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T cell and monocyte/macrophage activation markers associate with adverse outcome, but give limited prognostic value in anemic patients with heart failure: results from RED-HF

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Abstract

Background

Activated leukocytes may contribute to the development and progression of heart failure (HF). We investigated the predictive value of circulating levels of stable and readily detectable markers reflecting both monocyte/macrophage and T-cell activity, on clinical outcomes in HF patients with reduced ejection fraction (HFrEF).

Methods

The association between baseline plasma levels of soluble CD163 (sCD163), macrophage migration inhibitory factor (MIF), granulysin, soluble interleukin-2 receptor (sIL-2R), and activated leukocyte cell adhesion molecule (ALCAM) and the primary endpoint of death from any cause or first hospitalization for worsening of HF was evaluated using multivariable Cox proportional hazard models in 1541 patients with systolic HF and mild to moderate anemia, enrolled in the Reduction of Events by darbepoetin alfa in Heart Failure (RED-HF) trial. Modifying effects and interaction with darbepoetin alfa treatment were also assessed.

Results

All leukocyte markers, except granulysin, were associated with the primary outcome and all-cause death in univariate analysis (all p < 0.01) and remained significantly associated in multivariable analysis adjusting for conventional clinical variables (e.g. age, gender, BMI, NYHA class, creatinine, LVEF, etiology) and CRP. However, after final adjustment for TnT and NT-proBNP no associations were found with outcomes. No interaction with darbepoetin alpha treatment was observed for any marker.

Conclusions

Leukocyte activation markers sCD163, MIF, sIL-2R, and ALCAM were associated with adverse outcome in patients with HFrEF, but add little as prognostic markers on top of established biochemical risk markers.

Clinical Trial Registration

https://clinicaltrials.gov/ct2/show/NCT00358215.

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Authors and Affiliations

  1. Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Nydalen, P. B. 4950, 0424, Oslo, Norway

    Aurelija Abraityte, Pål Aukrust & Thor Ueland

  2. Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway

    Lars Gullestad

  3. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway

    Pål Aukrust

  4. Faculty of Medicine, University of Oslo, Oslo, Norway

    Aurelija Abraityte, Pål Aukrust & Thor Ueland

  5. Center for Heart Failure Research, University of Oslo, Oslo, Norway

    Aurelija Abraityte & Lars Gullestad

  6. K. G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway

    Pål Aukrust

  7. K. G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsö, Norway

    Thor Ueland

  8. Cleveland Clinic Foundation, Cleveland, USA

    Lei Kou & James Young

  9. VA Medical Center and University of Minnesota, Minneapolis, MN, USA

    Inder S. Anand

  10. BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

    John J. V. Mcmurray

  11. University Medical Center Groningen, Groningen, The Netherlands

    Dirk J. van Veldhuisen

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  1. Aurelija Abraityte
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Corresponding author

Correspondence to Thor Ueland.

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Conflict of interest

Inder Anand, John J. V. Mcmurray, Dirk J. van Veldhuisen and James Young are members of the RED-HF Executive Committee—no payments in the last 12 months. John J. V. Mcmurray has received travel and accommodation costs paid by Cytokinetics/Amgen in relation to advisory board and clinical trial meetings about omecamtiv mecarbil.

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Abraityte, A., Aukrust, P., Kou, L. et al. T cell and monocyte/macrophage activation markers associate with adverse outcome, but give limited prognostic value in anemic patients with heart failure: results from RED-HF. Clin Res Cardiol 108, 133–141 (2019). https://doi.org/10.1007/s00392-018-1331-2

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