxidative stress, OSA, and associated morbidities. However, and importantly, women and men may respond differently to this potential therapy. Thus, in middle- and older-aged women and men (aged 52–70 years who have been diagnosed with moderate-to-severe OSA), this randomized, crossover clinical trial, will address both the unique impacts of OSA on vascular function, and the critical need for sex-specific preventative therapies. The study is expected to reveal that: 1) women and men experience distinct profiles of adverse, intermediary cardiovascular consequences with OSA — revealed by oxidative stress, inflammation, and endothelial dysfunction; 2) PAP therapy differentially impacts overnight oxidative stress, inflammation, and endothelial function in women and men; and 3) NAC decreases oxidative stress in OSA but may do so unequally in men versus women, with women experiencing greater improvements in oxidative stress with NAC therapy compared to age-matched men. Accomplishing the study aims will lead to pioneering, translatable insights about OSA- induced changes and therapeutic response to intracellular antioxidant capacity. This will also facilitate development and implementation of targeted, sex-based interventions. Given the staggering public health burden of CVD in both men and women, targeting OSA as a treatable risk factor—and using the optimal treatment approaches for both women and men—is essential.
