Early Atherosclerotic Markers in Children with Familial Hypercholesterol

Summary Patients with familial hypercholesterolemia (FH) have an increased risk of premature atherosclerosis and coronary artery disease (CAD). Recently, inflammation has been suggested to play a major role in the development of atherosclerosis, and indeed children with FH have previously been suggested to have increased levels of selective inflammation markers. The aim of this study was to increase the knowledge about inflammation in the early steps of atherosclerosis. Sixty-two FH children (aged 7-20 years) and twenty-two sex- and age-matched control children were included. Quantification of the circulating proteins soluble (s)E-selectin, vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), adiponectin and leptin was performed in serum samples from each subject. Furthermore, gene expression levels of tumor necrosis factor á (TNFá), ICAM-1 and leptin receptor in peripheral blood mononuclear cells (PBMCs) were determined by quantitative reverse transcription polymerase chain reaction (Q-RT-PCR). The main results showed: i) FH children have increased TNFá gene expression levels and a tendency to increased sE-selectin levels compared to control children; ii) FH boys have enhanced sE-selectin and sVCAM-1 levels compared to FH girls; iii) FH boys above 15 years have increased levels of sE-selectin compared to age-matched FH girls; iv) FH boys below 15 years have enhanced levels of sVCAM-1 compared to FH girls in the same age group; v) FH girls have enhanced leptin levels compared to FH boys; vi) there was a tendency to enhanced leptin levels, whereas adiponectin levels were decreased in FH children above 15 years compared to FH children below 15 years. In conclusion, our results may support the notion of increased inflammation in FH children. Furthermore, the results may also indicate that the gender difference in the levels of early atherosclerotic markers may be established already in childhood and may thus partly explain the gender difference in the risk of CVD

Measurements of body fat is associated with markers of inflammation, insulin resistance and lipid levels in both overweight and in lean, healthy subjects

Background & aims: Low-grade inflammation is associated with fat mass in overweight. Whether this association exists in lean persons is unknown. Aims were to investigate associations between anthropometric measures of fat distribution and fat mass (% and kg) assessed by bioelectrical impedance analysis (BIA). Furthermore we wanted to investigate the relationship between fat mass and markers of insulin resistance, inflammation, and lipids in healthy subjects in different BMI categories. Methods: We compared 47 healthy overweight adults (BMI 26e40 kg/m2) and 40 lean (BMI 17e25 kg/ m2) matched for age and sex. Waist and hip circumferences, waist-to-hip ratio, waist-to-height ratio and triceps skinfold were used to evaluate fat distribution. BIA was used to estimate fat mass (% and kg). Markers of insulin resistance, lipids, inflammation and adipokines were measured. Results: Hip circumference was associated (P < 0.01) with BIA-assessed fat mass (%) in both groups (lean: regression coefficient B ¼ 0.4; overweight: B ¼ 0.5). An increase in hip circumference in all tertiles was associated with higher plasma levels of leptin, CRP and C-peptide in both groups. Conclusions: Fat mass may play a role in low-grade inflammation also in subjects within the normal range of BMI. Hip circumference may be a surrogate measure for fat mass in subjects in different BMI categories, and may be useful for identification of people with risk of developing overweight-related chronic disease

Substitution of TAG oil with diacylglycerol oil in food items improves the predicted 10 years cardiovascular risk score in healthy, overweight subjects

Dietary fat is normally in TAG form, but diacylglycerol (DAG) is a natural component of edible oils. Studies have shown that consumption of DAG results in metabolic characteristics that are distinct from those of TAG, which may be beneficial in preventing and managing obesity. The objective of the present study was to investigate if food items in which part of the TAG oil is replaced with DAG oil combined with high α-linolenic acid (ALA) content would influence metabolic markers. A 12-week double-blinded randomised controlled parallel-design study was conducted. The participants (n 23) were healthy, overweight men and women, aged 37–67 years, BMI 27–35 kg/m2, with waist circumference >94 cm (men) and >88 cm (women). The two groups received 20 g margarine, 11 g mayonnaise and 12 g oil per d, containing either high ALA and sn-1,3-DAG or high ALA and TAG. Substitution of TAG oil with DAG oil in food items for 12 weeks led to an improvement of the predicted 10 years cardiovascular risk score in overweight subjects by non-significantly improving markers of health such as total body fat percentage, trunk fat mass, alanine aminotransferase, systolic blood pressure, γ-glutamyl transferase, alkaline phosphatase and total fat-free mass. This may suggest that replacing TAG oil with DAG oil in healthy, overweight individuals may have beneficial metabolic effects

Children with familial hypercholesterolemia display changes in LDL and HDL function : A cross-sectional study

Publisher Copyright: © 2021 The Association for the Publication of the Journal of Internal Medicine.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.Peer reviewe

Effect of the fat composition of a single high-fat meal on inflammatory markers in healthy young women

The aim of the present study was to examine the effect of a single high-fat meal with different fat quality on circulating inflammatory markers and gene expression in peripheral blood mononuclear cells (PBMC) to elucidate the role of fat quality on postprandial inflammation. A postprandial study with fourteen healthy females consuming three test meals with different fat quality was performed. Test days were separated by 2 weeks. Fasting and postprandial blood samples at 3 and 6 h after intake were analysed. The test meal consisted of three cakes enriched with coconut fat (43 % energy as saturated fat and 1 % energy as a-linolenic acid (ALA)), linseed oil (14 % energy as ALA and 30 % energy as saturated fat) and cod liver oil (5 % energy as EPA and DHA and 5 % energy as ALA in addition to 31 % energy as saturated fat). In addition, ex vivo PBMC experiments were performed in eight healthy subjects investigating the effects of EPA and ALA on release and gene expression of inflammatory markers. The IL-8 mRNA level was significantly increased after intake of the cod liver oil cake at 6 h compared with fasting level, which was significantly different from the effect observed after the intake of linseed cake. In contrast, no effect was seen on circulating level of IL-8. In addition, ALA and EPA were shown to elicit different effects on the release and mRNA expression levels of inflammatory markers in PBMC cultured ex vivo, with EPA having the most prominent proinflammatory potentia

Lipoprotein (a) concentration is associated with plasma arachidonic acid in subjects with familial hypercholesterolemia

Elevated lipoprotein (a) (Lp[a]) is associated with cardiovascular disease (CVD) and is mainly genetically determined. Studies suggest a role of dietary fatty acids (FAs) in the regulation of Lp(a), however, no studies have investigated the association between plasma Lp(a) concentration and omega-6 FAs. We aimed to investigate whether plasma Lp(a) concentration was associated with dietary omega-6 FA intake, and plasma levels of arachidonic acid in subjects with familial hypercholesterolemia (FH). We included FH subjects with (n=68) and without (n=77) elevated Lp(a) defined as ≥75 nmol/L, and healthy subjects (n=14). Total fatty acid profile was analyzed by Gas Chromatography-Flame Ionization Detector analysis, and the daily intake of macronutrients (including the sum of omega-6 FAs: 18:2n-6, 20:2n-6, 20:3n-6 and 20:4n-6) were computed from completed food frequency questionnaires. FH subjects with elevated Lp(a) had higher plasma levels of arachidonic acid (AA) compared to FH subjects without elevated Lp(a) (P=0.03). Furthermore, both FH subjects with and without elevated Lp(a) had higher plasma levels of AA compared to controls (P<0.001). The multivariable analyses showed associations between dietary omega-6 FA intake and plasma levels of AA (P=0.02), and between plasma levels of Lp(a) and AA (P=0.006). Our data suggest a novel link between plasma Lp(a) concentration, dietary omega-6 FAs and plasma AA concentration, which may contribute to explain the small diet-induced increase in Lp(a) levels associated with lifestyle changes. Although the increase may not be clinically relevant, this association may be mechanistically interesting in understanding more of the role and regulation of Lp(a)

Effect of low carbohydrate high fat diet on LDL cholesterol and gene expression in normal-weight, young adults: A randomized controlled study

Background and aims: The effects of a low carbohydrate/high fat (LCHF) diet on health are debated. This study aims to explore the effects of a diet with less than 20 g carbohydrates per day (LCHF) on plasma low density lipoprotein cholesterol (LDL-C) in young and healthy adults. The secondary aim is the assessment of lipid profile and peripheral blood mononuclear cells (PBMC) gene expression. Methods: This was a randomized controlled parallel-designed intervention study. Participants were either assigned to a three-week LCHF diet or a control group continuing habitual diet ad libitum, in both groups. Results: In total, 30 healthy normal weight participants completed the study. Nine subjects did not complete it due to adverse events or withdrawn consent. In the LCHF diet group (n = 15), plasma LDL-C increased from (mean ± SD) 2.2 ± 0.4 mmol/l before intervention to 3.1 ± 0.8 after, while in the control group (n = 15), LDL-C remained unchanged: 2.5 ± 0.8 mmol/l (p < 0.001 between groups). There was a significant increase in apolipoprotein B, total cholesterol, high-density lipoprotein cholesterol, free fatty acids, uric acid and urea in the LCHF group versus controls. Plasma levels of triglycerides, lipoprotein (a), glucose, C-peptide or C-reactive protein (CRP), blood pressure, body weight or body composition did not differ between the groups. PBMC gene expression of sterol regulator element binding protein 1 (SREBP-1) was increased in the LCHF group versus controls (p ≤ 0.01). The individual increase in LDL-C from baseline varied between 5 and 107% in the LCHF group. Conclusions: An LCHF diet for three weeks increased LDL-C with 44% versus controls. The individual response on LCHF varied profoundly

Thirty percent of children and young adults with familial hypercholesterolemia treated with statins have adherence issues

Objective: To assess adherence to lipid lowering therapy (LLT), reasons for poor adherence, and achievement of LDL-C treatment goals in children and young adults with familial hypercholesterolemia (FH). Methods: Retrospective review of the medical records of 438 children that started follow-up at the Lipid Clinic, Oslo University hospital, between 1990 and 2010, and followed-up to the end of July 2019. Based on information on adherence to the LLT at the latest visit, patients were assigned to “good adherence” or “poor adherence” groups. Reasons for poor adherence were categorized as: “lack of motivation”, “ran out of drugs”, or “side effects”. Results: Three hundred and seventy-one patients were included. Mean (SD) age and follow-up time at the latest visit was 24.0 (7.1) and 12.9 (6.7) years; 260 patients (70%, 95% CI: 65–74%) had “good adherence” and 111 (30%, 95% CI: 25–35%) had “poor adherence”. “Lack of motivation” was the most common reason for poor adherence (n = 85, 23%). In patients with good adherence, compared to patients with poor adherence, age at latest visit (24.6 versus 22.0 years; p = 0.001), years of follow-up (13.5 versus 11.4 years; p = 0.003), and number of visits (8.1 versus 6.5 visits; p<0.001) were significantly higher, whereas LDL-C at the latest visit was lower, (3.1 (0.8) versus 5.3 (1.6) mmol/L; p<0.001) and percentage of patients reaching LDL-C treatment goal was higher, (34.5% versus 2.7%; p<0.001). Gender, BMI, age at first visit and premature cardiovascular disease in first degree relatives were not significantly associated with adherence. Conclusion: Thirty percent of young patients with FH had poor adherence to LLT, with lack of motivation as the main reason. Higher age, more visits and more years of follow-up were associated with good adherence

Long term follow-up of children with familial hypercholesterolemia and relatively normal LDL-cholesterol at diagnosis

Familial hypercholesterolemia (FH) is a genetic disorder with high low-density lipoprotein cholesterol (LDL-C) levels and high risk of cardiovascular disease. The long-term importance of carrying an FH mutation despite having relatively normal LDL-C levels in childhood is not known. We investigated the development of LDL-C levels and need of statin therapy in children with an FH mutation, with pretreatment LDL-C ≤ 4.1 mmol/L (~160 mg/dL), followed-up at lipid clinics in Oslo, Norway and Rotterdam, The Netherlands. Of 742 FH children, 109 (15%) had pretreatment LDL-C ≤ 4.1 mmol/L (~160 mg/dL) [mean (SD) 3.5 (0.5) mmol/L; (~130 (19) mg/dL)] measured at 11.8 (3.9) years of age [mean age (SD)]. After 8.2 (5.2) years [mean (SD)] of follow-up, 71.6% had started statin treatment. Therefore, all children carrying an FH mutation, independent of cholesterol levels, should receive follow-up at specialized lipid clinics for optimal and individualized treatment