BACKGROUND:The early vascular impact of metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study examined associations of steatosis in childhood and young adulthood with cardiovascular risk in adulthood. METHODS:Children with severe obesity were investigated for MASLD and cardiovascular risk, with 10-year follow-up. Hepatic steatosis was measured using proton magnetic resonance spectroscopy and cardiovascular risk by ultrasound carotid intima-media thickness (cIMT). Participants were categorised into four trajectory groups based on presence of steatosis in childhood and/or adulthood: 'absent', 'diminishing', 'adult-onset' and 'persistent'. Associations between steatosis (presence and change over time) and cIMT, and between childhood metabolic factors and cIMT progression, were evaluated. RESULTS:Of 52 participants, 46% had steatosis in childhood ('diminishing' or 'persistent'), and 46% in adulthood ('adult-onset' or 'persistent'). Childhood steatosis was not associated with cIMT in adulthood, whereas adulthood steatosis was independently associated with increased cIMT (mean difference 0.035 mm, 95% CI: 0.010-0.060 mm; p-adjusted = 0.008). Mean cIMT at follow-up increased progressively across steatosis trajectory groups; (adjusted p-for-trend = 0.003). Childhood steatosis was the only metabolic factor associated with cIMT progression (β = 0.006, p = 0.030). CONCLUSIONS:Hepatic steatosis in young adulthood is independently associated with increased cardiovascular risk, and childhood steatosis relates to cIMT progression, supporting early MASLD detection and prevention.

IntroductionHeterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder caused by pathogenic variants in the LDL-C metabolism. Lifelong exposure to elevated LDL-C levels leads to a high risk of premature cardiovascular disease. To reduce that risk, children with HeFH should be identified and treated with lipid-lowering therapy. The cornerstone consists of statins and ezetimibe, but not in all patients this lowers the LDL-C levels to treatment targets. For these patients, more intensive lipid-lowering therapy is needed.Areas coveredIn this review, we provide an overview of the monoclonal antibodies which are currently available or being tested for treating HeFH in childhood.Expert opinionMonoclonal antibodies that inhibit PCSK9 are first in line lipid-lowering treatment options if oral statin and ezetimibe therapy are insufficient, due to intolerance or very high baseline LDL-C levels. Both evolocumab and alirocumab have been shown to be safe and effective in children with HeFH. For children, evolocumab has been registered from the age of 10 years old and alirocumab from the age of 8 years old. The costs of these new agents are much higher than oral therapy, which makes it important to only use them in a selected patient population.

Familial hypercholesterolemia (FH) is one of the most common genetically inherited disorders in the world. Children with severe heterozygous FH (HeFH), i.e. untreated low-density lipoprotein cholesterol (LDL-C) levels above the 90th percentile for age and sex among FH mutation carriers, can have LDL-C levels that overlap levels of children with homozygous FH (HoFH), but treatment regimen and cardiovascular follow-up to prevent cardiovascular disease are less intensive in children with severe HeFH. In children with HoFH, subclinical atherosclerosis can already be present using computed tomography coronary angiography (CTCA). The question remains whether this is also the case in children with severe HeFH who have a high exposure to elevated LDL-C levels from birth onwards as well. We calculated the cumulative LDL-C exposure (CEtotal [mmol]) in four children with severe HeFH and performed computed tomography coronary angiography (CTCA). These children, aged 13, 14, 15 and 18 years, had CEtotal of 71.3, 97.8, 103.6 and 136.1 mmol, respectively. None of them showed abnormalities on cardiovascular imaging, despite high LDL-C exposure. The results of this study, do not give us an indication to recommend performing CTCA routinely in children with severe HeFH.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

PURPOSE OF REVIEW:Familial hypercholesterolemia leads to elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth onwards due to a pathogenetic variation in genes in cholesterol metabolism. Early screening to identify and subsequently treat children with familial hypercholesterolemia is crucial to reduce the risk of premature atherosclerotic cardiovascular disease (ASCVD). This review focuses on recent insights in the field of pediatric familial hypercholesterolemia. RECENT FINDINGS:Screening in childhood and early initiation of optimal lipid-lowering therapy (LLT) have shown promising outcomes in the prevention of ASCVD. In addition, cost-effectiveness research has demonstrated highly favorable results. With the availability of novel therapies, familial hypercholesterolemia has become a well treatable disease. SUMMARY:Children with familial hypercholesterolemia benefit from early detection and optimal treatment of their elevated LDL-C levels.

PURPOSE OF REVIEW:Accommodating fetal growth and development, women undergo multiple physiological changes during pregnancy. In recent years, several studies contributed to the accumulating evidence about the impact of gestational hyperlipidemia on cardiovascular risk for mother and child. This review aims to provide a comprehensive overview of the current research on lipid profile alterations during pregnancy and its associated (cardiovascular) outcomes for mother and child from a clinical perspective.RECENT FINDINGS:In a normal pregnancy, total and LDL-cholesterol levels increase by approximately 30-50%, HDL-cholesterol by 20-40%, and triglycerides by 50-100%. In some women, for example, with familial hypercholesterolemia (FH), a more atherogenic lipid profile is observed. Dyslipidemia during pregnancy is found to be associated with adverse (cardiovascular) outcomes for the mother (e.g. preeclampsia, gestational diabetes, metabolic syndrome, unfavorable lipid profile) and for the child (e.g. preterm birth, large for gestational age, preatherosclerotic lesions, unfavorable lipid profile).SUMMARY:The lipid profile of women during pregnancy provides a unique window of opportunity into the potential future cardiovascular risk for mother and child. Better knowledge about adverse outcomes and specific risk groups could lead to better risk assessment and earlier cardiovascular prevention. Future research should investigate implementation of gestational screening possibilities.

Background Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence. Methods In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in followup between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipidlowering therapies other than lipoprotein apheresis. Findings The overall cohort included 404 patients with a median age at diagnosis of 60 years (IQR 30-95) and median untreated plasma LDL cholesterol of 17.8 mmol/L (14.7-20.8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17.2 mmol/L (14.8-19.7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs - 31% [-36 to -25]; p<00001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 052 [95% CI 032-085]) and longer cardiovascular death-free survival (00301 [00021-04295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0.010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15.0 years [IQR 12.0-24.0] vs 30.5 years [19.0-33.8]; p=0.037). Interpretation Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life.

Background and Aims: Homozygous FH (HoFH) is a severe lipid disorder, which results in extremely elevated LDL-C, early ASCVD and can even lead to death in childhood. Drastic lipid lowering in HoFH is of vital importance to prevent premature ASCVD, but remains challenging. Evinacumab, a novel monoclonal antibody directed against ANGPTL3, has shown reductions in LDL-C levels up to 50% on top of background lipid-lowering therapy in HoFH patients ≥12 years of age. The aim of this study is to determine the effects of evinacumab in children with HoFH on treatment (goals) and coronary CT angiography (CCTA) results. Methods: Children (6-18 years old) with HoFH who were treated with evinacumab were eligible. General characteristics, as well as LDL-C levels, presence of ASCVD and CCTA results, were compared before and after the start of evinacumab. Results: Seven children were studied. LDL-C levels were further reduced with a mean 33% since the start of evinacumab, while reducing the frequency of apheresis in all patients from weekly to once per four weeks. One child even was prevented from starting apheresis. None of them developed ASCVD. Visual CCTA interpretation revealed subtle non-calcified plaques regression in three patients, while none of the patients had evident plaque progression. Conclusions: In HoFH children, treatment with evinacumab resulted in superior LDL-C target attainment, and allowed reduction in apheresis. Subtle non-calcified plaque regression was observed on repeat CCTA imaging in three patients, illustrating that the potential of evinacumab can play a crucial role in the treatment of these HoFH patients.

Familial hypercholesterolemia (FH) is a common genetic disorder of lipoprotein metabolism leading to premature atherosclerosis. From early onset, status and progression of atherosclerosis of the large peripheral arterial walls can be quantified by ultrasound intima-media thickness (IMT) measurements. Here we describe differences in IMT in treated and untreated FH patients versus unaffected controls over a broad age range. We conducted a systematic literature search using MEDLINE, EMBASE and Trials.gov up to April 2020 for studies addressing IMT in FH patients and controls. Our search yielded 558 articles of which 42 (6,143 participants) were included. Meta-analysis showed a mean (95%CI) difference between FH patients vs controls of 0.11 (95%CI 0.06-0.15) mm in carotid IMT (p<0.001), and 0.47 (0.19-0.74) mm in femoral IMT (p <0.001). We found a smaller mean (95%CI) difference in carotid IMT in treated FH patients vs controls: 0.05 (0.03-0.08) mm (p <0.001), than in untreated FH patients vs controls 0.12 (0.03-0.21) mm (p=0.009). When plotted against age, the mean (95%CI) difference in carotid IMT between FH patients vs controls increases with 0.0018 (-0.0007-0.0042) mm/year. This increase was smaller in treated vs untreated FH patients, when compared to controls (0.0023 (0.0021 to 0.0025) mm/year vs 0.0104 (0.0100-0.0108) mm/year, respectively). Our findings suggest that more robust earlier treatment initiation and achieving treatment targets could be beneficial to reduce cardiovascular risk in patients with FH.

Background and Aims : Patients with Homozygous Familial Hypercholesterolaemia (HoFH) require intensive combination lipid lowering therapy (LLT) from diagnosis to avoid premature atherosclerotic cardiovascular disease (ASCVD). However, not all LLT are licensed for use in children and adolescents. We aimed to compare use of LLT in children, adolescents and adults with HoFH.Methods: We extracted descriptive data from two international databases for patients who were <18 years old at the time of HoFH diagnosis. We analysed the relationship between number of LLT prescribed (including apheresis) and achieved LDL-C, stratified by age at last database record.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Conclusions: Although LDL-C generally remains uncontrolled in paediatric patients with HoFH, use of multiple LLT therapies including apheresis is associated with lower LDL-C levels. This emphasizes the importance of making combination therapies accessible to all patients with HoFH regardless of age to prevent premature ASCVD. Background and Aims : Patients with Homozygous Familial Hypercholesterolaemia (HoFH) require intensive combination lipid lowering therapy (LLT) from diagnosis to avoid premature atherosclerotic cardiovascular disease (ASCVD). However, not all LLT are licensed for use in children and adolescents. We aimed to compare use of LLT in children, adolescents and adults with HoFH. Methods: We extracted descriptive data from two international databases for patients who were <18 years old at the time of HoFH diagnosis. We analysed the relationship between number of LLT prescribed (including apheresis) and achieved LDL-C, stratified by age at last database record. Conclusions: Although LDL-C generally remains uncontrolled in paediatric patients with HoFH, use of multiple LLT therapies including apheresis is associated with lower LDL-C levels. This emphasizes the importance of making combination therapies accessible to all patients with HoFH regardless of age to prevent premature ASCVD.

Familial hypercholesterolaemia is a common, dominantly inherited disease that results in high concentrations of low-density lipoprotein cholesterol and in premature cardiovascular disease. To prevent cardiovascular disease and premature mortality, patients with the condition need to be identified and to start treatment early in life. In this Review, we discuss the treatment of heterozygous and homozygous familial hypercholesterolaemia in children, including lifestyle modifications, current pharmacological treatment options, and promising novel lipid-lowering treatments. In particular, these new therapies are expected to improve outcomes for patients with severe heterozygous familial hypercholesterolaemia or statin intolerance. For patients with homozygous familial hypercholesterolaemia, lipoprotein apheresis is currently the most valuable therapy available, but new approaches might reduce the need for this effective yet invasive, time-consuming, and expensive treatment.

A recent Dutch study in patients with familial hypercholesterolaemia (FH), suggests that long-term statin treatment initiated at childhood reduces the risk for cardiovascular events in adulthood. None of the patients developed rhabdomyolysis or other serious adverse effects. Early detection of FH is crucial for early treatment initiation. However, the Dutch cascade screening program ended at the end of 2013, at which point approximately 40,000 FH patients had not yet been identified. In order to trace this cohort, in 2014 the 'LEEFH' foundation (National Expertise Centre for Genetic Testing for Familial Cardiovascular Diseases) was set up. Family members of index patients are no longer actively approached to be tested, and as a result the number of detected family members has decreased significantly. These study findings underline the importance of actively screening the family members of index patients, including children and adolescents.

A recent Dutch study in patients with familial hypercholesterolaemia (FH), suggests that long-term statin treatment initiated at childhood reduces the risk for cardiovascular events in adulthood. None of the patients developed rhabdomyolysis or other serious adverse effects. Early detection of FH is crucial for early treatment initiation. However, the Dutch cascade screening program ended at the end of 2013, at which point approximately 40,000 FH patients had not yet been identified. In order to trace this cohort, in 2014 the 'LEEFH' foundation (National Expertise Centre for Genetic Testing for Familial Cardiovascular Diseases) was set up. Family members of index patients are no longer actively approached to be tested, and as a result the number of detected family members has decreased significantly. These study findings underline the importance of actively screening the family members of index patients, including children and adolescents.

BACKGROUND:Familial hypercholesterolemia is characterized by severely elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. The short-term efficacy of statin therapy in children is well established, but longer follow-up studies evaluating changes in the risk of cardiovascular disease are scarce.METHODS:We report a 20-year follow-up study of statin therapy in children. A total of 214 patients with familial hypercholesterolemia (genetically confirmed in 98% of the patients), who were previously participants in a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, were invited for follow-up, together with their 95 unaffected siblings. Participants completed a questionnaire, provided blood samples, and underwent measurements of carotid intima-media thickness. The incidence of cardiovascular disease among the patients with familial hypercholesterolemia was compared with that among their 156 affected parents.RESULTS:Of the original cohort, 184 of 214 patients with familial hypercholesterolemia (86%) and 77 of 95 siblings (81%) were seen in follow-up; among the 214 patients, data on cardiovascular events and on death from cardiovascular causes were available for 203 (95%) and 214 (100%), respectively. The mean LDL cholesterol level in the patients had decreased from 237.3 to 160.7 mg per deciliter (from 6.13 to 4.16 mmol per liter) - a decrease of 32% from the baseline level; treatment goals (LDL cholesterol <100 mg per deciliter [2.59 mmol per liter]) were achieved in 37 patients (20%). Mean progression of carotid intima-media thickness over the entire follow-up period was 0.0056 mm per year in patients with familial hypercholesterolemia and 0.0057 mm per year in siblings (mean difference adjusted for sex, -0.0001 mm per year; 95% confidence interval, -0.0010 to 0.0008). The cumulative incidence of cardiovascular events and of death from cardiovascular causes at 39 years of age was lower among the patients with familial hypercholesterolemia than among their affected parents (1% vs. 26% and 0% vs. 7%, respectively).CONCLUSIONS:In this study, initiation of statin therapy during childhood in patients with familial hypercholesterolemia slowed the progression of carotid intima-media thickness and reduced the risk of cardiovascular disease in adulthood. (Funded by the AMC Foundation.).

The National Heart, Lung and Blood Institute Panel on integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents recommended a universal screening approach that would include one-time testing of all children aged 9-11 years for dyslipidemia. This recommendation has raised controversy regarding the identification and treatment of lipid abnormalities in children. Despite these recommendations, universal screening has not become routine: 68% of pediatricians never/rarely/sometimes screened healthy 9- to 11-year-olds.12 One of the reasons against universal screening in children has been the lack of long-term studies evaluating the effectiveness of screening for dyslipidemia in childhood in delaying or reducing the incidence of cardiovascular-related events.