Associations of Excessive Sleepiness with Sleep Apnea Physiological Endo-phenotypes: The Multi-Ethnic Study of Atherosclerosis

Abstract Background Obstructive sleep apnea (OSA) is a heterogeneous disease characterized by several endo-phenotypes (mechanistic traits and physiological severity metrics) and variable associations with excessive daytime sleepiness (EDS). Examining the relationship of EDS with features of OSA may identify physiological processes that drive increased risk for adverse health outcomes in patients with OSA and EDS. Research Question Do variations in physiological endo-phenotypes identified from polysomnography associate with EDS in a general population, and do such associations vary by sex? Study Design and Methods Participants in the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 5 Sleep Study underwent polysomnography, actigraphy, and questionnaire assessment. Among participants with an apnea-hypopnea index 5 events/hour (n = 1783; mean, age 68.7 ± 9.1; 52% female), we examined associations between OSA endo-phenotypes including physiological severity measures (hypoxic burden, arousal intensity, event duration, heart rate response Δ HR), and endotypes (mechanistic traits: collapsibility, compensation, loop gain, and arousal threshold) with EDS (Epworth Sleepiness Scale, ESS 10). Poisson regression models with robust variance were used, adjusting for demographics, smoking, and other factors. Results EDS was found in 14% of the sample. An interquartile increase in hypoxic burden was associated with a 28% higher prevalence ratio (PR) of EDS (PR = 1.28; 95% CI: 1.10, 1.51) in models adjusted for demographic factors and smoking. An increased adjusted prevalence ratio of EDS was also associated with higher loop gain (1.26; 1.12, 1.42) and higher Δ HR (1.32; 1.01, 1.73). In sex-stratified analyses, EDS was associated with shorter respiratory event duration and higher compensation in females, and with hypoxic burden and high Δ HR in males (p value for sex interaction 0.05 for event duration). Associations did not materially change with adjustment for short sleep duration. Interpretation EDS was associated with several OSA endo-phenotypes. EDS was more strongly associated with shorter event duration in females, with trends for stronger associations for hypoxic burden and ΔHR in males. The physiological correlates of EDS in people with OSA may contribute to differences in OSA outcomes across symptom groups.