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Background and Aims: Elderly familial hypercholesterolemia (FH) patients are at high risk of coronary heart disease (CHD) due to high cholesterol burden and late onset of effective cholesterol-lowering therapies. A subset of these individuals remains free from any CHD event, indicating the potential presence of protective factors. Identifying possible cardioprotective gene expression profiles could contribute to our understanding of CHD prevention and future preventive treatment. Therefore, this study aimed to investigate gene expression profiles in elderly event-free FH patients., Methods: Expression of 773 genes was analysed using the Nanostring Metabolic Pathways Panel, in peripheral blood mononuclear cells (PBMCs) from FH patients ≥65 years without CHD (FH event-free, n = 44) and with CHD (FH CHD, n = 39), and from healthy controls ≥70 years (n = 39)., Results: None of the genes were differentially expressed between FH patients with and without CHD after adjusting for multiple testing. However, at nominal p < 0.05, we found 36 (5%) differentially expressed genes (DEGs) between the two FH groups, mainly related to lipid metabolism (e.g. higher expression of ABCA1 and ABCG1 in FH event-free) and immune responses (e.g. lower expression of STAT1 and STAT3 in FH event-free). When comparing FH patients to controls, the event-free group had fewer DEGs than the CHD group; 147 (19%) and 219 (28%) DEGs, respectively., Conclusions: Elderly event-free FH patients displayed a different PBMC gene expression profile compared to FH patients with CHD. Differences in gene expression compared to healthy controls were more pronounced in the CHD group, indicating a less atherogenic gene expression profile in event-free individuals. Overall, identification of cardioprotective factors could lead to future therapeutic targets., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MPB has received research grants and/or personal fees from Amgen and Sanofi, none of which are related to the content of this manuscript. JJC has received research grants and/or personal fees from Mills DA and Amgen, none of which are related to the content of this manuscript. AR has received personal fees from Rimfrost AS that are not related to the content of this manuscript. KR has received research grants and/or personal fees from Akcea, Amgen, Mills, Sanofi and Sunnovion, none of which are related to the content of this manuscript. KBH has received research grants and/or personal fees from Sanofi that are related to the content of this manuscript. The other authors have no financial relationships relevant to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Legumain is known to be regulated in atherosclerotic disease and may have both pro- and anti-atherogenic properties. The study aimed to explore legumain in individuals with familial hypercholesterolemia (FH), a population with increased cardiovascular risk. Plasma legumain was measured in 251 subjects with mostly genetically verified FH, of which 166 were adults (≥18 years) and 85 were children and young adults (<18 years) and compared to 96 normolipidemic healthy controls. Plasma legumain was significantly increased in the total FH population compared to controls (median 4.9 versus 3.3 pg/mL, respectively, p  < 0.001), whereof adult subjects with FH using statins had higher levels compared to non-statin users (5.7 versus 3.9 pg/mL, respectively, p  < 0.001). Children and young adults with FH ( p  = 0.67) did not have plasma legumain different from controls at the same age. Further, in FH subjects, legumain showed a positive association with apoB, and markers of inflammation and platelet activation (i.e. fibrinogen, NAP2 and RANTES). In the current study, we show that legumain is increased in adult subjects with FH using statins, whereas there was no difference in legumain among children and young adults with FH compared to controls. Legumain was further associated with cardiovascular risk markers in the FH population. However the role of legumain in regulation of cardiovascular risk in these individuals is still to be determined.

Background and Aims: Both Nordic and Mediterranean diets are considered healthy despite notable regional differences. Although these dietary patterns may lower cardiovascular risk, it is unclear if they improve the lipoprotein phenotype in children with familial hypercholesterolemia (FH). The aim is to determine the impact of Nordic and Mediterranean diets on the advanced lipoprotein profile in children with heterozygous FH (HeFH)., Methods: This was a cross-sectional study performed in children with FH recruited from the Lipid Clinics at Sant Joan University Hospital in Reus (Spain) and Oslo University Hospital (Norway). Two-hundred fifty-six children (mean age 10 y/o; 48% girls): 85 Spanish and 29 Norwegian FH children, and 142 non-FH healthy controls (119 from Spain and 23 from Norway) were included in the study. A pathogenic FH-associated genetic variant was present in 81% of Spanish children with FH and all Norwegian children with FH. An 1 H NMR based advanced lipoprotein test (Nightingale®) providing information on the particle number, size and lipid composition of 14 lipoprotein subclasses was performed and correlated to the dietary components., Results: Levels of LDL-C, HDL-C and triglycerides were not significantly different between the Nordic and Mediterranean FH groups. Spanish children with FH had more LDL particles, mainly of the large and medium LDL subclasses, than Norwegian FH children. Spanish FH children also had more HDL particles, mainly medium and small, than Norwegian FH children. The mean LDL size of Spanish FH children was larger, while the HDL size was smaller than that of the Norwegian FH children. The HDL particle number and size were the main determinants of differences between the two groups. In Norwegian children with FH, dietary total fat and MUFAs showed a significant correlation with all apolipoprotein B-containing lipoproteins and LDL size, whereas there was no correlation to SFA. A weaker association pattern was observed in the Spanish children., Conclusions: The lipoprotein profiles of Spanish and Norwegian children showed differences when studied by 1 H NMR. These differences were in part associated with differences in dietary patterns., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol (LDL-C) and increased risk of premature coronary heart disease (CHD). Cholesterol-lowering therapy (statins) reduces CHD risk, but have been available only in the last 25 years, thus, elderly FH patients have been exposed to elevated LDL-C levels most of their life. Surprisingly, some of these have never experienced any CHD event, raising the question whether they present CHD resistant characteristics. Identifying possible cardioprotective biomarkers could contribute to future CHD preventive treatment, therefore, we aimed to identify metabolic markers in event-free elderly FH subjects., Methods and Results: We used a high-throughput nuclear magnetic resonance (NMR) spectroscopy platform to quantify a large number of metabolites in serum samples from 83 FH patients ≥65 years, and analyze differences between subjects with (n = 39) and without (n = 44) CHD. Mean age was 70 years in both groups (57% and 38% female in the event-free group and CHD group, respectively). The event-free group had significantly higher levels of large and extra-large high-density lipoprotein (HDL) particles, and higher concentration of Apolipoprotein A1 (ApoA1) and cholesterol in HDL and HDL2 particles, compared to the CHD group (p ≤ 0.05 for all)., Conclusion: CHD resistant elderly FH patients have higher levels of large HDL particles. The mechanisms behind the event-free survival among these patients remain unclear; hence, a deeper understanding of the metabolic profile in event-free elderly FH subjects may lead to development of novel preventive therapies., Competing Interests: Declaration of competing interest Dr. Bogsrud has received research grants and/or personal fees from Amgen and Sanofi, none of which are related to the content of this manuscript. Dr. Christensen has received research grants and/or personal fees from Mills DA and Amgen, none of which are related to the content of this manuscript. Dr. Retterstøl has received research grants and/or personal fees from Akcea, Amgen, Mills, Sanofi and Sunnovion, none of which are related to the content of this manuscript. MD. Dr. Ulven has received research grants from Mills DA, TINE BA and Olympic Seafood, none of which are related to the content of this manuscript. Dr. Holven has received research grants and/or personal fees from TINE, Mills, Amgen, Sanofi and Olympic Seafood, none of which are related to the content of this manuscript. Msc. Melnes, Msc. Thorsen, Msc. Fossum, PhD Narverud have nothing to disclose., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The functional status of lipoprotein particles contributes to atherogenesis. The tendency of plasma low-density lipoprotein (LDL) particles to aggregate and the ability of igh-density lipoprotein (HDL) particles to induce and mediate reverse cholesterol transport associate with high and low risk for cardiovascular disease in adult patients, respectively. However, it is unknown whether children with familial hypercholesterolemia (FH) display lipoprotein function alterations., Hypothesis: We hypothesized that FH children had disrupted lipoprotein functions., Methods: We analyzed LDL aggregation susceptibility and HDL-apoA-I exchange (HAE), and activity of four proteins that regulate lipoprotein metabolism (cholesteryl ester transfer protein, lecithin-cholesterol acyltransferase, phospholipid transfer protein, and paraoxonase-1) in plasma samples derived from children with FH (n = 47) and from normocholesterolemic children (n = 56). Variation in lipoprotein functions was further explored using an nuclear magnetic resonance-based metabolomics profiling approach., Results: LDL aggregation was higher, and HAE was lower in FH children than in normocholesterolemic children. LDL aggregation associated positively with LDL cholesterol (LDL-C) and negatively with triglycerides, and HAE/apoA-I associated negatively with LDL-C. Generally, the metabolomic profile for LDL aggregation was opposite of that of HAE/apoA-I., Conclusions: FH children displayed increased atherogenicity of LDL and disrupted HDL function. These newly observed functional alterations in LDL and HDL add further understanding of the risk for atherosclerotic cardiovascular disease in FH children., (© 2021 The Association for the Publication of the Journal of Internal Medicine.)

Background and Aims: Both the Nordic and Mediterranean diets claim to have a beneficial effect on lipid metabolism and cardiovascular prevention. The objective of this study was to compare diets consumed by children with FH at the time of diagnosis in Norway and Spain and to study their relationship with the lipid profile., Methods and Results: In this cross-sectional study, we appraised the dietary intake in children (4-18 years old) with (n = 114) and without FH (n = 145) from Norway and Spain. We compared Nordic and Mediterranean diet composition differences and determined the association between food groups and lipid profiles., Results: The Spanish FH group had a higher intake of total fats (mainly monounsaturated fatty acids (MUFAs)), cholesterol and fibre, but a lower intake of polyunsaturated fatty acids (PUFAs) compared to the Norwegian FH group. The Norwegian children consumed more rapeseed oil, low-fat margarine and whole grains and less olive oil, eggs, fatty fish, meat, legumes and nuts. In the Norwegian FH group, fat and MUFAs were directly correlated with total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B and inversely correlated with high-density lipoprotein (HDL-C). In Spanish children with FH, the intake of fats (mainly MUFAs) was directly associated with HDL-C and apolipoprotein A1., Conclusions: Despite a similar lipid phenotype, diets consumed by children with FH in Norway and Spain have significant differences at time of diagnosis. Nutrition advice should be more adapted to local intake patterns than on specific nutrient composition., Competing Interests: Declarations of interest Prof. Holven reports grants and/or personal fees from Tine SA, Norway; Mills DA, Norway; Olympic Seafood, Norway; Amgen, United States; Sanofi, United States; Kaneka, Japan; and Pronova, United States; none of which are related to the content of this manuscript. Prof. Masana has received personal fees for lectures and advisory work from Sanofi, United States; Amgen, United States; Mylan, United States; and Servier, France; none of which are related to the content of this manuscript. The other authors have no relevant financial relationships to disclose., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Innate and adaptive immune responses are pivotal in atherosclerosis, but their association with early-stage atherosclerosis in humans is incompletely understood. In this regard, untreated children with familial hypercholesterolaemia may serve as a human model to investigate the effect of elevated low-density lipoprotein (LDL)-cholesterol., Objectives: We aimed to study the immunological and inflammatory pathways involved in early atherosclerosis by examining mRNA molecules in peripheral blood mononuclear cells (PBMCs) from children with FH., Methods: We analysed the level of 587 immune-related mRNA molecules using state-of-the-art Nanostring technology in PBMCs from children with (n = 30) and without (n = 21) FH, and from FH children before and after statin therapy (n = 10)., Results: 176 genes (30%) were differentially expressed between the FH and healthy children at P < 0.05. Compared to healthy children, the dysregulated pathways in FH children included the following: T cells (18/19); B cells (5/6); tumour necrosis factor super family (TNFSF) (6/8); cell growth, proliferation and differentiation (5/7); interleukins (5/9); toll-like receptors (2/5); apoptosis (3/7) and antigen presentation (1/7), where the ratio denotes higher expressed genes to total number of genes. Statin therapy reversed expression of thirteen of these mRNAs in FH children., Conclusion: FH children display higher PBMC expression of immune-related genes mapped to several pathways, including T and B cells, and TNFSF than healthy children. Our results suggest that LDL-C plays an important role in modulating expression of different immune-related genes, and novel data on the involvement of these pathways in the early atherosclerosis may represent future therapeutic targets for prevention of atherosclerotic progression., (© 2019 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication.)

Background and Aims: Individuals with familial hypercholesterolemia (FH) have elevated low-density lipoprotein cholesterol (LDL-C), accelerated atherosclerosis, and premature cardiovascular disease. Whereas children with lifestyle-induced dyslipidemias often present with complex lipid abnormalities, children with FH have isolated hypercholesterolemia. However, to the best of our knowledge, a comprehensive profiling of FH children is lacking. Therefore, we aimed to characterize the lipid-related and metabolic alterations associated with elevated LDL-C in children with FH and healthy children., Methods: We measured plasma metabolites in children with FH (n = 47) and in healthy children (n = 57) using a high-throughput nuclear magnetic resonance (NMR) spectroscopy platform, and compared the differences between FH and healthy children., Results: Both statin treated (n = 17) and non-statin treated FH children (n = 30) had higher levels of atherogenic ApoB-containing lipoproteins and lipids, and lipid fractions in lipoprotein subclasses, compared to healthy children (n = 57). FH children displayed alterations in HDL particle concentration and lipid content, compared with healthy children. Interestingly, the small HDL particles were characterized by higher content of cholesteryl esters, and lower levels of free cholesterol and phospholipids. Furthermore, plasma fatty acids were higher in non-statin treated FH children, particularly linoleic acid. Finally, acetoacetate and acetate were lower in FH children compared with healthy children., Conclusions: Hypercholesterolemia in children associates with diverse metabolic repercussions and is more complex than previously believed. In particular, we found that hypercholesterolemia in FH children was paralleled not only by increased atherogenic ApoB-containing lipoproteins and lipid fractions, but also alterations in HDL subfractions that suggest impaired reverse cholesterol transport., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Aims: Children with familial hypercholesterolemia (FH) have elevated LDL cholesterol from the first year of life, and represent a model of early-stage atherosclerosis. Data suggest that adults with FH have alterations in circulating monocyte subpopulations towards a more pro-inflammatory phenotype, but it is not known whether FH children have similar perturbations. In addition, there are no data on the distribution of lymphocyte subpopulations in FH children. The objective of the present study was to characterize the distributions of circulating monocyte and lymphocyte subpopulations in children with FH and healthy, normocholesterolemic children., Methods: Using flow cytometry analysis, we analyzed whole blood B- and T-cell subpopulations and monocyte subpopulations in FH (n = 23) and healthy (n = 20) children. Moreover, we measured serum markers of leukocyte and endothelial cell activation using EIA., Results: We found that FH children had monocytosis as well as a shift in the monocyte subpopulations. This shift was characterized by higher circulating pro-inflammatory and non-classical monocytes, and lower levels of classical monocytes, and seemed to be present only in FH children with low HDL cholesterol (HDL-C, below 1.3 mmol/L). Additionally, monocytes expressing CD18 and serum E-selectin were higher in FH children, in particular FH children with low HDL-C., Conclusions: FH children with low HDL-C had monocytosis as well as a shift in monocyte subpopulations towards a more pro-inflammatory phenotype. Our results suggest activation of monocytes at a very early stage of atherosclerosis in humans., (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.)