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Overnight changes in uric acid, xanthine oxidoreductase and oxidative stress levels and their relationships with sleep-disordered breathing in patients with coronary artery disease

Hypertension Research volume 46, pages 2293–2301 (2023)Cite this article

A Comment to this article was published on 06 September 2023

Abstract

Serum uric acid (UA) level is associated with the high cumulative incidence or prevalence of coronary artery disease (CAD), and hyperuricemia is considered as an independent risk marker for CAD. Sleep-disordered breathing (SDB) is also associated with an increased risk of CAD. Several studies have shown that SDB is associated with hyperuricemia, but the mechanisms are unclear. We measured serum levels of UA and xanthine oxidoreductase (XOR) activity and urinary levels of 8-hydroxy-2’-deoxyguanosine (8-OHdG), all of which were assessed at 6 p.m. and the following 6 a.m. in males with CAD. In addition, nocturnal pulse oximetry was performed for the night. Overall 32 eligible patients with CAD were enrolled. Serum UA levels significantly increased overnight. (5.32 ± 0.98 mg/dl to 5.46 ± 1.02 mg/dl, p < 0.001) Moreover, XOR activity and urinary 8-OHdG levels significantly increased from 6 p.m. to 6 a.m. Furthermore, 3% Oxygen desaturation index (ODI) was correlated with the overnight changes in XOR activity (r = 0.36, P = 0.047) and urinary 8-OHdG levels (r = 0.41, P = 0.02). In addition, 3%ODI was independently correlated with the changes in XOR activity (correlation coefficient, 0.36; P = 0.047) and 8-OHdG (partial correlation coefficient, 0.63; P = 0.004) in multivariable analyses. SDB severity was associated with the overnight changes in XOR activity and urinary 8-OHdG, suggesting that SDB may be associated with oxidative stress via UA production. This trial is registered at University Hospital Medical Information Network (UMIN), number: UMIN000021624.

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References

  1. Lee CH, Sethi R, Li R, Ho HH, Hein T, Jim MH, et al. Obstructive sleep apnea and cardiovascular events after percutaneous coronary intervention. Circulation. 2016;133:2008–17.

    Article  PubMed  Google Scholar 

  2. Peker Y, Hedner J, Kraiczi H, Löth S. Respiratory disturbance index: an independent predictor of mortality in coronary artery disease. Am J Respir Crit Care Med. 2000;162:81–6.

    Article  CAS  PubMed  Google Scholar 

  3. Mooe T, Franklin KA, Holmström K, Rabben T, Wiklund U. Sleep-disordered breathing and coronary artery disease: long-term prognosis. Am J Respir Crit Care Med. 2001;164:1910–3.

    Article  CAS  PubMed  Google Scholar 

  4. Yumino D, Tsurumi Y, Takagi A, Suzuki K, Kasanuki H. Impact of obstructive sleep apnea on clinical and angiographic outcomes following percutaneous coronary intervention in patients with acute coronary syndrome. Am J Cardiol. 2007;99:26–30.

    Article  PubMed  Google Scholar 

  5. Javaheri S, Barbe F, Campos-Rodriguez F, Dempsey JA, Khayat R, Javaheri S, et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol. 2017;69:841–58.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Floras JS. Sleep apnea and cardiovascular risk. J Cardiol. 2014;63:3–8.

    Article  PubMed  Google Scholar 

  7. Kasai T, Floras JS, Bradley TD. Sleep apnea and cardiovascular disease: a bidirectional relationship. Circulation. 2012;126:1495–510.

    Article  PubMed  Google Scholar 

  8. Linz D, Woehrle H, Bitter T, Fox H, Cowie MR, Böhm M, et al. The importance of sleep-disordered breathing in cardiovascular disease. Clin Res Cardiology: Off J Ger Card Soc. 2015;104:705–18.

    Article  Google Scholar 

  9. Karimzadeh F, Nami M, Boostani R. Sleep microstructure dynamics and neurocognitive performance in obstructive sleep apnea syndrome patients. J Integr Neurosci. 2017;16:127–42.

    Article  PubMed  Google Scholar 

  10. Alvarez-Sabin J, Romero O, Delgado P, Quintana M, Santamarina E, Ferre A, et al. Obstructive sleep apnea and silent cerebral infarction in hypertensive individuals. J Sleep Res. 2018;27:232–9.

    Article  PubMed  Google Scholar 

  11. Li L, Lu J, Xue W, Wang L, Zhai Y, Fan Z, et al. Target of obstructive sleep apnea syndrome merge lung cancer: based on big data platform. Oncotarget. 2017;8:21567–78.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Micarelli A, Liguori C, Viziano A, Izzi F, Placidi F, Alessandrini M. Integrating postural and vestibular dimensions to depict impairment in moderate-to-severe obstructive sleep apnea syndrome patients. J Sleep Res. 2017;26:487–94.

    Article  PubMed  Google Scholar 

  13. Yatsu S, Naito R, Kasai T, Matsumoto H, Shitara J, Shimizu M, et al. Influence of sleep-disordered breathing assessed by pulse oximetry on long-term clinical outcomes in patients who underwent percutaneous coronary intervention. Clin Res cardiology: Off J Ger Card Soc. 2018;107:711–8.

    Article  Google Scholar 

  14. Kuwabara M, Kanbay M, Hisatome I. Uric acid and hypertension because of arterial stiffness. Hypertension. 2018;72:582–4.

    Article  CAS  PubMed  Google Scholar 

  15. Liu Z, Chen T, Niu H, Ren W, Li X, Cui L, et al. The establishment and characteristics of rat model of atherosclerosis induced by hyperuricemia. Stem Cells Int. 2016;2016:1365257–7.

    Article  PubMed  Google Scholar 

  16. Chou YT, Chuang LP, Li HY, Fu JY, Lin SW, Yang CT, et al. Hyperlipidaemia in patients with sleep-related breathing disorders: prevalence & risk factors. Indian J Med Res. 2010;131:121–5.

    PubMed  Google Scholar 

  17. Hira HS, Shukla A, Kaur A, Kapoor S. Serum uric acid and lactate levels among patients with obstructive sleep apnea syndrome: which is a better marker of hypoxemia? Ann Saudi Med. 2012;32:37–42.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hirotsu C, Tufik S, Guindalini C, Mazzotti DR, Bittencourt LR, Andersen ML. Association between uric acid levels and obstructive sleep apnea syndrome in a large epidemiological sample. PloS One. 2013;8:e66891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Grum CM, Simon RH, Dantzker DR, Fox IH. Evidence for adenosine triphosphate degradation in critically-ill patients. Chest. 1985;88:763–7.

    Article  CAS  PubMed  Google Scholar 

  20. Ruiz García A, Sánchez Armengol A, Luque Crespo García Aguilar D, Romero Falcón A, Carmona Bernal C, Capote F. Blood uric acid levels in patients with sleep-disordered breathing. Arch Bronconeumol. 2006;42:492–500.

  21. Wysocka E, Cofta S, Piorunek T, Dziegielewska-Gesiak S, Bryl W, Torlinski L. Blood antioxidant status, dysglycemia and obstructive sleep apnea. Adv Exp Med Biol. 2013;756:121–9.

    Article  CAS  PubMed  Google Scholar 

  22. Hakoda M, Masunari N, Yamada M, Fujiwara S, Suzuki G, Kodama K, et al. Serum uric acid concentration as a risk factor for cardiovascular mortality: a longterm cohort study of atomic bomb survivors. J Rheumatol. 2005;32:906–12.

    CAS  PubMed  Google Scholar 

  23. Murase T, Nampei M, Oka M, Miyachi A, Nakamura T. A highly sensitive assay of human plasma xanthine oxidoreductase activity using stable isotope-labeled xanthine and LC/TQMS. J Chromatogr B, Anal Technol Biomed Life Sci. 2016;1039:51–8.

    Article  CAS  Google Scholar 

  24. Morrison B, Shenkin A, McLelland A, Robertson DA, Barrowman M, Graham S, et al. Intra-individual variation in commonly analyzed serum constituents. Clin Chem. 1979;25:1799–805.

    Article  CAS  PubMed  Google Scholar 

  25. Devgun MS, Dhillon HS. Importance of diurnal variations on clinical value and interpretation of serum urate measurements. J Clin Pathol. 1992;45:110–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sennels HP, Jørgensen HL, Goetze JP, Fahrenkrug J. Rhythmic 24-hour variations of frequently used clinical biochemical parameters in healthy young males–the Bispebjerg study of diurnal variations. Scand J Clin Lab Investig. 2012;72:287–95.

    Article  CAS  Google Scholar 

  27. Ozanturk E, Ucar ZZ, Varol Y, Koca H, Demir AU, Kalenci D, et al. Urinary uric acid excretion as an indicator of severe hypoxia and mortality in patients with obstructive sleep apnea and chronic obstructive pulmonary disease. Rev Port Pneumol (2006). 2016;22:18–26.

    CAS  PubMed  Google Scholar 

  28. Kayyali US, Donaldson C, Huang H, Abdelnour R, Hassoun PM. Phosphorylation of xanthine dehydrogenase/oxidase in hypoxia. J Biol Chem. 2001;276:14359–65.

    Article  CAS  PubMed  Google Scholar 

  29. Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol. 2004;555:589–606.

    Article  CAS  PubMed  Google Scholar 

  30. Xu L, Yang Y, Chen J. The role of reactive oxygen species in cognitive impairment associated with sleep apnea. Exp Ther Med. 2020;20:4.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Pilkauskaite G, Miliauskas S, Sakalauskas R. Reactive oxygen species production in peripheral blood neutrophils of obstructive sleep apnea patients. ScientificWorldJournal. 2013;2013:421763.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Vatansever E, Surmen-Gur E, Ursavas A, Karadag M. Obstructive sleep apnea causes oxidative damage to plasma lipids and proteins and decreases adiponectin levels. Sleep Breath = Schlaf Atm. 2011;15:275–82.

    Article  Google Scholar 

  33. Lavie L. Oxidative stress inflammation and endothelial dysfunction in obstructive sleep apnea. Front Biosci (Elite Ed). 2012;4:1391–403.

    Article  PubMed  Google Scholar 

  34. Yamauchi M, Nakano H, Maekawa J, Okamoto Y, Ohnishi Y, Suzuki T, et al. Oxidative stress in obstructive sleep apnea. Chest. 2005;127:1674–9.

    Article  CAS  PubMed  Google Scholar 

  35. Corte ED, Stirpe F. The regulation of rat liver xanthine oxidase. Involvement of thiol groups in the conversion of the enzyme activity from dehydrogenase (type D) into oxidase (type O) and purification of the enzyme. Biochem J. 1972;126:739–45.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Cantu-Medellin N, Kelley EE. Xanthine oxidoreductase-catalyzed reactive species generation: a process in critical need of reevaluation. Redox Biol. 2013;1:353–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lira AB, de Sousa Rodrigues CF. Evaluation of oxidative stress markers in obstructive sleep apnea syndrome and additional antioxidant therapy: a review article. Sleep Breath = Schlaf Atm. 2016;20:1155–60.

    Article  Google Scholar 

  38. Celec P, Jurkovičová I, Buchta R, Bartík I, Gardlík R, Pálffy R, et al. Antioxidant vitamins prevent oxidative and carbonyl stress in an animal model of obstructive sleep apnea. Sleep Breath = Schlaf Atm. 2013;17:867–71.

    Article  Google Scholar 

  39. Cofta S, Winiarska HM, Płóciniczak A, Bielawska L, Brożek A, Piorunek T, et al. Oxidative stress markers and severity of obstructive sleep apnea. Adv Exp Med Biol. 2019;1222:27–35.

    Article  CAS  PubMed  Google Scholar 

  40. Bogardus C, Lillioja S, Mott D, Reaven GR, Kashiwagi A, Foley JE. Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians. J Clin Investig. 1984;73:800–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Toyoki D, Shibata S, Kuribayashi-Okuma E, Xu N, Ishizawa K, Hosoyamada M, et al. Insulin stimulates uric acid reabsorption via regulating urate transporter 1 and ATP-binding cassette subfamily G member 2. Am J Physiol Ren Physiol. 2017;313:F826–34.

    Article  CAS  Google Scholar 

  42. Tanaka Y, Nagoshi T, Takahashi H, Oi Y, Yoshii A, Kimura H, et al. URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice. Mol Metab. 2022;55:101411.

    Article  CAS  PubMed  Google Scholar 

  43. Pan XF, Wang L, Pan A. Epidemiology and determinants of obesity in China. lancet Diabetes Endocrinol. 2021;9:373–92.

    Article  PubMed  Google Scholar 

  44. GBD Obesity C, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, et al. Health effects of overweight and obesity in 195 countries over 25 years. N. Engl J Med. 2017;377:13–27.

    Article  Google Scholar 

  45. Chaiamnuay P, Darmawan J, Muirden KD, Assawatanabodee P. Epidemiology of rheumatic disease in rural Thailand: a WHO-ILAR COPCORD study. Community Oriented Programme for the Control of Rheumatic Disease. J Rheumatol. 1998;25:1382–7.

    CAS  PubMed  Google Scholar 

  46. Kuo CF, Grainge MJ, See LC, Yu KH, Luo SF, Zhang W, et al. Epidemiology and management of gout in Taiwan: a nationwide population study. Arthritis Res Ther. 2015;17:13.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Lam B, Ip MS, Tench E, Ryan CF. Craniofacial profile in Asian and white subjects with obstructive sleep apnoea. Thorax. 2005;60:504–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, Ikebuchi Y, et al. Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population. Sci Transl Med. 2009;1:5ra11.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thanks the patients and all staff in Juntendo University Hospital for their important contributions.

Funding

This study was funded by Sanwa Kagaku Kenkyusho Co.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Megumi Shimizu, Takatoshi Kasai, Ryo Naito, Akihiro Sato, Sayaki Ishiwata, Shoichiro Yatsu, Jun Shitara, Hiroki Matsumoto, Azusa Murata, Takao Kato, Shoko Suda, Masaru Hiki & Hiroyuki Daida

  2. Cardiovascular Respiratory Sleep Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Takatoshi Kasai & Ryo Naito

  3. Sleep and Sleep Disordered Breathing Center, Juntendo University Hospital, Tokyo, Japan

    Takatoshi Kasai

  4. Intensive Care Unit and Department of Cardiology, Toranomon Hospital, Tokyo, Japan

    Masanari Kuwabara

  5. Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan

    Takayo Murase & Takashi Nakamura

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Correspondence to Takatoshi Kasai.

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Conflict of interest

TK received research funds from Sanwa Kagaku Kenkyusho Co. and ResMed. AS and RN are affiliated with a department endowed by Philips, ResMed, and Fukuda Denshi. HD reports honoraria from Amgen Astellas, Daiichi Sankyo, Kowa, MSD, and research grant from Canon, and scholarship grant from Otsuka, Sanofi, MSD, Daiichi Sankyo, Pfizer, Mitsubishi Tanabe, Astellas, Takeda, Teijin, Shionogi, Actelion, Kowa, Bayer, Boehringer Ingelheim, and courses endowed by Phillips, Resmed, Fukuda Denshi, Asahikasei, Inter-Reha, and Toho Holdings. Takayo Murase and Takashi Nakamura are employed by Sanwa Kagaku Kenkyusho Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Shimizu, M., Kasai, T., Naito, R. et al. Overnight changes in uric acid, xanthine oxidoreductase and oxidative stress levels and their relationships with sleep-disordered breathing in patients with coronary artery disease. Hypertens Res 46, 2293–2301 (2023). https://doi.org/10.1038/s41440-023-01331-w

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