Regularity in occurrence of respiratory-related events in sleep predicts cardiovascular disease and mortality

Background: Obstructive sleep apnea (OSA), as measured by the Apnea Hypopnea Index (AHI), is associated with adverse outcomes. Measures that characterize the temporal variability in events may provide information over and beyond a simple summary of event frequency as measured by the AHI. Research Question: To assess whether temporal variability in the occurrence of obstructive apnea/hypopneas during the night is associated with all-cause mortality or incident cardiovascular disease (CVD). Study Design and Methods: Data from the Sleep Heart Health Study (SHHS), a prospective multi-site community-based cohort were analyzed. For each person, the intervals between apnea/hypopnea events (inter-event interval; IEI) were used to calculate a coefficient of variation for their IEIs (IEICV). Risk for mortality (n=5, 701) and incident CVD (n=4, 373) were estimated by adjusted Cox proportional hazard models. Sensitivity analyses were conducted to test potential explanatory variables such as hypoxic burden and duration of uninterrupted sleep. Results: In 11. 8 years of follow-up (median, IQR 10. 6-12. 2), 1, 287 deaths occurred. After adjusting for potential confounders, including OSA severity, participants in the lowest quartile of IEICV (Q1) had a 40% higher risk of all-cause mortality compared with those in the highest quartile (Q4) (hazard ratio HR = 1. 40; 95% confidence interval CI, 1. 20-1. 64). In 11. 5 years of follow-up (IQR 7. 9-12. 7), 867 CVD events occurred. The adjusted hazard rate for CVD was 29% higher (HR=1. 29 1. 06-1. 56) for those with less variable IEI. Minimal reductions in effects sizes were observed after additional adjustment for hypoxic burden and additional novel and traditional covariates. In sensitivity analyses, adjusting for the longest bout of uninterrupted sleep without respiratory events attenuated the association for CVD incidence (HR=1. 15 0. 89-1. 50). Interpretation: The temporal distribution of respiratory events - specifically, less variability in inter-event intervals (more regular event occurrences) - is associated with higher mortality and incident CVD.