Intermediate-density Lipoprotein Research Articles

Exchanging carbohydrate or protein for fat improves lipid-related cardiovascular risk profile in overweight men and women when consumed ad libitum.

The impact of low-fat diets on the plasma lipoprotein profile is incompletely understood. We conducted two 16-week dietary studies to compare the effects of a moderate-fat (mod-FAT) baseline diet with isocaloric and ad libitum low-fat diets rich in either carbohydrates (high-CHO, n = 16) or protein (high-PRO, n = 19) on plasma lipids, post-heparin lipase activities, cholesteryl ester transfer protein, and phospholipid transfer protein. Switching from the mod-FAT to the isocaloric high-CHO diet lowered plasma high-density lipoprotein cholesterol concentrations (P < 0.001) and tended to increase triglyceride levels (P = 0.087). Cholesterol content in the larger, buoyant low-density lipoprotein (LDL) fractions decreased, whereas those of the very-low-density lipoprotein, intermediate-density lipoprotein, and smaller, denser LDL fractions tended to increase. These changes were largely reversed when subjects lost weight by consuming this high-CHO diet ad libitum. Switching from the mod-FAT diet to the isocaloric high-PRO diet did not increase cholesterol content in the small-dense LDL fraction and led to decreases in both LDL and high-density lipoprotein cholesterol in plasma (P < 0.001 for both).Consumption of the high-protein ad libitum diet accompanied by weight loss did not change plasma lipids further, except for a shift of cholesterol from dense low-density lipoprotein fractions to more buoyant low-density lipoprotein fractions. Cholesteryl ester transfer protein concentrations decreased with high-cholesterol feeding, whereas cholesteryl ester transfer protein concentrations and hepatic lipase and phospholipid transfer protein activities all decreased during high-protein feeding. Both high-CHO and high-PRO diets improve plasma lipid-related risk of cardiovascular disease when consumed ad libitum.

Effects of extended-release niacin on the postprandial metabolism of Lp(a) and ApoB-100-containing lipoproteins in statin-treated men with type 2 diabetes mellitus.

The effects of extended-release niacin (ERN; 1-2 g/d) on the metabolism of lipoprotein(a) (Lp(a)) and apolipoprotein (apo) B-100-containing lipoproteins were investigated in 11 statin-treated white men with type 2 diabetes mellitus in a randomized, crossover trial of 12-weeks duration. The kinetics of Lp(a) and very low-density lipoprotein (VLDL), intermediate-density lipoprotein, and low-density lipoprotein (LDL) apoB-100 were determined following a standardized oral fat load (87% fat) using intravenous administration of D3-leucine, gas chromatography-mass spectrometry, and compartmental modeling. ERN significantly decreased fasting plasma total cholesterol, LDL cholesterol, and triglyceride concentrations. These effects were achieved without significant changes in body weight or insulin resistance. ERN significantly decreased plasma Lp(a) concentration (-26.5%) and the production rates of apo(a) (-41.5%) and Lp(a)-apoB-100 (-32.1%); the effect was greater in individuals with elevated Lp(a) concentration. ERN significantly decreased VLDL (-58.7%), intermediate-density lipoprotein (-33.6%), and LDL (-18.3%) apoB-100 concentrations and the corresponding production rates (VLDL, -49.8%; intermediate-density lipoprotein, -44.7%; LDL, -46.1%). The number of VLDL apoB-100 particles secreted increased in response to the oral fat load. Despite this, total VLDL apoB-100 production over the 10-hour postprandial period was significantly decreased with ERN (-21.9%). In statin-treated men with type 2 diabetes mellitus, ERN decreased plasma Lp(a) concentrations by decreasing the production of apo(a) and Lp(a)-apoB-100. ERN also decreased the concentrations of apoB-100-containing lipoproteins by decreasing VLDL production and the transport of these particles down the VLDL to LDL cascade. Our study provides further mechanistic insights into the lipid-regulating effects of ERN.

Glucomannan and glucomannan plus spirulina added to pork significantly block dietary cholesterol effects on lipoproteinemia, arylesterase activity, and CYP7A1 expression in Zucker fa/fa rats.

Zucker fa/fa rats easily develop dyslipidemia and obesity. Restructured pork (RP) is a suitable matrix for including functional ingredients. The effects of glucomannan- RP or glucomannan plus spirulina-enriched RP on plasma lipid/lipoprotein levels, cytochrome P450 7A1 (CYP7A1) expression, and arylesterase activity in growing fa/fa rats fed high-energy, high-fat cholesterol-enriched diets were tested. Groups of six rats each received diet containing 15% control-RP (C), 15% glucomannan-RP diet (G), 15% glucomannan + spirulina-RP diet (GS), and same diets enriched with 2.4% cholesterol and 0.49% cholic acid (cholesterol-enriched control (HC), cholesterol-enriched glucomannan (HG), and cholesterol-enriched glucomannan + spirulina (HGS) diets) over a 7-week period. C diet induced obesity, severe hyperglycemia, moderate hypercholesterolemia, and hypertriglyceridemia. Those facts were not significantly modified by G or GS diets. G diet increased CYP7A1 expression but decreased the total cholesterol/high density lipoproteins (HDL)-cholesterol ratio (p < 0.05) vs. C diet. GS vs. G diet increased (p < 0.05) CYP7A1 expression. HC vs. C diet reduced food intake, body weight gain, and plasma glucose (p < 0.01) but increased cholesterolemia (p < 0.01), lipidemia (plasma cholesterol plus triglycerides) (p < 0.001), cholesterol/triglyceride ratio in very low density lipoproteins (VLDL), and HDL (p < 0.05), cholesterol transported by VLDL and intermediate density lipoproteins (IDL) + low density lipoproteins (LDL), total cholesterol/HDL-cholesterol ratio and CYP7A1 expression (at least p < 0.05). HG and HGS diets vs. HC noticeably reduced lipidemia (p < 0.001), normalized VLDL and IDL + LDL lipid composition, and increased CYP7A1 expression (p < 0.01) but did not modify the cholesterol/HDL-cholesterol ratio. HGS vs. HG decreased triglyceridemia, the triglyceride-glucose (TyG) index and increased arylesterase/HDL-cholesterol activity (p < 0.05). In conclusion, G- and GS-RP act as functional foods and notably blocked the dietary cholesterol effects. In addition, HGS-RP improved the glucomannan hypolipidemic effects, increased arylesterase/HDL-cholesterol activity, and decreased insulin resistance.

Remnant Lipoprotein Cholesterol and Mortality After Acute Myocardial Infarction: Further Evidence for a Hypercholesterolemia Paradox From the TRIUMPH Registry.

Remnants are partially hydrolyzed, triglyceride-rich lipoproteins that, like other apolipoprotein B-containing lipoproteins, are atherogenic. Prior observational studies suggest paradoxically better outcomes in hypercholesterolemic patients who sustain an acute myocardial infarction (AMI), one of several known recurrent risk paradoxes. To date, the association of directly measured remnant lipoprotein cholesterol (RLP-C) with survival after an AMI has not been examined. Higher RLP-C levels may be paradoxically associated with lower mortality. We examined 2465 AMI survivors in a prospective, 24-center US study of AMI outcomes. Lipoprotein cholesterol subfractions were directly measured by ultracentrifugation. RLP-C was defined as intermediate-density lipoprotein cholesterol (IDL-C) + very-low-density lipoprotein cholesterol subfraction 3 (VLDL3 -C). Given a linear relationship between RLP-C and mortality, we examined RLP-C by tertiles and continuously. Cox regression hazard ratios (HRs) were adjusted for the Global Registry of Acute Coronary Events (GRACE) score and 23 other covariates. Participants were age 58 ± 12 years (mean ± SD), and 68% were men. After 2 years of follow-up, 226 (9%) participants died. The mortality proportion was 12.4% in the lowest tertile of RLP-C (0-15 mg/dL), 8.5% in the middle tertile (16-23 mg/dL), and 6.8% in the highest tertile (24-120 mg/dL; P < 0.001). A 1-SD increase in RLP-C (11 mg/dL) predicted a 24% lower adjusted risk of 2-year mortality (HR: 0.76, 95% confidence interval [CI]: 0.64-0.91). Similar results were found for a 1-SD increase in IDL-C (HR per 8 mg/dL: 0.80, 95% CI: 0.67-0.96), VLDL3 -C (HR per 4 mg/dL: 0.74, 95% CI: 0.61-0.89), and very-low-density lipoprotein cholesterol (VLDL-C; HR per 8 mg/dL: 0.69, 95% CI: 0.55-0.85). Higher RLP-C levels were associated with lower mortality 2 years after AMI despite rigorous adjustment for known confounders. Unknown protective factors or a lead-time bias likely explains the paradox.

Endogenous Sex Steroid Hormones, Lipid Subfractions, and Ectopic Adiposity in Asian Indians.

Estradiol, testosterone (T), and sex hormone binding globulin (SHBG) levels are associated with lipid subfractions in men and women. Our objective was to determine if associations are independent from adipose tissue area among Asian Indians. We used data from 42 women and 57 Asian Indian men who did not use exogenous steroids or lipid-lowering medications. Lipoprotein subfractions including low-density lipoprotein cholesterol (LDL), very low-density lipoprotein cholesterol (VLDL), and intermediate density lipoprotein (IDL) were assessed by ion mobility spectrometry. Intra-abdominal adiposity was assessed by computed tomography. Multivariable regression models estimated the association between sex hormones with lipoprotein subfractions before and after adjustment for adiposity. Among women, lower logSHBG levels were associated with smaller logLDL particle size and higher logtriglycerides, logVLDL, and logIDL, although these associations were attenuated with adjustment for visceral adiposity in particular. Among women, lower logSHBG levels was significantly associated with lower logmedium LDL and logsmall LDL concentrations even after consideration of visceral and hepatic adiposity and insulin resistance as represented by the homeostasis model assessment of insulin resistance (HOMA-IR). Among men, lower logSHBG was also associated with smaller logLDL peak diameter size and higher logtriglycerides and logVLDL, even after adjustment for HOMA-IR and adiposity. Relationships between sex steroids and lipid subfractions were not significant among women. Among men, higher total testosterone was associated with higher logHDL and logLDL particle size, and lower logtriglycerides and logVLDL, but these associations were partially attenuated with adjustment for adiposity and HOMA-IR. Among Asian Indians, SHBG is associated with more favorable lipid subfraction concentrations, independent of hepatic and visceral fat.

Deficient serum 25-hydroxyvitamin D is associated with an atherogenic lipid profile: The Very Large Database of Lipids (VLDL-3) study

Cross-sectional studies have found an association between deficiencies in serum vitamin D, as measured by 25-hydroxyvitamin D (25[OH]D), and an atherogenic lipid profile. These studies have focused on a limited panel of lipid values including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Our study examines the relationship between serum 25(OH)D and an extended lipid panel (Vertical Auto Profile) while controlling for age, gender, glycemic status, and kidney function. We used the Very Large Database of Lipids, which includes US adults clinically referred for analysis of their lipid profile from 2009 to 2011. Our study focused on 20,360 subjects who had data for lipids, 25(OH)D, age, gender, hemoglobin A1c, insulin, creatinine, and blood urea nitrogen. Subjects were split into groups based on serum 25(OH)D: deficient (<20 ng/mL), intermediate (≥ 20-30 ng/mL), and optimal (≥ 30 ng/mL). The deficient group was compared to the optimal group using multivariable linear regression. In multivariable-adjusted linear regression, deficient serum 25(OH)D was associated with significantly lower serum HDL-C (-5.1%) and higher total cholesterol (+9.4%), non-HDL-C (+15.4%), directly measured LDL-C (+13.5%), intermediate-density lipoprotein cholesterol (+23.7%), very low-density lipoprotein cholesterol (+19.0%), remnant lipoprotein cholesterol (+18.4%), and TG (+26.4%) when compared with the optimal group. Deficient serum 25(OH)D is associated with significantly lower HDL-C and higher directly measured LDL-C, intermediate-density lipoprotein cholesterol, very low-density lipoproteins cholesterol, remnant lipoprotein cholesterol, and TG. Future trials examining vitamin D supplementation and cardiovascular disease risk should consider using changes in an extended lipid panel as an additional outcome measurement.

Lipoprotein Metabolism in APOB L343V Familial Hypobetalipoproteinemia.

Familial hypobetalipoproteinemia (FHBL) is a codominant disorder of lipoprotein metabolism characterized by decreased plasma concentrations of low-density lipoprotein (LDL)-cholesterol and apolipoprotein B (apoB). The objective was to examine the effect of heterozygous APOB L343V FHBL on postprandial triglyceride-rich lipoprotein (TRL) and fasting lipoprotein metabolism. Plasma incremental area under the curve apoB-48 and apoB-48 kinetics were determined after ingestion of a standardized oral fat load using compartmental modeling. Very low-density lipoprotein (VLDL)-, intermediate-density lipoprotein (IDL)-, and LDL-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. The postprandial incremental area under the curve (0-10 h) in FHBL subjects (n = 3) was lower for large TRL-triglyceride (-77%; P < .0001), small TRL-cholesterol (-83%; P < .001), small TRL-triglyceride (-88%; P < .001), and for plasma triglyceride (-70%; P < .01) and apoB (-63%; P < .0001) compared with controls. Compartmental analysis showed that apoB-48 production was lower (-91%; P < .05) compared with controls. VLDL-apoB concentrations in FHBL subjects (n = 2) were lower by more than 75% compared with healthy, normolipidemic control subjects (P < .01). The VLDL-apoB fractional catabolic rate (FCR) was more than 5-fold higher in the FHBL subjects (P = .07). ApoB production rates and IDL- and LDL-apoB FCRs were not different between FHBL subjects and controls. We conclude that when compared to controls, APOB L343V FHBL heterozygotes show lower TRL production with normal postprandial TRL particle clearance. In contrast, VLDL-apoB production was normal, whereas the FCR was higher in heterozygotes compared with lean control subjects. These mechanisms account for the marked hypolipidemic state observed in these FHBL subjects.

Body mass index correlates with atherogenic lipoprotein profile even in nonobese, normoglycemic, and normolipidemic healthy men

To establish a relationship between body mass index (BMI), lipid, and lipoprotein parameters among nonobese, normoglycemic, and normolipidemic healthy men without any cardiovascular, metabolic, or chronic diseases. A total of 297 healthy, nonsmoking males between 20 and 75 years were recruited. Exclusion criteria included familial hypercholesterolemia, any chronic diseases, and BMI ≥ 30 kg/m(2). Lipid and lipoprotein particles were determined by standard methods, with the use of ultracentrifugation and nuclear magnetic resonance (NMR). Cholesterol in remnant-like particles (RLPc) was also determined. These healthy volunteers were separated into two groups: normoweight (BMI > 19 kg/m(2) and <25 kg/m(2) [n = 143]) and overweight (BMI ≥ 25 kg/m(2) and <30 kg/m(2) [n = 154]). Overweight participants were older (P < .001) compared to normoweight. Both groups had low-density lipoprotein (LDL) cholesterol levels (<130 mg/dL) considered as desirable, and although both groups had plasma triglyceride levels within the nonpathological range, overweight participants presented with 30% higher triglyceride levels (P < .001) and 9% lower high-density lipoprotein cholesterol (P < .001) compared to normoweight individuals. Although LDL was comparable between groups, NMR analysis showed that overweight participants had 27% more total LDL particles due to a 16% decrease in large LDL (P < .001) and 70% increase in the smaller subclasses (P < .001). In overweight participants, NMR analysis also showed a 2-fold increase in large very low-density lipoprotein (P = .001), and 30% more medium very low-density lipoprotein particles (P = .020). Overweight participants also had 70% more intermediate-density lipoprotein particles (P = .010), a 30% decrease in large high-density lipoprotein particles (P < .001), and a 39% increase in RLPc levels (P = .005). Results were adjusted for age and fat intake. BMI correlates with a shift toward a more proatherogenic lipoprotein profile even in individuals whose lipid levels were not elevated.

Screening and advanced lipid phenotyping in familial hypercholesterolemia: The Very Large Database of Lipids Study-17 (VLDL-17)

Familial hypercholesterolemia (FH) is an autosomal dominant dyslipidemia characterized by defective low-density lipoprotein (LDL) clearance. The aim of this study was to compare Friedewald-estimated LDL cholesterol (LDL-C) to biologic LDL-C in individuals screening positive for FH and then further characterize FH phenotypes. We studied 1,320,581 individuals from the Very Large Database of Lipids, referred from 2009 to 2011 for Vertical Auto Profile ultracentrifugation testing. Friedewald LDL-C was defined as the cholesterol content of LDL-C, intermediate-density lipoprotein cholesterol, and lipoprotein(a) cholesterol (Lp(a)-C), with LDL-C representing biologic LDL-C. Using Friedewald LDL-C, we phenotypically categorized patients by the National Lipid Association guideline age-based screening thresholds for FH. In those meeting criteria, we categorized patients using population percentile-equivalent biologic LDL-C cutpoints and explored Lp(a)-C and remnant lipoprotein cholesterol (RLP-C) levels. Overall, 3829 patients met phenotypic criteria for FH by Friedewald LDL-C screening (FH+). Of those screening FH+, 78.8% were above and 21.2% were below the population percentile-equivalent biologic LDL-C. The mean difference in Friedewald biologic LDL-C percentiles was -0.01 (standard deviation, 0.17) for those above, and 1.92 (standard deviation, 9.16) for those below, respectively. Over 1 of 3 were found to have an elevated Lp(a)-C and over 50% had RLP-C greater than 95th percentile of the entire VLDL population. Of those who screened FH+, Friedewald and biologic LDL-C levels were closely correlated. Large proportions of the FH+group had excess levels of Lp(a)-C and RLP-C. Future studies are warranted to study these mixed phenotypic groups and determine the role for further risk stratification and treatment algorithms.

Relationship of the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio to the remainder of the lipid profile: The Very Large Database of Lipids-4 (VLDL-4) study.

High levels of the triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio are associated with obesity, metabolic syndrome, and insulin resistance. We evaluated variability in the remaining lipid profile, especially remnant lipoprotein particle cholesterol (RLP-C) and its components (very low-density lipoprotein cholesterol subfraction 3 and intermediate-density lipoprotein cholesterol), with variability in the TG/HDL-C ratio in a very large study cohort representative of the general U.S. We examined data from 1,350,908 US individuals who were clinically referred for lipoprotein cholesterol ultracentrifugation (Atherotech, Birmingham, AL) from 2009 to 2011. Demographic information other than age and sex was not available. Changes to the remaining lipid profile across percentiles of the TG/HDL-C ratio were quantified, as well as by three TG/HDL-C cut-off points previously proposed in the literature: 2.5 (male) and 2 (female), 3.75 (male) and 3 (female), and 3.5 (male and female). The mean age of our study population was 58.7 years, and 48% were men. The median TG/HDL-C ratio was 2.2. Across increasing TG/HDL-C ratios, we found steadily increasing levels of RLP-C, non-HDL-C and LDL density. Among the lipid parameters studied, RLP-C and LDL density had the highest relative increase when comparing individuals with elevated TG/HDL-C levels to those with lower TG/HDL-C levels using established cut-off points. Approximately 47% of TG/HDL-C ratio variance was attributable to RLP-C. In the present analysis, a higher TG/HDL-C ratio was associated with an increasingly atherogenic lipid phenotype, characterized by higher RLP-C along with higher non-HDL-C and LDL density.

Lipid subclasses profiles and oxidative stress in aggressive periodontitis before and after treatment.

Associations between dyslipidaemia, oxidative stress and periodontitis have emerged in recent years. However, there is a lack of studies investigating these associations in aggressive periodontitis (AgP) cases. The aim of this study was to investigate the lipid and oxidative stress profiles in patients with AgP, and to relate them to clinical variables and interleukin (IL)-6 genetic variants. Twelve non-smoking Caucasian patients with AgP selected based on their IL6 haplotypes underwent periodontal non-surgical and surgical treatment. Peripheral blood samples taken at baseline and at six different time-points after treatment were processed to determine IL-6 circulating levels, lipid profiles (cholesterol, triglycerides, high-density lipoprotein [HDL] and low-density lipoprotein [LDL] subclasses) and oxidative stress markers (glutathione and total lipid hydroperoxide levels). HDLs were the most prevalent lipoproteins, followed by intermediate-density lipoprotein, very-low-density lipoprotein and LDL. The LDL subclasses consisted mainly of the less atherogenic large LDL. The lipid profile did not consistently change after treatment up to 3 mo after surgery. Periodontal disease severity was associated with LDL levels and size. The IL6 haplotypes were associated with total cholesterol, triglycerides, HDL and LDL subclasses after adjusting for confounders. IL-6 circulating levels were associated with both very-low-density lipoprotein and lipid hydroperoxide levels. Based on these data, we conclude that both periodontal disease severity and IL6 haplotypes may influence lipid profiles in AgP.

Treatment of primary hypertriglyceridemia states – General approach and the role of extracorporeal methods

Hypertriglyceridemia (HTG) is a common metabolic disorder in which the concentration of very low density lipoproteins (VLDL) and of chylomicrons (CMs) is elevated in the plasma. HTG may be caused by primary and/or secondary causes and affected subjects may express HTG when children or in adulthood. In children and adults a genetic cause may underlie HTG which can be expressed as CMs a severe clinical picture known as Familial Hyperchylomicronemia due to lipoprotein lipase (LPL) or apolipoprotein (apo) CII deficiencies. Genetically determined HTG includes Familial Dysbetalipoproteinemia due to deficiency of apolipoprotein EIII of VLDL and Familial HTG. However, recent data suggest that classical Fredrickson phenotypes describing clinically HTG, which were once considered to be distinct based on biochemical features, have a shared genetic set up. The HTG has been classified according to a recent international paper: mild HTG: 2–10 mmol/L (176–882 mg/dL); severe HTG: > 10 mmol/L (>882 mg/dL) associated to CMs remnants, or Intermediate Density lipoprotein (IDL) like particles, and/or CMs. The treatment includes limitation of dietary content of saturated fat and alcohol, fibrates and omega3 fatty acids. When TG are severely elevated and associated to CMs the risk of acute pancreatitis suggests the use of more drastic therapeutic option such as therapeutic plasma exchange. This paper summarizes the experience with conventional plasmapheresis (Plasma-Exchange, PEX) and different Lipoprotein Apheresis methods with respect to acutely lowering TG levels in patients with normal TG, with mild and severe HTG. Upcoming promising therapies are gene therapy, novel apolipoprotein CIII inhibitors and lomitapide.

A multivariate genome-wide association analysis of 10 LDL subfractions, and their response to statin treatment, in 1868 Caucasians.

We conducted a genome-wide association analysis of 7 subfractions of low density lipoproteins (LDLs) and 3 subfractions of intermediate density lipoproteins (IDLs) measured by gradient gel electrophoresis, and their response to statin treatment, in 1868 individuals of European ancestry from the Pharmacogenomics and Risk of Cardiovascular Disease study. Our analyses identified four previously-implicated loci (SORT1, APOE, LPA, and CETP) as containing variants that are very strongly associated with lipoprotein subfractions (log10Bayes Factor > 15). Subsequent conditional analyses suggest that three of these (APOE, LPA and CETP) likely harbor multiple independently associated SNPs. Further, while different variants typically showed different characteristic patterns of association with combinations of subfractions, the two SNPs in CETP show strikingly similar patterns - both in our original data and in a replication cohort - consistent with a common underlying molecular mechanism. Notably, the CETP variants are very strongly associated with LDL subfractions, despite showing no association with total LDLs in our study, illustrating the potential value of the more detailed phenotypic measurements. In contrast with these strong subfraction associations, genetic association analysis of subfraction response to statins showed much weaker signals (none exceeding log10Bayes Factor of 6). However, two SNPs (in APOE and LPA) previously-reported to be associated with LDL statin response do show some modest evidence for association in our data, and the subfraction response proles at the LPA SNP are consistent with the LPA association, with response likely being due primarily to resistance of Lp(a) particles to statin therapy. An additional important feature of our analysis is that, unlike most previous analyses of multiple related phenotypes, we analyzed the subfractions jointly, rather than one at a time. Comparisons of our multivariate analyses with standard univariate analyses demonstrate that multivariate analyses can substantially increase power to detect associations. Software implementing our multivariate analysis methods is available at http://stephenslab.uchicago.edu/software.html.

Effect of Ezetimibe on Low‐and High‐Density Lipoprotein Subclasses in Sitosterolemia

Sitosterolemia (STSL) is a rare sterol disease manifested by very high plasma phytosterols (PS) with normal to high total cholesterol (TC) levels and increased atherosclerosis risk. Low density lipoprotein (LDL), intermediate density lipoprotein (IDL) and very lowdensity lipoprotein (VLDL) cholesterols are proatherogenic while high density lipoprotein (HDL) cholesterol is antiatherogenic. Ezetimibe (EZ), a sterol absorption inhibitor, can reduce plasma PS and TC levels in STSL but its effect on lipoprotein subclasses has not been studied. We evaluated the effect of EZ on lipoprotein subclasses in STSL patients (pts, n=8) taken off EZ for 14 wks then placed on EZ (10 mg/d) for 14 wks. Serum total lipids and subfractions were measured enzymatically or with the Lipoprint system. Data (mean±SEM) were analyzed by paired t‐test. EZ reduced serum TC (‐13±4%, p=0.02), VLDL (‐24±4%, p=0.002) and total LDL (‐17±6%, p=0.03) levels vs off EZ. Reduced LDL values were due to decreased IDLB and C (‐22±7 and ‐21±8%, p&lt;0.05), not to large, buoyant LDL subclasses (LDL1: ‐8±8%, p=0.23 and LDL2: +35±55%, p=0.17). LDL size did not change with EZ (275±0 vs 274±1 Å, p=0.18). EZ increased HDL levels (26±8%, p=0.008) due to increased intermediate (34±14%, p=0.02) and large (33±16%, p=0.06) HDL subclasses. These data suggest EZ can favorably affect LDL and HDL subfractions distribution, thus providing potential clinical benefit in STSL beyond reducing TC and PS accrual.Funded by NIH and CIHR

Circulating PCSK9 levels are positively correlated with NMR-assessed atherogenic dyslipidaemia in patients with high cardiovascular risk.

The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene regulates cholesterol homoeostasis by accelerating low-density lipoprotein receptor (LDLR) degradation resulting in the decreased catabolism of low-density lipoprotein (LDL) leading to hypercholesterolaemia. PCSK9 has also been related to other metabolic risk factors such as triglycerides (TGs) and glucose levels and body mass index (BMI). Therefore, our aim was to study the relationship between the PCSK9 and the lipid and lipoprotein profile. We studied 267 diabetic and metabolic syndrome patients who were not receiving any lipid-lowering therapy. We measured circulating lipids, cholesterol in remnant lipoproteins (RLPc) and PCSK9 levels. A detailed lipoprotein profile was determined based on NMR. Plasma PCSK9 levels were significantly and positively correlated with TG (r=0.136, P=0.033), total cholesterol (r=0.219, P<0.001) and apoB (apolipoprotein B; r=0.226, P=0.006) circulating levels and with an atherogenic profile of lipoprotein subclasses. In further detail, circulating PCSK9 levels were positively correlated with large very-low density lipoprotein (VLDL) particles, (r=0.210, P=0.001) and with their remnants, the intermediate-density lipoprotein (IDL) particles (r=0.206, P=0.001); positively correlated with smaller LDL particles (for small LDL: r=0.224, P<0.001; for medium small LDL: r=0.235, P<0.001; and for very small LDL: r=0.220, P<0.001); and with high-density lipoprotein (HDL) particles (r=0.146, P<0.001), which is mainly explained by the PCSK9 correlation with the smallest HDL particles (r=0.130, P=0.037). In addition, circulating PCSK9 levels were positively correlated with the pro-atherogenic circulating RLPc levels (r=0.171, P=0.006). All of the correlations were adjusted by age, gender and BMI. PCSK9 levels are significantly and positively correlated with atherogenic lipoproteins such as large VLDL, IDL, the smallest LDL, the smallest HDL particles and RLPc levels.

Etiology and management of dyslipidemia in children with chronic kidney disease and end-stage renal disease.

Lipids are essential components of cell membranes, contributing to cell fuel, myelin formation, subcellular organelle function, and steroid hormone synthesis. Children with chronic kidney disease (CKD) and end-stage renal disease (ESRD) exhibit various co-morbidities, including dyslipidemia. The prevalence of dyslipidemias in children with CKD and ESRD is high, being present in 39-65% of patients. Elevated lipid levels in children without renal disease are a risk factor for cardiovascular disease (CVD), while the risk for CVD in pediatric CKD/ESRD is unclear. The pathogenesis of dyslipidemia in CKD features various factors, including increased levels of triglycerides, triglyceride-rich lipoproteins, apolipoprotein C3 (ApoC-III), decreased levels of cholesterylester transfer protein and high-density lipoproteins, and aberrations in serum very low-density and intermediate-density lipoproteins. If initial risk assessment indicates that a child with advanced CKD has 2 or more co-morbidities for CVD, first-line treatment should consist of non-pharmacologic management such as therapeutic lifestyle changes and dietary counseling. Pharmacologic treatment of dyslipidemia may reduce the incidence of CVD in children with CKD/ESRD, but randomized trials are lacking. Statins are the only class of lipid-lowering drugs currently approved by the U.S. Food and Drug Administration (FDA) for use in the pediatric population. FDA-approved pediatric labeling for these drugs is based on results from placebo-controlled trial results, showing 30-50% reductions in baseline low-density lipoprotein cholesterol. Although statins are generally well tolerated in adults, a spectrum of adverse events has been reported with their use in both the clinical trial and post-marketing settings.

Lipoprotein metabolism in familial hypercholesterolemia: Serial assessment using a one-step ultracentrifugation method

ObjectivesIt is well known that familial hypercholesterolemia (FH) is a common inherited disorder that can markedly elevate the level of plasma LDL cholesterol. However, little data exists regarding the clinical impact of the plasma triglyceride (TG)-rich lipoprotein fraction, including VLDL and IDL, in FH. Thus, we assessed the hypothesis that the mutations in the LDL receptor modulate lipoprotein metabolism other than the LDL fraction. Design and methodsWe investigated plasma lipoprotein with a one-step ultracentrifugation method for 146 controls (mean age=61.4±17.1yr, mean LDL cholesterol=92.7±61.2mg/dl), 213 heterozygous mutation-determined FH subjects (mean age=46.0±18.0yr, mean LDL cholesterol=225.1±61.2mg/dl), and 16 homozygous/compound heterozygous mutation-determined FH subjects (mean age=26.9±17.1yr, mean LDL cholesterol=428.6±86.1mg/dl). In addition, we evaluated cholesterol/TG ratio in each lipoprotein fraction separated by ultracentrifugation. ResultsIn addition to total cholesterol and LDL cholesterol levels, VLDL cholesterol (19.5±10.4, 25.2±19.3, 29.5±21.4mg/dl, respectively) and IDL cholesterol (8.3±3.7, 16.8±11.5, 40.0±37.3mg/dl, respectively) exhibited a tri-model distribution according to their status in LDL receptor mutation(s). Moreover, the ratios of cholesterol/TG of each lipoprotein fraction increased significantly in heterozygous FH and homozygous/compound heterozygous FH groups, compared with that of controls, suggesting that the abnormality in LDL receptor modulates the quality as well as the quantity of each lipoprotein fraction. ConclusionsOur results indicate that cholesterol in TG-rich lipoproteins, including VLDL and IDL, are significantly higher in FH subjects, revealing a tri-modal distribution according to the number of LDL receptor mutations.

Relation of Fish Oil Supplementation to Markers of Atherothrombotic Risk in Patients With Cardiovascular Disease Not Receiving Lipid-Lowering Therapy

Fish oil supplementation (FOS) is known to have cardiovascular benefits. However, the effects of FOS on thrombosis are incompletely understood. We sought to determine if the use of FOS is associated with lower indices of atherothrombotic risk in patients with suspected coronary artery disease (sCAD). This is a subgroup analysis of consecutive patients with sCAD (n=600) enrolled in the Multi-Analyte, Thrombogenic, and Genetic Markers of Atherosclerosis study. Patients on FOS were compared with patients not on FOS. Lipid profile was determined by vertical density gradient ultracentrifugation (n=520), eicosapentaenoic acid+docosahexaenoic acid was measured by gas chromatography (n=437), and AtherOx testing was performed by immunoassay (n=343). Thromboelastography (n=419), ADP- and collagen-induced platelet aggregation (n=137), and urinary 11-dehydrothromboxane B2 levels (n=259) were performed immediately before elective coronary angiography. In the total population, FOS was associated with higher eicosapentaenoic acid+docosahexaenoic acid content (p<0.001), lower triglycerides (p=0.04), total very low-density lipoprotein cholesterol (p=0.002), intermediate-density lipoprotein cholesterol (p=0.02), and AtherOx levels (p=0.02) but not in patients on lipid-lowering therapy. Patients not on lipid-lowering therapy taking FOS had lower very low-density lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, remnant lipoproteins, triglycerides, low-density lipoprotein cholesterol, AtherOx levels, collagen-induced platelet aggregation, thrombin-induced platelet-fibrin clot strength, and shear elasticity (p<0.03 for all). In clopidogrel-treated patients, there was no difference in ADP-induced aggregation between FOS groups. Patients on FOS had lower urinary 11-dehydrothromboxane B2 levels regardless of lipid-lowering therapy (p<0.04). In conclusion, the findings of this study support the potential benefit of FOS for atherothrombotic risk reduction in sCAD with the greatest benefit in patients not receiving lipid-lowering therapy. Future prospective studies to compare FOS with lipid-lowering therapy and to assess the independent effects of FOS on thrombogenicity are needed.

Small-dense LDL/large-buoyant LDL ratio associates with the metabolic syndrome

ObjectiveHeterogeneous particles of intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) vary in atherogenesis. We investigated the association between the metabolic syndrome (MetS) score and lipoprotein subclasses. Design and methodsA total of 260 outpatients were scored into six groups, based on their number of MetS components. Lipoprotein subclass determined by polyacrylamide tube gel electrophoresis separates IDL particles into three midbands (MID-A to C) and LDL into larger-buoyant (LDL1 and LDL2) and small-dense LDL (LDL3 to LDL6). ResultsMean concentrations of VLDL, MIDC, LDL2, and LDL3 to LDL6 positively correlated with increasing MetS score, but those of MIDA, LDL1 and HDL-C inversely correlated. LDL2 and LDL3 to LDL6 increased while MIDA and LDL1 decreased with increasing visceral fat, HOMA-IR, and triglycerides, with a reverse pattern for HDL-C. MIDB and MIDC were unchanged. By logistic regression, LDL1 and LDL3 to LDL6 significantly associates with the MetS score (odds ratio=0.957 and 1.077, respectively). The ratio of (LDL3 to LDL6)/LDL1 in the presence of HDL-C, showed the strongest association with MetS. ConclusionsRespective subpopulations of IDL and LDL particles can vary in their ability to identify MetS. Because of the most strongly associated with MetS, (LDL3 to LDL6)/LDL1 ratio is proposed as an excellent marker for evaluating lipid metabolic status in patient with MetS.

Triglyceride-rich lipoproteins and coronary artery disease risk: new insights from human genetics.

Despite ample success in reducing coronary artery disease (CAD) risk through reduction of low-density lipoprotein cholesterol (LDL-C), there remains substantial residual risk.1–4 Recent prospective studies have demonstrated that elevated triglycerides (TGs) are independent predictors of CAD risk.5–9 Furthermore, TGs are strongly associated with incident CAD events in patients with low LDL-C levels treated with statin.10 Thus, triglyceride-rich lipoproteins (TRLs) offer a potentially orthogonal risk factor to LDL-C for lowering CAD risk, but only if TRLs are causally associated with atherosclerotic disease.11 Human genetics has the potential to reveal the causal relationships of biomarkers found to be associated with disease outcomes.12–15 For example, genetic variants associated with plasma LDL-C levels are consistently associated with CAD risk in the right direction,15–18 consistent with a causal relationship. Importantly, similar studies have causally implicated the key TG-regulating enzyme lipoprotein lipase (LPL) in CAD risk. A common gain-of-function LPL variant, S447X, confers an antiatherogenic lipid profile characterized by low levels of TGs, and in several studies, it has been associated with lower incidence of vascular disease or myocardial infarction (MI).19–25 Conversely, several loss-of-function (LOF) LPL variants associated with elevated TG levels have been reported to be associated with increased CAD risk.21,26 Furthermore, multiple genome-wide association studies in the last 5 years have identified common noncoding variants at the LPL gene locus associated with both TG and CAD risk in the same direction.27–29 Beyond LPL itself, common variants that influence TG levels are significantly associated with CAD risk even after adjusting for their effects on other lipid traits.30 Do et al30 surveyed 185 single-nucleotide polymorphisms (SNPs) that were genome-wide significantly associated with ≥1 plasma lipid trait and identified a subset of …