The cardiokine secreted Frizzled-related protein 3, a modulator of Wnt signalling, in clinical and experimental heart failure

Authors

  • E. T. Askevold,

    1. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
    3. Center for Heart Failure Research, University of Oslo, Oslo, Norway
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  • P. Aukrust,

    1. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
    3. Faculty of Medicine, University of Oslo, Oslo, Norway
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  • S. H. Nymo,

    1. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Center for Heart Failure Research, University of Oslo, Oslo, Norway
    3. Faculty of Medicine, University of Oslo, Oslo, Norway
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  • I. G. Lunde,

    1. Center for Heart Failure Research, University of Oslo, Oslo, Norway
    2. Institute for Experimental Medical Research, Oslo University Hospital Ullevål, University of Oslo, Oslo, Norway
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  • O. J. Kaasbøll,

    1. Center for Heart Failure Research, University of Oslo, Oslo, Norway
    2. Institute for Surgical Research, Oslo University Hospital Rikshospitalet, Oslo, Norway
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  • S. Aakhus,

    1. Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Center for Heart Failure Research, University of Oslo, Oslo, Norway
    3. Faculty of Medicine, University of Oslo, Oslo, Norway
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  • G. Florholmen,

    1. Center for Heart Failure Research, University of Oslo, Oslo, Norway
    2. Institute for Surgical Research, Oslo University Hospital Rikshospitalet, Oslo, Norway
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  • I. K. Ohm,

    1. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Center for Heart Failure Research, University of Oslo, Oslo, Norway
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  • M. E. Strand,

    1. Center for Heart Failure Research, University of Oslo, Oslo, Norway
    2. Institute for Experimental Medical Research, Oslo University Hospital Ullevål, University of Oslo, Oslo, Norway
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  • H. Attramadal,

    1. Center for Heart Failure Research, University of Oslo, Oslo, Norway
    2. Institute for Surgical Research, Oslo University Hospital Rikshospitalet, Oslo, Norway
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  • A. Fiane,

    1. Faculty of Medicine, University of Oslo, Oslo, Norway
    2. Department of Cardiothoracic Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway
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  • C. P. Dahl,

    1. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
    3. Center for Heart Failure Research, University of Oslo, Oslo, Norway
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  • A. V. Finsen,

    1. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
    3. Center for Heart Failure Research, University of Oslo, Oslo, Norway
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  • L. E. Vinge,

    1. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
    3. Center for Heart Failure Research, University of Oslo, Oslo, Norway
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  • G. Christensen,

    1. Center for Heart Failure Research, University of Oslo, Oslo, Norway
    2. Faculty of Medicine, University of Oslo, Oslo, Norway
    3. Institute for Experimental Medical Research, Oslo University Hospital Ullevål, University of Oslo, Oslo, Norway
    4. KG Jebsen Cardiac Research Center, University of Oslo, Oslo, Norway
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  • A. Yndestad,

    1. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Center for Heart Failure Research, University of Oslo, Oslo, Norway
    3. Faculty of Medicine, University of Oslo, Oslo, Norway
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  • L. Gullestad,

    1. Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Center for Heart Failure Research, University of Oslo, Oslo, Norway
    3. Faculty of Medicine, University of Oslo, Oslo, Norway
    4. KG Jebsen Cardiac Research Center, University of Oslo, Oslo, Norway
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  • R. Latini,

    1. IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, Italy
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  • S. Masson,

    1. IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, Italy
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  • L. Tavazzi,

    1. GVM Care & Research, Ettore Sansavini Health Science Foundation, Cotignola, Italy
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  • the GISSI-HF Investigators,

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    • The Members of the GISSI-HF investigators are given in Supplementary information of Data S1.
  • T. Ueland

    Corresponding author
    1. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
    2. Faculty of Medicine, University of Oslo, Oslo, Norway
    • Correspondence: Thor Ueland PhD, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, P.B. 4950 Nydalen, 0424 Oslo, Norway.

      (fax: 47-23073630, e-mail: thor.ueland@medisin.uio.no).

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Abstract

Objectives

Experimental studies have shown involvement of Wnt signalling in heart failure (HF). We hypothesized that secreted frizzled-related protein 3 (sFRP3), a modulator of Wnt signalling, is related to the progression of HF.

Design

Circulating sFRP3 was measured in 153 HF patients and compared with 25 healthy controls. The association of sFRP3 with mortality was evaluated in 1202 patients (GISSI-HF trial). sFRP3 mRNA expression was assessed in failing human and murine left ventricles (LV), and cellular localization was determined after fractioning of myocardial tissue. In vitro studies were carried out in cardiac fibroblasts subjected to cyclic mechanical stretch.

Results

(i) Heart failure patients had significantly raised serum sFRP3 levels compared with controls, (ii) during a median follow-up of 47 months, 315 patients died in the GISSI-HF substudy. In univariable Cox regression, tertiles of baseline sFRP3 concentration were significantly associated with all-cause and cardiovascular mortality. After adjustment for demographic and clinical variables, but not for CRP and NT-proBNP, the associations with mortality remained significant for the third tertile (all-cause, HR 1.45, = 0.011; cardiovascular, HR 1.66, = 0.003), (iii) sFRP3 mRNA expression was increased in failing human LV, with a decline following LV assist device therapy. LV from post-MI mice showed an increased sFRP3 mRNA level, particularly in cardiac fibroblasts, and (iv) mechanical stretch enhanced sFRP3 expression and release in myocardial fibroblasts.

Conclusion

There is an association between increased sFRP3 expression and adverse outcome in HF, suggesting that the failing myocardium itself contributes to an increase in circulating sFRP3.

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