Hyperlipidemias: Vissers MN

Huijgen R, Vissers MN, Defesche JC, Lansberg PJ, Kastelein JJ, Hutten BA. · Academic Medical Center, Department of Vascular Medicine, Meibergreef 9 (Room F4-146), 1105 AZ, Amsterdam, The Netherlands. · Expert Rev Cardiovasc Ther. · Pubmed #18402545 No free full text.

Abstract: Heterozygous familial hypercholesterolemia is associated with elevated levels of LDL-cholesterol and the development of premature cardiovascular disease. The condition is considerably under-diagnosed and under-treated. Statins are the first choice treatment for all patients with heterozygous familial hypercholesterolemia. For those patients who do not reach their treatment target or who are unable to use adequate statin dose, several alternative treatment modalities can be used, either as add-on therapy or as monotherapy. In this review the various treatment options are discussed.

Avis HJ, Vissers MN, Stein EA, Wijburg FA, Trip MD, Kastelein JJ, Hutten BA. · Academic Medical Centre, Department of Vascular Medicine, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Arterioscler Thromb Vasc Biol. · Pubmed #17569881 links to  free full text

Abstract: OBJECTIVE: Functional and morphological changes of the arterial wall already present in young children with heterozygous familial hypercholesterolemia (HeFH) suggest that treatment should be initiated early in life to prevent premature atherosclerotic cardiovascular disease. The purpose of this study was to assess the efficacy and particularly safety of statin therapy in children with HeFH. METHODS AND RESULTS: We performed a meta-analysis of randomized, double-blind, placebo-controlled trials evaluating statin therapy in children aged 8 to 18 years with HeFH. Six studies (n=798 children) with 12 to 104 weeks of treatment were included. Total cholesterol, LDL cholesterol, and apolipoprotein B were significantly reduced, whereas HDL cholesterol and apolipoprotein A1 were significantly increased by statin therapy. No statistically significant differences were found between statin- and placebo-treated children with respect to the occurrence of adverse events (RR 0.99; 95% CI: 0.79 to 1.25), sexual development (RR of advancing > or = 1 stage in Tanner classification 0.96; 95% CI: 0.79 to 1.17), muscle toxicity (RR of CK > or = 10 times the upper limit of normal [ULN] 1.38; 95% CI: 0.18 to 10.82), or liver toxicity (RR of > or = 3 times the ULN for ASAT 0.98; 95% CI: 0.23 to 4.26 and for ALAT 2.03; 95% CI: 0.24 to 16.95). We found a minimal difference in growth in favor of the statin group (0.33 cm; 95% CI: 0.03 cm to 0.63 cm). CONCLUSION: In addition to the fact that statin treatment is efficacious, our results support the notion that statin treatment in children with HeFH is safe. Thus, even though further studies are required to assess lifelong safety, statin treatment should be considered for all children aged 8 to 18 with HeFH.

van der Graaf A, Hutten BA, Kastelein JJ, Vissers MN. · Academic Medical Centre, Dept.Vascular Medicine, Meibergdreef 9 (room F4-159.2) 1105 AZ, Amsterdam, The Netherlands. · Expert Rev Cardiovasc Ther. · Pubmed #16716095 No free full text.

Abstract: Heterozygous familial hypercholesterolemia is associated with elevated low-density lipoprotein cholesterol levels and the development of premature cardiovascular disease. Despite this general statement, data regarding the incidence of cardiovascular disease in young women with familial hypercholesterolemia are lacking. In this review, information of age-specific incidence, risk factors and therapeutic avenues in women with heterozygous familial hypercholesterolemia are discussed.

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 Jongh S, Vissers MN, Rol P, Bakker HD, Kastelein JJ, Stroes ES. · Department of Vascular Medicine, Academic Medical Center Amsterdam, The Netherlands. · J Inherit Metab Dis. · Pubmed #12971422 No free full text.

Abstract: In adults with familial hypercholesterolaemia (FH), cholesterol lowering with statins has been shown to improve the endothelial function, a hallmark of early atherogenesis. Currently, therapeutic options for treating high cholesterol levels in FH children are limited. Plant sterols safely and effectively reduce serum cholesterol concentrations by inhibiting cholesterol absorption. Therefore, we evaluated the effect of plant sterols on cholesterol and vascular function in prepubertal children with FH. We included 41 children (5-12 years old) with FH in a double-blind crossover trial using spreads containing 2.3 g of plant sterols (mainly sitosterol and campesterol) per 15 g spread and a placebo spread for a 4-week period, separated by a 6-week washout period. Lipid levels and endothelial function were assessed after both 4-week treatment periods. Endothelial function was assessed as flow-mediated dilation (FMD) of the brachial artery using a wall tracking system. Data were compared to those of 20 healthy controls. Intake of 2.3 g plant sterols per day decreased total cholesterol (-11%) and low-density cholesterol (-14%) as compared to placebo spread in FH children. FH children treated with placebo spread were characterized by an impaired FMD compared to healthy control children (7.2% +/- 3.4% versus 10.1% +/- 4.2%, p < 0.005). However, the reduction of LDL in FH children did not improve FMD (placebo: 7.2% +/- 3.4% versus plant sterols: 7.7% +/- 4.1%). In conclusion, the present study shows a clear reduction of LDL cholesterol by plant sterol treatment. However, short-term plant sterol treatment does not improve the endothelial function in FH children.

van der Graaf A, Cuffie-Jackson C, Vissers MN, Trip MD, Gagné C, Shi G, Veltri E, Avis HJ, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. · J Am Coll Cardiol. · Pubmed #18940534 No free full text.

Abstract: OBJECTIVES: The study evaluated the efficacy and safety of long-term coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia (HeFH). BACKGROUND: Aggressive intervention to achieve lipid goals for adolescents with HeFH is recommended to reduce risk of premature cardiovascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled study, 248 male and female subjects ages >or=10 and <or=17 years with HeFH were randomized to receive: step 1: simvastatin 10, 20, or 40 mg/day plus ezetimibe 10 mg/day or placebo for 6 weeks, followed by step 2: simvastatin 40 mg/day plus ezetimibe 10 mg/day or placebo for 27 weeks; followed by step 3: all subjects received open-label simvastatin 10 or 20 mg/day (titrated to maximum 40 mg/day) plus ezetimibe 10 mg/day for 20 weeks. Safety was assessed throughout the study. RESULTS: Coadministered ezetimibe and simvastatin for 6 weeks (step 1) resulted in significantly greater mean reduction in low-density lipoprotein cholesterol (LDL-C) from baseline (49.5%) compared with simvastatin monotherapy (34.4%; p < 0.01) in pooled dose groups and in individual dose groups (46.7% vs. 30.4%, 49.5% vs. 34.3%, 52.1% vs. 38.6%, respectively; p < 0.01). At 33 weeks (step 2), ezetimibe-simvastatin subjects had a mean 54.0% reduction in LDL-C compared with a mean 38.1% reduction in simvastatin monotherapy subjects (p < 0.01). At 53 weeks (step 3), the pooled reduction in LDL-C was 49.1%. All treatment regimens were well tolerated throughout 53 weeks. CONCLUSIONS: Coadministration of ezetimibe with simvastatin was safe, well tolerated, and provided higher LDL-C reduction compared with simvastatin alone in adolescents with HeFH studied up to 53 weeks. (Effects of Ezetimibe With Simvastatin in the Therapy of Adolescents With Heterozygous Familial Hypercholesterolemia; NCT00129402).

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.

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.

Bouhali T, Brisson D, St-Pierre J, Tremblay G, Perron P, Laprise C, Vohl MC, Vissers MN, Hutten BA, Després JP, Kastelein JJ, Gaudet D. · Lipid Research Group and University of Montreal Community Genomic Medicine Center, Université de Montréal, Chicoutimi Hospital, 305 St. Vallier, Chicoutimi, Quebec G7H 5H6, Canada. · Atherosclerosis. · Pubmed #17123536 No free full text.

Abstract: Familial hypercholesterolemia (FH) is characterized by increased risk for premature coronary artery disease (CAD). This risk is exacerbated in the presence of abdominal obesity and insulin resistance. Low adiponectin is part of the clustering of metabolic abnormalities associated with abdominal obesity and insulin resistance. The present study, therefore, aims to examine the relationship between plasma adiponectin and age at CAD diagnosis in FH patients. Plasma adiponectin was measured by ELISA in 568 non-diabetic FH individuals of French-Canadian origin. CAD was defined according to strict clinical criteria. Prior to analyses, patients were grouped according to age and gender-specific tertiles of plasma adiponectin levels. Multivariate Cox proportional hazards regression was used to estimate the association between plasma adiponectin levels and age at diagnosis of CAD. Overall, FH patients in the lowest tertile of plasma adiponectin exhibited CAD at a significantly younger age (hazard ratio=1.73, confidence interval 95%: [1.19-2.53]; p=0.004). These results suggest that low plasma adiponectin is associated with an increased risk of premature CAD over and above the already exaggerated risk seen in FH patients.

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.

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.