Jessica Rodenburg

Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia.

Patients with familial hypercholesterolaemia have severe coronary-artery disease early in adult life. Whether lipid-lowering treatment should be started in childhood remains to be established. We therefore assessed 201 children heterozygous for familial hypercholesterolaemia and 80 unaffected siblings (both age ranges 8-18 years) with B-mode ultrasound to measure carotid wall intima-media thickness. Mean combined carotid intima-media thickness of heterozygotes was significantly greater than that of unaffected siblings (0.494 mm [SD 0.051] vs 0.472 [SD 0.049], p=0.002). A significant deviation in intima-media thickness was noted from age 12 years in children with familial hypercholesterolaemia. Findings on multivariate analysis showed LDL cholesterol, age, and sex to be strong and independent predictors of intima-media thickness. Since raised LDL cholesterol concentrations can be lowered efficiently, clinical studies are needed to investigate long-term safety and effectiveness of statin treatment in children with familial hypercholesterolaemia.

Statin treatment in children with familial hypercholesterolemia - The younger, the better

Background— We previously demonstrated in a randomized placebo-controlled trial that 2-year pravastatin treatment induced a significant regression of carotid intima-media thickness (IMT) in 8- to 18-year-old children with familial hypercholesterolemia. Subsequently, we continued to follow up these children to explore the relation between the age of statin initiation and carotid IMT after follow-up on statin treatment. We also examined safety aspects of statin therapy during this long-term follow-up. Methods and Results— All 214 children who initially participated in the previous placebo-controlled study were eligible for the follow-up study. After completion of the placebo-controlled study, all children continued treatment with pravastatin 20 or 40 mg, depending on their age. Blood samples were taken on a regular basis for lipids and safety parameters, and a carotid IMT measurement was performed after an average treatment period of 4.5 years. Follow-up data for 186 children were available for the statistical analyses. Multivariate analyses revealed that age at statin initiation was an independent predictor for carotid IMT after follow-up with adjustment for carotid IMT at initiation of statin treatment, sex, and duration of treatment. Early initiation of statin treatment was associated with a subsequently smaller IMT. Furthermore, no serious laboratory adverse events were reported during follow-up, and statin treatment had no untoward effects on sexual maturation. Conclusions— These data indicate that early initiation of statin treatment delays the progression of carotid IMT in adolescents and young adults. The present study shows for the first time that early initiation of statin therapy in children with familial hypercholesterolemia might be beneficial in the prevention of atherosclerosis in adolescence.

Family History and Cardiovascular Risk in Familial Hypercholesterolemia Data in More Than 1000 Children

Background—Elevated LDL cholesterol (LDL-C) levels in childhood predict cardiovascular disease (CVD) later in life. Familial hypercholesterolemia (FH) represents the paradigm of this relation. Methods and Results—The objectives of this study were to (1) establish the LDL-C level that provides the most accurate diagnosis of FH in children from families with known FH and (2) assess whether lipoprotein variation in these children is associated with premature CVD in relatives. Foremost, however, it was our objective to identify children with FH who are at high risk and in need of early intervention. A total of 1034 consecutive children from FH kindreds were investigated. First, LDL-C levels >3.50 mmol/L had a 0.98 post-test probability (95% CI, 0.96 to 0.99) of predicting the presence of an LDL receptor mutation. Second, children with FH in the highest LDL-C tertile (>6.23 mmol/L) had a 1.7-times higher incidence (95% CI, 1.24 to 2.36) of having a parent with FH suffering from premature CVD (P =0.001). In addition, such a parent was found 1.8 times more often (95% CI, 1.20 to 2.59) among children with FH who had HDL-C <1.00 mmol/L (P =0.004). Last, children with FH whose lipoprotein(a) was >300 mg/L had a 1.45-times higher incidence (95% CI, 0.99 to 2.13) of having a parent with FH suffering from premature CVD (P =0.05). Conclusions—In FH families, LDL-C levels allow accurate diagnosis of FH in childhood. Moreover, increased LDL-C and lipoprotein(a) and decreased HDL-C levels in children identify FH kindreds with the highest CVD risk.

Familial hypercholesterolemia in children.

Purpose of this review This review provides an update on recent advances in the diagnosis and management of children with familial hypercholesterolemia. Recent findings A large cross-sectional cohort study of paediatric familial hypercholesterolemia demonstrated that affected children had a 5-fold more rapid increase of carotid arterial wall intima-media thickness during childhood years than their affected siblings. This faster progression led to a significant deviation in terms of intima-media thickness from the age of 12 years and onwards. Low-density lipoprotein cholesterol was a strong and independent predictor of carotid artery intima-media thickness in these children, which confirms the pivotal role of low-density lipoprotein cholesterol for the development of atherosclerosis. In this condition lipid lowering by statin therapy is accompanied by carotid intima-media thickness regression in familial-hypercholesterolemic children, which suggests that initiation of low-density lipoprotein cholesterol-reducing medication in childhood already can inhibit or possibly reduce the faster progression of atherosclerosis. Furthermore, these trials demonstrated that statins are safe and do not impair growth or sexual development in these children. Conversely, products containing plant sterols reduced low-density lipoprotein cholesterol levels by 14%, but did not improve endothelial dysfunction as assessed by flow-mediated dilatation. Summary Children with familial hypercholesterolemia clearly benefit from lipid-lowering strategies. Statins are safe agents and have been proven to reduce elevated low-density lipoprotein cholesterol levels significantly. In addition, statins improve surrogate markers for atherosclerosis. Therefore these agents should become the pivotal therapy in children with familial hypercholesterolemia.

Increased inflammatory markers in children with familial hypercholesterolaemia.

Background  While data are abundant on increased levels of inflammatory markers in adult patients with hypercholesterolaemia, such data in children are limited. Therefore, we sought to investigate the degree and character of inflammation in children with heterozygous familial hypercholesterolaemia (FH) by measuring levels of neopterin, high‐sensitivity C‐reactive protein (hsCRP), and soluble CD40 ligand (sCD40L).

The Apolipoprotein ε4 Allele Confers Additional Risk in Children with Familial Hypercholesterolemia

Children with familial hypercholesterolemia (FH) exhibit substantial variance of LDL cholesterol. In previous studies, family members of children with FH were included, which may have influenced results. To avoid such bias, we studied phenotype in 450 unrelated children with FH and in 154 affected sib-pairs. In known families with classical FH, diagnosis was based on plasma LDL cholesterol above the age- and gender-specific 95th percentile. Girls had 0.47 ± 0.15 mmol/L higher LDL cholesterol, compared with boys (p = 0.002). Also in girls, HDL cholesterol increased by 0.07 ± 0.03 mmol/L per 5 y (pfor trend = 0.005); this age effect was not observed in boys. The distribution of apolipoprotein (apo) E genotypes was not significantly different between probands, their paired affected siblings, or a Dutch control population. Carriers with or without one ε4 allele had similar LDL and HDL cholesterol levels. Within the affected sib-pairs, the ε4 allele explained 72.4% of the variance of HDL cholesterol levels (−0.15 mmol/L, 95% confidence interval −0.24 to −0.05, p = 0.003). The effect of apoE4 on HDL cholesterol differed with an analysis based on probands or on affected sib-pairs. The affected sib-pair model used adjustment for shared environment, type of LDL receptor gene mutation, and a proportion of additional genetic factors and may, therefore, be more accurate in estimating effects of risk factors on complex traits. We conclude that the ε4 allele was associated with lower HDL cholesterol levels in an affected sib-pair analysis, which strongly suggests that apoE4 influences HDL cholesterol levels in FH children. Moreover, the strong association suggests that apoE4 carries an additional disadvantage for FH children.

Atherogenic Lipoprotein Particle Size and Concentrations and the Effect of Pravastatin in Children with Familial Hypercholesterolemia

OBJECTIVE To determine lipoprotein particle concentrations and size in children with familial hypercholesterolemia (FH) and investigate the effect of pravastatin therapy on these measures. STUDY DESIGN Lipoprotein particle concentrations and sizes were examined by nuclear magnetic resonance (NMR) spectroscopy in 144 children with FH and 45 unaffected siblings. The effect of pravastatin therapy (20 to 40 mg) on lipoprotein particle concentration and size were compared with placebo after 1 year of treatment, using analysis of covariance. RESULTS Compared with the unaffected siblings, the children with FH had significantly higher concentrations of very-low-density lipoprotein (VLDL) particles (115.6 nmol/L vs 51.2 nmol/L; P < .001) and low-density lipoprotein (LDL) particles (1726.8 nmol/L vs 955.3 nmol/L; P < .001), and lower concentrations of high-density lipoprotein (HDL) particles (23.2 micromol/L vs 26.9 micromol/L; P < .001). Compared with placebo, pravastatin therapy decreased the concentration of VLDL particles by 35.9 nmol/L (P < .001), of total LDL particles by 342.7 nmol/L (P < .001), of large LDL particles by 189.5 nmol/L (P < .001), and of small LDL particles by 156.2 nmol/L (P = .152), but increased the concentration of total HDL particles by 2.2 micromol/L (P < .001), of large HDL particles by 1.0 micromol/L (P = .006), and of medium HDL particles by 1.1 micromol/L (P = .003). VLDL particle size increased by 1.0 nm (P = .032). CONCLUSIONS Compared with their healthy siblings, children with FH have an atherogenic lipoprotein profile based on their lipoprotein distribution and lipoprotein particle diameter. Pravastatin therapy can improve, but not fully restore, these lipoprotein abnormalities toward normal levels in these children.

Paraoxonase genotype and carotid intima-media thickness in children with familial hypercholesterolemia

BACKGROUND Paraoxonase (PON) 1 is a high-density lipoprotein-associated enzyme that may protect against cardiovascular disease. METHOD We have studied the contribution of PON-1 and PON-2 single nucleotide polymorphisms (SNP; L55M, Q192R and T-107C, S311C) to the intima-media thickness of the common carotid artery in a population of children with classic familial hypercholesterolaemia. RESULTS The L-variant of the L55M SNP was associated with increased common carotid artery intima-media thickness when compared with the M-variant (P value for trend 0.03). No significant relationship was observed between the other SNP and common carotid artery intima-media thickness. CONCLUSIONS Our findings suggest that variation at the PON-1 locus contributes to early atherosclerosis in children with familial hypercholesterolaemia.

Management of hereditary dyslipidaemia; the paradigm of autosomal dominant hypercholesterolaemia

Inherited, or autosomal dominant, hypercholesterolaemia, with an average global prevalence of one in 500 individuals, is one of the most frequent inherited metabolic disorders. The disorder is associated with a high risk for premature cardiovascular disease (CVD) and death as a consequence of accelerated atherosclerosis. Although the molecular genetic basis is largely elucidated and effective medical treatment, in the form of inhibitors of intracellular cholesterol synthesis, is available, the disorder is severely underdiagnosed and undertreated. On the other hand, with the well-understood aetiology, the accurate diagnosis, the availability of sensitive predictive makers and efficacious therapy, this disorder can serve as a model for disease management: from early presymptomatic diagnosis, accurate prognosis, optimal treatment and large-scale screening to population-based prevention of CVD.