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Plasma osteoprotegerin, its correlates, and risk of heart failure: a prospective cohort study

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Abstract

Heart failure (HF) is a disabling condition involving complex vascular, neurohormonal and immune systems’ interactions. Osteoprotegerin (OPG), a bone-regulatory cytokine, has been suggested to play a key role in skeletal, vascular, and immune biology, with elevated levels observed in both experimental and clinical HF. In the present study we aimed to identify clinical OPG correlates and investigated whether elevated OPG, as a marker of HF vascular and immune activation, may interact with N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of HF neurohormonal activation, thus synergistically increasing HF risk. We used a case-cohort study, nested within the European Prospective Investigation into Cancer and Nutrition-Potsdam, comprising 2647 participants including 252 incident HF cases identified during a mean follow-up of 8.2 ± 1.6 years. In both men and women significant positive associations were observed between OPG and age, smoking, prevalent diabetes, C-reactive protein, sex hormone-binding globulin, and additionally prevalent coronary heart disease and uric acid in men only. In women, OPG was furthermore positively related to hypertension and fetuin-A. After multivariable adjustment each doubling of OPG was associated with a 3.01-fold increased HF risk (95 % CI 1.49–6.06) in men. A significant interaction was observed between OPG and NT-proBNP. In men, a combination of high levels of both OPG and NT-proBNP, compared to a combination of low levels, was associated with an approximately fivefold increased HF risk. In women, no associations were observed. These findings suggest that, in men, the activation of different immune, neurohormonal, and vascular pathophysiological pathways may confer increased HF risk.

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References

  1. Sharma R, Anker SD. Immune and neurohormonal pathways in chronic heart failure. Congest Heart Fail. 2002;8(1):23–48.

    Article  CAS  PubMed  Google Scholar 

  2. Fildes JE, Shaw SM, Yonan N, Williams SG. The immune system and chronic heart failure: is the heart in control? J Am Coll Cardiol. 2009;53(12):1013–20. doi:10.1016/j.jacc.2008.11.046.

    Article  CAS  PubMed  Google Scholar 

  3. Damas JK, Gullestad L, Aukrust P. Cytokines as new treatment targets in chronic heart failure. Curr Control Trials Cardiovasc Med. 2001;2(6):271–7.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Mori G, D’Amelio P, Faccio R, Brunetti G. The interplay between the bone and the immune system. Clin Dev Immunol. 2013;2013:720504. doi:10.1155/2013/720504.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Nybo M, Rasmussen LM. The capability of plasma osteoprotegerin as a predictor of cardiovascular disease: a systematic literature review. Eur J Endocrinol. 2008;159(5):603–8. doi:10.1530/EJE-08-0554.

    Article  CAS  PubMed  Google Scholar 

  6. Ueland T, Yndestad A, Oie E, Florholmen G, Halvorsen B, Froland SS, et al. Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure. Circulation. 2005;111(19):2461–8. doi:10.1161/01.CIR.0000165119.62099.14.

    Article  CAS  PubMed  Google Scholar 

  7. Ueland T, Jemtland R, Godang K, Kjekshus J, Hognestad A, Omland T, et al. Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction. J Am Coll Cardiol. 2004;44(10):1970–6. doi:10.1016/j.jacc.2004.06.076.

    Article  CAS  PubMed  Google Scholar 

  8. Omland T, Ueland T, Jansson AM, Persson A, Karlsson T, Smith C, et al. Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronary syndromes. J Am Coll Cardiol. 2008;51(6):627–33. doi:10.1016/j.jacc.2007.09.058.

    Article  CAS  PubMed  Google Scholar 

  9. Ueland T, Dahl CP, Kjekshus J, Hulthe J, Bohm M, Mach F, et al. Osteoprotegerin predicts progression of chronic heart failure: results from CORONA. Circ Heart Fail. 2011;4(2):145–52. doi:10.1161/CIRCHEARTFAILURE.110.957332.

    Article  CAS  PubMed  Google Scholar 

  10. Ueland T, Aukrust P, Dahl CP, Husebye T, Solberg OG, Tonnessen T, et al. Osteoprotegerin levels predict mortality in patients with symptomatic aortic stenosis. J Intern Med. 2011;270(5):452–60. doi:10.1111/j.1365-2796.2011.02393.x.

    Article  CAS  PubMed  Google Scholar 

  11. Venuraju SM, Yerramasu A, Corder R, Lahiri A. Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidity. J Am Coll Cardiol. 2010;55(19):2049–61. doi:10.1016/j.jacc.2010.03.013.

    Article  CAS  PubMed  Google Scholar 

  12. Lr P. A case-cohort design for epidemiologic cohort studies and disease prevention trials. Biometrika. 1986;73:1–11.

    Article  Google Scholar 

  13. Boeing H, Wahrendorf J, Becker N. EPIC-Germany—a source for studies into diet and risk of chronic diseases. European Investigation into Cancer and Nutrition. Ann Nutr Metab. 1999;43(4):195–204.

    Article  CAS  PubMed  Google Scholar 

  14. di Giuseppe R, Buijsse B, Hirche F, Wirth J, Arregui M, Westphal S, et al. Plasma fibroblast growth factor 23, parathyroid hormone, 25-hydroxyvitamin D3, and risk of heart failure: a prospective, case-cohort study. J Clin Endocrinol Metab. 2014;99(3):947–55. doi:10.1210/jc.2013-2963.

    Article  PubMed  Google Scholar 

  15. Wirth J, Buijsse B, di Giuseppe R, Fritsche A, Hense HW, Westphal S, et al. Relationship between N-terminal pro-brain natriuretic peptide, obesity and the risk of heart failure in middle-aged German adults. PLoS One. 2014;9(11):e113710. doi:10.1371/journal.pone.0113710.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Swedberg K, Cleland J, Dargie H, Drexler H, Follath F, Komajda M, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). Rev Esp Cardiol. 2005;58(9):1062–92.

    Article  PubMed  Google Scholar 

  17. Jacobs S, Kroger J, Floegel A, Boeing H, Drogan D, Pischon T, et al. Evaluation of various biomarkers as potential mediators of the association between coffee consumption and incident type 2 diabetes in the EPIC-Potsdam Study. Am J Clin Nutr. 2014;100(3):891–900. doi:10.3945/ajcn.113.080317.

    Article  CAS  PubMed  Google Scholar 

  18. Weikert C, Stefan N, Schulze MB, Pischon T, Berger K, Joost HG, et al. Plasma fetuin-a levels and the risk of myocardial infarction and ischemic stroke. Circulation. 2008;118(24):2555–62. doi:10.1161/CIRCULATIONAHA.108.814418.

    Article  CAS  PubMed  Google Scholar 

  19. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hopke PK, Liu C, Rubin DB. Multiple imputation for multivariate data with missing and below-threshold measurements: time-series concentrations of pollutants in the Arctic. Biometrics. 2001;57(1):22–33.

    Article  CAS  PubMed  Google Scholar 

  21. di Giuseppe R, Kuhn T, Hirche F, Buijsse B, Dierkes J, Fritsche A, et al. Plasma fibroblast growth factor 23 and risk of cardiovascular disease: results from the EPIC-Germany case-cohort study. Eur J Epidemiol. 2015;30(2):131–41. doi:10.1007/s10654-014-9982-4.

    Article  PubMed  Google Scholar 

  22. de Mutsert R, Jager KJ, Zoccali C, Dekker FW. The effect of joint exposures: examining the presence of interaction. Kidney Int. 2009;75(7):677–81. doi:10.1038/ki.2008.645.

    Article  PubMed  Google Scholar 

  23. Lieb W, Gona P, Larson MG, Massaro JM, Lipinska I, Keaney JF Jr, et al. Biomarkers of the osteoprotegerin pathway: clinical correlates, subclinical disease, incident cardiovascular disease, and mortality. Arterioscler Thromb Vasc Biol. 2010;30(9):1849–54. doi:10.1161/ATVBAHA.109.199661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Abedin M, Omland T, Ueland T, Khera A, Aukrust P, Murphy SA, et al. Relation of osteoprotegerin to coronary calcium and aortic plaque (from the Dallas Heart Study). Am J Cardiol. 2007;99(4):513–8. doi:10.1016/j.amjcard.2006.08.064.

    Article  CAS  PubMed  Google Scholar 

  25. Kiechl S, Schett G, Wenning G, Redlich K, Oberhollenzer M, Mayr A, et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation. 2004;109(18):2175–80. doi:10.1161/01.CIR.0000127957.43874.BB.

    Article  CAS  PubMed  Google Scholar 

  26. Gannage-Yared MH, Fares F, Semaan M, Khalife S, Jambart S. Circulating osteoprotegerin is correlated with lipid profile, insulin sensitivity, adiponectin and sex steroids in an ageing male population. Clin Endocrinol. 2006;64(6):652–8. doi:10.1111/j.1365-2265.2006.02522.x.

    Article  CAS  Google Scholar 

  27. Pascual-Figal DA, Tornel PL, Nicolas F, Sanchez-Mas J, Martinez MD, Gracia MR, et al. Sex hormone-binding globulin: a new marker of disease severity and prognosis in men with chronic heart failure. Rev Esp Cardiol. 2009;62(12):1381–7.

    Article  PubMed  Google Scholar 

  28. Wang HH, Xiang GD. Changes of plasma concentration of osteoprotegerin and its association with endothelial dysfunction before and after hypouricemic therapy in patients with hyperuricemia. Mod Rheumatol. 2015;25(1):123–7. doi:10.3109/14397595.2014.926852.

    Article  CAS  PubMed  Google Scholar 

  29. Rasul S, Ilhan A, Reiter MH, Todoric J, Farhan S, Esterbauer H, et al. Levels of fetuin-A relate to the levels of bone turnover biomarkers in male and female patients with type 2 diabetes. Clin Endocrinol. 2012;76(4):499–505. doi:10.1111/j.1365-2265.2011.04246.x.

    Article  CAS  Google Scholar 

  30. Roysland R, Masson S, Omland T, Milani V, Bjerre M, Flyvbjerg A, et al. Prognostic value of osteoprotegerin in chronic heart failure: the GISSI-HF trial. Am Heart J. 2010;160(2):286–93. doi:10.1016/j.ahj.2010.05.015.

    Article  PubMed  Google Scholar 

  31. Frioes F, Laszczynska O, Almeida PB, Silva N, Guimaraes JT, Omland T, et al. Prognostic Value of osteoprotegerin in acute heart failure. Can J Cardiol. 2015;31(10):1266–71. doi:10.1016/j.cjca.2015.04.003.

    Article  PubMed  Google Scholar 

  32. Aramburu-Bodas O, Garcia-Casado B, Salamanca-Bautista P, Guisado-Espartero ME, Arias-Jimenez JL, Barco-Sanchez A, et al. Relationship between osteoprotegerin and mortality in decompensated heart failure with preserved ejection fraction. J Cardiovasc Med. 2015;16(6):438–43. doi:10.2459/JCM.0000000000000229.

    Article  CAS  Google Scholar 

  33. Bansal N, Zelnick L, Robinson-Cohen C, Hoofnagle AN, Ix JH, Lima JA, et al. Serum parathyroid hormone and 25-hydroxyvitamin D concentrations and risk of incident heart failure: the multi-ethnic study of atherosclerosis. J Am Heart Assoc. 2014;3(6):e001278. doi:10.1161/JAHA.114.001278.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lutsey PL, Michos ED, Misialek JR, Pankow JS, Loehr L, Selvin E, et al. Race and vitamin d binding protein gene polymorphisms modify the association of 25-hydroxyvitamin d and incident heart failure: the ARIC (Atherosclerosis Risk in Communities) Study. JACC Heart Fail. 2015;3(5):347–56. doi:10.1016/j.jchf.2014.11.013.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Witberg G, Ayers CR, Turer AT, Lev E, Kornowski R, de Lemos J, et al. Relation of adiponectin to all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (from the Dallas Heart Study). Am J Cardiol. 2016;117(4):574–9. doi:10.1016/j.amjcard.2015.11.067.

    Article  CAS  PubMed  Google Scholar 

  36. Jankowska EA, Ponikowski P. Sex hormone-binding globulin and heart failure: a passive carrier of steroid hormones or an active hormone itself? Rev Esp Cardiol. 2009;62(12):1353–5.

    Article  PubMed  Google Scholar 

  37. Kecebas M, Gullulu S, Sag S, Besli F, Acikgoz E, Sarandol E, et al. Serum fetuin-A levels in patients with systolic heart failure. Acta Cardiol. 2014;69(4):399–405. doi:10.2143/AC.69.4.3036656.

    PubMed  Google Scholar 

  38. Schoppet M, Hofbauer LC, Brinskelle-Schmal N, Varennes A, Goudable J, Richard M, et al. Serum level of the phosphaturic factor FGF23 is associated with abdominal aortic calcification in men: the STRAMBO study. J Clin Endocrinol Metab. 2012;97(4):E575–83. doi:10.1210/jc.2011-2836.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang HL, Jin X. Relationship between serum adiponectin and osteoprotegerin levels and coronary heart disease severity. Genet Mol Res. 2015;14(3):11023–9. doi:10.4238/2015.September.21.15.

    Article  CAS  PubMed  Google Scholar 

  40. Shroff R, Long DA, Shanahan C. Mechanistic insights into vascular calcification in CKD. J Am Soc Nephrol. 2013;24(2):179–89. doi:10.1681/ASN.2011121191.

    Article  CAS  PubMed  Google Scholar 

  41. Michos ED, Vaidya D, Gapstur SM, Schreiner PJ, Golden SH, Wong ND, et al. Sex hormones, sex hormone binding globulin, and abdominal aortic calcification in women and men in the multi-ethnic study of atherosclerosis (MESA). Atherosclerosis. 2008;200(2):432–8. doi:10.1016/j.atherosclerosis.2007.12.032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Khundmiri SJ, Murray RD, Lederer E. PTH and vitamin D. Compr Physiol. 2016;6(2):561–601. doi:10.1002/cphy.c140071.

    Article  PubMed  Google Scholar 

  43. Jimbo R, Kawakami-Mori F, Mu S, Hirohama D, Majtan B, Shimizu Y, et al. Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency. Kidney Int. 2014;85(5):1103–11. doi:10.1038/ki.2013.332.

    Article  CAS  PubMed  Google Scholar 

  44. Fukumoto S. Vascular calcification—pathological mechanism and clinical application. Regulation of mineral metabolism and mineralization by FGF23. Clin Calcium. 2015;25(5):687–91.

    CAS  PubMed  Google Scholar 

  45. Demer LL, Tintut Y. Vascular calcification: pathobiology of a multifaceted disease. Circulation. 2008;117(22):2938–48. doi:10.1161/CIRCULATIONAHA.107.743161.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Omland T, Drazner MH, Ueland T, Abedin M, Murphy SA, Aukrust P, et al. Plasma osteoprotegerin levels in the general population: relation to indices of left ventricular structure and function. Hypertension. 2007;49(6):1392–8. doi:10.1161/HYPERTENSIONAHA.107.087742.

    Article  CAS  PubMed  Google Scholar 

  47. Helske S, Kovanen PT, Lindstedt KA, Salmela K, Lommi J, Turto H, et al. Increased circulating concentrations and augmented myocardial extraction of osteoprotegerin in heart failure due to left ventricular pressure overload. Eur J Heart Fail. 2007;9(4):357–63. doi:10.1016/j.ejheart.2006.10.015.

    Article  CAS  PubMed  Google Scholar 

  48. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93(9):1137–46. doi:10.1136/hrt.2003.025270.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Ahmed A, Nanda NC, Weaver MT, Allman RM, DeLong JF. Clinical correlates of isolated left ventricular diastolic dysfunction among hospitalized older heart failure patients. Am J Geriatr Cardiol. 2003;12(2):82–9.

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank the Human Study Centre (HSC) of the German Institute of Human Nutrition Potsdam-Rehbrücke, namely the trustee and the examination unit for the collection, the data hub for the processing, and the participants for the provision of the data, the biobank for the processing of the biological samples and the head of the HSC, Manuela Bergmann, for the contribution to the study design and leading the underlying processes of data generation.

Funding source

This work was supported by a grant from the Elsbeth Bonhoff Stiftung.

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Authors and Affiliations

  1. Research Group Cardiovascular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee, 114-116, 14558, Nuthetal, Germany

    Romina di Giuseppe, Juliane Menzel & Cornelia Weikert

  2. Institute of Epidemiology, Christian-Albrechts University Kiel, University Hospital Schleswig-Holstein (UK-SH), Campus Kiel, Niemannsweg 11, 24105, Kiel, Germany

    Romina di Giuseppe

  3. Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University, Magdeburg, Leipziger Str. 44, Building 26, 39120, Magdeburg, Germany

    Ronald Biemann & Berend Isermann

  4. Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee, 114-116, 14558, Nuthetal, Germany

    Janine Wirth & Heiner Boeing

  5. Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee, 114-116, 14558, Nuthetal, Germany

    Juliane Menzel & Matthias B. Schulze

  6. Human Nutrition Group, Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle (Saale), Von-Danckelmann-Platz 2, 06120, Halle (Saale), Germany

    Gabriele I. Stangl

  7. Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany

    Andreas Fritsche

  8. German Center for Diabetes Research (DZD), Neuherberg, Germany

    Juliane Menzel & Matthias B. Schulze

  9. Department of Food Safety, Federal Institute of Risk Assessment, Berlin, Germany

    Cornelia Weikert

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  1. Romina di Giuseppe
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  2. Ronald Biemann
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  3. Janine Wirth
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  6. Gabriele I. Stangl
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Correspondence to Romina di Giuseppe.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee of the Medical Association of the State of Brandenburg and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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di Giuseppe, R., Biemann, R., Wirth, J. et al. Plasma osteoprotegerin, its correlates, and risk of heart failure: a prospective cohort study. Eur J Epidemiol 32, 113–123 (2017). https://doi.org/10.1007/s10654-016-0172-4

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