Effects of the PPAR-δ agonist MBX-8025 on atherogenic dyslipidemia

ObjectiveDetermine the effects of treatment with a selective PPAR-δ agonist ± statin on plasma lipoprotein subfractions in dyslipidemic individuals.MethodsIon mobility analysis was used to measure plasma concentrations of subfractions of the full spectrum of lipoprotein particles in 166 overweight or obese dyslipidemic individuals treated with the PPAR-δ agonist MBX-8025 (50 and 100 mg/d) ± atorvastatin (20 mg/d) in an 8-week randomized parallel arm double blind placebo controlled trial.ResultsMBX-8025 at both doses resulted in reductions of small plus very small LDL particles and increased levels of large LDL, with a concomitant reduction in large VLDL, and an increase in LDL peak diameter. This translated to reversal of the small dense LDL phenotype (LDL pattern B) in ～90% of the participants. Modest increases in HDL particles were confined to the smaller HDL fractions. Atorvastatin monotherapy resulted in reductions in particles across the VLDL–IDL–LDL spectrum, with a significantly smaller reduction in small and very small LDL vs. MBX-8025 100 mg/d (?24.5 ± 5.3% vs. ?47.8 ± 4.9%), and, in combination with MBX-8025, a reversal of the increase in large LDL.ConclusionPPAR-δ and statin therapies have complementary effects in improving lipoprotein subfractions associated with atherogenic dyslipidemia.     

Glycation of LDL in non-diabetic people: Small dense LDL is preferentially glycated both in vivo and in vitro

ObjectiveLDL atherogenicity is frequently attributed to oxidative modification, but glycated LDL, which can participate in many of the cellular processes leading to atherosclerosis, generally circulates at higher concentration even in non-diabetic people. We tested the hypothesis that small-dense LDL, known to be most closely associated with coronary heart disease, undergoes more glycation than other LDL sub-fractions.Methods and resultsThe concentration of glycated apolipoprotein B (apo B) was measured in serum, LDL and its sub-fractions from 44 non-diabetic subjects. By ELISA serum glycated apoB concentration was 3.0 ± 1.1 mg/dl (mean ± S.D.) of which 84.6 ± 13.6% was in LDL. Of the glycated apo B in LDL 67.8 ± 21.9% was in small dense LDL (LDL3; D1.044-1.063 g/ml) whereas only 32.2 ± 21.9% was in more buoyant LDL subfractions (LDL1 and 2; D1.019–1.044 g/ml). The percentage of apo B present in LDL1 and 2 which was glycated was 1.8 ± 1.8% whereas in LDL3 it was 17.4 ± 18.5% (P < 0.001). Furthermore when LDL sub-fractions from non-diabetics (n = 29) were incubated with glucose (30–80 mmol/l) glycation of apo B in the denser LDL3 subfraction was significantly more pronounced than in less dense LDL subfractions.ConclusionSmall-dense LDL is more susceptible to glycation and this may contribute to the atherogenicity of small-dense LDL, even in non-diabetic people.     

Recently postmenopausal women have the same prevalence of subclinical carotid atherosclerosis as age and traditional risk factor matched men

ObjectiveTo compare the prevalence of subclinical atherosclerosis between postmenopausal women and men of similar age early after the onset of menopause.MethodsIn the first part of this cross-sectional study 186 non-diabetic young postmenopausal women (n = 101, menopausal age ≤10 years) and men (n = 85) aged 40–60 years without overt CVD were consecutively recruited from the outpatients clinics of an academic hospital. Subclinical carotid atherosclerosis was assessed by high-resolution ultrasonography. The presence of carotid atherosclerosis was defined as either increased carotid intima-media thickness (IMT > 0.9 mm) and/or the presence of plaques. In the second part, 1:1 matching for age and traditional risk factors (hyperlipidemia, smoking, hypertension and BMI) was performed between men and women of this cohort resulting in a matched sub-sample of 76 subjects.ResultsBy multivariate analysis, gender was not an independent determinant of any measure of carotid atherosclerosis. In the matched sub-sample, carotid IMT and the number of segments with atherosclerosis did not significantly differ between women and men (0.734 ± 0.119 mm and 1.47 ± 1.6 versus 0.717 ± 0.138 mm and 1.47 ± 1.5, p = 0.575 and p = 0.999, respectively). Also, the prevalence of increased IMT (60.5% in both genders), carotid plaques and subclinical atherosclerosis (31.6% and 63.2% versus 28.9% and 65.8%, p = 0.803 and p = 0.811, respectively) was similar between men and women.ConclusionsThe prevalence and severity of carotid atherosclerosis was similar between men and young postmenopausal women matched for traditional risk factors. Whether these women may be better risk stratified irrespective of gender should be further assessed in prospective studies.     

Effects of a low-calorie diet associated with weight loss on lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in healthy obese women

IntroductionPlatelet-activating factor acetylhydrolase (PAF-AH or Lp-PLA₂) is a Ca²⁺-independent phospholipase A₂ primarily associated in plasma with low density lipoproteins (LDL), especially with small dense LDL (sdLDL) particles. Increased plasma Lp-PLA₂ levels have been associated with increased cardiovascular risk in large clinical trials.AimTo assess the effects of weight loss on Lp-PLA₂ activity and to examine the association of Lp-PLA₂ activity changes with the alterations of sdLDL, the primary carrier of Lp-PLA₂ in plasma.MethodsTwenty-eight obese, non-diabetic women participated in a weight reduction program. Anthropometric parameters were assessed and parameters of glucose metabolism, lipid profile, Lp-PLA₂ activity, and LDL phenotype (using a 3% polyacrylamide gel-tube electrophoresis method), were determined at baseline and after 4 months of weight loss.ResultsA 10% diet-induced weight loss resulted in significant improvement in most parameters of lipid and glucose metabolism. Moreover, Lp-PLA₂ activity was significantly reduced (−10.2%, p < 0.01). Mean LDL particle diameter did not change after the weight loss program. The cholesterol levels of very low-density lipoprotein (VLDL) and large-buoyant LDL particles were significantly reduced, but neither the cholesterol levels of sdLDL particles nor the % proportion of the sdLDL-cholesterol over the total LDL-cholesterol were changed after the intervention program. Interestingly, the changes in Lp-PLA₂ activity were correlated with the changes of VLDL-cholesterol (r = 0.39, p < 0.05), but not with the changes of anthropometric or other lipid variables.ConclusionsA low-calorie diet associated with weight loss in obese women resulted in the significant reduction of the plasma levels of Lp-PLA₂, the potentially new predictor for incident atherosclerotic disease.     

Long-term follow-up of participants in a health promotion program for treated hypertensives (ADAPT)

Background and aimsImprovements in a lifestyle modification program for hypertensives were maintained 1 year later. Longer follow-up in such studies is limited; we therefore re-assessed participants after an additional 2 years in which there was no contact with program facilitators.Methods and resultsParticipants randomised to usual care (N = 118) or a 4-month lifestyle program (N = 123) were previously assessed after 4 months and 1 year. After a further 2 years, diet, alcohol intake, physical activity, weight, waist girth, ambulatory blood pressure (BP), blood lipids, glucose and insulin were measured (usual care N = 64; program N = 76). Statistically significant net changes, relative to usual care, included blood cholesterol (−0.2 mmol/L, 95% CI 0.1–0.4); physical activity (53 min/week, 95% CI 15–91); dietary saturated fat (−1.9% energy, 95% CI −0.1 to −3.8); fish (3.2 serves/month, 95% CI 0.7–5.7); vegetables (9.1 serves/month, 95% CI 3.2–15.1); and sweet foods (−6.2 serves/month, 95% CI −1.1 to −11.3). Between-group changes in weight (−0.7 kg, 95% CI −1.8–0.4), BP (systolic 1.4 mmHg, 95% CI −0.7–3.5)/diastolic 1.0 mmHg, 95% CI −0.3–2.4) and Framingham risk (usual care: men 12.1%, women 3.7%; program: men 12.2%; women 3.5%) did not differ significantly.ConclusionContinued reinforcement with long-term follow-up is needed in lifestyle modification programs.     

Plasminogen activator inhitor-1 associates with cardiovascular risk factors in healthy young adults in the Cardiovascular Risk in Young Finns Study

AimsHypofibrinolysis displayed by elevated serum plasminogen activator inhibitor 1 (PAI-1) level has been associated with cardiovascular disease (CVD) and its risk factors such as obesity and insulin resistance. However, no studies have examined associations between PAI-1 and CVD risk factors in healthy subjects. We examined associations between serum PAI-1, ultrasound markers of atherosclerosis and CVD risk factors and whether PAI-1 improves prediction of atherosclerosis over known risk factors in a cohort of asymptomatic adults.MethodsWe analyzed PAI-1 and CVD risk factors and assessed carotid intima-media thickness (cIMT), distensibility (CDist) and the presence of a carotid atherosclerotic plaque and flow-mediated dilation (FMD) ultrasonographically for 2202 adults (993 men and 1,209 women, aged 30–45 years) participating in the ongoing longitudinal cohort study, The Cardiovascular Risk in Young Finns Study. High cIMT was defined as >90th percentile and/or carotid plaque and low CDist and low FMD as <20th percentile.ResultsIn bivariate analyses, PAI-1 correlated directly with cIMT and the risk factors: blood pressure, BMI, waist and hip circumference, alcohol use, total and LDL-cholesterol, triglycerides, glomerular filtration rate, high-sensitivity CRP and glucose (all P < 0.005). PAI-1 was higher in men and increased with age. Inverse correlation was observed with CDist, HDL-cholesterol and adiponectin in both sexes, with testosterone and sex hormone binding globulin in men and with creatinine and oral contraceptive use in women (P < 0.005). Independent direct associations were observed between PAI-1 and waist circumference, serum triglycerides, insulin, alcohol use and age and inverse with serum creatinine, HDL-cholesterol and adiponectin. PAI-1 did not improve estimation of high cIMT, low CDist and low FMD over conventional risk factors (P for difference in area under curve ≥ 0.37).ConclusionPAI-1 was independently associated with several known CVD risk factors, especially obesity markers, in both men and women. However, addition of PAI-1 to known risk factors did not improve cross-sectional prediction of high cIMT, low CDist and low FMD suggesting that PAI-1 is not a clinically important biomarker in early atherosclerosis.     

Tyrosol, the major extra virgin olive oil compound, restored intracellular antioxidant defences in spite of its weak antioxidative effectiveness

Background and aimExtra virgin olive oil has been associated with a reduced incidence of risk factors for coronary heart disease also owing to the presence of antioxidant biophenols. This study compared the protective effects of tyrosol and hydroxytyrosol, two biophenols greatly different in antioxidant power, on J774 A.1-mediated oxidation of LDL.Methods and resultsCell-mediated oxidation of LDL was evaluated by TBARS formation, and relative electrophoretic mobility increase. Redox imbalance was studied by: (i) cytofluorimetric determination of intracellular ROS and GSH, and (ii) evaluation of GSH-related enzyme activities and gene expressions by colorimetric and RT-PCR analyses, respectively. The cellular uptake of the biophenols was evaluated by HPLC. Both biophenols inhibited cell-mediated oxidation of LDL but to a different extent (100% hydroxytyrosol vs 40% tyrosol), and counteracted the impairment of antioxidant cellular defence, i.e., GSH and related enzymes. Tyrosol was effective in inhibiting about 30% of ROS production only at later time-points (12 h for superoxide, 24 h for hydrogen peroxides). Interestingly, both biophenols were effective when added to the cells for 2 h and removed before LDL treatment. This was probably related to cell–biophenol interactions: hydroxytyrosol was rapidly found inside the cells (1.12 ± 0.05 ng/mg cell protein) and disappeared within 18 h, while tyrosol accumulated intracellularly with time (0.68 ± 0.09 vs 1.72 ± 0.13 ng/mg cell protein at minute 5 and hour 18, respectively).ConclusionsIn spite of its weak antioxidant activity, tyrosol was effective in preserving cellular antioxidant defences, probably by intracellular accumulation. These findings give further evidence in favour of olive oil consumption to counteract cardiovascular diseases.     

The implication of obesity on total antioxidant capacity in apparently healthy men and women: the ATTICA study

Background and aimWe evaluated the association of obesity with serum total antioxidant capacity (TAC), in a population-based sample of 3042 adults.Methods and resultsDuring 2001–2002 we randomly enrolled 1514 men (18–87 years old) and 1528 women (18–89 years old), from the Attica area in Greece into the study, and the sample was stratified by the age-sex distribution of the region (census 2001). Among several variables we also measured serum TAC and weight, height, waist and hip circumferences. Waist circumference greater than 102 cm for men and 88 cm for women was considered an indicator of central fat.Methods and resultsMean waist circumference was 98 ± 13 cm in men and 84 ± 22 cm in women (P < 0.001), while mean hip circumference was 106 ± 28 cm in men and 103 ± 13 cm in women (P < 0.001). Central fat prevailed in 53% of men and 45% of women (P < 0.001). Male participants with central fat exhibited 5% lower TAC concentrations compared to leaner individuals (214 ± 35 vs. 226 ± 33 μmol/L, P = 0.04) and female participants with central fat exhibited 7% lower TAC concentrations (256 ± 38 vs. 239 ± 27 μmol/L, P = 0.03). Similarly, obese or overweight male participants had 6% lower TAC concentrations compared to normal weight (217 ± 33 vs. 234 ± 39 μmol/L, P = 0.03) and female obese or overweight participants had 10% lower TAC concentrations (226 ± 32 vs. 250 ± 30 μmol/L, P = 0.02) compared to the others.ConclusionsOur results suggest an inverse relationship between body fat, central adiposity and antioxidant capacity, irrespective of age and various other potential confounders, namely smoking, physical activity, dietary habits, blood pressure, glucose levels, and lipid concentrations.     

The effects of low-dose fluvastatin and valsartan combination on arterial function: a randomized clinical trial

BackgroundAgeing progressively diminishes arterial functions, even in the absence of traditional risk factors. Our aim was to explore whether age-related arterial changes in middle-aged males could be reversed using short-term, low-dose fluvastatin/valsartan combination intervention.MethodsForty apparently healthy, middle-aged males (43.3 ± 5.8 years) were recruited in a double-blind, randomised intervention. Individuals received either 10 mg fluvastatin/20 mg valsartan daily or placebo over 30 days. The brachial artery flow mediated dilation (FMD), pulse wave velocity (PWV) and common carotid artery β-stiffness were assessed at baseline and after 30 days, and again 5–10 months after therapy discontinuation.ResultsArterial function variables significantly improved after 30 days of intervention; FMD improved by 167.7% (P < 0.001), PWV by 10.9% (P < 0.05) and β-stiffness by 18.8% (P < 0.01), whereas no changes were obtained in the placebo group. The favourable outcomes in the intervention group were accompanied by a significant decrease of high sensitivity-C reactive protein levels (1.8-fold; P < 0.05). In contrast, lipids and blood pressure remained unchanged. Surprisingly, the beneficial arterial effects were still present to a substantial degree 7 months after completing intervention (remaining % of initial improvement: FMD 82.1%, PWV 69.5% and β-stiffness 68.5%), but declined substantially after 10 months.ConclusionOur results indicate that age-related arterial changes, at least in middle-aged males, can be reversed. Short-term treatment with a low-dose fluvastatin/valsartan combination resulted in a large and long lasting improvement of arterial function.     

Effects of a phytosterol-enriched dairy product on lipids, sterols and 8-isoprostane in hypercholesterolemic patients: a multicenter Italian study

Background and aimsPlant sterols, added to several food sources, lower serum cholesterol concentrations. Plant sterol-induced cholesterol lowering is paralleled by a mild decrease in plasma levels of the antioxidant β-carotene, the amount of this decrease being considered clinically non-significant. Whether the effect on lipid profile of daily consumption of plant sterol-enriched low-fat fermented milk (FM) is paralleled by a concomitant variation in a reliable marker of the oxidative burden like plasma isoprostane levels is unresolved.Methods and resultsThe effect of plant sterol consumption on plasma lipid and isoprostane levels of hypercholesterolemic patients was evaluated in a multicenter, randomized double blind study. Hypercholesterolemic patients consumed a FM daily for 6 weeks. Subjects were randomized to receive either 1.6 g of plant sterol-enriched FM (n = 60) or control FM product (n = 56). After 6 weeks of plant sterol-enriched FM consumption, LDL cholesterol was reduced from 166.2 ± 2.0 to 147.4 ± 2.8 mg/dL (p = 0.01). A significant reduction was observed for total cholesterol (from 263.5 ± 2.6 to 231.0 ± 3.2 mg/dL, p = 0.01). There was greater LDL cholesterol lowering among hypercholesterolemic patients with higher LDL cholesterol at baseline. We found a reduction of plasma 8-isoprostane in patients taking plant sterol-enriched FM (from 43.07 ± 1.78 to 38.04 ± 1.14 pg/ml, p = 0.018) but not in patients taking the control product (from 42.56 ± 2.12 to 43.19 ± 2.0 pg/ml, p = NS). Campesterol and β-sitosterol levels were not influenced by phytosterol consumption.ConclusionsDaily consumption of low-fat plant sterol dairy product favourably changes lipid profile by reducing LDL-cholesterol, and may also have an anti-oxidative effect through a reduction of plasma isoprostanes.     

Propylthiouracil, independent of its antithyroid effect, produces endothelium-dependent vasodilatation through induction of nitric oxide bioactivity

ObjectivePropylthiouracil (PTU), independent of its antithyroid effect, is recently found to have a potent antiatherosclerotic effect. The aim of this study is to investigate whether PTU has a beneficial effect on endothelial function.Methods and resultsNinety patients with a history of hyperthyroidism receiving either PTU (n = 45) or methimazole (MMI) (n = 45) during the euthyroid status were enrolled in this study. Brachial artery endothelium-dependent (flow-mediated dilatation [FMD]) and endothelium-independent (nitroglycerin-mediated dilatation) responses were assessed by high-resolution ultrasound image. Data for these two groups were compared with those of 41 healthy control subjects. The FMD values were significantly increased in patients maintained on PTU versus those in the MMI and control groups (9.3 ± 4.4%, 3.4 ± 2.5%, and 3.6 ± 3.4%, respectively; P < 0.01). Nitroglycerin-mediated dilatation had no significant difference between the PTU, MMI, and control groups (17.4 ± 7.5%, 15.9 ± 6.1%, and 17.5 ± 6.8%, respectively; P = 0.455). On multivariate analysis, no significant relationship was found between the FMD and thyroid hormone index levels. To further elucidate whether PTU has a direct effect on endothelial function, the effect of PTU on isolated segments of Sprague–Dawley rat aorta was studied. Vasodilatation induced by PTU was endothelium-dependent and could be blocked by pretreatment with nitric oxide (NO) inhibitors. PTU also increased NO formation in aortic segments.ConclusionsThis study demonstrated that PTU produced endothelium-dependent vasodilatation through thyroid-independent and NO-mediated mechanisms that may contribute to its beneficial effect on atherosclerosis.     

Predicting flow-mediated dilation of brachial artery in systemic lupus erythematosus patients by reproducible and operator-independent inflammatory and immunologic markers and development of a novel score

BackgroundEarly detection of endothelial dysfunction in patients with systemic lupus erythematosus (SLE) is important since they show accelerated atherosclerosis and an increased risk of cardiovascular mortality.AimThe aim of the study was to describe the correlation of flow-mediated dilation (FMD) with common inflammatory and immunological markers in patients with SLE. An attempt was made to predict a model of FMD with the help of these markers.Material and methodsThe study included 44 treatment-naive SLE patients as per American College of Rheumatology (ACR) criteria (1982) and 44 age- and sex-matched healthy controls. Each group consists of 42 females and 2 males. FMD of the brachial artery by B-mode ultrasonography was performed in both groups to compare the FMD value. Serum hsCRP, fibrinogen, uric acid, fasting insulin, serum ferritin, total cholesterol, triglyceride, VLDL, LDL, and HDL levels were measured as markers of inflammation in SLE patients to determine whether there was any correlation with FMD.ResultsThere were no significant differences in age and gender between the SLE and control groups. The mean FMD was 16.85 ± 10.64 and 21.89 ± 4.6 among cases and controls, respectively. FMD was significantly less among SLE patients (p = 0.005). The hsCRP, uric acid, fibrinogen, insulin resistance, and ferritin values were found to have significant correlations with FMD values among treatment-naive SLE patients. Multiple linear regression by the ENTER method was used to predict a model of FMD: FMD = 48.252 − 1.565 hsCRP − 0.143 fibrinogen − 0.217 uric acid + 0.001 ferritin + 7.658 IR.ConclusionInflammatory markers of SLE, such as hsCRP, fibrinogen, insulin resistance, and uric acid positively correlate with FMD values. FMD can be predicted from the value of these biochemical parameters.     

Statin therapy prevents expansive remodeling in venous bypass grafts

BackgroundVenous grafts (VG) have high failure rates by 10 years in aortocoronary bypass surgery. We have previously shown that expansive remodeling followed by increased LDL retention are early atherosclerotic changes in experimental VG placed in the arterial circulation. The objective of this study was to determine whether statin therapy prevents these expansive remodeling changes.Methods and resultsReversed jugular vein-to-common carotid artery interposition graft was constructed in 27 cholesterol-fed (0.5%) rabbits. Rabbits were randomized either to control or atorvastatin (5 mg/kg/day) groups, starting two weeks prior to vein graft implantation and continuing until sacrifice at 1 or 12 weeks post-surgery. Ultrasound measurements of arterial luminal cross-sectional area (CSA) were done at day 3 and at 4, 8 and 12 weeks post-surgery. Histomorphometric measurements were performed following sacrifice at 12 weeks. Atorvastatin treatment significantly decreased total plasma cholesterol levels at 4, 8 and 12 weeks (12 weeks: 6.7 ± 4.2 mmol/L versus control 38.7 ± 10.6 mmol/L, p < 0.0002). Atorvastatin significantly reduced expansive remodeling at 4, 8 and 12 weeks (lumen CSA: 44.6 ± 6.6 mm² versus control 77.6 ± 10.7 mm², p < 0.0001). Intimal CSA by histomorphometry was also significantly reduced by atorvastatin at 12 weeks (5.59 ± 2.19 mm² versus control 9.57 ± 2.43 mm², p < 0.01). VG macrophage infiltration, MMP-2 activity and metalloelastase activity were reduced in the atorvastatin treated group.ConclusionAtorvastatin inhibits both expansive remodeling and intimal hyperplasia in arterialized VG, likely through inhibition of macrophage infiltration and reduction of tissue proteolytic activity. The mechanism proposed above may be important for preventing VG atherosclerosis and late VG failure.     

Lipoprotein(a) levels are increased in healthy young subjects with parental history of premature myocardial infarction

Background and aimMost but not all studies in children, adolescents and young adults with a family history of coronary artery disease have reported an increase in lipoprotein(a) (Lp(a)) concentrations. The aim of this study was to assess if healthy children, adolescents and young adults with a parental history of premature myocardial infarction (PHPMI) have increased Lp(a) levels and are at higher risk of elevated (>30 mg/dl) Lp(a) concentrations.Methods and resultsOne hundred fifty healthy children, adolescents and young adults with PHPMI (55% males; age 18 ± 6.7 years) and 150 age- (±1 year) and gender-matched control subjects participated in the study. Concentrations of total plasma cholesterol, low-density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, apolipoprotein (Apo) A-I and B, triglycerides and Lp(a) were determined after fasting for 14 h. Participants with PHPMI had higher concentrations of LDL-cholesterol (107.9 ± 31.1 vs. 99.2 ± 28.7 mg/dl, p = 0.01), Apo B (89.6 ± 26.4 vs. 82.8 ± 20.2 mg/dl, p = 0.011) and Lp(a) (26.7 ± 34.0 vs. 19.2 ± 23.2 mg/dl, p = 0.012) and lower HDL-cholesterol concentrations (47.9 ± 11.3 vs. 50.7 ± 13.9 mg/dl, p = 0.038) than participants without PHPMI. Thirty percent of PHPMI positive subjects had elevated Lp(a) concentrations vs. 16.7% of PHPMI negative subjects (p = 0.009; relative risk 2.14; 95% CI 1.23–3.73). In a conditional logistic regression analysis, Lp(a) concentration was significantly and independently associated with PHPMI.ConclusionsHealthy young subjects with PHPMI have increased Lp(a) levels, a higher risk for elevated Lp(a) concentrations within an unfavourable lipid profile.     

Moderate alcohol consumption and lipoprotein-associated phospholipase A2 activity

Background and aimsTo investigate the effect of moderate alcohol consumption on lipoprotein-associated phospholipase A2 activity, markers of inflammation and oxidative stress and whether these effects are modified by BMI.Methods and resultsEleven lean (BMI: 18.5–25 kg/m²) and 9 overweight (BMI > 27 kg/m²) men participated in a randomized controlled crossover trial. After consuming 3 cans of beer (40 g ethanol) or alcohol-free beer daily during 3 weeks, fasting blood samples were taken. HDL cholesterol increased by 18.2% (p < 0.001) after beer compared to alcohol-free beer, while LDL cholesterol decreased by 7.8% (p = 0.008). Lipoprotein-associated phospholipase A2 activity was not different (p = 0.23) between beer (47.5 ± 0.8) and alcohol-free beer (48.9 ± 0.8). High-sensitive C-reactive protein was unaffected, but urinary isoprostanes tended to increase (p = 0.09) after beer (114.0 ± 6.9) compared to alcohol-free beer (96.9 ± 6.5). An interaction between BMI and treatment (p < 0.05) on liver enzymes was observed, indicating an increase of liver enzymes after moderate alcohol consumption in overweight men only.ConclusionDespite profound effects on HDL and LDL cholesterol, moderate alcohol consumption did not affect lipoprotein-associated phospholipase A2 activity. Liver enzymes increased after alcohol consumption in overweight men only, suggesting a less favorable response to moderate alcohol consumption in overweight people.     

Arterial endothelial function and wall thickness in familial hypercholesterolemia and familial combined hyperlipidemia and the effect of statins. A systematic review and meta-analysis

BackgroundTo evaluate the impact of familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) on arterial properties and the effects of statins.MethodsWe meta-analyzed 51 studies providing data for 4,057 FH patients and 732 FCH patients with random-effects models, meta-regression analysis and publication bias analysis. The main outcomes of interest were (1) brachial artery flow-mediated dilation (FMD), (2) intima-media thickness (IMT), and (3) change of IMT and FMD after treatment with statins.ResultsCompared to normolipidemic controls, FH patients had lower FMD [pooled mean difference (MD): ?5.31%, 95% CI ?7.09 to ?3.53%, P < 0.001] and higher carotid IMT (pooled MD: 0.12 mm, 95% CI 0.09–0.15 mm, P < 0.001) and femoral IMT (pooled MD: 0.35 mm, 95% CI 0.18–0.51 mm, P < 0.001). FCH patients had lower FMD and increased IMT (pooled MD: ?3.60%, 95% CI ?6.69 to ?0.50%, P = 0.023; and 0.06 mm, 95% CI 0.04–0.08 mm, P < 0.001, respectively). Total and LDL-cholesterol was a significant determinant of FMD and carotid IMT in FCH patients and of FMD and femoral IMT in FH patients. In FH patients, statins improved FMD (pooled MD of change: 5.39%, 95% CI 2.86–7.92%, P < 0.001) and decreased carotid IMT (pooled MD of change: ?0.025 mm, 95% CI ?0.042 to ?0.009 mm, P = 0.003). Changes of both FMD and IMT with statins correlated with the duration × treatment intensity product in FH patients (both P < 0.01). Additionally, statins improved FMD in FCH patients (pooled MD of change: 2.06%, 95% CI 0.43–3.69%, P = 0.013). No significant publication bias was detected.ConclusionArterial properties are impaired in subjects with FH or FCH. Statins improve arterial function and structure in FH patients in a treatment intensity-related manner.     

Periodontal care may improve endothelial function

BackgroundPeriodontitis is a chronic, infectious, insidious disease of the tooth-supporting structures that causes a general inflammatory response. The aims of this study were to determine whether periodontitis is associated with endothelial dysfunction leading to cardiovascular events and whether proper management of periodontal disease would improve endothelial function and prevent cardiovascular events in the future.MethodsTwenty-two patients (12 women, 10 men; 40 ± 5 years old) took part in the study. All had severe periodontitis (without systemic disorders) and were all treated conservatively. Thirteen patients returned for a second visit after 3 months of treatment. Endothelial function and periodontal status were evaluated on entry into the study and 3 months following treatment. Ten age-matched, healthy volunteers without periodontal disease served as the control group.ResultsThere was a significant difference between the patient group and the healthy controls: FMD% 4.12 ± 3.96 vs. 16.60 ± 7.86% (p = 0.0000). Periodontitis improved significantly in all 13 patients who completed 3 months of treatment, and their endothelial function improved as well: FMD% 4.12 ± 3.96% vs. 11.12 ± 7.22% (p = 0.007). No difference was found in FID% before and after 3 months of treatment: 20.97 ± 10.66% vs.17.94 ± 6.23% (p = NS).ConclusionsPeriodontitis may be an insidious cause of endothelial dysfunction and cardiovascular events. Treating periodontitis can improve endothelial function and be an important preventive tool for cardiovascular disease.     

Vitamin D deficiency and endothelial dysfunction in non-dialysis chronic kidney disease patients

BackgroundCardiovascular (CV) events are common in patients with chronic kidney disease (CKD) but inadequately explained by traditional risk factors. Vitamin D deficiency is highly prevalent in CKD and has been proposed to be a non-traditional risk factor, but its relationship with vascular function is unknown.Methods and resultsThe aim of this study was to investigate the relationship between vitamin D levels and endothelial function in non-diabetes patients with mild to moderate CKD. Endothelial function was measured non-invasively using brachial artery flow mediated dilation (FMD). 25 hydroxy vitamin D levels were measured using electrochemiluminescence immunoassay.In 50 CKD patients (age 56 ± 11 years, BMI 25 ± 4 kg/m², 46% females, 14% smokers, 86% hypertensives, 52% with dyslipidaemia) the mean vitamin D level was 53 ± 33 nmol/L (21 ± 13 ng/L). The mean FMD was 3.8 ± 2.4%. Decreasing 25 hydroxy vitamin D levels were associated with decreasing FMD [r = 0.44, p = 0.001]. In multivariate analysis the association remained independent after adjustment with traditional risk factors (adjusted beta 0.451; t = 3.46; p < 0.002).Patients with low vitamin D (≤37.5 nmol/L) demonstrated low FMD compared to patients with vitamin D values >37.5 nmol/L (4.4 ± 2.5% vs. 2.5 ± 1.6%; p = 0.007); however the traditional risk factors were similar between the two groups.ConclusionThis is the first demonstration of an association of vitamin D deficiency with abnormal vascular endothelial function in non-dialysis CKD patients. Further studies with intervention and exploration of the mechanism are needed to establish a cause effect relationship.     

Do lipids and apolipoproteins predict coronary heart disease under statin and fibrate therapy in the primary prevention setting in community-dwelling elderly subjects? The 3C Study

PurposeTo evaluate associations of standard lipids and apolipoproteins with incident coronary heart disease (CHD) in older adults according to lipid-lowering treatment (LLT) in the primary prevention setting.MethodsWithin the 3C Study of men and women aged ≥65 years, standard lipids, apolipoproteins A-1 and B100 and hs-CRP were measured in baseline blood samples from 199 participants who developed a first CHD event over 4 years of follow-up and from 1081 subjects randomly selected from the initial cohort (case cohort study). Standardized hazard ratios (HRs) were estimated by the Cox proportional hazard model.ResultsIn the random sample, 75.3% were free of LLT (non-users), 11.5% received statins and 13.4% fibrates. Among the non-users, all lipid parameters were significantly associated with future CHD (n = 145) after adjustment for age, gender, study center and educational level, and their HRs were comparable. For instance, the HR for LDL-cholesterol was 1.38 (95% CI: 1.13–1.69). These associations also existed and were stronger among statin users (n = 27 CHD), as shown by an HR for LDL-cholesterol of 2.20 (95% CI: 1.27–3.81). Additional adjustment for traditional risk factors and hs-CRP marginally modified HR estimates in those receiving or not receiving statins. Among fibrate users (n = 27 CHD), significant associations were observed for triglycerides only (1.68; 95% CI = 1.04–2.72) in fully adjusted analyses.ConclusionIn older adults, standard lipids and apolipoproteins are stronger predictors of CHD in those receiving statins than in those who are not in the primary prevention setting. Under fibrate treatment, only triglycerides were independent predictors of CHD.     

Apolipoprotein B-48 as a determinant of endothelial function in obese subjects with type 2 diabetes mellitus: effect of fenofibrate treatment

ObjectiveElevated triglyceride-rich lipoproteins may contribute to endothelial dysfunction in obese diabetic subjects. We investigated the association between plasma concentrations of chylomicron-related particles and endothelial function, and the corresponding responses to fenofibrate treatment.MethodsPlasma apolipoprotein (apo) B-48 and remnant-like particle (RLP)-cholesterol concentrations were measured in 28 obese subjects with T2DM. Flow-mediated endothelium-dependent dilation (FMD) and glyceryl-trinitrate mediated dilatation (GTNMD) in the brachial artery during reactive hyperaemia were examined by high-resolution ultrasound technique.ResultsIn univariate analysis, plasma apoB-48 and RLP-cholesterol concentrations were inversely associated with brachial artery FMD (r = ?0.425 and ?0.423, respectively, P < 0.05), but not with GTNMD. In regression models including BMI and HOMA score, plasma apoB-48 was an independent predictors (P < 0.05) of brachial artery FMD (β coefficient = ?0.384). Replacing HOMA-IR score with plasma triglyceride, adiponectin or CRP concentrations did not alter the findings. The subjects were then randomized to a 12-week treatment period of either 200 mg micronized fenofibrate or matching placebo. Compared with the placebo group, fenofibrate treatment (200 mg daily for 12 weeks) achieved significant increase in FMD (+34%) and reduction in plasma triglyceride (?42%), apoB-48 (?52%) and RLP-cholesterol (?51%) concentrations. The increase in FMD with fenofibrate was significantly associated with the corresponding decrease in plasma apoB-48 (r = ?0.644, P < 0.02) concentrations.ConclusionsOur findings demonstrate an association between changes in lipid metabolism and improvement in endothelial function in patients with diabetic dyslipidaemia treated with fenofibrate that may involve the effect of apoB-48 on endothelium-dependent vasodilator function.