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Original research article
Biomarkers to diagnose ventricular dysfunction in childhood cancer survivors: a systematic review
  1. Jan M Leerink1,
  2. Simone J Verkleij1,
  3. Elizabeth A M Feijen2,3,
  4. Annelies M C Mavinkurve-Groothuis3,
  5. Milanthy S Pourier4,
  6. Kaisa Ylänen5,
  7. Wim J E Tissing6,
  8. Marloes Louwerens7,
  9. Marry M van den Heuvel3,
  10. Eline van Dulmen-den Broeder8,
  11. Andrica C H de Vries9,
  12. Cecile M Ronckers2,3,
  13. Heleen J H van der Pal3,
  14. Livia Kapusta10,11,
  15. Jacqueline Loonen4,
  16. Louise Bellersen12,
  17. Yigal M Pinto1,
  18. Leontien C M Kremer2,3,
  19. Wouter E M Kok1
  1. 1 Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Heart Center, Amsterdam, The Netherlands
  2. 2 Department of Pediatric Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
  3. 3 Department of Pediatric Oncology, Princess Máxima Centre, Utrecht, The Netherlands
  4. 4 Department of Pediatric Hematology and Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands
  5. 5 Department of Pediatrics, Tampere University Hospital, Tampere, Finland
  6. 6 Department of Pediatric Oncology, University Medical Centre Groningen, Beatrix Children’s Hospital, Groningen, The Netherlands
  7. 7 Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands
  8. 8 Department of Internal Medicine, VU University Medical Centre, Amsterdam, The Netherlands
  9. 9 Department of Pediatric Oncology, Erasmus Medical Centre, Rotterdam, The Netherlands
  10. 10 Department of Pediatric Cardiology, Radboud University Medical Centre, Amalia Children’s Hospital, Nijmegen, The Netherlands
  11. 11 Department of Pediatrics, Pediatric Cardiology Unit, Tel Aviv University, Tel Aviv Sourasky Medical Centre, Sackler School of Medicine, Tel Aviv, Israel
  12. 12 Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands
  1. Correspondence to Drs Jan M Leerink, Department of Cardiology, Amsterdam UMC, Amsterdam 1105 AZ, The Netherlands; j.m.leerink{at}


Objective To systematically review the literature and assess the diagnostic value of biomarkers in detection of late-onset left ventricular (LV) dysfunction in childhood cancer survivors (CCS) treated with anthracyclines.

Methods We systematically searched the literature for studies that evaluated the use of biomarkers for detection of LV dysfunction in CCS treated with anthracyclines more than 1 year since childhood cancer diagnosis. LV dysfunction definitions were accepted as an ejection fraction <50% or <55% and/or a fractional shortening <28%, <29% or <30%. Contingency tables were created to assess diagnostic accuracies of biomarkers for diagnosing LV dysfunction.

Results Of 1362 original studies screened, eight heterogeneous studies evaluating four different biomarkers in mostly asymptomatic CCS were included. In four studies, an abnormal N-terminal pro-B-type natriuretic peptide (NT-proBNP, cut-off range 63–125 ng/L) had low sensitivity (maximally 22%) and a specificity of up to 97% for detection of LV dysfunction. For troponin levels, in five studies one patient had an abnormal troponin value as well as LV dysfunction, while in total 127 patients had LV dysfunction without troponin elevations above cut-off values (lowest 0.01 ng/mL). Two studies that evaluated brain natriuretic peptide and nitric oxide were underpowered to draw conclusions.

Conclusions In individual studies, the diagnostic value of NT-proBNP for detection of LV dysfunction in CCS is limited. Troponins have no role in detecting late-onset LV dysfunction with cut-off values as low as 0.01 ng/mL. Further study on optimal NT-proBNP cut-off values for rule out or rule in of LV dysfunction is warranted.

  • systemic review
  • heart failure
  • cardiac imaging and diagnostics

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  • Contributors JML, SJV and WEMK contributed to the study design, literature search, critical appraisal of studies, drafting of the manuscript and contingency tables. All authors contributed to the critical revision of the manuscript.

  • Funding This study was funded by Dutch Heart Foundation grant CVON2015-21.

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.