TY - JOUR
T1 - Candidate Plasma Biomarkers to Detect Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors
T2 - A Case Control Study in the Dutch Childhood Cancer Survivor Study
AU - Leerink, Jan M.
AU - Feijen, Elizabeth A. M.
AU - Moerland, Perry D.
AU - de Baat, Esmee C.
AU - Merkx, Remy
AU - van der Pal, Helena J. H.
AU - Tissing, Wim J. E.
AU - Louwerens, Marloes
AU - van den Heuvel-Eibrink, Marry M.
AU - Versluys, A. Birgitta
AU - Asselbergs, Folkert W.
AU - Sammani, Arjan
AU - Teske, Arco J.
AU - van Dalen, Elvira C.
AU - van der Heiden-van der Loo, Margriet
AU - van Dulmen-den Broeder, Eline
AU - de Vries, Andrica C. H.
AU - Kapusta, Livia
AU - Loonen, Jacqueline
AU - Pinto, Yigal M.
AU - Kremer, Leontien C. M.
AU - Mavinkurve-Groothuis, Annelies M. C.
AU - Kok, Wouter E. M.
N1 - Funding Information: 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.
PY - 2022/7/19
Y1 - 2022/7/19
N2 - 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.
AB - 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.
KW - anthracycline-related cardiomyopathy
KW - biomarkers
KW - cancer therapy-related cardiac dysfunction
KW - cardio-oncology
KW - chemokine ligands
KW - childhood cancer survivors
UR - http://www.scopus.com/inward/record.url?scp=85134668276&partnerID=8YFLogxK
U2 - https://doi.org/10.1161/JAHA.121.025935
DO - https://doi.org/10.1161/JAHA.121.025935
M3 - Article
C2 - 35861824
SN - 2047-9980
VL - 11
SP - e025935
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 14
M1 - e025935
ER -