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Association of serum markers of oxidative stress with myocardial infarction and stroke: pooled results from four large European cohort studies

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Abstract

Oxidative stress contributes to endothelial dysfunction and is involved in the pathogenesis of myocardial infarction (MI) and stroke. However, associations of biomarkers of oxidative stress with MI and stroke have not yet been addressed in large cohort studies. A nested case–control design was applied in four population-based cohort studies from Germany, Czech Republic, Poland and Lithuania. Derivatives of reactive oxygen metabolites (d-ROMs) levels, as a proxy for the reactive oxygen species burden, and total thiol levels (TTL), as a proxy for the reductive capacity, were measured in baseline serum samples of 476 incident MI cases and 454 incident stroke cases as well as five controls per case individually matched by study center, age and sex. Statistical analyses were conducted with multi-variable adjusted conditional logistic regression models. d-ROMs levels were associated with both MI (odds ratio (OR), 1.21 [95% confidence interval (CI) 1.05–1.40] for 100 Carr units increase) and stroke (OR, 1.17 [95% CI 1.01–1.35] for 100 Carr units increase). TTL were only associated with stroke incidence (OR, 0.79 [95% CI 0.63-0.99] for quartiles 2–4 vs. quartile 1). The observed relationships were stronger with fatal than with non-fatal endpoints; association of TTL with fatal MI was statistically significant (OR, 0.69 [95% CI 0.51–0.93] for 100 μmol/L-increase). This pooled analysis of four large population-based cohorts suggests an important contribution of an imbalanced redox system to the etiology of mainly fatal MI and stroke events.

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References

  1. Frostegard J. Immunity, atherosclerosis and cardiovascular disease. BMC Med. 2013;11:117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Stocker R, Keaney JF Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004;84:1381–478.

    Article  CAS  PubMed  Google Scholar 

  3. Chen K, Keaney JF Jr. Evolving concepts of oxidative stress and reactive oxygen species in cardiovascular disease. Curr Atheroscler Rep. 2012;14:476–83.

    Article  CAS  PubMed  Google Scholar 

  4. Lee R, Margaritis M, Channon KM, Antoniades C. Evaluating oxidative stress in human cardiovascular disease: methodological aspects and considerations. Curr Med Chem. 2012;19:2504–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature. 2011;472:476–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Stephens JW, Khanolkar MP, Bain SC. The biological relevance and measurement of plasma markers of oxidative stress in diabetes and cardiovascular disease. Atherosclerosis. 2009;202:321–9.

    Article  CAS  PubMed  Google Scholar 

  7. Kotani K, Sakane N. C-reactive protein and reactive oxygen metabolites in subjects with metabolic syndrome. J Int Med Res. 2012;40:1074–81.

    Article  CAS  PubMed  Google Scholar 

  8. Marrocco I, Altieri F, Peluso I. Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxid Med Cell Longev. 2017;2017:6501046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Schöttker B, Brenner H, Jansen EH, Gardiner J, Peasey A, Kubinova R, et al. Evidence for the free radical/oxidative stress theory of ageing from the CHANCES consortium: a meta-analysis of individual participant data. BMC Med. 2015;13:300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shao B, Heinecke JW. HDL, lipid peroxidation, and atherosclerosis. J Lipid Res. 2009;50:599–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li C, Zhang WJ, Choi J, Frei B. Quercetin affects glutathione levels and redox ratio in human aortic endothelial cells not through oxidation but formation and cellular export of quercetin-glutathione conjugates and upregulation of glutamate-cysteine ligase. Redox Biol. 2016;9:220–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Masaki N, Sato A, Horii S, Kimura T, Toya T, Yasuda R, et al. Usefulness of the d-ROMs test for prediction of cardiovascular events. Int J Cardiol. 2016;222:226–32.

    Article  PubMed  Google Scholar 

  13. Peasey A, Bobak M, Kubinova R, Malyutina S, Pajak A, Tamosiunas A, et al. Determinants of cardiovascular disease and other non-communicable diseases in Central and Eastern Europe: rationale and design of the HAPIEE study. BMC Public Health. 2006;6:255.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Schöttker B, Saum KU, Jansen EH, Boffetta P, Trichopoulou A, Holleczek B, et al. Oxidative stress markers and all-cause mortality at older age: a population-based cohort study. J Gerontol A Biol Sci Med Sci. 2015;70:518–24.

    Article  CAS  PubMed  Google Scholar 

  15. Schöttker B, Haug U, Schomburg L, Köhrle J, Perna L, Müller H, et al. Strong associations of 25-hydroxyvitamin D concentrations with all-cause, cardiovascular, cancer, and respiratory disease mortality in a large cohort study. Am J Clin Nutr. 2013;97:782–93.

    Article  CAS  PubMed  Google Scholar 

  16. Boffetta P, Bobak M, Borsch-Supan A, Brenner H, Eriksson S, Grodstein F, et al. The Consortium on Health and Ageing: network of Cohorts in Europe and the United States (CHANCES) project—design, population and data harmonization of a large-scale, international study. Eur J Epidemiol. 2014;29:929–36.

    Article  PubMed  Google Scholar 

  17. Desquilbet L, Mariotti F. Dose-response analyses using restricted cubic spline functions in public health research. Stat Med. 2010;29:1037–57.

    PubMed  Google Scholar 

  18. Jansen E, Beekhof PK, Cremers JWJM, Viezeliene D, Muzakova V, Skalicky J. Short-term stability of biomarkers of oxidative stress and antioxidant status in human serum. ISRN Biomark. 2013;2013:5.

    Article  CAS  Google Scholar 

  19. Verde V, Fogliano V, Ritieni A, Maiani G, Morisco F, Caporaso N. Use of N,N-dimethyl-p-phenylenediamine to evaluate the oxidative status of human plasma. Free Radic Res. 2002;36:869–73.

    Article  CAS  PubMed  Google Scholar 

  20. Jansen E, Beekhof PK, Viezeliene D, Muzakova V, Skalicky J. Long-term stability of oxidative stress biomarkers in human serum. Free Radic Res. 2017;51:970–7.

    Article  CAS  PubMed  Google Scholar 

  21. Vassalle C, Bianchi S, Bianchi F, Landi P, Battaglia D, Carpeggiani C. Oxidative stress as a predictor of cardiovascular events in coronary artery disease patients. Clin Chem Lab Med. 2012;50:1463–8.

    Article  CAS  PubMed  Google Scholar 

  22. Hirata Y, Yamamoto E, Tokitsu T, Kusaka H, Fujisue K, Kurokawa H, et al. Reactive oxygen metabolites are closely associated with the diagnosis and prognosis of coronary artery disease. J Am Heart Assoc. 2015;4:e001451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hirata Y, Yamamoto E, Tokitsu T, Fujisue K, Kurokawa H, Sugamura K, et al. The pivotal role of a novel biomarker of reactive oxygen species in chronic kidney disease. Medicine (Baltimore). 2015;94:e1040.

    Article  CAS  Google Scholar 

  24. Xuan Y, Gao X, Holleczek B, Brenner H, Schöttker B. Prediction of myocardial infarction, stroke and cardiovascular mortality with urinary biomarkers of oxidative stress: Results from a large cohort study. Int J Cardiol. 2018 [epub ahead of print]. https://doi.org/10.1016/j.ijcard.2018.08.002.

  25. Vassalle C, Botto N, Andreassi MG, Berti S, Biagini A. Evidence for enhanced 8-isoprostane plasma levels, as index of oxidative stress in vivo, in patients with coronary artery disease. Coron Artery Dis. 2003;14:213–8.

    PubMed  Google Scholar 

  26. Vassalle C, Petrozzi L, Botto N, Andreassi MG, Zucchelli GC. Oxidative stress and its association with coronary artery disease and different atherogenic risk factors. J Intern Med. 2004;256:308–15.

    Article  CAS  PubMed  Google Scholar 

  27. Elesber AA, Best PJ, Lennon RJ, Mathew V, Rihal CS, Lerman LO, et al. Plasma 8-iso-prostaglandin F2alpha, a marker of oxidative stress, is increased in patients with acute myocardial infarction. Free Radic Res. 2006;40:385–91.

    Article  CAS  PubMed  Google Scholar 

  28. Steinberg D. The LDL modification hypothesis of atherogenesis: an update. J Lipid Res. 2009;50(Suppl):S376–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gargiulo S, Testa G, Gamba P, Staurenghi E, Poli G, Leonarduzzi G. Oxysterols and 4-hydroxy-2-nonenal contribute to atherosclerotic plaque destabilization. Free Radic Biol Med. 2017;111:140–50.

    Article  CAS  PubMed  Google Scholar 

  30. Hoseini Z, Sepahvand F, Rashidi B, Sahebkar A, Masoudifar A, Mirzaei H. NLRP3 inflammasome: its regulation and involvement in atherosclerosis. J Cell Physiol. 2018;233:2116–32.

    Article  CAS  PubMed  Google Scholar 

  31. Kameda K, Matsunaga T, Abe N, Hanada H, Ishizaka H, Ono H, et al. Correlation of oxidative stress with activity of matrix metalloproteinase in patients with coronary artery disease. Possible role for left ventricular remodelling. Eur Heart J. 2003;24:2180–5.

    Article  CAS  PubMed  Google Scholar 

  32. Icme F, Erel O, Avci A, Satar S, Gulen M, Acehan S. The relation between oxidative stress parameters, ischemic stroke, and hemorrhagic stroke. Turk J Med Sci. 2015;45:947–53.

    Article  CAS  PubMed  Google Scholar 

  33. Cherubini A, Ruggiero C, Polidori MC, Mecocci P. Potential markers of oxidative stress in stroke. Free Radic Biol Med. 2005;39:841–52.

    Article  CAS  PubMed  Google Scholar 

  34. Saeed SA, Shad KF, Saleem T, Javed F, Khan MU. Some new prospects in the understanding of the molecular basis of the pathogenesis of stroke. Exp Brain Res. 2007;182:1–10.

    Article  PubMed  Google Scholar 

  35. Duan X, Wen Z, Shen H, Shen M, Chen G. Intracerebral hemorrhage, oxidative stress, and antioxidant therapy. Oxid Med Cell Longev. 2016;2016:1203285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pandey KB, Mehdi MM, Maurya PK, Rizvi SI. Plasma protein oxidation and its correlation with antioxidant potential during human aging. Dis Markers. 2010;29:31–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vassalle C, Sciarrino R, Bianchi S, Battaglia D, Mercuri A, Maffei S. Sex-related differences in association of oxidative stress status with coronary artery disease. Fertil Steril. 2012;97:414–9.

    Article  CAS  PubMed  Google Scholar 

  38. Dantas AP, Franco MC, Silva-Antonialli MM, Tostes RC, Fortes ZB, Nigro D, et al. Gender differences in superoxide generation in microvessels of hypertensive rats: role of NAD(P)H-oxidase. Cardiovasc Res. 2004;61:22–9.

    Article  CAS  PubMed  Google Scholar 

  39. Bhatia K, Elmarakby AA, El-Remessy AB, Sullivan JC. Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2012;302:R274–82.

    Article  CAS  PubMed  Google Scholar 

  40. Nickelson KJ, Stromsdorfer KL, Pickering RT, Liu TW, Ortinau LC, Keating AF, et al. A comparison of inflammatory and oxidative stress markers in adipose tissue from weight-matched obese male and female mice. Exp Diabetes Res. 2012;2012:859395.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Fernandez-Sanchez A, Madrigal-Santillan E, Bautista M, Esquivel-Soto J, Morales-Gonzalez A, Esquivel-Chirino C, et al. Inflammation, oxidative stress, and obesity. Int J Mol Sci. 2011;12:3117–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fonseca-Alaniz MH, Takada J, Alonso-Vale MI, Lima FB. Adipose tissue as an endocrine organ: from theory to practice. J Pediatr (Rio J). 2007;83:S192–203.

    Article  Google Scholar 

  43. Pugliese G, Solini A, Bonora E, Orsi E, Zerbini G, Giorgino F, et al. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation provides a better definition of cardiovascular burden associated with CKD than the Modification of Diet in Renal Disease (MDRD) Study formula in subjects with type 2 diabetes. Atherosclerosis. 2011;218:194–9.

    Article  CAS  PubMed  Google Scholar 

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Funding

This project was funded by a grant from the German Research Foundation (Grant No. SCHO 1545/3-1) and a scholarship from the China Scholarship Council (CSC) to Yang Xuan. The CHANCES project was funded in the FP7 framework programme of DG-RESEARCH in the European Commission (Grant No. 242,244). The CHANCES project was coordinated by the Hellenic Health Foundation, Greece. Further funding sources of participating cohorts: The ESTHER study was funded by the Baden-Württemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany) and the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany). The HAPIEE study was funded by the Welcome Trust (064947 and 081081), the US National Institute on Ageing (R01 AG23522) and a grant from Mac Arthur Foundation. The authors are indebted to Mr. Piet Beekhof for the measurement of all oxidative stress biomarkers. We also acknowledge the work of Anne Peasey, Růžena Kubínová, Hynek Pikhart and Roman Topor-Madry in the conduct of the HAPIEE study.

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Authors and Affiliations

  1. Division of Clinical Epidemiology and Ageing Research, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany

    Yang Xuan, Ankita Anusruti, Kai-Uwe Saum, Xin Gao, Hermann Brenner & Ben Schöttker

  2. Network Aging Research, University of Heidelberg, Bergheimer Straße 20, 69120, Heidelberg, Germany

    Yang Xuan, Ankita Anusruti, Xin Gao, Hermann Brenner & Ben Schöttker

  3. Department Epidemiology and Public Health, University College London, 1-19 Torrington Place, London, WC1E 6BT, UK

    Martin Bobak

  4. Centre for Health Protection, National Institute for Public Health and the Environment, PO Box 1, 3720 BA, Bilthoven, The Netherlands

    Eugène H. J. M. Jansen

  5. Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland

    Andrzej Pająk

  6. Institute of Cardiology of Lithuanian, University of Health Sciences, Kaunas, Lithuania

    Abdonas Tamosiunas

  7. Saarland Cancer Registry, Präsident Baltz-Straße 5, 66119, Saarbrücken, Germany

    Bernd Holleczek

  8. Institute of Health Care and Social Sciences, FOM University, Essen, Germany

    Ben Schöttker

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  1. Yang Xuan
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  2. Martin Bobak
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Correspondence to Ben Schöttker.

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Xuan, Y., Bobak, M., Anusruti, A. et al. Association of serum markers of oxidative stress with myocardial infarction and stroke: pooled results from four large European cohort studies. Eur J Epidemiol 34, 471–481 (2019). https://doi.org/10.1007/s10654-018-0457-x

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