Doxorubicin-induced cardiovascular toxicity: a longitudinal evaluation of functional and molecular markers

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 intraperitoneally to young, male mice weekly for six weeks. In vivo cardiovascular function and ex vivo arterial stiffness and vascular reactivity were evaluated at baseline, during DOX therapy (week 2 and 4) and after therapy cessation (week 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 week 2 and 6, which recovered at week 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 week 2 and 6. Upregulated 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 to 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.

Dexrazoxane does not mitigate early vascular toxicity induced by doxorubicin in mice

“…This suggests that, in contrast to cardiotoxicity, DEXRA does not protect against DOX-induced vascular toxicity, at least in the evaluated acute setting. However, as we have previously shown that DOX-induced vascular toxicity displays a dynamic profile, characterised by initial hypocontraction (after 16h) [ 25 ], subsequent hypercontraction (after 6 days) [ 11 ] and an eventual increase in pro-inflammatory (glyco)proteins (after 6 injections) [ 34 ], further research investigating the protective capability of DEXRA against vascular toxicity from longer-term repetitive DOX dosing is still warranted.…”

Intravenous Thrombolysis for Pediatric Ischemic Stroke Secondary to Cancer Therapy-related Cardiac Dysfunction: A Case Report

“…Physicians should also consider the risk of thrombus formation (7) due to cardiac dysfunction when using diuretics for acute heart failure. In addition, animal studies (8) have shown that administering doxorubicin above a certain dose causes arterial stiffness and impaired endothelial dysfunction; therefore, a potential early but time-sensitive indication of future cardiotoxicity may occur.…”

Characterization of systolic and diastolic function, alongside proteomic profiling, in doxorubicin-induced cardiovascular toxicity in mice

“…and organs were collected and weighed for further analysis. For proteomics, murine cardiac tissue from a historical study was used, previously reported in Bosman et al [ 12 ]. These mice underwent the same treatment protocol as the animals used in this study.…”

“…Recently, we documented vascular toxicity, represented by endothelial cell (EC) dysfunction and arterial stiffness, as a predecessor to the reduced LVEF upon DOX treatment in mice [ 10 , 11 ]. Thereby, EC dysfunction was reversible after stopping DOX treatment [ 12 ]. Endothelial dysfunction contributes to vascular contractile alterations and reduced compliance in both heart and aorta, compromising cardiac relaxation and filling, which can ultimately lead to diastolic dysfunction, or heart failure with preserved ejection fraction (HFpEF) [ 13 , 14 ].…”