apoB Concentrations Research Articles

The size of apolipoprotein (a) is an independent determinant of the reduction in lipoprotein (a) induced by PCSK9 inhibitors.

Lipoprotein (a) [Lp(a)] is a lipoprotein species causatively associated with atherosclerosis. Unlike statins, PCSK9 inhibitors (PCSK9i) reduce Lp(a), but this reduction is highly variable. Levels of Lp(a) are chiefly governed by the size of its signature protein, apolipoprotein (a) [apo(a)]. Whether this parameter determines some of the reduction in Lp(a) induced by PCSK9i remains unknown. We aimed to investigate if the Lp(a) lowering efficacy of PCSK9i is modulated by the size of apo(a), which is genetically determined by the variable number of KIV domains present on that protein. The levels of Lp(a) and the size of apo(a) were assessed in plasma samples from 268 patients before and after treatment with PCSK9i. Patients were recruited at the Outpatient Lipid Clinic of the Charité Hospital (Berlin) between 2015 and 2020. They were hypercholesterolaemic at very high cardiovascular disease risk with low-density lipoprotein (LDL)-cholesterol levels above therapeutic targets despite maximally tolerated lipid-lowering therapy. Patients received either Alirocumab (75 or 150 mg) or Evolocumab (140 mg) every 2 weeks. Apo(a), apoB100, and apoE concentrations as well as apoE major isoforms were determined by liquid chromatography high-resolution mass spectrometry. Apo(a) isoforms sizes were determined by western blot. PCSK9i sharply reduced LDL-cholesterol (-57%), apoB100 (-47%), and Lp(a) (-36%). There was a positive correlation between the size of apo(a) and the relative reduction in Lp(a) induced by PCSK9i (r = 0.363, P = 0.0001). The strength of this association remained unaltered after adjustment for baseline Lp(a) levels and all other potential confounding factors. In patients with two detectable apo(a) isoforms, there was also a positive correlation between the size of apo(a) and the reduction in Lp(a), separately for the smaller (r = 0.350, P = 0.0001) and larger (r = 0.324, P = 0.0003) isoforms. The relative contribution of the larger isoform to the total concentration of apo(a) was reduced from 29% to 15% (P < 0.0001). The size of apo(a) is an independent determinant of the response to PCSK9i. Each additional kringle domain is associated with a 3% additional reduction in Lp(a). This explains in part the variable efficacy of PCSK9i and allows to identify patients who will benefit most from these therapies in terms of Lp(a) lowering.

Association of serum apolipoprotein B with retinal neurovascular structural alterations in patients with type 2 diabetes: an optical coherence tomography angiography study.

To investigate the association of serum apoB concentrations with retinal neurovascular structural alterations in type 2 diabetes patients without clinically visible retinopathy. Eyes with no clinically visible diabetic retinopathy (DR) from diabetic patients with or without dyslipidemia were included. Changes in retinal neural structures, including the ganglion cell layer (GCL) and peripapillary retinal nerve fiber layer (RNFL) thicknesses, and microvascular metrics, including macular vessel density (VD) and perfusion density (PD) of the superficial capillary plexus, were measured with optical coherence tomography angiography (OCTA). Correlations between inner retinal layer thickness and OCTA metrics were analyzed. The association of serum apoB and diabetic retinal neurovascular structures was identified with regression analysis. A total of 148 eyes in the diabetes group (n = 74) and dyslipidemia group (n = 74) were enrolled. GCL and RNFL thicknesses in patients in the dyslipidemia group were significantly thinner than those in the diabetes group (all p < 0.025). The total area of the VD and PD in the dyslipidemia group was also decreased compared to that of the diabetes group (p < 0.05) and was found to correlate with GCL and RNFL (all p < 0.01) thicknesses in all diabetic patients. Serum apoB levels were positively related to low-density lipoprotein (LDL) and total cholesterol (TC). Moreover, the average GCL thickness was significantly associated with serum apoB levels (all p < 0.05). GCL and RNFL thinning was significantly correlated with decreased retinal blood flow in diabetic patients with dyslipidemia. Strictly controlling serum lipids, especially apoB levels, might be an effective strategy for DR treatment.

Familial combined hyperlipidemia: current knowledge about pathophysiology, diagnostics and correction

The review is devoted to the current knowledge about pathophysiology, diagnostics and correction of familial combined hyperlipidemia (FCHL) that is considered to be the most frequent among primary dyslipidemias in general population (1 — 3 %) as well as among the patients survived after myocardial infarction (20 — 38 %). The current knowledge about genetic characterization of FCHL and its pathophysiology are adduced. FCHL is emphasized to be a heterogenic state and many of genetic determinants are involved in its development. Excessive concentration of apolipoprotein B (ApoB) — containing lipoproteins is shown to be the main biochemical sign of FCHL and hence, the genes of proteins participated in their metabolism could be claimed for genes‑candidates of FCHL. A special attention is paid to the diagnostics of FCHL, the most valuable diagnostic signs of FCHL are emphasized because FCHL is not monogenic disorder and due to its phenotype characterized by high levels of low‑density lipoprotein cholesterol and/or triglyceride (TG), this lipid disorder is not frequently diagnosed. A combination of concentrations of ApoB &gt; 120 mg/dl and TG &gt; 1.5 mmol/l (&gt; 133 mg/dl) with a family history of early cardiovascular debut could be used today for revelation of patients with a probable diagnosis of FCHL. The influence of FCHL on cardiovascular risk (CVR) that is partly realized through its association with metabolic comorbid conditions such as type 2 diabetes mellitus, metabolic syndrome, nonalcoholic fatty liver disease is considered. These comorbid conditions could play a role of etiological causes of cardiovascular disease and could increase a CVR through some common pathophysiological mechanisms such as insulin resistance of muscular and fat tissues and hepatic overproduction of very low‑density lipoproteins. The current approaches to FCHL correction in accordance with acting recommendations are elucidated. They consider its correction to be necessary as a primary atherogenic dyslipidemia and propose to start intervention from the influence on modified factors of CVR (smoking, alcohol consumption, excessive body mass, obesity). Some differential approaches to correction of lipid exchange disorders in FCHL from the beginning of the first line hypolipidemic agent (statin of fibrate) or their combined usage depended on dyslipidemia phenotype revealed during diagnostics of FCHL are discussed. Update combinations of hypolipidemic agents with an addition to statin and fibrate omega‑3 fatty acids, ezetimibe and inhibitors of PCSK9 (alirocumab, evolocumab) from the point of their influence on a reduction of CVR as well as on the components of dyslipidemia phenotype occurred in FCHL are considered.

Asymptomatic Carotid Atherosclerosis Cardiovascular Risk Factors and Common Hypertriglyceridemia Genetic Variants in Patients with Systemic Erythematosus Lupus.

SLE is associated with increased cardiovascular risk. The objective of this study was to determine the prevalence of asymptomatic carotid atherosclerosis to analyze its relationship with dyslipidemia and related genetic factors in a population of patients with SLE. Seventy-one SLE female patients were recruited. Carotid ultrasound, laboratory profiles, and genetic analysis of the ZPR1, APOA5, and GCKR genes were performed. SLE patients were divided into two groups according to the presence or absence of carotid plaques. Patients with carotid plaque had higher plasma TG (1.5 vs. 0.9 mmol/L, p = 0.001), Non-HDL-C (3.5 vs. 3.1 mmol/L, p = 0.025), and apoB concentrations (1.0 vs. 0.9 g/L, p = 0.010) and a higher prevalence of hypertension (80 vs. 37.5%, p = 0.003) than patients without carotid plaque. The GCKR C-allele was present in 83.3% and 16.7% (p = 0.047) of patients with and without carotid plaque, respectively. The GCKR CC genotype (OR = 0.026; 95% CI: 0.001 to 0.473, p = 0.014), an increase of 1 mmol/L in TG concentrations (OR = 12.550; 95% CI: 1.703 to 92.475, p = 0.013) and to be hypertensive (OR = 9.691; 95% CI: 1.703 to 84.874, p = 0.040) were independently associated with carotid atherosclerosis. In summary, plasma TG concentrations, CGKR CC homozygosity, and hypertension are independent predictors of carotid atherosclerosis in women with SLE.

Discordantly normal ApoB relative to elevated LDL-C in persons with metabolic disorders: A marker of atherogenic heterogeneity

ObjectiveA significant proportion of persons with metabolic syndrome (MetS), prediabetes, or type 2 diabetes (T2D) do not develop atherosclerotic cardiovascular disease (ASCVD).We sought to determine whether discordantly normal apolipoprotein B (ApoB) relative to elevated LDL-C may help to explain heterogeneity in ASCVD risk among persons with metabolic disorders. MethodsThere were 278 Bogalusa Heart Study participants with MetS (n=95), prediabetes (n=233), or T2D (n=31) and LDL-C ≥100 mg/dL who were free of carotid plaque at baseline (2001-02) and underwent carotid ultrasound at follow-up (2013-16). Multivariable modified Poisson regression estimated the long-term absence of carotid plaque for lower ApoB, continuously and categorically. ResultsParticipants were on average 36.1 years old at baseline, 61.5% were women, and 31.7% were black. A total of 50.7% had discordantly normal ApoB (<90 mg/dL) and the mean ApoB and LDL-C concentrations were 91.6 mg/dL and 137.7 mg/dL, respectively. In addition to having higher HDL-C and lower triglyceride values, individuals with ApoB <90 were more likely to maintain persistent absence of plaque compared to those with ApoB ≥90 (73.1% versus 58.4%, p=0.01). Contrastingly, there was no significant difference in the proportion of individuals who remained free of plaque with increasing LDL-C (p=0.45). Independent of traditional risk factors including LDL-C, each 10 mg/dL lower ApoB (RR=1.11, 95% CI: 1.03-1.19) and ApoB <90 (RR=1.22, 95% CI: 1.00-1.43) were significantly associated with the persistent absence of carotid plaque. ConclusionsOne-half of young persons with metabolic disorders and elevated LDL-C had discordantly normal ApoB and a low burden of carotid atherosclerosis over 13 years, suggesting that ApoB better represents the atherogenic lipid burden compared to LDL-C in this patient population. These results suggest a utility for assessing whether routine ApoB measurement can improve ASCVD risk stratification in young persons with metabolic disorders who have high triglycerides and low HDL-cholesterol.

Adherence to a Mediterranean diet, dyslipidemia and inflammation in familial hypercholesterolemia

Background and aimsFamilial Hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol (LDL-C) and high atherosclerosis risk. The impact of different dietary patterns on atherosclerosis biomarkers has been poorly studied in FH.This study verified the association of adherence to a Mediterranean diet with biomarkers of dyslipidemia and low-grade inflammation in molecularly proven FH adults from Brazil (BR) and Spain (SP). Methods and resultsIn this cross-sectional study adherence to the Mediterranean diet was assessed by a validated score and generalized estimating equations were used to evaluate its association with plasma LDL-C, apolipoprotein-B (ApoB) and high sensitivity C-reactive protein (hs-CRP) concentrations. We included 92 (mean age 45 years, 58.7% females) and 98 FH individuals (mean age 46.8 years, 60.2% females) respectively from BR and SP. FH causing variants did not differ between countries. LDL-C, ApoB and hs-CRP concentrations were higher in BR than in SP: 179 (135–250) and 161 (133–193) mg/dL; 141 (109–181) and 103 (88–134) mg/dL; and 1.6 (0.8–4.0) and 0.8 (0.4–1.5) mg/L respectively (all p < 0.001). Most of BR had low adherence (n = 77, 83.7%), while the majority of SP were divided into moderate (n = 35, 35.7%) and strong adherence to the Mediterranean diet (n = 37, 37.8%), p < 0.001. There was a significant inverse association of adherence to the Mediterranean diet score with higher LDL-C, ApoB, and hs-CRP after adjusting for socio economic parameters, caloric and fatty acid intakes as well as pharmacological lipid lowering therapies. ConclusionsHigher adherence to a Mediterranean diet was associated with better dyslipidemia and low-grade inflammation profiles in FH.

M2 Monocyte Polarization in Dialyzed Patients Is Associated with Increased Levels of M-CSF and Myeloperoxidase-Associated Oxidative Stress: Preliminary Results

Cardiovascular diseases represent a major issue in terms of morbidity and mortality for dialysis patients. This morbidity is due to the accelerated atherosclerosis observed in these patients. Atherosclerosis is a chronic inflammatory disease characterized by key players such as monocytes, macrophages, or oxidized LDLs. Monocytes-macrophages are classified into subsets of polarized cells, with M1 and M2 macrophages considered, respectively, as pro- and anti-inflammatory. (1) Methods: The monocyte subsets and phenotypes were analyzed by flow cytometry. These data were completed by the quantification of plasma M-CSF, IL-8, CRP, Mox-LDLs, Apo-B, Apo-AI, chloro-tyrosine, and homocitrulline concentrations. The statistical differences and associations between two continuous variables were assessed using the Mann–Whitney U test and Spearman’s correlation coefficient, respectively. (2) Results: Hemodialyzed patients showed a significant increase in their concentrations of CRP, M-CSF, and IL-8 (inflammation biomarkers), as well as chloro-tyrosine and homocitrulline (myeloperoxidase-associated oxidative stress biomarkers). Moreover, we observed a higher percentage of M2 monocytes in the plasma of hemodialysis patients as compared to the controls. (3) Conclusions: Our data suggest that oxidative stress and an inflammatory environment, which is amplified in hemodialysis patients, seems to favor an increase in the concentration of circulating M-CSF, therefore leading to an increase in M2 polarization among circulating monocytes.

Habitual coffee intake and plasma lipid profile: Evidence from UK Biobank

There is evidence that long-term heavy coffee consumption may adversely affect individuals' cardiovascular disease (CVD) risk. As hyperlipidemia is a well-established contributor to CVD risk, we investigated the association between habitual coffee intake and plasma lipid profile. We used data from up to 362,571 UK Biobank participants to examine phenotypic associations between self-reported coffee intake and plasma lipid profiles, including low-density-lipoproteins cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (total-C), triglycerides, and apolipoproteins A1 and B (ApoA1 and ApoB). Mendelian randomization (MR) analysis using genetically instrumented coffee intake was used to interrogate the causal nature of coffee-lipid associations. We observed a positive dose-dependent association between self-reported coffee intake and plasma concentration of LDL-C, ApoB and total-C, with the highest lipid levels seen among participants reported drinking >6 cups/day (Plinear trend≤ 3.24E-55 for all). Consistently, in MR analyses using genetically instrumented coffee intake one cup higher coffee intake was associated with a 0.07mmol/L (95% CI 0.03 to 0.12), 0.02g/L (95% CI 0.01 to 0.03), and 0.09mmol/L (95% CI 0.04 to 0.14) increase in plasma concentration of LDL-C, ApoB, and total-C, respectively. Our phenotypic and genetic analyses suggest that long-term heavy coffee consumption may lead to unfavourable lipid profile, which could potentially increase individuals' risk for CVD. These findings may have clinical relevance for people with elevated LDL cholesterol.

Obesity, dyslipidemia, and high blood pressure are associated with cardiovascular risk, determined using high-sensitivity C-reactive protein concentration, in young adults.

ObjectiveFew studies have investigated the relationships between high-sensitivity C-reactive protein (hs-CRP) concentration and conventional cardiometabolic markers in young adults. The aim of this study was to characterize the cardiometabolic profile of young adults who are at high cardiovascular risk, according to hs-CRP concentration.MethodsA cross-sectional study was conducted in 300 young adults (18 to 30 years old) from southern Mexico (n = 150 normal-weight and n = 150 obese). Their circulating lipid and glucose concentrations were measured using colorimetric enzymatic assays, and their hs-CRP, ApoA, and ApoB concentrations were measured using turbidimetric assays.ResultsThe most prevalent abnormalities in the participants with high cardiovascular risk, determined using an hs-CRP >28.57 nmol/L, were high waist circumference (85.7%), obesity (83.9%), high low-density lipoprotein-cholesterol (64.3%), low high-density lipoprotein-cholesterol (50%), Apo B in the highest tertile (39.3%), hypertriglyceridemia (35.7%), and high blood pressure (30.4%). In addition, there were strong associations between hs-CRP >28.57 nmol/L and obesity (odds ratio [OR] = 13.9), high waist circumference (OR = 8.0), hypertriglyceridemia (OR = 4.0), high blood pressure (OR = 3.4), hypercholesterolemia (OR = 2.8), and Apo B in the highest tertile (OR = 2.4).ConclusionThe principal cardiometabolic alterations associated with high cardiovascular risk, determined using hs-CRP, are obesity, dyslipidemia, and high blood pressure in young adults.

Abstract 15019: Differential Effects of Omega-3 Fatty Acid Combinations on the Inhibition of Oxidation Of Human Low-density Lipoproteins in vitro

Background: Omega-3 fatty acids (O3FAs) reduce levels of triglyceride but may also have additional atheroprotective benefits. Randomized trials have suggested potential clinical outcome differences among O3FAs formulations. Oxidative modification of low-density lipoproteins (LDL) contributes to endothelial dysfunction, inflammation, and other aspects of atherogenesis. Individual O3FAs have been shown to inhibit LDL oxidation to varying degrees, but the antioxidant effects of combining O3FAs is unknown. Objective: To compare the dose- and time-dependent antioxidant effects of eicosapentaenoic acid (EPA, 20:5) alone and in combination with either docosapentaenoic acid (DPA, 22:5) or docosahexaenoic acid (DHA, 22:6) in human LDL in vitro . Methods: Human LDL was isolated from healthy subjects and adjusted to a final ApoB concentration of 100 μg/mL in physiologic buffer (PBS) before being incubated with O3FAs at 37°C. The EPA levels in the combinations were fixed at either 2.0, 3.0, or 4.5 μM, while the DPA or DHA levels were set at 0, 0.5, 1.0, and 2.0 μM. Oxidation was initiated by copper sulfate (10 μM) and measured over time by formation of malondialdehyde (MDA), a lipid oxidation product. Results: When combined with EPA, both DPA and DHA increased inhibition of oxidation in a dose- and time-dependent manner, with DPA showing a greater effect and more prolonged inhibition. At high levels of EPA (4.5 μM), DPA showed significantly greater antioxidant activity than equimolar DHA; these differences were more apparent with time. After 8 hours, adding 1.0 μM DPA reduced MDA formation by 61% versus vehicle (3.10 ± 0.42 vs. 7.98 ± 0.56, p &lt;0.001), while adding 1.0 μM DHA only reduced MDA formation by 20% (6.40 ± 1.23, p &lt;0.05). When 2 μM DPA or DHA were added, after 10 hours only DPA still had a significant degree of inhibition versus vehicle (37%; 6.65 ± 0.95 vs. 8.21 ± 0.53, p &lt;0.05). Similar trends were observed in combinations containing 2.0 and 3.0 μM EPA. Conclusion: Adding DPA or DHA to EPA provide dose-dependent incremental antioxidant effects, with DPA providing a larger degree and a longer duration of inhibition. These observations highlight potential differences among O3FAs (and their combinations) in novel mechanisms of atheroprotection.

The impact on metabolic and reproductive diseases of low-carbohydrate and ketogenic diets

With low carbohydrate diets glucose becomes unavailable as a source of energy for our body, leading to the production of ketones from fatty acids in the liver. The increase in plasma ketones is known as nutritional ketosis. The available evidence from basic and clinical studies indicates that both low carbohydrate and high fat low carbohydrate diets are effective for weight loss and are better than non-intervention. However, low carbohydrate diet and ketogenic diets induce unique metabolic changes and consistently improve some markers of cardiovascular risk, lowering elevated blood glucose, insulin, triglycerides, ApoB and saturated fat concentrations, reducing small dense LDL particle numbers, glycated hemoglobin levels, blood pressure and body weight while increasing HDL-cholesterol concentrations and reversing non-alcoholic fatty liver disease. Low carbohydrate diets are an efficient strategy for the management of obesity and metabolic syndrome. They may also benefit patients with polycystic ovary syndrome. They must be prescribed by trained professionals to balance the risks and benefits for each individual patient. Future research is required to improve the knowledge about individual responses to dietary interventions, their safety, tolerance, efficacy and long-term effects.

The effect of vitamin D supplementation on serum concentrations of dehydroepiandrosterone, paraoxonase 1, apolipoproteins, free fatty acid and insulin in vitamin D deficient obese and overweight individuals under a low-calorie diet program: a randomized controlled trial

PurposeAdipose tissue accumulation by trapping vitamin D and reducing its level may cause serious side effects. The purpose of this study is to determine the effects of vitamin D supplementation on dehydroepiandrosterone (DHEA), paraoxonase 1 (PON 1), insulin, free fatty acid (FFA), apolipoprotein-AI (Apo-AI) and apolipoprotein B (Apo-B) concentration in obese and overweight participants under low-calorie diet (LCD) program.Design/methodology/approachHealthy overweight and obese individuals (n = 70) with vitamin D deficiency were randomly assigned into 2 groups to receive either vitamin D supplements (an oral 2,000 IU vitamin D supplement) or placebo for 8 weeks.FindingsAll the participants were given an LCD program during the intervention. Vitamin D supplementation led to a significant increase in the levels of 25(OH)D (vitamin D vs placebo groups: 36.6 ± 9.8 vs 19.9 ± 3.5 ng/mL, p < 0.001), PON 1 levels (vitamin D vs placebo groups: 80 ± 25 vs 58 ± 23.2 ng/mL, p = 0.001), DHEA concentration (vitamin D vs placebo groups: 2.3 ± 0.7 vs 1.5 ± 0.6 ng/mL, p < 0.001) and Apo-AI levels (vitamin D vs placebo groups 3.7 ± 0.5 vs 3 ± 0.5 mg/dL, p < 0.001). Besides, intake of vitamin D supplements led to a significant decrease in FFA (vitamin D vs placebo groups: 3.1 ± 0.75 vs 3.5 ± 0.5 ng/mL, p = 0.001). After adjusting the analyses based on baseline levels, age and baseline body mass index measures, significant changes were observed in the insulin levels (0.03 ± 0.06 vs −1.7 ± 0.6 µIU/ml, p = 0.04). But the authors did not find any significant difference in the concentration of Apo-B between groups (vitamin D vs placebo groups: 71.5 ± 35.5 vs 66.6 ± 28.5 mg/dL, p = 0.05).Originality/valueOverall vitamin D supplementation for eight weeks among vitamin D-deficient obese and overweight participants had beneficial effects on serum DHEA PON 1 FFA insulin and Apo- AI while it did not affect the Apo-B concentration.

High-density lipoproteins are a potential therapeutic target for age-related macular degeneration

Strong evidence suggests that dysregulated lipid metabolism involving dysfunction of the retinal pigmented epithelium (RPE) underlies the pathogenesis of age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly. A hallmark of AMD is the overproduction of lipid- and protein-rich extracellular deposits that accumulate in the extracellular matrix (Bruch's membrane (BrM)) adjacent to the RPE. We analyzed apolipoprotein A-1 (ApoA-1)-containing lipoproteins isolated from BrM of elderly human donor eyes and found a unique proteome, distinct from high-density lipoprotein (HDL) isolated from donor plasma of the same individuals. The most striking difference is higher concentrations of ApoB and ApoE, which bind to glycosaminoglycans. We hypothesize that this interaction promotes lipoprotein deposition onto BrM glycosaminoglycans, initiating downstream effects that contribute to RPE dysfunction/death. We tested this hypothesis using two potential therapeutic strategies to alter the lipoprotein/protein profile of these extracellular deposits. First, we used short heparan sulfate oligosaccharides to remove lipoproteins already deposited in both the extracellular matrix of RPE cells and aged donor BrM tissue. Second, an ApoA-1 mimetic, 5A peptide, was demonstrated to modulate the composition and concentration of apolipoproteins secreted from primary porcine RPE cells. Significantly, in a mouse model of AMD, this 5A peptide altered the proteomic profile of circulating HDL and ameliorated some of the potentially harmful changes to the protein composition resulting from the high-fat, high-cholesterol diet in this model. Together, these results suggest that targeting HDL interactions with BrM represents a new strategy to slow AMD progression in humans.

Efficacy and safety of statin use in children and adolescents with familial hypercholesterolaemia: A systematic review and meta–analysis of randomized–controlled trials

Statins are the mainstay of treatment for patients with familial hypercholesterolaemia (FH). However, their efficacy and safety in children and adolescents with FH has not been well-documented. The purpose of this study was to systematically investigate and meta-analyze the best available evidence from randomized-controlled trials (RCTs) regarding the efficacy and safety of statins in this population. A comprehensive search was conducted in PubMed, Scopus and Cochrane, up to 10 January 2020. Data were expressed as mean differences with 95% confidence intervals (CI). The I2 index was employed for heterogeneity. Ten RCTs were included in the qualitative and quantitative analysis (1191 patients, aged 13.3 ± 2.5 years). Compared with placebo, statins led to a mean relative reduction in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride and apolipoprotein B (apo-B) concentrations by −25.5% (95% CI −30.4%, −20.5%; I2 91%), −33.8% (95% CI −40.1%, −27.4%; I2 90%), −8.4% (95% CI −14.8%, −2.03%; I2 26%) and −28.8% (95% CI −33.9%, −23.6%; I2 83%), respectively. High-density lipoprotein cholesterol (HDL-C) was increased by 3.1% (95% CI 1.1%−5.2%; I2 0%). Statins were well-tolerated, with no significant differences in transaminase and creatine kinase levels or other adverse effects compared with placebo. Statins exerted no effect on growth or sexual development. Statins are quite effective in reducing TC, LDL-C, TG and apo-B and increasing HDL-C concentrations in children and adolescents with FH. No safety issues were seen with statin use.

Omega 3 Improves Both apoB100-containing Lipoprotein Turnover and their Sphingolipid Profile in Hypertriglyceridemia.

Evidence for an association between sphingolipids and metabolic disorders is increasingly reported. Omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) improve apolipoprotein B100 (apoB100)-containing lipoprotein metabolism, but their effects on the sphingolipid content in lipoproteins remain unknown. In subjects with hypertriglyceridemia, we analyzed the effect of n-3 LC-PUFAs on the turnover apoB100-containing lipoproteins and on their sphingolipid content and looked for the possible association between these lipid levels and apoB100-containing lipoprotein turnover parameters. Six subjects underwent a kinetic study before and after n-3 supplementation for 2 months with 1 g of fish oil 3 times day containing 360 mg of eicosapentaenoic acid (EPA) and 240 mg of docosahexaenoic acid (DHA) in the form of triglycerides. We examined apoB100-containing lipoprotein turnover by primed perfusion labeled [5,5,5-2H3]-leucine and determined kinetic parameters using a multicompartmental model. We quantified sphingolipid species content in lipoproteins using mass spectrometry. Supplementation decreased very low-density lipoprotein (VLDL), triglyceride, and apoB100 concentrations. The VLDL neutral and polar lipids showed increased n-3 LC-PUFA and decreased n-6 LC-PUFA content. The conversion rate of VLDL1 to VLDL2 and of VLDL2 to LDL was increased. We measured a decrease in total apoB100 production and VLDL1 production. Supplementation reduced the total ceramide concentration in VLDL while the sphingomyelin content in LDL was increased. We found positive correlations between plasma palmitic acid and VLDL ceramide and between VLDL triglyceride and VLDL ceramide, and inverse correlations between VLDL n-3 LC-PUFA and VLDL production. Based on these results, we hypothesize that the improvement in apoB100 metabolism during n-3 LC-PUFA supplementation is contributed to by changes in sphingolipids.

Apolipoprotein B Levels Predict Future Development of Hypertension Independent of Visceral Adiposity and Insulin Sensitivity.

BackgroundHigh plasma apolipoprotein B (apoB) levels have been shown to be associated with hypertension, central obesity, and insulin resistance in cross-sectional research. However, it is unclear whether apoB levels predict future hypertension independent of body composition and insulin sensitivity. Therefore, we prospectively investigated whether plasma apoB concentrations independently predicted the risk of hypertension in a cohort of Japanese Americans.MethodsA total of 233 normotensive Japanese Americans (77 men, 156 women; mean age, 46.4±11.0 years) were followed over 10 years to monitor them for the development of hypertension. Fasting plasma concentrations of apoB, glucose, and insulin were measured at baseline. Insulin sensitivity was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). The abdominal visceral and subcutaneous fat areas were measured at baseline using computed tomography. Logistic regression analysis was used to estimate the association between apoB concentrations and the odds of incident hypertension.ResultsThe 10-year cumulative incidence of hypertension was 21.5%. The baseline apoB level was found to be positively associated with the odds of incident hypertension over 10 years after adjustment for age, sex, body mass index, systolic blood pressure, abdominal visceral fat area, abdominal subcutaneous fat area, total plasma cholesterol concentration, diabetes status, and HOMA-IR at baseline (odds ratio and 95% confidence interval for a 1-standard deviation increase, 1.89 [1.06 to 3.37]; P=0.030).ConclusionHigher apoB concentrations predicted greater risks of future hypertension independent of abdominal visceral fat area and insulin sensitivity in Japanese Americans.

Lipidomic Assessment of Triacylglycerol and Cholesterol Ester Species After n-3 Polyunsaturated Fatty Acid Suppementation in Humans: Comparison of Response Phenotypes

Abstract Objectives Assess the differences in triacylglycerol (TAG) and cholesterol ester (CE) species in the plasma of individuals displaying heterogeneous lipid responses following long chain n-3 (LCn-3) polyunsaturated fatty acid supplementation. Methods We performed a targeted, mass spectrometry (MS), infusion-based lipidomic analysis on plasma samples obtained from a clinical study in which participants were supplemented with 3 g/day of LCn-3 in the form of fish oil capsules over a 6-week period. Triacylglycerol (TAG) species and cholesteryl esters (CE) were quantified for 130 participants pre- and post-supplementation. Results Based on the change of total TAG concentrations following supplementation, participants were segregated into three response phenotypes: (1) positive responders (R+; TAG decrease &amp;lt; 10%), (2) non-responders (NR; TAG changes +/− 10%), and (3) negative responders (R−; TAG increase &amp;gt; 10%) representing 87/130 (67%), 24/130 (18%), and 19/130 (15%) of the study samples, respectively. There were no phenotypic differences for age, sex, body-mass index, glycemia, or ApoB concentrations. Sparse partial least squares discriminant analysis separated the three phenotypes with component 1 attributed to changes in TAG 50–53: X with 0–3 desaturations with R + having reductions in these TAG. Separation along component 2 identified lower mass TAG 46–48: X with 1–3 desaturations likely containing 14:0. This latter effect impacted mostly NR and R- phenotypes. Analysis of individual TAG species per response phenotype revealed TAG species that did not align with the overall TAG response phenotype. Using the TAG response phenotype for grouping, we performed SPLDA analysis for CE responses. We observed that distinction of the TAG response phenotypes qualitatively applies to CE in which separation along component 1 (65% of variance) was due to differences in CE 18:0, 18:1, and 14:0. CE 20:5 was elevated equally (&amp;gt;300%) between all phenotypes indicating LCn-3 intake. However, CE 22:6 was elevated R− (86%) to a greater extent vs. Res+ (55%) and NR (49%) phenotypes. Conclusions Our data identify lipidomic signatures (TAG and CE) associated with LCn-3 response phenotypes in humans and provide insight into the variability of lipid metabolism in humans. Funding Sources USDA-NIFA, USDA-ARS and CIHR MOP-229,488.

ApoB48-Lipoproteins Are Associated with Cardiometabolic Risk in Adolescents with and without Polycystic Ovary Syndrome.

ContextAdolescents with polycystic ovary syndrome (PCOS) have increased incidence of cardiometabolic risk factors including dyslipidemia. Atherogenic apolipoprotein (apo) B-lipoprotein remnants are associated with increased cardiovascular disease (CVD) risk.ObjectiveThe aim of this study was to determine the concentrations of fasting plasma apoB-lipoprotein remnants, apoB48 and apoB100, and their association with cardiometabolic risk factors and androgen indices in adolescent girls with and without PCOS.Design, setting and participantsParticipants (n = 184) aged 17 years were recruited in the Menstruation in Teenagers Study from the Western Australian Pregnancy Cohort (Raine) Study.The main outcome measuresFasting plasma apo-B48 and -B100 lipoprotein remnant concentrations in adolescent girls with and without PCOS.ResultsFasting plasma apoB48-lipoprotein remnants but not apoB100-lipoprotein remnants were elevated in adolescent girls with increased cardiometabolic risk compared with those with lower cardiometabolic risk (13.91 ± 5.06 vs 12.09 ± 4.47 µg/mL, P < .01). ApoB48-lipoprotein remnants were positively correlated with fasting plasma triglycerides (b = .43, P < .0001). The prevalence of increased cardiometabolic risk factors was 2-fold higher in those diagnosed with PCOS (35.3%) than in those without PCOS (16.3%).Conclusion: Adolescents with PCOS have a 2-fold higher incidence of cardiometabolic risk factors than those without PCOS. Fasting apoB48-lipoprotein remnants are elevated in adolescent girls with a high prevalence of cardiometabolic risk factors.

Association of common gene-smoking interactions with elevated plasma apolipoprotein B concentration

BackgroundIncreased apolipoprotein (apo) B level (hyperapoB) is a strong predictor of cardiovascular disease (CVD), even in patients who achieve recommended LDL-Cholesterol (LDL-C) goals. ApoB level, an important correlate of metabolic syndrome (MetS), is influenced by several gene-environment interactions. Some of them are rare and can explain a large proportion of apoB variance, whereas others more common have variable effects. The aim of this study was to evaluate the association of interaction between smoking and common hyperapoB gene variants (PPARα-L162V, lipoprotein lipase loss-of function mutation, apo e4 allele or apo E2/2 genotype) with plasma apoB concentrations, according to the expression of MetS.MethodsThis study was performed among 1798 subjects. Smoking was defined as non/mild smokers vs. moderate-to-heavy smokers. ApoB levels were determined using nephelometry. Logistic regression models were used to document interactions between smoking habits and the presence of hyperapoB gene variants on the relative odds to exhibit increased plasma apoB concentrations.ResultsAround 29% of individuals with a low-risk lipid profile without MetS component had hyperapoB. Smoking and the presence of hyperapoB gene variants tended to be associated with higher plasma apoB levels even in presence of low-LDL-C. There was a significant interaction (P = 0.04) between the presence of ≥1 gene variants and smoking on the risk to exhibit hyperapoB among subjects with low risk profile in primary prevention.ConclusionsCombination of life habits assessment and some common genes variants may detect a significant proportion of patients with increased apoB levels, and therefore a higher risk of CVD, who could have been initially perceived as low-risk.

Higher ANGPTL3, apoC-III, and apoB48 dyslipidemia, and lower lipoprotein lipase concentrations are associated with dysfunctional visceral fat in adolescents with obesity

BackgroundWe hypothesized that adolescents with obesity have higher remnant B48 concentrations associated with lipoprotein lipase dysregulation. MethodsCross-sectional study of 32 adolescents with obesity and 27 control subjects. ResultsAs compared to lean controls, obese participants showed 35% higher concentrations of apoB48: 3.60 (2.93–4.30) vs 2.65 (1.64–3.68) ng/ml; 28% of apoC-III: (72.7 (58.6–89.7) vs 56.9 (44.8–79.8 ug/ml and 17% ANGPTL 3: (72.2 ± 20.2 vs 61.2 ± 19.2 ng/ml). This was accompanied by a 33% reduction in LPL: 13.1 ± 5.1 vs 18.9 ± 4.7 ng/ml. Obese participants had 25% lower adiponectin 2.9 (1.9–3.8) vs 4.4 (3.2.-5.2) μg/ml; 260% higher leptin 25.7 (11.2–44.8) vs 9.3 (2.8–20.7) ng/ml c and 83% higher Il-6: 2.2 (1.3–5.4) vs 1.2 (0.8–1.4) pg/ml. ApoC-III and ANGPTL3 correlated positively with VAI; ANGPTL3 negatively with HDL-C; LDL size and VLDL-C. ApoB48 correlated negatively with LDL-C. ConclusionsAdolescents with obesity show higher ANGPTL3 compounded with increased apoC-III associated with increased CR and lower LPL mass. This is associated with inflammation and visceral fat. The significance of these findings resides in that they shed light on a mechanism for TRL dyslipidemia in adolescents: increased LPL inhibition impairs VLDL and chylomicron catabolism leading to atherogenic remnants.