Department of Internal Medicine I, Cardiology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology & Immunology, National University of Singapore, Singapore, Singapore.
Front Immunol. 2023 Jan 24;13:1092704. doi: 10.3389/fimmu.2022.1092704. eCollection 2022.
Intravenous iron supplementation is an established therapy for patients with heart failure (HF) and concomitant iron deficiency reducing the risk of HF hospitalization. However, concerns persist regarding potential adverse vascular effects, since iron may induce oxidative stress, inflammation, and apoptosis of endothelial cells. To assess endothelial health following ferric carboxymaltose (FCM) administration, we analyzed the profile of circulating endothelial microvesicles (EMVs) and endothelial progenitor cells (EPCs) in a cohort of 23 HF patients using flow cytometry.
Compared to healthy subjects, baseline levels of CD31+/CD41- EMVs were higher and EMVs featured a more apoptotic phenotype in HF patients. Following FCM administration, EMV levels showed a rapid but transient increase and displayed an altered phenotype profile with dominant augmentation of EMVs expressing inducible markers CD62E and CD54, indicating endothelial inflammatory activation and injury. Levels of circulating vasoregenerative CD45lowCD34+KDR+ EPCs were lower in HF patients and FCM application resulted in an early decrease of EPCs followed by substantial mobilization into the circulation after one week. Levels of EMVs and EPCs returned to baseline values within two and four weeks, respectively. HF patients with additional chronic kidney disease showed an elevated EMV/EPC ratio and diminished EPC mobilization, suggesting impaired vascular repair capacity. Providing a mechanistic link, experiments with cultured endothelial cells revealed that FCM dose-dependently promotes endothelial apoptosis, increases expression of adhesion molecules and CXCL12, and triggers generation of EMVs.
Intravenous iron supplementation with FCM in HF patients induces a biphasic response with initial increased release of CD62E+ and CD54+ enriched EMVs and subsequent mobilization of EPCs, indicating endothelial dysfunction upon FCM and suggesting consecutive engagement of a defense program aimed to reconstitute vascular health.
静脉铁补充是治疗心力衰竭(HF)伴缺铁的患者的一种既定疗法,可以降低 HF 住院的风险。然而,人们仍然对潜在的不良血管影响存在担忧,因为铁可能会诱导内皮细胞的氧化应激、炎症和细胞凋亡。为了评估铁羧基麦芽糖(FCM)给药后内皮细胞的健康状况,我们使用流式细胞术分析了 23 例 HF 患者循环内皮微泡(EMV)和内皮祖细胞(EPC)的特征。
与健康受试者相比,HF 患者的基线 CD31+/CD41-EMV 水平较高,且 EMV 表现出更明显的凋亡表型。FCM 给药后,EMV 水平迅速但短暂升高,并表现出改变的表型特征,具有明显增加表达诱导标志物 CD62E 和 CD54 的 EMV,表明内皮炎症激活和损伤。HF 患者的循环血管再生 CD45lowCD34+KDR+EPC 水平较低,FCM 应用后 EPC 早期减少,一周后大量动员到循环中。EMV 和 EPC 水平分别在两周和四周内恢复到基线值。合并慢性肾脏病的 HF 患者的 EMV/EPC 比值升高,EPC 动员减少,提示血管修复能力受损。实验用培养的内皮细胞提供了一种机制联系,表明 FCM 剂量依赖性地促进内皮细胞凋亡,增加粘附分子和 CXCL12 的表达,并触发 EMV 的产生。
HF 患者静脉铁补充 FCM 会引起双相反应,最初增加 CD62E+和 CD54+丰富的 EMV 的释放,随后动员 EPC,表明 FCM 后内皮功能障碍,并提示随后进行旨在恢复血管健康的防御程序的参与。