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Importance: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH., Observations: In 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created., Conclusions and Relevance: By adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well.

Objective: The primary objective was to study the risk of acute myocardial infarction (AMI) and coronary heart disease (CHD) in patients with familial hypercholesterolaemia (FH) and compare with the risk in the general population., Methods: Patients with an FH mutation but without prior AMI (n=3071) and without prior CHD (n=2795) were included in the study sample during 2001-2009. We obtained data on all AMI and CHD hospitalisations in Norway. We defined incident cases as first time hospitalisation or out-of-hospital death due to AMI or CHD. We estimated standardised incidence ratios (SIRs) with 95% CIs with indirect standardisation using incidence rates for the total Norwegian population stratified by sex, calendar year and 1 year age groups as reference rates., Results: SIRs for AMI (95% CIs) were highest in the age group 25-39 years; 7.5 (3.7 to 14.9) in men and 13.6 (5.1 to 36.2) in women and decreased with age to 0.9 (0.4 to 2.1) in men and 1.8 (0.9 to 3.7) in women aged 70-79 years. Similarly, SIRs for CHD were highest among patients 25-39 years old; 11.1 (7.1-17.5) in men and 17.3 (9.6-31.2) in women and decreased 2.4 (1.4-4.2) in men and 3.2 (1.5-7.2) in women at age 70-79. For all age groups, combined SIRs for CHD were 4.2 (3.6-5.0) in men and 4.7 (3.9-5.7) in women., Conclusion: Patients with FH are at severely increased risk of AMI and CHD compared with the general population. The highest excess risk was in the youngest group aged 25-39 years, in both sexes., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background Patients with familial hypercholesterolemia have increased cardiovascular disease mortality but the magnitude of the increased risk is uncertain. The primary aim of this study was to investigate all causes of death and place and manner of deaths in a large sample of genotyped familial hypercholesterolemia patients. Design, methods and results In this registry study data on 5518 patients with genotyped familial hypercholesterolemia were linked to the Norwegian Cause of Death Registry during 1992-2013. Standardized mortality ratios and 95% confidence intervals (CIs) were estimated. There were in total 189 deaths. Cardiovascular disease was the most common cause of death (42.3%). Mean age at cardiovascular disease death was 64.5 years (range 33-91). Cardiovascular disease mortality including all cardiovascular disease deaths mentioning any place on the death certificate was significantly higher in familial hypercholesterolemia patients compared to the general Norwegian population under 70 years of age. Standardized mortality ratio (95% CI) was highest in the 20-39 years age group; 4.12 (1.85-9.18) decreasing to 0.77 (0.50-1.19) for those over 80 years. For total cardiovascular disease deaths occurring out of hospital, standardized mortality ratio was 12.35 (5.14-29.70) for those aged 20-39 years. Conclusion Familial hypercholesterolemia patients under 70 years of age have significantly higher cardiovascular disease mortality compared to the general Norwegian population. For those aged 20-39 years the risk of cardiovascular disease deaths occurring out of hospital was increased 12-fold. In spite of genotyped familial hypercholesterolemia and premature cardiovascular disease deaths, the majority of all death certificates did not include familial hypercholesterolemia among any of the contributing causes of death.

Background Familial hypercholesterolaemia increases the risk for cardiovascular disease. The primary aim of the present study was to describe sex differences in incidence and prevalence of cardiovascular disease leading to hospitalisation in a complete cohort of genotyped familial hypercholesterolaemia patients. Design and methods In this registry study data on 5538 patients with verified genotyped familial hypercholesterolaemia were linked to data on all Norwegian cardiovascular disease hospitalisations, and hospitalisations due to pre-eclampsia/eclampsia, congenital heart defects and diabetes. Results During 1994-2009 a total of 1411 of familial hypercholesterolaemia patients were hospitalised, and ischaemic heart disease was reported in 90% of them. Mean (SD) age at first hospitalisation and first re-hospitalisation was 45.1 (16.5) and 47.6 (16.3) years, respectively, with no sex differences ( P = 0.66 and P = 0.93, respectively). More men (26.9%) than women (24.1%) with familial hypercholesterolaemia were hospitalised ( P = 0.02). The median (25th-75th percentile) number of hospital admissions was four (two to seven) per familial hypercholesterolaemia patient, with no sex differences ( P = 0.87). Despite having familial hypercholesterolaemia at the time of hospitalisation, the diagnosis of familial hypercholesterolaemia was registered in only 45.7% of the patients at discharge. Conclusion Most cardiovascular disease hospitalisations were due to ischaemic heart disease. Familial hypercholesterolaemia patients were first time hospitalised at age 45.1 years, with no significant sex differences in age, which are important novel findings. The awareness and registration of the familial hypercholesterolaemia diagnosis during the hospital stays were disturbingly low.

Background and Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Guidelines recommend cholesterol-lowering medication from 8 to 10 years of age and dietary recommendations. Little is known about the diet of FH children and the effect of dietary counseling. The aim of the study was to describe the diet of FH children with respect to fat quality, and to investigate if dietary counseling improved lipid profile., Methods: Fifty-four FH children (5-18 years) were included in the study and dietary intake was recorded with a pre-coded food diary for four days. Information about plasma lipid levels was obtained., Results: Median intake of total fat, monounsaturated fat, polyunsaturated fat (PUFA) and saturated fat (SFA) was 30.8, 10.4, 5.9 and 12.0 E %, respectively. Among non-statin treated FH children, SFA intake was significantly correlated with TC, LDL-C and apolipoprotein (apo) B (rsp = 0.55; p = 0.004, rsp = 0.46; p = 0.02, and rsp = 0.45; p = 0.02, respectively), and PUFA/SFA ratio significantly inversely correlated with TC (rsp = -0.42; p = 0.03). Compared to the first visit, non-statin and non-plant sterol treated FH children (n = 10) had significantly reduced levels of TC (p < 0.01), LDL-C (p = 0.01), high-density lipoprotein cholesterol (p = 0.02), apo B (p = 0.05) and apo A-1 (p = 0.02) levels at a later visit., Conclusions: FH children had a higher intake of SFA than recommended and the SFA intake was positively correlated with plasma TC, LDL-C and apo B levels in FH children not using statins. Importantly, the plasma lipid profile was improved in FH children after dietary counseling where focus was on reducing intake of SFA and dietary cholesterol., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: Pregnancy exerts metabolic changes with increasing levels of total cholesterol and triglycerides as prominent features. Maternal hypercholesterolemia may thus contribute to an unfavorable in utero environment potentially influencing the susceptibility of adult cardiovascular disease in the offspring. We investigated the impact of maternal familial hypercholesterolemia (FH) on pre-treatment plasma lipids and C-reactive protein (CRP) levels in non-statin treated FH children., Methods: Children with FH (n = 1063) aged between 0 and 19 years were included. Of these, 500 had inherited FH maternally, 563 paternally and 97.6% had a verified FH mutation. Information about inheritance, mutation type and pretreatment levels of blood lipids and CRP was retrieved from the medical records., Results: There were no significant differences in the plasma levels of lipids and C-reactive protein (CRP) in children with maternal FH compared with children with paternal FH, (0.12 ≤ P ≤ 0.90). Independent of which parent transmitted FH, children with LDL receptor negative mutations had significantly higher levels of total and LDL cholesterol and Apolipoprotein (Apo) B, and lower levels of HDL cholesterol and ApoA1, compared with children with other LDL receptor mutations (P < 0.001)., Conclusion: Maternal inheritance of FH was not associated with detectable long-term effects in the offspring's phenotype measured by adverse lipid profiles and increased CRP levels, whereas a LDL receptor negative mutation was associated with an unfavorably phenotype in FH offspring. Our findings do not support the fetal origin of adulthood disease hypothesis, while at the same time not excluding the hypothesis since other pathways leading to atherosclerosis may be involved., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: There are little long-term data on patients with familial hypercholesterolemia (FH) who initiated lipid-lowering therapy during childhood., Objective: To study long-term outcomes in young adults with FH who participated in clinical trials on lipid-lowering therapy during childhood., Methods: Participants in at least 1 of 6 clinical trials that took place between 1999 and 2008 were interviewed in 2011 or 2013. Frequency of medical consultations, use of lipid-lowering therapy, lipid levels, side effects, diet, tobacco use, and emotional issues were investigated using information from interviews, blood samples and medical records., Results: Of the 118 individuals who participated in the trials, 67 (57%) were included. Median age was 25 years, and median time before follow-up was 10 years. Forty-eight (72%) participants were using statins at follow-up, 8 (12%) were also using ezetimibe, and 19 (28%) were not using any lipid-lowering therapy. Mean LDL-cholesterol (LDL-C) was 3.68 mmol/L in statin users and 6.08 mmol/L in non-users (P < .001). Only 6 (9%) participants reached treatment goal, ie, an LDL-C ≤2.5 mmol/L. Participants who attended a consultation ≤2 years before follow-up had a significantly lower LDL-C compared with those who had a consultation >2 years before follow-up (4.10 and 5.17 mmol/L, respectively; P = .02). Statin users had their last consultation more recently than non-users (median 1.4 and 2.2 years, respectively; P = .02)., Conclusions: Statins are underused in this population, and most patients have not reached treatment goal. Those with recent consultations had lower LDL-C levels and were more often statin users. Therefore, yearly consultations for young adults with FH seem warranted., (Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C ≥5 mmol/L (190 mg/dL), or an LDL-C ≥4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is ≥3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is <3.5 mmol/L (130 mg/dL) if >10 years, or ideally 50% reduction from baseline if 8-10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long-term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17,000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10(-4)). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.

Background: Untreated patients with familial hypercholesterolemia are at increased risk of premature cardiovascular death. The primary aim of this study was to investigate whether this is also the case in the statin era., Methods and Results: In this registry-based study, 4688 male and female patients from the Unit for Cardiac and Cardiovascular Genetics (UCCG) Registry with verified molecular genetic diagnosis of familial hypercholesterolemia in the period 1992-2010 were linked to the Norwegian Cause of Death Registry. Standardized mortality ratios and 95% CIs were estimated. There were 113 deaths. Mean age of death was 61.1 years. Cardiovascular disease was the most common cause of death (46.0%), followed by cancer (30.1%). Compared with the Norwegian population, cardiovascular disease mortality was significantly higher in the UCCG Registry in all age groups younger than 70 years (standardized mortality ratio 2.29, 95% CI 1.65 to 3.19 in men and women combined; standardized mortality ratio 2.00, 95% CI 1.32 to 3.04 in men; standardized mortality ratio 3.03, 95% CI 1.76 to 5.21 in women). No significant differences were found in all-cause mortality or cancer mortality., Conclusions: Despite prescription of lipid-lowering drugs, familial hypercholesterolemia patients still had significantly increased cardiovascular disease mortality compared with the general Norwegian population., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objective: Atherosclerosis is a multi-step process, where lipids, inflammatory and hemostatic mediators orchestrate plaque formation and progression, which subsequently may lead to myocardial infarction and ischemic stroke. Familial hypercholesterolemia (FH) is associated with increased risk of premature atherosclerosis due to the genetically determined elevated low density lipoprotein (LDL)-cholesterol seen in these individuals. Children with FH are suitable to investigate the isolated effect of elevated LDL-cholesterol on early markers of atherosclerosis. The aim of the present paper was to review the literature to summarize the findings of atherosclerotic markers in children with FH to better understand how elevated LDL-cholesterol per se promotes atherogenesis., Methods: We conducted a systematic literature search from the years 1990-2013, resulting in identification of 903 articles. In order to investigate whether intima-media thickness (IMT) is different in children with and without FH, we conducted a meta-analysis of the studies comparing FH children with a control group., Results: 37 original articles were included. Among these, 24 reported subclinical measurements, whereas other articles reported measurements of atherogenic lipids (n = 9), inflammatory markers (n = 10), hemostatic markers (n = 6) and other surrogate markers of atherosclerosis (n = 7). In the meta-analysis (n = 8), IMT was significantly thicker in children with FH than in control children (weighted mean difference 0.06, 95% confidence interval [0.01, 0.11])., Conclusion: Elevated LDL-cholesterol distinguishes children with and without FH, but these groups of children also differ in several other ways. In particular, children with FH display a variety of changes reflecting both the lipid and the inflammatory arm of atherosclerosis. The IMT-meta-analysis result strengthens the evidence of early atherosclerotic development in children with FH. In a clinical perspective, early diagnosing and treatment of children with FH is of high importance to attenuate development of the potential ongoing early atherosclerotic process in these individuals., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: The atherosclerotic process is driven by elevated Low-density lipoprotein (LDL)-cholesterol in combination with enhanced inflammatory responses. Several mediators participate in this complex inflammatory network including members of the tumour necrosis factor (receptor) superfamily. Familial hypercholesterolemia (FH) is associated with increased risk of developing premature atherosclerosis. Statin treatment may normalize LDL-cholesterol levels, but it is not known if the inflammatory responses are normalized in statin-treated FH patients., Methods: In long-term statin-treated FH subjects (n=33) and healthy controls (n=10) the expression of tumour necrosis factor (receptor) superfamily related genes in peripheral blood mononuclear cells (PBMC) were analyzed by real-time quantitative RT-PCR. TNFα release was measured in PBMC from patients and controls by immunoassay., Results: In FH patients with normal LDL-cholesterol, after a median of 17 years of statin treatment, our major findings were: (i) Gene expression of CD137, LIGHT (lymphotoxins inducible expression, competes with HSV glycoprotein D for HVEM, a receptor expressed on T-lymphocytes), HVEM (Herpesvirus entry mediator), the two TNFα Receptors (TNFR1 and TNFR2), TNF related apoptosis inducing ligand (TRAIL) and CD40 were increased in PBMC from FH patients compared to controls. (ii) The release of TNFα in PBMC from FH patients, in response to LPS was increased compared to controls. (iii) PBMC from FH patients had enhanced spontaneous release of TNFα when incubated in the presence of control serum and in particular in the presence of FH serum., Conclusion: Despite long-term statin therapy, an increased expression of several TNF related genes in PBMC isolated from FH patients was observed. Our findings may implicate a pathogenic role for inflammation and TNF related molecules in FH, and these findings suggest the possibility that novel treatment modalities beyond that of statins and lipid lowering drugs may be useful in FH subjects., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Familial hypercholesterolemia is an autosomal dominant disorder. Heterozygous familial hypercholesterolemia (FH) has an estimated incidence of 1 per 300-500 births and is characterized by increased serum total- and low-density lipoprotein-cholesterol levels and an increased risk of coronary heart disease. Early diagnosis and cholesterol-lowering treatment are essential to prevent premature coronary heart disease. Effective screening strategies are therefore of great importance. Screening can be done as selective or general population screening. There is no generally accepted screening program for FH in children and adolescents. In The Netherlands a systematic genetic family cascade screening program has been going on since 1994. In most countries there is no systematic screening for the disease, but clinical and genetic family cascade screening has been applied. Selective screening programs have failed to identify a large number of FH cases. Recommendations for general pediatric population screening have therefore emerged. Controversy exists as to which approach should be adopted. Family cascade screening has been estimated to be the most cost-effective screening method. No general pediatric screening program has been tested on a larger scale, validated or subjected to cost-benefit analyses.

Background: Homozygous familial hypercholesterolemia (FH) is a rare disorder that may affect 1 person per million. Early initiation of aggressive cholesterol-lowering therapy is essential to prevent premature coronary heart disease. Selective removal of low-density lipoprotein (LDL) by LDL apheresis is a reliable method of treatment., Methods and Results: Cholesterol efflux mediators of homozygous FH patients on weekly LDL apheresis were compared with those of age- and sex-matched heterozygous FH patients receiving oral medication only and with healthy control subjects. The data show that (1) compared with healthy controls, homozygous FH patients have significantly lower plasma levels of high-density lipoprotein cholesterol and apoA-I and significantly lower cholesterol-acceptor capacity of serum to promote cholesterol efflux from cholesterol-loaded THP-1 cells, combined with significantly lower peripheral blood mononuclear cell gene expression levels of ATP-binding cassette (ABC) transporter G1 and borderline-significantly lower levels of ABCA1 and scavenger receptor class B type I (SR-BI); and (2) compared with pre-LDL apheresis (a day before treatment), postapheresis (15 days later; on the day after the weekly treatment) levels of HDL cholesterol and apoA-I were significantly reduced, with no significant effect on cholesterol-acceptor capacity of serum or on peripheral blood mononuclear cell gene expression levels of the cellular transporters, except for a borderline-significant reduction in ABCA1 mRNA levels., Conclusions: The data showing decreased levels of cholesterol efflux mediators in plasma and cells may suggest that the overall cholesterol efflux capacity is impaired in homozygous FH patients. However, LDL apheresis may maintain cholesterol efflux capacity, despite a lowering levels of high-density lipoprotein cholesterol and apoA-I., (Copyright © 2013 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Patients with familial hypercholesterolaemia (FH) are characterized by high total and LDL cholesterol. Pregnant women with FH have higher absolute levels of total and LDL cholesterol, and a more pro-coagulant pattern compared with healthy pregnant women. Maternal hypercholesterolaemia has been shown to affect early atherosclerosis formation in the offspring. The aim of the present study was to investigate whether maternal FH leads to differences in plasma or serum levels of haemostatic and fibrinolytic markers in children with and without FH born of mothers with FH compared to control children born of non-FH mothers., Methods and Results: Children with (n=9) and without (n=7) FH born of mothers with FH, as well as control children (n=16) born of non-FH mothers were included in the study. The concentrations of tissue plasminogen activator, plasminogen activator inhibitor (PAI-1), tissue factor (TF), TF pathway inhibitor (TFPI), thrombomodulin, fibrinogen, prothrombin fragment 1+2 and von Willebrand Factor were measured. Our findings show i) higher levels of PAI-1 and TFPI in children with and without FH born of mothers with FH compared with control children, ii) lower levels of thrombomodulin in children with FH compared with control children, and iii) significant correlations between maternal PAI-1 levels during pregnancy and PAI-1 levels in the offspring., Conclusions: We found that maternal FH may confer an unfavourable phenotype by affecting haemostatic and fibrinolytic markers in offspring independent of the children's FH status. However, the association between maternal hypercholesterolaemia and haemostatic risk markers in the offspring needs to be further elucidated., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Matrix degradation within an atherosclerotic plaque is an important pathogenic factor in atherosclerosis, and is largely modulated by the balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors (i.e., tissue inhibitor of MMPs [TIMPs]). Familial hypercholesterolemia (FH) is a rare inherited disorder associated with premature coronary heart disease. The aim of the present study was to examine MMP-9 and TIMP-1 on plasma and cellular mRNA levels in homozygous FH patients (n=7) compared with age- and sex-matched heterozygous FH patients (n=6), and with healthy subjects (n=7), and to test whether once-weekly LDL-apheresis (three consecutive sessions) of homozygous FH patients show short-term effects on these variables., Results: The main findings were that (i) Compared to healthy control subjects, homozygous FH patients have significantly higher serum levels of MMP-9 and lower levels of TIMP-1, and consequently significantly higher MMP-9/TIMP-1 ratio, potentially reflecting higher MMP-9 activity. (ii) Peripheral blood mononuclear cells (PBMC) isolated from FH homozygotes have significantly higher mRNA levels of MMP-9 compared to cells from heterozygotes. (iii) TNFα-stimulated PBMC from FH homozygotes released borderline-significantly more MMP-9 than cells from heterozygotes and healthy controls. (iv) LDL-apheresis (one day before treatment versus fifteen days later, on the day after the weekly treatment) had no significant short-term effect on any of the MMP-9 and TIMP-1 variables measured in serum and cells., Conclusions: The data may suggest that homozygous FH patients have an enhanced matrix degrading potential as compared with heterozygous FH patients and healthy controls, potentially contributing to the increased cardiovascular risk observed in these patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Familial hypercholesterolaemia (FH) is associated with increased risk of premature atherosclerosis. Inflammation is a key event in atherogenesis, and we have previously reported an inflammatory imbalance between tumour necrosis factor (TNF)α and interleukin-10 in children with FH. Based on the potential role of TNF-related molecules in inflammation, we investigated the regulation of other members of the TNF superfamily (TNFSF)/TNF receptor superfamily (TNFRSF) in children and young adults with FH and matched healthy controls., Methods: Expression of TNFSF/TNFRSF genes in peripheral blood mononuclear cells (PBMCs) was quantified in children and young adults with FH prior to (n = 42) and after statin treatment (n = 10) and in controls (n = 25) by quantitative real-time polymerase chain reaction., Results: First we found that, compared with controls, the mRNA levels of OX40L, BAFFR and TRAILR1 were significantly higher, whereas TRAIL and TRAILR3 were significantly lower in children and young adults with FH. Secondly, levels of oxidized low-density lipoprotein (oxLDL) were significantly raised in the FH group, and correlated with the expression of OX40L, BAFFR and TRAILR1. Thirdly, oxLDL increased mRNA levels of BAFFR, TRAILR1 and TRAILR4 in PBMCs ex vivo from individuals with FH. Fourthly, OX40, acting through OX40L, enhanced the oxLDL-induced expression of matrix metalloproteinase-9 in THP-1 monocytes in vitro. Finally, after statin treatment in children with FH (n = 10), mRNA levels of OX40L and TRAILR1 decreased, whereas levels BAFF, TRAIL and TRAILR3 increased., Conclusion: Our findings suggest the involvement of some TNFSF/TNFRSF members and oxLDL in the early stages of atherogenesis; this may potentially contribute to the accelerated rate of atherosclerosis observed in individuals with FH., (© 2012 The Association for the Publication of the Journal of Internal Medicine.)

Background: Homozygous familial hypercholesterolemia (HoFH), which affects 1 in a million individuals, leads to extremely elevated levels of cholesterol and early-onset cardiovascular disease., Objective: The aim of this study was to assess all 7 HoFH patients treated with low-density lipoprotein (LDL) apheresis in Norway with respect to quality of life, clinical and laboratory assessments, and cardiovascular status., Methods: Apheresis treatment and assessment of cardiovascular status was performed at local hospitals but coordinated by the Lipid Clinic that has followed all patients since diagnosis. Quality of life was evaluated by a validated questionnaire., Results: Results are shown as median (min-max). LDL cholesterol at diagnosis (untreated) was 704 (592-1268) mg/dL (18.2 [15.3-32.8] mmol/L). Medication was initiated at age 9 (2-35) years, and apheresis treatment at age 10 (6-44) years. Regular once-weekly apheresis combined with the maximum-tolerable doses of a statin and ezetimibe reduced LDL cholesterol to 197 (170-282) mg/dL (5.1 [4.5-7.3] mmol/L) pre-apheresis and 85 (50-108) mg/dL (2.2 [1.3-2.8] mmol/L) post-apheresis. Calculated interval mean LDL cholesterol was 162 (135-220) mg/dL (4.2 [3.5-5.7] mmol/L). Duration of apheresis treatment was 11 (1-24) years. Cardiovascular manifestations progressed in most patients despite the apheresis treatment. The subjects' quality of life was comparable with that of a healthy population, with the exception of two patients, who were significantly affected by coronary disease., Conclusions: Well-tolerated, once-weekly LDL apheresis achieves lower interval mean LDL cholesterol levels between apheresis treatments than previously reported for apheresis every second week. However, progressions of cardiovascular manifestations still occurred, which highlights the importance of earlier and even more aggressive treatment and follow-up in HoFH., (Copyright © 2012 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Objective: Familial hypercholesterolemia (FH) is caused by defects in genes coding for proteins involved in low density lipoprotein (LDL) metabolism, and is associated with increased risk of premature coronary heart disease (CHD). The clinical phenotype of FH exhibits marked variability due to additional metabolic and environmental factors, and further biomarkers are required for appropriate risk assessment. The aim of the present study was to search for risk markers among FH patients., Methods and Results: Clinical and biochemical parameters of FH subjects with early CHD events (CHD-susceptible) and FH subjects with late or no CHD events (CHD-resistant) were compared. Our data show that CHD-susceptible FH patients had significantly higher Lipoprotein (Lp) (a) levels compared to CHD-resistant FH patients. When subdividing by gender, the main findings were that (i) CHD-susceptible women had significantly higher levels of both Lp(a), low density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B as compared to CHD-resistant women, and (ii) CHD-resistant women had significantly lower Lp(a) levels and higher high density lipoprotein (HDL) cholesterol and apoA-I levels compared to CHD-resistant men., Conclusions: The data suggest that Lp(a) may be an important coronary risk marker in FH patients, in particular in combination with elevated LDL cholesterol levels among female subjects. Thus, measurement of Lp(a) levels may help identifying high-risk individuals who could benefit from an aggressive therapy, including statins to reduce LDL-cholesterol to guideline-recommended levels., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

This study aimed to assess the efficacy and tolerability of atorvastatin in Tanner stage (TS) 1 patients ages 6 to 10 years and TS ≥ 2 patients ages 10 to <18 years with genetically confirmed heterozygous familial hypercholesterolemia (HeFH) and a low density lipoprotein cholesterol (LDL-C) level of 4 mmol/l (155 mg/dl) or higher. In this open-label, 8-week study, 15 TS 1 children were treated initially with atorvastatin 5 mg/day and 24 TS ≥ 2 children with 10 mg/day. Doses were doubled at week 4 if the LDL-C target (<3.35 mmol/l [130 mg/dl]) was not achieved. The efficacy variables were the percentage change from baseline in LDL-C, total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), and apolipoprotein (Apo) A-I and Apo B. Safety evaluations included clinical monitoring, subject-reported adverse events (AEs), vital signs, and clinical laboratory tests. The mean values for LDL-C, TC, VLDL-C, and Apo B decreased by week 2 among all TS 1 and TS ≥ 2 patients, whereas TG, HDL-C, and Apo A-I varied considerably from week to week. After 8 weeks, the mean reduction in LDL-C was -40.7% ± 8.4 for the TS 1 children and -39.7% ± 10.3 for the TS ≥ 2 children. For the TS 1 patients, the mean reductions were -34.1% ± 6.9 for TC and -6.0% ± 32.1 for TG. The corresponding changes for the TS ≥ 2 patients were -35.6% ± 9.5 for TC and -21.1% ± 29.7 for TG. Four patients experienced mild to moderate treatment-related AEs. No serious AEs or discontinuations were reported. Overall, no difference in safety or tolerability was observed between the younger and older cohorts. Across the range of exposures after atorvastatin 5 to 10 mg (TS 1) or atorvastatin 10 to 20 mg (TS ≥ 2) doses for 8 weeks, clinically meaningful reductions in LDL-C, TC, VLDL-C, and Apo were observed with atorvastatin in pediatric patients who had HeFH. Atorvastatin also was well tolerated in this population.

Objective: Familial hypercholesterolemia (FH) is associated with increased risk of premature atherosclerosis. Increasing evidence supports involvement of inflammation in atherogenesis. The inflammatory cytokine tumor necrosis factor (TNF)α has been regarded as a key mediator in the development of atherosclerosis due to its involvement in several stages in this process. We hypothesized that children with FH, as a model of early atherosclerosis, have different serum levels of inflammation markers than healthy control children., Methods: We measured serum levels of TNFα, as well as its endogenous inhibitors (i.e., soluble TNF receptors [sTNFR] 1 and 2) and the anti-inflammatory cytokine interleukin (IL)-10 in healthy children (7-20 years) with (n=102) and without (n=48) heterozygote FH as well as adult FH subjects (n=20) and healthy adult controls (n=16)., Results: The main findings were: Compared to control children, FH children had higher serum levels of TNFα, accompanied by lower sTNFRs levels, resulting in an increased TNFα/sTNFRs ratio (P<0.05), potentially reflecting enhanced TNFα activity. In contrast to the increased TNFα levels, FH children had decreased serum levels of IL-10 (P<0.01) resulting in an increased TNFα/IL-10 ratio (P<0.01). We did not observe any difference in the same parameters between adult subjects with and without FH., Conclusions: FH children are characterized by an inflammatory imbalance between TNFα and IL-10, potentially contributing to the accelerated atherosclerotic process in these individuals., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

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.

Abnormal hyperlipidemia characterizes pregnancy in familial hypercholesterolemia (FH), and is associated with vascular dysfunction. Hence, we compared blood flow in the feto- and uteroplacental circulation in FH and healthy reference women using Doppler velocimetry. The umbilical artery pulsatility index (PI) at gestational weeks 24 and 36, and the concomitant physiological decrease in PI, was similar in FH (n=10) and the reference group (n=143). The decrease in mean PI of both uterine arteries from week 24 to 36 was significant in the reference group, but not among the FH women. Plasma LDL-cholesterol measured between weeks 24 and 36 was not correlated with the decrease in umbilical PI in the FH group, or with the decrease in umbilical or mean uterine PI in the reference group. We conclude that pregnancy in FH might be associated with attenuated physiological decrease in mean PI of uterine arteries, possibly reflecting increased uteroplacental vascular resistance unrelated to plasma LDL-cholesterol levels.

Background: Too few familial hypercholesterolemia (FH) patients are diagnosed. The most cost-effective strategy to diagnose FH is to examine first-degree relatives of already diagnosed patients. This is referred to as cascade genetic screening., Methods and Results: One thousand eight hundred and five first-degree relatives of index patients with molecularly defined FH consented to cascade genetic screening by the use of molecular genetic testing. Of these, 44.8% were mutation carriers and 55.2% were noncarriers. Only 44.2% of the mutation carriers were on lipid-lowering drugs at the time of genetic testing. Of these, only 9.4% had a value for total serum cholesterol below 5 mM. Among adult mutation carriers who were not on lipid-lowering treatment at the time of genetic testing, reductions in total serum cholesterol and low-density lipoprotein cholesterol of 18.4% (p < 0.0001) and 25.3% (p < 0.0001), respectively, were observed 6 months after genetic testing. It is assumed that this improvement in the lipid profile is due to a definite diagnosis obtained by molecular genetic testing. By using the results of genetic testing as the gold standard for diagnosis of FH, data from a questionnaire filled out by the relatives showed that the use of clinical criteria to diagnose FH in general practice had a sensitivity of 46.2% and a specificity of 88.0%., Conclusions: The use of clinical diagnostic criteria to diagnose FH in general practice identifies only approximately 50% of FH patients. Molecular genetic testing as part of cascade genetic screening is an efficient tool to diagnose patients, leading to significant improvement in the lipid profile. It should therefore be implemented in clinical medicine., ((c) 2008 S. Karger AG, Basel)

Introduction: Patients with familial hypercholesterolemia (FH) are prone to premature cardiovascular disease. During pregnancy plasma lipids reach higher absolute values in FH than in healthy women. Pregnancy is associated with activation of coagulation and possibly also of vascular endothelium, which might further increase the risk of cardiovascular disease in FH. However, whether hemostatic and endothelial activation markers are increased in pregnant FH women compared with non-FH pregnancies, is unknown., Materials and Methods: Activation markers of hemostasis and endothelium were analyzed in blood samples collected prospectively from 22 heterozygous FH women during pregnancy and compared with those of a reference group of 149 healthy, pregnant women., Results: A procoagulant pattern was detected in both groups, but was more evident among FH women at least partly due to their enhanced thrombin generation, and because tissue factor pathway inhibitor type 1 increased in the reference group only. Furthermore, plasminogen activator inhibitor type 2 antigen increased more in FH than in the reference group. Whereas C-reactive protein, intercellular adhesion marker-1 and E-selectin did not change appreciably, vascular endothelial cell adhesion molecule 1 rose markedly in FH., Conclusion: Increased lipid levels as well as a net procoagulant activity and an enhanced endothelial activation possibly confer additional risks of cardiovascular disease among pregnant FH women.

Serum lipids increase during pregnancy. However, data are scarce for lipid changes in pregnant women with heterozygous familiar hypercholesterolemia (FH). The purpose of the present study was to examine plasma lipids and lipoproteins during pregnancy in women with FH. In 22 pregnant women blood samples were collected at gestational weeks 17-20 (baseline), 24, 30 and 36. Total- and LDL cholesterol increased significantly between baseline and gestational week 36 by 29% and 30%, respectively, compared to 25% and 34% in a reference group of 149 healthy pregnant women. Notably, the plasma lipid concentrations in the FH women were much higher than in the reference women. Triglycerides increased (P<0.05) by 116% and 103%, in the FH group and reference group, respectively. HDL cholesterol was unchanged in both groups. Moreover, apolipoprotein B increased significantly during pregnancy in the FH women, whereas apolipoprotein A1 and lipoprotein (a) were unchanged. Pregnancy outcomes in the FH group did not differ significantly from those in the reference group. In conclusion, the relative increase in plasma lipids was similar in pregnant women with FH and in healthy women, but the absolute magnitude was considerably larger in pregnant FH women.

Purpose: Knowledge about the ways patients perceive their vulnerability to disease is important for communication with patients about risk and preventive health measures. This interview study aimed to explore how patients with a diagnosis of heterozygous familial hypercholesterolemia understand and perceive their vulnerability to coronary heart disease., Methods: We did a qualitative study of 40 patients with familial hypercholesterolemia who were recruited through a lipid clinic in Norway. We elicited participants' perceptions about their vulnerability to heart disease in semistructured interviews. Data were analyzed by systematic text condensation inspired by Giorgi's phenomenological method., Results: We found that participants negotiated a personal and dynamic sense of vulnerability to coronary heart disease that was grounded in notions of their genetic and inherited risk. Participants developed a sense of their vulnerability in a 2-step process. First, they consulted their family history to assess their genetic and inherited risk, and for many a certain age determined when they could expect to develop symptoms of coronary heart disease. Second, they negotiated a personal sense of vulnerability by comparing themselves with their family members. In these comparisons, they accounted for individual factors, such as sex, cholesterol levels, use of lipid-lowering medications, and lifestyle. Participants' personal sense of vulnerability to heart disease could shift dynamically as a result of changes in situational factors, such as cardiac events in the family, illness experiences, or becoming a parent., Conclusions: Patients with a diagnosis of familial hypercholesterolemia negotiate a personal and dynamic sense of vulnerability to coronary heart disease that is grounded in their understanding of their genetic and inherited risk. Doctors should elicit patients' understanding of their family history and their personal vulnerability to individualize clinical management.

Familial hypercholesterolemia (FH) is associated with heterogeneity of the onset and severity of coronary heart disease (CHD). In this study, we investigated different low-grade proinflammatory markers and the atheroprotective function of the HDL3 subfraction in FH-patients (n = 13) with identical LDL-receptor mutations and in age- and sex-matched healthy controls (n = 11). Compared with healthy controls, FH-patients had greater gene expressions of the proatherogenic mediators TNF-alpha and IL-8 in circulating peripheral blood mononuclear cells. In addition, they had a higher serum concentration of intercellular adhesion molecule-1 (ICAM-1) and a lower net antioxidant capacity. FH-derived HDL3 with a high level of triglycerides had a reduced capacity to inhibit the release of IL-8 from TNF-alpha-stimulated human umbilical vein endothelial cells (HUVEC) [1.864 mg/L (1.461-2.208 mg/L) vs. 1.466 mg/L (1.225-1.643 mg/L); P < 0.05; median (range)], and a reduced capacity to promote cholesterol efflux from lipid-loaded macrophages [12% (12-14%) vs. 15% (14-18%); P < 0.05; median (range)] compared with HDL3 with a lower triglyceride content. Notably, the degree of inhibition of IL-8 release from HUVEC by HDL3 was correlated with the ability of HDL3 to promote cholesterol efflux (r = -0.80, P = 0.03). In conclusion, compared with healthy controls, FH-patients are characterized by higher levels of low-grade proinflammatory markers, and FH-derived HDL3 with high triglyceride content may be more proatherogenic. These triglyceride rich-HDL3 might be partly responsible for the phenotypic variation among FH-patients with identical LDL-receptor mutations.

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.

Objective: Increasing data support the involvement of chemokines in atherogenesis. However, although several studies have shown increased chemokine levels in adult patients, the literature is virtually devoid of data on chemokines in children with hypercholesterolemia., Methods and Results: We examined the gene expression of chemokines in peripheral blood mononuclear cells (PBMCs) from clinically healthy children with and without heterozygous familial hypercholesterolemia (FH). Our main findings were: (1) compared with healthy controls, PBMCs from FH children showed significantly higher mRNA levels of RANTES, but not of the other examined chemokines; (2) an opposite pattern was seen in adult FH subjects, with markedly enhanced expression of macrophage inflammatory peptide-1alpha, but not of RANTES; (3) this increased gene expression of RANTES in PBMCs from FH children seemed to reflect enhanced RANTES expression in monocytes but not in T cells; (4) FH children also had raised serum levels of neopterin, additionally suggesting monocyte/macrophage activation in these children; and (5) PBMCs from both FH children and controls showed enhanced release of interleukin 8 on RANTES stimulation in vitro., Conclusions: Our findings support a role of inflammation also in the early stages of atherogenesis possibly involving monocyte-derived RANTES as an important mediator.

Background: Subjects with familial hypercholesterolemia (FH) are associated with increased risk of premature atherosclerosis and coronary artery disease (CAD). However, onset of clinically manifested CAD varies widely among subjects with heterozygous FH. The purpose of this study was to investigate whether FH subjects with an identical mutation in the low-density lipoprotein (LDL) receptor gene have a high-density lipoprotein (HDL)3 that is characterized by a less atheroprotective functions than that of healthy controls and within subgroups of FH., Design: Twenty-two adults <75 years of age with FH and 17 healthy sex- and age-matched controls were included. HDL3 was isolated and the composition was characterized from each subject, and its ability to suppress tumor necrosis factor(TNF)-alpha stimulated expression of ICAM-1 on HUVEC was investigated. In addition, plasma level of soluble sICAM-1 and VCAM-1 was measured., Results: Compared to controls, FH subjects had lower content of phospholipids in their HDL3 subfraction and a higher serum ICAM-1 level. No differences in sVCAM-1 were observed. HDL3 isolated from FH with body mass index(BMI)>25 and from FH subjects with premature CAD contained higher content of triglycerides compared to the HDL3 from FH subjects with BMI<25 and without CAD, respectively. Most important, when testing the function of HDL3 in the two FH subgroups characterized by elevated BMI and premature CAD, lower inhibition of ICAM-1 expression on HUVEC was observed., Conclusions: The altered composition of HDL3 from FH subjects with BMI>25 and FH subjects with premature CAD may be responsible for a HDL3 subfraction with less protective properties assessed as inhibition of ICAM-1 expression on HUVEC consequently leading to more proatherogenic endothelial surface.

Objective: To study the compliance and changes in plasma lipids, plant sterols, fat-soluble vitamins and carotenoids in children and parents with familial hypercholesterolemia (FH) consuming a plant sterol ester-enriched (PSE) spread., Design: A 26-week open-label follow-up of children who had previously been studied in a controlled cross-over design. The parents were also included in the open-label arm of the study., Setting: Outpatient clinic for treatment of hyperlipidemia., Subjects: A total of 37 children (7-13 y) and 20 parents (32-51 y) diagnosed with 'definite' or 'possible' heterozygous FH. In all, 19 of the parents, but no children, used statins. All were patients at the Lipid Clinic, National Hospital in Oslo., Interventions: Subjects were recommended to eat 20 g/day of PSE spread as part of their lipid-lowering diet., Results: The mean intake of PSE spread was 13.7 and 16.5 g/days in the children and parents, respectively, corresponding to 1.2 and 1.5 g of plant sterols. Plasma total cholesterol decreased by 9.1% in both children (P<0.001) and parents (P=0.002). The corresponding decreases in LDL cholesterol were 11.4% (P<0.001) and 11.0% (P=0.012). Increases in serum lathosterol, campesterol and sitosterol, adjusted for total cholesterol, were observed in the children (31, 96, 48%, respectively, P<0.001) at the end of the controlled cross-over period. In the parents, serum campesterol and sitosterol, adjusted for total cholesterol, increased by 92 and 39%, respectively (P< 0.001). Lipid-adjusted serum alpha- and beta-carotene decreased by 17.4% (P=0.008) and 10.9% (P=0.018), respectively, in the children at the end of the controlled PSE period, but increased again during the follow-up. In the parents, serum alpha- and beta-carotene concentrations were unchanged, while serum lutein and lycopene decreased by 7.3% (P=0.037) and 14.6% (P=0.044), respectively., Conclusions: Sustained efficacy of cholesterol reduction and long-term compliance of PSE intake were demonstrated in this study.

Background: Patients with familial hypercholesterolaemia have increased risk of developing coronary heart disease. The most cost-effective way of diagnosing patients with familial hypercholesterolaemia is to perform genetic testing of close relatives of already diagnosed patients., Material and Methods: Probands with familial hypercholesterolaemia in whom the underlying mutation in the low-density lipoprotein receptor gene has been identified were informed that close relatives should also be tested., Results: Blood samples were taken for molecular genetic testing from 851 first-degree relatives of patients with familial hypercholesterolaemia; 47.8 % tested positively and 52.2 % negatively. Among those with positive tests, only 41.5 % were on lipid-lowering drugs and only 6.1 % had a value for total serum cholesterol < 5 mmol/l. Six months after testing, 81.9 % were on lipid-lowering drugs, at which time a mean reduction in total serum cholesterol of 21.2 % (p < 0.0001) was observed in patients aged 18 and above who were not on treatment at the time of testing., Interpretation: Molecular genetic testing for familial hypercholesterolaemia in a family-based strategy is a cost-effective way of diagnosing patients with this condition that leads to implementation of effective preventive measures.

The clinical diagnosis of familial hypercholesterolemia (FH) in children is based on family history and laboratory findings. The best available value of low-density lipoprotein cholesterol (LDL-C) for the diagnosis of FH in children is >3.50 mmol/L (>135 mg/dL) when FH runs in the family. Levels below this concentration were only found in 4.3% of children that had a mutation in the LDL-receptor gene. In contrast, children with LDL-C equal to or above 3.50 mmol/L had 0.98 posttest probability of FH. Untreated FH carries a substantial burden of morbidity and mortality if left untreated or if inadequately treated. The guidelines of the American National Cholesterol Education Program suggested that drug treatment should be considered from the age of 10 years if LDL-C levels are greater than or equal to 4.9 mmol/L (190 mg/dL) or greater than or equal to 4.1 mmol/L (158 mg/dL) in the presence of other cardiovascular risk factors, including a positive family history of premature cardiovascular disease. Impaired flow mediated dilatation was more pronounced in FH children with a positive family history of premature cardiovascular disease. The currently prescribed diet is sometimes considered to be monotonous and can lead to problems with compliance. A reduction of the total intake fat and saturated fatty acids is important. Plant sterolesters should be evaluated in young FH children and can supplement drug and diet therapy, with an additional reduction of 10 to 15% of LDL-C. The use of resins leads to poor compliance, and statins are recommended for FH children and adolescents when drug treatment is indicated. Pravastatin, simvastatin, and atorvastatin decrease LDL-C 30 to 40% without serious adverse events and have a high degree of compliance.

Aims: Familial hypercholesterolaemia (FH) is associated with increased risk of premature atherosclerosis and coronary artery disease (CAD). However, onset of clinically manifested CAD varies widely among patients with heterozygous FH, and we hypothesized that inflammatory mediators such as chemokines could contribute to atherogenesis in these patients., Methods and Results: We compared peripheral blood mononuclear cells (PBMCs) from FH patients with an identical mutation with PBMCs from sex- and age-matched healthy controls with respect to spontaneous and oxidized low density lipoprotein (oxLDL)-stimulated release of chemokines. Our main findings were: (1) PBMCs from FH patients spontaneously released significantly higher levels of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and interleukin (IL)-8, and had a significantly lower oxLDL-stimulatory ratio for MIP-1alpha and MIP-1beta than cells from healthy controls. (2) Spontaneous release of these chemokines correlated positively and stimulatory ratio correlated negatively with plasma concentrations of total and LDL cholesterol. (3) Among FH patients, release of MIP-1alpha, MIP-1beta and IL-8 from PBMCs varied with the presence of xanthomas/xanthelasms, smoking and gender. (4) In vitro studies showed that FH serum but not control serum was able to induce enhanced spontaneous release of chemokines in PBMCs from both FH patients and control subjects., Conclusions: Our data may suggest that a pathophysiological consequence of FH is enhanced chemokine responses, which in turn may promote recruitment and activation of leukocytes within the vessel wall, contributing to atherosclerosis as well as to the different phenotypes in these patients with an identical FH mutation.

Background: A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate LDL cholesterol-lowering efficacy, overall safety, and tolerability and the influence on growth and pubertal development of simvastatin in a large cohort of boys and girls with heterozygous familial hypercholesterolemia (heFH)., Methods and Results: A total of 173 heFH children (98 boys and 75 girls) were included in this study. After a 4-week diet/placebo run-in period, children with heFH were randomized to either simvastatin or placebo in a ratio of 3:2. Simvastatin was started at 10 mg/d and titrated at 8-week intervals to 20 and then 40 mg/d. During a 24-week extension period, the patients continued to receive simvastatin (40 mg) or placebo according to their assignment. After 48 weeks of simvastatin therapy, there were significant reductions of LDL cholesterol (-41%), total cholesterol (-31%), apolipoprotein B (-34%), VLDL cholesterol (-21%), and triglyceride (-9%) levels. HDL cholesterol and apolipoprotein A-I levels were increased by 3.3% and 10.4%, respectively (not significant). No safety issues became evident. Except for small decreases in dehydroepiandrosterone sulfate compared with placebo, there were no significant changes from baseline in adrenal, gonadal, and pituitary hormones in either treatment group., Conclusions: Simvastatin significantly reduced LDL cholesterol, total cholesterol, triglyceride, VLDL cholesterol, and apolipoprotein B levels and was well tolerated in children with heFH. There was no evidence of any adverse effect of simvastatin on growth and pubertal development. Therefore, simvastatin at doses up to 40 mg is a well-tolerated and effective therapy for heFH children.

Background: Naturally occurring plant sterol esters (SEs) favorably affect serum cholesterol concentrations in humans and could aid in the treatment of children with familial hypercholesterolemia (FH)., Objective: We studied the effect of SE-enriched spread on serum lipids, lipoproteins, carotenoids, fat-soluble vitamins, and physiologic variables in children with FH aged 7-12 y., Design: In a randomized, double-blind crossover study comprising two 8-wk interventions, 38 children with FH consumed 18.2 +/- 1.5 g SE spread/d, corresponding to 1.60 +/- 0.13 g SEs, or a control spread. Blood samples were analyzed at the start and end of each diet period., Results: Plasma LDL-cholesterol concentrations decreased by 10.2% (P = 0.003) during the SE period compared with the control period. Total cholesterol and apolipoprotein B concentrations were reduced by 7.4% (P = 0.007 and P = 0.020, respectively) during the SE period. No changes were observed in HDL cholesterol, triacylglycerol, or apolipoprotein A-I. Serum concentration of lipid-adjusted lycopene decreased by 8.1% (P = 0.015) in the SE period, with no changes in the other carotenoids. Lipid-adjusted retinol and alpha-tocopherol concentrations increased by 15.6% (P < 0.001) and 7.1% (P = 0.027), respectively. There was an increase (16.8%, P = 0.04) in alanine transaminase in the SE period, but this was explained by a significantly lower starting concentration in the SE period than in the control period. The children consumed a recommended American Heart Association Step I diet during both intervention periods., Conclusion: A daily intake of 1.6 g SEs induces an additional reduction in LDL-cholesterol concentrations in children with FH consuming a recommended diet.

An update on several aspects on familial hypercholesterolemia (FH) such as molecular basis, DNA diagnosis, clinical criteria for the diagnosis, treatment of adults and children and psychosocial aspects of FH is presented.

The first patients with xanthomatosis and cardiovascular disease were described in end of the 18th century. From 1925 to 1938, the Norwegian pathologist Francis Harbitz (1867-1950) published several reports on sudden death and xanthomatosis. Harbitz called attention to certain peculiarities of the xanthomatosis. Microscopically he found that the so-called foam cells are more marked and more characteristic than in senile arteriosclerosis. Carl Müller's (1886-1983) attention was directed to this form of cardiovascular disease by the publications of Harbitz. Based on his own studies of 17 families in Oslo over a short period from 1936, he published his final report in 1939. He described hereditary heart disease due to xanthomatosis and hypercholesterolaemia to be fairly common. It was demonstrated to be a dominant trait in the families. Hypercholesterolaemia was present, most marked in connection with xanthoma tuberosus, but there was no definitive relationship between hypercholesterolaemia and xanthomatous deposits in the skin. The occurrence of heart disease in families should direct attention to this disorder. Carl Müller postulated that causal and prophylactic treatment might prove to be of value, but more than 50 years passed before this was possible in the disorder that is now called familial hypercholesterolaemia.

Maternal hypercholesterolaemia has recently been shown to increase the number of fatty streaks in the foetal aorta, as well as subsequent progression of fatty streaks to more advanced lesions. We compared carotid intima-media thickness by B-mode ultrasonography in children who inherited familial hypercholesterolaemia from their mothers or fathers, hypothesizing that children whose mothers were hypercholesterolaemic during pregnancy had increased atherogenesis compared with children whose mothers did not have familial hypercholesterolaemia. We found that carotid intima-media thickness and prevalence of plaque did not differ between children with familial hypercholesterolaemia who inherited FH maternally or paternally.

The microsomal triglyceride transfer protein (MTP) has a key function in intracellular apolipoprotein (apo) B lipidation and secretion of very low density lipoprotein (VLDL). A recently discovered functional polymorphism in the promoter of the MTP gene (-493G/T) affects the plasma concentration of low density lipoprotein (LDL) cholesterol and the VLDL distribution between large and small particle species in healthy men. This phenotype is likely to be explained by an effect on VLDL synthesis. Against this background, we studied the effect of the MTP-493G/T polymorphism in a large cohort (217 men and 211 women) with heterozygous familial hypercholesterolemia (FH). A 40% to 50% lower serum triglyceride level was observed in homozygous carriers of the MTP-493 T allele (T/T, 0.93+/-0.34; G/T, 1.54+/-1.40; and G/G, 1.56+/-1.24 mmol/L; T/T vs G/T P=0.04, T/T vs G/G P=0.02). In contrast to the situation in healthy subjects, the MTP promoter polymorphism did not have a significant effect on the LDL cholesterol levels in FH subjects, although the same trend was observed (T/T, 7.31+/-1.87; G/T, 7. 80+/-2.12; and G/G, 7.91+/-2.31 mmol/L, NS). Adjustment for the apo E gene polymorphism by inclusion of subjects homozygous for the apo E3 allele only revealed a reciprocal high density lipoprotein cholesterol-elevating effect (T/T, 1.41+/-0.73; G/T, 1.18+/-0.27; and G/G, 1.16+/-0.29 mmol/L; T/T vs G/T P=0.06, T/T vs G/G P=0.04). This effect seemed to be sex-specific because it was accounted for by the female patients. In conclusion, the LDL cholesterol-lowering effect of the rare MTP gene promoter variant (MTP-493T) present in healthy subjects is shifted to a triglyceride-lowering effect in FH. These data suggest that the MTP gene has a role in modulating the clinical phenotype of FH.

A report of a World Health Organization consultation on familial hypercholesterolaemia (FH) was recently presented in Geneva. The report provides an update on several aspects of FH such as the molecular basis, DNA diagnosis, clinical criteria for the diagnosis, treatment of FH adults and children, the role of diet, psychosocial aspects of FH, contacting and helping relatives with FH and gives suggestions for government cooperation. The report is reviewed here.

Screening for structural alterations of the low density lipoprotein (LDL) receptor gene by Southern blot analysis revealed an abnormal band pattern in one subject with a clinical diagnosis of homozygous familial hypercholesterolemia (FH). The molecular defect was further characterized by polymerase chain reaction and cDNA sequencing. These analyses identified a 4.8 kb in-frame deletion of exons 2 and 3, where exon 1 was spliced to exon 4. This deletion is expected to produce a receptor that has lost the two first cysteine-rich repeats of the ligand-binding domain. Previously published data of in vitro site-directed mutagenesis has shown that binding of LDL to such a receptor is reduced to 70% of normal. A mild phenotype in our FH homozygote is consistent with that observation. In contrast, heterozygotes carrying this deletion have a relatively more severe phenotype that is comparable to that of heterozygotes carrying a null-allele. A severe phenotype was also found in a compound heterozygote carrying this deletion. Possible mechanisms for this phenotypic variability are discussed.-Rødningen, O. K., S. Tonstad, J. D. Medh, D. A. Chappell, L. Ose, and T. P. Leren. Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene.

Background: In individuals with familial hypercholesterolaemia (FH), ultrasonographic measurement of carotid intima-media thickness (IMT) and plaque may provide a non-invasive assessment of cardiovascular risk., Methods: We examined carotid artery IMT and its determinants in 79 non-smoking, normotensive, treated men and women with FH aged 26-46 years, and in 79 non-smoking, normotensive sex-, age- and body mass index-matched control subjects. FH was verified by molecular genetic analyses. The underlying mutation in the low-destiny lipoprotein receptor gene included a splice-site mutation, mutations predicted or shown to lead to class 2B mutations or other mutations that probably represent class I mutations (null alleles)., Results: The carotid bifurcation and common carotid artery IMT was increased in men with FH compared with control subjects (0.81 +/- 0.15 mm vs. 0.74 +/- 0.19 mm and 0.61 +/- 0.13 mm vs. 0.55 +/- 0.14 mm respectively; P < 0.05). The carotid bifurcation IMT was increased in women with FH compared with control subjects (0.74 +/- 0.17 vs. 0. 66 +/- 0.15; P = 0.005). More subjects with FH had carotid plaque (54% vs. 14%; P = 0.0001). In multivariate analysis, male gender, level of low-density lipoprotein-cholesterol, cholesterol-years score and xanthoma were associated with IMT and plaque in subjects with FH. FH subjects with class 2B mutations had lower cholesterol levels than subjects with mutations belonging to the other classes. They also had a tendency towards a decreased common carotid artery IMT., Conclusion: These findings confirm the importance of gender, xanthoma and lifetime cholesterol levels in relation to carotid atherosclerosis in FH. Whether the type of mutation causing FH modulates carotid artery IMT and plaque requires further study.

Familial hypercholesterolemia causes premature cardiovascular disease. Genetic screening of patients' relatives who have already been diagnosed has proved to be more efficient than screening in a general population. Privacy laws in Norway forbid physicians to directly contact persons with genetic disorders who are not their own patients. We examined attitudes towards this type of screening in a representative sample of the Norwegian population and a group of patients with familial hypercholesterolaemia. In both groups the majority showed a positive attitude towards physicians contacting relatives directly to detect individuals with familial hypercholesterolaemia. In both groups the majority wanted to know whether, based on the diagnosis of relatives, they might also be affected. Both groups wanted this information regardless of the risk of their being affected. We conclude that the privacy laws should be amended to conform with the attitudes of the population and the patients, thus enabling physicians to contact relatives directly.

In children with familial hypercholesterolemia, heterozygosity and homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase gene was associated with low serum folate and increased susceptibility to elevation of plasma total homocysteine during cholestyramine treatment. Because of the independent relationship between elevated plasma total homocysteine and cardiovascular disease, folate supplementation may be prudent in these children.