Background

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is an independent risk factor of cardiovascular disease and a target of treatment. Lp-PLA₂ levels in children have not been previously reported. The effect of statin therapy on Lp-PLA₂ mass and activity in children with familial hypercholesterolemia (FH) is also not known.

Methods

Lp-PLA₂ mass and activity levels were measured at baseline and after 2 years in 178 children with FH randomized to pravastatin or placebo and in 78 unaffected and untreated siblings. At the end of the randomized period, all FH children were then placed on pravastatin for an additional 2 years, and Lp-PLA₂ mass and activity levels were correlated with changes in carotid intima-media thickness during 4 years of follow-up.

Results

Baseline levels of Lp-PLA₂ mass and activity were significantly greater in children with FH compared with unaffected siblings (mass: 240.3 ± 41.6 vs 222.1 ± 36.5 ng/mL, P = .002; activity: 205.7 ± 41.6 vs 124.3±23.0 nmol/min/mL, P < .0001). In the randomized FH cohort, after 2 years treatment, Lp-PLA₂ mass (217.8 ± 35.0 vs 231.5 ± 34.8 ng/mL, P = .001) and activity (178.8 ± 37.3 vs 206.2 ± 33.5 nmol/min/mL, P < .0001) were significantly reduced by pravastatin compared with placebo. Change in Lp-PLA₂ activity was related to change in low-density lipoprotein cholesterol (pravastatin: r = 0.53, P < .0001, placebo: r = 0.23, P < .001) but change in Lp-PLA₂ mass was not related to change in low-density lipoprotein cholesterol. Baseline levels of Lp-PLA₂ mass and activity were not significantly associated with carotid intima-media thickness at baseline or at 4 years.

Conclusion

Lp-PLA₂ mass and activity are significantly elevated in children with heterozygous FH compared with unaffected siblings and are significantly reduced by pravastatin therapy.

Background

Statin therapy is recommended for children with familial hypercholesterolemia (FH), but most children do not reach treatment targets.

Objective

Here we present the design and results at baseline of the ongoing CHARON study, to evaluate the safety and efficacy of rosuvastatin.

Methods

This study comprises an international 2-year open label, titration-to-goal study in 198 children with heterozygous FH aged 6 to 18 years, with rosuvastatin in a maximum dose of 10 mg (<10 years of age) or 20 mg (older children). In addition, 64 unaffected siblings were enrolled as controls. The primary efficacy outcome is the change from baseline in low-density lipoprotein cholesterol, and the secondary outcome is the change in carotid intima-media thickness (c-IMT) in patients with FH compared with their siblings. The primary safety outcomes are growth and sexual maturation; secondary outcomes are the change in other lipoprotein levels and the incidence of adverse events, discontinuation rates, and abnormal laboratory values.

Results

At baseline, mean age of patients with FH was 12.1 ± 3.3 years, 44% were boys, and mean low-density lipoprotein cholesterol levels were 6.1 ± 1.3 mmol/L (235.9 ± 48.7 mg/dL). Mean c-IMT was 0.399 mm (95% CI, 0.392-0.406 mm) in children with FH versus 0.377 (95% CI, 0.366-0.388 mm) in unaffected siblings (P = .001).

Conclusions

At baseline, as expected according to on previous observations, children with FH proved to have a greater c-IMT than their healthy siblings. These differences had already occurred at a very young age, which emphasizes the importance of considering early statin initiation in this high-risk population.