Elevated YKL-40 and associations of inflammatory profiles with metabolic parameters in pediatric heterozygous familial hypercholesterolemia under pharmacological lipid-lowering therapy

INTRODUCTION: Excess LDL-cholesterol and chronic inflammation accelerate atherosclerosis in familial hypercholesterolemia (FH). In pediatric FH, the inflammatory phenotype, its role in cardiovascular risk stratification and its alterations under lipid-lowering therapy remain poorly understood. Therefore, we comprehensively profiled systemic inflammatory markers in pediatric heterozygous FH (HeFH) under different treatment modalities and investigated associations with liver enzymes and lipid parameters. METHODS: For this exploratory cross-sectional study, we prospectively enrolled 49 children with HeFH grouped as newly diagnosed, treatment-naïve (n = 11), diet-treated (n = 10) and pharmacologically treated with statins ± ezetimibe (n = 28), and 16 unaffected controls (overall median age 11 years; 58.8% female). Fasting blood samples were analyzed for routine laboratory parameters and quantification of 37 inflammatory markers using a multiplex immunoassay. RESULTS: While traditional inflammatory markers (CRP, IL-6) did not differ between groups, the macrophage activation marker chitinase-3-like protein 1 (YKL-40) was nominally elevated in pharmacologically treated patients vs. controls (p = 0.037). In this subgroup, markers of tissue remodelling and bone metabolism (osteopontin, osteocalcin) as well as immune activation (sCD30, sCD163) showed robust correlations with alkaline phosphatase and liver enzymes. Additionally, soluble TNF receptor 2 correlated inversely with HDL-cholesterol (r = -0.574, p = 0.009) and apolipoprotein A1 (r = -0.607, p = 0.009). CONCLUSION: In conclusion, pediatric HeFH patients receiving pharmacological therapy may exhibit persistent, potentially atherogenic macrophage activation reflected by elevated YKL-40 despite effective lipid lowering. The observed associations between immune markers and hepatic and bone metabolic parameters suggest pleiotropic effects of statins ± ezetimibe independent of lipid lowering.