Estimation of total collagen volume: a T1 mapping versus histological comparison study in healthy Landrace pigs.

Right ventricular biopsy represents the gold standard for the assessment of myocardial fibrosis and collagen content. This invasive technique, however, is accompanied by perioperative complications and poor reproducibility. Extracellular volume (ECV) measured through cardiovascular magnetic resonance (CMR) has emerged as a valid surrogate method to assess fibrosis non-invasively. Nonetheless, ECV provides an overestimation of collagen concentration since it also considers interstitial space. Our study aims to investigate the feasibility of estimating total collagen volume (TCV) through CMR by comparing it with the TCV measured at histology. Seven healthy Landrace pigs were acutely instrumented closed-chest and transported to the MRI facility for measurements. For each protocol, CMR imaging at 3T was acquired. MEDIS software was used to analyze T1 mapping and ECV for both the left ventricular myocardium (LVmyo) and left ventricular septum (LVseptum). ECV was then used to estimate TCVCMR at LVmyo and LVseptum following previously published formulas. Tissues were prepared following an established protocol and stained with picrosirius red to analyze the TCVhisto in LVmyo and LVseptum. TCV measured at LVmyo and LVseptum with both histology (8 ± 5 ml and 7 ± 3 ml, respectively) and T1-Mapping (9 ± 5 ml and 8 ± 6 ml, respectively) did not show any regional differences. TCVhisto and TCVCMR showed a good level of data agreement by Bland-Altman analysis. Estimation of TCV through CMR may be a promising way to non-invasively assess myocardial collagen content and may be useful to track disease progression or treatment response.

Novel measures of inflammation and insulin resistance are related to obesity and fitness in a diverse sample of 11-14 year olds: The HEALTHY Study.

BACKGROUND: GlycA is a novel serum marker of systemic inflammation. There is no information on GlycA in pediatric populations, how it differs by gender or its association with body mass index (BMI) or fitness. Lipoprotein insulin resistance index (LP-IR) is a serum measure of insulin resistance, which is related to changes in BMI group in adolescents, but its relationship with fitness is unknown. The current study examined the independent associations between fitness and BMI with GlycA and LP-IR among US adolescents. METHODS: Participants were 1664 US adolescents from the HEALTHY study with complete 6th and 8th grade BMI, fitness and blood data. GlycA and LP-IR were measured by nuclear magnetic resonance spectroscopy. Three BMI groups and three fitness groups were created. Linear mixed models examined associations between GlycA, LP-IR, fitness and BMI. RESULTS: LP-IR decreased between 6th and 8th grade. GlycA increased among girls but decreased among boys. At 8th grade, median GlycA values were 27 (7.6%) µmol l(-1) higher (381 versus 354) for girls than boys. Median GlycA 6th grade values were 9% higher in obese girls than healthy weight girls. Overall, there was strong evidence (P<0.001) that GlycA was higher in higher BMI groups. Fitness was negatively associated with GlycA (r=-0.37 and -0.35) and LP-IR (r=-0.34 and -0.18) at the 6th and 8th grade assessments. As BMI category increased and fitness category decreased, GlycA and LP-IR levels increased. Lowest GlycA was found in the low BMI/high fitness group. CONCLUSIONS: GlycA was associated with BMI and fitness among in US adolescents. These findings suggest that there are independent effects for BMI and fitness group with both GlycA and LP-IR. Future studies should validate the role of GlycA and LP-IR to evaluate the effects of interventions to modify obesity and fitness to improve systemic inflammation and insulin resistance.

GlycA, a novel marker of inflammation, is elevated in systemic lupus erythematosus.

BACKGROUND: GlycA is a novel marker of systemic inflammation detected by nuclear magnetic resonance (NMR) spectroscopy. In the general population, GlycA is correlated with inflammatory markers such as C-reactive protein (CRP) and associated with coronary heart disease and diabetes. The utility of GlycA in patients with systemic lupus erythematosus (SLE) has not been defined. Therefore, we tested the hypothesis that GlycA concentrations are elevated in patients with SLE and associated with other markers of inflammation and coronary atherosclerosis. METHODS: We compared concentrations of GlycA, detected by NMR, in 116 patients with SLE and 84 control subjects frequency-matched for age, sex, and race. SLE disease activity index (SLEDAI) and the SLE Collaborating Clinics damage index (SLICC) were calculated. Acute phase reactants, a panel of cytokines, and a lipid panel were measured. Electron beam computer tomography (EBCT) was used to quantify coronary artery calcification, a measure of coronary artery atherosclerosis. RESULTS: Patients with SLE had higher concentrations of GlycA (398 (350-445)) than control subjects (339 (299-391)) µmol/L, p < 0.001. In patients with SLE, concentrations of GlycA were significantly associated with sedimentation rate (rho = 0.43), C-reactive protein (rho = 0.59), e-selectin (rho = 0.28), intracellular adhesion molecule-1 (rho = 0.30), triglycerides (rho = 0.45), all p < 0.0023 to account for multiple comparisons, but not with creatinine, SLEDAI, SLICC, or coronary calcium scores. CONCLUSIONS: Concentrations of GlycA are higher in patients with SLE than control subjects and associated with markers of inflammation but not with SLE disease activity or chronicity scores or coronary artery calcification.

Subfractions and subpopulations of HDL: an update.

High-density lipoproteins (HDL) are classified as atheroprotective because they are involved in transport of cholesterol to the liver, known as "reverse cholesterol transport (RCT)" exerting antioxidant and anti-inflammatory activities. There is also evidence for cytoprotective, vasodilatory, antithrombotic, and anti-infectious activities for these lipoproteins. HDLs are known by structural, metabolic and biologic heterogeneity. Thus, different methods are able to distinguish several subclasses of HDL. Different separation techniques appear to support different HDL fractions as being atheroprotective or related with lower cardiovascular (CV) risk. However, HDL particles are not always protective. Modification of constituents of HDL particles (primarily in proteins and lipids) can lead to the decrease in their activity and induce proatherogenic properties, especially when isolated from patients with augmented systemic inflammation. According to available studies, it seems that HDL functionality may be a better therapeutic target than HDL cholesterol quantity; however, it is still disputable which subfractions are most beneficial. There is mounting evidence supporting HDL subclasses as an important biomarker to predict and/or reduce CV risk. In this review we discuss recent notices on atheroprotective and functional characteristic of different HDL subfractions. Also, we provide a brief overview of the different methods used by clinicians and researchers to separate HDL subfractions. Ongoing and future investigations will yield important new information if any given separation method might represent a 'gold standard', and which subfractions are reliable markers of CV risk and/or potential targets of novel, more focused, and effective therapies.

Lifestyle and metformin treatment favorably influence lipoprotein subfraction distribution in the Diabetes Prevention Program.

CONTEXT: Although intensive lifestyle change (ILS) and metformin reduce diabetes incidence in subjects with impaired glucose tolerance (IGT), their effects on lipoprotein subfractions have not been studied. OBJECTIVE: The objective of the study was to characterize the effects of ILS and metformin vs placebo interventions on lipoprotein subfractions in the Diabetes Prevention Program. DESIGN: This was a randomized clinical trial, testing the effects of ILS, metformin, and placebo on diabetes development in subjects with IGT. PARTICIPANTS: Selected individuals with IGT randomized in the Diabetes Prevention Program participated in the study. INTERVENTIONS: Interventions included randomization to metformin 850 mg or placebo twice daily or ILS aimed at a 7% weight loss using a low-fat diet with increased physical activity. MAIN OUTCOME MEASURES: Lipoprotein subfraction size, density, and concentration measured by magnetic resonance and density gradient ultracentrifugation at baseline and 1 year were measured. RESULTS: ILS decreased large and buoyant very low-density lipoprotein, small and dense low-density lipoprotein (LDL), and small high-density lipoprotein (HDL) and raised large HDL. Metformin modestly reduced small and dense LDL and raised small and large HDL. Change in insulin resistance largely accounted for the intervention-associated decreases in large very low-density lipoprotein, whereas changes in body mass index (BMI) and adiponectin were strongly associated with changes in LDL. Baseline and a change in adiponectin were related to change in large HDL, and BMI change associated with small HDL change. The effect of metformin to increase small HDL was independent of adiponectin, BMI, and insulin resistance. CONCLUSION: ILS and metformin treatment have favorable effects on lipoprotein subfractions that are primarily mediated by intervention-related changes in insulin resistance, BMI, and adiponectin. Interventions that slow the development of diabetes may also retard the progression of atherosclerosis.

Nuclear magnetic resonance-determined lipoprotein subclass profile in the DCCT/EDIC cohort: associations with carotid intima-media thickness.

AIMS: To relate nuclear magnetic resonance lipoprotein subclass profiles (NMR-LSP) and other lipoprotein-related factors with carotid intima-media thickness (IMT) in Type 1 diabetes. METHODS: Lipoprotein-related factors were determined in sera (obtained in 1997-1999) from 428 female [age 39 +/- 7 years (mean +/- SD)] and 540 male (age 40 +/- 7 years) Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) participants. NMR quantifies chylomicrons, three very low-density lipoprotein (VLDL) subclasses, intermediate density lipoprotein (IDL), three low-density lipoprotein (LDL) subclasses, two high-density lipoprotein (HDL) subclasses, mean VLDL, LDL and HDL size, and LDL particle concentration. Conventional lipids, ApoA1, ApoB and Lp(a) and in vitro LDL oxidizibility were also measured. IMT was determined (in 1994-1995) using high-resolution B-mode ultrasound. Relationships between IMT and lipoproteins were analysed by multiple linear regression, controlling for age, diabetes-related factors, and cardiovascular disease (CVD) risk factors. RESULTS: IMT associations with lipoproteins were stronger for the internal than the common carotid artery, predominantly involving LDL. Internal carotid IMT was positively (P < 0.05) associated with NMR-based LDL subclasses and particle concentration, and with conventional LDL-cholesterol and ApoB in both genders. Common carotid IMT was associated, in men only, with large VLDL, IDL, conventional LDL cholesterol and ApoB. CONCLUSIONS: NMR-LSP reveals significant associations with carotid IMT in Type 1 diabetic patients, even 4 years after IMT measurement. NMR-LSP may aid early identification of high-risk diabetic patients and facilitate monitoring of interventions. Longer DCCT/EDIC cohort follow-up will yield CVD events and IMT progression, permitting more accurate assessment of pre-morbid lipoprotein profiles as determinants of cardiovascular risk in Type 1 diabetes.

The prospective association between adiponectin and coronary artery disease among individuals with type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications Study.

AIMS/HYPOTHESIS: Recent findings suggest the potential involvement of adiponectin in obesity, diabetes and cardiovascular disease. We assessed the prospective association between adiponectin concentration and coronary artery disease in individuals with type 1 diabetes. METHODS: Participants were identified from the Pittsburgh Epidemiology of Diabetes Complications cohort, a prospective follow-up study of childhood-onset type 1 diabetes. At baseline, subjects had a mean age of 28 years, and a mean diabetes duration of 19 years. Cases (determined by physician-diagnosed angina, confirmed myocardial infraction, stenosis >or=50%, ischemic ECG or revascularization) were matched to the control subjects with respect to sex, age and diabetes duration. Samples and risk factors for analyses were identified from the earliest exam prior to incidence in cases. Sera and information on all covariates were available for 28 cases and 34 control subjects. Proportional hazards models were constructed including matching variables. RESULTS: Compared with those in men, adiponectin concentrations were elevated in females (p=0.009) and among individuals with macroalbuminuria (p=0.04). In multivariable analyses (adjusting for standard risk factors as well as lipoprotein measurements determined by nuclear magnetic resonance spectroscopy, E-selectin or antioxidants), adiponectin inversely predicted the incidence of coronary artery disease (hazard ratio=0.37 per 1 SD increase, 95% CI 0.19-0.73, p=0.004). CONCLUSIONS/INTERPRETATION: The results suggest that increased adiponectin concentration is prospectively associated with a lower risk of coronary artery disease type 1 diabetes. The potential of adiponectin determination as a useful marker of, and potential therapeutic target for, coronary artery disease prevention in type 1 diabetes should be further explored.

Heterozygosity for ABCA1 gene mutations: effects on enzymes, apolipoproteins and lipoprotein particle size.

A cohort of 13 female and 14 male heterozygotes for ATP binding cassette A1 (ABCA1) gene defects was directly compared with 13 and 14 unaffected female and male family members of almost exact same age. The activities of three proteins that play key roles in HDL metabolism were measured in addition to extensive lipid and (apo) lipoprotein subfraction analysis. Compared to controls, LCAT activity was reduced by 15% in affected subjects (P < 0.001) while PLTP activity was unaffected. Interestingly, CETP activity was elevated by 50% in the heterozygote siblings of one kindred but was unaffected in heterozygotes of the three other families. With respect to lipids, the heterozygotes had normal total cholesterol (TC), and LDL-cholesterol concentrations but presented with a trend towards increased triglyceride levels (13%; P = 0.08). HDL metabolism, by contrast, was severely affected as illustrated by 40% reductions in HDL-cholesterol (P < 0.001) with concomitant reductions in apoAI (25%; P < 0.001) levels and in lipoprotein subfraction LpAI (28%; P < 0.001), LpAI:AII (24%; P=0.014), and LpCIII:nonB (34%; P < 0.001) concentrations. We furthermore observed reduced average HDL particle size (5%; P = 0.004; 16% in female and 3.6% in male) and reduced plasma apoCIII concentration (15%; P = 0.006) while apoAII, apoAIV, apoE and apoB levels were unchanged. In conclusion, heterozygosity for ABCA1 defects was associated with reduced LCAT activity in absence of effects on PLTP activity. Of special interest was our finding that the effects of compromised ABCA1 function on HDL were more pronounced in women than in men.

Lipoprotein subclass measurements by nuclear magnetic resonance spectroscopy improve the prediction of coronary artery disease in Type 1 diabetes. A prospective report from the Pittsburgh Epidemiology of Diabetes Complications Study.

AIM/HYPOTHESIS: To examine whether nuclear magnetic resonance lipoprotein spectroscopy improves the prediction of coronary artery disease in patients with Type 1 diabetes, independently of conventional lipid and other risk factors. METHODS: A prospective nested case-control design of subjects with childhood onset Type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications Study was used. 59 controls were age-, sex- and duration-matched to 59 incident cases of coronary artery disease (fatal or non-fatal myocardial infarction, angina, coronary stenosis >50%) occurring during 10 years of follow-up. Lipid mass and particle concentrations of VLDL, LDL, and HDL subclasses, grouped into three size categories (large, medium, and small), were assessed prior to event with nuclear magnetic resonance spectroscopy. RESULTS: Univariate analyses showed that both lipid mass and particle concentrations of all three VLDL subclasses, small LDL, medium LDL, and medium HDL were increased in CAD cases compared to controls, while large HDL was decreased. Mean LDL and HDL particle sizes were lower in cases. In multivariate models using conventional lipid and non-lipid risk factors, triglycerides and overt nephropathy were the strongest predictors of CAD. Nuclear magnetic resonance measures further improved the prediction, i.e. large HDL particle concentration (OR=0.43, p=0.030), medium HDL mass (OR=3.79, p=0.026) and total VLDL particle concentration (OR=2.33, p=0.033). CONCLUSION/INTERPRETATION: While these results underscore the importance of triglycerides and overt nephropathy in CAD risk in Type 1 diabetic patients, they also suggest that nuclear magnetic resonance lipoprotein spectroscopy could further refine its prediction and show novel findings concerning HDL subclasses.

Loci for CETP, LPL, LIPC, and APOC3 affect plasma lipoprotein size and sub-population distribution in Hispanic and non-Hispanic white subjects: the Columbia University BioMarkers Study.

BACKGROUND AND AIM: The effect of genetic variation on plasma lipoproteins and their subfraction distribution was examined. METHODS AND RESULTS: Forty Hispanic men and 223 women and 42 non-Hispanic white men and 53 women participated in the study. Genotypes for cholesteryl ester transfer protein (CETP TaqIB), hepatic lipase (LIPC -480 C > T), lipoprotein lipase (LPL S447X), and apolipoprotein CIII (APOC3--455T > C) were determined by polymerase chain reaction. Lipoprotein particle size distribution was determined by nuclear magnetic resonance. For all but APOC3, genotype effects were homogeneous in the ethnic/racial groups and men and women. Effects were seen primarily in the women. Compared to women carriers of the common CETP B1 allele, B2B2 women had significantly higher plasma levels of high-density lipoprotein cholesterol (HDL-C) (16.4.0%, p = 0.001), reflected in the level of larger HDL particles (21.9%, p = 0.001), and larger mean particle size of HDL (2.3%, p = 0.01) and low-density lipoproteins (LDL) (1.3%, p = 0.02). Compared to LPL 447S homozygous women carriers of the LPL 447X allele had significantly lower levels of very-low-density lipoprotein-triglyceride (VLDL-TG) (21.0%, p = 0.02). For APOC3, there was significant gender:genotype interaction with the genotype differences seen only in the men. Compared to men homozygous for the -455T allele, carriers of -455C had higher levels of VLDL-TG (71.4%, p = 0.0001), reflected in a larger mean VLDL particle size (13.7%, p = 0.009). LIPC genotype was not associated with significant effects on any of these traits. CONCLUSION: These data confirm the role of genetic variants of CETP, LPL and APOC3 in determining the relationship between VLDL, LDL and HDL particles.

Association of the A/T54 polymorphism in the intestinal fatty acid binding protein with variations in plasma lipids in the Framingham Offspring Study.

We investigated the potential role of the genetic variation at the intestinal fatty acid binding protein gene (FABP2) in influencing lipid levels in a representative sample of the Framingham Offspring Study participants (n=1930). In men, the T54 allele was associated with significantly higher LDL-cholesterol (3.47+/-0.83 vs. 3.36+/-0.83 mmol/l; P<0.047), and ApoB (1.04+/-0.23 vs. 1.01+/-0.24 g/l; P<0.020) after adjustment for familial relationship, age, BMI, smoking, alcohol intake and the use of beta-blockers compared with the A54 allele. This relationship with ApoB continued to be significant after adjustment for APOE genotype (P<0.034). In women, the T54 allele was associated with significantly higher total-cholesterol (5.32+/-1.01 vs. 5.17+/-0.98 mmol/l; P<0.049) and LDL-cholesterol (3.31+/-0.93 vs. 3.18+/-0.85 mmol/l; P<0.023) after adjustment for covariates and menopausal status, estrogen therapy and APOE genotype. In men, the T54 allele was associated with significantly higher levels of small VLDL and lower levels of large HDL. Moreover, there was no significant relationship between FABP2 alleles and lipoprotein diameter or the prevalence of coronary heart disease in both genders. Our data are consistent with the T54 IFABP increasing the flux of lipids through the enterocyte leading to an increase in chylomicron secretion.

Oxidative dimerization in metallothionein is a result of intermolecular disulphide bonds between cysteines in the alpha-domain.

Upon storage under aerobic conditions metallothioneins (MTs) form a new species, which is characterized by a molecular mass approximately twice the size of monomeric MT and shifted (113/111)Cd- and (1)H-NMR resonances. The investigation of this oxidative dimerization process by NMR spectroscopy allowed us to structurally characterize this MT species that has been described to occur in vivo and might be synthesized under conditions of oxidative stress. The oxidative dimer was characterized by the formation of an intermolecular cysteine disulphide bond involving the alpha-domain, and a detailed analysis of chemical shift changes and intermolecular nuclear Overhauser effects points towards a disulphide bond involving Cys(36). In contrast to the metal-bridged (non-oxidative) dimerization, the metal-cysteine cluster structures in both MT domains remain intact and no conformational exchange or metal-metal exchange was observed. Also in contrast to the many recently reported oxidative processes which involve the beta-domain cysteine groups and result in the increased dynamics of the bound metal ions in this N-terminal domain, we found no evidence for any increased dynamics in the alpha-domain metals following this oxidation. Therefore these findings provide additional corroboration that metal binding in the C-terminal alpha-domain is rather tight, even under conditions of a changing cellular oxidation potential, compared with the more labile/dynamic nature of the metals in the N-terminal beta-domain cluster under similar conditions.

Association of the Sst-I polymorphism at the APOC3 gene locus with variations in lipid levels, lipoprotein subclass profiles and coronary heart disease risk: the Framingham offspring study.

Apolipoprotein (apo) CIII participates in the regulation of the metabolism of triglyceride-rich lipoproteins and it is a major component of chylomicrons and VLDL. The APOC3 gene is on chromosome 11q23 and is highly polymorphic. The less common allele (S2) of the SstI polymorphism on the 3' untranslated region of the APOC3 gene has been previously associated with increased triglycerides, total cholesterol (TC), and apoCIII levels and cardiovascular risk on several, but not all, studies. The aim of this study was to examine the association of this polymorphism with plasma lipid levels, lipoprotein subfractions and coronary heart disease (CHD) risk in a population-based study: The Framingham Offspring Study. The frequency of the S2 allele was 0.086, consistent with previous reports in Caucasian populations. In men, the S2 allele was associated with lower concentrations of high-density lipoprotein cholesterol (HDL-C; P<0.04) and HDL2-C (P<0.02) and a significant increase in apoCIII non-HDL (P<0.05). TG levels were higher in men carriers of the S2 allele, but this association did not reach statistical significance (P=0.30). Conversely, in women, the S2 allele was associated with increased TC (P<0.03), low-density lipoprotein cholesterol (LDL-C; P<0.03), and ApoB levels (P<0.04). Lipoproteins subfractions were also examined using nuclear magnetic resonance (NMR) spectroscopy. S2 male carriers had significantly lower concentrations of large LDL and a significant reduction in LDL particle size (P<0.04). In women, there was a significant increase in intermediate LDL particles (P<0.05) with no significant effect on lipoprotein diameters. We also examined the associations between the S2 allele and biochemical markers of glucose metabolism. In men, the S2 allele was associated with elevated fasting insulin concentrations (P<0.04), whereas no significant associations were observed in women. Despite the described associations with lipid and glucose metabolism related risk factors, we did not find any significant increase in CHD risk associated with the S2 allele in this population.

Racial differences in low-density lipoprotein particle size in families at high risk for premature coronary heart disease.

OBJECTIVE: Although small, dense low-density lipoprotein (LDL) has been implicated in atherogenesis and coronary heart disease (CHD) events, little is known about possible racial differences in LDL particle size. This study was designed to examine racial differences in the prevalence of small, dense LDL among 159 African-American and 477 White siblings of persons with premature (<60 years of age) CHD. METHODS AND RESULTS: This study examined fasting levels of total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, apolipoprotein B (ApoB), apolipoprotein A-1, and triglycerides, as well as factors known to be associated with small, dense LDL, including age, sex, obesity, hypertension, and diabetes. Relative LDL particle size was defined by the LDL cholesterol to ApoB ratio. Direct measurement of LDL particle size was obtained by proton NMR spectroscopy in a subset of 64 siblings. Despite similar levels of total and LDL cholesterol, White siblings were more likely to have low LDL cholesterol to ApoB ratios, indicative of atherogenic small, dense LDL, compared with African-American siblings. Multiple logistic regression analysis predicting the presence of LDL cholesterol/ApoB < or = 1.0 demonstrated that race (P = .009), triglyceride level (P = .0001), and diabetes (P = .02) were independent predictors, controlling for age and all other variables. Direct measurement of LDL particle size by NMR spectroscopy supported these findings. CONCLUSION: These findings provide the first known evidence that White individuals from a population at high risk for premature CHD have a greater probability of having a preponderance of small, dense LDL particles than do African Americans, independent of triglyceride levels, and despite comparable levels of total and LDL cholesterol.

Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction.

BACKGROUND: Human immunodeficiency virus protease inhibitors (HIV PIs) are associated with hyperlipidemia, hyperglycemia, and obesity; however, it is not known whether they increase risk of atherosclerotic vascular disease. The purposes of this study were to characterize the lipoprotein abnormalities associated with use of HIV PIs in individuals with HIV infection and to determine the pathophysiological significance of these changes by assessing their effect on endothelial dysfunction. METHODS AND RESULTS: This was a cross-sectional study of 37 adults with HIV-1 infection who were receiving antiretroviral therapy. Twenty-two were taking HIV PIs (group 1); 15 were not (group 2). Lipids and lipoproteins were measured by enzymatic techniques and nuclear magnetic resonance spectroscopic analysis. Flow-mediated vasodilation (FMD) of the brachial artery was measured by high-resolution ultrasound. Subjects in both groups were similar in regard to age, time since diagnosis of HIV infection, and CD4 cell count. Group 1 subjects had higher total cholesterol (5.68 versus 4.42 mmol/L, P=0.007) and triglyceride (4.43 versus 1.98 mmol/L, P=0.009) levels, characterized by elevated levels of IDL and VLDL. Subjects in group 1 had impaired FMD (2.6+/-4.6%), indicative of significant endothelial dysfunction. Group 2 subjects had normal FMD (8.1+/-6.7%, P=0.005). In group 1, chylomicron, VLDL, IDL, and HDL cholesterol levels predicted FMD. CONCLUSIONS: Use of HIV PIs is associated with atherogenic lipoprotein changes and endothelial dysfunction. Because these metabolic and vascular changes predispose to atherosclerosis, monitoring and treatment of dyslipidemia in patients taking these medications is warranted.

Distribution and correlates of high-density lipoprotein subclasses among children and adolescents.

Levels of high-density lipoprotein (HDL) cholesterol among children vary by sex and race/ethnicity and are correlated with age, obesity, and other characteristics. Several studies of adults have indicated that atherogenicity of HDL particles may vary by size, but there is little information on the distribution and correlates of HDL subfractions in early life. We used nuclear magnetic resonance (NMR) spectroscopy to determine the mean HDL particle size and levels of 3 HDL subclasses among 10- to 17-year-olds (n = 918). We found the mean HDL particle size to be (1) inversely associated with age among boys, (2) larger among girls than boys, and (3) larger among black children than among white children. These associations with particle size reflected contrasting associations with various HDL subclasses; among boys, for example, levels of large HDL decreased with age, whereas levels of small HDL remained constant (black boys) or tended to increase (white boys). Furthermore, relative weight and levels of both triglycerides and low-density lipoprotein (LDL) cholesterol were associated inversely with levels of large HDL, but positively with levels of small HDL. These contrasting associations suggest that the role of HDLC in coronary heart disease (CHD) may be more complex than previously thought, and that the analysis of HDL subclasses may improve the accuracy of CHD prediction.

Oral 17beta-estradiol and medroxyprogesterone acetate therapy in postmenopausal women increases HDL particle size.

Menopause is accompanied by changes in lipoprotein particles that include an increase in density of low density lipoproteins (LDL) and high density lipoproteins (HDL) particles. The effect of 3 months of oral hormone replacement therapy (HRT) on lipoprotein particle size in postmenopausal women who were randomized to (1) estrogen replacement therapy (ERT) alone (either 17beta-estradiol (1 mg) or conjugated equine estrogens (CEE) (0.625 mg); (2) combination therapy (17beta-estradiol plus medroxyprogesterone acetate (MPA) or CEE plus MPA); and (3) placebo were examined. Lipoprotein subclass concentrations and particle size were quantified by nuclear magnetic resonance spectroscopy (NMR). Combination HRT resulted in significant (P=0.002) increases in HDL particle size as compared with those on placebo formulations or ERT alone. Women assigned to combined HRT had lower concentrations of smaller HDL particles after 3 months (P=0.005) and higher concentrations of larger HDL particles (P=0.02), whereas women assigned to ERT or placebo experienced non-significant changes. In summary, combined HRT increases HDL particle size by altering concentrations of the smallest and largest HDL subspecies.

Effectiveness of high doses of simvastatin as monotherapy in mixed hyperlipidemia.

Twenty subjects with mixed hyperlipidemia participated in a 3-arm crossover trial to evaluate the effectiveness of high-dose simvastatin as monotherapy. Significant reductions were observed in atherogenic lipids and lipoproteins. The highest dose of simvastatin also resulted in significant increases in high-density lipoprotein cholesterol (21%) with a comparable increase in large, protective high-density lipoprotein particles.

Apolipoprotein epsilon2 allele is associated with an anti-atherogenic lipoprotein profile in children: The Columbia University BioMarkers Study.

OBJECTIVE: We examined associations between allelic variation in the apo epsilon gene, which codes for apolipoprotein E, and plasma lipid levels in children. MATERIALS AND METHODS: We analyzed genotype and fasting lipid levels, including lipid particle size by nuclear magnetic resonance spectroscopy, in 515 children from 297 families. RESULTS: Children carrying the apo epsilon2 allele (1 or 2 epsilon2 alleles; n = 45) had higher mean high-density lipoprotein (HDL) cholesterol level (49.5 +/- 13.0 vs 42.4 +/- 8.9 mg/dL) and lower mean low-density lipoprotein (LDL) cholesterol level (82.2 +/- 48.6 vs 105.9 +/- 45.0 mg/dL) compared with apo epsilon3/epsilon3 children (n = 322). Mean HDL size was larger and mean level of the atheroprotective large HDL subpopulation was higher among apo epsilon2 carriers compared with epsilon3/epsilon3 children (9.5 +/- 0.4 vs 9.3 +/-.4 nm, and 32.8 +/- 9.9 vs 27.6 +/- 8.2 mg/dL). In multivariate models adjusting for age, sex, ethnicity, family history, body mass index, and fasting triglyceride level, the apo epsilon2 allele was independently predictive of higher levels of HDL cholesterol and the large HDL subpopulation and of lower level of LDL cholesterol. CONCLUSION: The apo epsilon2 allele is associated with an anti-atherogenic lipid pattern in children.apolipoprotein epsilon, children, cholesterol.

Levels and correlates of LDL and VLDL particle sizes among children: the Bogalusa heart study.

Levels of lipids and lipoproteins among children vary by sex and race/ethnicity, and are correlated with age, obesity, and other characteristics. There is, however, little information on the distribution and correlates of low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) subclasses in early life. We used nuclear magnetic resonance (NMR) spectroscopy to determine mean LDL and VLDL particle sizes among 10- to 17-year-olds (n=918) who participated in the 1992-94 examination of the Bogalusa heart study. As compared with girls, boys had a smaller (0.1 nm) mean LDL particle size and a larger (0.9 nm) mean VLDL size; furthermore, the average size of VLDL particles increased with age among white boys but not among other children. Although there were also black/white differences in particle sizes, with black children having larger LDL and smaller VLDL particles, these racial contrasts could be attributed to differences in lipid levels. Levels of triglycerides, insulin, and relative weight were associated with the size of VLDL (positive) and LDL (negative) particles. These results suggest that the analysis of lipoprotein subclasses may provide a better understanding of the role of various risk factors in the development of coronary heart disease