Plasma PCSK9 levels in children and adolescents: evidence from an Italian outpatient paediatric clinic cohort at cardio-metabolic risk

Background and aim: Whether measuring circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma levels in cardiovascular contexts may be of use in the clinical practice remains uncertain. The aim of the present study was to investigate PCSK9 levels in a cohort of children and adolescents referred to a paediatric outpatient clinic for cardio-metabolic risk assessment. Methods and results: 332 children and adolescents were recruited between December 2014 and June 2024. Plasma PCSK9 enzyme-linked immunosorbent assay, glucose, insulin, fasting lipids, and uric acid were assessed, with calculation of non-high-density lipoprotein cholesterol (non-HDL-C), remnant cholesterol, and homeostasis model assessment index. The median age was 11.2 years, with 44.1% having initiated pubertal development, 81.9% were classified as excess weight and 16.3% as hypertensive. The median PCSK9 levels were 187.2 ng/mL. After adjustment for age and body mass index (BMI) z-score, the presence of lipid values above the clinical threshold was significantly associated with higher PCSK9 levels (p<0.01): total cholesterol ≥200 mg/dL (+51.7 ng/mL), non-HDL-C≥145 mg/dL (+43.6 ng/mL), remnant-cholesterol ≥30 mg/dL (+49.6 ng/mL), low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL (+34.1 ng/mL), and triglycerides above cut-offs (+49.2 ng/mL). Similarly, a positive parental history of dyslipidaemia was significantly associated with higher PCSK9 values (+39.9 ng/mL) (p<0.001). Conclusions: In a cohort of children and adolescents at cardio-metabolic risk, circulating PCSK9 levels were significantly associated with atherogenic lipid fractions, including LDL-C, non-HDL-C, triglycerides, and remnant cholesterol. These findings suggest that PCSK9 may play a broader role in lipid metabolism beyond LDL-C regulation, particularly in relation to triglyceride-rich lipoproteins.