Gender differences in short-term effects of atorvastatin on lipid profile, fibrinolytic parameters, and endothelial function

Background and aimLittle is known about the impact of gender on short-term effects of atorvastatin. We investigated the gender differences in the short-term lipid-lowering and pleiotropic effects of atorvastatin therapy.Methods and resultsSeventy-two consecutive patients including 48 women with primary hypercholesterolemia, were assigned prospectively to treatment with atorvastatin (10 mg/day) for 3 months. We measured fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS) as marker of lipid peroxide, fibrinolytic parameters, and endothelial function by flow-mediated vasodilation of the brachial artery (FMD), at baseline and after 3 months of therapy. We assessed the impact of gender on temporal differences in these parameters.In men, atorvastatin decreased total, low-density lipoprotein (LDL), and small, dense LDL-cholesterol concentrations, and increased FMD after 3 months. In women, atorvastatin decreased TBARS, triglyceride, and total, LDL, small, dense LDL, and remnant-like lipoprotein particle-cholesterol concentrations, and increased FMD after 3 months. Fibrinolytic parameters did not change significantly in either men or women. With respect to the percent change in those parameters after 3 months, TBARS (−17.6 ± 12.4 vs. −0.4 ± 18.8%, p < 0.01) and small, dense LDL-cholesterol (−96.7 ± 8.3 vs. −68.6 ± 29.7%, p < 0.01) decreased to a greater degree in women, although the relative changes in other parameters were similar between men and women.ConclusionsWe found gender differences in some of the lipid altering changes, including TBARS and small, dense LDL-cholesterol concentrations, after short-term atorvastatin therapy, which were greater in women. However, short-term atorvastatin therapy may be beneficial in improving endothelial function equally in both men and women.     

Effects of fenofibrate therapy on circulating adipocytokines in patients with primary hypertriglyceridemia

BackgroundWe investigated effects of fenofibrate therapy on endothelial dysfunction and adipocytokine profiles.MethodsA randomized, single-blind, placebo-controlled, cross-over study was conducted in 53 patients with primary hypertriglyceridemia. We administered placebo or fenofibrate 160 mg daily for 8 weeks.ResultsWhen compared with placebo, fenofibrate therapy substantially lowered plasma levels of TNF-α by 6 ± 3% (P = 0.014) and hsCRP from 1.10 to 0.90 mg/l (P = 0.004). When compared with placebo, fenofibrate therapy increased plasma levels of adiponectin by 17 ± 4% (P = 0.001), insulin sensitivity by 4 ± 1% (as assessed by QUICKI, P = 0.009), and decreased plasma levels of leptin and resistin by 4 ± 7% (P = 0.022) and 10 ± 3% (P = 0.001), respectively. There were correlations between percent changes in QUICKI and percent changes in adiponectin levels (r = 0.279, P = 0.043) or leptin (r = ?0.280, P = 0.042).ConclusionsFenofibrate therapy significantly reduced pro-inflammatory biomarkers and improved adipocytokines levels and insulin sensitivity in hypertriglyceridemic patients.     

Decreased heparin cofactor II activity is associated with impaired endothelial function determined by brachial ultrasonography and predicts cardiovascular events

BackgroundHeparin cofactor II (HCII) could inactivate thrombin after binding to dermatan sulfate at injured arterial walls, and has been shown to be a novel and independent antiatherosclerotic factor. However, the relation between plasma HCII activity and peripheral vascular endothelial function remains unclear.MethodsA total of 199 patients (mean age, 63 ± 14 years) were enrolled and followed up for a median period of 24 months. Endothelial function was assessed using brachial ultrasonography to determine endothelium dependent flow-mediated vasodilation (FMD). Cox regression analyses were conducted for the 199 subjects, with cardiovascular events being defined as myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), ischemic stroke, and peripheral artery revascularization.ResultsA total of 31 patients (16%) had cardiovascular events. Patients with cardiovascular events had significantly lower HCII activity (112 ± 34 versus 127 ± 34%, p = 0.027) and lower antithrombin III (ATIII) activity (82 ± 12 versus 88 ± 13%, p = 0.014) than those without events. By multivariate analysis, age (p = 0.012), hsCRP (p = 0.020) and HCII activity (p = 0.035) were correlated with FMD. Kaplan-Meier analysis was performed and showed plasma HCII (p = 0.036) and ATIII activities (p = 0.005) were predictors of cardiovascular events. By Cox regression analysis, plasma HCII activity (p = 0.026) could be an independent predictor of future cardiovascular events, but not ATIII.ConclusionsThe present study demonstrates that plasma HCII activity is positively correlated with endothelial vasodilator function. Furthermore, plasma HCII activity could be a predictor of future cardiovascular events in patients with suspected coronary artery disease, suggesting its role in atherosclerosis.     

Effects of fenofibrate on plasma oxidized LDL and 8-isoprostane in a sub-cohort of GOLDN participants

BackgroundFenofibrate significantly reduces circulating triglyceride (TG) concentrations, particularly in individuals with elevated levels. The purpose of the current study was to determine whether fenofibrate treatment reduces markers of oxidative stress, oxidized low density lipoprotein (ox-LDL) and 8-isoprostane (8-isoP), in a manner similar to TG where those with the highest levels show the greatest reductions.Materials/methodsThe concentrations of TG, 8-isoP, and ox-LDL were measured in plasma before and after 3 weeks of fenofibrate treatment (160 mg/d) in a sub-cohort (n = 187) of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study.ResultsData were divided into tertiles as determined by pre-treatment values of the respective target. Fenofibrate treatment resulted in significant reductions in TG concentrations by 24.2% (p < 0.0001), 41.9% (p < 0.0001), and 46.6% (p < 0.0001) in tertiles 1, 2, and 3, respectively. Significant reductions were also observed in ox-LDL of 7.2% (p = 0.0096), 8.5% (p = 0.0019) and 12.1% (p < 0.0001) in tertiles 1, 2, and 3, respectively. Finally, fenofibrate treatment resulted in a 32.7% increase (p = 0.0201) in 8-isoP levels in tertile 1, but a significant decrease of 34.4% (p < 0.0001) in tertile 3.ConclusionsThis study is the largest to date to demonstrate that fenofibrate reduces oxidative stress and the first to show a suppressive effect on 8-isoP levels in individuals with a high oxidative burden following short term (3 wk) drug therapy. Those with the highest baseline levels of ox-LDL and 8-isoP showed the greatest reductions following fenofibrate treatment. Given the role of oxidative stress in atherosclerosis and coronary heart disease, our observations may partially explain the efficacy of fenofibrate in reducing cardiovascular events in select patients.     

Significant differential effects of omega-3 fatty acids and fenofibrate in patients with hypertriglyceridemia

BackgroundOmega-3 fatty acids and fenofibrate are both used to treat patients with hypertriglyceridemia. However, a head-to-head comparison of the lipoprotein and metabolic effects of these two medicines has not been published.MethodsThis was a randomized, single-blind, placebo-controlled, parallel study. Age, sex, and body mass index were matched among groups. All patients were recommended to maintain a low fat diet. Fifty patients in each group were given placebo, omega-3 fatty acids 2 g (most commonly used dosage in Korean patients), or fenofibrate 160 mg, respectively daily for 2 months.ResultsOmega-3 fatty acids therapy decreased triglycerides by 21% and triglycerides/HDL cholesterol and improved flow-mediated dilation (P < 0.01), however, did not significantly change insulin, plasma adiponectin levels, and insulin sensitivity (determined by QUICKI) relative to baseline measurements. Fenofibrate therapy decreased total cholesterol, triglycerides by 29%, and triglycerides/HDL-cholesterol (all P < 0.01) and improved flow-mediated dilation when compared with baseline. When compared with placebo and omega-3 fatty acids, fenofibrate therapy decreased non-HDL cholesterol (P < 0.001) and triglycerides/HDL cholesterol (P = 0.016) while increasing HDL cholesterol (P < 0.001) and apolipoprotein AI (P = 0.001). Of note, when compared with omega-3 fatty acids, fenofibrate therapy decreased fasting insulin (P = 0.023) and increased plasma adiponectin (P = 0.002) and insulin sensitivity (P = 0.015).ConclusionsOmega-3 fatty acids and fenofibrate therapy promoted similar changes in triglycerides and endothelium-dependent dilation. However, fenofibrate therapy had substantially better effects on lipoprotein and metabolic profiles in patients with hypertriglyceridemia.     

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.     

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.     

Endothelial function and arterial stiffness in normotensive normoglycemic first-degree relatives of diabetic patients are independent of the metabolic syndrome

Background and aimThe aim of the present study was to investigate endothelial function and arterial stiffness in normotensive normoglycemic first-degree relatives (offspring) of diabetic subjects and to explore the relationship with the metabolic syndrome and its components.Methods and resultsForty-five healthy normotensive normoglycemic subjects (aged 18–42 years), 29 first-degree relatives of diabetic subjects (FDR) and 16 with no parental history of type 2 diabetes mellitus were studied. Endothelial function was measured as flow-mediated dilation of the brachial artery (FMD) and arterial stiffness as carotid-femoral pulse wave velocity (PWV). Insulin resistance was calculated by homeostasis model assessment (HOMA). Plasma levels of inflammation markers (hsCRP, TNF-α, IL-1β, CD40L, VCAM, and ICAM) were evaluated.Normotensive normoglycemic FDR presented a 33% lower flow-mediated dilation than the control group (9.8 ± 5.2 vs. 16.2 ± 7.6%, p < 0.01). FMD was reduced in FDR, with or without insulin resistance, whereas arterial stiffness was significantly increased only in FDR with insulin resistance. To investigate the role of FDR status independently of altered components of the metabolic syndrome, subjects with no altered components of the metabolic syndrome were compared according to their FDR status: FDR subjects with no altered components of the metabolic syndrome presented a blunted endothelial function (lower FMD: 11.2 ± 1.6 vs. 16.8 ± 2.0%, p < 0.05) and stiffer large arteries (higher PWV: 9.6 ± 0.3 vs. 8.8 ± 0.3 m/s, p < 0.05) than controls.ConclusionNormoglycemic first-degree relatives of diabetic subjects have blunted endothelial function and increased stiffness of the large arteries. These alterations are already present at a very young age, before any alteration in glycemic control or blood pressure values can be detected, and are independent of the presence of the metabolic syndrome and its altered components.     

Association of asymptomatic hyperuricemia and endothelial dysfunction in psoriatic arthritis

IntroductionCardiovascular disease is an increasingly recognized contributor to excess morbidity and mortality in psoriatic arthritis (PsA). Traditional cardiovascular risk factors do not adequately account for the extent of cardiovascular disease in PsA.Aim of the workTo examine the prevalence of subclinical atherosclerosis in patients with PsA to emphasize the potential role of serum uric acid on endothelial dysfunction, as an early predictor for atherosclerosis in PsA patients.Patients and methodsThis study included 60 PsA patients as well as 60 age and sex matched healthy controls. Assay of serum uric acid, interleukin-6 (IL-6) and soluble intercellular adhesion molecule-1 (sICAM-1) was done for all patients and controls. Patients were subjected to psoriasis area severity index (PASI) and assessment of disease activity. Patients and controls underwent brachial flow-mediated dilatation (FMD) assessment by color duplex sonography to determine endothelial dysfunction as well as extracranial carotid arteries assessment by high-resolution B-mode ultrasound to measure the common carotid intima-media thickness (CIMT) and the detection of atheromatous plaques.ResultsPsA patients have a high significant difference in CIMT, FMD of the brachial artery and mean levels of serum uric acid compared to healthy controls (p < 0.001). PsA patients with hyperuricemia have a high significant difference in CIMT and FMD of the brachial artery than those with normal serum uric acid. Serum uric acid levels showed a high significant positive correlation with each of CIMT, disease duration, markers of inflammation (ESR, CRP, IL-6, sICAM-1), disease activity score in 28 joints (DAS 28) and PASI (r = 0.71, 0.893, 0.956, 0.858, 0.853, 0.877, 0.907, 0.847, respectively, as p < 0.001). A high significant negative correlation was found between serum uric acid levels and FMD of the brachial artery as r = ?0.634, p < 0.001.ConclusionPatients with PsA have a high prevalence of subclinical atherosclerosis dependent on serum uric acid, suggesting that chronic systemic inflammation and endothelial dysfunction appear to be the link between asymptomatic hyperuricemia and atherosclerosis. Therefore, proper control of serum uric acid may play a preventive role in the development of atherosclerosis in PsA patients.     

Olive, soybean and palm oils intake have a similar acute detrimental effect over the endothelial function in healthy young subjects

Background and aimCurrently, more than 30% of the caloric intake in the Colombian population comes from vegetable oil consumption mainly by the ingestion of deep-fried foods. Recently, it has been reported that unsaturated fatty acid rich oils have a beneficial effect on the endothelial function. Nevertheless, it is well know that the deep-frying process alters the chemical composition of vegetable oils and can produce adverse effects in the endothelial function.ObjectiveTo evaluate the acute effect of the ingestion of large amounts of olive, soybean and palm oils, fresh and at two different deep-fry levels, on the glucose and lipid profiles and the endothelial function.Methods and resultsTen healthy young volunteers were included in the study. After performing a baseline evaluation of cardiovascular risk factors and drawing a fasting blood sample, subjects were exposed to a randomly assigned potato soup meal containing 60 mL of one of three different vegetable oils (olive, soybean and palm), either fresh or at one of two different deep-fry levels (10 and 20 fries, respectively). Flow-mediated vasodilation (FMD) was performed in fasting conditions and 3 h after the intake of the oil rich meal. Furthermore, blood samples were taken at these stages for the lipid profiles and plasma glucose determinations. All the meals resulted in a similar acute endothelial impairment (FMD decrease of 32.1%, confidence interval [CI] 95%, 28.0–36.2) and postprandial increase in triglycerides (27.03%, CI 95%, 20.5–33.3), independently of the type of oil ingested (p = 0.44) and regardless of its deep-fry level (p = 0.62). No correlation was found between endothelial impairment and postprandial triglyceride increment (r = −0.22, p = 0.09).ConclusionsNo difference was found in the acute adverse effect of the ingestion of different vegetable oils on the endothelial function. All the vegetable oils, fresh and deep-fried, produced an increase in the triglyceride plasma levels in healthy subjects.     

Urine α-Glutathione S-transferase, systemic inflammation and arterial function in juvenile type 1 diabetes

BackgroundDespite marked improvement in therapy and monitoring of patients with insulin-dependent (type 1) diabetes, diabetic nephropathy remains a serious complication, with subsequent end-stage renal disease in about 20% of cases.ObjectiveTo investigate in young patients with type 1 diabetes whether urine α-Glutathione S-transferase to creatinine ratio (α-GST:crea) relates to markers of systemic inflammation and subclinical vasculopathy.DesignChildren and adolescents (median age and diabetes duration 14 and 6 years, respectively) with type 1 diabetes screened in a previous study for proximal tubular (urine α-GST:crea ratio) and renal (plasma creatinine, cystatin C glomerular filtration rate (GFR), and timed urine albumin excretion rate (AER)) function were, within the same timeframe, also investigated for vascular (blood pressure, carotid artery intima–media thickness (IMT) and compliance (CAC), brachial artery flow-mediated dilatation (FMD) and plasma cyclic guanosine monophosphate (cGMP) and inflammatory (C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α)) profiles. Exposure to environmental tobacco smoke (ETS) was assessed through questionnaire (n = 67 respondents).ResultsNone of the patients (n = 69) had overt renal insufficiency. AER correlated with age (p = 0.01, r = 0.3), diabetes duration (p = 0.02, r = 0.3), FMD (p = 0.04, r = ? 0.3, n = 52), CAC (p = 0.03, r = ? 0.3, n = 62) and cGMP (p = 0.01, r = ? 0.3, n = 59). α-GST:crea was lower (p = 0.03) in patients than in controls. α-GST:crea appeared to be particularly lower in older patients (p = 0.004, r = ? 0.34 vs age), in those with worse diabetic control (p = 0.03, r = ? 0.26 vs HbA1c), and in those with lower carotid artery elasticity (p = 0.017, r = 0.3 vs CAC). Although ETS had no direct significant impact on α-GST:crea, α-GST:crea correlated with FMD only in patients with ETS (r = 0.5, p = 0.009, n = 13). α-GST:crea showed positive association with TNF-α (p = 0.01, r = 0.3).ConclusionIn children and adolescents with type 1 diabetes, lower levels of urine excretion of α-GST:crea appear to be associated with decreasing elasticity and endothelial vasomotor function of peripheral arteries, especially in patients with ETS. In contrast, higher levels of α-GST:crea are more common in patients with elevated markers of systemic inflammation. Large scale prospective studies are needed to clarify the meaning and mechanisms of this association.     

Endothelium-dependent vasodilation, insulin resistance and the metabolic syndrome in an elderly cohort: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study

BackgroundOnly a few previous studies have investigated endothelium-dependent vasodilation in the metabolic syndrome (MetS). In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, different techniques to assess vasodilation in conduit and resistance arteries were evaluated in relation to the MetS and insulin resistance.MethodsIn this population-based study, 1016 subjects aged 70 were evaluated by the invasive forearm technique with acetylcholine (EDV), brachial artery ultrasound to assess flow-mediated vasodilation (FMD) and pulse wave analysis with a beta-2 receptor agonist challenge, terbutaline.ResultsEDV was lower in subjects with the MetS (NECP/ATP III-criteria, prevalence 23%) compared to those without (p < 0.0001), and declined with increasing number of MetS criteria (p < 0.0001), after adjustment for coronary heart disease, stroke and cardiovascular medication. Also a reduced pulse wave response (p = 0.015), but not FMD (p = 0.64), was seen in those with the MetS. EDV and the pulse wave response, but not FMD, were inversely related to insulin resistance evaluated by the HOMA index. Also endothelium-independent vasodilation (EIDV) induced by intra-brachial infusion of sodium nitroprusside was impaired in subjects with MetS and in insulin resistance.ConclusionsVasodilation evaluated with the invasive forearm technique and pulse wave analysis with a beta-2 agonist, but not FMD, was reduced in elderly subjects with the MetS and was related to insulin resistance. Also EIDV showed the same pattern, suggesting a general deterioration in vasoreactivity mainly in resistance arteries in elderly subjects with the MetS.     

C-reactive protein levels are inversely correlated with the apolipoprotein B-48-containing triglyceride-rich lipoprotein production rate in insulin resistant men

The pro-inflammatory state and elevated plasma levels of post-prandial triglycerides (TG) are associated with increased cardiovascular disease risk. Recent studies suggested that the increase in the production rate of post-prandial lipoproteins observed in patients with insulin resistance (IR) may be caused, at least in part, by the dysregulation of intestinal insulin sensitivity triggered by inflammation.ObjectiveThe objective of the present study was to evaluate the association between IR, plasma C-reactive protein (CRP) levels and the kinetics of TG-rich lipoprotein (TRL) containing apolipoprotein (apo) B-48 in a large sample of insulin sensitive (IS) and IR men.MethodsThe in vivo kinetics of TRL apoB-48 were measured in 151 men following a primed-constant infusion of l-[5,5,5-D₃]leucine. IR subjects (n = 91) were characterized by fasting TG levels ≥ 1.5 mmol/L and an index of homeostasis model assessment of IR (HOMA-IR) ≥ 2.5 or type 2 diabetes, while IS subjects (n = 24) were characterized by an HOMA-IR index < 2.5 and TG levels < 1.5 mmol/L.ResultsIR subjects had higher TRL apoB-48 production rate (+ 202%; P < 0.0001) and CRP levels (+ 51%; P = 0.01) than IS subjects. TRL apoB-48 production rate and CRP levels were inversely correlated in IR subjects (r = − 0.32; P = 0.002). IR subjects with CRP levels above the median (2.20 mg/L) had lower TRL apoB-48 production rate than IR subjects with CRP levels below the median (Δ = − 24%; P < 0.05).ConclusionOur results confirm that IR is associated with increased TRL apoB-48 secretion and suggest that a higher inflammatory status is associated with decreased TRL apoB-48 secretion among IR subjects.     

Effect of omega-3 fatty acids supplementation on endothelial function: a meta-analysis of randomized controlled trials

ObjectiveInverse association was reported between omega-3 fatty acids (FAs) supplementation and the risk of cardiovascular disease. Identifying the effect of omega-3 FAs on endothelial function may contribute to explain the association. We conducted a meta-analysis to assess the effect of omega-3 FAs supplementation on endothelial function, as measured by flow-mediated dilation (FMD) and endothelium-independent vasodilation (EIV).MethodsRandomized placebo-controlled trials (RCTs) were identified from the databases of PubMed, EMBASE and Cochrane library by two investigators and the pooled effects were measured by weighted mean difference (WMD), together with 95% confidence intervals (CIs). Subgroup and meta-regression analyses were used to explore the source of between-study heterogeneity.ResultsTotally 16 eligible studies involving 901 participants were finally included in meta-analysis. Compared with placebo, omega-3 FAs supplementation significantly increased FMD by 2.30% (95% CI: 0.89–3.72%, P = 0.001), at a dose ranging from 0.45 to 4.5 g/d over a median of 56 days. Subgroup analyses suggested that the effect of omega-3 FAs on FMD might be modified by the health status of the participants or the dose of supplementation. Sensitivity analyses indicated that the protective effect of omega-3 on endothelial function was robust. No significant change in EIV was observed after omega-3 FAs supplementation (WMD: 0.57%; 95% CI: ?0.88 to 2.01%; P = 0.442).ConclusionSupplementation of omega-3 fatty acids significantly improves the endothelial function without affecting endothelium-independent dilation.     

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.     

Arterial pulse wave velocity in relation to carotid intima-media thickness, brachial flow-mediated dilation and carotid artery distensibility: the Cardiovascular Risk in Young Finns Study and the Health 2000 Survey

ObjectiveIncreased arterial pulse wave velocity (PWV) is a strong predictor of cardiovascular events and mortality. The data regarding the relationships between PWV and other indices of vascular damage is limited and partly controversial. We conducted the present study to examine PWV in relation to non-invasive measures of early atherosclerosis (brachial flow-mediated dilation [FMD], carotid intima-media thickness [IMT]) and local arterial stiffness (carotid artery distensibility [Cdist]).MethodsThe study population consisted of 1754 young adults (aged 30–45 years, 45.5% males) participating in the Cardiovascular Risk in Young Finns Study (YFS), and of 336 older adults (aged 46–76 years, 43.2% males) participating in the Health 2000 Survey. FMD was measured only in the YFS cohort. FMD, IMT and Cdist were assessed by ultrasound, and PWV was measured using the whole-body impedance cardiography device.ResultsIn young adults, FMD and IMT were not associated with PWV independently of cardiovascular risk factors. Moreover, FMD status was not found to modulate the association between cardiovascular risk factors and PWV. In older adults, PWV and IMT were directly and independently associated (β = 1.233, p = 0.019). In both cohorts, PWV was inversely related with Cdist, and this relation remained significant (p < 0.04) in models adjusted for cardiovascular risk factors.ConclusionsThe current findings suggest that PWV reflects a different aspect of vascular damage than FMD or IMT in young adults, whereas in older adults the information provided by PWV and IMT may be, to some extent, similar as regards subclinical vascular damage. The present observations also suggest that PWV and Cdist represent, at least in part, a similar adverse vascular wall process.     

Circulating level of microparticles and their correlation with arterial elasticity and endothelium-dependent dilation in patients with type 2 diabetes mellitus

ObjectiveThis study was designed to measure the circulating level of microparticles (MP) in patients with type 2 diabetes mellitus versus healthy volunteers and to evaluate their correlation with arterial elasticity and endothelium-dependent dilation.MethodsFlow cytometry was used to measure the circulating levels of MP, including annexinV+MP, platelet-derived microparticles (PMP), leukocyte-derived microparticles (LMP) and endothelial microparticles (EMP), in 63 patients with type 2 diabetes mellitus and 29 healthy volunteers. Brachial ankle pulse wave velocity (baPWV) and endothelium-dependent flow-mediated dilation (FMD) of the brachial artery were also measured.ResultsThe levels of annexinV+MP, PMP, LMP, CD31+/CD42?EMP and CD51+EMP increased significantly in diabetic patients compared with healthy controls (P < 0.001). Correlation analysis showed that HbA_1c was positively correlated to CD31+/CD42?EMP (r_s = 0.337, P = 0.008) and CD51+EMP (r_s = 0.266, P = 0.038). FMD in diabetic patients was significantly lower than that in healthy individuals (P = 0.007). FMD was negatively correlated to CD31+/CD42?EMP (r_s = ?0.441, P = 0.008) and CD51+EMP (r_s = ?0.405, P = 0.016). baPWV level in diabetic patients was significantly higher than that in healthy individuals (P < 0.001). baPWV was positively correlated to CD31+/CD42?EMP (r_s = 0.497, P < 0.001) and CD51+EMP (r_s = 0.428, P = 0.001). Multiple regression analysis indicated that EMP was an independent risk factor of FMD and baPWV.ConclusionsThe circulating level of microparticles increases in patients with type 2 diabetes. The level of endothelial microparticles is closely associated with vascular dysfunction.     

Effect of fenofibrate therapy on paraoxonase1 status in patients with low HDL-C levels

ObjectivesWe evaluated the effect of micro-coated fenofibrate on lipid parameters, high sensitivity C-reactive protein and paraoxonase1 levels in dyslipidemic patients with low high-density lipoproteins levels. In addition, the effects of the paraoxonase1 polymorphisms on lipid and paraoxonase1 responses to fenofibrate therapy were examined.MethodsA total of 61 dyslipidemic patients with low high-density lipoproteins levels were recruited into this study to receive micro-coated fenofibrate (160 mg/day) for 12 weeks. Lipid parameters, C-reactive protein, paraoxonase1 concentration and activity were measured at baseline and after 6 and 12 weeks of fenofibrate treatment. Four polymorphisms in both the coding (L55M and Q192R) and regulatory regions (T-108C and G-909C) of human paraoxonase1 were also quantified.ResultsMicro-coated fenofibrate significantly decreased total cholesterol, triglycerides, non-high-density lipoprotein cholesterol, oxidized low-density lipoprotein and apolipoprotein-B levels after 6 and 12 weeks (all p < 0.001). While high-density lipoprotein and apolipoprotein AI levels were significantly increased by 14.7% and 6.9%, respectively, after 6 weeks and by 17.3% and 7.2%, respectively, after 12 weeks (all p < 0.01). There were no significant differences in the mean of low-density lipoprotein and C-reactive protein after fenofibrate treatment. There were significant increases in paraoxonase1 concentration and activity by 7.7% and 5.7% after 6 weeks and by 14.6% and 10.1% after 12 weeks, respectively (all p < 0.01). After micro-coated fenofibrate therapy, a significantly positive correlation between the change in high-density lipoprotein and the changes in paraoxonase1 concentration and activity was observed (p = 0.001). On the other hand, the changes in paraoxonase1 activity were significantly and negatively correlated with the changes in triglycerides (p = 0.007). The therapeutic response of lipid parameters to micro-coated fenofibrate was independent of paraoxonase1 polymorphisms. However, paraoxonase1 Q192R and T-108C polymorphisms significantly affected the increase in paraoxonase1 activity (the highest increase in 192QQ and ?108TT) and paraoxonase1 concentration (the highest increase in ?108TT).ConclusionLipid-modifying therapy with micro-coated fenofibrate in patients with low high-density lipoprotein levels not only reduced atherogenic lipids (total cholesterol, triglycerides, oxidized low-density lipoprotein and apolipoprotein-B) and increased atheroprotective lipids but also increased paraoxonase1 concentration and activity. Increasing paraoxonase1 levels by fenofibrate may play an important role in decreasing low-density lipoprotein oxidation.     

Inflammation modulates human HDL composition and function in vivo

ObjectivesInflammation may directly impair HDL functions, in particular reverse cholesterol transport (RCT), but limited data support this concept in humans.Methods and resultsWe employed low-dose human endotoxemia to assess the effects of inflammation on HDL and RCT-related parameters in vivo. Endotoxemia induced remodelling of HDL with depletion of pre-β1a HDL particles determined by 2-D gel electrophoresis (?32.2 ± 9.3% at 24 h, p < 0.05) as well as small (?23.0 ± 5.1%, p < 0.01, at 24 h) and medium (?57.6 ± 8.0% at 16 h, p < 0.001) HDL estimated by nuclear magnetic resonance (NMR). This was associated with induction of class II secretory phospholipase A2 (～36 fold increase) and suppression of lecithin:cholesterol acyltransferase activity (?20.8 ± 3.4% at 24 h, p < 0.01) and cholesterol ester transfer protein mass (?22.2 ± 6.8% at 24 h, p < 0.001). The HDL fraction, isolated following endotoxemia, had reduced capacity to efflux cholesterol in vitro from SR-BI and ABCA1, but not ABCG1 transporter cell models.ConclusionsThese data support the concept that “atherogenic-HDL dysfunction” and impaired RCT occur in human inflammatory syndromes, largely independent of changes in plasma HDL-C and ApoA-I levels.     

Increased plasma levels of NGAL, a marker of neutrophil activation, in patients with abdominal aortic aneurysm

ObjectiveNeutrophil gelatinase-associated lipocalin (NGAL) plasma concentrations have been associated with cardiovascular diseases. We aimed to assess the association of NGAL with abdominal aortic aneurysm (AAA).MethodsNGAL concentrations were analyzed by Western blotting in conditioned medium of polymorphonuclear neutrophils (PMNs) from AAA patients (n = 22) and controls (n = 11), and also in aortic biopsies from AAA patients and healthy controls (n = 10). Plasma NGAL concentrations were measured by ELISA in three groups of subjects from France (n = 60), Spain (n = 75) and Australia (n = 100) and associated with AAA presence and growth.ResultsPMNs isolated from AAA patients secreted significantly greater amounts of NGAL than PMNs from controls. Luminal thrombus released large amounts of NGAL compared to abluminal AAA thrombus, AAA wall and healthy aortic media. Plasma NGAL concentrations were significantly higher in patients with AAA than controls from France [115 (78–200) vs. 94 (72–114) ng/ml, p < 0.001]. NGAL plasma concentrations in AAA patients from Spain correlated with other markers of thrombus activity (plasmin–antiplasmin complexes and D-dimer). Furthermore, a positive correlation between plasma NGAL and retrospective AAA growth (rho = 0.4, p = 0.01) was observed, which remained significant after adjusting for other risk factors. Plasma NGAL was only weakly associated with prospective growth in both Spanish and Australian patients.ConclusionsNGAL is released by PMNs and by the luminal part of AAA thrombus. NGAL plasma levels were increased in AAA patients compared with healthy subjects and correlated with retrospective AAA growth. Further studies in larger subjects groups are needed to confirm the association between NGAL and AAA presence and growth.