Publication
Title
Doxorubicin-induced cardiovascular toxicity : a longitudinal evaluation of functional and molecular markers
Author
Abstract
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. Translational perspective DOX induced arterial stiffness and endothelial dysfunction, which preceded impairment of left ventricular systolic function. Hence, arterial stiffness and endothelial dysfunction represent potential early, functional markers of future cardiovascular dysfunction in patients receiving DOX. Of note, DOX-induced arterial stiffness and endothelial dysfunction were transient, highlighting the importance of timing for evaluating these vascular parameters in patients. Furthermore, anthracycline-induced cardiotoxicity patients showed elevated SERPINA3 and THBS1 in plasma, raising awareness for a role of these proteins in cardiovascular toxicity with possible diagnostic value in DOX-treated patients.
Language
English
Source (journal)
Cardiovascular research / European Society of Cardiology [Biot] - London
Publication
London : 2023
ISSN
0008-6363 [print]
1755-3245 [online]
DOI
10.1093/CVR/CVAD136
Volume/pages
119 :15 (2023) , p. 2579-2590
ISI
001062520800001
Pubmed ID
37625456
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
The investigation of arterial stiffness as a potential marker in cardio-oncology.
The pathophysiological role of physical exercise in the development of (left ventricular) myocardial fibrosis during viral myocarditis.
From hit to lead: inducing basal autophagy for treating cardiovascular diseases.
Discovering the role of titin (TTN) in anthracycline-induced cardiac dysfunction in breast cancer.
MicroRNA in heart failure: Exercise as a tool to discover candidate microRNA for therapy and personalized medicine.
Pharmacology of cardiovascular aging.
Is arterial stiffness an overlooked marker in cardio-oncology?
INnovation in Safety Pharmacology for Integrated cardiovascular safety assessment to REduce adverse events and late stage drug attrition (INSPIRE).
Discovering the role of titin (TTN) in anthracycline-induced cardiac dysfunction in breast cancer.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 20.10.2023
Last edited 10.03.2024
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