P650Lipopolysaccharide-nuclear factor-kappa B pathway and lipoprotein apheresis effects in patients with familial hypercholesterolemia and coronary artery disease

Background: Inflammation may play an important role in atherosclerosis in familial hypercholesterolemia (FH). Lipopolysaccharide (LPS)-nuclear factor-kappa B (NF-κB) pathway is a routine signal process activated in inflammatory status. However, the LPS-NF-κB axis status and the impact of lipoprotein apheresis (LA) on this pathway in patients with FH and coronary artery disease (CAD) has not been clarified. Methods: A genetically diagnosed FH cohort who presented stable CAD (n=63) was compared with 63 non-FH CAD and 63 non-FH non-CAD controls matched by sex and age. Plasma LPS levels and NF-κB activity were compared among them. In vitro LPS-induced interleukin-6 (IL-6) production by mononuclear cells from 16 FH cases without previous statin use was measured and compared with their respective matched control groups. Subsequently, these 16 FH patients underwent LA. Blood samples were regularly taken for measuring LPS and NF-κB. Findings: FH plus CAD had higher LPS levels and NF-κB activity than CAD and non-CAD controls (all p<0.01). LPS-induced IL-6 production by mononuclear cells of FH plus CAD was also much higher compared with control groups (both p<0.01). Moreover, plasma LPS levels (p<0.001) and NF-κB activity (p<0.01) were dramatically reduced after apheresis in FH patients. Interpretation: Genetically confirmed FH patients with CAD had a marked activation of LPS-NF-κB axis, while LA significantly attenuated this key inflammatory pathway, suggesting that inflammation may be an important therapeutic target for FH patients. Funding Statement: This work was partially supported by the Capital Health Development Fund [201614035] and CAMS Major Collaborative Innovation Project [2016-I2M-1-011] awarded to Dr. J.J.L. Declaration of Interests: R.D.S. has received honoraria related to consulting, speaker and/or research activities from Amgen, Akcea, Astra Zeneca, Biolab, Esperion, Kowa, Novo-Nordisk, Merck and Sanofi/Regeneron. Ethics Approval Statement: The study complied with the Declaration of Helsinki and Title 45, US Code of Federal Regulations, Part 46, Protection of Human Subjects, Revised November 13, 2001, effective December 13, 2001, and was approved by the hospital’s ethical review board (Fu Wai Hospital & National Center for Cardiovascular Diseases, Beijing, China). Each participant provided written, informed consent before enrollment.