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 - 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 currently 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 anthracycline 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 characteristics, 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 currently 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 anthracycline 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 characteristics, 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 - 10.1161/JAHA.121.025935
DO - 10.1161/JAHA.121.025935
M3 - Article
C2 - 35861824
SN - 2047-9980
VL - 11
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 14
M1 - e025935
ER -