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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
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.
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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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