除了心脏毒性外，化疗药物阿霉素（DOX）还会引起血管毒性，表现为动脉硬度和内皮功能障碍。这两个参数对心血管风险分层具有重要意义，因为它们是一般人群未来心血管事件的独立预测因子。然而，DOX引起的心血管毒性的时间进程仍不清楚。此外，目前用于心血管毒性的生物标志物不够充分。在这里，我们在小鼠模型中纵向评估了DOX引起的心血管毒性的功能和分子标志物。分子标志物在病人的血浆中得到了进一步验证。DOX（4 mg/kg）或生理盐水（对照组）每周腹腔注射给年轻的雄性小鼠，持续六个星期。在基线、DOX治疗期间（第2周和第4周）和治疗停止后（第6周、第9周和第15周）评估体内心血管功能和离体动脉硬度和血管反应性。左心室射血分数（LVEF）在第4周开始下降。DOX在第2周时增加了体内和离体的动脉硬度，但随后恢复正常。重要的是，DOX引起的动脉硬度在LVEF下降之前出现。此外，DOX在第2周和第6周时使内皮依赖性血管舒张功能受损，但在第9周和第15周恢复正常。相反，DOX治疗组的苯肾上腺素收缩反应一直较高。此外，主动脉组织的蛋白组学分析发现THBS1和SERPINA3在第2周和第6周上调。上调的THBS1和SERPINA3在随访期间持续存在。最后，我们在病人的血浆中量化了THBS1和SERPINA3。与年龄匹配的对照病人（LVEF ≥ 60%）相比，具有蒽环类药物引起的心脏毒性（AICT；LVEF < 50%）的癌症幸存者显示出较高水平的THBS1和SERPINA3。DOX增加了动脉硬度并损害内皮功能，这两者都在LVEF减少之前出现。在DOX治疗停止后，血管功能恢复正常，而心脏功能仍然存在问题。此外，我们确定了SERPINA3和THBS1作为DOX引起的心血管毒性的有希望的生物标志物，并在AICT患者中进行了验证。©2023年作者。由牛津大学出版社代表欧洲心脏病协会出版。

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.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%).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.© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.