High-density Lipoprotein Subfractions Research Articles

Effect of classic ketogenic diet treatment on lipoprotein subfractions in children and adolescents with refractory epilepsy

ObjectiveThe aim of this study was to evaluate the effects of the classic ketogenic diet (KD) on low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subfractions in children and adolescents with refractory epilepsy. MethodsThis prospective study recruited children and adolescents of either sex, whose epilepsy was refractory to treatment with multiple drugs. To be included, the patient had to have an indication for treatment with the KD and be treated as an outpatient. At baseline and after 3 and 6 mo of the KD, lipid profile (total cholesterol [TC], triacylglycerols [TG], LDL cholesterol [LDL-C], and HDL cholesterol [HDL-C]), apolipoproteins (apoA-I and apoB), 10 subfractions of HDL, 7 subfractions of LDL, LDL phenotype, and LDL size were analyzed using the Lipoprint system. ResultsThe lipid profile components (TC, TG, LDL-C, HDL-C, apoA-I, and apoB) increased during the 3-mo follow-up, and remained consistent after 6 mo of treatment. Similarly, non-HDL-C, TC/HDL-C, LDL-C/HDL-C, and apoB/apoA-I ratios, representing atherogenic particles, significantly increased. In contrast, qualitative lipoprotein characteristics progressively changed during the follow-up period. Small LDL subfractions increased, and this profile was related with reduced LDL size (27.3 nm to 26.7 nm). The LDL phenotype became worse; 52.1% of the patients had a non-A phenotype after 6 mo of the KD. Small HDL subfractions decreased only after 6 mo of the KD. ConclusionsKD treatment promotes negative changes in lipoprotein size and phenotype, contributing to atherogenic risk in these patients.

High density lipoprotein subfractions and paraoxonase 1 in children.

The Lipoprint system (Quantimetrix Corp., CA, USA), enables the determination of 10 high density lipoprotein (HDL) subfractions in contrast to the 5 HDL subfractions that can be determined by ultracentrifuge analysis. HDL subfractions, and their relationships to the arylesterase (PON1-A) and lactonase (PON1-L) activities of paraoxonase 1 (PON1), together with total-, very low density lipoprotein- and low density lipoprotein (LDL)-cholesterol and LDL subfractions were investigated in the serum of 27 mildly hypercholesterolemic children and 21 healthy controls. Our results suggest the antiatherogenity of large HDL (L-HDL) subfractions and the atherogenity of small HDL (S-HDL) subfractions in the study groups. However, the relationship between the intermediate HDL (I-HDL) subfractions with the LDL subfractions and other lipoproteins did not suggest that I-HDL subfractions are antiatherogenic. No significant association between PON1-A and the HDL subfractions was found. In contrast, PON1-L activity positively correlated with the antiatherogenic large HDL1 subfraction and negatively with intermediate HDL subfractions 4, 5 and 6. Our results contribute to the knowledge of the roles of total HDL and ten individual HDL subfractions in children and adolescents.

A case–control study on reduced HDL2b in patients with polycystic ovarian syndrome

High-density lipoprotein (HDL) is an important factor associated with the increasing risk of future ischaemic heart disease. In this study, we analyzed serum HDL2b level in the patients with polycystic ovary syndrome (PCOS). Total of 60 female patients with PCOS was enrolled for assessment and another 60 non-PCOS females with matched age and weight were selected as control. A highly sensitive microfluidic chip was employed to analyze the serum HDL subfractions. Serum HDL2b and HDL2b/HDL ratio were decreased in PCOS group than those in the control group (p < 0.05). Pearson correlation analysis revealed that serum HDL2b level was negatively correlated with body mass index, waist circumference, waist-to-hip ratio, INS0, HOMA-IR, T, estradiol, triglyceride (TG) and low-density lipoprotein (LDL)-C; and the ratio of HDL2b/HDL was negatively correlated with T, TG and LDL-C. Stepwise multiple regression analyses showed a reverse correlation for HDL2b and its ratio to HDL with hyperandrogenism. The results suggested that a reduction of serum HDL2b and its ratio to total serum HDL in PCOS patients by using the microfluidic chip method assessment. Hyperandrogenism was the main factor to affect HDL2b and its ratio to total HDL in PCOS patients, and it might increase the incidence of atherosclerosis as well as the risk of coronary heart disease.

Lifestyle intervention enhances high-density lipoprotein function among patients with metabolic syndrome only at normal low-density lipoprotein cholesterol plasma levels

Metabolic syndrome (MetS) is associated with altered lipoprotein metabolism and impairment in the functionality of small, dense high-density lipoprotein (HDL) particles secondary to compositional alterations. The objective of this study was to investigate the capacity of a lifestyle program to improve the composition and antioxidative function (AOX) of small dense HDL3c in MetS. Patients with MetS (n=33) not taking lipid-lowering drugs were recruited to follow a 12-week educational program to reduce caloric intake and to increase physical activity. HDL subfractions were preparatively isolated by isopycnic density-gradient ultracentrifugation. AOX of HDL3c was assessed as its capacity to inhibit low-density lipoprotein oxidation induced by an azoinitiator. AOX of HDL3c was significantly improved (mean reduction in the propagation rate of low-density lipoprotein oxidation by HDL3c, -6.8%, P=.03) and systemic oxidative stress, assessed as plasma levels of 8-isoprostanes, tended to decrease in normocholesterolemic MetS patients (low-density lipoprotein cholesterol [LDL-C] < 130mg/dL) but not in patients with elevated LDL-C levels and in the whole study population. In both the whole study population and the normocholesterolemic subgroup, lifestyle intervention resulted in a significant degree of normalization of HDL3c composition, (enrichment in apolipoprotein A-I and cholesteryl esters, depletion in triglycerides), which was more pronounced at LDL-C < 130mg/dL. In patients with MetS, a lifestyle program improves AOX of small, dense HDL in subjects with normal LDL-C levels. Correction of HDL composition, involving partial normalization of apoA-I content and core lipid composition, 2 central features of the lipid hydroperoxide-inactivating capacity of HDL, may account for this effect.

Abstract 623: Effect of High-intensity Statin Therapy on High-density Lipoprotein (HDL) Subfractions and Regression of Coronary Atheroma: The SATURN Trial

Aim: Statin therapy can slow the progression of coronary atherosclerosis. However, the clinical factors underlying the beneficial effects of statin therapy on disease progression remain poorly understood. We examined the relationship of circulating HDL subfractions with measures of coronary atheroma following long-term high-intensity statin therapy. Methods: Serial coronary intravascular ultrasound (IVUS) was utilized in SATURN to monitor changes in atheroma burden [percent atheroma volume (PAV)] in 915 patients with coronary artery disease, treated with rosuvastatin (40 mg) or atorvastatin (80 mg) daily for 24 months. Results: Baseline levels of total HDL-C, apo E-containing HDL-C (apoE HDL-C), HDL 3 -C and HDL 2 -C did not differ significantly between treatment groups. Compared with the atorvastatin-treated group, rosuvastatin-treated patients demonstrated greater increases in levels of total HDL-C (4.4% vs. -1.8%, p&lt;0.001), apoE HDL-C (8.5% vs. -3.3%, p&lt;0.001), HDL 3 -C (3.3% vs. -2.7%, p&lt;0.001) and HDL 2 -C (7.0% vs. -0.7%, p&lt;0.001). The alterations in apo E HDL-C and HDL 3 -C levels were associated with PAV regression in rosuvastatin-treated patients (β=-0.84, p=0.018 and β=-1.10, p=0.056, respectively) but not in the atorvastatin-treated group (β=0.41, p=0.22 and β=0.71, p=0.22 for apo E HDL-C and HDL 3 -C, respectively). Conclusions: Rosuvastatin therapy resulted in favorable changes in HDL subfractions and on-treatment levels of apoE HDL-C and HDL 3 -C were associated with greater disease regression.

The effects of apolipoprotein B depletion on HDL subspecies composition and function

HDL cholesterol (HDL-C) efflux function may be a more robust biomarker of coronary artery disease risk than HDL-C. To study HDL function, apoB-containing lipoproteins are precipitated from serum. Whether apoB precipitation affects HDL subspecies composition and function has not been thoroughly investigated. We studied the effects of four common apoB precipitation methods [polyethylene glycol (PEG), dextran sulfate/magnesium chloride (MgCl2), heparin sodium/manganese chloride (MnCl2), and LipoSep immunoprecipitation (IP)] on HDL subspecies composition, apolipoproteins, and function (cholesterol efflux and reduction of LDL oxidation). PEG dramatically shifted the size distribution of HDL and apolipoproteins (assessed by two independent methods), while leaving substantial amounts of reagent in the sample. PEG also changed the distribution of cholesterol efflux and LDL oxidation across size fractions, but not overall efflux across the HDL range. Dextran sulfate/MgCl2, heparin sodium/MnCl2, and LipoSep IP did not change the size distribution of HDL subspecies, but altered the quantity of a subset of apolipoproteins. Thus, each of the apoB precipitation methods affected HDL composition and/or size distribution. We conclude that careful evaluation is needed when selecting apoB depletion methods for existing and future bioassays of HDL function.

High-density lipopoprotein antioxidant capacity, subpopulation distribution and paraoxonase-1 activity in patients with systemic lupus erythematosus.

BackgroundThe causes of increased cardiovascular risk in systemic lupus erythematosus (SLE) are not understood thoroughly, although presence of traditional cardiovascular risk factors and disease-specific agents were also proposed. In this study, we investigated the quantitative changes in the lipid profile, as well as qualitative characteristics of high-density lipoprotein (HDL) and markers of inflammation and disease activity in SLE patients.MethodsLipoprotein levels were determined in 51 SLE patients and 49 healthy controls, matched in age and gender. HDL antioxidant capacity was determined spectrophotometrically with a cell-free method of hemin-induced low-density lipoprotein (LDL) oxidation. Polyacrylamide gel-electrophoresis was used for HDL subfraction analysis. Human paraoxonase-1 (PON1) activity, apolipoprotein A1 (ApoA1) and oxidized LDL concentrations, as well as interleukin-6, high-sensitivity C-reactive protein, serum amyloid A and monocyte chemotactic protein-1 levels were determined.ResultsHDL-cholesterol and ApoA1 concentrations decreased significantly in SLE subjects. Also, PON1 arylesterase activity (125.65 ± 26.87 vs. 148.35 ± 39.34 U/L, p = 0.001) and total HDL antioxidant capacity (165.82 ± 58.28 % vs. 217.71 ± 54.36 %, p < 0.001) were significantly reduced in patients compared to controls. Additionally, all HDL subfraction concentrations were significantly decreased in patients, while the levels of the examined inflammatory markers were significantly elevated in SLE subjects. The latter correlated positively with disease activity, and negatively with HDL concentration and total HDL antioxidant capacity, respectively. PON1 arylesterase activity and erythrocyte sedimentation rate were independent predictors of total HDL antioxidant capacity.ConclusionsInduced by the systemic inflammation, altered composition and antioxidant activity may diminish the anti-atherogenic effect of HDL and therefore may contribute to the increased cardiovascular risk of SLE patients.

Lipoprotein subfractions by nuclear magnetic resonance are associated with tumor characteristics in breast cancer.

BackgroundHigh-Density Lipoprotein (HDL)-cholesterol, has been associated with breast cancer development, but the association is under debate, and whether lipoprotein subfractions is associated with breast tumor characteristics remains unclear.MethodsAmong 56 women with newly diagnosed invasive breast cancer stage I/II, aged 35–75 years, pre-surgery overnight fasting serum concentrations of lipids were assessed, and body mass index (BMI) was measured. All breast tumors were immunohistochemically examined in the surgical specimen. Serum metabolomics of lipoprotein subfractions and their contents of cholesterol, free cholesterol, phospholipids, apolipoprotein-A1 and apolipoprotein-A2, were assessed using nuclear magnetic resonance. Principal component analysis, partial least square analysis, and uni- and multivariable linear regression models were used to study whether lipoprotein subfractions were associated with breast cancer tumor characteristics.ResultsThe breast cancer patients had following means: age at diagnosis: 55.1 years; BMI: 25.1 kg/m2; total-Cholesterol: 5.74 mmol/L; HDL-Cholesterol: 1.78 mmol/L; Low-Density Lipoprotein (LDL)-Cholesterol: 3.45 mmol/L; triglycerides: 1.18 mmol/L. The mean tumor size was 16.4 mm, and the mean Ki67 hotspot index was 26.5 %. Most (93 %) of the patients had estrogen receptor (ER) positive tumors (≥1 % ER+), and 82 % had progesterone receptor (PgR) positive tumors (≥10 % PgR+). Several HDL subfraction contents were strongly associated with PgR expression: Apolipoprotein-A1 (β 0.46, CI 0.22–0.69, p < 0.001), HDL cholesterol (β 0.95, CI 0.51–1.39, p < 0.001), HDL free cholesterol (β 2.88, CI 1.28–4.48, p = 0.001), HDL phospholipids (β 0.70, CI 0.36–1.04, p < 0.001). Similar results were observed for the subfractions of HDL1-3. We observed inverse associations between HDL phospholipids and Ki67 (β -0.25, p = 0.008), and in particular between HDL1’s contents of cholesterol, phospholipids, apolipoprotein-A1, apolipoprotein-A2 and Ki67. No association was observed between lipoproteins and ER expression.ConclusionOur findings hypothesize associations between different lipoprotein subfractions, and PgR expression, and Ki 67 % in breast tumors. These findings may have clinical implications, but require confirmation in larger studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-016-0225-4) contains supplementary material, which is available to authorized users.

High-Density Lipoprotein Subfractions and Cholesterol Efflux Capacities After Infusion of MDCO-216 (Apolipoprotein A-IMilano/Palmitoyl-Oleoyl-Phosphatidylcholine) in Healthy Volunteers and Stable Coronary Artery Disease Patients.

To determine effects of single ascending doses of MDCO-216 on high-density lipoprotein (HDL) subfractions in relation to changes in cholesterol efflux capacity in healthy volunteers and in patients with stable angina pectoris. Doses of 5- (in volunteers only), 10-, 20-, 30-, and 40-mg/kg MDCO-216 were infused during 2 hours, and plasma and serum were collected during 30 days. Plasma levels of HDL subfractions were assessed by 2-dimensional gel electrophoresis, immunoblotting, and image analysis. Lipoprotein particle concentrations and sizes were also assessed by proton nuclear magnetic resonance ((1)H-NMR). There was a rapid dose-dependent increase of total apolipoprotein A-I (apoA-I) in pre-β1, α-1, and α-2 HDL levels and decrease in α-3 and α-4 HDL. Using a selective antibody apoA-IMilano was detected in the large α-1 and α-2 HDL on all doses and at each time point. ApoA-IMilano was also detected at the α-4 position but only at high doses. (1)H-NMR analysis similarly showed a rapid and dose-dependent shift from small- to large-sized HDL particles. The increase of basal and ATP-binding cassette transporter A1-mediated efflux capacities reported previously correlated strongly and independently with the increase in pre-β1-HDL and α-1 HDL, but not with that in α-2 HDL. On infusion, MDCO-216 rapidly eliminates small HDL and leads to formation of α-1 and α-2 HDL containing both wild-type apoA-I and apoA-IMilano. In this process, endogenous apoA-I is liberated appearing as pre-β1-HDL. In addition to pre-β1-HDL, the newly formed α-1 HDL particle containing apoA-I Milano may have a direct effect on cholesterol efflux capacity.

Large HDL Subfraction But Not HDL-C Is Closely Linked With Risk Factors, Coronary Severity and Outcomes in a Cohort of Nontreated Patients With Stable Coronary Artery Disease: A Prospective Observational Study.

High-density lipoprotein (HDL) is highly heterogeneous in its size and composition. Till now, the link of HDL subfractions to coronary risk is less clear. We aimed to investigate the associations of HDL subfractions with traditional risk factors (RFs), coronary severity, and outcomes in a cohort of nontreated patients with stable coronary artery disease (CAD).We prospectively enrolled 591 eligible patients. Baseline HDL subfractions were separated by Lipoprint system. HDL subfractions (large, medium, and small) and HDL-cholesterol (HDL-C) levels were dichotomized into low and high group according to the 50 percentile. Coronary severity was evaluated by SYNTAX, Gensini, and Jeopardy scoring systems. Patients were followed up annually for major adverse cardiovascular events (MACEs). Cox proportional hazards’ models were used to evaluate the risk of HDL subfractions on MACEs.Patients with high large HDL-C levels had a decreased number of RFs. Significantly, large HDL-C levels were negatively associated with coronary severity assessed by SYNTAX and Gensini score (both P < 0.05). New MACEs occurred in 67 (11.6%) patients during a median 17.0 months follow-up. Moreover, the log-rank test revealed that there was a significant difference between high and low large HDL-C groups in event-free survival analysis (P = 0.013), but no differences were observed in total HDL-C groups and medium or small HDL-C groups (both P > 0.05). In particular, the multivariate Cox-proportional hazards model revealed that high large HDL-C was associated with lower MACEs risk (hazard ratio [95% confidence interval] 0.531 [0.295–0.959]) independent of potential confounders.Higher large HDL-C but not medium, small, or total HDL-C is associated with lower cardiovascular risk, highlighting the potential beneficial of HDL subfractionation.

The Effect of apoM Polymorphism Associated with HDL Metabolism on Obese Korean Adults

Background: Apolipoprotein M (apoM) is a recently identified apolipoprotein associated with high-density lipoprotein (HDL) in coronary artery disease (CAD), but the association between apoM polymorphism and obesity has not been reported. Aim: To investigate the association between apoM polymorphism and obesity prevalence in 584 Korean adults. Methods: A total of 584 individuals aged between 30 and 80 years were recruited from Yonsei Medical Center in Seoul, Korea, and divided into obese (OB; body mass index, BMI ≥25) and nonobese (non-OB; BMI <25) groups. Anthropometric variables, lipid profiles, insulin-resistant profiles, reverse cholesterol transport (RCT) enzymes, HDL subfraction, and apoM polymorphism were determined. Results: In OB with T-855C polymorphism, TT genotype carriers significantly showed 6.2% higher diastolic blood pressure (DBP), 1.3% lower amount of HDL2b subfraction, and 19.7% higher lecithin-cholesterol acyltransferase (LCAT) mass than TC+CC carriers. OB subjects with the T allele of T-778C polymorphism significantly demonstrated 43% higher plasma insulin, 17.7% higher total cholesterol, 26.7% higher triglyceride, 40.7% higher leptin, 1.6% lower HDL2b, and 12.6% higher LCAT mass than those with the C allele. These results were reversed in non-OB with T-778C polymorphism regarding HDL subfractions and RCT enzymes. Conclusion: apoM T-855C and T-778C polymorphisms were found to be associated with obesity by regulating HDL metabolism, and the T alleles of apoM T-778C were shown to be more strongly correlated.

Subfractions of high-density lipoprotein (HDL) and dysfunctional HDL in chronic kidney disease patients.

A number of studies have shown that chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease (CVD). Chronic kidney disease is characterized by significant disturbances in lipoprotein metabolism, including differences in quantitative and qualitative content of high-density lipoprotein (HDL) particles. Recent studies have revealed that serum HDL cholesterol levels do not predict CVD in CKD patients; thus CKD-induced modifications in high-density lipoprotein (HDL) may be responsible for the increase in CV risk in CKD patients. Various methods are available to separate several subclasses of HDL and confirm their atheroprotective properties. However, under pathological conditions associated with inflammation and oxidation, HDL can progressively lose normal biological activities and be converted into dysfunctional HDL. In this review, we highlight the current state of knowledge on subfractions of HDL and HDL dysfunction in CKD.

Hepatitis C virus G1b infection decreases the number of small low-density lipoprotein particles.

To investigate how hepatitis C virus (HCV) G1b infection influences the particle number of lipoproteins. The numbers of lipoprotein particles in fasting sera from 173 Japanese subjects, 82 with active HCV G1b infection (active HCV group) and 91 with cleared HCV infection (SVR group), were examined. Serum lipoprotein was fractionated by high-performance liquid chromatography into twenty fractions. The cholesterol and triglyceride concentrations in each fraction were measured using LipoSEARCH. The number of lipoprotein particles in each fraction was calculated using a newly developed algorithm, and the relationship between chronic HCV G1b infection and the lipoprotein particle number was determined by multiple linear regression analysis. The median number of low-density lipoprotein (LDL) particles was significantly lower in the active HCV group [1182 nmol/L, interquartile range (IQR): 444 nmol/L] than in the SVR group (1363 nmol/L, IQR: 472 nmol/L, P < 0.001), as was that of high-density lipoprotein (HDL) particles (14168 nmol/L vs 15054 nmol/L, IQR: 4114 nmol/L vs 3385 nmol/L, P = 0.042). The number of very low-density lipoprotein (VLDL) particles was similar between the two groups. Among the four LDL sub-fractions, the number of large LDL particles was similar between the two groups. However, the numbers of medium (median: 533.0 nmol/L, IQR: 214.7 nmol/L vs median: 633.5 nmol/L, IQR: 229.6 nmol/L, P < 0.001), small (median: 190.9 nmol/L, IQR: 152.4 nmol/L vs median: 263.2 nmol/L, IQR: 159.9 nmol/L; P < 0.001), and very small LDL particles (median: 103.5 nmol/L, IQR: 66.8 nmol/L vs median: 139.3 nmol/L, IQR: 67.3 nmol/L, P < 0.001) were significantly lower in the active HCV group than in the SVR group, respectively. Multiple linear regression analysis indicated an association between HCV G1b infection and the decreased numbers of medium, small, and very small LDL particles. However, active HCV infection did not affect the number of large LDL particles or any sub-fractions of VLDL and HDL particles. HCV G1b infection decreases the numbers of medium, small, and very small LDL particles.

Decrease of small dense LDL and lipoprotein-associated phospholipase A2 due to human growth hormone treatment in short children with growth hormone deficiency and small for gestational age status.

Growth hormone deficiency (GHD) and small for gestational age (SGA) status are associated with cardiovascular risks. We therefore, investigated antiatherogenic effects of growth hormone (GH). Subfractions of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), lipoprotein-associated phospholipase A2 (Lp-PLA2), and high-sensitivity C-reactive protein (hsCRP) were measured at baseline, after 8 and 52 weeks of GH treatment in 51 short children born SGA (n=33) or with GHD (n=18). The overall group showed post-treatment reductions of LDL cholesterol (LDL-C) (p=0.016), small-dense LDL cholesterol (sdLDL-C, p<0.001), Lp-PLA2 (p<0.001), and hsCRP (p=0.005), but increase of HDL2a cholesterol (HDL2a-C, p=0.025). SGA children revealed significant correlations between Lp-PLA2 and LDL-C and sdLDL-C both before and after GH, significant reductions of sdLDL-C, Lp-PLA2, hsCRP, and an increase of HDL2a-C. GHD children showed the same lipid responses, though not significantly. Children with GHD or born SGA may benefit from GH by growth acceleration and reduction of cardiovascular long-term risks.

Large high-density lipoprotein particle number is independently associated with microvascular function in patients with well-controlled low-density lipoprotein concentration: A vasodilator stress magnetic resonance perfusion study

Abnormalities in total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides are associated with microvascular dysfunction. Recent studies suggest that lipid subfractions better predict atherogenic burden than a routine lipid panel. We sought to determine, whether lipid subfractions are more strongly associated with microvascular function and subclinical atherosclerosis, than conventional lipid measurements using vasodilator stress cardiovascular magnetic resonance (CMR). Twenty-four adults referred for risk stratification from a lipid clinic with low-density lipoprotein cholesterol (LDL-C) <100 mg/dL underwent vasodilator CMR. Time-intensity curves generated from stress and rest perfusion images were used to determine the area under the curve (AUC) for the mid-ventricular slice myocardium and the left ventricular (LV) cavity. Myocardial perfusion reserve index (MPRi) was defined as stress to rest ratio of mid-ventricular myocardium AUC, normalized to LV cavity AUC. Lipid panels that included subfractions of LDL and high-density lipoprotein (HDL) were measured using nuclear magnetic resonance testing. The association between MPRi and lipid parameters was examined using univariate linear regression; lipid components statistically correlated with MPRi (P < .05) were then subjected to multivariate analysis. Univariate regression analysis showed MPRi was associated with HDL-C, triglycerides, large HDL-P, and small LDL-P; no association was found between MPRi and total cholesterol, LDL-C, total LDL-P, or total HDL-P. Using multivariate analysis, large HDL-P was independently associated with MPRi. In patients with LDL-C <100 mg/dL, large HDL-P is independently associated with CMR-derived myocardial perfusion reserve, a surrogate for microvascular function and subclinical atherosclerosis. Further studies using lipid subfractions to better understand cardiovascular risks are warranted.

Proteomic and lipidomic analyses of paraoxonase defined high density lipoprotein particles: Association of paraoxonase with the anti-coagulant, protein S.

Characterizing high density lipoprotein (HDL) particles and their relevance to HDL function is a major research objective. One aim is to identify functionally distinct particles. To try to limit both functional and compositional heterogeneity the present study focused on paraoxonase-1 (PON1) as a target for isolation of a minor HDL subfraction. Immunoaffinity techniques were applied to isolate PON1-containing HDL (P-HDL) and total HDL (T-HDL), which were subsequently characterized and compared. Analyses of the lipidomes showed significant differences between the fractions in the relative concentrations of individual lipid subspecies, notably reduced levels of unsaturated lysophosphatidylcholine (p < 0.05) in P-HDL (reflected in a significantly reduced total lysophosphatidylcholine polyunsaturated fatty acid content, p < 0.004). Significant differences were also observed for the proteomes. P-HDL was highly enriched in the anti-coagulant, vitamin K activated protein S (prot S) (p < 0.0001), and alpha2 macroglobulin (p < 0.01), compared to T-HDL. Conversely, procoagulant proteins kininogen 1 and histidine-rich glycoprotein were largely excluded from P-HDL. Immunoabsorption of PON1 from plasma significantly reduced prot S anti-coagulant activity. The P-HDL lipidome and proteome showed significant differences from T-HDL. Enrichment in anti-coagulation proteins indicates complementary functionalities within P-HDL particles and underlines their anti-atherosclerotic potential.

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.

Abstract 12788: Adiponectin Modulates the Cardiovascular Risk Associated With Obesity: Results From the Framingham Offspring Study

Objectives: Our objective was to examine the interrelationships of cardiovascular disease (CVD) risk factors with obesity, lipoproteins and their subfractions, markers of glucose homeostasis, and the inflammation markers adiponectin, and C reactive protein (hs-CRP). Methods: We measured fasting plasma lipids, low-density lipoprotein (LDL)-C, small dense LDL-C (sdLDL-C), high-density lipoprotein (HDL)-C, HDL subfractions, triglycerides, glucose, insulin, adiponectin, and hs-CRP in 2,691 male and female participants (median age 58 years) in cycle 6 of the Framingham Offspring Study. We carried out univariate and multivariate statistical analyses. Results: In both men and women the presence of obesity compared to those of normal weight was significantly (P&lt;0.05) associated with: 1) a 60% increase in the prevalence of CVD, 2) a two to three fold higher prevalence of major CVD risk factors (hypertension, diabetes, and low HDL-C &lt; 40 mg/dL), 3) a doubling of plasma levels of hsCRP, insulin, and triglycerides, 4) increased sdLDL-C, and 5) significant decreases in adiponectin and the levels of apoA-I in very large protective α-1 HDL. Surprisingly there was no relationship of obesity with levels of LDL-C in men. By multivariate analysis, in both men and women, adiponectin level emerged as the statistically most important parameter determining the variability of HDL-C and apoA-I levels in very large α-1 HDL, and sdLDL-C, while for systolic blood pressure age was the most important determinant, and for hsCRP levels it was plasma insulin levels. Interestingly over half of obese subjects were not hypertensive or prediabetic, and less than 20% had premature CVD or diabetes. By tertile analysis in obese subjects, low adiponectin was associated with a doubling of the prevalence of diabetes, and significant increases in triglycerides, and sdLDL-C (men only), and significant decreases in HDL-C and apoA-I in large α-1 HDL. Conclusions: Our data indicate that the prevalence of CVD and its risk factors increases with body mass index, and that the level of circulating adiponectin is a significant determinant of cardiovascular risk, especially diabetes prevalence, and levels of LDL and HDL subfractions in obese subjects.

Overt hypothyroidism is associated with blood inflammatory biomarkers dependent of lipid profile

To investigate the association between inflammatory biomarkers and overt hypothyroidism (OH). We measured inflammatory cytokines, interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) as well as cell-free DNA (cf-DNA) levels in 40 OH patients and 40 healthy controls. Total cholesterol, high and low density lipoprotein subfractions, triglyceride, fibrinogen, and D-dimer were recorded. Increased inflammatory profile was evidenced through significant elevations in the concentrations of all cytokines and cf-DNA levels in the OH group. Lipids and prothrombotic markers were also increased in hypothyroid subjects. A significant association between the inflammatory cytokines and lipid profile was observed. A multivariate analysis showed that this result was independent of the sex, age and BMI status of the subjects. Hypothyroidism is associated with proinflammatory state. Lipid abnormalities have a stronger influence on inflammation, increasing cardiovascular risk and atherosclerosis development in hypothyroidism.

Distribution of High-Density Lipoprotein Subfractions and Hypertensive Status: A Cross-Sectional Study.

The exact mechanisms of hypertension contributing to atherosclerosis have not been fully elucidated. Although multiple studies have clarified the association with low-density lipoprotein (LDL) subfractions, uncertainty remains about its relationship with high-density lipoprotein (HDL) subfractions. Therefore, we aimed to comprehensively determine the relationship between distribution of HDL subfractions and hypertensive status.A total of 953 consecutive subjects without previous lipid-lowering drug treatment were enrolled and were categorized based on hypertension history (with hypertension [n = 550] or without hypertension [n = 403]). Baseline clinical and laboratory data were collected. HDL separation was performed using the Lipoprint System.Plasma large HDL-cholesterol (HDL-C) and large HDL percentage were dramatically lower whereas the small HDL-C and small HDL percentage were higher in patients with hypertension (all P < 0.05). The antihypertensive drug therapy was not associated with large or small HDL subfractions (on treatment vs not on treatment, P > 0.05; combination vs single drug therapy, P > 0.05). However, the blood pressure well-controlled patients have significantly lower small HDL subfraction (P < 0.05). Moreover, large HDL-C and percentage were inversely whereas small HDL percentage was positively associated with incident hypertension after adjusting potential confounders (all P < 0.05). In the multivariate model conducted in patients with and without hypertension separately, the cardio-protective value of large HDL-C was disappeared in patients with hypertension (OR 95%CI: 1.011 [0.974-1.049]).The distribution of HDL subfractions is closely associated with hypertensive status and hypertension may potentially impact the cardio-protective value of large HDL subfraction.