Center for Laboratory Medicine, University Hospital Münster, Germany.
Atherosclerosis. 2013 Sep;230(1):164-70. doi: 10.1016/j.atherosclerosis.2013.07.007. Epub 2013 Jul 22.
Several studies demonstrated decreased severity and incidence of cardiac allograft vasculopathy (CAV) in heart transplant recipients receiving immunosuppressive therapy with everolimus. However, data regarding the influence of everolimus on risk factors predisposing to CAV are hitherto limited. We here systematically evaluated cardiovascular risk factors in heart transplanted patients, who underwent conversion to everolimus or were maintained on conventional therapy with calcineurin inhibitors (CNI).
50 Patients receiving everolimus and 91 patients receiving CNI in addition to mycophenolate mofetil and low-dosed steroids were included in the study. CAV risk factors were determined in plasma or urine using standard enzymatic or immunochemical methods.
No significant differences were observed between both groups with regard to lipid (total, LDL- and HDL-cholesterol), metabolic (glucose, insulin), inflammatory (C-reactive protein, IL-6, myeloperoxidase) and cardiac (troponin I, NT-proBNP) risk factors. However, significantly lower activity of lipoprotein-associated phospholipase A2 (Lp-PLA2) and a negative correlation between the Lp-PLA2 activity and the everolimus concentration were observed in plasmas from everolimus-treated patients. Conversion to everolimus significantly lowered Lp-PLA2 activity in heart transplant recipients. Studies in vitro revealed reduced Lp-PLA2 expression in hepatocytes and macrophages pre-exposed to everolimus. In addition, reduced plasma markers of oxidative stress including oxidized LDL, 8-iso-prostaglandin F2α and protein carbonyls were noted in heart transplant recipients receiving everolimus therapy.
Our results suggest that everolimus specifically lowers plasma activity and cellular production of Lp-PLA2 and thereby dampens oxidative stress. These effects may additionally contribute to the reduced CAV incidence observed in heart transplant recipients receiving everolimus therapy.
几项研究表明，在接受依维莫司免疫抑制治疗的心脏移植受者中，心脏移植血管病（CAV）的严重程度和发生率降低。然而，迄今为止，关于依维莫司对导致 CAV 的易患因素的影响的数据有限。我们在这里系统地评估了接受依维莫司转换或继续接受钙调神经磷酸酶抑制剂（CNI）加吗替麦考酚酯和低剂量类固醇治疗的心脏移植患者的心血管危险因素。
本研究纳入 50 例接受依维莫司治疗的患者和 91 例接受 CNI 治疗的患者。使用标准酶学法或免疫化学法在血浆或尿液中测定 CAV 危险因素。
两组患者在血脂（总胆固醇、LDL-胆固醇和 HDL-胆固醇）、代谢（葡萄糖、胰岛素）、炎症（C 反应蛋白、IL-6、髓过氧化物酶）和心脏（肌钙蛋白 I、NT-proBNP）危险因素方面无显著差异。然而，在依维莫司治疗患者的血浆中，脂蛋白相关磷脂酶 A2（Lp-PLA2）的活性显著降低，且 Lp-PLA2 活性与依维莫司浓度呈负相关。依维莫司转换治疗显著降低了心脏移植受者的 Lp-PLA2 活性。体外研究表明，依维莫司预先暴露于肝细胞和巨噬细胞中可降低 Lp-PLA2 的表达。此外，接受依维莫司治疗的心脏移植受者的血浆氧化应激标志物如氧化 LDL、8-异前列腺素 F2α 和蛋白羰基也降低。
我们的结果表明，依维莫司特异性降低血浆中 Lp-PLA2 的活性和细胞产生，从而减轻氧化应激。这些作用可能有助于降低接受依维莫司治疗的心脏移植受者的 CAV 发生率。
