Hyperlipidemias: Wiegman A

Rodenburg J, Vissers MN, Daniels SR, Wiegman A, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, the Netherlands, and Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Ohio, USA. · Pediatr Endocrinol Rev. · Pubmed #16456497 No free full text.

Abstract: In the last decades, there has been an important progression in the development and assessment of various cholesterol-lowering agents. Until recently, in children under age 10, the focus of treatment has been on dietary and lifestyle adjustments. For children older than 10 years, bile acid-binding resins were also recommended if LDL-C levels remained high after dietary adjustment. However, the lipid-lowering effect of bile acid-binding resins is modest at best and long-term compliance is often poor. In contrast, HMG-CoA reductase inhibitors (statins) are currently widely used in adults and are considered the first choice in the treatment of hypercholesterolemia. In the last few years, several randomized trials have shown that statins are also effective in reducing LDL cholesterol levels in children and seem safe at least in the short term. Another novel development is the cholesterol-lowering agent, ezetimibe, which inhibits cholesterol absorption in the intestine. Although efficacy and safety data in children are still lacking, ezetimibe has a good safety profile in adults, either as monotherapy or in combination with a statin. Lastly, two other classes of lipid-lowering drugs include fibrates and nicotinic acid, but most agree that the side effect profile precludes their use in children except in extreme circumstances. Overall, therapeutic options to lower cholesterol levels in children are expanding.

Rodenburg J, Vissers MN, Trip MD, Wiegman A, Bakker HD, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Semin Vasc Med. · Pubmed #15861313 No free full text.

Abstract: The recommended therapy of hypercholesterolemia in children consists of dietary modification and bile acid-binding resins. Unfortunately, the lipid-lowering efficacy of bile acid-binding resins is modest, and moreover, long-term compliance is poor because of side effects. In contrast, hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are widely used in adults and are considered to be the first choice in the treatment of hypercholesterolemia in that age category. In the last few years, several randomized trials have been conducted to evaluate the efficacy, safety, and tolerability of statin therapy in both children and adolescents. In this article, we review statin therapy in hypercholesterolemic children in terms of efficacy, safety, pharmacokinetics, and psychosocial functioning. Statins are not only effective in reducing low-density lipoprotein cholesterol levels in children with familial hypercholesterolemia but also improve endothelial function and reduce the progressive thickening of the intima media complex of the carotid arteries. Statins seem safe at the longer term in children in terms of plasma levels of liver enzymes and liver function, creatine kinase levels, and muscle function, as well as growth and sexual development. Long-term follow-up studies are needed to assess whether statin treatment started early in children with familial hypercholesterolemia can prevent future cardiovascular events.

Rodenburg J, Vissers MN, Wiegman A, Trip MD, Bakker HD, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands. · Curr Opin Lipidol. · Pubmed #15243213 No free full text.

Abstract: 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.

de Groot E, Hovingh GK, Wiegman A, Duriez P, Smit AJ, Fruchart JC, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. · Circulation. · Pubmed #15198964 links to  free full text

Abstract: Large observational studies and atherosclerosis regression trials of lipid-modifying pharmacotherapy have established that intima-media thickness of the carotid and femoral arteries, as measured noninvasively by B-mode ultrasound, is a valid surrogate marker for the progression of atherosclerotic disease. To exploit fully the potential of ultrasound imaging in atherosclerosis research, standardized and strictly implemented imaging protocols should be used in both observational studies and applied clinical research. This article describes such a protocol developed at the Academic Medical Center of the University of Amsterdam, the Netherlands. Results are presented from a study that estimated atherosclerosis progression from childhood into old age by measuring intima-media thickness in subjects with familial hypercholesterolemia compared with healthy controls.

Wiegman A, Hutten BA, de Groot E, Rodenburg J, Bakker HD, Büller HR, Sijbrands EJ, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · JAMA. · Pubmed #15265847 links to  free full text

Abstract: CONTEXT: Children with familial hypercholesterolemia have endothelial dysfunction and increased carotid intima-media thickness (IMT), which herald the premature atherosclerotic disease they develop later in life. Although intervention therapy in the causal pathway of this disorder has been available for more than a decade, the long-term efficacy and safety of cholesterol-lowering medication have not been evaluated in children. OBJECTIVE: To determine the 2-year efficacy and safety of pravastatin therapy in children with familial hypercholesterolemia. DESIGN: Randomized, double-blind, placebo-controlled trial that recruited children between December 7, 1997, and October 4, 1999, and followed them up for 2 years. SETTING AND PARTICIPANTS: Two hundred fourteen children with familial hypercholesterolemia, aged 8 to 18 years and recruited from an academic medical referral center in the Netherlands. INTERVENTION: After initiation of a fat-restricted diet and encouragement of regular physical activity, children were randomly assigned to receive treatment with pravastatin, 20 to 40 mg/d (n = 106), or a placebo tablet (n = 108). MAIN OUTCOME MEASURES: The primary efficacy outcome was the change from baseline in mean carotid IMT compared between the 2 groups over 2 years; the principal safety outcomes were growth, maturation, and hormone level measurements over 2 years as well as changes in muscle and liver enzyme levels. RESULTS: Compared with baseline, carotid IMT showed a trend toward regression with pravastatin (mean [SD], -0.010 [0.048] mm; P =.049), whereas a trend toward progression was observed in the placebo group (mean [SD], +0.005 [0.044] mm; P =.28). The mean (SD) change in IMT compared between the 2 groups (0.014 [0.046] mm) was significant (P =.02). Also, pravastatin significantly reduced mean low-density lipoprotein cholesterol levels compared with placebo (-24.1% vs +0.3%, respectively; P<.001). No differences were observed for growth, muscle or liver enzymes, endocrine function parameters, Tanner staging scores, onset of menses, or testicular volume between the 2 groups. CONCLUSION: Two years of pravastatin therapy induced a significant regression of carotid atherosclerosis in children with familial hypercholesterolemia, with no adverse effects on growth, sexual maturation, hormone levels, or liver or muscle tissue.

van der Graaf A, Rodenburg J, Vissers MN, Hutten BA, Wiegman A, Trip MD, Stroes ES, Wijburg FA, Otvos JD, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands. · J Pediatr. · Pubmed #18492534 No free full text.

Abstract: 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.

Defesche JC, Schuurman EJ, Klaaijsen LN, Khoo KL, Wiegman A, Stalenhoef AF. · Department of Vascular Medicine, Academic Medical Centre at the University of Amsterdam, Amsterdam, The Netherlands. · Clin Genet. · Pubmed #18400033 No free full text.

Abstract: In a large group of patients with the clinical phenotype of familial hypercholesterolemia, such as elevated low-density lipoprotein (LDL) cholesterol and premature atherosclerosis, but without functional mutations in the genes coding for the LDL receptor and apolipoprotein B, we examined the effect of 128 seemingly neutral exonic and intronic DNA variants, discovered by routine sequencing of these genes. Two variants, G186G and R385R, were found to be associated with altered splicing. The nucleotide change leading to G186G resulted in the generation of new 3'-splice donor site in exon 4 and R385R was associated with a new 5'-splice acceptor site in exon 9 of the LDL receptor gene. Splicing of these alternate splice sites leads to an in-frame 75-base pair deletion in a stable mRNA of exon 4 in case of G186G and R385R resulted in a 31-base pair frame-shift deletion in exon 9 and non-sense-mediated mRNA decay.

Rodenburg J, Vissers MN, Wiegman A, van Trotsenburg AS, van der Graaf A, de Groot E, Wijburg FA, Kastelein JJ, Hutten BA. · Academic Medical Centre, Department of Vascular Medicine, University of Amsterdam, The Netherlands. · Circulation. · Pubmed #17664376 links to  free full text

Abstract: 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.

ter Avest E, Sniderman AD, Bredie SJ, Wiegman A, Stalenhoef AF, de Graaf J. · Department of Medicine, Division of General Internal Medicine, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands. · Clin Sci (Lond). · Pubmed #17054424 No free full text.

Abstract: The aim of the present study was to delineate the mechanism(s) responsible for the increased secretion of VLDL (very-low-density lipoprotein) particles in patients with FCH (familial combined hyperlipidaemia). In 194 young adults (<25 years of age) recruited from families with FCH, we investigated how plasma lipids, (apo)lipoproteins and BMI (body mass index) varied with age. Furthermore, we performed a 5-year follow-up study of clinical and biochemical characteristics of a subset of this population (n=85) stratified by apoB (apolipoprotein B) levels (below or above the 75th percentile adjusted for age and gender). Plasma apoB concentration (r=0.45, P<0.0001), triacylglycerol (triglyceride) concentration (r=0.45, P<0.0001), LDL (low-density lipoprotein) subfraction profile (r=-0.46, P<0.0001) and BMI (r=0.51, P<0.0001) were significantly associated with age. Plasma apoB concentration in the hyperapoB group was already elevated at a young age, whereas other characteristics of FCH, as observed in adults, including triacylglycerol levels >1.5 mmol/l and/or small-dense LDL, were observed only sporadically. After the 5-year follow-up, BMI increased in both groups, and this increase was associated with changes in apoB (r=0.27, P<0.05), triacylglycerol (r=0.30, P<0.01), VLDL cholesterol (r=0.22, P<0.05), VLDL triacylglycerol (r=0.25, P<0.05) and high-density lipoprotein cholesterol (r=-0.27, P<0.05). In conclusion, we have found indirect evidence of a primary, presumably genetically determined, increase in plasma apoB concentration occurring early in life of offspring from families with FCH. However, aging-related post-maturation increases in adipose tissue mass also appear to contribute to an aggravation and/or modulation of this genetically determined apoB overproduction.

Roest M, Rodenburg J, Wiegman A, Kastelein JJ, Voorbij HA. · Research Laboratory of the Department of Clinical Chemistry, University Medical Center, Utrecht, The Netherlands. · Eur J Cardiovasc Prev Rehabil. · Pubmed #16926679 No free full text.

Abstract: 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.

Rodenburg J, Vissers MN, Wiegman A, Miller ER, Ridker PM, Witztum JL, Kastelein JJ, Tsimikas S. · Department of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands. · J Am Coll Cardiol. · Pubmed #16682304 No free full text.

Abstract: OBJECTIVES: To assess the role of oxidized phospholipids (OxPLs) in children with familial hypercholesterolemia (FH) and the effect of pravastatin. BACKGROUND: Oxidized phospholipids are a major component of oxidized low-density lipoprotein (OxLDL) and are bound to lipoprotein (a) [Lp(a)]. The significance of OxPL markers in children is unknown. METHODS: Children with FH were randomized to placebo (n = 88) or pravastatin (n = 90) after instruction on American Heart Association step II diet. Unaffected siblings (n = 78) served as controls. The OxPL content on apolipoprotein B-100 (apoB) detected by antibody E06 (OxPL/apoB ratio), immunoglobulin (Ig)G and IgM immune complexes per apoB (IC/apoB) and on all apoB particles (total apoB-IC = IC/apoB multiplied by plasma apoB levels), autoantibodies to malondialdehyde (MDA)-low-density lipoprotein (LDL), Lp(a), and apoB levels were measured at baseline and after two years of treatment. RESULTS: Compared with unaffected siblings, children with FH had significantly lower levels of OxPL/apoB but higher levels of IgG and IgM total apoB-IC and IgM MDA-LDL autoantibodies. From baseline to two-year follow-up, compared with placebo pravastatin treatment resulted in a greater mean percentage change in apoB (-18.7% vs. 0.3%; p = 0.001), total IgG apoB-IC (-31.9% vs. -12.2%; p < 0.001), and total IgM apoB-IC (-25.5% vs. 13.2%; p = 0.001). Interestingly, pravastatin also resulted in higher OxPL/apoB (48.7% vs. 29.3%; p = 0.028) and Lp(a) levels (21.9% vs. 10.7%; p = 0.044). CONCLUSIONS: Compared with unaffected siblings, children with FH are characterized by elevated levels of apoB-IC and IgM MDA-LDL autoantibodies. Compared with placebo, pravastatin led to a greater reduction in apoB-IC but also to a greater increase in OxPL/apoB and Lp(a), which may represent a novel mechanism of mobilization and clearance of OxPL.

Jakulj L, Vissers MN, Rodenburg J, Wiegman A, Trip MD, Kastelein JJ. · Department of Vascular Medicine, and Emma Children's Hospital, Academic Medical Centre, Amsterdam, the Netherlands. · J Pediatr. · Pubmed #16647412 No free full text.

Abstract: OBJECTIVE: To examine the effect of plant stanols on lipids and endothelial function in pre-pubertal children with familial hypercholesterolemia (FH). STUDY DESIGN: Children with FH (n=42), aged 7-12 years, were enrolled in a double-blind crossover trial, in which they consumed 500 mL of a low-fat yogurt enriched with 2.0 g of plant stanols and 500 mL of a low-fat placebo yogurt for 4 weeks, separated by a 6-week washout period. Lipid profiles and endothelial function were assessed after both consumption periods. Endothelial function was measured as flow-mediated dilation (FMD) of the brachial artery. RESULTS: This daily intake of 2.0 g of stanols significantly decreased the levels of total cholesterol (TC) by 7.5% and low-density lipoprotein cholesterol (LDL-C) by 9.2% as compared with placebo. High-density lipoprotein cholesterol and triglyceride levels remained unaltered. The reduction of LDL-C levels did not improve FMD, which was 10.5%+/-5.1% after plant stanol consumption and 10.6%+/-5.0% after placebo consumption, respectively (P=.852). CONCLUSION: This study demonstrates that plant stanols reduce LDL-C levels in children with FH without improving endothelial function.

Ueland T, Vissers MN, Wiegman A, Rodenburg J, Hutten B, Gullestad L, Ose L, Rifai N, Ridker PM, Kastelein JJ, Aukrust P, Semb AG. · Research Institute for Internal Medicine, Section of Endocrinology, Rikshospitalet, University of Oslo, Norway. · Eur J Clin Invest. · Pubmed #16506958 No free full text.

Abstract: 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). MATERIALS AND METHODS: In the present study, we compared the concentration of inflammatory markers in children suffering from heterozygous FH (n = 207) with those in unaffected siblings (n = 84). Furthermore, we investigated the effect of 2-year treatment with pravastatin (20-40 mg qd) or placebo on plasma levels of those markers. RESULTS: Our main finding was that serum levels of neopterin and hsCRP were significantly higher in FH children compared with healthy siblings, whereas sCD40L was not. Body mass index and high-density lipoprotein cholesterol levels were significant independent predictors of hsCRP and neopterin. Furthermore, pravastatin therapy decreased neopterin, but not hsCRP and sCD40L, in the FH children, but these changes were not different from the placebo group. CONCLUSION: These findings indicate low-grade monocyte/macrophage hyperactivity in the early stages of atherogenesis, but our findings also suggest that inflammation as well as anti-inflammatory effects of statins are less prominent features of atherosclerosis in FH children than in FH adults.

De Groot E, Hovingh GK, Zwinderman AH, Wiegman A, Smit AJ, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands. · Int Angiol. · Pubmed #16355094 No free full text.

Abstract: AIM: Atherosclerosis is a slow disease process of arterial walls with onset decades prior to its clinical manifestations. Lifelong follow-up data may help to identify and understand the pathophysiology of this process. These longitudinal data are scarce. Using a standardized imaging and image analysis protocol, we acquired cross-sectional data of carotid and femoral arterial wall segments in populations at different cardiovascular disease risk. METHODS: B-mode ultrasound intima-media thickness (IMT) data of carotid and femoral arteries were acquired in individuals at high cardiovascular disease risk: 44 young adolescents with familial hypercholesterolemia (FH), 248 adult FH patients and 184 patients with coronary artery disease (CAD), as well as in disease free unaffected individuals, 44 young adolescents, 26 middle-aged adults and 48 senior adults. RESULTS: Per patient combined average IMT (SD) and % of lesions in the high risk populations were 0.55 (0.05) mm, 0.1%, 0.86 (0.18) mm, 15%, and 0.9 (0.18) mm, 18%, respectively. In the unaffected groups these values were 0.53 (0.03) mm, 0%, 0.59 (0.07) mm, 0%, and 0.77 (0.12) mm, 8%. Of all arterial segments, the far wall of the common femoral artery (CFA) of the FH patients exhibited the highest absolute IMT (1.12 [0.61] mm), the most rapid estimated IMT increase since adolescence (+0.58 mm) and the highest percentage of lesions (39% of CFA measurements). CONCLUSIONS: Regardless of location, carotid and femoral arterial walls increase in thickness with age and cardiovascular disease risk. This increase in thickness and prevalence of lesions is not similarly distributed among anatomical segments. The strong preponderance in arterial wall segments with the highest estimated atherosclerosis progression indicates the existence of a threshold value beyond which plaque formation is greatly increased. In the set of arterial locations we studied, this process might be best represented by the far wall of the CFA.

Koeijvoets KC, Rodenburg J, Hutten BA, Wiegman A, Kastelein JJ, Sijbrands EJ. · Department of Internal Medicine and Vascular Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Circulation. · Pubmed #16286607 links to  free full text

Abstract: BACKGROUND: The lipid-lowering effects of statin therapy show considerable interindividual variation in patients with familial hypercholesterolemia (FH). Whether the type of LDL receptor mutation predicts the response to statin treatment is not yet established. We analyzed the relationship between LDL receptor genotype and response to pravastatin treatment in children with FH using carotid intima-media thickness (IMT) to measure efficacy. METHODS AND RESULTS: In a randomized, placebo-controlled, double-blind, 2-year trial with pravastatin, 193 children had genetically confirmed FH and were included in the present substudy. At baseline, children with null alleles had higher LDL cholesterol levels (difference, 0.94+/-0.19 mmol/L [SEM]; P<0.001) and a greater carotid IMT (difference, 0.019+/-0.01 mm; P=0.02) compared with children with receptor-defective mutations. The decrease in carotid IMT during the trial was not significantly different in children with null alleles and receptor-defective mutations (0.018+/-0.012 and 0.012+/-0.010 mm; 2-way ANCOVA, P=0.7). After 2 years of treatment, the children with null alleles continued to have greater carotid IMT than children with receptor-defective mutations (difference, 0.016+/-0.01 mm; P=0.02). LDL cholesterol lowering tended to be less in carriers of null alleles compared with carriers of receptor-defective mutations (1.30+/-0.25 and 1.85+/-0.20 mmol/L; 2-way ANCOVA, P=0.08). CONCLUSIONS: In FH children, we found that the null allele genotype was associated with a greater carotid IMT, higher LDL cholesterol levels, and a nonsignificant tendency to attenuated LDL cholesterol lowering compared with receptor-defective mutations. Null alleles identify FH patients at the highest cardiovascular disease risk who may benefit from more aggressive treatment started in childhood.

Koeijvoets KC, Wiegman A, Rodenburg J, Defesche JC, Kastelein JJ, Sijbrands EJ. · Department of Internal Medicine, Erasmus Medical Centre-D435, P.O. Box 2040, 3000 AC Rotterdam, The Netherlands. · Atherosclerosis. · Pubmed #15823280 No free full text.

Abstract: Studies on the clinical consequences of different low-density lipoprotein (LDL) receptor genotypes in adult patients have yielded conflicting results. We hypothesized that children with familial hypercholesterolemia (FH) provide a better model to perform genotype-phenotype analyses than adults. We tested this hypothesis and assessed the effect of LDL receptor genotypes on lipoprotein levels and on parental risk of cardiovascular disease (CVD) in a pediatric FH cohort. We identified 75 different LDL receptor mutations in 645 children with heterozygous FH; in these children, null alleles were clearly associated with more elevated LDL cholesterol levels compared to receptor-defective mutations. Familial factors explained 50.4% of the variation in LDL cholesterol levels of this pediatric cohort compared to only 9.5% in adults. Parental CVD risk was not significantly different between carriers of null alleles and receptor-defective mutations (RR, 1.22; 95% CI, 0.76-1.95; p=0.4). The N543H/2393del9 mutation was associated with a less deteriorated lipid profile and the parents had less often CVD relative to parents with other mutations (RR, 0.39; 95% CI, 0.20-0.78; p=0.008). We could confirm that children with FH provide a better model to perform genotype-phenotype analyses. In particular, children with null alleles had significantly more elevated LDL cholesterol levels than carriers of other alleles but this was not associated with higher risk of CVD in the parents. Nonetheless, a specific LDL receptor mutation was associated with less deteriorated lipoprotein levels and a milder CVD risk.

Rodenburg J, Wiegman A, Vissers MN, Kastelein JJ, Stalenhoef AF. · Department of Vascular Medicine (F4-159.2), Academic Medical Centre, University of Amsterdam, the Netherlands. · Neth J Med. · Pubmed #15209474 links to  free full text

Abstract: We describe a 9-year-old Iranian boy with tuberous xanthomas, elevated LDL-cholesterol levels of 15.5 mmol/l, and vague complaints of chest pain while playing soccer. The consanguineous parents of the boy had normal cholesterol concentrations, which indicated an autosomal recessive disorder rather than autosomal dominant familial hypercholesterolaemia. The diagnosis of autosomal recessive hypercholesterolaemia (ARH) was confirmed by the presence of a mutation in the phosphotyrosine binding domain of a putative adaptor protein, which prevents normal internalisation of the LDL receptor (LDLR) in the liver. The clinical phenotype of ARH is similar to that of classical homozygous familial hypercholesterolaemia caused by defects in the LDLR gene, but it is more variable, generally less severe, and more responsive to lipid-lowering therapy. The patient's complaints of chest pain were not caused by ischaemia as was tested by an exercise and 24-hour electrocardiogram and by a myocardial perfusion scan. His LDL-C dropped by about 6o% after being treated with a combination of 40 mg atorvastatin and 10 mg ezetimibe.

Wiegman A, de Groot E, Hutten BA, Rodenburg J, Gort J, Bakker HD, Sijbrands EJ, Kastelein JJ. · Department of Paediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands. · Lancet. · Pubmed #15070569 No free full text.

Abstract: 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.

Wiegman A, Rodenburg J, de Jongh S, Defesche JC, Bakker HD, Kastelein JJ, Sijbrands EJ. · Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. · Circulation. · Pubmed #12654602 links to  free full text

Abstract: 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.

Wiegman A, Sijbrands EJ, Rodenburg J, Defesche JC, de Jongh S, Bakker HD, Kastelein JJ. · Emma Children's Hospital/Academic Medical Center, University of Amsterdam, The Netherlands. · Pediatr Res. · Pubmed #12646733 No free full text.

Abstract: 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 epsilon4 allele had similar LDL and HDL cholesterol levels. Within the affected sib-pairs, the epsilon4 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 epsilon4 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.