Large Very Low Density Lipoprotein Research Articles

Changes in soluble LDL receptor and lipoprotein fractions in response to diet in the DIETFITS weight loss study

Circulating levels of the soluble ligand-binding ectodomain of the LDL receptor (sLDLR) that is proteolytically cleaved from the cell surface have been shown to correlate with plasma triglycerides, but the lipid and lipoprotein effects of longitudinal changes in sLDLR have not been examined. We sought to assess associations between changes in sLDLR and detailed lipoprotein measurements between baseline and 6 months in participants in the DIETFITS (Diet Intervention Examining The Factors Interacting with Treatment Success) weight loss trial who were randomly assigned to the low-fat (n = 225) or low-carbohydrate (n = 236) diet arms. sLDLR was assayed using a proteomic procedure, lipids and apoprotein (apo) B and apoAI were measured by standard assays, and lipoprotein particle subfractions were quantified by ion mobility methodology. Changes in sLDLR were significantly positively associated with changes in plasma cholesterol, triglycerides, apoB, large-sized and medium-sized VLDL, and small and very small LDL, and inversely with changes in large LDL and HDL. The lipoprotein subfraction associations with sLDLR were independent of age, sex, diet, and BMI, but all except for large LDL were reduced to insignificance when adjusted for triglyceride change. Principal component analysis identified three independent clusters of changes in lipoprotein subfractions that accounted for 78% of their total variance. Change in sLDLR was most strongly correlated with change in the principal component that was loaded positively with large VLDL and small and very small LDL and negatively with large LDL and HDL. In conclusion, sLDLR is a component of a cluster of lipids and lipoproteins that are characteristic of atherogenic dyslipidemia.

#207 : Mendelian Randomization Study Reveals a Casual Effect of Blood Lipids and Apolipoprotein on Uterine Fibroids

Background and Aims: Despite an early insight into the risk factors of uterine fibroids (UFs), there is still controversy about the roles of blood lipids and apolipoprotein on UFs. Therefore, to provide more reliable evidence, we investigated the causal effect of blood lipids and apolipoprotein on the risk of UFs through Mendelian randomization (MR). Method: We utilized the large genome-wide association studies of blood lipids and apolipoprotein as instruments and integrated them in the inverse-variance-weighted (IVW) model in two-sample MR to investigate their causal relationship in large sample sizes. To eliminate potential pleiotropy, we listed a conclusive table of genes related to confounding factors, such as body mass index, waist circumference, blood pressure, glucose, hypertension, the metabolic syndrome and smoking and removed the repeated SNPs in the exposure data.To adjust for multiple comparisons, the statistical significance of the MR effect estimates was evaluated in a false discovery rate correlation of less than 5%. Neither pleiotropy nor heterogeneity was reported in all MR sensitivity analysis, including IVW, MR-Egger, simple median, weighted median, weighted mode and Mendelian Randomization Pleiotropy Residual Sum and Outlier methods. Results: Total triglycerides, very low-density lipoprotein (VLDL) cholesterol, including large, medium and small VLDL particles and free cholesterol in large VLDL cholesterol showed positive association with UFs. Meanwhile, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1, free cholesterol in small and medium VLDL and total cholesterol are not statistically related to the development of UFs. Conclusion: Exposure to various aberrant blood lipids increases the risk of UFs, providing genetic evidence for the vital role of aberrant lipid levels in the pathogenesis of UFs. Meanwhile, our results provided genetic insights suggesting intervention in blood lipids might be a prospective strategy in the early prevention and treatment of UFs.

Cholesterol and low-density lipoprotein as a cause of psoriasis: Results from bidirectional Mendelian randomization.

Psoriasis is an inflammatory disease that affects many people. However, the causal effect of lipid metabolism on psoriasis has not yet been verified. This study aimed to identify the genetic relationship between serum lipid levels and psoriasis. Bidirectional two-sample Mendelian randomization (MR) was used to analyse the causal relationship between cholesterol and psoriasis. The outcome of the forward causality test was psoriasis. In the analysis of reverse causality, psoriasis was exposed, and 79 single-nucleotide polymorphisms were detected in the genome-wide association study (GWASs) database from the IEU GWASs Project. MR-Egger regression, inverse variance-weighted, weighted median, weighted mode and simple mode were used for the MR analyses. The level of triglyceride, lipase member N, chylomicrons, extremely large very low-density lipoprotein (VLDL) particles, high-density lipoprotein (HDL) cholesterol levels, cholesterol esters in large HDL, cholesterol esters in medium HDL and cholesterol esters in medium VLDL have not affected the development of psoriasis. However, total cholesterol, total free cholesterol, low-density lipoprotein (LDL) cholesterol levels, cholesterol esters in large VLDL and cholesterol esters in medium LDL were unidirectional causal effects on psoriasis. Bidirectional two-sample MR analysis indicated that high levels of total cholesterol, total free cholesterol, LDL cholesterol, cholesterol esters in large VLDL and cholesterol esters in medium LDL are genetic risk factors for psoriasis.

Adherence to the Mediterranean diet and nuclear magnetic resonance spectroscopy biomarkers in older individuals at high cardiovascular disease risk: cross-sectional and longitudinal analyses

BackgroundThe Mediterranean diet (MedDiet) has been related to a decreased risk of cardiovascular disease (CVD) and diabetes. ObjectivesWe aimed to prospectively assess the relationship between adherence to the MedDiet and advanced lipoprotein subclass profiles and glucose metabolism and inflammation markers, as determined by nuclear magnetic resonance (NMR) spectroscopy. DesignWe conducted cross-sectional and longitudinal analyses within the framework of the PREvención con DIeta MEDiterránea study in 196 participants from the Reus-Tarragona center. Adherence to the MedDiet was assessed using a 14-item validated questionnaire [Mediterranean Diet Adherence Score (MEDAS)]. Plasma lipoprotein subclasses and molecular metabolite profiles were determined using NMR spectra collected on a Vantera Clinical Analyzer at baseline and after 1 y of follow-up. Baseline and 1-y categories of MEDAS were related to measures of lipoprotein atherogenicity and diabetes risk using multivariable-adjusted analysis of covariance models. ResultsCompared with participants in the lowest category of baseline MEDAS, those in the highest category showed higher concentrations of total high-density lipoprotein (HDL) particles and H1P HDL, lower concentrations of very low-density lipoprotein (VLDL)-triglyceride, smaller size of VLDL, and lower concentrations of very large VLDL, as well as lower concentrations of branched-chain amino acids, leucine, and GlycA and reduced Diabetes Risk Index (DRI) scores. In addition, participants who increased by 3 or more points in their 1-y MEDAS showed an increase in concentrations of H7P-HDL, H5P-HDL, and citrate, and reduced acetone and DRI scores compared with those with lesser adherence increases. ConclusionsIn older adults at high cardiometabolic risk, higher MEDAS was associated with modest beneficial changes in lipoprotein and glucose metabolism. The results suggest that lipoprotein subclass distribution and glycemic control are potential mechanisms behind the well-known salutary effects of MedDiet on CVD and diabetes risk. Future clinical trials exploring the effects of the MedDiet on advanced lipoprotein subclass profiles and glucose metabolism markers are needed to confirm the results of our study. Trial registration numberThis trial was registered at controlled-trials.com as ISRCTN35739639.

Plant-based diet indices and lipoprotein particle subclass profiles: A cross-sectional analysis of middle- to older-aged adults

Background and aimsPlant-based diets (PBDs) are associated with favourable lipid profiles and cardiometabolic outcomes. However, limited data regarding PBD indices (PDIs) and lipoprotein subclasses exist. We examined overall PDI, healthful PDI (hPDI) and unhealthful PDI (uPDI) associations with lipid and lipoprotein profiles. MethodsThis cross-sectional analysis includes 1,986 middle- to older-aged adults from the Mitchelstown Cohort. The PDI, hPDI and uPDI scores were calculated from validated food frequency questionnaires. Higher PDI, hPDI and uPDI scores indicate a more PBD, healthful PBD and unhealthful PBD, respectively. Lipoprotein particle size and subclass concentrations were measured using nuclear magnetic resonance spectroscopy. Relationships between PDIs and lipid and lipoprotein profiles were examined via correlation and regression analyses adjusted for covariates. ResultsIn fully adjusted regression analyses, higher PDI scores were associated with lower high-density lipoprotein (HDL) cholesterol concentrations and more triglyceride-rich lipoprotein and small very low-density lipoprotein (VLDL) particles. Higher hPDI scores were negatively associated with non-HDL cholesterol concentrations, large VLDL and small HDL particles, the Lipoprotein Insulin Resistance Index (LP-IR) score and VLDL particle size. Higher uPDI scores were associated with lower HDL cholesterol and greater triglyceride concentrations and more medium and large VLDL, total LDL, small LDL and total non-HDL particles, less large LDL and large HDL particles, a greater LP-IR score, greater VLDL particle size and smaller LDL and HDL particle size. ConclusionsThis study provides novel evidence regarding associations between PBD quality and lipoprotein subclasses. A more unhealthful PBD was robustly associated with a more pro-atherogenic lipoprotein profile.

Maternal first trimester metabolic profile in pregnancies with transposition of the great arteries.

Higher maternal body mass index (BMI) and abnormal glucose metabolism during early pregnancy are associated with congenital heart defects in the offspring, but the exact mechanisms are unknown. We evaluated the association between maternal first trimester metabolic profile and transposition of the great arteries (TGA) in the offspring in a matched case-control study with 100 TGA mothers and 200 controls born in Finland during 2004-2014. Cases and controls were matched by birth year, child sex, and maternal age and BMI. Serum samples collected between 10- and 14-weeks of gestation were analyzed for 73 metabolic measures. Conditional logistic regression was used to assess the risk for TGA in the offspring, and a subgroup analysis among mothers with high BMI was conducted. Higher concentrations of four subtypes of extremely large very-low-density lipoprotein (VLDL) particles and one of large VLDL particles were observed in TGA mothers. This finding did not reach statistical significance after multiple testing correction. The pooled odds ratio (OR) of the all metabolic variables was slightly higher in TGA mothers in the subgroup with maternal BMI over 25 (OR 1.25) and significantly higher in the subgroup with maternal BMI over 30 (OR 1.95) compared to the original population (OR 1.18). Our findings indicate that an abnormal maternal early pregnancy metabolic profile might be associated with TGA in the offspring, especially in obese mothers. A trend indicating altered VLDL subtype composition in TGA pregnancies warrants further research.

Spotlight on very-low-density lipoprotein as a driver of cardiometabolic disorders: Implications for disease progression and mechanistic insights.

Very-low-density lipoprotein (VLDL) is the only lipoprotein containing apolipoprotein B that is secreted from the liver, where VLDL is assembled from apolipoproteins, cholesterol, and triglycerides. The primary function of VLDL is to transport cholesterol and other lipids to organs and cells for utilization. Apart from its role in normal biologic processes, VLDL is also known to contribute to the development of atherosclerotic cardiovascular disease. Large VLDL particles, which are subclassified according to their size by nuclear magnetic resonance spectrometry, are significantly correlated not only with atherosclerosis, but also with insulin resistance and diabetes incidence. VLDL can also be subclassified according to surface electrical charge by using anion-exchange chromatography. The most electronegative VLDL subclass is highly cytotoxic to endothelial cells and may contribute to coronary heart disease. In addition, electronegative VLDL contributes to the development of atrial remodeling, especially in patients with metabolic syndrome, which is an established risk factor for atrial fibrillation. In this review, we focus on the VLDL subclasses that are associated with apolipoprotein alterations and are involved in cardiometabolic disease. The postprandial enhancement of VLDL’s pathogenicity is a critical medical issue, especially in patients with metabolic syndrome. Therefore, the significance of the postprandial modification of VLDL’s chemical and functional properties is extensively discussed.

Obesity-associated metabolites in relation to type 2 diabetes risk: A prospective nested case-control study of the CARRS cohort.

AimsTo determine whether obesity‐associated metabolites are associated with type 2 diabetes (T2DM) risk among South Asians.Materials and MethodsSerum‐based nuclear magnetic resonance imaging metabolomics data were generated from two South Asian population‐based prospective cohorts from Karachi, Pakistan: CARRS1 (N = 4017) and CARRS2 (N = 4802). Participants in both cohorts were followed up for 5 years and incident T2DM was ascertained. A nested case‐control study approach was developed to select participants from CARRS1 (Ncases = 197 and Ncontrols = 195) and CARRS2 (Ncases = 194 and Ncontrols = 200), respectively. First, we investigated the association of 224 metabolites with general obesity based on body mass index and with central obesity based on waist‐hip ratio, and then the top obesity‐associated metabolites were studied in relation to incident T2DM.ResultsIn a combined sample of the CARRS1 and CARRS2 cohorts, out of 224 metabolites, 12 were associated with general obesity and, of these, one was associated with incident T2DM. Fifteen out of 224 metabolites were associated with central obesity and, of these, 10 were associated with incident T2DM. The higher level of total cholesterol in high‐density lipoprotein (HDL) was associated with reduced T2DM risk (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.53, 0.86; P = 1.2 × 10−3), while higher cholesterol esters in large very‐low‐density lipoprotein (VLDL) particles were associated with increased T2DM risk (OR 1.90, 95% CI 1.40, 2.58; P = 3.5 × 10−5).ConclusionTotal cholesterol in HDL and cholesterol esters in large VLDL particles may be an important biomarker in the identification of early development of obesity‐associated T2DM risk among South Asian adults.

Atherogenic lipidomics profile in healthy individuals with low cardiorespiratory fitness: The HUNT3 fitness study

Background and aimsLow cardiorespiratory fitness is a strong and independent risk factor for cardiovascular disease (CVD). Serum profiling of healthy individuals with large differences in cardiorespiratory fitness may therefore reveal early biomarkers of CVD development. Thus, we aimed to identify circulating lipoprotein subfractions differentially expressed between groups of individuals with large differences in cardiorespiratory fitness, measured as maximal oxygen uptake (VO2max). MethodsHealthy subjects (40–59 years) were selected from the third wave of the Trøndelag health study (HUNT3) based on having an age-dependent high VO2max (47.1 ± 7.7 mL kg−1·min−1, n = 103) or low VO2max (31.4 ± 4.9 mL kg−1·min−1, n = 108). The individuals were matched on gender, age, physical activity level and fasting status. Results99 lipoprotein subfractions were quantified in serum samples using nuclear magnetic resonance (NMR) lipidomics. Standard clinical analyses showed similar levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol between the groups, and slightly higher levels of triglycerides in participants with low VO2max. Thirteen lipoprotein subfractions were increased in the low VO2max group compared to the high VO2max group (p < 0.005), including mainly large very low-density lipoprotein (VLDL) subfractions. In addition, triglyceride levels in small-sized HDL and LDL particles were increased in participants with low VO2max. Correlation analyses between VO2max and lipoproteins subfractions displayed a negative correlation between VO2max and the levels of cholesterol and phospholipids in the small HDL particles. The lipoprotein profile of individuals with low VO2max is similar to the profile of insulin resistant individuals. ConclusionsLow VO2max was associated with enrichment of large VLDL particles, as well as an increased triglycerides content in the small and dense HDL and LDL particles. This unfavorable lipid profile is likely to be involved in the strong associations between VO2max and CVD.

Sex-specific associations of adiposity with cardiometabolic traits in the UK: A multi-life stage cohort study with repeat metabolomics.

BackgroundSex differences in cardiometabolic disease risk are commonly observed across the life course but are poorly understood and may be due to different associations of adiposity with cardiometabolic risk in females and males. We examined whether adiposity is differently associated with cardiometabolic trait levels in females and males at 3 different life stages.Methods and findingsData were from 2 generations (offspring, Generation 1 [G1] born in 1991/1992 and their parents, Generation 0 [G0]) of a United Kingdom population-based birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). Follow-up continues on the cohort; data up to 25 y after recruitment to the study are included in this analysis. Body mass index (BMI) and total fat mass from dual-energy X-ray absorptiometry (DXA) were measured at mean age 9 y, 15 y, and 18 y in G1. Waist circumference was measured at 9 y and 15 y in G1. Concentrations of 148 cardiometabolic traits quantified using nuclear magnetic resonance spectroscopy were measured at 15 y, 18 y, and 25 y in G1. In G0, all 3 adiposity measures and the same 148 traits were available at 50 y. Using linear regression models, sex-specific associations of adiposity measures at each time point (9 y, 15 y, and 18 y) with cardiometabolic traits 3 to 6 y later were examined in G1. In G0, sex-specific associations of adiposity measures and cardiometabolic traits were examined cross-sectionally at 50 y. A total of 3,081 G1 and 4,887 G0 participants contributed to analyses. BMI was more strongly associated with key atherogenic traits in males compared with females at younger ages (15 y to 25 y), and associations were more similar between the sexes or stronger in females at 50 y, particularly for apolipoprotein B–containing lipoprotein particles and lipid concentrations. For example, a 1 standard deviation (SD) (3.8 kg/m2) higher BMI at 18 y was associated with 0.36 SD (95% confidence interval [CI] = 0.20, 0.52) higher concentrations of extremely large very-low-density lipoprotein (VLDL) particles at 25 y in males compared with 0.15 SD (95% CI = 0.09, 0.21) in females, P value for sex difference = 0.02. By contrast, at 50 y, a 1 SD (4.8 kg/m2) higher BMI was associated with 0.33 SD (95% CI = 0.25, 0.42) and 0.30 SD (95% CI = 0.26, 0.33) higher concentrations of extremely large VLDL particles in males and females, respectively, P value for sex difference = 0.42. Sex-specific associations of DXA-measured fat mass and waist circumference with cardiometabolic traits were similar to findings for BMI and cardiometabolic traits at each age. The main limitation of this work is its observational nature, and replication in independent cohorts using methods that can infer causality is required.ConclusionsThe results of this study suggest that associations of adiposity with adverse cardiometabolic risk begin earlier in the life course among males compared with females and are stronger until midlife, particularly for key atherogenic lipids. Adolescent and young adult males may therefore be high priority targets for obesity prevention efforts.

A metabolomic index based on lipoprotein subfractions and branched chain amino acids is associated with incident hypertension

ObjectiveThe present study aims to evaluate the performance of the Diabetes Risk Index (DRI), a metabolomic index based on lipoprotein particles and branched chain amino acids, on the incidence of newly developed hypertension in a large community dwelling cohort. MethodsThe DRI was calculated by combining 6 lipoprotein parameters [sizes of very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), concentrations of large VLDL, small LDL, and large HDL particles], and the concentrations of valine and leucine. DRI scores were estimated in 4169 participants from the PREVEND prospective cohort. Cox proportional hazards regression was used to evaluate the association of DRI scores with incident hypertension. ResultsDuring a median follow-up of 8.6 years, 924 new hypertension cases were ascertained. In analyses adjusted for age and sex, there was a significant association between DRI and incident hypertension with a hazard ratio (HR) per 1 SD increase of 1.45 (95% CI 1.36,1.54; p < 0.001). After additional adjustment for traditional risk factors, the HR remained significant (HRadj 1.21, 95% CI 1.10, 1.33, p <0.001). Likewise, subjects in the top quartile of DRI presented with a higher risk of hypertension (HRadj 1.64, 95% CI 1.28, 2.10, p <0.001). Furthermore, the net reclassification improvement assessment improved after the addition of DRI to a traditional risk model (p <0.001), allowing proper reclassification of 34% of the participants. ConclusionHigher DRI scores were associated with an increased risk of incident hypertension. Such association was independent of traditional clinical risk factors for hypertension.

Comparing dietary score associations with lipoprotein particle subclass profiles: A cross-sectional analysis of a middle-to older-aged population

Lipoprotein particle concentrations and size are associated with increased risk for atherosclerosis and premature cardiovascular disease. Studies also suggest that certain dietary behaviours may be cardioprotective. Limited comparative data regarding any dietary score/index-lipoprotein particle subclass associations exist. Thus, our objective was to assess relationships between the Dietary Approaches to Stop Hypertension (DASH), Health Eating Index-2015 (HEI-2015), Mediterranean Diet (MD) and Energy-adjusted Dietary Inflammatory Index (E-DII™) scores and plasma lipids and lipoprotein profiles to test the hypothesis that healthier diet (better quality and more anti-inflammatory) would be associated with a more favourable lipoprotein profile. This was a cross-sectional study of 1862 men and women aged 46-73 years, randomly selected from a large primary care centre in Ireland. DASH, HEI-2015, MD and E-DII scores were derived from food frequency questionnaires. Lipoprotein subclass particle concentrations and size were determined using nuclear magnetic resonance spectroscopy. Correlation and multivariate-adjusted linear regression analyses with correction for multiple testing were performed to examine dietary score relationships with lipoprotein particle subclasses. In fully adjusted models, higher diet quality or a more anti-inflammatory diet was associated with less large and medium very low-density lipoprotein (VLDL) (DASH and HEI-2015), intermediate-density lipoprotein (IDL) (DASH, MD and E-DII) and small high-density lipoprotein (HDL) (DASH, HEI-2015 and E-DII) particles. After accounting for multiple testing, relationships with large VLDL (DASH: β=-0.102, p=.037), IDL (DASH: β=-0.089, p=.037) and small HDL (DASH: β=-0.551, p=.014 and E-DII: β=0.483, p=.019) concentrations persisted. These findings provide evidence that better diet quality, determined by the DASH score, may be more closely associated with a more favourable lipoprotein particle subclass profile in middle-to older-aged adults than the HEI-2015, MD and E-DII scores. A less pro-atherogenic lipoprotein status may be a potential mechanism underlying the cardioprotective effects of higher dietary quality.

Long-term fasting improves lipoprotein-associated atherogenic risk in humans

PurposeDyslipidemia is a major health concern associated with an increased risk of cardiovascular mortality. Long-term fasting (LF) has been shown to improve plasma lipid profile. We performed an in-depth investigation of lipoprotein composition.MethodsThis observational study included 40 volunteers (50% men, aged 32–65 years), who underwent a medically supervised fast of 14 days (250 kcal/day). Changes in lipid and lipoprotein levels, as well as in lipoprotein subclasses and particles, were measured by ultracentrifugation and nuclear magnetic resonance (NMR) at baseline, and after 7 and 14 fasting days.ResultsThe largest changes were found after 14 fasting days. There were significant reductions in triglycerides (TG, − 0.35 ± 0.1 mmol/L), very low-density lipoprotein (VLDL)-TG (− 0.46 ± 0.08 mmol/L), VLDL-cholesterol (VLDL-C, − 0.16 ± 0.03 mmol/L) and low-density lipoprotein (LDL)-C (− 0.72 ± 0.14 mmol/L). Analysis of LDL subclasses showed a significant decrease in LDL1-C (− 0.16 ± 0.05 mmol/L), LDL2-C (− 0.30 ± 0.06 mmol/L) and LDL3-C (− 0.27 ± 0.05 mmol/L). NMR spectroscopy showed a significant reduction in large VLDL particles (− 5.18 ± 1.26 nmol/L), as well as large (− 244.13 ± 39.45 nmol/L) and small LDL particles (− 38.45 ± 44.04 nmol/L). A significant decrease in high-density lipoprotein (HDL)-C (− 0.16 ± 0.04 mmol/L) was observed. By contrast, the concentration in large HDL particles was significantly raised. Apolipoprotein A1 decreased significantly whereas apolipoprotein B, lipoprotein(a), fibrinogen and high-sensitivity C-reactive protein were unchanged.ConclusionOur results suggest that LF improves lipoprotein levels and lipoprotein subclasses and ameliorates the lipoprotein-associated atherogenic risk profile, suggesting a reduction in the cardiovascular risk linked to dyslipidemia.Trial RegistrationStudy registration number: DRKS-ID: DRKS00010111 Date of registration: 03/06/2016 “retrospectively registered”.

Physicochemical Properties of Lipoproteins Assessed by Nuclear Magnetic Resonance as a Predictor of Premature Cardiovascular Disease. PRESARV-SEA Study.

Some lipoprotein disorders related to the residual risk of premature cardiovascular disease (PCVD) are not detected by the conventional lipid profile. In this case-control study, the predictive power of PCVD of serum sdLDL-C, measured using a lipoprotein precipitation method, and of the physicochemical properties of serum lipoproteins, analyzed by nuclear magnetic resonance (NMR) techniques, were evaluated. We studied a group of patients with a first PCVD event (n = 125) and a group of control subjects (n = 190). Conventional lipid profile, the size and number of Very Low Density Lipoproteins (VLDL), Low Density Lipoproteins (LDL), High Density Lipoproteins (HDL) particles, and the number of particles of their subclasses (large, medium, and small) were measured. Compared to controls, PCVD patients had lower concentrations of all LDL particles, and smaller and larger diameter of LDL and HDL particles, respectively. PCVD patients also showed higher concentrations of small dense LDL-cholesterol (sdLDL), and triglycerides (Tg) in LDL and HDL particles (HDL-Tg), and higher concentrations of large VLDL particles. Multivariate logistic regression showed that sdLDL-C, HDL-Tg, and large concentrations of LDL particles were the most powerful predictors of PCVD. A strong relationship was observed between increased HDL-Tg concentrations and PCVD. This study demonstrates that beyond the conventional lipid profile, PCVD patients have other atherogenic lipoprotein alterations that are detected by magnetic resonance imaging (MRI) analysis.

Very Low-Density Lipoprotein Cholesterol May Mediate a Substantial Component of the Effect of Obesity on Myocardial Infarction Risk: The Copenhagen General Population Study.

Individuals with obesity have higher concentrations of very low-density lipoprotein (VLDL)cholesterol and increased risk of myocardial infarction. We hypothesized that VLDL cholesterol explains a fraction of the excess myocardial infarction risk in individuals with obesity. We included 29010 individuals free of myocardial infarction at baseline, nested within 109751 individuals from the Copenhagen General Population Study. During 10 years of follow-up, 2306 individuals developed myocardial infarction. Cholesterol content in large and small VLDLs, in intermediate-density lipoprotein (IDL), and in LDL was measured directly with nuclear magnetic resonance spectroscopy. Median concentrations of cholesterol in large and small VLDLs were 0.12 mmol/L (interquartile range [IQR], 0.07-0.20 mmol/L; 4.5 mg/dL [IQR, 2.6-6.9 mg/dL]) and 0.6 mmol/L (IQR, 0.5-0.8 mmol/L; 25 mg/dL [IQR, 20-30 mg/dL]) in individuals with obesity vs 0.06 mmol/L (IQR, 0.03-0.1 mmol/L; 2.2 mg/dL [IQR, 1.1-3.8 mg/dL]), and 0.5 mmol/L (IQR, 0.4-0.6 mmol/L; 20 mg/dL (IQR, 16-25 mg/dL]) in individuals with normal weight; in contrast, concentrations of IDL and LDL cholesterol were similar across body mass index (BMI) categories. Cholesterol in large and small VLDLs combined explained 40% (95% CI, 27%-53%) of the excess risk of myocardial infarction associated with higher BMI. In contrast, IDL and LDL cholesterol did not explain excess risk of myocardial infarction, whereas systolic blood pressure explained 17% (11%-23%) and diabetes mellitus explained 8.6% (3.2%-14%). VLDL cholesterol explains a large fraction of excess myocardial infarction risk in individuals with obesity. These novel findings support a focus on cholesterol in VLDL for prevention of myocardial infarction and atherosclerotic cardiovascular disease in individuals with obesity.

Habitual Fish Consumption, n-3 Fatty Acids, and Nuclear Magnetic Resonance Lipoprotein Subfractions in Women.

BackgroundSupplementation with omega‐3 (n‐3) fatty acid or dietary fish may protect against atherosclerosis, but the potential mechanisms are unclear. Prior studies found modest triglyceride‐lowering effects and slight increases in LDL (low‐density lipoprotein) cholesterol. Limited evidence has examined n‐3 effects on more detailed lipoprotein biomarkers.Methods and ResultsWe conducted a study of 26 034 healthy women who reported information on fish and n‐3 intake from a 131‐item food‐frequency questionnaire. We measured plasma lipids, apolipoproteins, and nuclear magnetic resonance spectroscopy lipoproteins and examined their associations with dietary intake of fish, total n‐3, and the n‐3 subtypes (eicosapentaenoic, docosahexaenoic, and α‐linolenic acids). Top‐ versus bottom‐quintile intake of fish and n‐3 were significantly associated with lower triglyceride and large VLDL (very‐low‐density lipoprotein) particles. Fish intake, but not total n‐3, was positively associated with total cholesterol, LDL cholesterol, apolipoprotein B, and larger LDL size, but only α‐linolenic acid was associated with lower LDL cholesterol. Total n‐3, docosahexaenoic acid, and α‐linolenic acid intake were also positively associated with larger HDL (high‐density lipoprotein) size and large HDL particles. High eicosapentaenoic acid intake was significantly associated with only a decreased level of VLDL particle concentration and VLDL triglyceride content. The n‐3 fatty acids had some similarities but also differed in their associations with prospective cardiovascular disease risk patterns.ConclusionsHigher consumption of fish and n‐3 fatty acids were associated with multiple measures of lipoproteins that were mostly consistent with cardiovascular prevention, with differences noted for high intake of eicosapentaenoic acid versus docosahexaenoic acid and α‐linolenic acid that were apparent with more detailed lipoprotein phenotyping. These hypothesis‐generating findings warrant further study in clinical trials.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000479.

High-frequency metabolite profiling and the incidence of recurrent cardiac events in patients with post-acute coronary syndrome

Purpose: The aim of this study was to study temporal changes in metabolite profiles in patients with post-acute coronary syndrome (ACS), in particular prior to the development of recurrent ACS (reACS).Methods: BIOMArCS (BIOMarker study to identify the Acute risk of a Coronary Syndrome) is a prospective study including patients admitted for ACS, who underwent high-frequency blood sampling during 1-year follow-up. Within BIOMArCS, we performed a nested case-cohort analysis of 158 patients (28 cases of reACS). We determined 151 metabolites by nuclear magnetic resonance in seven (median) blood samples per patient. Temporal evolution of the metabolites and their relation with reACS was assessed by joint modelling. Results are reported as adjusted (for clinical factors) hazard ratios (aHRs).Results: Median age was 64 (25th–75th percentiles; 56–72) years and 78% were men. After multiple testing correction (p < 0.001), high concentrations of extremely large very low density lipoprotein (VLDL) particles (aHR 1.60/SD increase; 95%CI 1.25–2.08), very large VLDL particles (aHR 1.60/SD increase; 95%CI 1.25–2.08) and large VLDL particles (aHR 1.56/SD increase; 95%CI 1.22–2.05) were significantly associated with reACS. Moreover, these longitudinal particle concentrations showed a steady increase over time prior to reACS. Among the other metabolites, no significant associations were observed.Conclusion: Post-ACS patients with persistent high concentrations of extremely large, very large and large VLDL particles have increased risk of reACS within 1 year.

Comparison of nonfasting and fasting lipoprotein subfractions and size in 15,397 apparently healthy individuals: An analysis from the VITamin D and OmegA-3 TriaL

Elevated postprandial triglycerides reflect a proatherogenic milieu, but underlying mechanisms are unclear. We examined differences between fasting and nonfasting profiles of directly measured lipoprotein size and subfractions to assess if postprandial triglycerides reflected increases in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and remnants, or small dense lipid depleted LDL (sdLDL) particles. We conducted a cross-sectional analysis of 15,397 participants (10,135 fasting; 5262 nonfasting [<8hours since last meal]) from the VITamin D and OmegA-3 TriaL. Baseline cholesterol subfractions were measured by the vertical auto profile method and particle subfractions by ion mobility. We performed multivariable linear regression adjusting for cardiovascular and lipoprotein-modifying risk factors. Mean age (SD) was 68.0years (±7.0), with 50.9% women. Adjusted mean triglyceride concentrations were higher nonfasting by 17.8±1.3%, with higher nonfasting levels of directly measured VLDL cholesterol (by 3.5±0.6%) and total VLDL particles (by 2.0±0.7%), specifically large VLDL (by 12.3±1.3%) and medium VLDL particles (by 5.3±0.8%), all P<.001. By contrast, lower concentrations of low density lipoprotein (LDL) and IDL cholesterol and particles were noted for nonfasting participants. sdLDL cholesterol levels and particle concentrations showed no statistically significant difference by fasting status (-1.3±2.1% and 0.07±0.6%, respectively, P>.05). Directly measured particle and cholesterol concentrations of VLDL, not sdLDL, were higher nonfasting and may partly contribute to the proatherogenicity of postprandial hypertriglyceridemia. These differences, although statistically significant, were small and may not fully explain the increased risk of postprandial hypertriglyceridemia.

The Systemic Redox Status Is Maintained in Non-Smoking Type 2 Diabetic Subjects Without Cardiovascular Disease: Association with Elevated Triglycerides and Large VLDL.

Decreased circulating levels of free thiols (R-SH, sulfhydryl groups) reflect enhanced oxidative stress, which plays an important role in the pathogenesis of cardiometabolic diseases. Since hyperglycemia causes oxidative stress, we questioned whether plasma free thiols are altered in patients with type 2 diabetes mellitus (T2DM) without cardiovascular disease or renal function impairment. We also determined their relationship with elevated triglycerides and very low density lipoproteins (VLDL), a central feature of diabetic dyslipidemia. Fasting plasma free thiols (colorimetric method), lipoproteins, VLDL (nuclear magnetic resonance spectrometry), free fatty acids (FFA), phospholipid transfer protein (PLTP) activity and adiponectin were measured in 79 adult non-smoking T2DM subjects (HbA1c 51 ± 8 mmol/mol, no use of insulin or lipid lowering drugs), and in 89 non-smoking subjects without T2DM. Plasma free thiols were univariately correlated with glucose (r = 0.196, p < 0.05), but were not decreased in T2DM subjects versus non-diabetic subjects (p = 0.31). Free thiols were higher in subjects with (663 ± 84 µmol/L) versus subjects without elevated triglycerides (619 ± 91 µmol/L; p = 0.002). Age- and sex-adjusted multivariable linear regression analysis demonstrated that plasma triglycerides were positively and independently associated with free thiols (β = 0.215, p = 0.004), FFA (β = 0.168, p = 0.029) and PLTP activity (β = 0.228, p = 0.002), inversely with adiponectin (β = −0.308, p < 0.001) but not with glucose (β = 0.052, p = 0.51). Notably, the positive association of free thiols with (elevated) triglycerides appeared to be particularly evident in men. Additionally, large VLDL were independently associated with free thiols (β = 0.188, p = 0.029). In conclusion, circulating free thiols are not decreased in this cohort of non-smoking and generally well-controlled T2DM subjects. Paradoxically, higher triglycerides and more large VLDL particles are likely associated with higher plasma levels of thiols, reflecting lower systemic oxidative stress.

Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis

Obeticholic acid (OCA), a farnesoid X receptor agonist, increases total and low-density lipoprotein cholesterol (LDL-C) in patients with non-alcoholic steatohepatitis. In the present study, we aimed to evaluate the impact of OCA therapy on lipoprotein sub-particles. This study included 196 patients (99 OCA group and 97 placebo group) who were enrolled in the FLINT trial and had samples available for lipid analysis and liver biopsies at enrollment and end-of-treatment (EOT) at 72 weeks. Very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particles were evaluated at baseline, 12 and 72 weeks after randomization, and 24 weeks following EOT. Baseline lipoprotein profiles were similar among OCA and placebo groups. OCA did not affect total VLDL particle concentrations, but OCA vs. placebo treatment was associated with decreased large VLDL particle concentration at 12 weeks (baseline-adjusted mean: 6.8 vs. 8.9 nmol/L; p = 0.002), mirrored by an increase in less atherogenic, small VLDL particle concentration (33.9 vs. 28.0 nmol/L; p = 0.02). After 12 weeks, total LDL particle concentration was higher in the OCA group than the placebo group (1,667 vs. 1,329 nmol/L; p <0.0001), characterized by corresponding increases in both less atherogenic, large-buoyant LDL (475 vs. 308 nmol/L; p ≤0.001) and more atherogenic small-dense LDL particles (1,015 vs. 872 nmol/L; p = 0.002). The changes in LDL particle concentrations were similar between treatment groups (OCA and placebo) 24 weeks following EOT due to improvement in the OCA cohort. Compared to placebo, a reduction in total HDL particle concentration, particularly large and medium HDL particles, was noted in the OCA-treated patients, but this resolved after drug discontinuation. OCA therapy is associated with increases in small VLDL particles, large and small LDL particles, and a reduction in HDL particles at 12 weeks. These lipoprotein concentrations reverted to baseline values 24 weeks after drug discontinuation. Non-alcoholic steatohepatitis is a chronic liver disease that is associated with an increased risk of developing cirrhosis and cardiovascular disease. Recently, obeticholic acid (OCA), a farnesoid X receptor agonist, improved liver disease but led to an increase in cholesterol. However, the impact of OCA on cholesterol is not well understood. In the present study, we show that OCA therapy is associated with a detrimental increase in lipoprotein levels, which improves after drug discontinuation. ClinicalTrials.gov numbers: NCT01265498.