Abstract
Objectives
To explore the relationship between total bilirubin (TBil) and stroke risk in older patients with obstructive sleep apnea syndrome (OSAS).
Methods
A total of 1,007 patients with OSAS without stroke history aged ≥ 60 years and with complete serum TBil records were enrolled in this study. The median follow-up was 42 months. Participants were divided into four groups based on the quartile of the baseline serum TBil concentration. Multivariate Cox proportional hazards analysis and restricted cubic spline (RCS) were used to investigate the association of TBil with the incidence of new-onset stroke.
Results
The PRIMARY part: the third quantile TBil level group had the lowest prevalence of stroke among the four groups. The RCS functions depicted a J-type curve relationship between TBil (3.3–33.3 µmol/L) and stroke (nonlinear P < 0.05). When the TBil level was in the range of 3.3 to 11.5 µmol/L, the possible protective influence of bilirubin against stroke in patients with OSAS enhanced with an increasing TBil level. However, when the TBil level exceeded 11.5 µmol/L and gradually increased, the effect of TBil on stroke risk became more and more pronounced. The SECONDARY part: for every 1 µmol/L increase in TBil levels in the range of 11.5 to 33.3 µmol/L, the risk of stroke in patients with OSAS increased by 16.2% (P < 0.001). In addition, there was a higher risk in women with OSAS (hazard ratio (HR)=1.292, 95% confidence interval (95%CI): 1.093–1.528; P = 0.003). Moreover, an increased TBil level alone was significantly associated with stroke in subjects aged < 75 years (HR: 1.190, 95%CI: 1.069–1.324), patients with mild-to-moderate OSAS (HR: 1.215, 95%CI: 1.083–1.364), and individuals without atrial fibrillation (AF) (HR: 1.179, 95%CI: 1.083–1.285) within a TBil level in the range of 11.5 to 33.3 µmol/L.
Conclusions
Both lower and higher bilirubin levels may increase the risk of stroke in older persons with OSAS, and there was a J-type dose-response relationship. The risk of stroke was lowest when the TBil level was approximately 11.5 µmol/L.
Similar content being viewed by others
References
GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019 May;18(5):439–458. doi: https://doi.org/10.1016/S1474-4422(19)30034-1.
Campbell BCV, Khatri P. Stroke. Lancet. 2020 Jul 11;396(10244):129–142. doi: https://doi.org/10.1016/S0140-6736(20)31179-X.
Puy L, Cordonnier C. Stroke research in 2021: insights into the reorganisation of stroke care. Lancet Neurol. 2022;21(1):2–3. doi:https://doi.org/10.1016/S1474-4422(21)00410-5.
Javaheri S, Peker Y, Yaggi HK, Bassetti CLA. Obstructive sleep apnea and stroke: The mechanisms, the randomized trials, and the road ahead. Sleep Med Rev. 2022 Feb;61:101568. doi: https://doi.org/10.1016/j.smrv.2021.101568.
Brown DL, Yadollahi A, He K, Xu Y, Piper B, Case E, et al. Overnight Rostral Fluid Shifts Exacerbate Obstructive Sleep Apnea After Stroke. Stroke. 2021 Oct;52(10):3176–3183. doi: https://doi.org/10.1161/STROKEAHA.120.032688.
Dyken ME, Im KB. Obstructive sleep apnea and stroke. Chest. 2009;136(6):1668–1677. doi:https://doi.org/10.1378/chest.08-1512.
Islam T, McConnell R, Gauderman WJ, Avol E, Peters JM, Gilliland FD. Ozone, oxidant defense genes, and risk of asthma during adolescence. Am J Respir Crit Care Med. 2008 Feb 15;177(4):388–95. doi: https://doi.org/10.1164/rccm.200706-863OC.
Kovtunovych G, Eckhaus MA, Ghosh MC, Ollivierre-Wilson H, Rouault TA. Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution. Blood. 2010 Dec 23;116(26):6054–6062. doi: https://doi.org/10.1182/blood-2010-03-272138.
Wei Y, Liu C, Lai F, Dong S, Chen H, Chen L, et al. Associations between serum total bilirubin, obesity and type 2 diabetes. Diabetol Metab Syndr. 2021 Dec 7;13(1):143. doi: https://doi.org/10.1186/s13098-021-00762-0.
Hao H, Guo H, Ma RL, Yan YZ, Hu YH, Ma JL, et al. Association of total bilirubin and indirect bilirubin content with metabolic syndrome among Kazakhs in Xinjiang. BMC Endocr Disord. 2020 Jul 22;20(1):110. doi: https://doi.org/10.1186/s12902-020-00563-y.
Horsfall LJ, Nazareth I, Petersen I. Cardiovascular events as a function of serum bilirubin levels in a large, statin-treated cohort. Circulation. 2012;126(22):2556–2564. doi:https://doi.org/10.1161/CIRCULATIONAHA.112.114066.
Zhong P, Wu D, Ye X, Wang X, Zhou Y, Zhu X, et al. Association of circulating total bilirubin level with ischemic stroke: a systemic review and meta-analysis of observational evidence. Ann Transl Med. 2019 Jul;7(14):335. doi: https://doi.org/10.21037/atm.2019.06.71.
Zhang XB, Cheng HJ, Yuan YT, Chen Y, Chen YY, Chiu KY, et al. Atorvastatin attenuates intermittent hypoxia-induced myocardial oxidative stress in a mouse obstructive sleep apnea model. Aging (Albany NY). 2021 Jul 21;13(14):18870–18878. doi: https://doi.org/10.18632/aging.203339.
Xie JY, Liu WX, Ji L, Chen Z, Gao JM, Chen W, et al. Relationship between inflammatory factors and arrhythmia and heart rate variability in OSAS patients. Eur Rev Med Pharmacol Sci. 2020 Feb;24(4):2037–2053. doi: https://doi.org/10.26355/eurrev_202002_20382.
Yosunkaya S, Kutlu R, Vatansev H. Effects of smoking on patients with obstructive sleep apnea syndrome. Clin Respir J. 2021 Feb;15(2):147–153. doi: https://doi.org/10.1111/crj.13278.
von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. Int J Surg. 2014 Dec;12(12):1495–1499. doi: https://doi.org/10.1016/j.ijsu.2014.07.013.
Gerstenslager B, Slowik JM. Sleep Study. 2021 Aug 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. PMID: 33085294.
Su X, Gao Y, Xu W, Li J, Chen K, Gao Y, et al. Association Cystatin C and Risk of Stroke in Elderly Patients With Obstructive Sleep Apnea: A Prospective Cohort Study. Front Neurosci. 2021 Dec 15;15:762552. doi: https://doi.org/10.3389/fnins.2021.762552.
Rundo JV, Downey R 3rd. Polysomnography. Handb Clin Neurol. 2019;160:381–392. doi: https://doi.org/10.1016/B978-0-444-64032-1.00025-4.
Baiardi S, Cirignotta F. La diagnosi clinic-strumentale della Sindrome delle Apnee Ostrutiive nel Sonno (OSAS) [The clinical diagnosis of Obstructive Sleep Apnea Syndrome (OSAS)]. Med Lav. 2017 Aug 28;108(4):267–275. Italian. doi: https://doi.org/10.23749/mdl.v108i4.6414.
Pippitt K, Li M, Gurgle HE. Diabetes Mellitus: Screening and Diagnosis. Am Fam Physician. 2016 Jan 15;93(2):103–109. Erratum in: Am Fam Physician. 2016 Oct 1;94(7):533. PMID: 26926406.
Claeys MJ, Mullens W, Vandekerckhove Y, Duytschaever M, De Maeyer C, Pasquet A. Summary of 2016 ESC guidelines on heart failure, atrial fibrillation, dyslipidaemia and cardiovascular prevention. Acta Cardiol. 2017 Dec;72(6):610–615. doi: https://doi.org/10.1080/00015385.2017.1319681.
Webster AC, Nagler EV, Morton RL, Masson P. Chronic Kidney Disease. Lancet. 2017 Mar 25;389(10075):1238–1252. doi: https://doi.org/10.1016/S0140-6736(16)32064-5.
Fan Y, Huang JJ, Sun CM, Qiao N, Zhang HX, Wang H, et al. Prevalence of dyslipidaemia and risk factors in Chinese coal miners: a cross-sectional survey study. Lipids Health Dis. 2017 Aug 23;16(1):161. doi: https://doi.org/10.1186/s12944-017-0548-9.
Chinese Society of Neurology, and Chinese Stroke Society (2019). Diagnostic criteria of cerebrovascular diseases in China 2019. Chin. J. Neurol. 52, 710–715. doi: https://doi.org/10.3760/cma.j.issn.1006-7876.
Mulaik MW. ICD-10: stroke. Radiol Manage. 2012 Jan–Feb;34(1):16–17. PMID: 22413607.
Wei Y, Zhou JH, Zhang ZW, Tan QY, Zhang MY, Li J, et al. [Application of restricted cube spline in cox regression model]. Zhonghua Yu Fang Yi Xue Za Zhi. 2020 Oct 6;54(10):1169–1173. Chinese. doi: https://doi.org/10.3760/cma.j.cn112150-20200804-01092.
Krumsiek J, Mittelstrass K, Do KT, Stückler F, Ried J, Adamski J, et al. Gender-specific pathway differences in the human serum metabolome. Metabolomics. 2015;11(6):1815–1833. doi:https://doi.org/10.1007/s11306-015-0829-0.
Zanussi JT, Zhao J, Dorn CA, Liu G, Feng Q, Wei W, et al. Identifying Potential Therapeutic Applications and Diagnostic Harms of Increased Bilirubin Concentrations: A Clinical and Genetic Approach. Clin Pharmacol Ther. 2022;111(2):435–443. doi:https://doi.org/10.1002/cpt.2441.
Liu Y, Wang J, Zeng WZ, Lyu QS. Nonlinear relationship between serum total bilirubin levels and initial ischemic stroke in patients with non-valvular atrial fibrillation. J Int Med Res. 2020 Oct;48(10):300060520962347. doi: https://doi.org/10.1177/0300060520962347.
Peres BU, Allen AJH, Shah A, Fox N, Laher I, Almeida F, et al. Obstructive Sleep Apnea and Circulating Biomarkers of Oxidative Stress: A Cross-Sectional Study. Antioxidants (Basel). 2020 Jun 2;9(6):476. doi: https://doi.org/10.3390/antiox9060476.
Kritikou I, Basta M, Vgontzas AN, Pejovic S, Liao D, Tsaoussoglou M, et al. Sleep apnoea, sleepiness, inflammation and insulin resistance in middle-aged males and females. Eur Respir J. 2014 Jan;43(1):145–155. doi: https://doi.org/10.1183/09031936.00126712.
Nocentini A, Bonardi A, Pratesi S, Gratteri P, Dani C, Supuran CT. Pharmaceutical strategies for preventing toxicity and promoting antioxidant and anti-inflammatory actions of bilirubin. J Enzyme Inhib Med Chem. 2022 Dec;37(1):487–501. doi: https://doi.org/10.1080/14756366.2021.2020773.
Li C, Wu W, Song Y, Xu S, Wu X. The Nonlinear Relationship Between Total Bilirubin and Coronary Heart Disease: A Dose-Response Meta-Analysis. Front Cardiovasc Med. 2022 Jan 5;8:761520. doi: https://doi.org/10.3389/fcvm.2021.761520.
Chen Z, He J, Chen C, Lu Q. Association of Total Bilirubin With All-Cause and Cardiovascular Mortality in the General Population. Front Cardiovasc Med. 2021 Jun 18;8:670768. doi: https://doi.org/10.3389/fcvm.2021.670768.
Sagheb Asl E, Taheraghdam A, Rahmani F, Javadrashid R, Golzari SEJ, Ghaemian N, et al. Determination of the Predictive Value of Serum Bilirubin in Patients with Ischemic Stroke: A Prospective Descriptive Analytical Study. Adv Pharm Bull. 2018 Nov;8(4):715–719. doi: https://doi.org/10.15171/apb.2018.080.
Perlstein TS, Pande RL, Creager MA, Weuve J, Beckman JA. Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES 1999–2004. Am J Med. 2008 Sep;121(9):781–788.e1. doi: https://doi.org/10.1016/j.amjmed.2008.03.045.
Fu K, Garvan CS, Heaton SC, Nagaraja N, Doré S. Association of Serum Bilirubin with the Severity and Outcomes of Intracerebral Hemorrhages. Antioxidants (Basel). 2021 Aug 25;10(9):1346. doi: https://doi.org/10.3390/antiox10091346.
Choi Y, Lee SJ, Spiller W, Jung KJ, Lee JY, Kimm H, et al. Causal Associations Between Serum Bilirubin Levels and Decreased Stroke Risk: A Two-Sample Mendelian Randomization Study. Arterioscler Thromb Vasc Biol. 2020 Feb;40(2):437–445. doi: https://doi.org/10.1161/ATVBAHA.119.313055.
Schieffer KM, Bruffy SM, Rauscher R, Koltun WA, Yochum GS, Gallagher CJ. Reduced total serum bilirubin levels are associated with ulcerative colitis. PLoS One. 2017 Jun 8;12(6):e0179267. doi: https://doi.org/10.1371/journal.pone.0179267.
Lapenna D, Ciofani G, Pierdomenico SD, Giamberardino MA, Ucchino S, Davì G. Association of serum bilirubin with oxidant damage of human atherosclerotic plaques and the severity of atherosclerosis. Clin Exp Med. 2018 Feb;18(1):119–124. doi: https://doi.org/10.1007/s10238-017-0470-5.
Stein JH, Ribaudo HJ, Hodis HN, Brown TT, Tran TT, Yan M, et al. A prospective, randomized clinical trial of antiretroviral therapies on carotid wall thickness. AIDS. 2015 Sep 10;29(14):1775–1783. doi: https://doi.org/10.1097/QAD.0000000000000762.
Polak JF, Pencina MJ, O’Leary DH, D’Agostino RB. Common carotid artery intima-media thickness progression as a predictor of stroke in multi-ethnic study of atherosclerosis. Stroke. 2011 Nov;42(11):3017–3021. doi: https://doi.org/10.1161/STROKEAHA.111.625186.
Chow YL, Teh LK, Chyi LH, Lim LF, Yee CC, Wei LK. Lipid Metabolism Genes in Stroke Pathogenesis: The Atherosclerosis. Curr Pharm Des. 2020;26(34):4261–4271. doi: https://doi.org/10.2174/1381612826666200614180958.
Ma X, Zheng X, Liu S, Zhuang L, Wang M, Wang Y, et al. Relationship of circulating total bilirubin, UDP-glucuronosyltransferases 1A1 and the development of non-alcoholic fatty liver disease: a cross-sectional study. BMC Gastroenterol. 2022 Jan 5;22(1):6. doi: https://doi.org/10.1186/s12876-021-02088-7.
Jacobs JW, Bastarache L, Thompson MA. Laboratory Predictors of Hemolytic Anemia in Patients With Systemic Loxoscelism. Am J Clin Pathol. 2022 Apr 1;157(4):566–572. doi: https://doi.org/10.1093/ajcp/aqab169.
Xu J, Dai L, Zhang Y, Wang A, Li H, Wang Y, et al. Severity of Nonalcoholic Fatty Liver Disease and Risk of Future Ischemic Stroke Events. Stroke. 2021 Jan;52(1):103–110. doi: https://doi.org/10.1161/STROKEAHA.120.030433.
Francque SM, van der Graaff D, Kwanten WJ. Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications. J Hepatol. 2016 Aug;65(2):425–443. doi: https://doi.org/10.1016/j.jhep.2016.04.005.
Bianco A, Dvořák A, Capková N, Gironde C, Tiribelli C, Furger C, et al. The Extent of Intracellular Accumulation of Bilirubin Determines Its Anti- or Pro-Oxidant Effect. Int J Mol Sci. 2020 Oct 30;21(21):8101. doi: https://doi.org/10.3390/ijms21218101.
Zucker SD, Horn PS, Sherman KE. Serum bilirubin levels in the U.S. population: gender effect and inverse correlation with colorectal cancer. Hepatology. 2004 Oct;40(4):827–835. doi: https://doi.org/10.1002/hep.20407.
Wagner KH, Wallner M, Mölzer C, Gazzin S, Bulmer AC, Tiribelli C, et al. Looking to the horizon: the role of bilirubin in the development and prevention of age-related chronic diseases. Clin Sci (Lond). 2015 Jul;129(1):1–25. doi: https://doi.org/10.1042/CS20140566.
Kim SY, Park SC. Physiological antioxidative network of the bilirubin system in aging and age-related diseases. Front Pharmacol. 2012 Mar 14;3:45. doi: https://doi.org/10.3389/fphar.2012.00045.
Vaz AR, Falcão AS, Scarpa E, Semproni C, Brites D. Microglia Susceptibility to Free Bilirubin Is Age-Dependent. Front Pharmacol. 2020 Jul 14;11:1012. doi: https://doi.org/10.3389/fphar.2020.01012.
Chan MTV, Wang CY, Seet E, Tam S, Lai HY, Chew EFF, et al. Postoperative Vascular Complications in Unrecognized Obstructive Sleep Apnea (POSA) Study Investigators. Association of Unrecognized Obstructive Sleep Apnea With Postoperative Cardiovascular Events in Patients Undergoing Major Noncardiac Surgery. JAMA. 2019 May 14;321(18):1788–1798. doi: https://doi.org/10.1001/jama.2019.4783.
Freedman B, Potpara TS, Lip GY. Stroke prevention in atrial fibrillation. Lancet. 2016 Aug 20;388(10046):806–817. doi: https://doi.org/10.1016/S0140-6736(16)31257-0.
Acknowledgments: Not applicable.
Funding
Funding: This study was supported by Military Health Care Project (23BJZ27 and 22BJZ52), Military experimental animal special research project (SYDW_KY[2021]04), and Military Equipment Construction Application Research Project (LB20211A010013). The funders had no direct role in the design, data collection, analysis, interpretation, or writing of the manuscript.
Author information
Authors and Affiliations
Contributions
Author contributions: LL, XsQ and LF contributed to the research design, data interpretation, and critically revised the manuscript. HhW, FfF and ZjH contributed to the data acquisition. XfS, JhL and ZZ collected the data and the samples. LbZ, YhG and KlL contributed to data interpretation and wrote the manuscript. WhX and XhL contributed to design and make the RCS figures. All authors gave final approval and agreed to be accountable for all aspects of this work.
Corresponding authors
Ethics declarations
Ethics statement: The studies involving human participants were reviewed and approved by the Ethics Committee of Chinese PLA General Hospital (S2020-397-02).
Conflict of interest statement: The authors declare that the study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Gao, Y., Zhao, L., Li, K. et al. The J-shape Association between Total Bilirubin and Stroke in Older Patients with Obstructive Sleep Apnea Syndrome: A Multicenter Study. J Nutr Health Aging 27, 692–700 (2023). https://doi.org/10.1007/s12603-023-1965-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12603-023-1965-2