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.

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.

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).

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.

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.

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.

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.

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.

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.

Altered leukocyte distribution under hypercholesterolemia: A cross-sectional study in children with familial hypercholesterolemia.

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.

Lack of Effects of a Single High-Fat Meal Enriched with Vegetable n-3 or a Combination of Vegetable and Marine n-3 Fatty Acids on Intestinal Peptide Release and Adipokines in Healthy Female Subjects.

Peptides released from the small intestine and colon regulate short-term food intake by suppressing appetite and inducing satiety. Intake of marine omega-3 (n-3) fatty acids (FAs) from fish and fish oils is associated with beneficial health effects, whereas the relation between intake of the vegetable n-3 fatty acid α-linolenic acid and diseases is less clear. The aim of the present study was to investigate the postprandial effects of a single high-fat meal enriched with vegetable n-3 or a combination of vegetable and marine n-3 FAs with their different unsaturated fatty acid composition on intestinal peptide release and the adipose tissue. Fourteen healthy lean females consumed three test meals with different fat quality in a fixed order. The test meal consisted of three cakes enriched with coconut fat, linseed oil, and a combination of linseed and cod liver oil. The test days were separated by 2 weeks. Fasting and postprandial blood samples at 3 and 6 h after intake were analyzed. A significant postprandial effect was observed for cholecystokinin, peptide YY, glucose-dependent insulinotropic polypeptide, amylin and insulin, which increased, while leptin decreased postprandially independent of the fat composition in the high-fat meal. In conclusion, in healthy, young, lean females, an intake of a high-fat meal enriched with n-3 FAs from different origin stimulates intestinal peptide release without any difference between the different fat compositions.

Dietary counseling is associated with an improved lipid profile in children with familial hypercholesterolemia.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Guidelines recommend cholesterol-lowering medication from 8 to 10 years of age and dietary recommendations. Little is known about the diet of FH children and the effect of dietary counseling. The aim of the study was to describe the diet of FH children with respect to fat quality, and to investigate if dietary counseling improved lipid profile. METHODS: Fifty-four FH children (5-18 years) were included in the study and dietary intake was recorded with a pre-coded food diary for four days. Information about plasma lipid levels was obtained. RESULTS: Median intake of total fat, monounsaturated fat, polyunsaturated fat (PUFA) and saturated fat (SFA) was 30.8, 10.4, 5.9 and 12.0 E %, respectively. Among non-statin treated FH children, SFA intake was significantly correlated with TC, LDL-C and apolipoprotein (apo) B (rsp = 0.55; p = 0.004, rsp = 0.46; p = 0.02, and rsp = 0.45; p = 0.02, respectively), and PUFA/SFA ratio significantly inversely correlated with TC (rsp = -0.42; p = 0.03). Compared to the first visit, non-statin and non-plant sterol treated FH children (n = 10) had significantly reduced levels of TC (p < 0.01), LDL-C (p = 0.01), high-density lipoprotein cholesterol (p = 0.02), apo B (p = 0.05) and apo A-1 (p = 0.02) levels at a later visit. CONCLUSIONS: FH children had a higher intake of SFA than recommended and the SFA intake was positively correlated with plasma TC, LDL-C and apo B levels in FH children not using statins. Importantly, the plasma lipid profile was improved in FH children after dietary counseling where focus was on reducing intake of SFA and dietary cholesterol.

Maternal inheritance does not predict cholesterol levels in children with familial hypercholesterolemia.

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.

An acute bout of exercise modulate the inflammatory response in peripheral blood mononuclear cells in healthy young men.

CONTEXT: Exercise increases the levels of circulating inflammatory mediators. OBJECTIVE: Does an acute bout of exercise affect the mRNA gene expression level of inflammatory markers in peripheral blood mononuclear cells (PBMCs) and contribute to the circulating levels of inflammatory mediators? MATERIALS AND METHODS: Ten healthy, non-smoking men (22-28 years old) performed 1-hour cycling at 70% of VO2 max. RESULTS: The gene transcripts of CXCL16, IL-1ß, IL-8, COX-2, TXB21 and GATA3 were significantly up-regulated in PBMCs. Serum levels of CXCL16, IL-6, TNFα and IL-10 were also significantly increased after exercise. DISCUSSION AND CONCLUSION: Increased mRNA transcription of inflammatory genes in PBMCs may contribute to increased level of inflammatory markers after an acute bout of exercise. The increased mRNA levels of GATA-3 and TXB21 may indicate that T cell lymphocytes are activated and secrete cytokines into the circulation. It needs to be further investigated if exercise changes the Th1/Th2 balance.

Markers of atherosclerotic development in children with familial hypercholesterolemia: a literature review.

OBJECTIVE: Atherosclerosis is a multi-step process, where lipids, inflammatory and hemostatic mediators orchestrate plaque formation and progression, which subsequently may lead to myocardial infarction and ischemic stroke. Familial hypercholesterolemia (FH) is associated with increased risk of premature atherosclerosis due to the genetically determined elevated low density lipoprotein (LDL)-cholesterol seen in these individuals. Children with FH are suitable to investigate the isolated effect of elevated LDL-cholesterol on early markers of atherosclerosis. The aim of the present paper was to review the literature to summarize the findings of atherosclerotic markers in children with FH to better understand how elevated LDL-cholesterol per se promotes atherogenesis. METHODS: We conducted a systematic literature search from the years 1990-2013, resulting in identification of 903 articles. In order to investigate whether intima-media thickness (IMT) is different in children with and without FH, we conducted a meta-analysis of the studies comparing FH children with a control group. RESULTS: 37 original articles were included. Among these, 24 reported subclinical measurements, whereas other articles reported measurements of atherogenic lipids (n = 9), inflammatory markers (n = 10), hemostatic markers (n = 6) and other surrogate markers of atherosclerosis (n = 7). In the meta-analysis (n = 8), IMT was significantly thicker in children with FH than in control children (weighted mean difference 0.06, 95% confidence interval [0.01, 0.11]). CONCLUSION: Elevated LDL-cholesterol distinguishes children with and without FH, but these groups of children also differ in several other ways. In particular, children with FH display a variety of changes reflecting both the lipid and the inflammatory arm of atherosclerosis. The IMT-meta-analysis result strengthens the evidence of early atherosclerotic development in children with FH. In a clinical perspective, early diagnosing and treatment of children with FH is of high importance to attenuate development of the potential ongoing early atherosclerotic process in these individuals.

Subjects with familial hypercholesterolemia are characterized by an inflammatory phenotype despite long-term intensive cholesterol lowering treatment.

OBJECTIVE: The atherosclerotic process is driven by elevated Low-density lipoprotein (LDL)-cholesterol in combination with enhanced inflammatory responses. Several mediators participate in this complex inflammatory network including members of the tumour necrosis factor (receptor) superfamily. Familial hypercholesterolemia (FH) is associated with increased risk of developing premature atherosclerosis. Statin treatment may normalize LDL-cholesterol levels, but it is not known if the inflammatory responses are normalized in statin-treated FH patients. METHODS: In long-term statin-treated FH subjects (n=33) and healthy controls (n=10) the expression of tumour necrosis factor (receptor) superfamily related genes in peripheral blood mononuclear cells (PBMC) were analyzed by real-time quantitative RT-PCR. TNFα release was measured in PBMC from patients and controls by immunoassay. RESULTS: In FH patients with normal LDL-cholesterol, after a median of 17 years of statin treatment, our major findings were: (i) Gene expression of CD137, LIGHT (lymphotoxins inducible expression, competes with HSV glycoprotein D for HVEM, a receptor expressed on T-lymphocytes), HVEM (Herpesvirus entry mediator), the two TNFα Receptors (TNFR1 and TNFR2), TNF related apoptosis inducing ligand (TRAIL) and CD40 were increased in PBMC from FH patients compared to controls. (ii) The release of TNFα in PBMC from FH patients, in response to LPS was increased compared to controls. (iii) PBMC from FH patients had enhanced spontaneous release of TNFα when incubated in the presence of control serum and in particular in the presence of FH serum. CONCLUSION: Despite long-term statin therapy, an increased expression of several TNF related genes in PBMC isolated from FH patients was observed. Our findings may implicate a pathogenic role for inflammation and TNF related molecules in FH, and these findings suggest the possibility that novel treatment modalities beyond that of statins and lipid lowering drugs may be useful in FH subjects.

Cholesterol efflux mediators in homozygous familial hypercholesterolemia patients on low-density lipoprotein apheresis.

BACKGROUND: Homozygous familial hypercholesterolemia (FH) is a rare disorder that may affect 1 person per million. Early initiation of aggressive cholesterol-lowering therapy is essential to prevent premature coronary heart disease. Selective removal of low-density lipoprotein (LDL) by LDL apheresis is a reliable method of treatment. METHODS AND RESULTS: Cholesterol efflux mediators of homozygous FH patients on weekly LDL apheresis were compared with those of age- and sex-matched heterozygous FH patients receiving oral medication only and with healthy control subjects. The data show that (1) compared with healthy controls, homozygous FH patients have significantly lower plasma levels of high-density lipoprotein cholesterol and apoA-I and significantly lower cholesterol-acceptor capacity of serum to promote cholesterol efflux from cholesterol-loaded THP-1 cells, combined with significantly lower peripheral blood mononuclear cell gene expression levels of ATP-binding cassette (ABC) transporter G1 and borderline-significantly lower levels of ABCA1 and scavenger receptor class B type I (SR-BI); and (2) compared with pre-LDL apheresis (a day before treatment), postapheresis (15 days later; on the day after the weekly treatment) levels of HDL cholesterol and apoA-I were significantly reduced, with no significant effect on cholesterol-acceptor capacity of serum or on peripheral blood mononuclear cell gene expression levels of the cellular transporters, except for a borderline-significant reduction in ABCA1 mRNA levels. CONCLUSIONS: The data showing decreased levels of cholesterol efflux mediators in plasma and cells may suggest that the overall cholesterol efflux capacity is impaired in homozygous FH patients. However, LDL apheresis may maintain cholesterol efflux capacity, despite a lowering levels of high-density lipoprotein cholesterol and apoA-I.