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Doxorubicin-induced cardiovascular toxicity: a longitudinal evaluation of functional and molecular markers
AIMS: Apart from cardiotoxicity, the chemotherapeutic doxorubicin (DOX) induces vascular toxicity, represented by arterial stiffness and endothelial dysfunction. Both parameters are of interest for cardiovascular risk stratification as they are independent predictors of future cardiovascular events...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676457/ https://www.ncbi.nlm.nih.gov/pubmed/37625456 http://dx.doi.org/10.1093/cvr/cvad136 |
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author | Bosman, Matthias Krüger, Dustin Van Assche, Charles Boen, Hanne Neutel, Cédric Favere, Kasper Franssen, Constantijn Martinet, Wim Roth, Lynn De Meyer, Guido R Y Cillero-Pastor, Berta Delrue, Leen Heggermont, Ward Van Craenenbroeck, Emeline M Guns, Pieter-Jan |
author_facet | Bosman, Matthias Krüger, Dustin Van Assche, Charles Boen, Hanne Neutel, Cédric Favere, Kasper Franssen, Constantijn Martinet, Wim Roth, Lynn De Meyer, Guido R Y Cillero-Pastor, Berta Delrue, Leen Heggermont, Ward Van Craenenbroeck, Emeline M Guns, Pieter-Jan |
author_sort | Bosman, Matthias |
collection | PubMed |
description | AIMS: Apart from cardiotoxicity, the chemotherapeutic doxorubicin (DOX) induces vascular toxicity, represented by arterial stiffness and endothelial dysfunction. Both parameters are of interest for cardiovascular risk stratification as they are independent predictors of future cardiovascular events in the general population. However, the time course of DOX-induced cardiovascular toxicity remains unclear. Moreover, current biomarkers for cardiovascular toxicity prove insufficient. Here, we longitudinally evaluated functional and molecular markers of DOX-induced cardiovascular toxicity in a murine model. Molecular markers were further validated in patient plasma. METHODS AND RESULTS: DOX (4 mg/kg) or saline (vehicle) was administered intra-peritoneally to young, male mice weekly for 6 weeks. In vivo cardiovascular function and ex vivo arterial stiffness and vascular reactivity were evaluated at baseline, during DOX therapy (Weeks 2 and 4) and after therapy cessation (Weeks 6, 9, and 15). Left ventricular ejection fraction (LVEF) declined from Week 4 in the DOX group. DOX increased arterial stiffness in vivo and ex vivo at Week 2, which reverted thereafter. Importantly, DOX-induced arterial stiffness preceded reduced LVEF. Further, DOX impaired endothelium-dependent vasodilation at Weeks 2 and 6, which recovered at Weeks 9 and 15. Conversely, contraction with phenylephrine was consistently higher in the DOX-treated group. Furthermore, proteomic analysis on aortic tissue identified increased thrombospondin-1 (THBS1) and alpha-1-antichymotrypsin (SERPINA3) at Weeks 2 and 6. Up-regulated THBS1 and SERPINA3 persisted during follow-up. Finally, THBS1 and SERPINA3 were quantified in plasma of patients. Cancer survivors with anthracycline-induced cardiotoxicity (AICT; LVEF < 50%) showed elevated THBS1 and SERPINA3 levels compared with age-matched control patients (LVEF ≥ 60%). CONCLUSIONS: DOX increased arterial stiffness and impaired endothelial function, which both preceded reduced LVEF. Vascular dysfunction restored after DOX therapy cessation, whereas cardiac dysfunction persisted. Further, we identified SERPINA3 and THBS1 as promising biomarkers of DOX-induced cardiovascular toxicity, which were confirmed in AICT patients. |
format | Online Article Text |
id | pubmed-10676457 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-106764572023-08-25 Doxorubicin-induced cardiovascular toxicity: a longitudinal evaluation of functional and molecular markers Bosman, Matthias Krüger, Dustin Van Assche, Charles Boen, Hanne Neutel, Cédric Favere, Kasper Franssen, Constantijn Martinet, Wim Roth, Lynn De Meyer, Guido R Y Cillero-Pastor, Berta Delrue, Leen Heggermont, Ward Van Craenenbroeck, Emeline M Guns, Pieter-Jan Cardiovasc Res Original Article AIMS: Apart from cardiotoxicity, the chemotherapeutic doxorubicin (DOX) induces vascular toxicity, represented by arterial stiffness and endothelial dysfunction. Both parameters are of interest for cardiovascular risk stratification as they are independent predictors of future cardiovascular events in the general population. However, the time course of DOX-induced cardiovascular toxicity remains unclear. Moreover, current biomarkers for cardiovascular toxicity prove insufficient. Here, we longitudinally evaluated functional and molecular markers of DOX-induced cardiovascular toxicity in a murine model. Molecular markers were further validated in patient plasma. METHODS AND RESULTS: DOX (4 mg/kg) or saline (vehicle) was administered intra-peritoneally to young, male mice weekly for 6 weeks. In vivo cardiovascular function and ex vivo arterial stiffness and vascular reactivity were evaluated at baseline, during DOX therapy (Weeks 2 and 4) and after therapy cessation (Weeks 6, 9, and 15). Left ventricular ejection fraction (LVEF) declined from Week 4 in the DOX group. DOX increased arterial stiffness in vivo and ex vivo at Week 2, which reverted thereafter. Importantly, DOX-induced arterial stiffness preceded reduced LVEF. Further, DOX impaired endothelium-dependent vasodilation at Weeks 2 and 6, which recovered at Weeks 9 and 15. Conversely, contraction with phenylephrine was consistently higher in the DOX-treated group. Furthermore, proteomic analysis on aortic tissue identified increased thrombospondin-1 (THBS1) and alpha-1-antichymotrypsin (SERPINA3) at Weeks 2 and 6. Up-regulated THBS1 and SERPINA3 persisted during follow-up. Finally, THBS1 and SERPINA3 were quantified in plasma of patients. Cancer survivors with anthracycline-induced cardiotoxicity (AICT; LVEF < 50%) showed elevated THBS1 and SERPINA3 levels compared with age-matched control patients (LVEF ≥ 60%). CONCLUSIONS: DOX increased arterial stiffness and impaired endothelial function, which both preceded reduced LVEF. Vascular dysfunction restored after DOX therapy cessation, whereas cardiac dysfunction persisted. Further, we identified SERPINA3 and THBS1 as promising biomarkers of DOX-induced cardiovascular toxicity, which were confirmed in AICT patients. Oxford University Press 2023-08-25 /pmc/articles/PMC10676457/ /pubmed/37625456 http://dx.doi.org/10.1093/cvr/cvad136 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Article Bosman, Matthias Krüger, Dustin Van Assche, Charles Boen, Hanne Neutel, Cédric Favere, Kasper Franssen, Constantijn Martinet, Wim Roth, Lynn De Meyer, Guido R Y Cillero-Pastor, Berta Delrue, Leen Heggermont, Ward Van Craenenbroeck, Emeline M Guns, Pieter-Jan Doxorubicin-induced cardiovascular toxicity: a longitudinal evaluation of functional and molecular markers |
title | Doxorubicin-induced cardiovascular toxicity: a longitudinal evaluation of functional and molecular markers |
title_full | Doxorubicin-induced cardiovascular toxicity: a longitudinal evaluation of functional and molecular markers |
title_fullStr | Doxorubicin-induced cardiovascular toxicity: a longitudinal evaluation of functional and molecular markers |
title_full_unstemmed | Doxorubicin-induced cardiovascular toxicity: a longitudinal evaluation of functional and molecular markers |
title_short | Doxorubicin-induced cardiovascular toxicity: a longitudinal evaluation of functional and molecular markers |
title_sort | doxorubicin-induced cardiovascular toxicity: a longitudinal evaluation of functional and molecular markers |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676457/ https://www.ncbi.nlm.nih.gov/pubmed/37625456 http://dx.doi.org/10.1093/cvr/cvad136 |
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