Lappegård Knut Tore, Enebakk Terje, Thunhaug Hilde, Ludviksen Judith Krey, Mollnes Tom Eirik, Hovland Anders
Coronary Care Unit, Division of Internal Medicine, Nordland Hospital, Bodø, Norway; Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway.
Dialysis Unit, Division of Internal Medicine, Nordland Hospital, Bodø, Norway.
J Clin Lipidol. 2016 Nov-Dec;10(6):1481-1487. doi: 10.1016/j.jacl.2016.09.001. Epub 2016 Sep 13.
Low-density lipoprotein (LDL) apheresis is an extracorporeal treatment modality used in high-risk coronary patients. It may, however, induce complement activation and downstream inflammation due to bio-incompatibility.
We explored changes in soluble inflammatory markers when changing from LDL apheresis to the novel PCSK9 inhibitor evolocumab.
Three patients with familial hypercholesterolemia participated. Blood samples (EDTA plasma) for complement activation and markers of inflammation were obtained before (baseline) and after LDL apheresis week at 0 and before biweekly administration of evolocumab at weeks 1, 3, 5, and 7. Complement activation was measured by ELISA and cytokines by multiplex technology.
Complement activation products C3a and Bb were both significantly higher after LDL apheresis compared to baseline (P = .01), returned to baseline levels before administration of evolocumab and remained low through week 7. C4d was unchanged during LDL apheresis, whereas TCC was slightly higher after apheresis compared to baseline and week 7 without statistical difference. MCP-1 was higher after LDL apheresis compared to baseline (P = .04), returned to baseline levels before administration of evolocumab and remained low through week 7. There were minor changes for other cytokines including TNF, IFN-γ, MIP-1α, MIP-1β, with some higher and some lower after apheresis; however, none of these changes were statistically significant. Fibrinogen and CRP were lower after LDL apheresis and had returned to levels comparable to baseline at week 7, statistically significant however only for fibrinogen.
LDL apheresis activated the alternative complement system significantly as reflected by an increase in C3a and Bb. PCSK9 inhibition did not affect complement or cytokines during 7 weeks follow-up.
低密度脂蛋白（LDL）单采术是用于高危冠心病患者的一种体外治疗方式。然而，由于生物不相容性，它可能会诱导补体激活及下游炎症反应。
我们探究了从LDL单采术转换为新型前蛋白转化酶枯草溶菌素9（PCSK9）抑制剂依洛尤单抗时可溶性炎症标志物的变化。
三名家族性高胆固醇血症患者参与研究。在LDL单采术第0周前（基线）、LDL单采术后、以及在第1、3、5和7周每两周给予依洛尤单抗前采集血样（乙二胺四乙酸血浆），用于检测补体激活情况及炎症标志物。通过酶联免疫吸附测定法检测补体激活情况，采用多重技术检测细胞因子。
与基线相比，LDL单采术后补体激活产物C3a和Bb均显著升高（P = 0.01），在给予依洛尤单抗前恢复至基线水平，并在第7周一直保持较低水平。C4d在LDL单采术期间无变化，而总补体活性（TCC）在单采术后比基线和第7周略高，但无统计学差异。与基线相比，LDL单采术后单核细胞趋化蛋白-1（MCP-1）升高（P = 0.04），在给予依洛尤单抗前恢复至基线水平，并在第7周一直保持较低水平。包括肿瘤坏死因子（TNF）、干扰素-γ（IFN-γ）、巨噬细胞炎性蛋白-1α（MIP-1α）、巨噬细胞炎性蛋白-1β（MIP-1β）在内的其他细胞因子有轻微变化，单采术后有些升高有些降低；然而，这些变化均无统计学意义。LDL单采术后纤维蛋白原和C反应蛋白（CRP）降低，在第7周恢复至与基线相当的水平，不过只有纤维蛋白原具有统计学意义。
如C3a和Bb升高所示，LDL单采术显著激活了替代补体系统。在7周的随访期间，PCSK9抑制对补体或细胞因子无影响。
