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The purpose of this study was to assess metformin effects on high-density lipoprotein (HDL) composition of patients with HIV-associated lipodystrophy (LDHIV). Twenty-four adult outpatients were enrolled to receive metformin (1700 mg/d) during 6 months, but 2 were lost to follow-up and 6 stopped the drug due to adverse events (gastrointestinal in 5, and excessive weight loss in 1). From the 16 subjects who completed the study, 69% were female. At baseline, 3 and 6 months, we assessed: weight, waist and hip circumferences, blood pressure, fasting glucose and insulin, homeostasis model assessment of insulin resistance (HOMA2-IR), lipids, and HDL subfractions by microultracentrifugation. At 0 and 6 months, body fat distribution was assessed by computed tomography (CT) scan (L4 and middle femur). Metformin use was associated with reduction of mean weight (-2.4Kg at 6 months; p < 0.001), body mass index, waist, waist-to-hip ratio and a marked decrease in blood pressure (p < 0.001). Subcutaneous (p = 0.01) and total abdominal fat (p = 0.002) were reduced, but no change was found in visceral or thigh fat. No difference was detected on plasma glucose, insulin, HOMA2-IR, cholesterol or triglycerides, except for an increase in HDL3DScholesterol (from 21 mg/dL to 24 mg/dL, p = 0.002) and a reduction of nascent HDL (the fraction of plasma HDL-cholesterol not associated to subfractions HDL2 or HDL3) (p = 0.008). Adverse effects were very common, but most were gastrointestinal and mild. Thus, metformin use in LDHIV increases HDL3DScholesterol (probably due to improved maturation of HDL) and decreases blood pressure, weight, waist, and subcutaneous truncal fat, making this an attractive option for preventing cardiovascular disease in this population. [ABSTRACT FROM AUTHOR]

To investigate the influence of climate on hospitalizations of sickle cell anemia (SCA) adults and children, we analyzed the health and meteorological parameters from a metropolis (1999-2018). 1462 hospitalizations were coded for SCA patients in crisis (M:F = 715:747) and 1354 hospitalizations for SCA patients without crisis (M:F = 698:656) [age = 22.9 vs 15.2 years and duration of hospitalization (DoH) = 5.7 vs 4.4 days, respectively,]. More hospitalizations were for adults than children in crisis, and for children than adults without crisis. More children and adults were hospitalized in winter andspring than in summer and autumn     Hospitalizations correlated positively with humidity (lag -5), maximum pressure (lag -2), mean pressure (lag -2), and thermal amplitude (lag -2), and negatively with maximum temperature (lag -3). DoH positively correlated with minimum temperature (lag -4). Understanding these complex associations would induce attitudinal/behavioral modifications among patients and their caregivers.

Background: Increased cholesterol absorption and reduced synthesis are processes that have been associated with cardiovascular disease risk in a controversial way. However, most of the studies involving markers of cholesterol synthesis and absorption include conditions, such as obesity, diabetes, dyslipidemia, which can be confounding factors. The present study aimed at investigating the relationships of plasma cholesterol synthesis and absorption markers with cardiovascular disease (CVD) risk factors, cIMT (carotid intima-media thickness), and the presence of carotid plaques in asymptomatic subjects., Methods: A cross-sectional study was carried out in 270 asymptomatic individuals and anthropometrical parameters, fasting plasma lipids, glucometabolic profiles, high-sensitivity C-reactive protein (hs-CRP), markers of cholesterol synthesis (desmosterol and lathosterol), absorption (campesterol and sitosterol), cIMT, and the presence of atherosclerotic plaques were analyzed., Results: Among the selected subjects aged between 19 and 75 years, 51% were females. Age, body mass index, systolic and diastolic blood pressure, total cholesterol, non-HDL-C, triglycerides, glucose, and lathosterol/sitosterol ratios correlated positively with cIMT ( p ≤ 0.05). Atherosclerotic plaques were present in 19% of the subjects. A direct association of carotid plaques with campesterol, OR = 1.71 (95% CI = 1.04-2.82, p ≤ 0.05) and inverse associations with both ratios lathosterol/campesterol, OR = 0.29 (CI = 0.11-0.80, p ≤ 0.05) and lathosterol/sitosterol, OR = 0.45 (CI = 0.22-0.95, p ≤ 0.05) were observed in univariate logistic regression analysis., Conclusions: The findings suggested that campesterol may be associated with atherosclerotic plaques and the lathosterol/campesterol or sitosterol ratios suggested an inverse association. Furthermore, synthesis and absorption of cholesterol are inverse processes, and the absorption marker, campesterol, may reflect changes in body cholesterol homeostasis with atherogenic potential.

Background: This study aimed to evaluate the associations between Lipoprotein (a) ‒ Lp(a) levels and carotid Intima-Media Thickness (cIMT) and with carotid plaques in healthy subjects because of previous contradictory data., Methods: A total of 317 healthy normolipidemic subjects (20‒77 years old) were selected. The cIMT and atherosclerotic plaques were determined by B-mode ultrasonography. Mann-Whitney tests were performed to compare the groups according to Lp(a) levels and to explore the associations between Lp(a), carotid plaques, and cIMT, logistic and linear regression analyses were performed., Results: Studied population (51% females, median age 43 years old) presented carotid plaques and cIMT ≥ 0.9 mm in 23% and 18% of the participants, respectively. The group with Lp(a) levels > 30 mg/dL presented significantly higher age and atherosclerotic plaques. Indeed, multivariate linear regression analysis showed a significant association between Lp(a), age, and race. On the other hand, logistic regression analysis demonstrated that the subjects with Lp(a) > 30 mg/dL have a significantly high risk of carotid plaques., Conclusion: The data from the present study indicate that Lp(a) levels above 30 mg/dL contribute to the development of carotid plaques even in apparently healthy participants., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Several proteins are involved in cholesterol homeostasis, as scavenger receptor class B type I and ATP-binding cassette (ABC) transporters including ABCA1, ABCG1, ABCG5, and ABCG8. This study aimed to determine the effects of single nucleotide variants (SNVs) rs2275543 (ABCA1), rs1893590 (ABCG1), rs6720173 (ABCG5), rs6544718 (ABCG8), and rs5888 (SCARB1) on plasma lipids, lipoproteins, and adiposity markers in an asymptomatic population and its sex-specific effects. Volunteers (n = 590) were selected and plasma lipids, lipoproteins, and adiposity markers (waist-to-hip and waist-to-height ratios, lipid accumulation product and body adiposity index) were measured. Genomic DNA was isolated from peripheral blood cells according to the method adapted from Gross-Bellard. SNVs were detected in the TaqMan® OpenArray® Real-Time polymerase chain reaction platform and data analyses were performed using the TaqMan® Genotyper Software. The rs2275543*C point to an increase of high-density lipoprotein size in females while in males very-low-density lipoprotein, cholesterol, and triglycerides were statistically lower (P value < 0.05). The rs1893590*C was statistically associated with lower apolipoprotein A-I levels and higher activities of paraoxonase-1 and cholesteryl ester transfer protein (P value < 0.05). The rs6720173 was statistically associated with an increase in cholesterol and low-density lipoprotein cholesterol in males; moreover, rs6544718*T reduced adiposity markers in females (P value < 0.05). Regarding the rs5888, a decreased adiposity marker in the total population and in females occurred (P value < 0.05). Multivariate analysis of variance showed that SNVs could influence components of high-density lipoprotein metabolism, mainly through ABCG1 (P value < 0.05). The ABCA1 and ABCG5 variants showed sex-specific effects on lipids and lipoproteins, while SCARB1 and ABCG8 variants might influence adiposity markers in females. Our data indicate a possible role of ABCG1 on HDL metabolism., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Non-cholesterol sterols are transported in plasma lipoproteins and are consequently important in cholesterol metabolism. We investigated the distribution of non-cholesterol sterol precursors of cholesterol synthesis (NCSPCS), oxysterols, and phytosterols in lipoproteins of healthy subjects differing according to HDL-Cholesterol (HDL-C) plasma levels. Elevated NCSPCS (desmosterol, lathosterol) in the High HDL group suggests that HDL exports these sterols from cells, but not the cholesterol metabolite 24-OHC which was higher in the Low HDL group than in the High HDL group. 27-hydroxycholesterol (27OH-C) plasma levels did not differ between groups. Percentage of NCSPCS and phytosterols predominates in LDL, but did not differ between groups. Thirty percent of desmosterol and lathosterol are present in HDL, with the High HDL group carrying higher percentage of these sterols. A high percentage of campesterol and sitosterol in HDL suggests that phytosterols are absorbed by enterocytes, and that HDL could be a marker of the ABCA1/ApoA1 intestinal activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nunes, da Silva, Ferreira, Assis, Cazita, Nakandakare, Zago, de Faria and Quintão.)

Purpose: Sodium-glucose cotransporter 2 inhibitors increase glucagon secretion by pancreatic alpha cells and the susceptibility to ketoacidosis. On the other hand, growth hormone (GH) stimulates peripheral lipolysis and provides free fatty acids (FFA) for ketogenesis; however, it remains unresolved whether GH directly impacts hepatic ketogenesis. We aimed to investigate the role of physiologic GH levels in promoting ketogenesis in prediabetic or type 2 diabetic patients under empagliflozin treatment., Methods: Sixteen patients (11 women, 5 men) with prediabetes or type 2 diabetes mellitus, aged 55.6 ± 4.7 years and with a mean BMI of 30.7 ± 4.8 kg/m 2 and HbA1c 7.1 ± 1.6% (means ± SD), participated in this study. All of them were submitted to three mixed-meal tests: they received placebo at -60 min (test 1), and empagliflozin 25 mg (test 2, 21st day) and empagliflozin 25 mg plus pegvisomant 30 mg were administered subcutaneously 36 h before (test 3, 28th day). After test 1, all patients were instructed to take empagliflozin 25 mg daily., Results: The empagliflozin treatment decreased the plasma concentrations of glucose by 14% (P < 0.01), FFA by 23% (P < 0.01), and the insulin/glucagon ratio by 26% (P < 0.01), and it increased β-hydroxybutyrate by 44% (P < 0.05). The GH receptor block by pegvisomant restored the plasma β-hydroxybutyrate to baseline levels., Conclusions: We conclude that GH has a direct effect on promoting the ketogenesis environment in patients treated with empagliflozin.

The common genetic variant in the promoter region of the hepatic lipase gene [LIPC -250G/A(rs2070895)] has an ambiguous association with cardiovascular disease. In this context, our study was performed to identify the relationships between the rs2070895 with carotid atherosclerosis, plasma lipids, and parameters of reverse cholesterol transport. A total of 285 normolipidemic and asymptomatic participants from an initial sample of 598,288 individuals (inclusion criteria: LDL-C ≤130 mg/dL and triglycerides ≤150 mg/dL; age: 20-75 years, both genders; confirmation of clinical, anthropometric and laboratory data; attended all visits; DNA was achieved to perform genetic analysis) were enrolled and the rs2070895 variant was genotyped by TaqMan® OpenArray® Plataform. Carotid intima-media thickness and the screening of atherosclerotic plaques were determined by B-mode ultrasonography. The rs2070895 genotype frequencies were 0.44, 0.41, and 0.15 (GG, GA, and AA, respectively). Logistic regression analysis showed that the risk of having plaques was increased in participants carrying the AA or AG genotypes (OR = 3.90; 95% CI = 1.54-10.33), despite an increase in high-density lipoprotein cholesterol levels, HDL diameter and apolipoprotein A-I, as compared to the GG genotype. Hepatic lipase and endogenous lecithin cholesterol acyl transferase activities were reduced (38% and 19%, respectively) and lipoprotein lipase was increased by 30% (AA vs GG). Our results provide evidence that the AA or AG genotypes of the rs2070895 were associated with carotid atherosclerosis in apparently healthy participants, probably as a consequence of reduced reverse cholesterol transport and accumulation of HDL subfraction 2 rich in triglycerides and depleted in cholesteryl esters that could become dysfunctional., (© 2020 AOCS.)

Background and Aim: Obesity-related decline in high-density lipoprotein (HDL) functions such as cholesterol efflux capacity (CEC) has supported the notion that this lipoprotein dysfunction may contribute for atherogenesis among obese patients. We investigated if potentially other HDL protective actions may be affected with weight gain and these changes may occur even before the obesity range in a cross-sectional analysis., Methods and Results: Lipid profile, body mass index (BMI), biochemical measurements, and carotid intima-media thickness (cIMT) were obtained in this cross-sectional study with 899 asymptomatic individuals. Lipoproteins were separated by ultracentrifugation and HDL physical-chemical characterization, CEC, antioxidant activity, anti-inflammatory activity, HDL-mediated platelet aggregation inhibition were measured in a randomly-selected subgroup (n = 101). Individuals with increased HDL-C had an attenuated increase in cIMT with elevation of BMI (interaction effect β = -0.054; CI 95% -0.0815, -0.0301). CEC, HDL-C, HDL size and HDL-antioxidant activity were negatively associated with cIMT. BMI was inversely correlated with HDL-mediated inhibition of platelet aggregation (Spearman's rho -0.157, p < 0.03) and CEC (Spearman's rho -0.32, p < 0.001), but surprisingly it was directly correlated with the antioxidant activity (Spearman's rho 0.194, p = 0.052). Thus, even in non-obese, non-diabetic individuals, increased BMI is associated with a wide change in protective functions of HDL, reducing CEC and increasing antioxidant activity. In these subjects, decreased HDL concentration, size or function are related to increased atherosclerotic burden., Conclusion: Our findings demonstrate that in non-obese, non-diabetic individuals, the increasing values of BMI are associated with impaired protective functions of HDL and concomitant increase in atherosclerotic burden., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: The transport of lipids from the artery wall is one of the most essential anti-atherogenic functions of high-density lipoprotein (HDL). Recent reports of changes in the HDL composition, during myocardial infarction (MI), suggest that this function may be altered., Methods: Forty-one consecutive patients with ST-segment elevation MI enrolled at the Brasilia Heart Study were selected. The following HDL-related measures were determined upon admission (D1) and on the fifth day (D5) after MI: C-reactive protein, CETP and PLTP activity, HDL composition, efflux of cholesterol from J774 macrophages to HDL, and transfer of unesterified and esterified cholesterol, triglycerides and phospholipids from a donor nanoemulsion to HDL., Results: From D1 to D5, the activity of CETP decreased by 25%, but PLTP activity remained unchanged. Esterified cholesterol (-23%) and phospholipid (-9.5%) contents of HDL decreased. Transfer of triglycerides (-36.5%) and esterified cholesterol (-14.7%) to HDL from nanoemulsions was reduced, but other lipids transfers were unchanged. Cholesterol efflux to HDL was also diminished by 8.5% (p=0.04) on D5 compared to D1. It was more pronounced in patients above the 75th percentile of C-reactive protein., Conclusions: After an MI, a simultaneous decrease in lipid transfer to HDL and in the capacity of HDL to efflux cholesterol from cells occurs. Thus, HDL with inferior atheroprotective properties may be generated in the acute post-MI period., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Considering the growing knowledge and perspectives on microRNAs (miRNAs) that control high-density lipoprotein cholesterol (HDL-C) levels and metabolism, this study aimed at evaluating whether hsa-miR-33a and hsa-miR-128a are differentially expressed in peripheral blood mononuclear cells from asymptomatic individuals with low and high HDL-C, as well as at investigating the potential relationships with ATP binding cassete transporter A1 (ABCA1) expression, cholesterol efflux capacity and other parameters related with reverse cholesterol transport. In addition, the associations with cardiovascular risk were investigated by carotid-intima media thickness (cIMT). Asymptomatic volunteers of both genders (n=51) were classified according to HDL-C (mg/dL) in hypoalphalipoproteinemics (hypo, HDL-C ≤3 9), hyperalphalipoproteinemics (hyper, HDL-C ≥ 68) and controls (CTL, HDL-C ≥ 40<68). cIMT, lipids, lipoproteins, HDL size and volume, C reactive protein and insulin were determined, as well as the activities of several proteins and enzymes related to HDL metabolism. In a subgroup of 19 volunteers the cellular cholesterol efflux and HDL composition were determined. Total RNA was extracted from peripheral blood mononuclear cells for relative quantification experiments. Hypo volunteers presented significantly higher levels of triglycerides, VLDL-C and insulin; in addition, HDL size and volume decreased when compared with CTL and hyper. Regarding gene expression analysis, the hyper group presented a decrease of 72% in hsa-miR-33a and higher mRNA expression of ABCA1 and ABCG1 when compared with CTL. No significant differences in hsa-miR-128a expression, cholesterol efflux, cIMT or plaques were found. Further studies are necessary to elucidate the mechanisms underlying the complex miRNA network, regulating cellular cholesterol homeostasis in humans and its clinical repercussions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Current data indicate that the size of high-density lipoprotein (HDL) may be considered an important marker for cardiovascular disease risk. We established reference values of mean HDL size and volume in an asymptomatic representative Brazilian population sample (n=590) and their associations with metabolic parameters by gender., Methods: Size and volume were determined in HDL isolated from plasma by polyethyleneglycol precipitation of apoB-containing lipoproteins and measured using the dynamic light scattering (DLS) technique., Results: Although the gender and age distributions agreed with other studies, the mean HDL size reference value was slightly lower than in some other populations. Both HDL size and volume were influenced by gender and varied according to age. HDL size was associated with age and HDL-C (total population); non- white ethnicity and CETP inversely (females); HDL-C and PLTP mass (males). On the other hand, HDL volume was determined only by HDL-C (total population and in both genders) and by PLTP mass (males)., Conclusions: The reference values for mean HDL size and volume using the DLS technique were established in an asymptomatic and representative Brazilian population sample, as well as their related metabolic factors. HDL-C was a major determinant of HDL size and volume, which were differently modulated in females and in males., (Copyright © 2015 Elsevier B.V. All rights reserved.)

ATP binding cassette transporter G1 (ABCG1) promotes lipidation of nascent high-density lipoprotein (HDL) particles, acting as an intracellular transporter. SNP rs1893590 (c.-204A > C) of ABCG1 gene has been previously studied and reported as functional over plasma HDL-C and lipoprotein lipase activity. This study aimed to investigate the relationships of SNP rs1893590 with plasma lipids and lipoproteins in a large Brazilian population. Were selected 654 asymptomatic and normolipidemic volunteers from both genders. Clinical and anthropometrical data were taken and blood samples were drawn after 12 h fasting. Plasma lipids and lipoproteins, as well as HDL particle size and volume were determined. Genomic DNA was isolated for SNP rs1893590 detection by TaqMan(®) OpenArray(®) Real-Time PCR Plataform (Applied Biosystems). Mann-Whitney U, Chi square and two-way ANOVA were the used statistical tests. No significant differences were found in the comparison analyses between the allele groups for all studied parameters. Conversely, significant interactions were observed between SNP and age over plasma HDL-C, were volunteers under 60 years with AA genotype had increased HDL-C (p = 0.048). Similar results were observed in the group with body mass index (BMI) < 25 kg/m(2), where volunteers with AA genotype had higher HDL-C levels (p = 0.0034), plus an increased HDL particle size (p = 0.01). These findings indicate that SNP rs1893590 of ABCG1 has a significant impact over HDL-C under asymptomatic clinical conditions in an age and BMI dependent way.

Introduction: Cholesterol undergoes oxidation via both enzymatic stress- and free radical-mediated mechanisms, generating a wide range of oxysterols. In contrast to oxidative stress-driven metabolites, enzymatic stress-derived oxysterols are scarcely studied in their association with atherosclerotic disease in humans., Methods: 24S-hydroxycholesterol (24S-HC), 25-hydroxycholesterol (25-HC), and 27-hydroxycholesterol (27-HC) were assessed in plasma and arteries with atherosclerotic plaques from 10 patients (54-84 years) with severe peripheral artery disease (PAD) as well as arteries free of atherosclerotic plaques from 13 individuals (45-78 years, controls)., Results: Plasma 25-HC was higher in PAD individuals than in controls (6.3[2] vs. 3.9[1.9] ng/mgCol; p = 0.004). 24S-HC and 27-HC levels were, respectively, five- and 20-fold higher in the arterial tissue of PAD individuals than in those of the controls (p = 0.016 and p = 0.001). Plasma C-reactive protein correlated with plasma 24-HC (r = 0.51; p = 0.010), 25-HC (r = 0.75; p < 0.001), 27-HC (r = 0.48; p = 0.015), and with tissue 24S-HC (r = 0.4; p = 0.041) and 27-HC (r = 0.46; p = 0.023)., Conclusion: Arterial intima accumulation of 27-HC and 24S-HC is associated with advanced atherosclerotic disease and systemic inflammatory activity in individuals with severe PAD.

Background: Misclassification of patients as low cardiovascular risk (LCR) remains a major concern and challenges the efficacy of traditional risk markers. Due to its strong association with cholesterol acceptor capacity, high-density lipoprotein (HDL) size has been appointed as a potential risk marker. Hence, we investigate whether HDL size improves the predictive value of HDL-cholesterol in the identification of carotid atherosclerotic burden in individuals stratified to be at LCR., Methods and Findings: 284 individuals (40-75 years) classified as LCR by the current US guidelines were selected in a three-step procedure from primary care centers of the cities of Campinas and Americana, SP, Brazil. Apolipoprotein B-containing lipoproteins were precipitated by polyethylene glycol and HDL size was measured by dynamic light scattering (DLS) technique. Participants were classified in tertiles of HDL size (<7.57; 7.57-8.22; >8.22 nm). Carotid intima-media thickness (cIMT) <0.90 mm (80th percentile) was determined by high resolution ultrasonography and multivariate ordinal regression models were used to assess the association between cIMT across HDL size and levels of lipid parameters. HDL-cholesterol was not associated with cIMT. In contrast, HDL size >8.22 nm was independently associated with low cIMT in either unadjusted and adjusted models for age, gender and Homeostasis Model Assessment 2 index for insulin sensitivity, ethnicity and body mass index (Odds ratio 0.23; 95% confidence interval 0.07-0.74, p = 0.013)., Conclusion: The mean HDL size estimated with DLS constitutes a better predictor for subclinical carotid atherosclerosis than the conventional measurements of plasma HDL-cholesterol in individuals classified as LCR.

Objective: Recent data suggests that cholesteryl ester transfer protein (CETP) activity may interact with acute stress conditions via inflammatory-oxidative response and thrombogenesis. We investigated this assumption in patients with ST-elevation myocardial infarction (STEMI)., Methods: Consecutive patients with STEMI (n = 116) were enrolled <24-h of symptoms onset and were followed for 180 days. Plasma levels of C-reactive protein (CRP), interleukin-2 (IL-2), tumor necrosis factor (TNFα), 8-isoprostane, nitric oxide (NOx) and CETP activity were measured at enrollment (D1) and at fifth day (D5). Flow-mediated dilation (FMD) was assessed by ultrasound and coronary thrombus burden (CTB) was evaluated by angiography., Results: Neither baseline nor the change of CETP activity from D1 to D5 was associated with CRP, IL-2, TNFα, 8-isoprostane levels or CTB. The rise in NOx from D1 to D5 was inferior [3.5(-1; 10) vs. 5.5(-1; 12); p < 0.001] and FMD was lower [5.9(5.5) vs. 9.6(6.6); p = 0.047] in patients with baseline CETP activity above the median value than in their counterparts. Oxidized HDL was measured by thiobarbituric acid reactive substances (TBARS) in isolated HDL particles and increased from D1 to D5, and remaining elevated at D30. The change in TBARS content in HDL was associated with CETP activity (r = 0.72; p = 0.014) and FMD (r = -0.61; p = 0.046). High CETP activity at admission was associated with the incidence of sudden death and recurrent MI at 30 days (OR 12.8; 95% CI 1.25-132; p = 0.032) and 180 days (OR 3.3; 95% CI 1.03-10.7; p = 0.044)., Conclusions: An enhanced CETP activity during acute phase of STEMI is independently associated with endothelial dysfunction and adverse clinical outcome., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Acute phase response modifies high-density lipoprotein (HDL) into a dysfunctional particle that may favor oxidative/inflammatory stress and eNOS dysfunction. The present study investigated the impact of this phenomenon on patients presenting ST-elevation myocardial infarction (STEMI)., Methods: Plasma was obtained from 180 consecutive patients within the first 24-h of onset of STEMI symptoms (D1) and after 5 days (D5). Nitrate/nitrite (NOx) and lipoproteins were isolated by gradient ultracentrifugation. The oxidizability of low-density lipoprotein incubated with HDL (HDLaoxLDL) and the HDL self-oxidizability (HDLautox) were measured after CuSO4 co-incubation. Anti-inflammatory activity of HDL was estimated by VCAM-1 secretion by human umbilical vein endothelial cells after incubation with TNF-α. Flow-mediated dilation (FMD) was assessed at the 30(th) day (D30) after STEMI., Results: Among patients in the first tertile of admission HDL-Cholesterol (<33 mg/dL), the increment of NOx from D1 to D5 [6.7(2; 13) vs. 3.2(-3; 10) vs. 3.5(-3; 12); p = 0.001] and the FMD adjusted for multiple covariates [8.4(5; 11) vs 6.1(3; 10) vs. 5.2(3; 10); p = 0.001] were higher than in those in the second (33-42 mg/dL) or third (>42 mg/dL) tertiles, respectively. From D1 to D5, there was a decrease in HDL size (-6.3 ± 0.3%; p < 0.001) and particle number (-22.0 ± 0.6%; p < 0.001) as well as an increase in both HDLaoxLDL (33%(23); p < 0.001) and HDLautox (65%(25); p < 0.001). VCAM-1 secretion after TNF-a stimulation was reduced after co-incubation with HDL from healthy volunteers (-24%(33); p = 0.009), from MI patients at D1 (-23%(37); p = 0.015) and at D30 (-22%(24); p = 0.042) but not at D5 (p = 0.28)., Conclusion: During STEMI, high HDL-cholesterol is associated with a greater decline in endothelial function. In parallel, structural and functional changes in HDL occur reducing its anti-inflammatory and anti-oxidant properties., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: HDL is considered the most important mechanism for the excretion of intracellular cholesterol. The liver is the only organ capable to metabolize cholesterol into bile acid. The enzymatic conversion of cholesterol to bile acid is dependent on the cytochrome P450 microsomal system which is also responsible for the generation of oxysterols. The latter's plasma concentrations may reflect the metabolic processes of specific tissues where they are generated. The objective of this study was to investigate in healthy individuals who differ according to their HDL levels the concentration of oxysterols and relate it to the HDL-dependent cell cholesterol efflux rate., Methods: 24-Hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol were determined in plasma by GLC/mass spectrometry in 107 healthy subjects with low HDL (HDL-C<1.03mmol/l) and high HDL cholesterol (HDL-C>1.55mmol/l). HDL-dependent in vitro cell cholesterol efflux rate was measured in 29 cases., Results: No differences were found in plasma oxysterol concentrations between the Low HDL and High HDL groups. There was a significant negative correlation between HDL-C and 27-hydroxycholesterol. Plasma oxysterol concentrations were significantly lower in female than in male subjects. The Low HDL male group had higher 27-hydroxycholesterol than the High HDL male group. Cell cholesterol efflux rate was lower in Low HDL than in High HDL and related inversely with 27-hydroxycholesterol., Conclusion: As compared to High HDL, Low HDL men have increased 27-hydroxycholesterol plasma level that may circumvent their reduced cell cholesterol efflux rate., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Reduced plasma concentration of high-density lipoprotein cholesterol (HDL-C) is associated with vulnerability to oxidative stress and propensity to endothelial dysfunction. Niacin directly activates both GPR-109A in leukocytes and the heme oxygenase-1 pathway, promoting strong anti-inflammatory and antioxidative effects, as well as induces immediate production of prostaglandin D2, leading to endothelial vasodilation., Objective: This study investigated the short-term effects of extended-release niacin (ERN) administered with or without the prostaglandin D2 receptor antagonist laropiprant on endothelial function in patients with low HDL-C., Methods: Asymptomatic men and women aged between 20 and 60 years who had plasma HDL-C levels <40 mg/dL were treated with ERN monotherapy 1 g/d or ERN/laropiprant 1 g/20 mg (ERN/LRP) in a crossover study design. The sequence of treatments was decided by simple randomization. Plasma samples and flow-mediated dilation (FMD) of the brachial artery were obtained at baseline, day 7 of treatment period 1, day 7 of washout, and day 7 of treatment period 2., Results: Eighteen patients were enrolled (mean [SD] age, 42 [17] years; 11 men). Triglyceride levels decreased by 4% and 3%, and HDL size decreased by 5.8% and 6.2%, with ERN and ERN/LRP, respectively (both, P < 0.05). There were no changes in HDL-C levels or in cholesteryl esterase transfer protein activity with either treatment. The median increases in FMD were 4.5% and 4.1% with ERN and ERN/LRP, which receded after washout. On intergroup analysis, there were no differences with respect to variation in plasma HDL-C, triglycerides, C-reactive protein, direct bilirubin, or FMD., Conclusions: In these patients, the addition of laropiprant did not influence the effects of niacin on endothelial function. Based on these findings, short-term niacin treatment might improve endothelial function in patients with low HDL-C levels. ClinicalTrials.gov identifier: NCT01942291., (Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.)

Regardless of its effect on the concentrations of serum cholesterol, statins exert pleiotropic effects, including the regulation of endothelial function, reduced oxidative stress and inflammation, as well as a slight improvement in the concentrations of high density lipoprotein (HDL). However, its role on the composition of HDL is not yet established. The aim of this study was to evaluate the composition of HDL subfractions, HDLsub>2 and HDL3, after 14 days of placebo and atorvastatin (10 mg/day) use in 30 asymptomatic volunteers. The serum parameters and the HDL subfractions compositions were determined using radiometric, nephelometric and biochemical enzymatic methods. We observed significant reductions of total cholesterol, low density lipoprotein (LDL) and apolipoprotein B-100 by 28%, 40% and 38%, respectively. The analyses of chemical composition of the subfractions revealed a lower lipid protein ratio in HDL2, suggesting enrichment in proteins, and also lower in HDL3, probably by an increase in the number of particles. Several mechanisms can be suggested for the effects observed after the use of atorvastatin, such as a possible action on the reverse cholesterol transport (decreased activity of hepatic lipase and increased phospholipid transfer protein, PLTP), which would explain the enrichment of HDL. The results suggest that statin use may be relevant in the primary prevention of atherosclerosis not only by its lowering effect on LDLcholesterol and its anti-inflammatory effect but also by beneficial changes in HDL subfractions.

Background: We have searched if plasma high density lipoprotein-cholesterol (HDL-C) concentration interferes simultaneously with whole-body cholesterol metabolism and insulin sensitivity in normal weight healthy adult subjects., Methods: We have measured the activities of several plasma components that are critically influenced by insulin and that control lipoprotein metabolism in subjects with low and high HDL-C concentrations. These parameters included cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), lecithin cholesterol acyl transferase (LCAT), post-heparin lipoprotein lipase (LPL), hepatic lipase (HL), pre-beta-₁HDL, and plasma sterol markers of cholesterol synthesis and intestinal absorption., Results: In the high-HDL-C group, we found lower plasma concentrations of triglycerides, alanine aminotransferase, insulin, HOMA-IR index, activities of LCAT and HL compared with the low HDL-C group; additionally, we found higher activity of LPL and pre-beta-₁HDL concentration in the high-HDL-C group. There were no differences in the plasma CETP and PLTP activities., Conclusions: These findings indicate that in healthy hyperalphalipoproteinemia subjects, several parameters that control the metabolism of plasma cholesterol and lipoproteins are related to a higher degree of insulin sensitivity.

Assessment of lipid profile parameters has been considered a cornerstone in classifying individuals and populations at risk for cardiovascular disease. Recently, however, preliminary data have raised the possibility of seasonal variations in these parameters, which may cause under- or overestimation. Biological rhythms and seasonal variation of lipid profile was investigated in 227 359 consecutive individuals who underwent health checkups in primary care centers between 2008 and 2010. Plasma low-density lipoprotein cholesterol (LDL-C) >130 mg/dL was 8% more prevalent during winter than summer, with a larger difference among women and middle-aged adults (p < 0.001). High-density lipoprotein cholesterol (HDL-C) <40 mg/dL and triglycerides (TG) >150 mg/dL were respectively 9% and 5% more prevalent during the summer (p < 0.001). Variation amplitude was 3.4 ± 0.3 mg/dL for HDL-C (p = 0.005), 7 ± 2 mg/dL for LDL-C (p = 0.047), and 12 ± 9 mg/dL for TG (p = 0.058). Based on a large population sample, this study confirms the existence of biological rhythms and seasonal variation in lipid profile. This finding must be particularly accounted for in cross-sectional analyses of relative risk, prevalence, or the rate of goal achievement for lipid parameters.

Unlabelled: Sterol 27-hydroxylase converts cholesterol to 27-hydroxycholesterol (27-OHC) which is widely distributed among tissues and is expressed at high levels in the vascular endothelium and macrophages. There is a continuous flow of this oxysterol from the tissues into the liver, where it is converted to bile acids., Objective: Measure plasma concentrations of 27-OHC in subjects that differ according to their plasma HDL-C concentration., Methods: Healthy men presenting low HDL-C (<1.03 mmol/L), n=18 or high HDL-C (>1.55 mmol/L), n=18, BMI<30 kg/m² were recruited after excluding secondary causes that might interfere with their plasma lipid concentrations such as smoking, heavy drinking and diabetes. Blood samples were drawn after a 12h fasting period for the measurement of 27-OHC by the combined GC/MS analysis utilizing deuterium-label internal standards., Results: The plasma ratio 27-OHC/total cholesterol (median and range nmoL/mmoL) was 50.41 (27.47-116.00) in the High HDL-C subjects and 63.34 (36.46-91.18) in the Low HDL-C subjects (p=0.0258)., Conclusion: Our data indicate that the production of 27-OHC by extrahepatic tissues and its transport to the liver may represent an alternative pathway for a deficient reverse cholesterol transport system when plasma HDL-C is low., (© 2013.)

This review examines the interactions between plasma high density lipoprotein (HDL) metabolism and whole-body cholesterol economy. More specifically, this review addresses three questions: 1) does plasma HDL-C concentration correlate with the parameters of whole-body cholesterol metabolism? 2) Do variations in cholesterol metabolism interfere with plasma HDL-C concentrations? 3) Are the markers of cholesterol synthesis and intestinal absorption specifically under the control of plasma HDL? The following answers were provided to each question, respectively: 1) plasma HDL influences whole-body cholesterol synthesis rate but the evidence that HDL modifies the total amount of cholesterol absorbed by the intestine is not clearly supported by present investigations; 2) there are suggestions that changes in whole body cholesterol metabolism rates do not interfere with plasma HDL-C concentrations; 3) markers of cholesterol synthesis and absorption may specifically be controlled by plasma HDL-C concentrations regarding the genetic causes of extremely low HDL-C concentrations, although within the general population plasma HDL-C concentration is likely ascribed to insulin resistance or diabetes mellitus., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Metabolic predictors and the atherogenicity of oxidized LDL (oxLDL) and the specific antibodies against oxLDL (oxLDL Ab) are unclear and controversial., Methods: In 107 adults without atherosclerotic manifestations, we measured oxLDL and oxLDL Ab, and also the activities of CETP, PLTP, lipases and the carotid intima-media thickness (cIMT). Comparisons were performed for the studied parameters between the lowest and the highest tertile of oxLDL and oxLDL Ab, and the relationships between studied variables were evaluated., Results: Subjects with higher oxLDL Ab present reduced hepatic lipase activity and borderline increased cIMT. In the highest oxLDL tertile, besides the higher levels of total cholesterol, LDL-C and apoB100, we found reduced CETP activity and higher cIMT. A significant correlation between oxLDL Ab and cIMT, independent of oxLDL, and a borderline correlation between oxLDL and cIMT independent of oxLDL Ab were found. In the multivariate analysis, apoAI was a significant predictor of oxLDL Ab, in contrast to regulation of oxLDL by apoB100, PLTP and inverse of CETP., Conclusions: In adults without atherosclerotic disease, the metabolic regulation and carotid atherosclerosis of oxLDL Ab and oxLDL groups, characterized a dual trait in oxLDL Ab, as a contributor to carotid atherosclerosis, much less so than oxidized LDL, and with a modest atheroprotective role., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Cholesteryl ester transfer protein (CETP) plays a major role in lipid metabolism, but studies on the association of CETP polymorphisms with risks of cardiovascular disease are inconsistent. This study investigated whether the CETP gene I405V and Taq1B polymorphisms modified subclinical atherosclerosis in an asymptomatic Brazilian population sample., Methods: The polymorphisms were analyzed using polymerase chain reaction in 207 adult volunteers. Serum lipid profiles, oxLDL Ab titers, C-reactive protein and tumor necrosis factor-α concentrations and CETP and phospholipid transfer protein (PLTP) activities were determined, and common carotid artery intima-media thickness (cIMT) was measured using ultrasonography., Results: No differences in cIMT were observed between the presence or absence of the minor B2 and V alleles in either polymorphism. However, inverse correlations between mean cIMT and CETP activity in the presence of these polymorphisms were observed, and positive correlations of these polymorphisms with PLTP activity and oxLDL Ab titers were identified. Moreover, logistic multivariate analysis revealed that the presence of the B2 allele was associated with a 5.1-fold (CI 95%, OR: 1.26 - 21.06) increased risk for cIMT, which was equal and above the 66th percentile and positively interacted with age. However, no associations with the V allele or CETP and PLTP activities were observed., Conclusions: None of the studied parameters, including CETP activity, explained the different relationships between these polymorphisms and cIMT, suggesting that other non-determined factors were affected by the genotypes and related to carotid atherosclerotic disease.

This is a qualitative research based on the social phenomenology approach, performed in 2010 with eight adolescents who experienced abortion and were assisted in a philanthropic hospital institution in the state of Minas Gerais. This research aimed at understanding the experience and care needs regarding adolescents in an abortion situation. The results show that the pregnancy impact led to the fear of non acceptance by the family and at the same time, the feeling of happiness for the possibility of being a mother. The abortion experience was marked by suffering and the care provided was considered satisfactory, being highlighted the need for more attention and information. The adolescents plan to continue their studies and have in mind the possibility of a new pregnancy. The planning of preventive actions aimed at this audience, and the development of new scientific investigations that include the perspective of family members and health professionals begin to emerge.

Objective: Enhanced sodium intake increases volume overload, oxidative stress and production of proinflammatory cytokines. In animal models, increased sodium intake favours ventricular dysfunction after myocardial infarction (MI). The aim of this study was to investigate, in human subjects presenting with ST-segment elevation MI (STEMI), the impact of sodium intake prior the coronary event., Methods: Consecutive patients (n=372) admitted within the first 24 h of STEMI were classified by a food intake questionnaire as having a chronic daily intake of sodium higher (HS) or lower (LS) than 1.2 g in the last 90 days before MI. Plasma levels of 8-isoprostane, interleucin-2 (IL-2), tumour necrosis factor type α (TNF-α), C-reactive protein (CRP) and brain natriuretic peptide (BNP) were measured at admission and at the fifth day. Magnetic resonance imaging was performed immediately after discharge. Total mortality and recurrence of acute coronary events were investigated over 4 years of follow-up., Results: The decrease of 8-isoprostane was more prominent and the increase of IL-2, TNF-α and CRP less intense during the first 5 days in LS than in HS patients (p<0.05). Sodium intake correlated with change in plasma BNP between admission and fifth day (r=0.46; p<0.0001). End-diastolic volumes of left atrium and left ventricle were greater in HS than in LS patients (p<0.05). In the first 30 days after MI and up to 4 years afterwards, total mortality was higher in HS than in LS patients (p<0.05)., Conclusion: Excessive sodium intake increases oxidative stress, inflammatory response, myocardial stretching and dilatation, and short and long-term mortality after STEMI., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The aim of the study was to verify whether post-menopausal hormone replacement therapy (HRT) modifies autoantibody titers against oxidized low-density lipoprotein (LDL) (anti-LDLoxi), against epitopes of oxidized apolipoprotein B100 and common carotid intima-media thickness (IMT) in these women. Sixty-eight women in pre-menopause (PMW) and 216 in post-menopause (POMW) were recruited; eighty-three had undergone HRT for at least 12 months, where 48 received conjugated estrogens alone (EHRT) and 35 received conjugated estrogen and medroxyprogesterone acetate (CHRT). ELISA was used to determine autoantibodies. Lipoprotein lipase (LPL), hepatic lipase (HL), cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP) activities were assayed by radiometric methods. IMT was measured using Doppler ultrasound. Anti-oxidized LDL and anti-D antibodies increased by 40% (p ≤ 0.003) and 42% (p ≤ 0.006), respectively, with menopause. There was a surprising and significant 7% reduction in anti-D2 antibody titers with HRT (p ≤ 0.050), indicating a positive effect of treatment on the immune response to oxidized LDL. Combined HRT decreased activities of HL and LPL. HRT did not change common carotid IMT, which was increased by 32% as expected after menopause (p ≤ 0.030). This study describes, for the first time, the protective effect of HRT on decreasing autoantibody titers against oxidized apolipoprotein B in LDL.

Lipid abnormalities in children have become more common in recent decades. This trend is related to the increase in overweight and obesity. The 2002 National Health and Nutrition Examination Survey reported that the percentage of risk for overweight and overweight in children aged > 6 years is 31%, higher than the previous surveys. Serum lipids tend to increase quickly up to 6 months of age and reach values very close to adult values by age 2. As suggested by the American Heart Association, serum lipid values for children and adolescents (2-19 years old) are considered abnormal when total cholesterol is >200 mg/dL, high-density lipoprotein is <35 mg/dL, low-density lipoprotein is >130 mg/dL, and triglycerides are >150 mg/dL. Dyslipidemia can be found in patients with malnutrition, a severe condition that needs prompt nutrition intervention. This report describes a case of malnutrition causing severe dyslipidemia in a newborn. Primary dyslipidemia was excluded by the presence of primary malnutrition, normal response to a postheparin lipoprotein lipase activity test, a favorable clinical course after nutrition intervention, and relatives' blood lipid levels close to normal that did not indicate familial dyslipidemia. The child was fed fat-free milk formula supplemented with medium-chain triglycerides and had adequate weight gain with a decrease in blood lipids. Subsequently the formula was changed to regular milk-based formula, and the child maintained adequate growth rate. Although blood lipids never returned to normal values for age and sex, they were lower than before treatment.

Background: The relationship between CETP and postprandial hyperlipemia is still unclear. We verified the effects of varying activities of plasma CETP on postprandial lipemia and precocious atherosclerosis in asymptomatic adult women., Methods: Twenty-eight women, selected from a healthy population sample (n = 148) were classified according to three CETP levels, all statistically different: CETP deficiency (CETPd ≤ 4.5%, n = 8), high activity (CETPi ≥ 23.8, n = 6) and controls (CTL, CETP ≥ 4.6% and ≤ 23.7%, n = 14). After a 12 h fast they underwent an oral fat tolerance test (40 g of fat/m² of body surface area) for 8 hours. TG, TG-rich-lipoproteins (TRL), cholesterol and TRL-TG measurements (AUC, AUIC, AR, RR and late peaks) and comparisons were performed on all time points. Lipases and phospholipids transfer protein (PLTP) were determined. Correlation between carotid atherosclerosis (c-IMT) and postprandial parameters was determined. CETP TaqIB and I405V and ApoE-ε3/ε2/ε4 polymorphisms were examined. To elucidate the regulation of increased lipemia in CETPd a multiple linear regression analysis was performed., Results: In the CETPi and CTL groups, CETP activity was respectively 9 and 5.3 higher compared to the CETPd group. Concentrations of all HDL fractions and ApoA-I were higher in the CETPd group and clearance was delayed, as demonstrated by modified lipemia parameters (AUC, AUIC, RR, AR and late peaks and meal response patterns). LPL or HL deficiencies were not observed. No genetic determinants of CETP deficiency or of postprandial lipemia were found. Correlations with c-IMT in the CETPd group indicated postprandial pro-atherogenic associations. In CETPd the regression multivariate analysis (model A) showed that CETP was largely and negatively predicted by VLDL-C lipemia (R² = 92%) and much less by TG, LDL-C, ApoAI, phospholipids and non-HDL-C. CETP (model B) influenced mainly the increment in ApoB-100 containing lipoproteins (R² = 85% negatively) and phospholipids (R² = 13%), at the 6(th)h point., Conclusion: The moderate CETP deficiency phenotype included a paradoxically high HDL-C and its sub fractions (as earlier described), positive associations with c-IMT, a postprandial VLDL-C increment predicting negatively CETP activity and CETP activity regulating inversely the increment in ApoB100-containing lipoproteins. We hypothesize that the enrichment of TG content in triglyceride-rich ApoB-containing lipoproteins and in TG rich remnants increases lipoproteins' competition to active lipolysis sites,reducing their catabolism and resulting on postprandial lipemia with atherogenic consequences.

Background: The rat has been a mainstay of physiological and metabolic research, and more recently mice. This study aimed at characterizing the postprandial triglyceride profile of two members of the Muridae family: the Wistar rats (Rattus norvegicus albinus) and C57BL/6 mice (Mus musculus) plus comparing them to the profile obtained in humans., Methods: Thirty-one male and twelve female Wistar rats, ten C57BL/6 male and nine female mice received a liquid meal containing fat (17%), protein (4%) and carbohydrates (4%), providing 2 g fat/Kg. Thirty-one men and twenty-nine women received a standardized liquid meal containing fat (25%), dextromaltose (55%), protein (14%), and vitamins and minerals (6%), and providing 40 g of fat per square meter of body surface. Serial blood samples were collected at 2, 4, 6, 8 and 10 h after the ingestion in rats, at 1, 2, 3, 4, 5 and 6 h in mice and in humans at 2, 4, 6 and 8 h. Wilcoxon and Mann-Whitney tests were used., Results/discussion: The triglyceride responses were evaluated after the oral fat loads. Fasting and postprandial triglyceridemia were determined sequentially in blood sample. AUC, AUIC, AR, RR and late peaks were determined., Conclusions: Rats are prone to respond in a pro-atherogenic manner. The responses in mice were closer to the ones in healthy men. This study presents striking differences in postprandial triglycerides patterns between rats and mice not correlated to baseline triglycerides, the animal baseline body weight or fat load in all animal groups.

Objective: Clinical trials of statins during myocardial infarction (MI) have differed in their therapeutic regimes and generated conflicting results. This study evaluated the role of the timing and potency of statin therapy on its potential mechanisms of benefit during MI., Methods and Results: ST-elevation MI patients (n=125) were allocated into 5 groups: no statin; 20, 40, or 80 mg/day simvastatin starting at admission; or 80 mg/day simvastatin 48 hours after admission. After 7 days, all patients switched their treatment to 20 mg/day simvastatin for an additional 3 weeks and then underwent flow-mediated dilation in the brachial artery. As of the second day, C-reactive protein (CRP) differed between non-statin users (12.0±4.1 mg/L) and patients treated with 20 (8.5±4.0 mg/L), 40 (3.8±2.5 mg/L), and 80 mg/day (1.4±1.5 mg/L), and the daily differences remained significant until the seventh day (P<0.0001). The higher the statin dose, the lower the elevation of interleukin-2 and tumor necrosis factor-α, the greater the reduction of 8-isoprostane and low-density lipoprotein(-), and the greater the increase in nitrate/nitrite levels during the first 5 days (P<0.001). Later initiation of statin was less effective than its early introduction in relation to attenuation of CRP, interleukin-2, tumor necrosis factor-α, 8-isoprostane, and low-density lipoprotein(-), as well as in increase in nitrate/nitrite levels (P<0.0001). At the 30th day, there was no longer a difference in lipid profile or CRP between groups; the flow-mediated dilation, however, was proportional to the initial statin dose and was higher for those who started the treatment early (P=0.001)., Conclusions: This study demonstrates that the timing and potency of statin treatment during MI are key elements for their main mechanisms of benefit. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00906451.

Cholesteryl ester transfer protein (CETP) exerts a profound impact on high-density lipoprotein (HDL) metabolism and, consequently, on the risk of atherosclerosis development and cardiovascular mortality. Here, we review the complex relationship between CETP and atherosclerosis based upon the experimental, clinical, and epidemiological studies. In addition, we discuss the recent findings that expand the functions of CETP to new areas of interest such as Alzheimer's disease, inflammation, and obesity., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: The antiatherogenic functions of high density lipoprotein (HDL-C) include its role in reverse cholesterol transport, but to what extent the concentration of HDL-C interferes with the whole-body cholesterol metabolism is unknown. Therefore, we measured markers of body cholesterol synthesis (desmosterol and lathosterol) and of intestinal cholesterol absorption (campesterol and β-sitosterol) in healthy subjects that differ according to their plasma HDL-C concentrations., Methods: Healthy participants presented either low HDL-C (< 40 mg/dl, n=33, 17 male and 16 female) or high HDL-C (> 60 mg/dl, n=33, 17 male and 16 female), BMI< 30 kg/m², were paired according to age and gender, without secondary factors that might interfere with their plasma lipid concentrations. Plasma concentrations of non-cholesterol sterols were measured by the combined GC-MS analysis., Results: Plasma desmosterol did not differ between the two groups; however, as compared with the high HDL-C participants, the low HDL-C participants presented higher concentration of lathosterol and lower concentration of the intestinal cholesterol absorption markers campesterol and β-sitosterol., Conclusion: Plasma concentrations of HDL, and not the activities of LCAT and CETP that regulate the reverse cholesterol transport system, correlate with plasma sterol markers of intestinal cholesterol absorption directly, and of cholesterol synthesis reciprocally., (Copyright © 2010 Elsevier B.V. All rights reserved.)

To determine whether hyperalphalipoproteinemia modifies carotid intima-media thickness (cIMT) and/or influences the relationship of clinical and biochemical parameters with cIMT. This study was conducted on 169 asymptomatic individuals, classified as hyperalphalipoproteinemic (Hyper-A) (Hyper-A, n = 71, HDL-C > or =68 mg/dL) and controls (CTL) (CTL, n = 98, HDL-C >32 and <68 mg/dL). Enzymatic, nephelometric and ultracentrifugation methods were used for biochemical determinations. Hepatic lipase (HL), lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP) and phospholipids transfer protein (PLTP) activities were measured by radiometric exogenous methods. The prevalence of dyslipidemia, hypertension, smoking, sedentariness, postmenopausal women, coronary artery disease (CAD) and familial history of CAD were determined. High resolution beta-mode carotid ultrassonography was performed. The Hyper-A group was older and had higher frequencies of hypercholesterolemia (40%), hypertension (31%), sedentariness (37%) and postmenopausal women (1%). In Hyper-A individuals, the mean cIMT after adjustment for age and gender was similar between the groups (0.85 +/- 0.24 mm Hyper-A versus 0.69 +/- 0.17 mm CTL). In multivariate models, age was a significant predictor of cIMT in Hyper-A (R (2) = 0.04, p < or = 0.001), independently of other clinical or biochemical factors. In contrast to CTL, where age (R (2) = 0.63 p < or = 0.001), male sex (R (2) = 0.03, p < or = 0.001), blood pressure (R (2) = 0.006, p < or = 0.001) and HDL-C (R (2) = 0.02, p < 0.022) accounted for the cIMT variations. Despite an increased prevalence of cardiovascular risk factors in Hyper-A and resistance of carotid thickness to modulation by metabolic and anthropometric factors (except age), the similarity in cIMT between Hyper-A and healthy individuals emphasizes the atheroprotective effects of HDL.

Objectives: Experimental and in vitro evidences have established that reactive oxygen species (ROS) generated by vascular wall cells play a key role in atherogenesis. Here, we evaluated the rate of ROS generation by resting peripheral monocytes in naive hyperlipidemic subjects., Design and Methods: Primary hypercholesterolemic, combined hyperlipidemic, and normolipidemic individuals were studied. ROS generation and the mitochondrial electrical transmembrane potential were estimated by flow cytometry. Plasma oxidized (ox) LDL levels and lipid profile were measured by ELISA and enzymatic colorimetric methods., Results: Both hyperlipidemic groups presented significantly higher rates of monocyte ROS generation and elevated plasma levels of ox-LDL. Combined hyperlipidemic subjects presented increased levels of small dense LDL and insulin. Significant positive correlations between monocyte ROS generation and ox-LDL concentrations were found in pooled data., Conclusions: These data provide evidence that ROS production by circulating monocytes from hyperlipidemic subjects may contribute to the systemic oxidative stress and possibly to atherogenesis.

Background: Few studies have evaluated seasonal variations of biochemical parameters routinely analyzed in clinical laboratories. Rhythmic patterns for lipids and lipoproteins have been demonstrated and have been the object of research, mainly because of their demonstrated association with coronary artery disease. This study evaluated the occurrence of biological rhythms on serum lipids and lipoproteins and the effects of sex and age on the rhythms in a Brazilian hospital outpatient population., Methods: Retrospective laboratory study was carried out to evaluate the results of total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C) and triglycerides (TG), from individuals registered at a university referral hospital over 8 years. The studied population was composed of individuals of both sexes and all ages totaling 38,579 participants and 301,934 measurements. Statistical analyses were carried out using the SAS program and the temporal analysis used the Cosinor method., Results: TG rhythm was present only in females. All other parameters were equally rhythmic in both sexes. Regarding age, HDL-C presented rhythms in all age groups, but TC and LDL-C showed seasonality only for those > 13 years, TG did not present rhythms in all age groups., Conclusion: Effects of sex and age on biological rhythms detected in TC, LDL-C and HDL-C should be considered a significant cause of pre-analytical variation in these laboratory tests.

Background: Dyslipidemia is diagnosed through the determination of plasma lipid profiles. This study is aimed at establishing the prevalence of dyslipidemia in a Brazilian out-patient population by using a hospital laboratory cohort., Methods: Lipid profiles of 22,542 individuals from both sexes, aged 20 to 124 years, and registered at the University Hospital of the State University of Campinas, a standard of reference for hospital treatment in the state of São Paulo, Brazil, were retrospectively analyzed from 2000 to 2003. The cut-off values for cholesterol (C), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) were determined as recommended by the National Cholesterol Education Program. Statistical analyses were carried out using the SPSS program., Results: Altered C, LDL-C and TG were found in 44%, 38% and 37% of adults and in 55%, 48% and 41% of the elderly, respectively; 35% of adults and 32% of the elderly presented undesirable low HDL-C. Combined dyslipidemia was very prevalent., Conclusion: Dyslipidemia was a serious public health problem in the studied population, especially among women and the elderly. The mixed phenotype of hypercholesterolemia and hypertriglyceridemia was the most prevalent. The results of this study were validated by their agreement with previously studied non-hospital Brazilian populations.

Objective: Low levels of high density lipoprotein-cholesterol (HDL-C) are highly prevalent in subjects presenting premature atherosclerosis. It is indeterminate as to whether high cardiovascular risk in low HDL-C subjects occurs concomitantly with elevated oxidative stress and/or with biologically dysfunctional HDL particles., Methods and Results: Systemic oxidative stress (as plasma 8-isoprostanes) was 2.3-fold elevated (p<0.05) in normocholesterolemic, normotriglyceridemic, normoglycemic low HDL-C subjects (plasma HDL-C, <40 mg/dL; n=8) as compared to normolipidemic controls (n=15). HDL subfractions (HDL2b, 2a, 3a, 3b and 3c) isolated by density gradient ultracentrifugation from low HDL-C subjects displayed significantly lower (-21 to -43%, p<0.05) specific antioxidative activity (sAA; capacity to protect LDL from oxidation on a unit particle mass or on a particle number basis) as compared to controls. Altered chemical composition (core triglyceride enrichment, cholesteryl ester depletion) paralleled antioxidative dysfunction of HDL subfractions. Plasma 8-isoprostane levels negatively correlated with sAA of HDL subfractions and positively correlated with the total cholesterol/HDL-C ratio, which was significantly elevated in the low HDL-C phenotype., Conclusions: Low HDL-C subjects display elevated oxidative stress and possess HDL particle subspecies with attenuated intrinsic antioxidative activity which is intimately related to their altered chemical composition.

Background: Human immunodeficiency virus (HIV) infection is very prevalent in Brazil. HIV therapy has been recently associated with coronary heart disease (CHD). Dyslipidemia is a major risk factor for CHD that is frequently described in HIV positive patients, but very few studies have been conducted in Brazilian patients evaluating their lipid profiles., Methods: In the present work, we evaluated the frequency and severity of dyslipidemia in 257 Brazilian HIV positive patients. Two hundred and thirty-eight (93%) were submitted to antiretroviral therapy (224 treated with protease inhibitors plus nucleoside reverse transcriptase inhibitors, 14 treated only with the latter, 12 naive and 7 had no records of treatment). The average time on drug treatment with antiretroviral therapy was 20 months. None of the patients was under lipid lowering drugs. Cholesterol, triglyceride, phospholipid and free fatty acids were determined by enzymatic colorimetric methods. Lipoprotein profile was estimated by the Friedewald formula and Fredrickson's phenotyping was obtained by serum electrophoresis on agarose. Apolipoprotein B and AI and lipoprotein "a" were measured by nephelometry., Results: The Fredrickson phenotypes were: type IIb (51%), IV (41%), IIa (7%). In addition one patient was type III and another type V. Thirty-three percent of all HIV+ patients presented serum cholesterol levels >or= 200 mg/dL, 61% LDL-cholesterol >or= 100 mg/dL, 65% HDL-cholesterol below 40 mg/dL, 46% triglycerides >or= 150 mg/dL and 10% have all these parameters above the limits. Eighty-six percent of patients had cholesterol/HDL-cholesterol ratio >or= 3.5, 22% increased lipoprotein "a", 79% increased free fatty acids and 9% increased phospholipids. The treatment with protease inhibitors plus nucleoside reverse transcriptase inhibitors increased the levels of cholesterol and triglycerides in these patients when compared with naïve patients. The HDL-cholesterol (p = 0.01) and apolipoprotein A1 (p = 0.02) levels were inversely correlated with the time of protease inhibitor therapy while total cholesterol levels had a trend to correlate with antiretroviral therapy (p = 0.09)., Conclusion: The highly varied and prevalent types of dyslipidemia found in Brazilian HIV positive patients on antiretroviral therapies indicate the urgent need for their early diagnosis, the identification of the risk factors for CHD and, when needed, the prompt intervention on their lifestyle and/or with drug treatment.

We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo) AI, lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP), or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/CETP, LCAT/AI/CETP, and non-transgenic) after four months on an atherogenic diet. The extent of atherosclerosis was assessed by morphometric analysis of lipid-stained areas in the aortic roots. The relative influence (R2) of genotype, sex, total cholesterol, and its main sub-fraction levels on atherosclerotic lesion size was determined by multiple linear regression analysis. Whereas apo AI (R2 = 0.22, P < 0.001) and CETP (R2 = 0.13, P < 0.01) expression reduced lesion size, the LCAT (R2 = 0.16, P < 0.005) and LCAT/AI (R2 = 0.13, P < 0.003) genotypes had the opposite effect. Logistic regression analysis revealed that the risk of developing atherosclerotic lesions greater than the 50th percentile was 4.3-fold lower for the apo AI transgenic mice than for non-transgenic mice, and was 3.0-fold lower for male than for female mice. These results show that apo AI overexpression decreased the risk of developing large atherosclerotic lesions but was not sufficient to reduce the atherogenic effect of LCAT when both transgenes were co-expressed. On the other hand, CETP expression was sufficient to eliminate the deleterious effect of LCAT and LCAT/AI overexpression. Therefore, increasing each step of the reverse cholesterol transport per se does not necessarily imply protection against atherosclerosis while CETP expression can change specific atherogenic scenarios.

Atherosclerotic disease remains a leading cause of death in westernized societies, and reactive oxygen species (ROS) play a pivotal role in atherogenesis. Mitochondria are the main intracellular sites of ROS generation and are also targets for oxidative damage. Here, we show that mitochondria from atherosclerosis-prone, hypercholesterolemic low-density lipoprotein (LDL) receptor knockout mice have oxidative phosphorylation efficiency similar to that from control mice but have a higher net production of ROS and susceptibility to develop membrane permeability transition. Increased ROS production was observed in mitochondria isolated from several tissues, including liver, heart, and brain, and in intact mononuclear cells from spleen. In contrast to control mitochondria, knockout mouse mitochondria did not sustain a reduced state of matrix NADPH, the main source of antioxidant defense against ROS. Experiments in vivo showed faster liver secretion rates and de novo synthesis of triglycerides and cholesterol in knockout than in control mice, suggesting that increased lipogenesis depleted the reducing equivalents from NADPH and generated a state of oxidative stress in hypercholesterolemic knockout mice. These data provide the first evidence of how oxidative stress is generated in LDL receptor defective cells and could explain the increased LDL oxidation, cell death, and atherogenesis seen in familiar hypercholesterolemia.

Context: Plasma phospholipid transfer protein mediates the transfer of phospholipids from triglyceride-rich lipoproteins, very low density lipoproteins and low density lipoproteins to high density lipoproteins, a process that is also efficient between high density lipoprotein particles. It promotes a net movement of phospholipids, thereby generating small lipid-poor apolipoprotein AI that contains particles and subfractions that are good acceptors for cell cholesterol efflux., Case Report: We measured the activity of plasma phospholipid transfer protein in two cholestatic patients, assuming that changes in activity would occur in serum that was positive for lipoprotein X. Both patients presented severe hypercholesterolemia, high levels of low density lipoprotein cholesterol and, in one case, low levels of high density lipoprotein cholesterol and high levels of phospholipid serum. The phospholipid transfer activity was close to the lower limit of the reference interval. To our knowledge, this is the first time such results have been presented. We propose that phospholipid transfer protein activity becomes reduced under cholestasis conditions because of changes in the chemical composition of high density lipoproteins, such as an increase in phospholipids content. Also, lipoprotein X, which is rich in phospholipids, could compete with high density lipoproteins as a substrate for phospholipid transfer protein.

Smoking is a leading cause of atherosclerosis acting trough a wide spectrum of mechanisms, notably the increase of the proatherogenic effect of dyslipidemia. However, a severe atherosclerotic disease is frequently observed in smokers who do not present an overt dyslipidemia. In the present study, we sought to determine if abnormalities in lipid metabolism occur in normolipidemic smokers, focusing especially on the components of intravascular remodeling of high-density lipoprotein (HDL) For this purpose, we measured lipid transfer proteins and enzymes involved in the reverse cholesterol transport (RCT) system in 29 adults: 15 smokers and 14 controls. The blood samples were drawn in the fasting state, immediately after the smokers smoked 1 cigarette. The composition of HDL particles was analyzed after isolation of HDL fractions by microultracentrifugation. We observed that normolipidemic smokers present higher total plasma and HDL phospholipids (PL) (P < .05), 30% lower postheparin hepatic lipase (HL) activity (P < .01), and 40% lower phospholipid transfer protein (PLTP) activity (P < .01), as compared with nonsmokers. The plasma cholesteryl ester transfer protein (CETP) mass was 17% higher in smokers as compared with controls (P < .05), but the endogenous CETP activity corrected for plasma triglycerides (TG) was in fact 57% lower in smokers than in controls (P < .01). Lipid transfer inhibitor protein activity was also similar in both groups. In conclusion, the habit of smoking induces a severe impairment of many steps of the RCT system even in the absence of overt dyslipidemia. Such an adverse effect might favor the atherogenicity of smoking.