Endothelial dysfunction and vascular stiffness in response to anthracycline treatment

Abstract Background Cancer therapy-related cardiac dysfunction (CTRCD) is a major side effect of anthracycline chemotherapy (AC). Apart from cardiac effects, early vascular toxicity has been described and increased vascular stiffness and endothelial dysfunction are associated with future cardiac events. Whether vascular dysfunction has a role as an early, potential modifiable biomarker for CTRCD, is not clear. Purpose To assess the dynamics of endothelial function and vascular stiffness in response to AC. Methods In this single-centre cohort study, female breast cancer patients scheduled for AC were prospectively enrolled (01/2020-05/2023). Cardiac evaluation (echocardiography, hs-troponin I (hs-TnI) and NT-proBNP) and vascular function measurements were performed at 5 timepoints: before chemotherapy (T0), directly after taxane chemotherapy (T1), at the end of AC (T2), and at three (T3) and twelve months after chemotherapy (T4). CTRCD was defined according to the ESC guidelines. Endothelial function was assessed non-invasively, with flow mediated dilatation (FMD) and peripheral arterial tonometry (PAT), vascular stiffness was measured by Pulse Wave Velocity (PWV). Results Baseline and treatment characteristics of the 33 included patients are displayed in Figure 1. Cardiac function declined overall after exposure to AC, as evidenced by a reduction in LVEF (p=0.009), worsening of GLS (p=0.014) and a significant rise in hs-TnI (p0.001). There was a trend for higher NT-proBNP levels (p=0.054). Overall, 20 patients developed mild CTRCD (60.6%), while five (15.2%) developed moderate CTRCD. After AC, blood pressure decreased and heart rate increased significantly (p0.001). Endothelial function measured by FMD did not show a significant change during follow-up (p=0.096) but measurement by PAT showed a significant decline after AC (corrected reactive hyperaemia index fRHI p=0.043). Interestingly, PWV, corrected for diastolic blood pressure (DBP), declined after chemotherapy (p=0.014). A decline in endothelial function became evident after taxane chemotherapy, worsened following AC, and normalized during longer follow-up. In contrast, the decrease in vascular stiffness remained apparent up to one year after AC. The observed changes in fRHI and PWV were independent of the development of CTRCD (repeated measure ANOVA with CTRCD as factor: p=0.606 and 0.549 respectively). Conclusion There is an overall decline in systolic cardiac function and a high incidence of (asymptomatic) CTRCD in patients with breast cancer treated with taxane and AC. We observed an early and transient endothelial dysfunction. Surprisingly vascular stiffness shows a lasting decrease in the first year after AC, which is at least partly driven by a sustained decline in arterial blood pressure. These observed changes in vascular function were not related to the occurrence of CTRCD. Therefore, further work is needed to elucidate the longer-term effects of AC on vascular function.Figure 1For image description, please refer to the figure legend and surrounding text. Figure 2For image description, please refer to the figure legend and surrounding text.