Respiratory self-similarity is a sleep apnea endotype that predicts cardiovascular disease related mortality

STUDY OBJECTIVES: Pathological respiratory chemoreflex activation (high loop gain) in sleep apnea may activate the carotid body and induce excessive sympathetic nerve output, and independently add to the risk of adverse outcomes. This study aims to determine whether a high loop gain of the respiratory control system during sleep, estimated by respiratory self-similarity (SS) and the algorithm-derived central respiratory event index (CREI), is associated with new-onset cardiovascular disease (CVD) and CVD-related mortality. METHODS: A secondary analysis of The Sleep Heart Health Study (SHHS) and Multi-Ethnic Study of Atherosclerosis (MESA). High SS% and CREI were defined as the highest quartile. Lasso regression and restricted cubic spline assessed the relationship between SS%, CREI and CVD, CVD-mortality and all-cause mortality. A cumulative incidence function and a Fine-Gray subdistribution hazard model were used to evaluate this outcome accounting for competing risks. RESULTS: In adjusted models with age as a categorical variable divided by 65 years old, the highest quartile of SS% (HR 1.693, p: 0.017 in MESA and HR 1.240, p : 0.009 in SHHS) was associated with the incidence of CVD and was more prominent in males. A positive relationship between SS% (MESA: HR 1.429, p: 0.039; SHHS HR1.176, p:0.018 ) for the continuous metrics and CVD mortality in both cohorts was more apparent in men than in women. The categorical high-exposure association with CVD mortality was not consistent across cohorts.The associations were significantly attenuated when adjusted by age as a continuous metric. CONCLUSIONS: An endotype of sleep apnea reflecting high loop gain is associated with CVD and CVD mortality, especially in males.