Elevated serum levels of proinflammatory cytokines and biomarkers of matrix remodeling in never-treated patients with familial hypercholesterolemia

Background: Familial hypercholesterolemia (FH) is a common inherited disorder of lipoprotein metabolism, whose origin involves mutations in the gene coding for the low-density lipoprotein receptor protein. Although FH is monogenic, wide variation occurs in the onset and severity of atherosclerosis in these patients. Methods: Since data on levels of inflammatory proteins and/or active factors in FH patients who have never received lipid-lowering treatment are lacking, serum levels of MMP-3, active MMP-9 and TIMP-1 as well as pro-inflammatory cytokines (TNF-alpha, IL-18) were determined in never-treated homozygous FH Moroccan patients (n = 4) and compared to those of heterozygous FH subjects (n = 7) and of healthy control subjects (n = 5). Results: When compared to controls, homozygous FH patients exhibited levels of active MMP-9 and TIMP-I (p < 0.05), and of both high sensitive-CRP and IL-18 which were significantly elevated (p < 0.05 and p < 0.01, respectively). In heterozygous FH patients, intermediate values between FH hornozygotes and healthy controls were observed for these markers, with the exception of MMP-9 activity whose levels were significantly elevated (p < 0.05). Multivariate analysis revealed a positive correlation between apolipoprotein B, TIMP-1 and IL-18 levels, and between hs-CRP and IL-18 (p < 0.01). Conclusions: Although the sample size of this FH group was limited, our data suggest that nontreated homozygous FH patients, and to a lesser degree heterozygous FH patients, exhibit not only a markedly proinflammatory vascular state but also pronounced extracellular matrix remodeling, as reflected by elevated circulating levels of inflammatory cytokines and MMPs. (c) 2005 Elsevier B.V. All rights reserved.