Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy.

BACKGROUND: Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. OBJECTIVE: We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. METHODS: A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. RESULTS: The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. CONCLUSIONS: For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.

Lipoprotein-associated phospholipase A2 activity is increased in patients with definite familial hypercholesterolemia compared with other forms of hypercholesterolemia.

BACKGROUND AND AIM: Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays a key role in atherosclerosis development. It is considered a marker of increased risk of cardiovascular disease (CVD) and plaque vulnerability. Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol and a higher prevalence of early CVD. Our aim was to evaluate the differences in Lp-PLA2 activity in a population of hypercholesterolemic patients with and without definite FH. METHODS AND RESULTS: Hypercholesterolemic patients were consecutively recruited. Definite FH was defined according to Dutch Lipid Clinic Network criteria ≥8. All patients underwent routine clinical examination and biological assessments and Lp-PLA2 activity was measured in blood samples. Among 469 patients, 118 had a definite diagnosis of FH. Lp-PLA2 activity was significantly higher in definite FH patients compared to non-definite FH patients (206.5 ± 54.5 vs. 180.8 ± 48.4 nmol/min/mL, p < 0.0001). Lp-PLA2 positively correlated with total cholesterol, LDL-C and apolipoprotein B and negatively with HDL-C and apolipoprotein A-1. In multivariate analysis, definite FH diagnosis, LDL-C, HDL-C and statin treatment remained correlates of Lp-PLA2 independently of systolic blood pressure. CONCLUSIONS: Lp-PLA2 activity was higher in definite FH than in non-definite FH patients independently of LDL-C levels and statin treatment. These results highlight the particular phenotype of FH subjects among hypercholesterolemic patients. As increased Lp-PLA2 activity suggests, FH patients exhibit higher arterial inflammation that may contribute to their high cardiovascular risk. Our results reinforce the potential beneficial role of statins pleiotropic effects and the need for proper identification and treatment of FH patients.

Association of fasting serum insulin and cancer mortality in a healthy population - 28-year follow-up of the French TELECOM Study.

AIMS: Epidemiologic, pharmacoepidemiologic and pathophysiologic evidence points consistently to an association between type 2 diabetes and cancer. This association could be explained by hyperinsulinemia induced by insulin resistance. We studied the association between fasting serum insulin (FSI) and cancer mortality in a population of non-diabetic individuals. METHODS: We followed 3117 healthy workers (50.2% women), included in the TELECOM cohort study, between 1985 and 1987; their median age was 38 years (Q1-Q3=30-50). Baseline FSI was measured by radioimmunoassay, the INSI-PR method. People with diabetes or cancer at baseline were excluded. Vital status and causes of death were available until December 2013. The association between FSI and cancer deaths was analysed by sex, using a Cox proportional hazards model with age as the time scale, adjusting for body mass index, smoking habits, alcohol consumption, occupational category and ethnic origin. RESULTS: After a 28-year follow-up, 330 (10.6%) deaths were reported, among which, 150 were cancer-related (80 men, 70 women). In men, the association between FSI and death by cancer was J-shaped: compared to the average FSI of 7.1mU/L, men with 5mU/L and 12.9mU/L had respectively adjusted hazard-ratios (HR) of 1.88 (95% confidence interval, 1.00-3.56) and 2.30 (95% CI, 1.34-3.94). Among women, no significant association was found (adjusted HR, 1.03; 95% CI, 0.96-1.11) for an increase of 1mU/L in FSI. CONCLUSION: These results strengthen the hypothesis of an independent risk of cancer death associated with extreme values of FSI, mainly the highest, among men, but not among women.

Integrative studies implicate matrix metalloproteinase-12 as a culprit gene for large-artery atherosclerotic stroke.

BACKGROUND: Ischaemic stroke and coronary heart disease are important contributors to the global disease burden and share atherosclerosis as the main underlying cause. Recent evidence from a genome-wide association study (GWAS) suggested that single nucleotide polymorphisms (SNP) near the MMP12 gene at chromosome 11q22.3 were associated with large-vessel ischaemic stroke. Here, we evaluated and extended these results by examining the relationship between MMP12 and atherosclerosis in clinical and experimental studies. METHODS AND RESULTS: Plasma concentrations of MMP12 were measured at baseline in 3394 subjects with high-risk for cardiovascular disease (CVD) using the Olink ProSeek CVD I array. The plasma MMP12 concentration showed association with incident cardiovascular and cerebrovascular events (130 and 67 events, respectively, over 36 months) and carotid intima-media thickness progression (P = 3.6 × 10-5 ). A GWAS of plasma MMP12 concentrations revealed that SNPs rs499459, rs613084 and rs1892971 at chr11q22.3 were independently associated with plasma MMP12 (P < 5 × 10-8 ). The lead SNPs showed associations with mRNA levels of MMP12 and adjacent MMPs in atherosclerotic plaques. MMP12 transcriptomic and proteomic levels were strongly significantly increased in carotid plaques compared with control arterial tissue and in plaques from symptomatic versus asymptomatic patients. By combining immunohistochemistry and proximity ligation assay, we demonstrated that MMP12 localizes to CD68 + macrophages and interacts with elastin in plaques. MMP12 silencing in human THP-1-derived macrophages resulted in reduced macrophage migration. CONCLUSIONS: Our study supports the notion that MMP12 is implicated in large-artery atherosclerotic stroke, functionally by enhancing elastin degradation and macrophage invasion in plaques.

[Development and evaluation of ExSel Test to screen for excess salt intake in hypertensive subjects]. / Mise au point et évaluation de l'ExSel Test pour dépister une consommation excessive de sel chez les patients hypertendus.

OBJECTIVE: Development of a test to screen excess salt intake (ESI) in hypertensive patients. METHODS: Hypertensive subjects living in Paris area have been included. A 24-hour urinary sodium collection has been performed the day before the visit for a day hospital. A food diary was completed on the day of the urine collection and validated after an interview with a dietetician. An ESI was defined by a urinary sodium ≥ 200mmol/d. Clinical or food characteristics associated to an ESI were retained for the ExSel Test variables. A ROC curve was performed to determine the optimal score for the ExSel Test in detection of ESI in hypertensive patients. RESULTS: One hundred and forty-eight hypertensive patients have been included living in the Île-de-France area. ESI was observed in 19% with a higher frequency in men. Seven major determinants of ESI have been identified and are the questions that constitute the ExSel Test. A positive response assigns points: man (1); BMI > 30 (2); bread 4 or 5 pieces per day (1) or more than 6 pieces; cheese at least 1 time per day (2); charcuterie at least 2 times per week (2); use of processed broth or pilaf (1); food rich in hidden salt (pizza, cheeseburger, quiche, shrimp, potato chips, smoked fish, olive) at least 2 times per week (1). The ROC curve analysis shows that a score of 5 or more has the best Youden index with a sensitivity of 0.63, specificity of 0.95, PPV of 0.75, NPV of 0.92. CONCLUSIONS: In hypertensive subjects, an excessive salt intake can be detected by the realization of the ExSel Test based only on a simple food-questionnaire and some clinical parameters. For a clinical use of the ExSel Test, an electronic version is available on http://www.comitehta.org.

Prognostic value of liver fibrosis and steatosis biomarkers in type-2 diabetes and dyslipidaemia.

BACKGROUND: In cardiometabolic disorders, non-alcoholic fatty liver disease is frequent and presumably associated with increased mortality and cardiovascular risk. AIM: To evaluate the prognostic value of non-invasive biomarkers of liver fibrosis (FibroTest) and steatosis (SteatoTest) in patients with type-2 diabetes and/or dyslipidaemia. METHODS: A total of 2312 patients with type-2 diabetes and/or dyslipidaemia were included and prospectively followed up for 5-15 years. The cardiovascular Framingham-risk score was calculated; advanced fibrosis and severe steatosis, were defined by FibroTest >0.48 and SteatoTest >0.69, respectively, as previously established. RESULTS: During a median follow-up of 12 years, 172 patients (7.4%) died. The leading causes of mortality were cancer (31%) and cardiovascular-related death (20%). The presence of advanced fibrosis [HR (95% CI)] [2.98 (95% CI 1.78-4.99); P < 0.0001] or severe steatosis [1.86 (1.34-2.58); P = 0.0002] was associated with an increased risk of mortality. In a multivariate Cox model adjusted for confounders: the presence of advanced fibrosis was associated with overall mortality [1.95 (1.12-3.41); P = 0.02]; advanced fibrosis at baseline [n = 50/677; 1.92 (1.04-3.55); P = 0.04] and progression to advanced fibrosis during follow-up [n = 16/127; 4.8 (1.5-14.9); P = 0.007] were predictors of cardiovascular events in patients with type-2 diabetes. In patients with a Framingham-risk score ≥20%, the presence of advanced fibrosis was predictive of cardiovascular events [2.24 (1.16-4.33); P < 0.05]. CONCLUSIONS: Liver biomarkers, such as FibroTest and SteatoTest, have prognostic values in patients with metabolic disorders. FibroTest has prognostic value for predicting overall survival in patients with type-2 diabetes and/or dyslipidaemia. In type-2 diabetes, FibroTest predicted cardiovascular events and improved the Framingham-risk score.

Improvement in LDL-cholesterol levels of patients with familial hypercholesterolemia: can we do better? Analysis of results obtained during the past two decades in 1669 French subjects.

BACKGROUND: Heterozygous Familial Hypercholesterolemia (heFH) is an autosomal disease that affects about 1/500 people. It is characterized by markedly elevated plasma LDL-cholesterol (C) levels and an increased risk of cardiovascular disease (CVD). The aim of this study was to measure changes in LDL-C levels in heFH patients over two decades, and to evaluate if patients achieved LDL-C targets. METHODS: Data from 1669 heFH patients in five academic French centers were recorded between 1988 and 2011. RESULTS: The mean LDL-C concentrations under medical care improved between 1988 and 2011 (245 mg/dL before 1995, 164 mg/dL after 2009; p < 0.0001). However, mean LDL-C level and the number of patients treated with statins (79.3%) have not improved since 2005. In patients registered and treated after 2005 (n = 616), only 10.4% reached target LDL-C levels of <100 mg/dL. Indeed, 29.4% (n = 181) were treated with a maximal therapy (statins with a potency of >45% LDL-C reduction plus at least another lipid-lowering agent). Despite maximal treatment, only 18.8% of these heFH patients (n = 34/181) reached target LDL-C levels of <100 mg/dL. In addition, 75.3% of patients with CVD did not reach the LDL-C of <100 mg/dL. CONCLUSION: This study demonstrates that after significant improvement over the past two decades, the mean LDL-C levels in heFH French patients has remained stable since 2005. We also show that most heFH patients are not achieving their recommended LDL-C goals: this highlights the need for improved treatment and for new therapeutics in this population.

Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy.

RATIONALE: Xanthomatosis associated with monoclonal gammopathy includes hyperlipidaemic xanthoma (HX), normolipidaemic xanthoma (NX) and necrobiotic xanthogranuloma (NXG). All three pathologies are characterized by skin or visceral lesions related to cholesterol accumulation, monoclonal immunoglobulin (MIg) and hypocomplementemia. The pathophysiology underlying NXG remains unknown although the involvement of MIg is suspected. OBJECTIVE: To provide further insights into the pathophysiology of NXG, we evaluated the plasma lipid phenotype, mechanisms involved in cellular cholesterol accumulation and role of MIg in an analysis of blood and plasma markers of inflammation in 16 patients with xanthomatosis [NXG (n = 8) and NX (n = 8)] associated with monoclonal IgG relative to the relevant controls. RESULTS: The lipid profile of patients with NXG was characterized by a low HDL-C phenotype and an abnormal distribution of HDL particles. Sera from patients with NXG induced cholesterol accumulation in human macrophages. This accumulation was due in part to a significant reduction in the HDL capacity to promote cholesterol efflux from macrophages, which was not found in the case of NX. The MIg of NXG and NX patients was tested positively by ELISA to recognize a large spectrum of lipoproteins. High plasma levels of pro-inflammatory cytokines (TNFα and IL-6), soluble cytokine receptors (sIL-6R, sTNFRI and sTNFRII), adhesion molecules (VCAM-1 and ICAM-1) and chemokines (MCP-1, IL-8 and MIP-1α) were observed in both patients with NXG and NX, revealing a specific xanthoma inflammatory signature which was inversely correlated with plasma levels of anti-inflammatory HDL. However, patients with NXG were distinguished by elevated levels of IL-15 and a marked increase in the rate of intermediate CD14++CD16+ monocytes. CONCLUSION: This study revealed that NXG is characterized by impaired macrophage lipid homeostasis associated with a systemic inflammatory profile that may result from the interaction of MIg and lipoproteins.

Effect of high-dose pitavastatin on glucose homeostasis in patients at elevated risk of new-onset diabetes: insights from the CAPITAIN and PREVAIL-US studies.

AIMS: Statin treatment may impair glucose homeostasis and increase the risk of new-onset diabetes mellitus, although this may depend on the statin, dose and patient population. We evaluated the effects of pitavastatin 4 mg/day on glucose homeostasis in patients with metabolic syndrome in the CAPITAIN trial. Findings were validated in a subset of patients enrolled in PREVAIL-US. METHODS: Participants with a well defined metabolic syndrome phenotype were recruited to CAPITAIN to reduce the influence of confounding factors. Validation and comparison datasets were selected comprising phenotypically similar subsets of individuals enrolled in PREVAIL-US and treated with pitavastatin or pravastatin, respectively. Mean change from baseline in parameters of glucose homeostasis (fasting plasma glucose [FPG], glycated hemoglobin [HbA1c], insulin, quantitative insulin-sensitivity check index [QUICKI] and homeostasis model of assessment-insulin resistance [HOMA-IR]) and plasma lipid profile were assessed at 6 months (CAPITAIN) and 3 months (PREVAIL-US) after initiating treatment. RESULTS: In CAPITAIN (n = 12), no significant differences from baseline in HbA1c, insulin, HOMA-IR and QUICKI were observed at day 180 in patients treated with pitavastatin. A small (4%) increase in FPG from baseline to day 180 (P < 0.05), was observed. In the validation dataset (n = 9), no significant differences from baseline in glycemic parameters were observed at day 84 (all comparisons P > 0.05). Similar results were observed for pravastatin in the comparison dataset (n = 14). CONCLUSIONS: Other than a small change in FPG in the CAPITAIN study, neutral effects of pitavastatin on glucose homeostasis were observed in two cohorts of patients with metabolic syndrome, independent of its efficacy in reducing levels of atherogenic lipoproteins. The small number of patients and relatively short follow-up period represent limitations of the study. Nevertheless, these data suggest that statin-induced diabetogenesis may not represent a class effect.

Interpretation of lipoprotein-associated phospholipase A2 levels is influenced by cardiac disease, comorbidities, extension of atherosclerosis and treatments.

PURPOSE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker secreted in the atherosclerotic plaque. Blood levels of Lp-PLA2 predict future cardiovascular events in patients with ischemic disease and heart failure. This association seems to be independent of traditional cardiovascular risk factors. The aims of our study were (1) to assess relationships between Lp-PLA2 levels, cardiac disease and treatments; (2) to evaluate the association of Lp-PLA2 level with the severity of angiographic coronary artery disease (CAD) and the extracoronary atherosclerosis. METHODS: Between December 2009 and June 2010, 494 subjects were recruited from a population scheduled for diagnostic coronary angiography. Routine clinical (age, gender, BMI and treatment), cardiac (echocardiography, coronarography, carotid ultrasonography) and biochemical parameters were recorded for all patients. Lp-PLA2 mass concentration was assessed in serum with a Plac®-test turbidimetric immunoassay. Control Lp-PLA2 values were specifically obtained in 61 healthy subjects aged 44.5 ± 17.6 years (range: 25 to 59 years) without known cardiovascular risk factors (diabetes, smoking, hypertension, dyslipidemia) or cardiac treatment. RESULTS: In healthy controls, mean Lp-PLA2 level was 163 ± 43 µg/L (166 ± 45 µg/L in men and 159 ± 39 µg/L in women, non significant difference). In our cohort of 494 patients (69.8% men) aged 64.2 ± 16.7 years, the main etiologies of cardiomyopathies were ischemic (40%), valvular (22%), cardiac failure with left ventricular (LV) dysfunction (14%), infection (5%) and aortic aneurysm (7%). Mean Lp-PLA2 levels were 216 ± 17 µg/L. Lp-PLA2 correlated with age, BMI, current smoking, history of hypertension but not with diabetes and gender. The bivariate analysis showed a significant correlation between Lp-PLA2, and BMI (p=0.001) but no correlation with serum creatinine or NYHA status. A multivariate correlation showed that Lp-PLA2 was associated with total cholesterol, LDL-cholesterol and apoB (r=0.95, p<0.0001) but not with Lp(a). We observed that Lp-PLA2 was significantly associated with treatments such as statins and ACEi/ARA2 but not with ß-blockers, antiaggregant drugs or diuretics. Lp-PLA2 levels were significantly higher in patients with CAD than in patients without CAD (223 ± 54 vs. 208 ± 52 µg/L, respectively; p<0.007). Moreover, Lp-PLA2 levels were significantly higher in patients with the most extensive angiographic CAD [single (n=24)=215.2 ± 52 µg/L; two (n=55)=222 ± 53 µg/L and three vessels (n=140)=251.9 ± 53.7 µg/L, respectively; p<0.0001]. Patients with heart failure, sepsis or aortic aneurysm had increased Lp-PLA2 levels: 256.2 ± 46.8; 226.7 ± 47.3; 218.1 ± 38.9 µg/L, respectively, as compared to controls (p<0.0001). In patients with carotid artery disease, Lp-PLA2 significantly increased with the severity of atherosclerosis. Mean Lp-PLA2 levels were 218.8 ± 51 µg/L in the group without any stenosis (n=108), 224 ± 51 µg/L in the group with mild stenosis (n=101), and 231 ± 46 µg/L in the group with severe stenosis (n=22); p=0.004. CONCLUSION: This study clearly shows that interpretation of Lp-PLA2 levels needs a good assessment of cardiac parameters and treatments, especially statins and ACEi/ARA2. Lp-PLA2 levels are significantly associated with coronary heart disease and with the extension of extra coronary disease after adjustment for age and gender.

LDL oxidative modification and carotid atherosclerosis: results of a multicenter study.

OBJECTIVE: Serum LDL conjugated diene concentration is a marker of oxidative modification of LDL. We investigated the relationship between LDL conjugated dienes and cross-sectional subclinical atherosclerosis assessed by carotid IMT in high-risk subjects of a multicenter study. METHODS: Serum LDL conjugated dienes and ultrasonographically assessed carotid intima-media thickness (IMT(mean), IMT(max) and IMT(mean-max)) were available for 553 subjects from Finland, France, Italy, the Netherlands, and Sweden. RESULTS: In multivariate regression analysis, gender (p < 0.001), age (p < 0.001), systolic blood pressure (IMT(mean), p = 0.01; IMT(mean-max), p = 0.05) and serum LDL conjugated dienes (p = 0.02 for both IMT(mean) and IMT(mean-max)) were the strongest determinants of IMT variation, adjusted for study center, ultrasound videotape reader and serum LDL cholesterol. Pack-years of smoking, added into the regression model, did not destroy the significant association between increased serum LDL conjugated dienes and IMT. Ratio of LDL conjugated dienes to LDL particle cholesterol was higher in subjects of Northern recruiting centers than of Southern centers (r = 0.39, p < 0.0001). CONCLUSIONS: There was a cross-sectional association between in vivo increased LDL oxidative modification and subclinical atherosclerosis after adjustment for traditional risk factors. The subjects in Northern countries of Europe had more oxidatively modified lipids per cholesterol in LDL particle than subjects in Southern countries.

National differences in screening programmes for cardiovascular risks could obstruct understanding of cardiovascular prevention studies in Europe.

INTRODUCTION: In North-West Europe, cardiovascular disease is still a major cause of death and despite several efforts (e.g. European guidelines and conferences) cardiovascular risk factors are still inconsistently diagnosed and treated. METHODS: We evaluated the first consultations of patients in two cardiovascular referral clinics in France and the Netherlands, while evaluating the differences in national guidelines and between the profiles of patients at their first consultation. RESULTS: Notable differences exist between the two locally used guidelines in their programmes of cardiovascular risk assessment and their definition of LDL-cholesterol target levels. With regard to the LDL-cholesterol levels, more patients are 'on target' when using the French guideline than when using the Dutch guideline. Evaluation of the patient's profile at first presentation showed that the LDL-cholesterol levels were significantly lower in the Dutch patients (n = 77) compared with the French patients (n = 119). Dutch patients used significantly more statins than French patients. CONCLUSION: Despite the small study population included in this study, we found that comparison of daily care (as part of a primary prevention programme) is rather difficult due to several national differences in the approach to patients. All these factors combined should be taken into account, when discussing and extrapolating results obtained from analysis of cardiovascular prevention programmes.

Manganese superoxide dismutase dimorphism relationship with severity and prognosis in cardiogenic shock due to dilated cardiomyopathy.

The aim was to determine (a) Ala-16Val-SOD2 dimorphisms; (b) allelic frequency and phenotype of a common Pro-Leu polymorphism in GPx1, in a cohort of patients with a cardiogenic shock (CS) due to dilated cardiomyopathy without acute coronary syndrome. Consecutive patients with de novo CS that worsened a dilated (DCM) or ischemic (ICM) cardiomyopathy. Congenital heart disease, pacemaker and other shock aetiologies were excluded. To determine oxidative stress (OS), this study evaluated lipid peroxidation, protein oxidation and erythrocyte GPx, SOD and catalase activities. Ala16Val-SOD2 (dbSNP: rs4880) and Pro198Leu-GPx1 (dbSNP: rs1050450) polymorphisms were studied by allelic discrimination using fluorogenic probes and the 5'nuclease (TaqMan) assay. Twenty-four patients (with ICM (n = 8) or DCM (n = 16), age = 57.5 ± 10.7 years, LVEF = 25.3 ± 8.5%, NT-proBNP levels = 8540 ± 1703 ng/L) were included during a 15 month follow-up. OS parameters were significantly higher in patients than in controls. Distribution of MnSOD genotypes was 47% Val/Val-variant, 29.5% Ala/Val and 23.5% Ala/Ala-variants. Severity of CS was more important in patients with Val/Val-variant and can be put in parallel with NT-proBNP levels (Val/Val-variant: 11 310 ± 3875 ng/L vs Ala/Ala-variant: 6486 ± 1375 ng/L and Ala/Val-variant: 6004 ± 2228 ng/L; p < 0.05) and hemodynamic support duration (144.6 vs Ala/Val-variant: 108.8 h and Ala/Ala-variant: 52.5 h; p < 0.05) with a positive correlation (Spearman rho = 0.72, p < 0.05). Moreover, Val/Val-variant significantly influenced the mortality (Spearman rho = 0.67, p < 0.05), but not the morbidity (p = 0.3). Distribution of GPx genotypes was 64% Pro/Pro, 18% Pro/Leu and 18% Leu/Leu. GPx-variants influenced neither GPx activities nor cardiac events. In conclusion, CS was associated with markers of increased OS. GPx polymorphism did not influence the GPx activity. Only the Val-encoding MnSOD allele was significantly correlated with the severity and prognosis of CS.

Why GPs do not follow computerized guidelines: an attempt of explanation involving usability with ASTI guiding mode.

Clinical decision support systems (CDSSs) have the potential to increase guideline adherence, but factors of success are not well understood. ASTI-GM is an on demand guideline-based CDSS where the user interactively characterizes her patient by browsing the system knowledge base to obtain the recommended treatment. We conducted a web-based evaluation of ASTI-GM as a before-after study to assess whether the system improves general practitioners' (GPs) performance and how they would use it. Five clinical cases had to be solved, as usual in the before phase, and using ASTI-GM in the after phase. On a 2-month period, 266 GPs participated and 1,981 prescription orders were collected. The overall guideline adherence rate increased from 27.2% to 64.3%. Only 56.4% of ASTI-GM uses corresponded to a "good use" of the system. Adherence increased from 28.5% to 86.1% in the sub-group of "good uses", whereas it only increased from 28.1% to 36.6% in the complementary sub-group. Reasons for non "good uses" of CDSSs should be investigated since they impede their potential impact.

Switching the nucleoside reverse transcriptase inhibitor backbone to tenofovir disoproxil fumarate + emtricitabine promptly improves triglycerides and low-density lipoprotein cholesterol in dyslipidaemic patients.

OBJECTIVES: To assess the impact of switching to tenofovir disoproxil fumarate + emtricitabine on lipid parameters. METHODS: HIV-infected patients with plasma viral load <400 copies/mL, fasted triglycerides from 2.3 to 11.4 mmol/L and/or fasted low-density lipoprotein (LDL)-cholesterol >4.1 mmol/L were randomized to switch the nucleoside reverse transcriptase inhibitor (NRTI) backbone to fixed-dose combination tenofovir disoproxil fumarate + emtricitabine or to maintain the baseline antiretroviral regimen (the control group). The study has been registered with ClinicalTrials.gov under the identifier NCT00323492. RESULTS: Ninety-one patients were included in the intent-to-treat (ITT) analysis with triglycerides 2.4 mmol/L and LDL-cholesterol 4.0 mmol/L (median values). At week 12, the median changes from baseline of triglycerides were -0.5 mmol/L (-25%; n = 46) and -0.1 mmol/L (-6%; n = 45) in the tenofovir disoproxil fumarate + emtricitabine and control groups, respectively, indicating a difference of -0.4 mmol/L (P = 0.034) [95% confidence interval (CI): -0.9 to -0.0]. Similarly for LDL-cholesterol, changes of -0.4 mmol/L (-9%) and -0.1 mmol/L (-1%) were observed in the tenofovir disoproxil fumarate + emtricitabine and control groups, respectively, indicating a difference of -0.4 mmol/L (P = 0.031) [95% CI: -0.7 to -0.0]. The proportion of patients with LDL-cholesterol >4.1 mmol/L decreased from 48% at baseline to 26% at week 12 in the tenofovir disoproxil fumarate + emtricitabine group versus no change in the control group. No virological failure was observed during the study. CONCLUSIONS: Switching to tenofovir disoproxil fumarate + emtricitabine in dyslipidaemic HIV-infected patients improves triglycerides and LDL-cholesterol.

Parallel increase of plasma apoproteins C-II and C-III in Type 2 diabetic patients.

AIMS: To determine plasma levels of apoprotein (apo) C-II and apoprotein C-III in Type 2 diabetic patients and to examine the clinical and biological factors that are associated with elevated apoC concentrations. METHODS: We measured apoC-II and apoC-III in total plasma and in non-high-density lipoprotein fractions by an immunoturbidimetric assay in 88 Caucasian Type 2 diabetic patients and in 138 healthy control subjects. RESULTS: Plasma levels of both apoC-II and apoC-III were increased in Type 2 diabetic patients. The clinical conditions associated with an increase of plasma apoC-II and apoC-III were abdominal obesity, body mass index, poor glycaemic control and lack of insulin treatment. However, when multivariate analysis was used, plasma apoCs levels correlated with triglyceride levels only. The apoC-III/apoC-II ratio was similar in the Type 2 diabetic and control subjects. CONCLUSIONS: Our study shows the parallel increase of apoC-II and C-III in Type 2 diabetic patients. This parallel increase is related to hypertriglyceridaemia only.

[Adherence to national guidelines for lipid management in a department of endocrinology]. / Prise en charge des patients dyslipidémiques : analyse des écarts entre le référentiel et la pratique dans un centre hospitalier.

OBJECTIVES: National guidelines for lipid management have been updated in March 2005 by the French Health Products Safety Agency (Afssaps). The objective of this study was to assess clinical practices based on these recommendations in a department of endocrinology specialized in the management of dyslipidemic patients. MATERIALS AND METHODS: A sample of patients was independently selected among those referred to our outpatient clinic for assessment of hyperlipidemia. We analyzed retrospectively whether the management of dyslipidemia in these patients was consistent with national guidelines. RESULTS: We included 62 patients. At admission, 61% of patients had a lipid-lowering treatment that was consistent with the guidelines and a LDL-cholesterol value below the target level. At discharge, the lipid-lowering treatment was modified in 27% of patients. The changes were consistent with Afssaps guidelines in 79% of patients. Cases of non-compliance with the guidelines were explained by a lower threshold of LDL-cholesterol target in patients with carotid plaques and no changes because LDL-cholesterol was just above the LDL-cholesterol target. CONCLUSION: Lipid management was consistent with Afssaps guidelines in a majority of patients. However, this study emphasized unresolved problems in lipid management, such as the question of integrating arterial status in the therapeutic decision.

[Prevalence of sleep apnea in men with metabolic syndrome and controlled hypertension]. / Prévalence et déterminants du syndrome d'apnée du sommeil chez des hommes ayant un syndrome métabolique et une hypertension artérielle contrôlée.

BACKGROUND: Abdominal obesity and high blood pressure (HBP) are known to be associated with sleep apnea syndrome (SAS). Resistant hypertension commonly leads physicians to prescribe a sleep record because the prevalence of SAS is high in patients with resistant hypertension. Data on the prevalence of SAS in patients with treated and controlled hypertension are lacking. Moreover, while the metabolic syndrome (MS) and insulin resistance frequently occur in association with SAS, few studies have evaluated the prevalence of SAS in patients with MS. Epworth sleepiness scale (ESS) is often proposed to identify patients at high risk for sleep disorders and for which a sleep record should be prescribed. The reliability of this test to identify SAS has not been studied in patients with MS. OBJECTIVES: (i) To assess the prevalence of SAS in men with MS, (ii) to study the relationship between controlled hypertension and SAS in patients with MS, (iii) to assess the reliability of the ESS to diagnose SAS in patients with MS. METHODS: Among 135 men hospitalized for MS, the 125 who had no history of SAS were systematically evaluated by a nocturnal polygraphy was systematically performed in the 125 men without known SAS at the admission. An excessive daytime sleepiness was assessed by the ESS. Results of analyses in patients with controlled HBP (<130/85 mmHg with antihypertensive drug(s), n=41) were compared with those in patients with normotension (<130/85 mmHg without treatment, n=32). RESULTS: The prevalence of SAS (apnea-hypopnea index (AHI) >or=15/h) in men with MS was 44% in the whole population, 28.1% in the subgroup of patients with normotension and 61.0% in patients with treated and controlled HBP. A severe SAS (AHI >or=30/h) was respectively present in 6.3% and 34.1% of patients with normotension and controlled HTA (p<0.01). Compared with patients without SAS, those with SAS displayed higher blood pressure and BMI. Logistic regression analysis showed that controlled HTA was a determinant of SAS which persisted after adjustment for BMI. As suggested by the ROC curve, the ESS is not a good tool to identify patients with SAS. With a threshold of 11/24 the positive and negative values of this scale were of 0.20 and 0.47. CONCLUSION: The prevalence of SAS is high in men with MS. The ESS does not identify patients who should undergo a nocturnal record. Because a severe SAS is found in nearly one third of patients with MS and controlled HBP, we suggest that a nocturnal record should be systematically proposed to these patients irrespective of the degree of daytime sleepiness assessed by questionnaires.

Lessons from france: the cardiovascular prevention clinic in the la pitié-salpêtrière hospital in paris.

Cardiovascular disease is the principal cause of morbidity and mortality in the Netherlands. In this background, various initiatives have been launched to reduce the frequency of cardiovascular disease. One of those is the creation of clinical units with a special focus on prevention of cardiovascular disease. Hitherto, the prevention programmes of these clinics have been heterogeneous and therefore difficult to compare with respect to results. Similar developments in creating clinical initiatives concerning prevention of cardiovascular disease are found across Europe. With this in mind, lessons could be learned from each other's experiences. In our contribution, we would like to present the Cardiovascular Prevention Clinic in the Pitié- Salpêtrière Hospital in Paris, France, as an interesting example of a well-acknowledged cardiovascular prevention clinic that combines both daily clinical care and cardiovascular science. (Neth Heart J 2007;15:22-6.).

Screening for liver disease using non-invasive biomarkers (FibroTest, SteatoTest and NashTest) in patients with hyperlipidaemia.

BACKGROUND: Mortality related to complications of cirrhosis is increasing in patients with insulin-resistance factors. Hyperlipidaemic patients have multiple risk factors of insulin resistance. It is impossible to perform liver biopsy in such a large number of hyperlipidaemic patients to identify patients with advanced liver fibrosis or with steatohepatitis (non-alcoholic steatohepatitis, NASH). AIMS: To use the non-invasive biomarkers, FibroTest (FT), SteatoTest and NashTest, and to assess the prevalence of advanced liver disease in a large population of hyperlipidaemic patients. METHODS: A consecutive cohort of hyperlipidaemic patients was followed prospectively in a lipid centre and the sera were analysed retrospectively. RESULTS: A total of 2834 subjects were included: 1909 hyperlipidaemic patients and 925 blood donors (BD). Advanced fibrosis was identified by FT in 53/1909 (2.8%) hyperlipidaemic patients vs. 0/925 BD (0%) (P < 0.0001); advanced steatosis in 569/1893 hyperlipidaemic patients (30.1%) vs. 8/164 (4.9%) BD (P < 0.0001) and NASH in 132/1893 (7%) vs. 0/164 (0%), respectively (P < 0.0001). There was a highly significant and linear association between the number of metabolic syndrome factors and liver disease prevalence - the highest being for type 2 diabetics: advanced steatosis 66%, NASH 24% and advanced fibrosis 6%. CONCLUSIONS The prevalence of fibrosis, steatosis and NASH in hyperlipidaemic patients appears to be high (3%, 30% and 7%, respectively). Biomarkers could be useful for screening of advanced fibrosis and NASH in patients with several metabolic syndrome factors, to prevent liver mortality.