Candidate Plasma Biomarkers to Detect Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors: A Case Control Study in the Dutch Childhood Cancer Survivor Study

Jan M. Leerink*, Elizabeth A.M. Feijen, Perry D. Moerland, Esmee C. de Baat, Remy Merkx, Helena J.H. van der Pal, Wim J.E. Tissing, Marloes Louwerens, Marry M. van den Heuvel-Eibrink, A. Birgitta Versluys, Folkert W. Asselbergs, Arjan Sammani, Arco J. Teske, Elvira C. van Dalen, Margriet van der Heiden-Van der Loo, Eline van Dulmen-Den Broeder, Andrica C.H. de Vries, Livia Kapusta, Jacqueline Loonen, Yigal M. PintoLeontien C.M. Kremer, Annelies M.C. Mavinkurve-Groothuis, Wouter E.M. Kok

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

BACKGROUND: Plasma biomarkers may aid in the detection of anthracycline-related cardiomyopathy (ACMP). However, the cur-rently available biomarkers have limited diagnostic value in long-term childhood cancer survivors. This study sought to identify diagnostic plasma biomarkers for ACMP in childhood cancer survivors. METHODS AND RESULTS: We measured 275 plasma proteins in 28 ACMP cases with left ventricular ejection fraction <45%, 29 anthracycline-treated controls with left ventricular ejection fraction ≥53% matched on sex, time after cancer, and anthracy-cline dose, and 29 patients with genetically determined dilated cardiomyopathy with left ventricular ejection fraction <45%. Multivariable linear regression was used to identify differentially expressed proteins. Elastic net model, including clinical char-acteristics, was used to assess discrimination of proteins diagnostic for ACMP. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the inflammatory markers CCL19 (C-C motif chemokine ligands 19) and CCL20, PSPD (pulmonary surfactant protein-D), and PTN (pleiotrophin) were significantly upregulated in ACMP compared with controls. An elastic net model selected 45 proteins, including NT-proBNP, CCL19, CCL20 and PSPD, but not PTN, that discriminated ACMP cases from controls with an area under the receiver operating characteristic curve (AUC) of 0.78. This model was not superior to a model including NT-proBNP and clinical characteristics (AUC=0.75; P=0.766). However, when excluding 8 ACMP cases with heart failure, the full model was superior to that including only NT-proBNP and clinical characteristics (AUC=0.75 versus AUC=0.50; P=0.022). The same 45 proteins also showed good discrimination between dilated cardiomyopathy and controls (AUC=0.89), underscoring their association with cardiomyopathy. CONCLUSIONS: We identified 3 specific inflammatory proteins as candidate plasma biomarkers for ACMP in long-term childhood cancer survivors and demonstrated protein overlap with dilated cardiomyopathy.

Original languageEnglish
Article numbere025935
JournalJournal of the American Heart Association
Volume11
Issue number14
DOIs
Publication statusPublished - 19 Jul 2022

Bibliographical note

Sources of Funding: This work was supported by the Dutch Heart Foundation (CVON2015-21), Amsterdam University Funding, and Stichting Kinderen Kankervrij/Odasstichting. Dr Asselbergs is supported by University College London Hospitals National Institute for Health and Care Research Biomedical Research Centre

Publisher Copyright:
© 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

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