Plasma legumain in familial hypercholesterolemia: associations with statin use and cardiovascular risk markers.

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.

What characterizes event-free elderly FH patients? A comprehensive lipoprotein profiling.

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.

Differential effects of bariatric surgery and lifestyle interventions on plasma levels of Lp(a) and fatty acids.

BACKGROUND: Limited evidence suggests that surgical and non-surgical obesity treatment differentially influence plasma Lipoprotein (a) [Lp(a)] levels. Further, a novel association between plasma arachidonic acid and Lp(a) has recently been shown, suggesting that fatty acids are a possible target to influence Lp(a). Here, the effects of bariatric surgery and lifestyle interventions on plasma levels of Lp(a) were compared, and it was examined whether the effects were mediated by changes in plasma fatty acid (FA) levels. METHODS: The study includes two independent trials of patients with overweight or obesity. Trial 1: Two-armed intervention study including 82 patients who underwent a 7-week low energy diet (LED), followed by Roux-en-Y gastric bypass and 52-week follow-up (surgery-group), and 77 patients who underwent a 59-week energy restricted diet- and exercise-program (lifestyle-group). Trial 2: A clinical study including 134 patients who underwent a 20-week very-LED/LED (lifestyle-cohort). RESULTS: In the surgery-group, Lp(a) levels [median (interquartile range)] tended to increase in the pre-surgical LED-phase [17(7-68)-21(7-81)nmol/L, P = 0.05], but decreased by 48% after surgery [21(7-81)-11(7-56)nmol/L, P < 0.001]. In the lifestyle-group and lifestyle-cohort, Lp(a) increased by 36%[14(7-77)-19(7-94)nmol/L, P < 0.001] and 14%[50(14-160)-57(19-208)nmol/L, P < 0.001], respectively. Changes in Lp(a) were independent of weight loss. Plasma levels of total saturated FAs remained unchanged after surgery, but decreased after lifestyle interventions. Arachidonic acid and total n-3 FAs decreased after surgery, but increased after lifestyle interventions. Plasma FAs did not mediate the effects on Lp(a). CONCLUSION: Bariatric surgery reduced, whereas lifestyle interventions increased plasma Lp(a), independent of weight loss. The interventions differentially influenced changes in plasma FAs, but these changes did not mediate changes in Lp(a). TRIAL REGISTRATION: Trial 1: Clinicaltrials.gov NCT00626964. Trial 2: Netherlands Trial Register NL2140 (NTR2264).

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

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.

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

Elevated lipoprotein(a) (Lp(a)) is associated with CVD and is mainly genetically determined. Studies suggest a role of dietary fatty acids (FA) in the regulation of Lp(a); however, no studies have investigated the association between plasma Lp(a) concentration and n-6 FA. We aimed to investigate whether plasma Lp(a) concentration was associated with dietary n-6 FA intake and plasma levels of arachidonic acid (AA) in subjects with familial hypercholesterolaemia (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 FA profile was analysed by GC-flame ionisation detector analysis, and the daily intake of macronutrients (including the sum of n-6 FA: 18 : 2n-6, 20 : 2n-6, 20 : 3n-6 and 20 : 4n-6) were computed from completed FFQ. FH subjects with elevated Lp(a) had higher plasma levels of AA compared with 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 with controls (P < 0·001). The multivariable analyses showed associations between dietary n-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 n-6 FA and plasma AA concentration, which may 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).

Delayed postprandial TAG peak after intake of SFA compared with PUFA in subjects with and without familial hypercholesterolaemia: a randomised controlled trial.

Postprandial hypertriacylglycerolaemia is associated with an increased risk of developing CVD. How fat quality influences postprandial lipid response is scarcely explored in subjects with familial hypercholesterolaemia (FH). The aim of this study was to investigate the postprandial response of TAG and lipid sub-classes after consumption of high-fat meals with different fat quality in subjects with FH compared with normolipidaemic controls. A randomised controlled double-blind cross-over study with two meals and two groups was performed. A total of thirteen hypercholesterolaemic subjects with FH who discontinued lipid-lowering treatment 4 weeks before and during the study, and fourteen normolipidaemic controls, were included. Subjects were aged 18-30 years and had a BMI of 18·5-30·0 kg/m2. Each meal consisted of a muffin containing 60 g (70 E%) of fat, either mainly SFA (40 E%) or PUFA (40 E%), eaten in a random order with a wash-out period of 3-5 weeks between the meals. Blood samples were collected at baseline (fasting) and 2, 4 and 6 h after intake of the meals. In both FH and control subjects, the level of TAG and the largest VLDL sub-classes peaked at 2 h after intake of PUFA and at 4 h after intake of SFA. No significant differences were found in TAG levels between meals or between groups (0·25≤P≤0·72). The distinct TAG peaks may reflect differences in the postprandial lipid metabolism after intake of fatty acids with different chain lengths and degrees of saturation. The clinical impact of these findings remains to be determined.

Severe hypertriglyceridemia in Norway: prevalence, clinical and genetic characteristics.

BACKGROUND: There is a lack of comprehensive patient-datasets regarding prevalence of severe hypertriglyceridemia (sHTG; triglycerides ≥10 mmol/L), frequency of co-morbidities, gene mutations, and gene characterization in sHTG. Using large surveys combined with detailed analysis of sub-cohorts of sHTG patients, we here sought to address these issues. METHODS: We used data from several large Norwegian surveys that included 681,990 subjects, to estimate the prevalence. Sixty-five sHTG patients were investigated to obtain clinical profiles and candidate disease genes. We obtained peripheral blood mononuclear cells (PBMC) from six male patients and nine healthy controls and examined expression of mRNAs involved in lipid metabolism. RESULTS: The prevalence of sHTG was 0.13 (95% CI 0.12-0.14)%, and highest in men aged 40-49 years and in women 60-69 years. Among the 65 sHTG patients, a possible genetic cause was found in four and 11 had experienced acute pancreatitis. The mRNA expression levels of carnitine palmitoyltransferase (CPT)-1A, CPT2, and hormone-sensitive lipase, were significantly higher in patients compared to controls, whereas those of ATP-binding cassette, sub-family G, member 1 were significantly lower. CONCLUSIONS: In Norway, sHTG is present in 0.1%, carries considerable co-morbidity and is associated with an imbalance of genes involved in lipid metabolism, all potentially contributing to increased cardiovascular morbidity in sHTG.

Gene expression profiling in elderly patients with familial hypercholesterolemia with and without coronary heart disease.

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.

Dietary fat quality, plasma atherogenic lipoproteins, and atherosclerotic cardiovascular disease: An overview of the rationale for dietary recommendations for fat intake.

The scientific evidence supporting the current dietary recommendations for fat quality keeps accumulating; however, a paradoxical distrust has taken root among many researchers, clinicians, and in parts of the general public. One explanation for this distrust may relate to an incomplete overview of the totality of the evidence for the link between fat quality as a dietary exposure, and health outcomes such as atherosclerotic cardiovascular disease (ASCVD). Therefore, the main aim of the present narrative review was to provide a comprehensive overview of the rationale for dietary recommendations for fat intake, limiting our discussion to ASCVD as outcome. Herein, we provide a core framework - a causal model - that can help us understand the evidence that has accumulated to date, and that can help us understand new evidence that may become available in the future. The causal model for fat quality and ASCVD is comprised of three key research questions (RQs), each of which determine which scientific methods are most appropriate to use, and thereby which lines of evidence that should feed into the causal model. First, we discuss the link between low-density lipoprotein (LDL) particles and ASCVD (RQ1); we draw especially on evidence from genetic studies, randomized controlled trials (RCTs), epidemiology, and mechanistic studies. Second, we explain the link between dietary fat quality and LDL particles (RQ2); we draw especially on metabolic ward studies, controlled trials (randomized and non-randomized), and mechanistic studies. Third, we explain the link between dietary fat quality, LDL particles, and ASCVD (RQ3); we draw especially on RCTs in animals and humans, epidemiology, population-based changes, and experiments of nature. Additionally, the distrust over dietary recommendations for fat quality may partly relate to an unclear understanding of the scientific method, especially as applied in nutrition research, including the process of developing dietary guidelines. We therefore also aimed to clarify this process. We discuss how we assess causality in nutrition research, and how we progress from scientific evidence to providing dietary recommendations.

Elevated serum MMP-9/TIMP-1 ratio in patients with homozygous familial hypercholesterolemia: effects of LDL-apheresis.

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.

Young women with familial hypercholesterolemia have higher LDL-cholesterol burden than men: Novel data using repeated measurements during 12-years follow-up.

Background and aims: The concentration and the duration of exposure to low-density lipoprotein cholesterol (LDL-C) (LDL-C burden) is an important determinant of risk for cardiovascular disease and thresholds has recently been estimated. Individuals with familial hypercholesterolemia (FH) have increased risk of premature cardiovascular disease. The overall aim of the present study was to describe differences in LDL-C level and LDL-C burden in females and males with FH visiting an outpatient lipid clinic from a young age, using multiple LDL-C measurements during a follow-up time of 12 years. First, we aimed to study if the LDL-C concentration and the LDL-C burden is different between females and males at ages 0-10, 10-20, 20-30 and >30 years. Second, we aimed to estimate the subject-specific LDL-C burden at age 19 and 30 years, and the proportion of female and male patients that reach suggested LDL-C thresholds indicating high risk of ASCVD. Methods: Data was retrospectively collected from medical records of 438 subjects (207 girls and 231 boys) with FH, referred to the Lipid Clinic, Oslo University Hospital below the age of 19 years. The LDL-C burden was estimated based on repeated LDL-C measurements over time. Results: Subjects were followed over a period of mean 12.0 (SD 7.0) years, with median 10 years (7-17; 25-75 percentiles, minimum 2), with median 6 (4-9; 25-75 percentiles, minimum 2) available LDL-C measurements, starting at mean age 11 (SD 3.9) years. There was a difference in both LDL-C and LDL-C burden between sexes at different ages. On average, males had lower LDL-C over time, although this difference was less pronounced with age and males also had lower estimated LDL-C burden over time, and this difference was further exacerbated with age. Conclusion: Our study shows that young women with FH have a higher LDL-C burden than their male counterparts, potentially explaining the increased excess CVD risk seen among these. It underscores the importance of careful-follow up and early treatment initiation both prior to and after pregnancies in order to limit statin-free periods.

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 α-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 pro-inflammatory potential.

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.

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.

Subjects with familial hypercholesterolemia have lower aortic valve area and higher levels of inflammatory biomarkers.

BACKGROUND: Reduction of the aortic valve area (AVA) may lead to aortic valve stenosis with considerable impact on morbidity and mortality if not identified and treated. Lipoprotein (a) [Lp(a)] and also inflammatory biomarkers, including platelet derived biomarkers, have been considered risk factor for aortic stenosis; however, the association between Lp(a), inflammatory biomarkers and AVA among patients with familial hypercholesterolemia (FH) is not clear. OBJECTIVE: We aimed to investigate the relation between concentration of Lp(a), measurements of the aortic valve including velocities and valve area and circulating inflammatory biomarkers in adult FH subjects and controls. METHODS: In this cross-sectional study aortic valve measures were examined by cardiac ultrasound and inflammatory markers were analyzed in non-fasting blood samples. The study participants were 64 FH subjects with high (n = 29) or low (n = 35) Lp(a), and 14 healthy controls. RESULTS: Aortic valve peak velocity was higher (p = 0.02), and AVA was lower (p = 0.04) in the FH patients compared to controls; however, when performing multivariable linear regression, there were no significant differences. Furthermore, there were no significant differences between the high and low FH Lp(a) groups regarding the aortic valve. FH subjects had higher levels of platelet-derived markers CD40L, PF4, NAP2 and RANTES compared to controls (0.003 ≤ P ≤ 0.03). This result persisted after multiple linear regression. CONCLUSIONS: Middle-aged, intensively treated FH subjects have higher aortic valve velocity, lower AVA, and higher levels of the platelet-derived markers CD40L, PF4, NAP2 and RANTES compared to healthy control subjects. The aortic valve findings were not significant after multiple linear regression, whereas the higher levels of platelet-derived markers were maintained.

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 ±â€¯SD) 2.2 ±â€¯0.4 mmol/l before intervention to 3.1 ±â€¯0.8 after, while in the control group (n = 15), LDL-C remained unchanged: 2.5 ±â€¯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.

Sex differences in cholesterol levels from birth to 19 years of age may lead to increased cholesterol burden in females with FH.

BACKGROUND: The increased risk of cardiovascular disease in familial hypercholesterolemia (FH) is caused by increased cholesterol burden from birth. Even small elevation in cholesterol level accumulates over time and aggravates atherosclerosis. OBJECTIVES: The aim of the present study was to describe the lipid profile across sex and age in a large cohort of untreated children and adolescents with FH, as this have not clearly been described. METHODS: FH children (438 girls, 452 boys) not receiving lipid-lowering therapy, aged 0 to 19 years were included and divided into 4 age groups (<5, 5-9, 10-14, and 15-19 years). Information was retrieved from the medical records. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non-HDL cholesterol (non-HDL-C) were studied in relation to sex and age by multiple linear regression analysis. RESULTS: Girls with FH as compared to boys had significantly higher TC, LDL-C, and non-HDL-C (P < .001 for all) levels with mean (95% confidence interval) differences of 0.48 mmol/L (0.28, 0.68) (18.6 g/dL), 0.39 mmol/L (0.19, 0.59) (15.08 mg/dL), and 0.42 mmol/L (0.22, 0.63) (16.24 mg/dL), respectively. These estimates did not change after adjustment for age. We also observed sex differences for HDL-C; girls had higher HDL-C in the youngest (<5 years, P = .05) and oldest age groups (15-19 years, P < .001). CONCLUSIONS: FH girls have higher levels of TC, LDL-C, and non-HDL-C levels than boys from birth up to 19 years of age. This may contribute significantly to the total lifelong cholesterol burden in FH women.

Comprehensive lipid and metabolite profiling of children with and without familial hypercholesterolemia: A cross-sectional study.

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.