Common genetic variants do not associate with CAD in familial hypercholesterolemia.

In recent years, multiple loci dispersed on the genome have been shown to be associated with coronary artery disease (CAD). We investigated whether these common genetic variants also hold value for CAD prediction in a large cohort of patients with familial hypercholesterolemia (FH). We genotyped a total of 41 single-nucleotide polymorphisms (SNPs) in 1701 FH patients, of whom 482 patients (28.3%) had at least one coronary event during an average follow up of 66 years. The association of each SNP with event-free survival time was calculated with a Cox proportional hazard model. In the cardiovascular disease risk factor adjusted analysis, the most significant SNP was rs1122608:G>T in the SMARCA4 gene near the LDL-receptor (LDLR) gene, with a hazard ratio for CAD risk of 0.74 (95% CI 0.49-0.99; P-value 0.021). However, none of the SNPs reached the Bonferroni threshold. Of all the known CAD loci analyzed, the SMARCA4 locus near the LDLR had the strongest negative association with CAD in this high-risk FH cohort. The effect is contrary to what was expected. None of the other loci showed association with CAD.

Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial.

AIMS: A randomized, double-blind, placebo-controlled study was conducted to investigate the safety and efficacy of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, in patients who are statin intolerant and at high risk for cardiovascular disease (CVD). METHODS AND RESULTS: Thirty-three subjects, not receiving statin therapy because of statin intolerance, received a weekly subcutaneous dose of 200 mg mipomersen or placebo (2:1 randomization) for 26 weeks. The primary endpoint was per cent change in LDL cholesterol (LDL-c) from the baseline to Week 28. The other efficacy endpoints were per cent change in apoB and lipoprotein a [Lp(a)]. Safety was determined using the incidence of treatment-emergent adverse events (AEs) and clinical laboratory evaluations. After 26 weeks of mipomersen administration, LDL-c was reduced by 47 ± 18% (P < 0.001 vs. placebo). apoB and Lp(a) were also significantly reduced by 46 and 27%, respectively (P < 0.001 vs. placebo). Four mipomersen (19%) and two placebo subjects (17%) discontinued dosing prematurely due to AEs. Persistent liver transaminase increases ≥ 3× the upper limit of normal were observed in seven (33%) subjects assigned to mipomersen. In selected subjects, liver fat content was assessed, during and after treatment, using magnetic resonance spectroscopy. Liver fat content in these patients ranged from 0.8 to 47.3%. Liver needle biopsy was performed in two of these subjects, confirming hepatic steatosis with minimal inflammation or fibrosis. CONCLUSION: The present data suggest that mipomersen is a potential therapeutic option in statin-intolerant patients at high risk for CVD. The long-term follow-up of liver safety is required. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00707746.

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

BACKGROUND: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. METHODS: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. FINDINGS: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. INTERPRETATION: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. FUNDING: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

Monocyte gene expression signature of patients with early onset coronary artery disease.

The burden of cardiovascular disease (CVD) cannot be fully addressed by therapy targeting known pathophysiological pathways. Even with stringent control of all risk factors CVD events are only diminished by half. A number of additional pathways probably play a role in the development of CVD and might serve as novel therapeutic targets. Genome wide expression studies represent a powerful tool to identify such novel pathways. We compared the expression profiles in monocytes from twenty two young male patients with premature familial CAD with those from controls matched for age, sex and smoking status, without a family history of CVD. Since all patients were on statins and aspirin treatment, potentially affecting the expression of genes in monocytes, twelve controls were subsequently treated with simvastatin and aspirin for 6 and 2 weeks, respectively. By whole genome expression arrays six genes were identified to have differential expression in the monocytes of patients versus controls; ABCA1, ABCG1 and RGS1 were downregulated in patients, whereas ADRB2, FOLR3 and GSTM1 were upregulated. Differential expression of all genes, apart from GSTM1, was confirmed by qPCR. Aspirin and statins altered gene expression of ABCG1 and ADBR2. All finding were validated in a second group of twenty four patients and controls. Differential expression of ABCA1, RSG1 and ADBR2 was replicated. In conclusion, we identified these 3 genes to be expressed differently in CAD cases which might play a role in the pathogenesis of atherosclerotic vascular disease.

Maps of open chromatin guide the functional follow-up of genome-wide association signals: application to hematological traits.

Turning genetic discoveries identified in genome-wide association (GWA) studies into biological mechanisms is an important challenge in human genetics. Many GWA signals map outside exons, suggesting that the associated variants may lie within regulatory regions. We applied the formaldehyde-assisted isolation of regulatory elements (FAIRE) method in a megakaryocytic and an erythroblastoid cell line to map active regulatory elements at known loci associated with hematological quantitative traits, coronary artery disease, and myocardial infarction. We showed that the two cell types exhibit distinct patterns of open chromatin and that cell-specific open chromatin can guide the finding of functional variants. We identified an open chromatin region at chromosome 7q22.3 in megakaryocytes but not erythroblasts, which harbors the common non-coding sequence variant rs342293 known to be associated with platelet volume and function. Resequencing of this open chromatin region in 643 individuals provided strong evidence that rs342293 is the only putative causative variant in this region. We demonstrated that the C- and G-alleles differentially bind the transcription factor EVI1 affecting PIK3CG gene expression in platelets and macrophages. A protein-protein interaction network including up- and down-regulated genes in Pik3cg knockout mice indicated that PIK3CG is associated with gene pathways with an established role in platelet membrane biogenesis and thrombus formation. Thus, rs342293 is the functional common variant at this locus; to the best of our knowledge this is the first such variant to be elucidated among the known platelet quantitative trait loci (QTLs). Our data suggested a molecular mechanism by which a non-coding GWA index SNP modulates platelet phenotype.

Assessment of carotid atherosclerosis in normocholesterolemic individuals with proven mutations in the low-density lipoprotein receptor or apolipoprotein B genes.

BACKGROUND: Genetic cascade screening for heterozygous familial hypercholesterolemia (FH) revealed that 15% of individuals given this diagnosis do not exhibit elevated low-density lipoprotein cholesterol (LDL-C) levels. We assessed whether cardiovascular risk for these individuals differs from that of hypercholesterolemic FH heterozygotes and unaffected relatives. METHODS AND RESULTS: Individuals aged 18 to 55 years were recruited within 18 months after genetic screening. Three groups were studied: subjects given a molecular diagnosis of FH and with LDL-C levels at genetic screening below the 75th percentile (FH-low), subjects with FH and an LDL-C level above the 90th percentile (FH-high), and subjects without FH (no-FH). We measured carotid intima-media thickness (IMT) by ultrasonography. Differences in carotid IMT among the groups were assessed using multivariate linear regression analyses. Mean carotid IMT of 114 subjects in the FH-low group (0.623 mm; 95% CI, 0.609 to 0.638 mm) was significantly smaller than that of 162 subjects in the FH-high group (0.664 mm; 95% CI, 0.648 to 0.679 mm; P<0.001) and did not significantly differ from the mean carotid IMT in 145 subjects in the no-FH group (0.628 mm; 95% CI, 0.613 to 0.642 mm; P=0.67). CONCLUSIONS: Our findings suggest that the risk of cardiovascular disease in patients with FH to a large extent is related to LDL-C levels and not to the presence of a mutation per se. Consequently, this study cautiously suggests that individuals with an FH genotype without expression of hypercholesterolemia may not require a pharmaceutical intervention that is as aggressive as the standard for subjects with FH.

Family history of premature coronary heart disease and risk prediction in the EPIC-Norfolk prospective population study.

OBJECTIVE: The value of a family history for coronary heart disease (CHD) in addition to established cardiovascular risk factors in predicting an individual's risk of CHD is unclear. In the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort, the authors tested whether adding family history of premature CHD in first-degree relatives improves risk prediction compared with the Framingham risk score (FRS) alone. METHODS AND RESULTS: This study comprised 10,288 men and 12,553 women aged 40-79 years participating in the EPIC-Norfolk cohort who were followed for a mean of 10.9±2.1 years (mean±SD). The authors computed the FRS as well as a modified score taking into account family history of premature CHD. A family history of CHD was indeed associated with an increased risk of future CHD, independent of established risk factors (FRS-adjusted HR of 1.74 (95% CI 1.56 to 1.95) for family history of premature CHD). However, adding family history of CHD to the FRS resulted in a negative net reclassification of 2%. In the subgroup of individuals estimated to be at intermediate risk, family history of premature CHD resulted in an increase in net reclassification of 2%. The sensitivity increased with 0.4%, and the specificity decreased 0.8%. CONCLUSION: Although family history of CHD was an independent risk factor of future CHD, its use did not improve classification of individuals into clinically relevant risk categories based on the FRS. Among study participants at intermediate risk of CHD, adding family history of premature CHD resulted in, at best, a modest improvement in reclassification of individuals into a more accurate risk category.

Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function.

Within the healthy population, there is substantial, heritable, and interindividual variability in the platelet response. We explored whether a proportion of this variability could be accounted for by interindividual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 subjects representing the normal range of platelet responsiveness within a cohort of 500 subjects, we identified 63 genes in which transcript levels correlated with variation in the platelet response to adenosine diphosphate and/or the collagen-mimetic peptide, cross-linked collagen-related peptide. Many of these encode proteins with no reported function in platelets. An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypo thesis for LRRFIP1 [leucine-rich repeat (in FLII) interacting protein 1]. Morpholino-based silencing in Danio rerio identified a modest role for commd7 and a significant effect for lrrfip1 as positive regulators of thrombus formation. Proteomic analysis of human platelet LRRFIP1-interacting proteins indicated that LRRFIP1 functions as a component of the platelet cytoskeleton, where it interacts with the actin-remodeling proteins Flightless-1 and Drebrin. Taken together, these data reveal novel proteins regulating the platelet response.

Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia.

To investigate the impact of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, on intra-hepatic triglyceride content (IHTG content), we conducted a randomized, double-blind, placebo-controlled study in 21 patients with familial hypercholesterolemia (FH). Subjects received a weekly subcutaneous dose of 200 mg mipomersen or placebo for 13 weeks while continuing conventional lipid lowering therapy. The primary endpoint was change in IHTG content from week 0 to week 15 as measured by localized proton magnetic resonance spectroscopy (1H-MRS). Thirteen weeks of mipomersen administration reduced LDL-cholesterol by 22.0 (17.8) % and apoB by 19.9 (17.4) % (both P < 0.01). One of 10 patients (10%) in the mipomersen-treated group developed mild hepatic steatosis at week 15, which was reversible following mipomersen discontinuation. For the group, there was a trend toward an increase in IHTG content [placebo; baseline: 1.2% and week 15: 1.1%; change -0.1 (0.9). Mipomersen; baseline: 1.2% and week 15: 2.1%; change 0.8 (1.7) (P = 0.0513)]. Mipomersen administration for 13 weeks to subjects with FH is associated with a trend toward an increase in IHTG content. Future studies evaluating the effects of long-term use of mipomersen reaching more profound reductions in apoB are required prior to broader use of this compound.

ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia: the CAPTIVATE randomized trial.

CONTEXT: Inhibition of acyl coenzyme A:cholesterol acyltransferase (ACAT), an intracellular enzyme involved in cholesterol accumulation, with pactimibe was developed to assist in the prevention of cardiovascular disease. OBJECTIVE: To evaluate the efficacy and safety of pactimibe in inhibition of atherosclerosis. DESIGN, SETTING, AND PATIENTS: A prospective, randomized, stratified, double-blind, placebo-controlled study (Carotid Atherosclerosis Progression Trial Investigating Vascular ACAT Inhibition Treatment Effects [CAPTIVATE]) of 892 patients heterozygous for familial hypercholesterolemia conducted at 40 lipid clinics in the United States, Canada, Europe, South Africa, and Israel between February 1, 2004, and December 31, 2005. Study was terminated on October 26, 2005. INTERVENTION: Participants received either 100 mg/d of pactimibe (n = 443) or matching placebo (n = 438), in addition to standard lipid-lowering therapy. MAIN OUTCOME MEASURES: Carotid atherosclerosis, assessed by ultrasound carotid intima-media thickness (CIMT), at baseline, 12, 18, and 24 months. Maximum CIMT was the primary end point and mean CIMT the secondary end point. RESULTS: Because pactimibe failed to show efficacy in the intravascular coronary ultrasound ACTIVATE study, the CAPTIVATE study was terminated prematurely after a follow-up of 15 months. After 6 months of treatment with pactimibe, low-density lipoprotein cholesterol increased by 7.3% (SD, 23%) compared with 1.4% (SD, 28%) in the placebo group (P = .001). The carotid ultrasonographic scans of the 716 patients with at least 2 scans and obtained at least 40 weeks apart were analyzed. Maximum CIMT measurements did not show a pactimibe treatment effect (difference, 0.004 mm; 95% confidence interval [CI], -0.023 to 0.015 mm; P = .64); however, the less variable mean CIMT measurement revealed an increase of 0.014 mm (95% CI, -0.027 to 0.000 mm; P = .04) in patients administered pactimibe vs placebo. Major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) occurred more often in patients administered pactimibe vs placebo (10/443 [2.3%] vs 1/438 [0.2%]; P = .01). CONCLUSIONS: In patients with familial hypercholesterolemia, pactimibe had no effect on atherosclerosis as assessed by changes in maximum CIMT compared with placebo but was associated with an increase in mean CIMT as well as increased incidence of major cardiovascular events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00151788.

Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia.

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

Diabetes mellitus type 2 is associated with higher levels of myeloperoxidase.

BACKGROUND: Diabetes mellitus type 2 is linked to augmented endothelial dysfunction and accelerated atherosclerosis. Myeloperoxidase plays an important role in the initiation, progression, and the complications of atherosclerosis. We investigated whether myeloperoxidase levels are increased in diabetic patients. MATERIAL/METHODS: We compared baseline plasma myeloperoxidase levels in diabetic and nondiabetic patients with mild, stable anginal complaints (Canadian Cardiovascular Society I-II/IV) and performed multivariate linear regression analyses to adjust for possible confounding factors. RESULTS: A total of 440 patients were recruited from the outpatient clinic of cardiology, 268 patients with and 172 without diabetes mellitus type 2. Levels of myeloperoxidase were significantly higher in diabetic patients (median, 141 pM; interquartile range, 115-171 pM) than in nondiabetic patients (median, 126 pM; interquartile range, 105-167 pM) (P=0.01). Diabetes mellitus type 2, age in years, current smoking status, presence of hypercholesterolemia, and use of calcium antagonists and ACE inhibitors were associated with logarithmically transformed myeloperoxidase levels. Of these variables, diabetes mellitus type 2 (beta 0.096, SE 0.038, P=0.01); age (beta 0.01, SE 0.002, P<0.001), and current smoking (beta 0.166, SE 0.05, P=0.001) remained independently associated with myeloperoxidase levels in multivariate analysis. The linear regression coefficient of diabetes mellitus type 2 in relation to myeloperoxidase was 0.092 in univariate linear regression and 0.078 after adjusting for age, current smoking, and use of ACE inhibitors and calcium antagonists. CONCLUSIONS: Diabetes mellitus type 2 is associated with mildly increased levels of myeloperoxidase, independent of other clinical variables. This association may contribute to the accelerated progression of atherosclerosis in diabetics.

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.

Simvastatin with or without ezetimibe in familial hypercholesterolemia.

BACKGROUND: Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown. METHODS: We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries. RESULTS: The primary outcome, the mean (+/-SE) change in the carotid-artery intima-media thickness, was 0.0058+/-0.0037 mm in the simvastatin-only group and 0.0111+/-0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol level was 192.7+/-60.3 mg per deciliter (4.98+/-1.56 mmol per liter) in the simvastatin group and 141.3+/-52.6 mg per deciliter (3.65+/-1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups. CONCLUSIONS: In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097 [ClinicalTrials.gov].).

Myeloperoxidase levels are not associated with carotid atherosclerosis progression in patients with familial hypercholesterolemia.

INTRODUCTION: Myeloperoxidase (MPO), an antimicrobial enzyme of the innate immune system, has been proposed to exert a wide array of pro-atherogenic effects throughout all stages of the atherosclerotic process. In view of the potent anti-inflammatory effects of statins in vitro, we evaluated the impact of statin therapy on plasma MPO levels in patients with heterozygous familial hypercholesterolemia (FH), treated with either intensive or conventional lipid-lowering therapy. Furthermore, we evaluated the relation between MPO levels and atherosclerosis progression, as determined by intima media thickness (IMT). METHODS: We measured plasma MPO levels, lipoprotein profiles, high sensitivity-C-reactive protein (hs-CRP) as well as IMT of carotid artery segments in 122 FH patients at baseline and after 2-year treatment with atorvastatin 80 mg or simvastatin 40 mg QD. RESULTS: Baseline median MPO values were 147pM (interquartile range (IQR) 122-217) and 144pM (IQR 118-216) and these increased significantly to 221pM (IQR 144-290) and 255pM (IQR 152-324) during 2-year follow-up in both the atorvastatin 80 mg and simvastatin 40 mg group, respectively. There was no correlation between MPO levels and IMT progression, change in lipoproteins or hs-CRP. CONCLUSION: In FH patients, statins do not prevent an increase in MPO levels during follow-up. Moreover, MPO levels are not associated with atherosclerosis progression in these patients.

Diagnosing familial hypercholesterolaemia: the relevance of genetic testing.

AIMS: We assembled a cohort of patients with familial hypercholesterolaemia (FH) for both basic and clinical research. We used a set of established diagnostic criteria to define FH. Some put forward that a definite diagnosis of FH is made when a mutation in the LDL-receptor (LDLR) gene is identified. We therefore set out to determine in these patients whether patients with a DNA diagnosis would differ significantly from those diagnosed clinically. METHODS AND RESULTS: We randomly selected 4000 hypercholesterolaemic patients from the Dutch Lipid Clinic network database. Phenotypical data were acquired by reviewing medical records. After review of medical records, 2400 patients could be defined as having FH. An LDLR mutation was identified in 52.3% of these patients. Patients with and without an LDLR mutation demonstrated different clinical and laboratory characteristics. Low-density lipoprotein cholesterol was higher in patients with an LDLR mutation, whereas triglycerides were higher in patients without an LDLR mutation. The phenotypic differences between the groups remained even after stratification for the presence or absence of tendon xanthomas. CONCLUSION: Despite the use of stringent clinical criteria to define FH patients, two cohorts could be identified within our study population, namely those patients with and those without an LDLR mutation. Our findings suggest that among those without an LDLR mutation, patients with other causes of dyslipidaemia may be present. These observations underline the relevance of genetic testing in FH for clinical practice, for screening purposes, and for research involving these patients.

Plant stanols do not restore endothelial function in pre-pubertal children with familial hypercholesterolemia despite reduction of low-density lipoprotein cholesterol levels.

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.

Long-term safety and efficacy of high-dose atorvastatin treatment in patients with familial hypercholesterolemia.

In the 2-year Atorvastatin versus Simvastatin on Atherosclerosis Progression extension study, patients with familial hypercholesterolemia who continued to take atorvastatin 80 mg for an additional 2 years had complete arrest of the progression of mean carotid intima-media thickness (0.89 mm at the start vs 0.90 mm at the end of the study, p = 0.58). In contrast, patients previously taking simvastatin 40 mg had significant regression of intima-media thickness (0.95 mm at the start vs 0.92 mm at the end of the study, p = 0.01). Therefore, both placebo- and statin-treated patients with familial hypercholesterolemia are best treated with high-dose atorvastatin, a therapeutic regimen that induces atherosclerosis regression and is safe and well tolerated over a 4-year period.

Regression of carotid and femoral artery intima-media thickness in familial hypercholesterolemia: treatment with simvastatin.

OBJECTIVE: To investigate whether high-dose simvastatin therapy could reduce carotid and femoral artery intima-media thickness (IMT) in patients with familial hypercholesterolemia (FH) to prevent cardiovascular disease. BACKGROUND: Imaging of arterial walls with B-mode ultrasonography is increasingly used as a noninvasive surrogate marker of cardiovascular disease. Intervention trials using this modality have shown that by reducing risk factors, progression of atherosclerosis was inhibited. METHODS: After a washout period of 6 weeks, all patients with FH started monotherapy with simvastatin, 80 mg/d, for 2 years. The primary end point was the change (in millimeters) of the mean combined far-wall IMT of predefined carotid and femoral arterial segments at 2 years. RESULTS: We included a total of 153 patients with FH. Mean +/- SD combined baseline IMT was 1.07 +/- 0.23 mm. After treatment with simvastatin for 2 years, this IMT decreased by a mean of 0.081 mm (95% confidence interval, -0.109 to -0.053; P<.001), with its largest reduction in the femoral artery (-0.283 mm; P<.001). An actual decrease of combined IMT was seen in 69.8% of all patients. CONCLUSIONS: High-dose simvastatin therapy reduces arterial wall IMT in more than two thirds of the patients, with its largest effect on the femoral artery. Furthermore, patients with FH who were treated with both statin and antihypertensive medication experienced a significantly greater benefit in terms of IMT reduction.