Sex differences in obstructive sleep apnea phenotypes, the multi-ethnic study of atherosclerosis

Study Objectives: The bases for sex disparities in obstructive sleep apnea (OSA), is poorly understood. We quantified the influences of event definitions, sleep-state, and body position on apnea-hypopnea indices (AHIs) in men and women, and evaluated sex differences in pathophysiological endotypes. Methods: Polysomnography (PSG) data were analyzed from 2057 participants from the multi-ethnic study of atherosclerosis. Alternative AHIs were compared using various desaturation and arousal criteria. Endotypes (loop gain, airway collapsibility, arousal threshold) were derived using breath-by-breath analysis of PSG signals. Regression models estimated the extent to which endotypes explained sex differences in AHI. Results: The sample (mean 68.5 +/- 9.2 years) included 54% women. OSA (AHI4P >= 15/h, defined by events with =4% desaturations) was found in 41.1% men and 21.8% women. Compared to AHI4P, male/female AHI ratios decreased by 5%-10% when using 3%-desaturation and/or arousal criteria; p < 0.05. REM-OSA (REM-AHI >= 15/h) was similar in men and women regardless of event desaturation criteria. REM-AHI4P >= 15/h was observed in 57% of men and women each. In NREM, AHI4P in men was 2.49 (CI95: 2.25, 2.76) of that in women. Women demonstrated lower loop gain, less airway collapsibility, and lower arousal threshold in NREM (ps < 0.0005). Endotypes explained 30% of the relative sex differences in NREM-AHI4P. Conclusions: There are significant sex differences in NREM-AHI levels and in physiological endotypes. Physiological endotypes explained a significant portion of the relative sex differences in NREM-AHI. Definitions that use 4%-desaturation criteria under-estimate AHI in women. Combining NREM and REM events obscures OSA prevalence in REM in women. Statement of Significance This is the first study to quantify the influences of desaturations, arousals, sleep-state, and position on apnea-hypopnea index (AHI) in men and women, and to evaluate sex differences in obstructive sleep apnea (OSA) physiological endotypes in a large, diverse population. Our results suggest that sex differences in OSA are influenced by state-specific mechanisms that are reflected by polysomnographic estimates of airway collapsibility, loop gain, and arousal threshold. Protective mechanisms during NREM sleep do not substantively protect women from airway collapse during REM sleep. The relatively high REM-AHI in women is of clinical significance given growing evidence of the association between REM-OSA and adverse cardiovascular outcomes. Since current guidelines do not directly address REM-AHI for treatment, our data suggest women may be disproportionately under-treated for OSA based on the total AHI, which predominantly reflects NREM-AHI.