Pathophysiology Underlying Demographic and Obesity Determinants of Sleep Apnea Severity

Abstract

Rationale: Sleep apnea is the manifestation of key endotypic traits, including greater pharyngeal collapsibility, reduced dilator muscle compensation, and elevated chemoreflex loop gain. Objectives: We investigated how endotypic traits vary with obesity, age, sex, and race/ethnicity to influence sleep apnea disease severity (apnea-hypopnea index [AHI]). Methods: Endotypic traits were estimated from polysomnography in a diverse community-based cohort study (Multi-Ethnic Study of Atherosclerosis, N = 1,971; age range, 54-93 yr). Regression models assessed associations between each exposure (continuous variables per 2 standard deviations [SDs]) and endotypic traits (per SD) or AHI (events/h), independent of other exposures. Generalizability was assessed in two independent cohorts. Results: Greater AHI was associated with obesity (+19 events/h per 11 kg/m² [2 SD]), male sex (+13 events/h vs. female), older age (+7 events/h per 20 yr), and Chinese ancestry (+5 events/h vs. White, obesity adjusted). Obesity-related increase in AHI was best explained by elevated collapsibility (+0.40 SD) and greater loop gain (+0.38 SD; percentage mediated, 26% [95% confidence interval (CI), 20-32%]). Male-related increase in AHI was explained by elevated collapsibility (+0.86 SD) and reduced compensation (-0.40 SD; percentage mediated, 57% [95% CI, 50-66%]). Age-related AHI increase was explained by elevated collapsibility (+0.37 SD) and greater loop gain (+0.15 SD; percentage mediated, 48% [95% CI, 34-63%]). Increased AHI with Chinese ancestry was explained by collapsibility (+0.57 SD; percentage mediated, 87% [95% CI, 57-100]). Black race was associated with reduced collapsibility (-0.30 SD) and elevated loop gain (+0.29 SD). Similar patterns were observed in the other cohorts. Conclusions: Different subgroups exhibit different underlying pathophysiological pathways to sleep apnea, highlighting the variability in mechanisms that could be targeted for intervention.

Keywords: endotype; epidemiology; pathophysiology; precision medicine.

Figure 1.

Effects of demographics and obesity on apnea–hypopnea index (AHI) (A) and primary endotypic traits (B–D) in the MESA study (Multi-Ethnic Study of Atherosclerosis). Squares and horizontal lines indicate the strength of each association (β with 95% confidence interval). Reference group for race/ethnicity is White. Note that the nonlinear scaling for AHI is due to the square root transformation; results were back transformed for interpretability. BMI = body mass index; SD = standard deviation.

Figure 2.

Replication of effects of obesity and demographics on apnea–hypopnea index and primary endotypic traits in the CFS (Cleveland Family Study) and MrOS (Osteoporotic Fractures in Men Study) studies. Data from the MESA study (Multi-Ethnic Study of Atherosclerosis) are repeated for comparison. Squares and horizontal lines indicate the strength of each association (β with 95% confidence interval [CI]). Meta-analysis results for the three cohorts are also shown (diamond describes β and 95% CI). Sample sizes were as follows: MESA, n = 1,971; CFS, n = 537; MrOS, n = 2,608. SD standardization was based on data from MESA to facilitate comparison across cohorts. Results for Hispanic and Chinese participants could not be reassessed in the additional cohorts. BMI = body mass index; SD = standard deviation.