Atherogenic Lipoprotein Subfractions Research Articles

Contribution of Lipoprotein(a) to polygenic risk of coronary artery disease: A prospective UK Biobank analysis

Abstract Background Lipoprotein(a) (Lp[a]) is a highly atherogenic lipoprotein subfraction that may contribute to polygenic risk of coronary artery disease (CAD), but the extent of this contribution is unknown. Purpose Our objective was to estimate the contribution of Lp(a) to polygenic risk of CAD and to evaluate the respective contributions of Lp(a) and a CAD polygenic risk score (PRS) to CAD. Methods 372,385 UK Biobank participants of European ancestry free of CAD at baseline were included. Plasma Lp(a) levels were measured and a CAD-PRS was calculated using LDpred2. Over the median follow-up of 12.6 years, 13,538 participants had incident CAD (myocardial infarction, coronary artery bypass grafting or coronary angioplasty). Results The LPA region contribution to the CAD-PRS-mediated CAD risk was modest (6.5%). Lp(a) levels significantly increased the predictive performance of a CAD-PRS including age and sex in Cox regression (C-statistic 0.751 versus 0.746, difference = 0.005 (95% CI, 0.004-0.006). Compared to participants in the top CAD-PRS quintile with Lp(a) levels ≥125 nmol/L (CAD event rate 6.6%), the hazard ratio for incident CAD in participants in the bottom CAD-PRS quintile with Lp(a) levels <25 nmol/L was 0.18 (95% CI, 0.17-0.20, p=6.41e-241, CAD event rate 2.0%). Conclusions Compared to individuals with a high genetic risk of CAD (high CAD-PRS and high Lp(a) levels), those with a low genetic risk had an 82% lower CAD risk. These results highlight a substantial contribution of genetic risk factors to CAD and that accurate estimation of genetic risk of CAD should consider blood levels of Lp(a).

Contribution of Lipoprotein(a) to Polygenic Risk Prediction of Coronary Artery Disease: A Prospective UK Biobank Analysis.

Lp(a) (lipoprotein[a]) is a highly atherogenic lipoprotein subfraction that may contribute to polygenic risk of coronary artery disease (CAD), but the extent of this contribution is unknown. Our objective was to estimate the contribution of Lp(a) to polygenic risk of CAD and to evaluate the respective contributions of Lp(a) and a CAD polygenic risk score (PRS) to CAD. A total of 372 385 UK Biobank participants of European ancestry free of CAD at baseline were included. Plasma Lp(a) levels were measured and a CAD-PRS was calculated using the LDpred2 algorithm. Over the median follow-up of 12.6 years, 13 538 participants had incident CAD (myocardial infarction, coronary artery bypass grafting, or coronary angioplasty). The LPA region contribution to the CAD-PRS-mediated CAD risk was modest (7.2% [95% CI, 6.1-8.3]). Lp(a) levels significantly increased the predictive performance of a CAD-PRS including age and sex in Cox regression (C statistic 0.751 versus 0.746, difference, 0.005 [95% CI, 0.004-0.006]). Compared with participants in the bottom CAD-PRS quintile with Lp(a) levels <25 nmol/L (CAD event rate, 1.4%), the hazard ratio for incident CAD in participants in the top CAD-PRS quintile with Lp(a) levels ≥125 nmol/L was 5.45 (95% CI, 4.93-6.03; P=9.35×10-242, CAD event rate 6.6%). Compared with individuals with a low genetic risk of CAD (low CAD-PRS and low Lp[a] levels), those with a high genetic risk (high CAD-PRS and high Lp[a] levels) had a 5-fold higher CAD risk. These results highlight a substantial contribution of genetic risk factors to CAD and that accurate estimation of genetic risk of CAD may need to consider blood levels of Lp(a).

The impact of sleep apnea syndrome on the altered lipid metabolism and the redox balance

BackgroundObstructive sleep apnea (OSA) is a disorder with a significant risk for cardiovascular diseases. Dyslipidemia and redox imbalance belong to potential mechanisms linking OSA with the development of vascular diseases. The main aim of this study was the evaluation of the presence of lipid abnormalities in OSA patients, focusing on small dense low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subfractions and determination of the redox imbalance by evaluating the marker of oxidative damage to plasma lipids - lipoperoxides.MethodsThe study included 15 male subjects with polysomnographically confirmed OSA and 16 male healthy controls. Plasma levels of total cholesterol, LDL and HDL and their subfractions, triacylglycerols and lipoperoxides were determined in all study individuals. Plasma LDL and HDL subfractions were separated by the Lipoprint system which is a polyacrylamide gel electrophoresis. Lipoperoxide levels were determined spectrophotometrically.ResultsOSA patients had significantly higher triacylglycerols, total cholesterol and LDL-cholesterol compared to healthy controls. HDL cholesterol was not significantly different. Of the LDL and HDL subfractions, OSA patients had significantly lower levels of atheroprotective LDL1 and large HDL subfractions and significantly higher levels of atherogenic small dense LDL3–7 and HDL8–10 subfractions. Lipoperoxide levels in patients with OSA were significantly elevated compared to healthy individuals.ConclusionThe lipoprotein pro-atherogenic phenotype was found in individuals with OSA characterized by increased levels of atherogenic lipoprotein subfractions and reduced levels of atheroprotective subfractions. In addition, a plasma redox imbalance was found in patients with OSA compared to controls by detecting higher oxidative damage to lipids. Abnormalities in lipoprotein levels in patients with OSA, as well as the redox imbalance, could lead to an acceleration of the atherosclerotic process in predisposed individuals and thus represent a significant risk factor for vasular diseases.

Gender differences in LDL and HDL subfractions in atherogenic and nonatherogenic phenotypes

ObjectivesThe aim of our study was to examine the role of low density lipoprotein (LDL)-subfractions in individuals with the atherogenic and non-atherogenic phenotype and the gender differences in lipoprotein subfractions including small dense LDL (sdLDL) and small high density lipoprotein (sHDL) subfractions representing the most atherogenic lipoprotein subfractions. Design & methods35 persons in the atherogenic group (AG) (with sdLDL3–7 subfractions ≥6 mg/dl) and 104 individuals in the non-atherogenic group (NAG) (sdLDL3–7 subfractions <6 mg/dl) were included in our study. To analyze plasma lipoprotein subfractions, a polyacrylamide gel electrophoresis–the Lipoprint system was used. ResultsMales compared to females in the AG had significantly higher levels of atherogenic lipoprotein subfractions such as HDL8, HDL9 and HDL10. All participants in AG had significantly lower levels of intermediate density lipoprotein IDL-A than those in NAG but significantly higher levels of IDL-B and IDL-C. Males in the AG compared to NAG had significantly lower levels of LDL1 and higher levels of LDL2 and LDL3–7 subfractions. In the NAG LDL2 positively correlated with sHDL subfractions while in the AG with the large HDL subfraction. ConclusionResults of our study demonstrate more atherogenic profile in males compared to females and a double role of LDL2 subfraction in the atherogenic process depending on the phenotype (atherogenic/non-atherogenic) of individuals.

Colchicine's effects on lipoprotein particle concentrations in adults with metabolic syndrome: A secondary analysis of a randomized controlled trial

Colchicine has received renewed interest for its potential beneficial effects in secondary prevention of cardiovascular disease. This was presumed to be primarily because of its anti-inflammatory effects; however, limited data exist regarding colchicine's impact on other cardiovascular risk factors. The aim of this study was to examine if colchicine's anti-inflammatory actions would lead to reduced circulating concentrations of oxidized low-density lipoprotein (oxLDL) in metabolically unhealthy individuals. We also examined if colchicine would improve concentrations of other atherogenic lipoprotein subfractions. This is a secondary analysis of a double-blind, randomized, placebo-controlled pilot study in which 40 adults with metabolic syndrome were randomized to colchicine 0.6mg or placebo twice daily for 3 months. Blood samples were collected in the fasted state. OxLDL was measured using enzyme-linked immunosorbent assay. Nuclear magnetic resonance spectroscopy was used to measure other lipoprotein particle subfraction concentrations. Compared with placebo, colchicine reduced markers of inflammation, including C-reactive protein, erythrocyte sedimentation rate, and GlycA (P<.01). Concentrations of oxLDL (P=.019) and small LDL (P=.022) appeared significantly increased in the colchicine arm. Colchicine had no significant effect on other lipoprotein subfractions or lipoprotein particle sizes (all P>.05). Although colchicine may have benefit in secondary prevention of cardiovascular disease in at-risk individuals, we found no evidence that these effects are because of improvements in circulating atherogenic lipoprotein particle concentrations. Further studies are needed to confirm whether colchicine increases circulating oxLDL and small LDL levels in adults with metabolic syndrome. If true, additional research is warranted to elucidate the mechanisms underlying these associations.

Elevated resting heart rate is associated with the severity of coronary artery disease in non-treated patients who underwent coronary angiography: potential role of lipoprotein subfractions

Objective: To assess the association between resting heart rate (RHR) and lipoprotein subfractions to provide potential evidence for the relationship between RHR and severity of CAD.Methods: A total of 1119 consecutive non-treated subjects scheduled for coronary angiography were enrolled. High-density lipoprotein (HDL) and low-density lipoprotein (LDL) separation were performed by Lipoprint System. The link of RHR with lipoprotein subfractions was assessed.Results: Increased RHR was significantly associated with higher triglyceride, total cholesterol, non-HDL-cholesterol, and apolipoprotein B (all p < .01). Furthermore, data indicated that higher RHR was related to more severe CAD (all p < .05). In the following linear regression models, we observed that higher RHR (HRh bpm) was significantly associated with lower large HDL (β = –0.073, p = .024) and higher small LDL subfraction (β = 0.103, p = .005) after adjusting for potential confounders.Conclusions: Increased RHR was associated with more severe CAD, which may be partly due to the significant relation to atherogenic lipoprotein subfractions.

TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD

Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic β-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.

The association of circulating microRNA-30c with atherogenic lipoprotein subfractions and composition

Circulating miR-30c has been linked to various aspects of cholesterol homeostasis. The aim of this study was to determine the association of circulating miR-30c with the atherogenic lipoprotein subfractions. Samples from subjects who were given placebo (n=22) in a randomised, double-blind crossover study were used. Subjects were divided into non-atherogenic lipoprotein phenotype (Non-ALP; n=12; triglycerides <2.0mmol/L) and atherogenic lipoprotein phenotype (ALP; n=10; triglycerides ≥2.0mmol/L) groups. All lipid and lipoprotein measurements, RNA extraction and reverse transcription-quantitative real-time polymerase chain reaction were undertaken using standard procedures. Subjects with ALP weighed significantly more than their non-ALP counterparts (p=0.023). In the non-ALP group there was significant correlation between miR-30c and components within VLDL1, namely triglyceride which showed a negative association (p=0.035) whereas phospholipids and cholesterol-ester were both positively correlated (p=0.025 and 0.014, respectively). In contrast, in the ALP group there was a significant correlation between the expression of miR-30c and components within VLDL2, namely triglyceride, which was positively associated (p=0.013). This study reveals specificity with regards to the effect of miR-30c on VLDL subfractions based on the individual's lipoprotein phenotype and implicates roles for microsomal-triglyceride transfer-protein and cholesteryl-ester-transfer-protein in LDL and VLDL metabolism, respectively.

Early-stage atherosclerosis in poloxamer 407-induced hyperlipidemic mice: pathological features and changes in the lipid composition of serum lipoprotein fractions and subfractions.

BackgroundThe aims of this study were to evaluate the effect of poloxamer 407 administration on atherogenic serum lipoprotein fractions and subfractions associated with cholesterol, triglycerides and phospholipids, as well as the onset of early atherosclerosis, in mice.MethodsMice were administered either sterile saline or poloxamer 407 (to induce a dose-controlled hyperlipidemia) for 1 month and then sacrificed at 1, 4 and 10 days after the last dose of poloxamer 407. Systolic and diastolic blood pressure, the activity of a cysteine protease (cathepsin B) in cardiac and liver tissue, and histological/morphological examination of heart and liver specimens was performed for each group of mice at each time point. Lastly, small angle X-ray scattering was utilized to analyze the lipoprotein fractions and subfractions associated with cholesterol, triglycerides and phospholipids for both groups of mice at each time point. Statistical analysis was performed using one-way, analysis-of-variance with post hoc analysis to determine significantly different mean values, while correlation analysis employed the Spearman test.ResultsPoloxamer 407-treated mice revealed significant hyperlipidemia, moderately elevated blood pressure, general lipidosis in liver cells, increased cysteine protease activity in heart tissue, and contractile-type changes in cardiomyocytes. Similar to humans, the onset of atherosclerosis in poloxamer 407-treated mice was characterized by a steady increase in serum low-density, intermediate-density and very-low-density lipoprotein fractions, as well as very-low-density lipoprotein subfractions.ConclusionsWe would propose that the sustained elevation of serum atherogenic lipoprotein fractions and subfractions induced by the administration of poloxamer 407 to mice resulted in the morphological changes we observed in both heart and liver cells, which are suggested to precede atherosclerosis, since this is a well-established mouse model of atherosclerosis. Since most of the cellular, biochemical and physiological changes documented in the present study using poloxamer 407-treated mice are related to the symptoms of early atherosclerosis in humans, it is suggested that the poloxamer 407-induced mouse model of hyperlipidemia and atherosclerosis might prove beneficial as an experimental animal model with which to evaluate the pathological features observed in early-stage atherosclerosis.

Atherogenic Lipoprotein Subfractions Determined by Ion Mobility and First Cardiovascular Events After Random Allocation to High-Intensity Statin or Placebo: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial.

Cardiovascular disease (CVD) can occur in individuals with low low-density lipoprotein (LDL) cholesterol (LDL-C). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-C and high C-reactive protein who were randomized to high-intensity statin or placebo. In 11 186 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) participants, we tested whether lipids, apolipoproteins, and ion mobility-measured particle concentrations at baseline and after random allocation to rosuvastatin 20 mg/d or placebo were associated with first CVD events (n=307) or CVD/all-cause death (n=522). In placebo-allocated participants, baseline LDL-C was not associated with CVD (adjusted hazard ratio [HR] per SD, 1.03; 95% confidence interval [CI], 0.88-1.21). In contrast, associations with CVD events were observed for baseline non-high-density lipoprotein (HDL) cholesterol (HR, 1.18; 95% CI, 1.01-1.38), apolipoprotein B (HR, 1.28; 95% CI, 1.11-1.48), and ion mobility-measured non-HDL particles (HR, 1.19; 95% CI, 1.05-1.35) and LDL particles (HR, 1.21; 95% CI, 1.07-1.37). Association with CVD events was also observed for several LDL and very-low-density lipoprotein subfractions but not for ion mobility-measured HDL subfractions. In statin-allocated participants, CVD events were associated with on-treatment LDL-C, non-HDL cholesterol, and apolipoprotein B; these were also associated with CVD/all-cause death, as were several LDL and very-low-density lipoprotein subfractions, albeit with a pattern of association that differed from the baseline risk. In JUPITER, baseline LDL-C was not associated with CVD events, in contrast with significant associations for non-HDL cholesterol and atherogenic particles: apolipoprotein B and ion mobility-measured non-HDL particles, LDL particles, and select subfractions of very-low-density lipoprotein particles and LDL particles. During high-intensity statin therapy, on-treatment levels of LDL-C and atherogenic particles were associated with residual risk of CVD/all-cause death. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Circulating non–HDL-C levels were more relevant to atherogenic lipoprotein subfractions compared with LDL-C in patients with stable coronary artery disease

Conflicting results have been yielded as to whether low-density lipoprotein (LDL) cholesterol (LDL-C) or non-high-density lipoprotein (HDL) cholesterol (non-HDL-C) is a better marker of coronary artery disease (CAD) risk. Recently, plasma LDL and HDL subfractions have been suggested to be more accurately reflecting the lipoproteins' atherogenicity. We sought to compare the relationship between LDL-C or non-HDL-C and lipoprotein subfractions. We conducted a cross-sectional study in 351 consecutive stable CAD patients without lipid-lowering therapy. The LDL and HDL separations were performed using the Lipoprint System. The LDL-C levels were measured directly, and the non-HDL-C levels were calculated. The cholesterol concentrations of LDL (large, medium, and small) and HDL (small) particles were increased (all P<.001) by non-HDL-C or LDL-C quartiles, whereas the mean LDL particle size and cholesterol concentrations of HDL (large) were decreased (both P<.001) by non-HDL-C quartiles. In age- and gender-adjusted analysis, the cholesterol in small LDL was much strongly related to non-HDL-C than to LDL-C (r=0.539 vs 0.397, both P<.001). Meanwhile, the mean LDL particle size was more closely associated with non-HDL-C than LDL-C (r=-0.336 vs r=-0.136, both P<.05). Significantly, the cholesterol in large HDL was negatively correlated with non-HDL-C (r=-0223, P<.001) but not with LDL-C. These correlations were further confirmed by the fully adjusted multivariable linear regression analysis. Non-HDL-C, in comparison to LDL-C, was more relevant to atherogenic lipoprotein subfractions in patients with stable CAD, supporting that it may be better in assessing cardiovascular risk.

Lipoprotein subfraction cholesterol distribution is more atherogenic in insulin resistant adolescents with type 1 diabetes.

Adolescents with type 1 diabetes (T1D) often have a less atherogenic-appearing fasting lipid profile than controls, despite increased rates of cardiovascular disease (CVD) as adults. We previously reported an atherogenic lipoprotein subfraction cholesterol distribution associated with insulin resistance (IR) in T1D adults. We sought to determine if T1D youth have more atherogenic profile than controls via a cross-sectional study. Following 3 days of controlled diet and restricted exercise, fasting plasma samples were drawn from 28 T1D youth [50% female, age 15.3 ± 2 yr, body mass index (BMI) 48%ile; diabetes duration 73 ± 52 months, hemoglobin A1c (HbA1c) 8.3 ± 1.4%] and 17 non-diabetic controls (47% female, age: 15.0 ± 2 yr, BMI 49%ile) prior to a hyperinsulinemic euglycemic clamp. Lipoproteins were fractionated by fast protein liquid chromatography (FPLC) and lipoprotein cholesterol distribution determined. Outcome measures were IR assessed by glucose infusion rate (GIR) and FPLC lipoprotein subfraction cholesterol distribution. T1D youth were more IR (GIR 9.1 ± 3.6 vs. 14.7 ± 3.9 mg/kg/min, p < 0.0001) and had more cholesterol distributed as small dense low density lipoprotein-cholesterol (LDL-C) and less as large buoyant high density lipoprotein-cholesterol (HDL-C) than controls (p < 0.05), despite no differences in the fasting lipid panel. T1D girls lacked the typical female less-atherogenic profile, whereas control girls tended to have a shift toward less dense LDL-C and HDL-C vs. control boys. Among T1D, IR but not HbA1c was associated with a more atherogenic lipoprotein profile. Normal weight T1D youth, especially females, had more atherogenic LDL-C and HDL-C distributions which correlated with lower insulin sensitivity. IR may contribute to the increased CVD burden in T1D.

Relationship between plasma phospholipase A2 concentrations and lipoprotein subfractions in patients with stable coronary artery disease

BackgroundBoth increased lipoprotein-associated phospholipase A2 (Lp-PLA2) concentrations and atherogenic lipoprotein subfractions have been shown to reflect unfavourable cardiovascular risk. However, the correlation between Lp-PLA2 and lipoprotein subfractions in patients with coronary artery disease (CAD) has not been assessed yet. MethodsA total of 324 consecutive subjects who were not treated with lipid-lowering drugs were enrolled (angiographically proven CAD: n=253; non-CAD: n=71). Plasma Lp-PLA2 concentrations were measured using ELISA. The low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subfractions were determined by Lipoprint System. ResultsPlasma Lp-PLA2 concentrations were higher in patients with CAD compared with those without CAD (153.61±78.73 vs. 131.41±65.49ng/ml, p=0.028). The univariable correlation analysis revealed that Lp-PLA2 concentrations were positively correlated with the cholesterol concentrations of each LDL subfractions and the intermediate as well as small HDL subfractions, while negatively linked with the LDL particle size and large HDL-cholesterol (HDL-C) concentrations in CAD group. However, no similar results were observed in the non-CAD group. Furthermore, multivariable regression analysis was performed in patients with CAD and showed that plasma Lp-PLA2 concentrations were independently correlated with the cholesterol concentrations of each LDL subfractions [large LDL-cholesterol (LDL-C): β=0.263, p<0.001; intermediate LDL-C: β=0.327, p<0.001; small LDL-C: β=0.135, p=0.033] and small HDL-C (β=0.133, p=0.034). ConclusionLp-PLA2 concentrations were positively associated with all LDL subfractions and small HDL subfraction, suggesting an interaction between Lp-PLA2 and lipoprotein subfraction phenotypes in the status of CAD.

Systemic Inflammatory Markers Are Closely Associated with Atherogenic Lipoprotein Subfractions in Patients Undergoing Coronary Angiography.

Objective. To investigate the relationship between inflammatory markers and atherogenic lipoprotein subfractions. Methods. We studied 520 eligible subjects who were not receiving any lipid-lowering therapy. The inflammatory markers including white blood cell (WBC) count, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, erythrocyte sedimentation rate (ESR), and D-dimer were measured. A multimarker inflammatory index was developed. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) separation processes were performed using Lipoprint System. Results. In age- and sex-adjusted analysis, several inflammatory markers (WBC count, hs-CRP, fibrinogen, and ESR) were positively related to circulating non-HDL cholesterol and remnant cholesterol (p < 0.05, all). Among lipoprotein subfractions, we observed a positive association of inflammatory markers with very low-density lipoprotein cholesterol, small LDL cholesterol, and LDL score (p < 0.05, all). Meanwhile, a negative association was detected between inflammatory markers and mean LDL particle size (p < 0.05) or large HDL cholesterol (p < 0.05). Moreover, we found that the relationships between multimarker index quartiles and small LDL cholesterol, LDL score, and mean LDL particle size were slightly stronger in patients with CAD. Conclusions. Systemic inflammatory markers are positively correlated with small LDL cholesterol and LDL score while being negatively linked with mean LDL particle size and large HDL cholesterol, highlighting the potential contribution to increased cardiovascular risk.

Nonalcoholic steatohepatitis is associated with an atherogenic lipoprotein subfraction profile.

BackgroundNonalcoholic steatohepatitis (NASH) carries an increased risk of cardiovascular disease (CVD) relative to the general population. We sought to evaluate whether differences in lipoprotein subfractions in obese patients with and without NASH contributes to this difference in CVD risk.FindingsIon mobility analysis was performed on 78 individuals with obesity undergoing weight loss surgery. All individuals had standard of care liver biopsies performed during surgery. Patients with NASH had significantly smaller peak LDL diameter (P = 0.02, 219.0 Å vs. 222.6 Å), and levels of IDL2 (P = 0.01, 104. nmol/L vs. 133.4 nmol/L) and HDL2b (P = 0.05, 676.7 nmol/L vs. 880.1 nmol/L) compared to those without NASH. NASH patients had significantly higher LDL-IVb levels than those without NASH (P = 0.02, 49.0 nmol/L vs. 37.1 nmol/L).The inverse association of LDL peak diameter with NASH remained significant after adjustment for diabetes (P = 0.02). HDL2b levels were inversely correlated with hepatocyte ballooning and NASH and these remained significant after adjustment for diabetes (P = 0.0017 and P = 0.007, respectively). IDL2 levels were inversely correlated with NASH, hepatocyte ballooning and fibrosis stage but these were not significant after adjustment for diabetes.ConclusionsThe lipoprotein subfraction profile in subjects with NASH is characterized by small peak LDL diameter, reduced HDL2b levels and elevated LDL-IVb levels. These changes may contribute to the increased CVD seen in patients with NASH.

Estudio de las subfracciones lipoproteicas tras el tratamiento de simvastatina y ezetimiba, en monoterapia o combinado, en pacientes hiperlipidémicos

IntroductionCoadministration of drugs is common in the pharmacologic treatment of dyslipidemia, with statins and ezetimibe generally constituting the medication of choice. By acting at different levels, the combination of these drugs allows the therapeutic objective to be achieved. However, it is not known how these drugs qualitatively affect the composition of lipoprotein subfractions, which differ in size and atherogenic potential. We set out to evaluate this effect as well as their anti-inflammatory effects. MethodsThirty-nine hyperlipidemic patients were randomly assigned to one of 2 groups: one received simvastatin (40mg/day) and the other received ezetimibe (10mg/day) for 4 weeks, after which both groups were administered combined therapy for an additional 4-week period. Lipid profile, lipoprotein subfractions of LDL and HDL, and inflammatory parameters were evaluated. ResultsAn improvement was detected in most lipid parameters after administration of hypolipemic drugs as monotherapy. Treatment with simvastatin vs ezetimibe reduced LDLc by 40.2% vs 19.6% and non-HDLc by 37.1% vs 18.8%, respectively. Coadministration of the two pharmacological agents induced a reduction of LDLc of up to 57%. Only simvastatin induced alterations in the levels of triglycerides (−18.6%) and HDLc (+7.4%). Simvastatin also reduced the smaller HDL subfractions and increased the larger ones. In addition, it lowered the percentage of sdLDL and increased the diameter of the LDL particles, and produced a significant reduction in TNFα. ConclusionsThe coadministration of simvastatin and ezetimibe has an additive cholesterol-lowering effect. Furthermore, only simvastatin reduces atherogenic lipoprotein subfractions and exerts anti-inflammatory effects over longer periods of time.

Stronger associations of sagittal abdominal diameter with atherogenic lipoprotein subfractions than waist circumference in middle-aged US white and Japanese men

Both sagittal abdominal diameter (SAD) and waist circumference (WC) highly correlate with visceral adipose tissue (VAT) being linked to an atherogenic lipoprotein profile. However, it is uncertain whether SAD is a better correlate of atherogenic lipoprotein subfractions than WC. We examined relative associations of SAD vs WC with lipoprotein subfractions for US white and Japanese men, concurrently examining the associations of VAT vs subcutaneous adipose tissue with lipoprotein subfractions. A population-based sample of 260 white and 282 Japanese men aged 40 to 49 years was examined for VAT and subcutaneous adipose tissue by computed tomography; SAD and WC by a portable sliding-beam caliper and a measuring tape, respectively; and lipoprotein subfractions by nuclear magnetic resonance spectroscopy. Both SAD and WC were significantly and positively associated with large very low-density lipoprotein and total and small low-density lipoprotein particle concentrations, and inversely associated with large high-density lipoprotein particle concentration for both white and Japanese men. In body mass index–adjusted regression models, the significant associations of SAD remained for both white and Japanese men, whereas those of WC became nonsignificant for white men. When SAD and WC were simultaneously included into the body mass index–adjusted models, the associations of SAD remained significant and statistically stronger than those of WC for both white and Japanese men. Furthermore, the pattern of the associations of SAD with those lipoprotein subfractions was comparable to that of the associations of VAT. Sagittal abdominal diameter was comparable to VAT and stronger than WC in the associations with atherogenic lipoprotein subfractions for middle-aged, nondiabetic, white and Japanese men.

Association of fasting and nonfasting serum triglycerides with cardiovascular disease and the role of remnant-like lipoproteins and small dense LDL

The magnitude of the contribution of serum triglycerides to cardiovascular disease risk and the mechanisms by which triglyceride-rich lipoproteins exert their effect on the vascular wall are largely unknown. Postprandial lipemia likewise has been linked to atherosclerosis, but large prospective studies assessing the magnitude of this association are also lacking. Hypertriglyceridemia is characterized by the presence of cholesterol-rich remnant-like lipoproteins and small dense LDL particles, both of which are believed to contribute to cardiovascular disease risk. Several large prospective cohort studies and a meta-analysis have been published recently, investigating the association of fasting and nonfasting serum triglycerides with cardiovascular disease. Fasting triglycerides increase the adjusted hazard ratios for cardiovascular disease risk 1.7 x (comparing upper with lower tertile), and nonfasting levels around 2.0 x. Measurement of nonfasting triglycerides may be more feasible and more informative, but standardization of a test meal is necessary. For clinical practice, the concentration of the atherogenic lipoprotein subfractions in hypertriglyceridemia may be reflected best by measuring apolipoprotein B. Nonfasting triglyceride levels may replace fasting levels in assessing cardiovascular disease risk once standard reference values have been developed. Several atherogenic lipoprotein subfractions can be measured by including apolipoprotein B in addition to HDL, (nonfasting) triglycerides and LDL cholesterol.

Inhibition of CETP by Torcetrapib Attenuates the Atherogenicity of Postprandial TG-Rich Lipoproteins in Type IIB Hyperlipidemia

The purpose of this study was to evaluate the impact of torcetrapib on atherogenic TG-rich lipoprotein subfractions in the postprandial phase in Type IIB hyperlipidemia. The quantitative and qualitative features of the postprandial profile of TG-rich lipoproteins were determined at baseline, after treatment for 6 weeks with 10 mg/d atorvastatin, and subsequently with an atorvastatin/torcetrapib combination (10/60 mg/d) in Type IIB patients (n=18). After ingestion of a standardized mixed meal, TG-rich lipoprotein subfractions were evaluated over 8 hours after each experimental period. On a background of atorvastatin, torcetrapib significantly attenuated the incremental postprandial area under the curve (iAUC 0 to 8 hours) for VLDL-1 (-40%), and the AUC 0 to 8 hours for VLDL-2 (-53%), with minor effect on chylomicron iAUC (-24%); concomitantly, the CE/TG ratio in both VLDL-1 and VLDL-2 was significantly reduced (-27% to -42%). Such reduction was attributable to torcetrapib-mediated attenuation of postprandial CE transfer to Chylomicrons (-17%) and VLDL-1 (-33%). Marked reduction in postprandial VLDL-1 levels was associated with apoE enrichment. On a background of atorvastatin, torcetrapib attenuated the quantitative and qualitative features of the atherogenic postprandial profile of chylomicrons, VLDL-1 and VLDL-2. Such changes reflect the sum of torcetrapib-mediated effects on TG-rich lipoprotein production, intravascular remodeling, and catabolism.

Plasma LDL and HDL characteristics and carotenoid content are positively influenced by egg consumption in an elderly population1

BackgroundApproximately 1/3 of individuals have a high plasma response to dietary cholesterol (hyper-responders). Although increases in both LDL and HDL cholesterol have been observed, limited data exist regarding effects of egg consumption on lipoprotein subclasses and circulating carotenoids.Methods29 postmenopausal women (50–68 y) and 13 men (60–80 y) were assigned to either 3 eggs (EGG, 640 mg cholesterol/d) or an equal volume of cholesterol-free egg substitute (SUB, 0 mg cholesterol/d) for 30 d. Following a 3 wk wash out, subjects crossed over to the alternate diet. Individuals with a response to dietary cholesterol > 2.2 mg/dL for each additional 100 mg of dietary cholesterol were classified as hyper-responders while hypo-responders were those with a response ≤ to 2.2 mg/dL. Nuclear Magnetic Resonance (NMR) spectroscopy determined LDL and HDL size & particle concentrations. Dietary records were used to evaluate carotenoid consumption.ResultsHyper-responders had higher concentrations of both LDL (LDL-C) and HDL (HDL-C) cholesterol after EGG. In contrast, the concentrations of plasma LDL-C and HDL-C did not differ between the EGG and SUB for the hypo-responders. After EGG, hyper-responders had larger (≥ 21.2 nm) less atherogenic LDL particle (P < 0.001) and larger HDL particle (> 8.8 nm) (P < 0.01), with no significant difference in the total number of LDL or HDL particles. Regardless of response classification, all individuals had an increase in plasma lutein (from 32.4 ± 15.2 to 46.4 ± 23.3 ng/L) and zeaxanthin (from 8.8 ± 4.8 to 10.7 ± 5.8 ng/L) during EGG, yet hyper-responders displayed higher concentrations of carotenoids when compared to hypo-respondersConclusionThese findings suggest that the increases in LDL-C and HDL-C due to increased egg consumption in hyper-responders are not related to an increased number of LDL or HDL particles but, to an increase in the less atherogenic lipoprotein subfractions. Also, increases in plasma carotenoids after EGG may provide a valuable dietary source for this population.