Sara Raselli

Carotid Artery Intima-media Thickness in Nonalcoholic Fatty Liver Disease

PURPOSE To evaluate, in patients with nonalcoholic fatty liver disease with no or mild alterations of liver function tests, carotid artery intima-media thickness and the presence of plaques and to define determinants of vascular damage. METHODS A paired-sample case-control study: 125 patients with nonalcoholic fatty liver disease and 250 controls, without a prior diagnosis of diabetes, hypertension, and cardiovascular disease, matched for sex, age, and body mass index. B-mode ultrasound was used for evaluation of carotid intima-media thickness and presence of small plaques. RESULTS A significant difference in mean values of intima-media thickness (0.89+/-0.26 and 0.64+/-0.14 mm, P = .0001) and prevalence of plaques (26 [21%] and 15 [6%], P < .001) was observed in nonalcoholic fatty liver disease patients and controls. Variables significantly associated with intima-media thickness higher than 0.64 mm (median value in controls), in both patients and controls were: age (P = .0001), systolic blood pressure (P = .004), total and low-density lipoprotein cholesterol (P < or = .02 and P = .01, respectively), fasting glucose (P = .0001), and cardiovascular risk (P = .0001) and, only in controls, metabolic syndrome (P = .0001), HOMA-insulin resistance (P = .01), and body mass index (P = .0003). At multivariate logistic regression performed in the overall series of subjects, independent risk predictors of intima-media thickness higher than 0.64 mm were presence of steatosis (odds ratio [OR] = 6.9), age (OR 6.0), and systolic blood pressure (OR 2.3). CONCLUSION Patients with nonalcoholic fatty liver disease, even with no or mild alterations of liver tests, should be considered at high risk for cardiovascular complications.

Leptin:Adiponectin Ratio Is an Independent Predictor of Intima Media Thickness of the Common Carotid Artery

Background and Purpose— The evaluation of the leptin:adiponectin ratio (L:A) has been suggested as an atherosclerotic index in patients with type 2 diabetes and a useful parameter to assess insulin resistance in patients with and without diabetes. Methods— We investigated, therefore, the relationship between L:A ratio and intima media thickness (IMT), an independent predictor of cardiovascular disease, in 110 healthy males. Results— L:A ratio was significantly correlated to body mass index, waist, hip, waist-to-hip ratio, systolic blood pressure, IMT, high-density lipoprotein, apolipoprotein A-I, glucose, and the homeostasis model of insulin resistance–revised. No significant correlation was observed with age, diastolic blood pressure, low-density lipoprotein, triglycerides, apolipoprotein B, ApoB/ApoA-I ratio, insulin, alanine transaminase, &ggr;-glutamyl-transferase, and resistin. In addition, when the relationship between IMT and adiponectin or leptin alone was analyzed, only leptin plasma levels significantly associated with IMT (r=0.301, P<0.01). In a multiple regression analysis including in the statistical model the risk factors known to affect IMT (age, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, triglycerides, total cholesterol, body mass index, glucose, and L:A ratio), we observed that only age, L:A, and glucose were independent predictors of IMT. As expected, obese subjects (body mass index >30 kg/m2) showed a significantly higher L:A ratio compared with nonobese subjects (1.20 versus 0.42, respectively, P<0.001); in addition, subjects with the metabolic syndrome showed a significantly higher L:A ratio level (0.79) compared with subjects without (0.52) (P<0.01). Conclusions— We show here that the L:A ratio is a powerful independent predictor of IMT in healthy subjects and correlates with several anthropometric, metabolic, and clinical parameters better than each single adipokine.

Circulating soluble receptor for advanced glycation end products is inversely associated with body mass index and waist/hip ratio in the general population

Advanced glycation end products, AGEs, and its specific receptor, RAGE, are involved in vascular complications. A role for the soluble form of RAGE (sRAGE), which acts as a decoy for AGE, has been documented in patients with diabetes but no information is available in non-diabetic subjects. The aim of this study was to investigate the association of plasma levels of sRAGE with cardiometabolic risk factors in the general population. In addition we evaluated the relation of the common -374A/T polymorphism of RAGE with plasma levels of sRAGE. One hundred and seventy-six healthy subjects free of diabetes or coronary artery disease untreated for hypertension, dyslipidemia or cardiometabolic related diseases were randomly selected for this study from the general population. Plasma sRAGE were negatively and significantly correlated with BMI, waist/hip circumference ratio and fasting glycemia, while a positive correlation was observed with apolipoprotein A-I. These correlations were observed mainly in women who showed significantly higher sRAGE levels (1744+/-660 pg/mL vs 1414+/-649 pg/mL; P<0.05). In a stepwise regression analysis waist circumference was independently associated with sRAGE and, when waist circumference was excluded, BMI was independently associated with sRAGE. Finally in overweight subjects (BMI>25 kg/m(2)) plasma sRAGE was significantly lower compared to lean subjects (1460+/-640 pg/mL vs 1710+/-693 pg/mL; P<0.05). In healthy subjects plasma levels of sRAGE were negatively correlated with BMI and waist/hip ratio supporting a possible protective role for these proteins before any evidence of diabetic or vascular complications.

Small dense LDL and VLDL predict common carotid artery IMT and elicit an inflammatory response in peripheral blood mononuclear and endothelial cells

OBJECTIVE The presence of small dense LDL has been associated with increased cardiovascular risk and with the progression of coronary and carotid atherosclerosis in case-control and prospective studies. The aim of this study was to investigate the relation between different lipoprotein subfractions with intima-media thickness of the common carotid artery in a free-living, healthy population, and to evaluate whether in patients with comparable LDL-C, the different lipoprotein subclasses differently affected the expression of chemokines, cytokines and adhesion molecules in peripheral blood mononuclear and endothelial cells. METHODS AND RESULTS The lipoprotein cholesterol profile and the LDL buoyancy (LDL-RF) were evaluated in a cohort of 156 healthy subjects randomly selected from the PLIC (Progressione Lesione Intimale Carotidea) study. The LDL-RF was directly and significantly correlated to weight, body mass index, waist, hip, waist/hip ratio, triglycerides, fasting glycemia and intima media thickness (IMT) of the common carotid artery and inversely related to HDL-C. After multivariate statistical analysis, IMT was independently associated with age, LDL-RF and HDL-C and among the lipoprotein subclasses, only those corresponding to triglyceride-rich lipoproteins (TGRL) and small dense LDL (sdLDL) independently predicted IMT variance. Peripheral blood mononuclear cells (PBMC) isolated from patients with the predominance of sdLDL (pattern B) had an increased mRNA expression of pro-inflammatory molecules compared to PBMC from patients with the predominance of large LDL (pattern A); in endothelial cells TGRL from pattern B subjects and much less those from pattern A induced the expression of pro-inflammatory genes while sdLDL from either pattern A or B subjects were less effective and showed comparable effects. CONCLUSION LDL-relative flotation rate significantly correlates with several cardiometabolic parameters. Furthermore cholesterol levels lipoprotein subfractions within the TGRL and sdLDL density range are independent predictors of IMT variance and are associated with a pro-inflammatory activation of PBMC and endothelial cells.

Effects of Fractalkine Receptor Variants on Common Carotid Artery Intima-Media Thickness

Background and Purpose— Fractalkine receptor (CX3CR1) plays a key role during atherogenesis. CX3CR1 has 2 common coding polymorphisms, namely V249I and T280M, that have been associated with interindividual differences in susceptibility to atherosclerosis. In the present study, we investigated the possible association between CX3CR1variants and intima-media thickness (IMT). Methods— We genotyped 1256 samples from the Progression of Lesions in the Intima of the Carotid (PLIC) study (a prospective population-based study) for the presence of the V249 and the M280 variants of CX3CR1. Results— Significantly reduced IMT was observed in subjects with the MM280 genotype (0.57±0.12 mm) compared with subjects with the TT (0.65±0.14 mm) or the TM (0.65±0.13 mm) genotype. No difference in IMT was observed within carrier of the II249, VI249, or VV249 genotype. Subjects with combined genotype VI249/MM280 and II249/MM280 showed a reduced IMT. Conclusions— The presence of the M280 polymorphism of the fractalkine receptor is associated with a decreased common carotid artery IMT, whereas the presence of the I249 polymorphism does not play a major role on the progression of carotid atherosclerosis.

Role of Vitamin E-Coated Membrane in Reducing Advanced Glycation End Products in Hemodialysis Patients: A Pilot Study

Introduction: Advanced glycation end products (AGEs) are markers of oxidative stress. Aims: To assess if a vitamin-E-coated dialyzer affects plasma AGE levels and endothelial function in hemodialysis patients. Methods: 16 patients were dialyzed with a synthetic modified cellulose membrane (SMC, n = 8) or a vitamin E-coated dialyzer (n = 8), respectively. At week 32 endothelial function was determined as brachial artery flow-mediated dilatation (FMD). Total AGEs, free pentosidine (FP), protein-bound pentosidine (BP) and autoantibodies against oxidized LDL (ox-LDL-autoantibodies) were assessed at baseline (T0) and at 16, 32, 40 and 42 weeks (T16, T32, T40 and T42). Results: At T16 and T32 FP and BP were lower in vitamin E than in SMC (T 16: 88.7 ± 8.96 vs. 124.2 ± 11.90 pmol/ml plasma; p = 0.04, and 22.9 ± 2.99 vs. 32.8 ± 2.98 pmol/mg proteins; p = 0.04. T32: 78.7 ± 8.54 vs. 123.7 ± 10.15 pmol/ml plasma; p = 0.007, and 19.9 ± 2.0 vs. 33.67 ± 2.41 pmol/mg proteins; p = 0.001). In vitamin E, AGEs were lower at T32, T40 and T42 (946.7 ± 80.91 vs. 1,351.2 ± 179.33 AU/ml, p = 0.05; 986.9 ± 59.63 vs. 1,509.9 ± 154.17 AU/ml, p = 0.013; 890.3 ± 73.70 vs. 1,453.9 ± 153.16 AU/ml, p = 0.009). At T32 AGEs, ox-LDL autoantibodies and FMD were inversely correlated (R = –0.70 p = 0.007 and R = –0.59, p = 0.04, respectively). Conclusions: Vit E-coated membrane reduces plasma AGEs levels and AGEs values are negatively correlated with FMD.

Plasma adiponectin levels in chronic kidney disease patients: Relation with molecular inflammatory profile and metabolic status

BACKGROUND AND AIM Adiponectin (ADPN) exerts anti-inflammatory and cardio protective effects and is associated with decreased cardiovascular risk, however its role in patients with chronic kidney disease is unclear. METHODS AND RESULTS We investigated the correlation between plasma ADPN levels, the progression of CVD and CKD and the inflammatory gene expression profile of peripheral blood mononuclear cells in patients from the NephroPLIC study (a prospective study aimed at addressing the progression of cardiovascular damage in relation to kidney dysfunction). Plasma ADPN levels were directly correlated with age, HDL-C and creatinine, and inversely with BMI, triglycerides and glomerular filtration rate (GFR). Multiple regression analysis identified plasma creatinine and HDL as the independent factors associated with ADPN plasma levels. In peripheral blood mononuclear cells (PBMC), the mRNA expression of MCP-1, CD40, Cox-2, TLR4, PAI-1, TNF alpha, resistin and RAGE was up-regulated in the group with higher GFR and higher ADPN plasma levels compared to that with low GFR and ADPN plasma levels. Patients with similar GFR values showed no differences in the gene expression profile of PBMC although ADPN levels were associated with decreased CRP and IL-6 plasma levels and decreased IMT and heart left ventricular mass. CONCLUSION In CKD patients who are not in dialysis ADPN plasma levels are associated with a reduced renal excretory function, but correlate inversely with the determinants of the metabolic syndrome such as glucose, triglycerides and BMI, and directly with HDL. Furthermore, in patients with a similar degree of renal impairment, ADPN plasma levels are associated with a better cardiometabolic profile, despite no significant difference being observed in the gene expression pattern of PBMC.

HDL and endothelial function: from molecular mechanisms to clinical observations

In addition to their role in reverse cholesterol transport, high-density lipoprotein (HDL) exerts several beneficial effects, including the prevention and correction of endothelial dysfunction. HDL promotes proliferation of the endothelium and decreases endothelial apoptosis; it plays a key role in vasorelaxation by increasing the release of nitric oxide and prostacyclin through inducing the expression and activity of endothelial nitric oxide synthase and the coupling of cyclo-oxygenase 2 and prostacyclin synthase. In addition, HDL affects coagulation, fibrynolisis, platelet adhesion, expression of adhesion molecules and protease, and exerts anti-oxidant activity. These effects are achieved at the gene expression level and are dependent upon the activation of several intracellular signaling pathways, including PI3 kinase/Akt, extracellular signal-related kinase 1/2, protein kinase C (PKC) and p38 mitogen-activated protein kinase. The complexity of the signaling pathways modulated by HDL reflects the diffe...