Oxygen overshoot burden of central sleep apnea and its association with cardiovascular outcomes.

PURPOSE: The role of oxidative stress in central sleep apnea (CSA) remains unknown. We examined whether "oxygen overshoot burden"-a measure of cumulative oxygen saturation levels above baseline-is associated with major adverse cardiovascular events (MACE) in CSA. METHODS: We analyzed 7530 participants from the Sleep Heart Health Study (SHHS; age 64 years; 47.0% male) and the Osteoporotic Fractures in Men Study (MrOS; age 76 years; 100% male). Oxygen overshoot burden was defined as the area under the SpO2 curve above a stable sleep baseline (wakefulness baseline was also considered). In primary analysis, oxygen overshoot burden was modeled continuously. In secondary analyses, participants were classified as having CSA, obstructive sleep apnea (OSA), or no sleep apnea, and stratified by high (≥ median) versus low oxygen overshoot burden. Cox models adjusted for covariates were used to estimate hazard ratios (HRs) for MACE. RESULTS: Over a follow-up of 8.92 years, 2258 MACE events occurred. Oxygen overshoot burden (continuous) was associated with increased MACE risk, with stronger associations among individuals with any central apneas (p = 0.003 and p = 0.02 for sleep and wakefulness baselines, respectively). In secondary analyses, participants with CSA and high oxygen overshoot burden had higher MACE incidence (54.6%) than controls (25.6%; HR 1.45 [95%CI = 1.16,1.82]; p = 0.001). In contrast, CSA with low oxygen overshoot burden and OSA with high or low oxygen overshoot burden showed MACE risk comparable to controls. Results were robust to adjustment for AHI, central apnea index, loop gain, and hypoxic burden. CONCLUSIONS: Oxygen overshoot burden in CSA is independently associated with increased MACE risk and may improve risk stratification in sleep-disordered breathing. These findings require validation in larger, more diverse populations given sample limitations and potential pulse oximetry bias across skin pigmentation. CURRENT KNOWLEDGE/STUDY RATIONALE: Oxidative stress may contribute to cardiovascular risk in central sleep apnea (CSA), but the clinical significance of post-apneic oxygen overshoot is unknown. We examined whether oxygen overshoot burden, representing cumulative oxygen saturation above baseline, is associated with major adverse cardiovascular events (MACE). STUDY IMPACT: Greater oxygen overshoot burden was associated with increased cardiovascular risk in individuals with central sleep apnea but not in those with obstructive sleep apnea. These findings identify a potential high-risk central sleep apnea phenotype and suggest that oxygen overshoot burden may improve cardiovascular risk stratification and inform future mechanistic and interventional studies.