European Journal of Epidemiology

, Volume 32, Issue 2, pp 113–123 | Cite as

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

  • Romina di Giuseppe
  • Ronald Biemann
  • Janine Wirth
  • Juliane Menzel
  • Berend Isermann
  • Gabriele I. Stangl
  • Andreas Fritsche
  • Heiner Boeing
  • Matthias B. Schulze
  • Cornelia Weikert


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.


Myocardial failure Cytokine Determinants Additive interaction 



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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

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.

Supplementary material

10654_2016_172_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 15 kb)


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Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Romina di Giuseppe
    • 1
    • 2
  • Ronald Biemann
    • 3
  • Janine Wirth
    • 4
  • Juliane Menzel
    • 1
    • 5
    • 8
  • Berend Isermann
    • 3
  • Gabriele I. Stangl
    • 6
  • Andreas Fritsche
    • 7
  • Heiner Boeing
    • 4
  • Matthias B. Schulze
    • 5
    • 8
  • Cornelia Weikert
    • 1
    • 9
  1. 1.Research Group Cardiovascular EpidemiologyGerman Institute of Human Nutrition Potsdam-RehbrückeNuthetalGermany
  2. 2.Institute of EpidemiologyChristian-Albrechts University Kiel, University Hospital Schleswig-Holstein (UK-SH)KielGermany
  3. 3.Institute of Clinical Chemistry and PathobiochemistryOtto-von-Guericke University, MagdeburgMagdeburgGermany
  4. 4.Department of EpidemiologyGerman Institute of Human Nutrition Potsdam-RehbrückeNuthetalGermany
  5. 5.Department of Molecular EpidemiologyGerman Institute of Human Nutrition Potsdam-RehbrückeNuthetalGermany
  6. 6.Human Nutrition Group, Institute of Agricultural and Nutritional SciencesMartin Luther University Halle-Wittenberg, Halle (Saale)Halle (Saale)Germany
  7. 7.Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Department of Internal MedicineUniversity of TübingenTübingenGermany
  8. 8.German Center for Diabetes Research (DZD)NeuherbergGermany
  9. 9.Department of Food SafetyFederal Institute of Risk AssessmentBerlinGermany

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