Yuxin Wang,1,* Xiaona Wang,1,2,* Jinmei Luo,1 Bintao Qiu,3 Rong Huang,1 Yi Xiao1 

1Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Central Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jinmei Luo, Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, People’s Republic of China, Email palmljm@126.com

Purpose: There are currently no ideal indicators for predicting the cardiovascular risk of obstructive sleep apnea (OSA). This study aimed to employ urinary metabolomics to detect early cardiovascular risk in patients with moderate-to-severe OSA.
Patients and Methods: Male participants who underwent polysomnography from November 2020 to May 2021 were screened. Clinical data, polysomnography data and urine samples were collected. Untargeted metabolomics analyses of urine were performed. Multivariate analyses and receiver operating characteristic (ROC) curve analyses were subsequently performed to identify potential biomarkers. Associations between metabolites and clinical indicators and cardiovascular risk were examined through linear regression analyses with interaction and mediation analyses.
Results: Thirty-six male participants were included in the study, comprising 22 males with moderate-to-severe OSA and 14 age-matched controls, with an average age of 39.6 ± 9.2 years. We identified 65 metabolites in the study, involving pathways including pyrimidine, androgen, estrogen, vitamin B6 and sulfate/sulfite metabolism. Among them, epinephrine sulfate was the most significantly altered metabolite. ROC analyses highlighted that epinephrine sulfate had the highest area under the curve (AUC=0.883) for detecting moderate-to-severe OSA. Epinephrine sulfate was statistically correlated with OSA severity, hypoxia-related indicators (apnea-hypopnea index: r=0.685; oxygen desaturation index: r=0.743, p< 0.0001), arterial stiffness (arterial augmentation index: r=0.361, p=0.031) and long-term cardiovascular risk (Framingham cardiovascular risk: r=0.375, p=0.024). Linear regression analysis revealed that epinephrine sulfate was significantly associated with an increased in the Framingham risk (β = 0.004, 95% CI = 0.000– 0.009, p = 0.049), with the effect partly mediated by systolic blood pressure (27.6%) and not moderated by other factors. Additionally, it also significantly associated with the increased in the arterial augmentation index (β = 0.019, 95% CI = 0.000– 0.037, p = 0.046), with the effect fully mediated by blood pressure and not moderated by other indices statistically.
Conclusion: There are significant metabolic pathway alterations in moderate-to-severe OSA patients. Urinary epinephrine sulfate markedly predicts early cardiovascular risk in OSA patients.

Keywords: metabolomics, Framingham cardiovascular risk score, epinephrine sulfate, obstructive sleep apnea