Candidate plasma biomarkers to detect anthracycline-related cardiomyopathy in childhood cancer survivors: a case control study in the Dutch Childhood Cancer Survivor Study

Leerink, J.M.; Feijen, E.A.M.; Moerland, P.D.; Baat, E.C. de; Merkx, R.; Pal, H.J.H. van der; ... ; Kok, W.E.M. (2022)

Article / Letter to editor

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.

• anthracycline-related cardiomyopathy
• biomarkers
• cancer therapy-related cardiac dysfunction
• cardio-oncology
• chemokine ligands
• childhood cancer survivors

• All authors: Leerink, J.M.; Feijen, E.A.M.; Moerland, P.D.; Baat, E.C. de; Merkx, R.; Pal, H.J.H. van der; Tissing, W.J.E.; Louwerens, M.; Heuvel-Eibrink, M.M. van den; Versluys, A.B.; Asselbergs, F.W.; Sammani, A.; Teske, A.J.; Dalen, E.C. van; Heiden-van der Loo, M. van der; Dulmen-den Broeder, E. van; Vries, A.C.H. de; Kapusta, L.; Loonen, J.; Pinto, Y.M.; Kremer, L.C.M.; Mavinkurve-Groothuis, A.M.C.; Kok, W.E.M.
• Date: 2022-07-19
• Journal: Journal of the American Heart Association Cardiovascular and Cerebrovascular Disease
• Volume: 11
• Issue: 14
• DOI: doi:10.1161/JAHA.121.025935