Atherogenic Particles Research Articles

ATHEROGENIC LIPOPROTEIN PARTICLE SUBCLASSES AND RESIDUAL CARDIOVASCULAR RISK: AN ANALYSIS OF THE JUPITER TRIAL

Despite potent statin therapy, residual risk of CVD events remains unacceptably high. Atherogenic lipoprotein particles and subclass distribution on statin therapy may identify markers of residual risk. Among 11,984 participants in JUPITER ([NCT00239681][1]; AstraZeneca) with lipoproteins measured

Apolipoprotein B improves risk assessment of future coronary heart disease in the Framingham Heart Study beyond LDL-C and non-HDL-C.

Analyses using conventional statistical methodologies have yielded conflicting results as to whether low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) or apolipoprotein B (apoB) is the best marker of the apoB-associated risk of coronary heart disease. The aim of this study was to determine the additional value of apoB beyond LDL-C or non-HDL-C as a predictor of coronary heart disease. For each patient from the Framingham Offspring Cohort aged 40-75 years (n = 2966), we calculated the extent to which the observed apoB differed from the expected apoB based on their LDL-C or non-HDL-C. We added this difference to a Cox model predicting new onset coronary heart disease over a maximum of 20 years adjusting for standard risk factors plus LDL-C or non-HDL. The difference between observed and expected apoB over LDL-C or non-HDL-C was highly prognostic of future coronary heart disease events: adjusted hazard ratios 1.26 (95% confidence interval: 1.15, 1.37) and 1.20 (1.11, 1.29), respectively, for each standard deviation increase beyond expected apoB levels. When this difference between observed and expected apoB was added to standard coronary heart disease prediction models including LDL-C or non-HDL-C, prediction improved significantly (likelihood ratio test p-values <0.0001) and discrimination c-statistics increased from 0.72 to 0.73. The corresponding relative integrated discrimination improvements were 11% and 8%, respectively. apoB improves risk assessment of future coronary heart disease events over and beyond LDL-C or non-HDL-C, which is consistent with coronary risk being more closely related to the number of atherogenic apoB particles than to the mass of cholesterol within them.

Association between LDL-C, Non HDL-C, and Apolipoprotein B Levels with Coronary Plaque Regression.

BackgroundPrevious reports have inferred a linear relationship between LDL-C and changes in coronary plaque volume (CPV) measured by intravascular ultrasound. However, these publications included a small number of studies and did not explore other lipid markers.ObjectiveTo assess the association between changes in lipid markers and regression of CPV using published data.MethodsWe collected data from the control, placebo and intervention arms in studies that compared the effect of lipidlowering treatments on CPV, and from the placebo and control arms in studies that tested drugs that did not affect lipids. Baseline and final measurements of plaque volume, expressed in mm3, were extracted and the percentage changes after the interventions were calculated. Performing three linear regression analyses, we assessed the relationship between percentage and absolute changes in lipid markers and percentage variations in CPV.ResultsTwenty-seven studies were selected. Correlations between percentage changes in LDL-C, non-HDL-C, and apolipoprotein B (ApoB) and percentage changes in CPV were moderate (r = 0.48, r = 0.47, and r = 0.44, respectively). Correlations between absolute differences in LDL-C, non‑HDL-C, and ApoB with percentage differences in CPV were stronger (r = 0.57, r = 0.52, and r = 0.79). The linear regression model showed a statistically significant association between a reduction in lipid markers and regression of plaque volume.ConclusionA significant association between changes in different atherogenic particles and regression of CPV was observed. The absolute reduction in ApoB showed the strongest correlation with coronary plaque regression.

The apolipoprotein B/apolipoprotein A-I ratio as a potential marker of plasma atherogenicity.

Background. The apolipoprotein (apo) B/apoA-I ratio represents the balance between apoB-rich atherogenic particles and apoA-I-rich antiatherogenic particles, and this ratio is considered to be a marker of cardiovascular risk. Although many studies have demonstrated the importance of the apoB/apoA-I ratio in predicting the presence or absence of cardiovascular disease, less is known about apoB/apoA-I ratio as a marker of plasma atherogenicity. Methods. A total of 157 normolipidemic men aged 20–59 years were included in the study. The plasma levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), apoA-I, apoB, and apoE were determined after a 12 h fasting period. Results. The median of the apoB/apoA-I ratio in the studied normolipidemic subjects was 0.52, with values ranging from 0.19 to 2.60. The percentage of subjects with the apoB/apoA-I ratio exceeding 0.9 (the accepted risk value of cardiovascular disease) was 19.1%. The subjects with apoB/apoA-I>0.9 were characterized by higher TG levels and atherogenic index of plasma (AIP) and lower values of ratio of low-density lipoprotein cholesterol (LDL-C) to apoB (LDL-C/apoB) and apoE levels compared with men with apoB/apoA-I<0.9. Conclusion. Despite normolipidemia, the subjects with the unfavorable apoB/apoA-I ratio had more atherogenic lipid profile.

Discordance analysis and the Gordian Knot of LDL and non-HDL cholesterol versus apoB.

Conventional methods, comparing the concentration of cholesterol to particle number as indices of cardiovascular risk, have not produced consistent results, in large part, because they treat these variables as independent and unrelated. However, although highly correlated, apolipoprotein B particles may contain a normal mass of cholesterol or may be cholesterol-depleted or cholesterol-enriched. Discordance analysis compares the predictive power of LDL-C and non-HDL-C to apolipoprotein B and LDL particle numbers in patients in whom they differ, that is, in whom they are discordant. The advantage of discordance analysis is that the results are not diluted by concordant data in which risk predictions cannot differ. The evidence, to date, consistently demonstrates that apolipoprotein B and LDL particle numbers are more accurate indices of cardiovascular risk than LDL-C or non-HDL-C. Discordance analysis is a methodological advance that allows the clinical value of closely correlated variables to be determined and demonstrates that cardiovascular risk is more closely related to the number of atherogenic particles than to the total mass of cholesterol within them.

Effects of icosapent ethyl on lipoprotein particle concentration and size in statin-treated patients with persistent high triglycerides (the ANCHOR Study)

Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid ethyl ester approved at a dose of 4 g/day as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe hypertriglyceridemia (TG ≥ 500 mg/dL). In this prespecified exploratory analysis from the ANCHOR study of patients at high cardiovascular risk with TG ≥ 200 and <500 mg/dL despite statin control of low-density lipoprotein cholesterol, we assessed the effects of IPE on lipoprotein particle concentration and size and examined correlations of atherogenic particles with apolipoprotein B (ApoB). Nuclear magnetic resonance spectroscopy was used to measure lipoprotein particle concentration and size. Compared with placebo (n = 211), IPE 4 g/day (n = 216) significantly reduced concentrations of: total (12.2%, P = .0002), large (46.4%, P < .0001), and medium (12.1%, P = .0068) very-low-density lipoprotein (VLDL) particles; total (7.7%, P = .0017) and small (13.5%, P < .0001) LDL particles; and total (7.4%, P < .0001) and large (31.0%, P < .0001) high-density lipoprotein particles. Atherogenic lipoprotein particles (total VLDL and total LDL) correlated with ApoB at baseline (R(2) = 0.57) and week 12 (R(2) = 0.65) as did total LDL particle concentration at baseline (R(2) = 0.53) and week 12 (R(2) = 0.59). Compared with placebo, IPE 4 g/day significantly reduced VLDL (7.7%, P < .0001) and high-density lipoprotein (1.2%, P = .0014) particle sizes with a modest but significant increase in LDL particle size (0.5%, P = .0031). Compared with placebo, treatment with IPE 4 g/day for 12 weeks reduced key atherogenic lipoprotein particle concentrations. At both baseline and end of study, atherogenic lipoprotein concentrations correlated with ApoB.

Discordance between apolipoprotein B and low-density lipoprotein particle number is associated with insulin resistance in clinical practice

Discordance between measures of atherogenic lipoprotein particle number (apolipoprotein B [ApoB] and low-density lipoprotein [LDL] particle number by nuclear magnetic resonance spectroscopy [LDL-PNMR]) is not well understood. Appropriate treatment considerations in such cases are unclear. To assess discordance between apoB determined by immunoassay and LDL-PNMR in routine clinical practice, and to characterize biomarker profiles and other clinical characteristics of patients identified as discordant. Two retrospective cohorts were evaluated. First, 412,013 patients with laboratory testing performed by Health Diagnostic Laboratory, Inc., as part of routine care; and second, 1411 consecutive patients presenting for risk assessment/reduction at 6 US outpatient clinics. Discordance was quantified as a percentile difference (LDL-PNMR percentile - apoB percentile) and attainment of percentile cutpoints (LDL-PNMR≥1073nmol/L or apoB≥69mg/dL). A wide range of cardiovascular risk factors were compared. ApoB and LDL-PNMR values were highly correlated (R(2)=0.79), although substantial discordance was observed. Similar numbers of patients were identified as at-risk by LDL-PNMR when apoB levels were < 69mg/dL (5%-6%) and by apoB values when LDL-PNMR was <1073nmol/L (6%-7%). Discordance (LDL-PNMR>apoB) was associated with insulin resistance, smaller LDL particle size, increased systemic inflammation, and low circulating levels of "traditional" lipids, whereas discordance (apoB>LDL-PNMR) was associated with larger LDL particle size, and elevated levels of lipoprotein(a) and lipoprotein-associated phospholipase A2 (Lp-PLA2). Discordance between apoB and LDL-PNMR in routine clinical practice is more widespread than currently recognized and may be associated with insulin resistance.

Abstract 12078: Obese Girls With PCOS Have Evidence of Vascular Stiffening and Left Ventricular Hypertrophy Which Relate to Insulin Resistance

Introduction: Women with polycystic ovarian syndrome (PCOS) have evidence of greater plaque formation and vascular disease by the third decade of life compared to women without PCOS. We previously reported that obese girls with PCOS have a more atherogenic lipoprotein particle size profile compared to controls. It was unknown these youth also already had evidence of cardiac or vascular disease and plaque development. Hypothesis: We hypothesized that adolescent girls with PCOS have evidence of vascular stiffness and plaque formation. Methods: Sedentary, non-diabetic, obese girls with PCOS (OBP; N=38, age 14.9±0.2 years, BMI% 98.1±0.3) and without PCOS (OB; N=14, age 14±0.5 years, BMI% 97.4±0.7) were enrolled. Girls with clinical hypertension, renal disease or structural cardiac abnormalities were excluded. Measures included carotid IMT (CIMT), resting echocardiogram, blood pressure, serum lipid profile, and insulin sensitivity assessed with a hyperinsulinemic euglycemic clamp. Calculated measures included carotid beta- stiffness index and distention. Results: Resting blood pressures were normal for age and similar between groups. OBP had greater carotid vascular stiffness than OB (βstiffness 1.91±0.08U OB vs 2.19±0.09 OBP, p=0.01; Distention 0.23±0.17mm OB vs 0.18±0.01 OBP, P=0.0007), and there was evidence of greater left ventricular posterior wall thickness (0.79±0.03cm OB vs 0.88±0.02 OBP; P=0.02) and intraventricular wall thickness (0.77±0.04cm OB vs 0.86±0.02 OBP; P=0.04). There was no difference in CIMT between OBP and OB (0.45±0.02cm OB vs 0.48±0.01 OBP, P&gt;0.1). However, OBP were also more insulin resistant than OB (glucose infusion rate 18.3±2.3 mg/leankg/min OB vs 10.4±1.6 OBP, P=0.0007), which correlated with left ventricular posterior wall thickness (R=-0.50, P&lt;0.001). Conclusions: Obese normotensive girls with PCOS have vascular stiffening and left ventricular remodeling which relate to insulin resistance. They do not yet have increased CIMT, however, they have insulin resistance and a more atherogenic lipid profile, indicating that the substrate for imtimal-medial thickening and plaque formation is present. Interventions to prevent cardiovascular disease should begin in adolescence.

Participation in a Social-Support Physical Activity Intervention Modestly Improves Lipoprotein Cholesterol Distribution Among Postpartum Sedentary Hispanic Women.

The effects of moderate intensity walking on lipoprotein remodeling in postpartum Hispanic women are unknown. Sedentary postpartum Hispanic women (28.2 ± 5.6 y; BMI = 29.3 ± 3.3 kg/m2) participating in a social support physical activity (PA) intervention, were randomly assigned to a 12-month walking program (walkers; n = 22; target 150 min/wk, moderate intensity) or a control group (nonwalkers; n = 22). Fasting lipids and cholesterol distribution within low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles were measured at baseline (BL), 6 months, and 12 months. Walkers had an 11% increase and nonwalkers a 7% decrease in HDL cholesterol from 6 to 12 months (P = .0367) without an effect on LDL cholesterol. Whereas nonwalkers had virtually no change in mean LDL particle size, walkers had a borderline reduction in LDL size from BL (268.7 ± 4.1 Å) to 6 months (266.9 ± 4.9 Å), followed by a significant increase in size by 12 months (269.7 ± 4.1 Å; P = .011). The proportion of cholesterol in large LDL particles decreased by 15% from BL to 6 months, but subsequently increased 25% by 12 months among walkers; changes among nonwalkers were smaller and in opposite direction (4% and -3%, respectively; P = .0004). Participation in the social-support PA intervention resulted in slightly increased HDL cholesterol concentrations and a modest and beneficial shift toward larger, less atherogenic LDL particles.

The effects of treatment on lipoprotein subfractions evaluated by polyacrylamide gel electrophoresis in patients with autoimmune hypothyroidism and hyperthyroidism.

BackgroundAtherogenic dyslipoproteinemia is one of the most important risk factor for atherosclerotic changes development. Hypothyroidism is one of the most common causes of secondary dyslipidemias which results from reduced LDL clearance and therefore raised levels of LDL and apoB. Association between small dense LDL (sdLDL) presentation and thyroid status has been examinated using polyacrylamide gel electrophoresis for lipoprotein subfractions evaluation.Methods40 patients with diagnosed autoimmune hypothyroidism and 30 patients with autoimmune hyperthyroidism were treated with thyroxine replacement or thyreo-suppressive treatment. In both groups lipid profiles, LDL subractions, apolipoproteins (apoA1, apoB), apoA1/apoB ratio and atherogenic index of plazma (AIP) were examined before treatment and in state of euthyreosis.ResultsThyroxine replacement therapy significantly reduced levels of total cholesterol (TC), LDL, triglycerides (TG) and also decreased levels of sdLDL (8,55±11,671 vs 0,83±1,693mg/dl; p<0,001), apoB and AIP. For estimation of atherogenic lipoprotein profile existence an AIP evaluation seems to be better than apoB measurement because of the more evident relationship with sdLDL (r=0,538; p<0,01). Thyreo-suppressive therapy significantly increased levels of TC, LDL, TG and apoB. The sdLDL was not found in hyperthyroid patients.ConclusionsAtherogenic lipoprotein profile was present in 52.5% of hypothyroid subjects, which is higher prevalence than in normal, age-related population. Substitution treatment leads to an improvement of the lipid levels, TG, apoB, AIP and LDL subclasses. It significantly changed the presentation of sdLDL – we noticed shift to large, less atherogenic LDL particles. Significantly positive correlation between sdLDL and TAG; sdLDL and VLDL alerts to hypertriglyceridemia as a major cardiovascular risk factor.

Effect of Citrus Bergamot Polyphenol Extract on Patients With Nonalcoholic Fatty Liver Disease

Introduction: To determine whether bergamot polyphenolic fraction (BPF), a proprietary extract from a unique antioxidant-rich citrus fruit (bergamot) known to be beneficial in subjects with metabolic syndrome and dyslipidemias, could significantly improve hepatic structure and function in patients with both metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Methods: One hundred seven patients who met the NCEP-ATP III criteria for metabolic syndrome and had ultrasonic evidence of severe NAFLD (hepato-renal index 2.5-3.5) after exclusion of alcohol, viral, and immune disorders were admitted to the study. Before and after 120 days of BPF 650 mg twice a day, all patients had full lipid analysis including lipoprotein fractionation (NMR), fasting glucose, ALT, AST, steato test, γ-GT, TNF-α (ELISA), CRP, and ultrasonographic hepatorenal tests. Results: Hepatic tests include: steato test (baseline: 0.74 ± 0.12; after 120 days BPF: 0.44 ± 0.09), ALT (U/L) (baseline: 54 ± 5.4; after 120 days BPF: 36 ± 5.3), AST (U/L) (baseline: 52. ± 6.4; after 120 days BPF: 41 ± 5.2), γ-GT (IU/L) (baseline: 38 ± 5.2; after 120 days BPF: 29.33 ± 1.1), hepatorenal index (baseline: 2.8 ± 0.4; after 120 days BPF: 1.5 ± 0.5). Inflammatory tests include: Hs-CRP (mcg/dL) (baseline: 1.2 + 0.8; after 120 days BPF: 0.94 + 0.6) and TNF-α (pg/mL) (baseline: 14.4 ± 1.9; after 120 days BPF: 10.7 ± 1.7). Metabolic tests include: fasting glucose (mg/mL) (baseline: 118 ± 1.4; after 120 days BPF: 98 ± 0.8). All values p<0.05. Standard lipid levels (TC, LDL, HDL, TG, IDL, VLDL) were significantly improved as were the size, density and number of all atherogenic lipoprotein particles (e.g., small dense LDL, NMR, LDL particle number). Conclusion: Bergamot polyphenolic extract (BPF) derived from the Calabrian bergamot citrus fruit is a potent anti-oxidant, AMP kinase activator, and HMG-CoA reductase inhibitor that has been proven to address all components of the metabolic syndrome. In a group of 107 patients with confirmed NAFLD and metabolic syndrome, BPF given twice per day before meals significantly improved all measured biochemical and ultrasonographic characteristics of both NAFLD and metabolic syndrome in 120 days without reported side effects. There was a striking improvement in hepatic function (biochemical) and structure (echogenic visual loss of hepatic fat) accompanied by lower levels of inflammation. As there is a dearth of proven therapeutic options for NAFLD and metabolic syndrome, this study suggests that BPF may be a safe and important therapeutic option for these conditions. Disclosure - James E. Ehrlich--consultant for Nat Health Solutions, distributor of BergaMet. Ross Walker--consultant for Nat Health Solutions. Vincenzo Mollace--consultant for Nat Health Solutions.Figure 1

SORT1 protective allele is associated with attenuated postprandial: lipaemia in young adults.

Elevated levels of lipids and lipoproteins have strong genetic determinants and are recognized as key risk factors for atherogenesis and cardiovascular disease, particularly in the postprandial state. The aim of the study to determine whether young adults, when stratified by genotype at the rs646776 variant of the 1p13 locus, displayed differential postprandial responses to an oral fat tolerance test. Participants (n=30) received a high-fat mixed meal (91 g; 55% kcal from fat) after an overnight fast and a fat-exclusion meal (3.9 g; 6% kcal from fat) at 8 hours postprandially. Blood samples were obtained at t=0, 2, 4, 6, 8, and 24 hours for lipoprotein analyses via nuclear magnetic resonance profiling. Carriers of the minor, protective allele (TC/CC) displayed lower fasting (TC/CC, 30.1±3.0 nmol/L versus TT, 48.8±5.1 nmol/L; P<0.01) and mean postprandial (TC/CC, 44.2±3.1 nmol/L versus TT, 57.0±4.5 nmol/L; P=0.03) very low-density lipoprotein and chylomicron particle number in addition to triglyceride content when compared with individuals homozygous for the major, risk allele (TT). We report a novel association between the SORT1 1p13 locus and extent of postprandial lipaemia. These results provide evidence of decreased exposure to atherogenic particles in carriers of the minor SORT1 allele, suggesting relative protection against cardiovascular disease when compared with TT homozygotes.

GENDER SPECIFIC DIFFERENCES IN A NEW APOE-/-:INS2+/AKITA MOUSE MODEL OF HYPERGLYCEMIA-INDUCED ATHEROSCLEROSIS

PURPOSE: People with diabetesmellitus have a 2 to 4-fold increased risk of cardiovascular disease (CVD). Despite a vast amount of research, the underlying mechanisms that predispose individuals with diabetes to the development of CVD are unclear. Thus, to further our understanding of how diabetes promotes CVD and to begin to delineate how gender may influence pathogenesis, we have established, characterized and manipulated a new model of hyperglycemia-induced atherosclerosis: the apoE:Ins2 mouse. METHODS: Ins2 is anautosomaldominantmutation(C96Y)that induces juvenile-onset hyperglycemia in the absence of obesity. Ins2 Akita male mice were crossed to apoE female mice, which spontaneously develop atherosclerosis. At 5 weeks of age, male/female apoE:Ins2 mice were castrated/ovariectomized and fed a standard chow diet until the 25 weeks of age whenmice were euthanized and organs were harvested. Metabolic parameters and atherosclerotic developmentweremonitored and analyzed through the whole study. RESULTS: Male apoE:Ins2 developed persistent hyperglycemia. At 25 weeks of age, lesions from hyperglycemic mice were 3-4 times larger, with significantly larger necrotic cores, and presented calcifiedregions,comparedtonormoglycemicapoEmales.Castrated maleapoE:Ins2miceshowedareductioninbloodglucoselevels which correlated to a lack of testosterone, an improvement of several metabolic parameters, and a partial amelioration of atherosclerosis. Female apoE:Ins2 presented transient hyperglycemia that normalized by 15 weeks of age. Despite the transient hyperglycemia, larger atherosclerotic lesions were observed at 15 weeks of age compared to apoE females. Ovariectomized female apoE:Ins2 Akita mice presented chronic hyperglycemia and accelerated atherosclerosis relatively similar to male apoE:Ins2 mice. Estradiol levels were compensated in all ovariectomized mice suggesting a role for progesterone in the maintenance of euglycemia. CONCLUSION: We have developed gender-specific models of chronic and transient hyperglycemia-induced atherosclerosis. In both genders, sexual hormones impacted atherosclerosis through at least 3 mechanisms: i) the effect on insulin secretion and its regulation of the glucose levels, ii) the effect on lipid metabolism and the bioavailability of atherogenic lipoprotein particles, and iii) the protective effect directly exerted on the vasculature. CDA

Nonpharmacological Lipoprotein Apheresis Reduces Arterial Inflammation in Familial Hypercholesterolemia

BackgroundPatients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk. ObjectivesThis study used 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients. MethodsIn total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls. All subjects underwent FDG-PET imaging at baseline. Twelve FH patients who met the criteria for lipoprotein apheresis underwent apheresis procedures followed by a second FDG-PET imaging 3 days (range 1 to 4 days) after apheresis. Subsequently, the target-to-background ratio (TBR) of FDG uptake within the arterial wall was assessed. ResultsIn FH patients, the mean arterial TBR was higher compared with healthy controls (2.12 ± 0.27 vs. 1.92 ± 0.19; p = 0.03). A significant correlation was observed between baseline arterial TBR and LDL-C (R = 0.37; p = 0.03) that remained significant after adjusting for statin use (β = 0.001; p = 0.02) and atherosclerosis risk factors (β = 0.001; p = 0.03). LDL-C levels were significantly reduced after lipoprotein apheresis (284 ± 118 mg/dl vs. 127 ± 50 mg/dl; p < 0.001). There was a significant reduction of arterial inflammation after lipoprotein apheresis (TBR: 2.05 ± 0.31 vs. 1.91 ± 0.33; p < 0.02). ConclusionsThe arterial wall of FH patients is characterized by increased inflammation, which is markedly reduced after lipoprotein apheresis. This lends support to a causal role of apoprotein B–containing lipoproteins in arterial wall inflammation and supports the concept that lipoprotein-lowering therapies may impart anti-inflammatory effects by reducing atherogenic lipoproteins.

Relationship between plasma apolipoprotein B concentrations and LDL particle number

Many subjects with relatively normal, or even optimal, levels of low-density lipoprotein cholesterol (LDL-C) have increased atherogenic lipoprotein particle concentrations (apolipoprotein B (apoB) and LDL particle number (LDL-P) determined by nuclear magnetic resonance spec- troscopy (NMR)). Numerous analyses have demonstrated that apoB and LDL-P predict the risk of future cardiovascular events more robustly than LDL-C, as estimated using the Friedewald equation. Little is known about the relationship between an individual's apoB and LDL-P level, and whether the relationship is comparable at different levels of LDL-C. The aim of this study was to examine the correlation between plasma apoB and LDL-P levels and specifically to evaluate the heterogeneity of LDL-P at low levels of apoB (, the 20th population percentile (78 mg/dL)). Data were derived from a group of consecutive patients added to a large, single laboratory database (LipoScience, Inc.) during a 1-week period in which a standard lipid profile, apoB, and LDL-P levels were available. When risk categories were assigned to the subjects using the Framingham Offspring Study's population percentiles for apoB and LDL-P, there was good agreement between the two measures when LDL-C levels were high ($160 mg/dL). However, among individuals with low LDL-C and apoB, NMR analysis could identify a subgroup of individuals with potentially

Oxidized low density lipoprotein and total antioxidant capacity in type-2 diabetic and impaired glucose tolerance Saudi men.

BackgroundOxidative modification of low density lipoproteins (LDL) convert these native particles into pathogenic, immunogenic and atherogenic particles. Factors enhance LDL oxidation are poorly understood, especially in conditions of hyperglycemia. The present study was conducted to investigate which metabolic conditions are associated with the promotion of LDL oxidation in different glycemic situations.MethodsAdult male participants (274) were selected from patients admitted to the outpatient department of Diabetes Center in Al-Noor Specialized Hospital in Makkah and other citizens and residents in the city. The studied group was classified into three sub-groups: Group-I: control group of non-diabetic normal subjects, Group-II: subjects with impaired glucose tolerance (IGT) and Group-III: cases of type-2 diabetes mellitus (DM). Measurement of fasting blood glucose, 2 hour post-prandial blood glucose, glycosylated hemoglobin (HbA1c), triglycerides, serum cholesterol, HDL-cholesterol, LDL-cholesterol, ox-LDL, Total Antoxidant capacity (TAC) and Malondialdehyde (MDA) were performed. The obtained results were statistically analyzed.ResultsOxidation of native LDL increase nearly two folds in Type-2 DM group compared to controls. There is also significant increase in Ox-LDL of IGT group compared to controls. The correlation between Ox-LDL concentration and HbA1c in the whole population of the study confirms the increased Ox-LDL in subjects with hyperglycemia. A negative correlation exists between the concentration of Ox-LDL and total antioxidant capacity (TAC) in each studied group and in the whole population of the study as well. A positive correlation also exists between Ox-LDL concentrations and LDL values, more clear in controls and Type-2 DM, while this correlation was not significant in IGT group. The ratio of LDL oxidation as expressed by ox-LDL/LDL was increased in IGT group compared to control. More significant increase was observed in type-2 DM group.ConclusionWe concluded that the concentration of Ox-LDL increased in subjects with type-2 DM and IGT compared to controls. Moreover, oxidation of native LDL was associated with low levels of TAC and positively correlated with LDL levels, total cholesterol, HbA1c, body mass index (BMI) and increased age.

Pre-diabetes in overweight youth and early atherogenic risk

PurposeTo compare atherogenic lipoprotein particles and vascular smooth muscle biomarkers in overweight youth with pre-diabetes (PD) vs. normal glucose tolerance (NGT). Methods144 adolescents (60 black, 84 white; 102 female; PD=45, NGT=99) aged 10–19years underwent a fasting blood draw and 2-h OGTT. Lipoprotein particle size and subclass concentration and vascular smooth muscle biomarkers (ICAM-1, VCAM-1 and E-selectin) were compared between youth with PD and NGT. ResultsCompared with NGT, PD adolescents had smaller LDL (mean±SE: 20.5±0.1 vs. 21.0±0.1nm; P=0.002) and HDL (8.62±0.05 vs. 8.85±0.04nm; P=0.013) size and elevated medium small (159.2±10.3 vs. 123.8±6.4nmol/L; P=0.037) and very small (626.3±45.4 vs. 458.5±26.4nmol/L; P=0.032) LDL particle concentrations, after adjustment for race and BMI. Further adjusting for fasting insulin or visceral adiposity obviated these differences between the groups except for LDL size. ICAM-1 and E-selectin did not differ in youth with PD but correlated with LDL and HDL size, and small LDL particle concentrations. ConclusionsOverweight adolescents with PD have an atherogenic lipoprotein profile of small LDL and HDL size and increased concentrations of small LDL, moderated by insulin resistance and visceral adiposity, but independently driven by dysglycemia for LDL size. Associations between smooth muscle biomarkers and lipoproteins could be an early signal heralding the atherogenic process. It remains to be determined if correction of dysglycemia and associated lipoprotein abnormalities in obese youth could prove effective in halting this process.

Determinants of VLDL composition and apo B-containing particles in familial combined hyperlipidemia

BackgroundIn familial combined hyperlipidemia (FCHL) the severity of the dyslipidemia is determined by an overproduction of VLDL (very low density lipoprotein) particles and by its abnormal lipid composition. However, few are known regarding the metabolic factors that determine these abnormalities. We investigated the impact of metabolic factors on the number of atherogenic particles (apolipoprotein B level (apoB)) and the triglyceride content of very low-density lipoproteins (VLDLs-TG). MethodsA cross-sectional study done in FCHL subjects and gender and age-matched healthy subjects.A clinical assessment, lipid profile and plasma concentrations of insulin, apolipoprotein CIII (apo CIII), apolipoprotein AII (apo AII), high sensitive C-reactive protein (HS-CRP), adiponectin and leptin were documented in 147 FCHL patients and 147 age-matched healthy subjects. Multivariate regression models were performed to investigate the independent determinants of VLDL-TG and apo B levels adjusting for confounding factors. ResultsThe variables that determined the VLDL-triglyceride content as a surrogate of VLDL composition were apo CIII (β=0.365, p<0.001), insulin (β=0.281, p<0.001), Apo AII (β=0.145, p<0.035), and adiponectin levels (β=−0.255, p<0.001). This model explained 34% of VLDL composition (VLDL-TG) variability. However, none of these variables were independent contributors of apo B-containing particles. ConclusionsIn patients with FCHL apo CIII, apo AII and adiponectin are major novel factors determining the VLDL particle composition. However, such factors do not explain apo B-containing particles.

Short communication: effects of omega-3 fatty acids on triglycerides and high-density lipoprotein subprofiles in HIV-infected persons with hypertriglyceridemia.

Hypertriglyceridemia and low high-density lipoprotein (HDL)-cholesterol (HDL-C) may contribute to a presumed accelerated risk for cardiovascular disease in HIV-infected individuals. We evaluated the effect of omega-3 fatty acid treatment on triglycerides, low-density lipoprotein (LDL)-C, HDL-C, and HDL subpopulations. Forty-one HIV-seropositive subjects with hypertriglyceridemia (≥150 mg/dl) on active antiretroviral therapy were enrolled in this placebo-controlled, double-blind, randomized, crossover trial comparing the effects of omega-3 fatty acid treatment (1.9 g EPA and 1.5 g DHA) on triglycerides, LDL-C, HDL-C, and HDL subpopulations. An independent sample t-test was used to assess the study start to posttreatment change for all components. After omega-3 fatty acid treatment, triglyceride levels decreased 63.2±86.9 mg/dl (p<0.001). No significant changes in total cholesterol, LDL-C, or HDL-C were found. Within HDL subpopulations, significant changes were seen in the most atheroprotective HDL particles, α-1, which increased by 2.5±5.6 mg/dl (p<0.05), and preα-1, which increased by 0.6±1.0 mg/dl (p<0.001). Preα-3, a presumably atherogenic HDL particle, decreased by 0.5±0.9 mg/dl (p<0.01). Omega-3 fatty acid treatment significantly lowered triglyceride levels in HIV-positive patients with moderate hypertriglyceridemia. While no study-wide improvements in LDL-C or HDL-C were detected, the HDL subpopulation profile changed in a beneficial way suggesting more cardioprotection after treatment.

Dianas terapéuticas en el tratamiento de las dislipemias: colesterol no unido a lipoproteínas de alta densidad y colesterol unido a lipoproteínas de alta densidad

Atherogenic dyslipidemia (AD) consists of the combination of an increase in very low density lipoproteins (VLDL), which results in increased plasma triglyceride (TG) levels, with a reduction of levels of high-density lipoprotein bound cholesterol (HDL-C), also accompanied by a high proportion of small and dense LDL particles. AD is considered the main cause of the residual risk of experiencing cardiovascular disease (CVD), which is still presented by any patient on treatment with statins despite maintaining low-density lipoprotein bound cholesterol (LDL-C) levels below the values considered to be the objective. Non-HDL cholesterol (non-HDL-c) reflects the number of atherogenic particles present in the plasma. This includes VLDL, intermediate density lipoproteins (IDL) and LDL. Non-HDL-c provides a better estimate of cardiovascular risk than LDL-c, especially in the presence of hypertriglyceridemia or AD. The European guidelines for managing dyslipidemia recommend that non-HDL-c values be less than 100 and 130mg/dL for individuals with very high and high cardiovascular risk, respectively. However, these guidelines state that there is insufficient evidence to suggest that raising HDL-c levels incontrovertibly results in a reduction in CVD. Therefore, the guidelines do not set recommended HDL-c levels as a therapeutic objective. The guidelines, however, state that individuals with AD on treatment with statins could benefit from an additional reduction in their risk by using fibrates.