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BACKGROUND: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.METHODS: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.RESULTS: Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p CONCLUSION: Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis.

Background Adaptive T‐cell response is promoted during atherogenesis and results in the differentiation of naïve CD4 + T cells to effector and/or memory cells of specialized T‐cell subsets. Aim of this work was to investigate the relationship between circulating CD4 + T‐cell subsets and atherosclerosis. Methods and Results We analyzed 57 subsets of circulating CD4 + T cells by 10‐parameter/8‐color polychromatic flow cytometry (markers: CD3/CD4/CD45RO/CD45RA/CCR7/CCR5/CXCR3/HLA‐DR) in peripheral blood from 313 subjects derived from 2 independent cohorts. In the first cohort of subjects from a free‐living population ( n =183), effector memory T cells (T EM : CD3 + CD4 + CD45RA − CD45RO + CCR7 − cells) were strongly related with intima‐media thickness of the common carotid artery, even after adjustment for age ( r =0.27; P EM and low‐density lipoproteins was observed. In the second cohort ( n =130), T EM levels were significantly increased in patients with chronic stable angina or acute myocardial infarction compared with controls. HLA‐DR + T EM were the T EM subpopulation with the strongest association with the atherosclerotic process ( r =0.37; P EM (identified as CD4 + CD44 + CD62L − ) were significantly increased in low‐density lipoprotein receptor and apolipoprotein E deficient mice compared with controls and were correlated with the extent of atherosclerotic lesions in the aortic root ( r =0.56; P Conclusions Circulating T EM cells are associated with increased atherosclerosis and coronary artery disease in humans and in animal models and could represent a key CD4 + T‐cell subset related to the atherosclerotic process. ( J Am Heart Assoc 2012;1:27‐41.)

Introduction: The National Cholesterol Education Program and the American Heart Association considered a dietary therapy as a primary approach to prevent and treat hyperlipemia and hypertension. Mediterranean diet has been promoted as a model of healthy eating and widely recognized for favorable effects on lipid profile. Objective: We investigated whether the adherence to dietary recommendations have any significant benefit on cardiovascular risk factors. A cohort of 2141 of subjects attending our center was recruited by collaborating General Practitioners who participate in the PLIC Study. Methods: Participants completed a week quantitative food questionnaire, which was analized on a subgroup of 338 subjects at enrolment (V1) and after two years of follow up (V2). Daily energy intake in Kcal, lipid, protein, carbohydrates in percentage of total energy, monounsatured (MUFA), saturated (SFA), polyunsaturated fatty acids (PUFA) in g/die, cholesterol in mg/die was calculated from the food questionnaires. Cardiovascular risk (CVR) was estimated according Framingham algorithm. Results: Subjects which adhered to AHA step 1 diet showed a significantly lower total cholesterol, 213.88 ± 43.00 vs 220.19 ± 39.3 mg/dL, LDL-cholesterol, 139.80 ± 76.36 vs 142.75 ± 35.60 mg/dL (p < 0.01 for both) as compared to subjects with an impaired dietary pattern while no differences were observed for HDL cholesterol. Conclusions: Changes in dietary profiles are associated with an improved lipid profile and therefore remain one of the more favorable nutritional models in the primary prevention of cardiovascular disease.

Objective— Regulatory T (Treg) cells play a protective role in experimental atherosclerosis. In the present study, we investigated whether the levels of circulating Treg cells relate to the degree of atherosclerosis in carotid and coronary arteries. Methods and Results— We studied 2 distinct populations: (1) 113 subjects, selected from a free-living population (carotid study), in which we measured the intima-media thickness of the common carotid artery, as a surrogate marker of initial atherosclerosis; and (2) 75 controls and 125 patients with coronary artery disease (coronary study): 36 with chronic stable angina, 50 with non-ST-elevation acute coronary syndrome, 39 with ST-elevation acute myocardial infarction. Treg-cell levels were evaluated by flow cytometry (Treg cells identified as CD3 + CD4 + CD25 high CD127 low ) and by mRNA expression of forkhead box P3 or of Treg-associated cytokine interleukin 10. In the carotid study, no correlation was observed between Treg-cell levels and intima-media thickness. No differences in Treg-cell levels were observed comparing rapid versus slow intima-media thickness progressors from a subgroup of patients (n=65), in which prospective data on 6-year intima-media thickness progression were available. In the coronary group, Treg-cell levels were not altered in chronic stable angina patients. In contrast, nonunivocal variations were observed in patients suffering an acute coronary syndrome (with a Treg-cell increase in ST-elevation acute myocardial infarction and a Treg-cell decrease in non-ST-elevation acute coronary syndrome patients). Conclusion— The results suggest that determination of circulating Treg-cell levels based on flow cytometry or mRNA assessment is not a useful indicator of the extent or severity of atherosclerosis.

Objective Triglyceride-rich lipoproteins (TGRLs) are a cardiovascular risk factor and induce endothelial dysfunction. In the present study, we investigated the effects of post-prandial TGRLs from type IV hyperlipidemic subjects on endothelial activation addressing the effects of the lipoproteins on intracellular pathways and gene expression. Methods Thirty fasted hypertriglyceridemic patients were given an oral fat load (OFL) and blood samples were collected before the OFL (T0) and 2, 4, 6 and 8 h thereafter. Endothelial function, determined as flow-mediated dilatation of the brachial artery, was assessed at the same time points. TGRLs were isolated at T0 and T4 (PP-TGRL) for in vitro studies. Results Compared with TGRLs, PP-TGRLs induced to a larger extent phosphorylation of p38 MAPK, CREB and IKB-α in human endothelial cells and increased the DNA binding activity of CREB, NFAT and NF-κB. Furthermore, PP-TRGLs upregulated the expression of several pro-inflammatory genes including vascular cell adhesion molecule-1 (VCAM-1), PECAM-1, ELAM-1, intercellular adhesion molecule-1 (ICAM-1), P-selectin, MCP-1, interleukin-6 (IL-6), TLR-4, CD40, ADAMTS1 and PAI-1. Conclusion These effects may relate to the severe impairment of endothelial function seen during the post-prandial phase in hypertriglyceridemic patients.

The essential role of the RDI activities in sustaining economic performance and convergence represents a key statement of the revised Lisbon Strategy. These activities are financed and promoted at European level through large Community Programs and Initiatives. Romania’s active participation to these programs represents at the same time a challenge and an opportunity. The challenge is generated by the need to reduce the gap with the developed countries of the EU. Some of the opportunities are: better turning to account of the Romanian scientific and technical potential, better integration into the European Research Area, and not least, more efficient absorption of EU’s research funds The present paper is aimed to highlight ways to intensifying Romania’s participation to the European Research Programs.

Background and aim Non-alcoholic fatty liver disease (NAFLD) is associated not only with liver related morbidity and mortality but also with an increased risk of cardiovascular disease. Aim: to evaluate in patients with NAFLD and in matched Controls after 10 years of follow-up 1 the incidence of major cardiovascular and cerebral events 2 the progression of vascular damage. Methods: Clinical and cardio-metabolic data were collected in 125 NAFLD patients and 250 age and gender matched Controls at baseline and 10 years later. Incidence of cardiovascular and cerebral events was recorded. By ultrasonography, carotid intima-media thickness (cIMT), presence of plaques and presence of fatty liver were evaluated. Results: 25% of the overall series was lost to follow-up. Sixty-eight (37%) Controls developed steatosis. Major cardiovascular events were observed in thirty-five subjects (17/91 (19%) NAFLD and 18/182 (10%) Controls), with an estimated cumulative risk significantly higher in NAFLD than in Controls, log-rank test for equality of failure functions p = 0.007. At multivariate analysis, presence of plaques (hazard ratio 5.08 (95% C.I. 2.56–10.96) and of steatosis (hazard ratio 1.99 (1.01–3.94)) were the strongest predictors for cardiovascular events. Grade of steatosis, ALT and GGT levels were higher in NAFLD patients who developed cardiovascular events. cIMT value after 10 years was significantly higher in NAFLD than in Controls, but the mean progression rate was higher in Controls (0.015 and 0.006 mm/year, p = 0.001). In conclusion our results suggest that NAFLD has to be included among risk factors for cardiovascular damage and underline the utility to evaluate, once NAFLD is diagnosed, the presence of atherosclerotic lesions.

Inducible degrader of the low density lipoprotein receptor (IDOL), is an E3 ubiquitin ligase that negatively modulates low density lipoprotein receptor (LDL-R) expression. Genome-wide association studies (GWAS) indicated that genetic variants in IDOL gene contributes to variation in LDL-C plasma levels and the detailed analysis of a specific locus resulted in the identification of the functional common single nucleotide polymorphism (SNP) rs9370867 (c.G1025A, p.N342S) associates with increased LDL-R degradation and increased LDL-C levels. These findings, however, were not confirmed in two other independent cohorts and no data about the impact of this variant on atherosclerosis progression and cardiovascular risk are available. Aim of this study was to investigate the association between a functional variant in IDOL and atherosclerosis progression in an Italian general population. 1384 subjects enrolled in the PLIC study (Progression of Lesions in the Intima of Carotid) were genotyped by Q-PCR allelic discrimination and the association with anthropometric parameters, plasma lipids and the carotid intima media thickness (cIMT) and the impact on cardiovascular disease (CVD) incidence were investigated. The N342S variant was not associated with changes of the plasma lipid profile among GG, AG or AA carriers, including total cholesterol (249±21, 249±19 and 248±21 mg/dl respectively), LDL-C (158±25, 161±22 and 160±23 mg/dL), cIMT (0.74±0.14, 0.75±0.17 and 0.77±0.15 mm) and CVD incidence. In agreement, the expression of LDLR and the uptake of LDL was similar in macrophages derived from GG and AA carriers. Taken together our findings indicate that the N342S variant does not impact plasma lipid profile and is not associated with atherosclerosis progression and CVD in the general population, suggesting that other variants in the IDOL gene might be functionally linked with cholesterol metabolism.

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.

A recent study conducted by Accenture revealed that 30% of the strategic alliances are considered to be a success. Why are these companies not fulfilling their expectations? Among the subjects debated in this article we can find those referring to integrating in the partner’s value chain, selecting the right partner, choosing the type of alliance best suited, options for developing the alliance and the importance of building trust and dedication in order to become successful.

The objective of this work was to study whether changes in remnant lipoprotein (RLP) plasma levels during the postprandial phase relate to alterations of the endothelial function. Fasted patients (15 moderately dyslipidemic men) were given an oral fat load (OFL), and blood samples were collected before the OFL ingestion (T0) and 2, 4, 6, and 8 h (T2, T4, T6, T8) thereafter. Endothelial function, determined as flow-mediated dilatation (FMD) of the brachial artery, was assessed at the same time points. Triglyceridemia peaked between T4 (5.48 +/- 0.64 mmol/liter) and T6 (5.34 +/- 0.89 mmol/liter) and decreased at 8 h (4.36 +/- 0.87 mmol/liter) after the OFL. FMD decreased significantly 6 h after the OFL consumption (from 16.03 +/- 1.32% to 11.53 +/- 1.42%, P < 0.01). Cholesterol in RLPs increased steadily up to 6 h and decreased at 8 h (T0 0.53 +/- 0.10, T6 0.81 +/- 0.11, T8 0.73 +/- 0.13 mmol/liter). Fasting levels of triglycerides and cholesterol-RLPs (C-RLPs) correlated significantly with FMD at baseline. The decrease in endothelial function at 6 h also significantly correlated with the area under the curve of triglycerides (R = 0.53, P = 0.04). Postprandial C-RLPs (area under the curve), however, showed the best correlation with the decrease of FMD (R = 0.63, P = 0.012). The correlation persisted in a multivariate analysis. We concluded that C-RLPs contribute significantly to the endothelial dysfunction occurring during the postprandial lipemia.

The molecular mechanisms underlying the relationship between elevated plasma concentration of triglyceride-rich lipoproteins and coronary artery disease remain uncertain; evidence is accumulating to suggest that endothelial dysfunction is involved. In the present work, we addressed two major questions: First, we investigated the gene expression pattern and intracellular pathways in human endothelial cells incubated with very low density lipoproteins (VLDL) and oxidative modified VLDL (Ox-VLDL). Second, we investigated whether changes in RLP plasma levels during the postprandial phase relate to alterations of the endothelial function. Results and conclusion: Among 8411 genes spotted on the array, 1620 (19.2%) were expressed under basal condition. VLDL predominantly activated the ERK1/2 pathway while P38 MAPK was the main target of Ox-VLDL, and CREB and NF-KB were activated by both VLDL and Ox-VLDL. VLDL induced MMP-2 and TGF alpha expression. Ox-VLDL was found to induce IL-15 and MIF expression, promote the generation of reactive oxygen species and exert a cytotoxic effect, thus sustaining inflammation and endothelial damage. These findings confirm the involvement of VLDL and Ox-VLDL in endothelial dysfunction and suggest new genes and molecular mechanisms involved in these actions. Moreover, cholesterol in RLPs contributes significantly to the endothelial dysfunction occurring during the postprandial lipemia.

OBJECTIVE Carotid intima-media thickness (CIMT) is a marker of subclinical organ damage and predicts cardiovascular disease (CVD) events in the general population. It has also been associated with vascular risk in people with diabetes. However, the association of CIMT change in repeated examinations with subsequent CVD events is uncertain, and its use as a surrogate end point in clinical trials is controversial. We aimed at determining the relation of CIMT change to CVD events in people with diabetes. RESEARCH DESIGN AND METHODS In a comprehensive meta-analysis of individual participant data, we collated data from 3,902 adults (age 33–92 years) with type 2 diabetes from 21 population-based cohorts. We calculated the hazard ratio (HR) per standard deviation (SD) difference in mean common carotid artery intima-media thickness (CCA-IMT) or in CCA-IMT progression, both calculated from two examinations on average 3.6 years apart, for each cohort, and combined the estimates with random-effects meta-analysis. RESULTS Average mean CCA-IMT ranged from 0.72 to 0.97 mm across cohorts in people with diabetes. The HR of CVD events was 1.22 (95% CI 1.12–1.33) per SD difference in mean CCA-IMT, after adjustment for age, sex, and cardiometabolic risk factors. Average mean CCA-IMT progression in people with diabetes ranged between −0.09 and 0.04 mm/year. The HR per SD difference in mean CCA-IMT progression was 0.99 (0.91–1.08). CONCLUSIONS Despite reproducing the association between CIMT level and vascular risk in subjects with diabetes, we did not find an association between CIMT change and vascular risk. These results do not support the use of CIMT progression as a surrogate end point in clinical trials in people with diabetes.

Objective: Familial hypobetalipoproteinemia (FHBL) is autosomal codominant disorder of lipoprotein metabolism characterized by low plasma levels of total cholesterol (TC), low-density lipoproteincholesterol (LDL-C) and apolipoprotein B (apoB) below the 5 th percentile of the distribution in the population. Patients with the clinical diagnosis of homozygous FHBL (Ho-FHBL) are extremely rare and few patients have been characterized at the molecular level. Here we report the medical history and the molecular characterization of one paediatric patient with clinical features of Ho-FHBL. Methods: A one month old infant with failure to thrive, severe hypocholesterolemia and acanthocytosis was clinically and genetically characterized. Molecular characterization of the proband and her parents was performed by direct sequencing of the APOB gene and functional role of the identified mutations was assessed by the minigene methodology. Results: The proband was found carrying two novel splicing mutations of the APOB gene (c.3696þ1G > C and c.3697-1G > A). CHOK1H8 cells expressing minigenes harbouring the mutations showed that these two mutations were associated with the retention of intron 23 and skipping of exon 24, resulting in two truncated apoB fragments of approximate size of 26e28 % of ApoB-100 and the total absence of apoB. Conclusion: We describe the first case of Ho-FHBL due to two splicing mutations affecting both the donor and the acceptor splice sites of the same intron of the APOB gene occurring in the same patient. The clinical management of the proband is discussed and a review of the clinical and genetic features of the published Ho-FHBL cases is reported.

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, γ-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 30 kg/m 2 ) showed a significantly higher L:A ratio compared with nonobese subjects (1.20 versus 0.42, respectively, P P 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.

BACKGROUND AND AIM: Patients with systemic lupus erythematosus (SLE) have a higher prevalence of subclinical atherosclerosis and higher risk of cardiovascular (CV) events compared to the general population. The relative contribution of CV-, immune- and disease-related risk factors to accelerated atherogenesis in SLE is unclear. METHODS AND RESULTS: Fifty SLE patients with long-lasting disease (mean age 44 ± 10 years, 86% female) and 50 sex- and age-matched control subjects were studied. Common carotid artery intima-media thickness (CCA-IMT) was used as a surrogate marker of atherosclerosis. We evaluated traditional and immune- and disease-related factors, assessed multiple T-cell subsets by 10-parameter-eight-colour polychromatic flow cytometry and addressed the effect of pharmacological therapies on CCA-IMT. In SLE patients, among several cardiometabolic risk factors, only high-density lipoprotein levels (HDL) and their adenosine triphosphate-binding cassette transporter 1 (ABCA-1)-dependent cholesterol efflux capacity were markedly reduced (p

Objective To examine the association between cardiometabolic risk factors and visceral adipose tissue (VAT) measurements using a dual-energy X-ray absorptiometry (DXA) based approach. Design and Methods An analysis of cross-sectional relationships between DXA VAT measured using CoreScan (GE Healthcare) and cardiometabolic indicators was conducted on a sample of 939 subjects (541 females and 398 males; average age, 56 years; average BMI, 26 kg/m2) who had previously undergone a total body DXA scan as well as measurements of key cardiometabolic risk factors. Results Sex-specific, age-adjusted multivariable regression analysis showed that for both men and women, DXA VAT was significantly associated with increased odds of hypertension, impaired fasting glucose, metabolic syndrome, and type 2 diabetes (P < 0.001). After additional model adjustment for BMI and waist circumference, the odds ratio (per SD change in VAT) for type 2 diabetes was 2.07 for women and 2.25 for men. Similarly, the odds ratio for metabolic syndrome for women was 3.46 and for men was 1.75. Conclusions VAT measured using DXA showed a significant association with cardiometabolic risk factors and disease. These relationships persist after statistical adjustment for age, BMI, and waist circumference. DXA VAT may provide a new accessible option for quantifying VAT-related cardiometabolic risk.

Objectives Patients with chronic kidney disease (CKD) often present with reduced plasma HDL cholesterol (HDL-C) levels. Whether this reduction in an epiphenomenon or is involved in disease progression is unclear. The aim of this study was to investigate the relation between HDL-C levels/function and CKD progression in patients with different degrees of disease. Design A total of 176 patients with CKD [glomerular filtration rate (GFR) 50.3 ± 29.1 mL min−1] were recruited and followed for up to 84 months. Lipid profile, metabolic status and kidney function were evaluated at predetermined times. Age-matched control subjects were selected from the PLIC study (n = 453). Scavenger receptor class B member 1 (SR-BI) and ATP-binding cassette transporter A1 (ABCA-1)-dependent efflux of cholesterol were measured in CKD patients and in age-matched control subjects. Results Low HDL-C levels, diabetes and hypertension were associated with reduced GFR. At follow-up, low HDL-C levels were associated with earlier entry in dialysis or doubling of the plasma creatinine level (P = 0.017); HDL-C levels were the only lipid parameter that affected the progression of CKD (hazard ratio 0.951, 95% confidence interval 0.917–0.986, P = 0.007), independently of the presence of diabetes. Only SR-BI-mediated serum cholesterol efflux was significantly reduced in the group of CKD patients with low HDL-C levels compared to the control group. Conclusions CKD patients with low levels of plasma HDL-C have a poor prognosis. HDL functionality is also impaired in renal dysfunction. These data support the relevance of HDL in influencing CKD progression.

Background and Aims Epicardial adipose tissue (EAT) has been proposed as a cardiometabolic and hepatic fibrosis risk factor in patients with non alcoholic fatty liver disease (NAFLD). Aim of this study was to evaluate the role of EAT in NAFLD by analyzing 1) the association between EAT, the other metabolic parameters and the severity of steatosis 2) the relationship between cardiovascular (cIMT, cplaques, E/A), liver (presence of NASH and significant fibrosis) damage and metabolic risk factors including EAT 3) the relationship between EAT and genetic factors strongly influencing liver steatosis. Methods In a cross-sectional study, we considered 512 consecutive patients with NAFLD (confirmed by biopsy in 100). EAT, severity of steatosis, carotid intima-media thickness (cIMT) and plaques were evaluated by ultrasonography and results analysed by multiple linear and logistic regression models. Variables independently associated with EAT (mm) were female gender (p = 0.003), age (p = 0.001), BMI (p = 0.01), diastolic blood pressure (p = 0.009), steatosis grade 2 (p = 0.01) and 3 (p = 0.04), fatty liver index (p = 0.001) and statin use (p = 0.03). Variables independently associated with carotid IMT were age (p = 0.0001), hypertension (p = 0.009), diabetes (p = 0.04), smoking habits (p = 0.04) and fatty liver index (p = 0.02), with carotid plaques age (p = 0.0001), BMI (p = 0.03), EAT (p = 0.02),) and hypertension (p = 0.02), and with E/A age (p = 0.0001), diabetes (p = 0.005), hypertension (p = 0.04) and fatty liver index (p = 0.004). In the 100 patients with available liver histology non alcoholic steatohepatitis (NASH) was independently associated with EAT (p = 0.04) and diabetes (p = 0.054) while significant fibrosis with EAT (p = 0.02), diabetes (p = 0.01) and waist circumference (p = 0.05). No association between EAT and PNPLA3 and TM6SF2 polymorphisms was found. Conclusion In patients with NAFLD, EAT is associated with the severity of liver and vascular damage besides with the known metabolic risk factors.

Background A relationship between systemic inflammation and increased cardiovascular risk is often postulated. Simple and affordable clinical predictors of increased cardiovascular risk in patients with autoimmune disease, however, are not yet available in the clinical practice. Objectives To address the role of clinical, serological markers of disease activity, and of classical cardiovascular risk factors (CVRF) in predicting the carotid intima-media thickness (c-IMT) progression at 5 years (Δc-IMT) in patients with the prototypic autoimmune disease systemic lupus erythematosus (SLE). Methods Clinical and biochemical data including SLEDAI were collected at baseline and at five years of follow up from 50 patients with SLE and 50 age- and gender-matched healthy controls. C-IMT was also measured at baseline and at 5 years to evaluate progression. Results A higher SLEDAI score at baseline correlated with a faster Δc-IMT (0.007 (0.006) mm/year vs 0.003 (0.001) mm/year when compared to controls, P=0.026), irrespectively of the presence of CVRF and of the serological profile. Patients with higher SLEDAI score at baseline also experienced disease flares more frequently (p=0.037) than those with milder disease at baseline. Patients with a higher disease activity during follow up had also a faster Δc-IMT when compared to those with a persistently low disease activity (0.008 (0.004) mm/year vs -0.006 (0.004) mm/year, P=0.021). Elevated LDL-C levels were the only CVRF associated with disease flare-up; this might a consequence of the aggressive immunosuppressant therapy in those patients. Conclusions Patient with SLE show an increased cardiovascular risk as estimated by the c-IMT. Disease activity and in particular disease flares accelerate the progression of the vascular damage. Disclosure of Interest None declared

Carotid intima media thickness (IMT) progression is increasingly used as a surrogate for vascular risk. This use is supported by data from a few clinical trials investigating statins, but established criteria of surrogacy are only partially fulfilled. To provide a valid basis for the use of IMT progression as a study end point, we are performing a 3-step meta-analysis project based on individual participant data. Objectives of the 3 successive stages are to investigate (1) whether IMT progression prospectively predicts myocardial infarction, stroke, or death in population-based samples; (2) whether it does so in prevalent disease cohorts; and (3) whether interventions affecting IMT progression predict a therapeutic effect on clinical end points. Recruitment strategies, inclusion criteria, and estimates of the expected numbers of eligible studies are presented along with a detailed analysis plan. (Am Heart J 2010; 159: 730-736.e2.)

BACKGROUND: PCSK9 plays a key role in plasma cholesterol metabolism by modulating the expression of LDL receptors. OBJECTIVE AND METHODS: In this study we investigated the effects of two common polymorphism of the PCSK9 gene (E670G and I474V) on the intima media thickness of the common carotid artery and the possible relation with polymorphisms of apolipoprotein E in 1541 middle aged subjects selected from the general population enrolled in the PLIC study and confirmed the major findings in a second free-living population enrolled in the Ventimiglia study. RESULTS: 670G carriers showed significantly increased plasma total cholesterol, LDL-cholesterol, and Apo levels B while no significant differences were observed between carriers of the I474V SNP. IMT was significantly increased in 670G carriers compared to individuals homozygous for the E allele (0.640+/-0.102mm vs. 0.652+/-0.092mm, P

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.

The article analyses the possibilities for Romanian small and medium enterprises to internationalize as Born Globals. Small and medium enterprises in European economies and all over the world are more and more exposed to global pressures induced by globalization and market integration processes, which amplifies the need to be competitive and confront international markets through internationalization. Small and medium enterprises internationalization is an amplifying phenomenon, which has been the topic of wide spread research efforts in the last decades. The most recent trend in this field is the Born Global model, which points out to small and medium enterprises that show very rapid and intensive international growth right from or close to inception. In order to investigate the small and medium enterprises internationalization possibilities as Born Globals, several major underlying factors of the emergence of Born Globals are considered, representing both internal and external push and pull forces to internationalization. The applicability of the Born Global model of internationalization for Romanian small and medium enterprises is outlined by the examination of each factor’s triggering role in the current Romanian context. Based on this analysis, consequent policy recommendations for stimulating the Romanian small and medium enterprises internationalization as Born Globals are proposed.

The article analyses the role knowledge plays in the internationalization process of small and medium enterprises. Small and medium enterprises are considered from a knowledge-based view, an extension of the resource-based view of the firm, with knowledge as the most strategically significant resource of a firm and the basis for building and sustaining competitive advantage in nowadays complex, dynamic environment. Knowledge may be thus viewed as an essential determinant of small and medium enterprises internationalization processes. The assigned models of small and medium enterprises internationalization refer to this role, and an examination of the different approaches allows for an integrated view of the ways in which knowledge may determine, influence and support small and medium enterprises internationalization. Small and medium enterprises internationalization strategy development implies several specific phases which are analyzed in order to identify the knowledge necessities for internationalizing small and medium enterprises. Knowledge is then object of certain knowledge processes which include knowledge acquirement, through creation or acquisition, use, handling and development, and revaluation, that are further analyzed according to their specificity related to small and medium enterprises internationalization. A special focus is placed on the process of knowledge acquirement, as the main premise of the internationalization process. These considerations are applied in the case of Romanian small and medium enterprises, providing proposals regarding possible ways of integrating knowledge in the process of internationalization and facilitating their access to knowledge.

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; P0.05). 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 (BMI25 kg/m(2)) plasma sRAGE was significantly lower compared to lean subjects (1460+/-640 pg/mL vs 1710+/-693 pg/mL; P0.05). 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.

Although widely used in lipid lowering therapy, HMG CoA reductase inhibitors or statins (even when administered at high doses) are frequently insufficient to achieve guideline-recommended LDL-C goals for many patients with hypercholesterolemia in everyday clinical practice. Often over half of patients do not achieve LDL-C goal on the initial dose of statin and most of these patients do not reach goal neither after 6 months. Thus, a wide therapeutic gap exists between target LDL-C levels and those typically achieved in clinical practice. A recent and more effective therapeutic strategy, therefore, is to treat the two main sources of cholesterol simultaneously (production of cholesterol, mainly in the liver, and absorption of cholesterol in the intestine) with a complementary mechanism of action, by co-administering ezetimibe, a novel agent inhibiting cholesterol absorption, together with a statin, which inhibits cholesterol production in the liver. Ezetimibe can be effectively co-administered with any dose of any statin and, compared with single inhibition of cholesterol production, afforded by statins alone, provides consistently greater reductions in LDL-C through Dual Inhibition of both cholesterol production and absorption. Here we summarize the pivotal role of both the liver and intestine in the overall balance of cholesterol in the body and describe the clinical impact and relevance of inhibiting both sources of cholesterol either by using ezetimibe/simvastatin as a single tablet or co-administering ezetimibe together with any dose of any statin.

Objective. Resistin is an adipokine that has been suggested to be correlated with markers of inflammation and to be predictive of coronary atherosclerosis and type II diabetes in humans. A common single nucleotide polymorphism (SNP) (−420C/G) in the promoter of resistin is associated with increased resistin plasma levels and susceptibility to type II diabetes. The aim of this study was to investigate the association of the -420C/G polymorphism with metabolic syndrome, obesity, myocardial infarction and kidney disease. Design and results. First we studied 1542 subjects from the PLIC study (a population based cohort). GG carriers showed an higher prevalence of obesity and metabolic syndrome as well as increased plasma triglycerides levels, BMI, systolic and diastolic blood pressure and cardiovascular risk according to Framingham algorithm (P

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.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.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 (Por = .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).Patients with nonalcoholic fatty liver disease, even with no or mild alterations of liver tests, should be considered at high risk for cardiovascular complications.