Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Étude des différences phénotypiques selon l'héritabilité maternelle ou paternelle de la mutation génétique dans l'hypercholestérolémie familiale T

Introduction : l’hypercholestérolémie familiale (HF) se transmet sur un mode autosomique dominant et entraîne un sur-risque cardiovasculaire. En France, un registre mis en place par la NSFA suit les patients HF. En cas de transmission maternelle, le fœtus est exposé in utero à des taux de LDL-C maternels très élevés [1]. En nous appuyant sur le concept des « origines développementales de la santé et des maladies » [2], notre objectif était d’étudier l’effet de l’héritabilité maternelle ou paternelle de la mutation génétique sur la survenue d’événements cardiovasculaires (CV).Méthodes : sur 513 patients du registre marseillais de l’HF, 138 patients dont l’origine parentale a été retrouvée avaient la mutation. Nous avons comparé les 2 groupes héritabilité maternelle (64 patients, groupe HM) et héritabilité paternelle (74 patients, groupe HP) sur la survenue d’événements cardiovasculaires. La méthode de régression logistique a été utilisée pour déterminer les facteurs prédictifs de survenue d’événements CV.Résultats : à l’inclusion, les groupes étaient comparables sauf le groupe HM qui était plus hypertendu (25% vs 9,4%, p=0,01), plus traité par anti-PCSK9 (20,3 vs 5,4%, p=0,008) et avec moins d’antécédents CV familiaux précoces (28,6 vs 51,4 %, p=0,007). 35,9 % des patients HM (n=23/64) et 27% des patients HP (n=20/74) ont fait un évènement CV (p=0,26). Ils étaient comparables sur l’âge du 1er évènement, le LDL-C maximal, l’âge de début des statines, la lipoprotéine (a). Les facteurs prédictifs d’évènement CV étaient le sexe (p=0,0004), l’âge de début des statines (p=0,00003), le LDL-c max (p=0,009) et la Lp(a) (p=0,007). En analyse multivariée, l’hérédité n’est pas associée au risque d’évènement CV (risque HP vs HM : OR=0,34, p=0,076. Le sexe, l’âge de début des statines et le taux de Lp(a) restent significativement associés au risque d’évènement CV (OR=0,3, p=0,044 pour les femmes ; OR=1,08, p=0,001 pour un début plus tardif des statines ; OR=6,98, p=0.0096 pour Lp(a)).Conclusion : l’héritabilité n’a pas d’effet statistiquement significatif sur la survenue d’événements CV à l’âge adulte. Cependant, il semblerait exister une tendance à une protection quand la mutation est héritée du père. Cette étude devra être étendue à l’ensemble des patients HF hétérozygotes avec diagnostic génétique du registre REFERCHOL afin d’augmenter la puissance de l’étude et voir si les tendances se confirment.[1] Claudio Napoli, Christopher K Glass, Joseph L Witztum et al, Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. THE LANCET · Vol 354 · October 9, 1999[2] Barker DJ, The origins of the developmental origins theory. J Intern Med. 2007 May;261(5):412

Hyperlipidaemia in diabetes: are there particular considerations for next-generation therapies?

International audienceAbstract Dyslipidaemias are major cardiovascular risk factors, especially in people with diabetes. In this area, next-generation therapies targeting circulating lipoparticle metabolism (LDL, VLDL, chylomicrons, HDL) have recently been approved by the European and US medical agencies, including anti- proprotein convertase subtilisin/kexin 9 (PCSK9) antibodies; an siRNA targeting PCSK9; bempedoic acid, which targets ATP citrate lyase; an antisense oligonucleotide targeting apolipoprotein C-III; an anti-angiopoietin-like 3 antibody; and a purified omega-3 fatty acid, icosapent ethyl. Other therapies are in different phases of development. There are several important considerations concerning the link between these new lipid-lowering therapies and diabetes. First, since concerns were first raised in 2008 about an increased risk of new-onset diabetes mellitus (NODM) with intensive statin treatment, each new lipid-lowering therapy is being evaluated for its associated risk of NODM, particularly in individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance). Second, people with diabetes represent a large proportion of those at high or very high cardiovascular risk in whom these lipid-lowering drugs are currently, or will be, prescribed. Thus, the efficacy of these drugs in subgroups with diabetes should also be closely considered, as well as any potential effects on glycaemic control. In this review, we describe the efficacy of next-generation therapies targeting lipoprotein metabolism in subgroups of people with diabetes and their effects on glycaemic control in individuals with diabetes and prediabetes and in normoglycaemic individuals. Graphical Abstrac

Growth-Friendly Tax Structures: An Indicator-Based Approach

This paper designs a horizontal indicator-based assessment methodology aimed at identifying those EU countries presenting a potential need and scope for shifting taxation away from labour to other tax bases less detrimental to growth. The assessment methodology, as a first step, selects a set of indicators measuring specific aspects of tax policy. Subsequently, for each individual indicator, performance thresholds are calculated based on a benchmarking approach. Finally, a screening algorithm based on commonly accepted findings from the relevant economic literature is used to assess the overall performance of a country in two policy areas, namely the need for a tax shift and the scope for it. Various robustness checks are performed.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Effectiveness of Roux-en-Y Gastric Bypass vs Sleeve Gastrectomy on Lipid Levels in Type 2 Diabetes: a Meta-analysis

International audienceIntroduction Obesity and its co-morbidities, including type 2 diabetes (T2DM) and dyslipidemia, are accompanied by excess cardiovascular morbi-mortality. Aside from excess low density lipoprotein-cholesterol (LDL-C), atherogenic dyslipidemia (AD), mainly characterized by elevated triglycerides and decreased high density lipoprotein-cholesterol (HDL-C) levels, is often present in T2DM obese patients. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), has become a reference treatment in that population. However, the respective effects of RYGB vs SG on lipid metabolism in T2DM patients have been rarely studied.Methods A meta-analysis of randomized controlled trials, comparing the effects of RGYBG vs SG on lipid metabolism 12 months after surgery in T2DM patients, was performed.Results Four studies including a total of 298 patients (151 patients in the RYGB and 147 patients in the SG group) were examined. Despite a greater decrease in body mass index and greater improvement in glycemic control in RYGB compared to SG. RYGB vs SG was more effective in reducing total cholesterol, LDL-C, and non-HDL-C levels (mean difference [MD] -26.10 mg/dL, 95 % CI -38.88 to -13.50, p<0.00001; [MD] -20.10 mg/dL, 95 % CI - 27.90 to -12.20, p<0.00001 and MD 31.90 mg/ dl, 95 % CI -46.90 to -16.80, p<0.00001, respectively).Conclusions The superiority of RYGB vs SG in reducing LDL-C, with an effect comparable to a moderate-intensity statin, suggests RYBG should be favored in hypercholesterolemic T2DM patients in order to further reduce cardiovascular risk

Low Density Lipoprotein Cholesterol Decreases the Expression of Adenosine A2A Receptor and Lipid Rafts-Protein Flotillin-1: Insights on Cardiovascular Risk of Hypercholesterolemia

International audienceHigh blood levels of low-density lipoprotein (LDL)-cholesterol (LDL-C) are associated with atherosclerosis, mainly by promoting foam cell accumulation in vessels. As cholesterol is an essential component of cell plasma membranes and a regulator of several signaling pathways, LDL-C excess may have wider cardiovascular toxicity. We examined, in untreated hypercholesterolemia (HC) patients, selected regardless of the cause of LDL-C accumulation, and in healthy participants (HP), the expression of the adenosine A2A receptor (A2AR), an anti-inflammatory and vasodilatory protein with cholesterol-dependent modulation, and Flotillin-1, protein marker of cholesterol-enriched plasma membrane domains. Blood cardiovascular risk and inflammatory biomarkers were measured. A2AR and Flotillin-1 expression in peripheral blood mononuclear cells (PBMC) was lower in patients compared to HP and negatively correlated to LDL-C blood levels. No other differences were observed between the two groups apart from transferrin and ferritin concentrations. A2AR and Flotillin-1 proteins levels were positively correlated in the whole study population. Incubation of HP PBMCs with LDL-C caused a similar reduction in A2AR and Flotillin-1 expression. We suggest that LDL-C affects A2AR expression by impacting cholesterol-enriched membrane microdomains. Our results provide new insights into the molecular mechanisms underlying cholesterol toxicity, and may have important clinical implication for assessment and treatment of cardiovascular risk in HC

Role of growth hormone in hepatic and intestinal triglyceride-rich lipoprotein metabolism

International audienceBackground: Elevated plasma concentrations of hepatic- and intestinally-derived triglyceride-rich lipoproteins (TRL) are implicated in the pathogenesis of atherosclerotic cardiovascular disease and all-cause mortality. Excess of TRL is the driving cause of atherogenic dyslipidemia commonly occurring in insulin-resistant individuals such as patients with obesity, type 2 diabetes and metabolic syndrome. Interestingly, growth hormone (GH)-deficient individuals display similar atherogenic dyslipidemia, suggesting an important role of GH and GH deficiency in the regulation of TRL metabolism.Objective: We aimed to examine the direct and/or indirect role of GH on TRL metabolism.Methods: We investigated the effect on fasting and postprandial hepatic-TRL and intestinal-TRL metabolism of short-term (one month) withdrawal of GH in 10 GH-deficient adults.Results: After GH withdrawal, we found a reduction in fasting plasma TRL concentration (significant decrease in TRL-TG, TRL-cholesterol, TRL-apoB-100, TRL-apoC-III and TRL-apoC-II) but not in postprandial TRL response. This reduction was due to fewer fasting TRL particles without a change in TG per particle and was not accompanied by a change in postprandial TRL-apoB-48 response. Individual reductions in TRL correlated strongly with increases in insulin sensitivity and decreases in TRL-apoC-III.Conclusion: In this relatively short term 'loss of function' human experimental model, we have shown an unanticipated reduction of hepatic-TRL particles despite increase in total body fat mass and reduction in lean mass. These findings contrast with the atherogenic dyslipidemia previously described in chronic GH deficient states, providing a new perspective for the role of GH in lipoprotein metabolism

Maternal Inheritance of Familial Hypercholesterolemia Gene Mutation Predisposes to Coronary Atherosclerosis as Assessed by Calcium Score in Adulthood

International audienceBackground: Animal studies have demonstrated that fetal exposure to high maternal cholesterol levels during pregnancy predisposes to aortic atheroma in the offspring. In humans, little is known about the consequences of this exposure on the development of atherosclerotic cardiovascular disease later in life. We wanted to assess whether maternal/paternal inheritance of familial hypercholesterolemia (FH) gene mutation could be associated with subclinical coronary atherosclerosis. Methods: We retrospectively included 1350 patients, followed in the French registry of FH, with a documented genetic diagnosis. We selected 556 age- and sex-matched pair of patients based on the sex of the parents who transmitted the FH gene mutation, free of coronary cardiovascular event, and with a subclinical coronary atherosclerosis evaluation assessed using coronary artery calcium (CAC) score. We performed univariate and multivariate analysis to assess the individual effect of parental inheritance of the FH gene mutation on the CAC score. Results: In the whole population, patients with maternal inheritance of FH gene mutation (n=639) less frequently had a family history of premature cardiovascular events (27.7% versus 45%, P <0.0001) and were 2 years older (46.9±16.8 versus 44.7±15.9 years old, P =0.02) than those with paternal inheritance (n=711). There was no difference in the prevalence of cardiovascular events between the two groups. In the matched subgroup, maternal inheritance was significantly associated with an increase in CAC score value by 86% (95% CI, 23%–170%; P =0.003), a 1.81-fold risk of having a CAC score ≥100 Agatston units (95% CI, 1.06–3.11; P =0.03), and a 2.72-fold risk of having a CAC score ≥400 Agatston units (95% CI, 1.39–5.51; P =0.004) when compared with paternal inheritance in multivariate analysis. Conclusions: Maternal inheritance of FH gene mutation was associated with more severe subclinical coronary atherosclerosis assessed by CAC score and may be considered as a potential cardiovascular risk factor