Childhood cancer survivors (CCS) are at increased risk of developing heart disease due to the cardiotoxic effects of oncological treatment. This study aimed to investigate the long-term cardiotoxic effects of cancer therapy in CCS using a multimodal approach combining cardiac magnetic resonance (CMR) imaging and circulating blood biomarkers. A total of 117 CCS (mean age 24.7 ± 5.2 years), at least five years post-treatment and in complete remission, were prospectively enrolled. All participants underwent CMR, including T1 mapping, and blood analysis for biomarkers of endothelial damage and oxidative stress. Parameters were compared with sex- and age-matched healthy control groups. Anthracycline treatment was administered in 82.9% of CCS (mean cumulative doxorubicin equivalent dose 231.7 ± 92.0 mg/m²). Left ventricular ejection fraction and mitral annular plane systolic excursion were significantly reduced in CCS compared to controls (59.0 ± 5.5% vs. 67.2 ± 6.9%, p < 0.001; 12.5 ± 1.7 mm vs. 13.9 ± 2.2 mm, p = 0.001). Late gadolinium enhancement was detected in four CCS. No significant differences in global native T1 relaxation time or extracellular volume were observed. N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels remained within normal limits but correlated with native T1, ECV, and MAPSE. Levels of myeloperoxidase, big endothelin-1, and ischemia-modified albumin were significantly higher than in controls. Subclinical myocardial changes were detected in long-term CCS using CMR and circulating biomarkers. These findings support the utility of a multimodal approach for the early identification of individuals at increased cardiovascular risk after childhood cancer treatment.

1 st Department of Internal Medicine Cardioangiology St Anne's University Hospital Brno Pekařská 53 60200 Brno Czech Republic

Department of Biochemistry Faculty of Medicine Masaryk University Kamenice 5 62500 Brno Czech Republic

Department of Biomedical Engineering Brno University of Technology Technicka 12 61600 Brno Czech Republic

Department of Children's Oncology University Hospital Brno Masaryk University Černopolní 9 61300 Brno Czech Republic

Department of Medical Imaging St Anne's University Hospital Brno Pekařská 53 60200 Brno Czech Republic

Department of Pathophysiology Faculty of Medicine Masaryk University Kamenice 5 62500 Brno Czech Republic

Faculty of Medicine Masaryk University Kamenice 5 62500 Brno Czech Republic

Institute of Hematology and Blood Transfusion U Nemocnice 1 12800 Prague Czech Republic

International Clinical Research Center St Anne's University Hospital Brno Pekařská 53 60200 Brno Czech Republic

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Lipshultz, S. E., Alvarez, J. A., & Scully, R. E. (2008). Anthracycline associated cardiotoxicity in survivors of childhood cancer. PubMed DOI

van der Pal, H. J., van Dalen, E. C., Hauptmann, M., Kok, W. E., Caron, H. N., et al. (2010). Cardiac function in 5-year survivors of childhood cancer: A long-term follow-up study. PubMed DOI

Mulrooney, D. A., Yeazel, M. W., Kawashima, T., Mertens, A. C., Mitby, P., et al. (2009). Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: Retrospective analysis of the Childhood Cancer Survivor Study Cohort. PubMed DOI PMC

van Dalen, E. C., Michiels, E. M., Caron, H. N., & Kremer, L. C. (2010). Different anthracycline derivates for reducing cardiotoxicity in cancer patients. PubMed DOI

Reulen, R. C., Winter, D. L., Frobisher, C., Lancashire, E. R., Stiller, C. A., et al. (2010). Long-term cause-specific mortality among survivors of childhood cancer. PubMed DOI

Haddy, N., Diallo, S., El-Fayech, C., Schwartz, B., Pein, F., et al. (2016). Cardiac diseases following childhood cancer treatment: Cohort study. PubMed DOI

Diller, L., Chow, E. J., Gurney, J. G., Hudson, M. M., Kadin-Lottick, N. S., et al. (2009). Chronic disease in the Childhood Cancer Survivor Study Cohort: A review of published findings. PubMed DOI PMC

Smith, L. A., Cornelius, V. R., Plummer, C. J., Levitt, G., Verrill, M., et al. (2010). Cardiotoxicity of anthracycline agents for the treatment of cancer: Systematic review and meta-analysis of randomised controlled trials. PubMed DOI PMC

Lotrionte, M., Biondi-Zoccai, G., Abbate, A., Lanzetta, G., D’Ascenzo, F., et al. (2013). Review and Meta-Analysis of incidence and clinical predictors of anthracycline cardiotoxicity. PubMed DOI

Yeh, E. T. H., & Bickford, C. L. (2009). Cardiovascular complications of cancer therapy: Incidence, Pathogenesis, Diagnosis, and management. PubMed DOI

Khasraw, M., Bell, R., & Dang, C. (2012). Epirubicin: Is it like doxorubicin in breast cancer? A clinical review. PubMed DOI

van der Pal, H. J., van Dalen, E. C., van Delden, E., van Dijk, I. W., Kok, W. E., et al. (2012). High risk of symptomatic cardiac events in childhood cancer survivors. PubMed DOI

Kremer, L. C. M., van Dalen, E. C., Offringa, M., & Voûte, P. A. (2002). Frequency and risk factors of Anthracycline-Induced clinical heart failure in children: A systematic review. PubMed DOI

Chung, W. B., Yi, J. E., Jin, J. Y., Choi, Y. S., Park, C. S., et al. (2013). Early cardiac function monitoring for detection of subclinical doxorubicin cardiotoxicity in young adult patients with breast cancer. PubMed DOI PMC

Todaro, M. C., Oreto, L., Qamar, R., Paterick, T. E., Carerj, S., et al. (2013). Cardioncology: State of the heart. PubMed DOI

Lyon, A. R., López-Fernández, T., Couch, L. S., Asteggiano, R., Aznar, M. C., et al. (2022). 2022 ESC guidelines on Cardio-Oncology developed in collaboration with the European hematology association (EHA), the European society for therapeutic radiology and oncology (ESTRO) and the international Cardio-Oncology society (IC-OS). PubMed DOI

Mawad, W., Mertens, L., Pagano, J. J., Riesenkampff, E., Reichert, M. J. E., et al. (2021). Effect of anthracycline therapy on myocardial function and markers of fibrotic remodelling in childhood cancer survivors. PubMed DOI PMC

Giusca, S., Korosoglou, G., Montenbruck, M., Geršak, B., Schwarz, A. K., et al. (2021). Multiparametric early detection and prediction of cardiotoxicity using myocardial Strain, T1 and T2 Mapping, and biochemical markers: A longitudinal cardiac resonance imaging study during 2 years of Follow-Up. PubMed DOI PMC

Altaha, M. A., Nolan, M., Marwick, T. H., Somerset, E., Houbois, C., et al. (2020). Can quantitative CMR tissue characterization adequately identify cardiotoxicity during chemotherapy?: Impact of temporal and observer variability. PubMed DOI

Harries, I., Berlot, B., Ffrench-Constant, N., Williams, M., Liang, K., et al. (2021). Cardiovascular magnetic resonance characterisation of anthracycline cardiotoxicity in adults with normal left ventricular ejection fraction. PubMed DOI

Haslbauer, J. D., Lindner, S., Valbuena-Lopez, S., Zainal, H., Zhou, H., et al. (2019). CMR imaging biosignature of cardiac involvement due to cancer-related treatment by T1 and T2 mapping. PubMed DOI

Jordan, J., Vasu, S., Morgan, T., D’Agostino, R., Meléndez, G., et al. (2016). Anthracycline-Associated T1 mapping characteristics are elevated independent of the presence of cardiovascular comorbidities in cancer survivors. PubMed DOI PMC

Neilan, T. G., Coelho-Filho, O. R., Shah, R. V., Feng, J. H., Pena-Herrera, D., et al. (2013). Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline-based chemotherapy. PubMed DOI PMC

Quyam, S., Steeden, J., Muthurangu, V., Chowdhury, T., & Hughes, M. (2015). Characterisation of anthracycline cardiotoxicity in long-term childhood cancer survivors using conventional and novel CMR techniques: Probing the pathology. DOI

Tham, E. B., Haykowsky, M. J., & Chow, K. (2013). Diffuse myocardial fibrosis by T1-mapping in children with subclinical anthracycline cardiotoxicity: Relationship to exercise capacity, cumulative dose and remodeling. PubMed DOI PMC

Thavendiranathan, P., Shalmon, T., Fan, C.-P., Houbois, C., Amir, E., et al. (2023). Comprehensive cardiovascular magnetic resonance tissue characterization and cardiotoxicity in women with breast cancer. PubMed DOI PMC

Tong, X., Li, V. W., Liu, A. P., So, E. K., Chan, Q., et al. (2019). Cardiac magnetic resonance T1 mapping in adolescent and young adult survivors of childhood cancers. PubMed DOI

Toro-Salazar, O. H., Gillan, E., O’Loughlin, M. T., Burke, G. S., Ferranti, J., et al. (2013). Occult cardiotoxicity in childhood cancer survivors exposed to anthracycline therapy. PubMed DOI

Boutin, G., Yuzugulen, J., & Pranjol, M. Z. I. (2023). Endothelin-based markers for endothelial dysfunction in chemotherapy-induced cardiotoxicity. PubMed DOI PMC

Shaito, A., Aramouni, K., Assaf, R., Parenti, A., Orekhov, A., et al. (2022). Oxidative stress-induced endothelial dysfunction in cardiovascular diseases. PubMed DOI

van der Zanden, S. Y., Qiao, X., & Neefjes, J. (2021). New insights into the activities and toxicities of the old anticancer drug doxorubicin. PubMed DOI PMC

Lázničková, P., Kepák, T., Hortová-Kohoutková, M., Horváth, L., Sheardová, K., et al. (2020). Childhood survivors of High-Risk neuroblastoma show signs of immune recovery and not Immunosenescence. PubMed DOI PMC

Lázničková, P., Bendíčková, K., Kepák, T., & Frič, J. (2021). Immunosenescence in childhood cancer survivors and in elderly: A comparison and implication for risk stratification. PubMed DOI PMC

Feijen, E. A. M., Leisenring, W. M., Stratton, K. L., Ness, K. K., van der Pal, H. J. H., et al. (2019). Derivation of anthracycline and anthraquinone equivalence ratios to doxorubicin for late-onset cardiotoxicity. PubMed DOI PMC

Ehrhardt, M. J., Leerink, J. M., Mulder, R. L., Mavinkurve-Groothuis, A., Kok, W., et al. (2023). Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group. PubMed DOI

Panovský, R., Pešl, M., Máchal, J., Holeček, T., Feitová, V., et al. (2021). Quantitative assessment of left ventricular longitudinal function and myocardial deformation in Duchenne muscular dystrophy patients. PubMed DOI PMC

Schulz-Menger, J., Bluemke, D. A., Bremerich, J., Flamm, S. D., Fogel, M. A., et al. (2013). Standardized image interpretation and post processing in cardiovascular magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR) board of trustees task force on standardized post processing. PubMed DOI PMC

Bar–Or, D., Lau, E., & Winkler, J. V. (2000). A novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia—a preliminary report. PubMed DOI

Zhou, B.-Y., Guo, Y.-L., Wu, N.-Q., Zhu, C.-G., Gao, Y., et al. (2017). Plasma big endothelin-1 levels at admission and future cardiovascular outcomes: A cohort study in patients with stable coronary artery disease. PubMed DOI

Romano, A., Sollazzo, F., Rivetti, S., Morra, L., Servidei, T., et al. (2024). Evaluation of metabolic and cardiovascular risk measured by laboratory biomarkers and cardiopulmonary exercise test in children and adolescents recovered from brain tumors: The CARMEP study. PubMed DOI PMC

Atas, E., Kismet, E., Kesik, V., Karaoglu, B., Aydemir, G., et al. (2015). Cardiac troponin-I, brain natriuretic peptide and endothelin-1 levels in a rat model of doxorubicin-induced cardiac injury. PubMed DOI

Reichlin, T., Socrates, T., Egli, P., Potocki, M., Breidthardt, T., et al. (2010). Use of myeloperoxidase for risk stratification in acute heart failure. PubMed DOI

Tretjakovs, P., Jurka, A., Bormane, I., Mikelsone, I., Elksne, K., et al. (2012). Circulating adhesion molecules, matrix metalloproteinase-9, plasminogen activator inhibitor-1, and myeloperoxidase in coronary artery disease patients with stable and unstable angina. PubMed DOI

Dean, M., Kim, M. J., Dimauro, S., Tannenbaum, S., Graham, G., et al. (2023). Cardiac and noncardiac biomarkers in patients undergoing anthracycline chemotherapy – a prospective analysis. PubMed DOI PMC

Bar-Or, D., Curtis, G., Rao, N., Bampos, N., & Lau, E. (2001). Characterization of the Co2 + and Ni2 + binding amino-acid residues of the N-terminus of human albumin. PubMed DOI

Bhagavan, N. V., Lai, E. M., Rios, P. A., Yang, J., Ortega-Lopez, A. M., et al. (2003). Evaluation of human serum albumin cobalt binding assay for the assessment of myocardial ischemia and myocardial infarction. PubMed DOI

Luan, X.-D., Zhao, K.-H., Hou, H., Gai, Y.-H., Wang, Q.-T., et al. (2017). Changes in ischemia-modified albumin in myocardial toxicity induced by anthracycline and docetaxel chemotherapy. PubMed DOI PMC

Ma, Y., Kang, W., Bao, Y., Jiao, F., & Ma, Y. (2013). Clinical significance of ischemia-modified albumin in the diagnosis of doxorubicin-induced myocardial injury in breast cancer patients. PubMed DOI PMC

Sadurska, E., Zaucha-Prażmo, A., Brodzisz, A., Kowalczyk, J., & Beń-Skowronek, I. (2018). Premature atherosclerosis after treatment for acute lymphoblastic leukemia in childhood. PubMed DOI

Brouwer, C. A. J., Postma, A., Vonk, J. M., Zwart, N., van den Berg, M. P., et al. (2011). Systolic and diastolic dysfunction in long-term adult survivors of childhood cancer. PubMed DOI

Wolf, C. M., Reiner, B., Kühn, A., Hager, A., Müller, J., et al. (2020). Subclinical cardiac dysfunction in childhood cancer survivors on 10-years follow-up correlates with cumulative anthracycline dose and is best detected by cardiopulmonary exercise testing, circulating serum biomarker, speckle tracking echocardiography, and tissue Doppler imaging. PubMed DOI PMC

Merkx, R., Leerink, J., Baat, E., Feijen, E., Kok, W., et al. (2022). Asymptomatic systolic dysfunction on contemporary echocardiography in Anthracycline-Treated Long-Term childhood cancer survivors: A systematic review. PubMed DOI PMC

Jordan, J. H., Castellino, S. M., Meléndez, G. C., Klepin, H. D., Ellis, L. R., et al. (2018). Left ventricular mass change after anthracycline chemotherapy. PubMed DOI PMC

Modi, K., Joppa, S., Chen, K.-H., Athwal, P. S. S., Okasha, O., et al. (2021). Myocardial damage assessed by late gadolinium enhancement on cardiovascular magnetic resonance imaging in cancer patients treated with anthracyclines and/or trastuzumab. PubMed DOI PMC