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Summary Background & aims Blood levels of polyunsaturated fatty acids (PUFAs) are under control of endogenous synthesis via Δ5- and Δ6-desaturases, encoded by the FADS1 and FADS2 genes, respectively and of diet. Genome-wide associations studies (GWAS) reported associations between polymorphisms in FADS1–FADS2 and variations in plasma concentrations of PUFAs, HDL- and LDL-cholesterol and triglycerides. However, it is not established whether dietary PUFAs intake modulates these associations. We assessed whether dietary linoleic acid (LA) or α-linolenic acid (ALA) modulate the association between the FADS1 rs174547 polymorphism (a GWAS hit) and lipid and anthropometric phenotypes. Methods Dietary intakes of LA and ALA, FADS1 rs174547 genotypes, lipid and anthropometric variables were determined in three French population-based samples (n = 3069). These samples were stratified according to the median dietary LA (<9.5 and ≥9.5 g/d) and ALA (<0.80 and ≥0.80 g/d) intakes. The meta-analysis was performed using a random-effect. Results Our meta-analysis confirmed the association between rs174547 and plasma lipid levels and revealed an association with waist circumference and body mass index. These associations were not modified by dietary ALA intake (all p-interaction > 0.05). In contrast, the associations with HDL-cholesterol levels, waist circumference and BMI were modulated by the dietary intake of LA (p interaction < 0.05). In high LA consumers only, the rs174547 minor allele was significantly associated with lower HDL-cholesterol levels (β = −0.05 mmol/L, p = 0.0002). Furthermore, each copy of the rs174547 minor allele was associated with a 1.58 cm lower waist circumference (p = 0.0005) and a 0.46 kg m−2 lower BMI (p = 0.01) in the low LA intake group, but not in the high LA intake group. Conclusions The present study suggests that dietary LA intake may modulate the association between the FADS gene variants and HDL-cholesterol concentration, waist circumference and BMI. These gene–nutrient interactions, if confirmed, suggest that subjects carrying the rs174547 minor allele might benefit from low dietary LA intakes. [ABSTRACT FROM AUTHOR]

Background Blood polyunsaturated fatty acid (PUFA) levels are determined by diet and by endogenous synthesis via Δ5- and Δ6-desaturases (encoded by the FADS1 and FADS2 genes, respectively). Genome-wide association studies have reported associations between FADS1-FADS2 polymorphisms and the plasma concentrations of PUFAs, HDL- and LDL-cholesterol, and triglycerides. However, much remains unknown regarding the molecular mechanisms explaining how variants affect the function of FADS1-FADS2 genes. Objective Here, we sought to identify the functional variant(s) within the FADS gene cluster. Methods To address this question, we (1) genotyped individuals (n = 540) for the rs174547 polymorphism to confirm associations with PUFA levels used as surrogate estimates of desaturase activities and (2) examined the functionality of variants in linkage disequilibrium with rs174547 using bioinformatics and luciferase reporter assays. Results The rs174547 minor allele was associated with higher erythrocyte levels of dihomo-γ-linolenic acid and lower levels of arachidonic acid, suggesting a lower Δ5-desaturase activity. In silico analyses suggested that rs174545 and rs174546, in perfect linkage disequilibrium with rs174547, might alter miRNA binding sites in the FADS1 3′UTR. In HuH7 and HepG2 cells transfected with FADS1 3′UTR luciferase vectors, the haplotype constructs bearing the rs174546T minor allele showed 30% less luciferase activity. This relative decrease reached 60% in the presence of miR-149-5p and was partly abolished by cotransfection with an miR-149-5p inhibitor. Conclusion This study identifies FADS1 rs174546 as a functional variant that may explain the associations between FADS1-FADS2 polymorphisms and lipid-related phenotypes. Highlights • The rs174547 polymorphism is associated with n-6 polyunsaturated fatty acid levels in erythrocytes. • Among the 25 polymorphisms of the rs174547 haplotype block, rs174546 is functional. • The rs174546 minor allele triggers FADS1 gene downregulation. • The rs174546 minor allele creates an miR-149-5p binding site in the FADS1 3′UTR. [ABSTRACT FROM AUTHOR]

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: We investigated the association between the rs9939609 (T>A) polymorphism in the FTO (fat mass– and obesity-associated) gene and obesity- and type 2 diabetes mellitus–related phenotypes in the French Multinational MONItoring of Trends and Determinants in CArdiovascular Disease (MONICA) Study (n = 3367). In the study, TA or AA subjects had higher body mass index (BMI) (P = .017), waist circumference (P = .017), and hip (P = .01) circumference in an A allele dose-dependent manner. The A allele was also significantly associated with higher plasma insulin levels (P = .05), higher insulin resistance index (homeostasis model assessment) (P = .02), and higher systolic blood pressure (P = .003); but these associations disappeared after adjustment for BMI. In the study, 598 subjects were obese (BMI ≥30 kg/m2); and 2769 subjects were not obese (BMI <30 kg/m2). Subjects bearing the A allele of rs9939609 had a higher risk of obesity (adjusted odds ratio [95% confidence interval] = 1.29 [1.06-1.58], P = .01) compared with TT subjects. Moreover, the homozygous AA genotype of rs9939609 was associated with a higher risk of type 2 diabetes mellitus (odds ratio = 1.45 [1.05-1.99], P = .02, 283 subjects with and 2601 subjects without type 2 diabetes mellitus), independently of BMI. In conclusion, the role of the A allele of the FTO rs9939609 polymorphism on the risk of obesity and type 2 diabetes mellitus was confirmed in the French MONICA Study. [Copyright &y& Elsevier]

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: The plasma level of high-density lipoprotein cholesterol (HDL-C) is known to be inversely associated with cardiovascular risk. However, besides lifestyle, gene polymorphism may influence the HDL-C concentration. The aim of this study was to investigate the possibility of interactions between CETP, PPARA, APOE, and APOAI polymorphisms and HDL-C, apolipoprotein (apo) A-I, lipoprotein (Lp) A-I, and Lp A-I:A-II in a sample selected from the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study population who remained free of cardiovascular events over 5 years of follow-up. Healthy individuals (857) were randomly selected for genotyping the PRIME study subjects. The population was selected so as to provide 25% of subjects in the lowest tertile of HDL-C (≤28 mg/dL) in the whole PRIME study sample, 25% of subjects in the highest tertile of HDL-C (≥73 mg/dL), and 50% of subjects in the medium tertile of HDL-C (28-73 mg/dL). Genotyping was performed by using a polymerase chain reaction system with predeveloped TaqMan allelic discrimination assay. The CETP A373P rare allele c was less frequent in the group of subjects with high HDL-C, apo A-I, Lp A-I, and Lp A-I:A-II concentrations. Apolipoprotein A-I and Lp A-I were also found to be higher in the presence of the ɛ2 allele coding for APOE. The effect of the CETP A373P rare allele c on HDL-C was independent of all tested parameters except triglycerides. The respective effect of these polymorphisms and triglycerides on cardiovascular risk should be evaluated prospectively. [Copyright &y& Elsevier]

The Epidemiological Study of Myocardial Infarction Study which enrolled 9758 apparently healthy men aged 50–59 years, is a prospective cohort study designed to evaluate markers of coronary risk. Soluble forms of the intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels were measured in plasma obtained at baseline from 317 subjects who suffered a coronary event during the 5-year follow-up and in twice the number of control subjects who were matched for center, age and day of inclusion in a nested case-control design. The relative risk associated with the highest compared with the lowest thirds of ICAM-1 (>625 versus <502 ng/ml) was 2.45 (95% CI: 1.64–3.65, P<0.001) without adjustment; it decreased moderately (RR: 2.09; 95% CI: 1.34–3.24, P<0.001) after control for lipid and non-lipid factors and remained significantly elevated after adjustment for C-reactive protein (CRP) (RR: 1.90; 95% CI: 1.21–2.96, P=0.005). Plasma ICAM-1 was essentially associated with the risk of myocardial infarction or coronary death and also with angina pectoris. Subjects with CRP presented elevated coronary risk only if ICAM-1 was high. An elevated level of VCAM-1 was not associated with any risk of future acute coronary event, or with angina pectoris. This data indicates that plasma levels of ICAM-1 may serve as risk markers for future coronary events whatever their clinical presentation and that risk is better defined using simultaneous measurements of ICAM-1 and CRP than any of these levels separately. [Copyright &y& Elsevier]

The incidence of coronary heart disease is higher in Northern Ireland than in France. These differences have not been adequately explained. We have investigated the associations of plasma fibrinogen concentration and factor VII activity with the incidence of coronary heart disease in a prospective cohort study involving 10 600 men aged 50–59 living in four regions (Lille, Strasbourg, and Toulouse in France, Belfast in Northern Ireland). Baseline fibrinogen and factor VII were measured in 9489 men free of coronary heart disease at entry (7167 in France and 2322 in Northern Ireland). Over 5 years of follow-up, 161 participants developed myocardial infarction (MI) or coronary death (100 in France and 61 in Belfast) and 151 developed angina pectoris (94 in France and 57 in Belfast). The risk of future coronary events was 1.9 times higher in Belfast than in France (95% confidence interval: 1.5–2.4). Baseline mean levels of fibrinogen were significantly higher in Belfast than in France and they were higher in participants who experienced coronary events compared with those who did not in both countries. The age-adjusted relative risk of coronary heart disease associated with a rise of one standard deviation in fibrinogen level was 1.56 (95% confidence interval: 1.29–1.95, P<0.0001) in the whole cohort. This association remained significant after adjustment for other cardiovascular risk factors (relative risk:1.36; 95% confidence interval: 1.14–1.68; P<0.0001). There was no clear geographical variation in factor VII and no significant association between factor VII levels and the risk of coronary events was observed. Classic risk factors explained 25% of the excess risk of coronary heart disease in Belfast compared with France, while fibrinogen alone accounted for 30%. These findings add to the epidemiological evidence that elevated fibrinogen is a major risk factor for coronary heart disease. [Copyright &y& Elsevier]

Background In clinical trials, lowering cardiovascular risk factors (RF) reduce cardiovascular (CV) morbidity and mortality. Nonetheless, few data exist on general population. Purpose We assessed theimpact of the control of RF at baseline on long-term all-cause and CV mortality in French general population. Methods Analysis was based on the participants aged 35-64 of the Third French MONICA population-based survey on RF (1995-1996). Vital status was obtained 18 years after inclusion. Statistical analysis was based on multivariable Cox modelling. We assessed the impact of the control (according to the threshold recommended in the guidelines currently used at the time of recruitment) of high blood pressure, high LDL-cholesterol, diabetes and smoking. Results In our study, 3402 subjects were included. Half were men and 2.5% had history of Coronary Heart Disease. Moreover 569(17%) subjects had 2 or more non-controlled RF, 1194(35%) had 1 non-controlled RF, 770(23%) had all RF controlled under treatment (or were former smokers) and 869(25%) had none RF. During the follow-up, 389 deaths occurred (76 due to a CV cause). Considering all-cause mortality, after adjustment for centre, age, gender, educational level, proxies of alcohol consumption plus medical history of chronic disease, the hazard ratio(HR) for subjects presented 1 non-controlled RF and for subjects presented 2 or more non-controlled RF was 1.38[1.03-1.83](p=0.029) and 1.80[1.33-2.43](p<0.001), respectively, as compared to subjects presented all RF controlled. For subjects presented none RF, adjusted HR was 0.66[0.44-0.98] (p=0.042). Considering CV mortality, adjusted HR for subjects presented 1 non-controlled RF and for subjects presented 2 or more non-controlled RF was 1.70[0.84-3.42](p=0.138) and 3.67[1.85-7.29](p<0.001), respectively, as compared to subjects presented all RF controlled or none RF. Conclusions Failing to control RF increases significantly long-term all-cause and cardiovascular mortality. [ABSTRACT FROM AUTHOR]

Purpose: To assess ten-year change in the prevalence of the metabolic syndrome among French subjects using the National Cholesterol Education Program (NCEPATP III) criteria with the American Diabetes Association''s updated definition of elevated fasting glucose (≥ 1g/l). Two definitions were assessed, one taking into account a treatment for hypertension and for elevated triglycerides or reduced high-density lipoprotein (HDL) cholesterol (Met2) and the other not (Met). Methods: Two cross-sectional representative surveys of the general population were carried out in 1996 and 2006 in three French areas: the Urban Community of Lille in the North, the districts of Bas-Rhin in the East and of Haute-Garonne in the South. Inhabitants aged 35-64 years were randomly recruited from electoral rolls after stratification on gender, 10 year-age group and town size. Standardized sociodemographic, medical and anthropometric data were collected and a fasted blood sample was analysed centrally. Prevalences in the age group 35-64 years were adjusted for the French population of year 2000. Results: A total of 3405 subjects in 1996 and 3554 subjects in 2006 were included in the analyses. In both years the metabolic syndrome was more common among men than among women and increased with age. The age-adjusted prevalences [95% confidence interval] of Met were 26.3% [23.9-28.7] and 18.1% [16.1-20.1] in 1996 and 23.1% [20.9-25.3] and 15.1% [13.3-16.9] in 2006, in men and women respectively. The equivalent results for Met2 were 30.5%, 21.5%, 24.8% and 16.4%. The age-adjusted prevalence of Met (Met2) decreased significantly by 12.1% (18.7%) in men and 16.6% (23.7%) in women. Of the five Met criteria, decreasing trends were observed in the prevalence of high blood pressure, elevated fasting glucose, low HDL cholesterol. By contrast, prevalence of abdominal obesity appeared unchanged whereas prevalence of hypertriglyceridemia increased significantly. Conclusions: In France, the prevalence of the metabolic syndrome tended to decline in the last decade in both genders, particularly in women. [Copyright &y& Elsevier]

Purpose: The beneficial effect of lipid-lowering drugs on cardiovascular mortality is well established, but long term safety data remain scarce. The aim of this study was to assess 10-year risk of cancer mortality according to blood lipid levels and lipid-lowering drug exposure, in the French general population. Methods: Our analysis was based on the Third French MONICA Cross-sectional survey on cardiovascular risk factors (1995-1996). Participants aged 35-64 years were randomly recruited from French polling lists. Subjects with a history of cancer at baseline were excluded from the analysis. Vital status and cause of mortality were obtained 10 years after inclusion. Results: There were 3262 participants and 177 deaths were recorded (78 due to cancer). The sample was mainly composed of subjects in primary cardiovascular prevention (96%) and comprised 64% of normolipidemic, 25% of untreated dyslipidemic (total cholesterol ≥ 6.5mmol/L or triglycerides ≥ 3.5mmol/L) and 11% of dyslipidemic subjects treated with a lipid-lowering drug (4% statin, 6% fibrate). After adjustment for centre, age, smoking, gamma-glutamyl transpeptidase and mean corpuscular volume, which were all significantly associated with cancer mortality, the hazard ratio (HR) for cancer mortality in subjects with non HDL-cholesterol < 3.5mmol/L was 2.83 [95% confidence interval: 1.73-4.62]. The adjusted HR in subjects with HDL-cholesterol < 0.9mmol/L was 2.87 [1.63-5.06]. The adjusted HR in subjects on lipid-lowering drug as compared to untreated subjects was 0.31 [0.11-0.85]. Conclusion: In this cohort mainly composed of primary prevention subjects, low HDL- and low non HDL-cholesterol levels were associated with increased cancer mortality, whereas risk of cancer death was reduced in users of lipid-lowering drugs. This suggests that the impact of low cholesterol on cancer risk may be different in subjects with spontaneously low levels and in those for whom cholesterol is lowered by lipid-lowering drugs. [Copyright &y& Elsevier]

Little is known about sex difference of middle-term mortality rates in patients surviving an ACS and about comparison with mortality rates in the corresponding healthy population. Our aims were: 1/to review the sex difference mortality at short-term (28 day) in ACS patients, 2/to describe short-term mortality in relation with middle-term mortality (4 years), 3/to compare sex difference of middle-term mortality in patients surviving an ACS with the corresponding population. 6022 patients hospitalized for a first ACS registered in the Strasbourg (BR), Lille and Toulouse (HG) MONICA registries, between 2009 and 2011 were included. ACS were defined as STEMI, NSTEMI, or unstable angina (UA). Mean follow-up was 50.3 months. 3025 patients (50.2%) were STEMI, 1571 (26.1%) NSTEMI and 1426 (23.6%) UA. Short-term mortality was 6.7% in men vs 9.0% in women for STEMI (p=0.05), 4.7% vs 4.2% for NSTEMI (p=0.67) and 5.2% vs 6.6% for UA (p=0.29). Middle-term mortality was 7.4% in men and 8.5% in women for STEMI (p=0.39), 11.5% vs 11.9% for NSTEMI (p=0.82) and 8.6% vs 10.9% for UA (p=0.20). The small higher short-term and middle-term mortality in women was removed after adjustment for age and center. In men the middle-term risk of death for STEMI compared with the corresponding population was 3.05 [2.32-4.02] in HG, 2.88 [2.25-3.68] in BR and 2.34 [1.83-2.99] in Lille. In women the risk of death was 6.80 [4.03-11.5], 5.04 [3.04-8.37] and 6.40 [4.28-9.58] in HG, BR and Lille respectively. Considering males and females together, middle-term mortality of STEMI for HG was in relation to the regional population 3.26 [2.56-4.15] and to the French population 4.17 [3.27-5.32], for BR 3.53 [2.83-4.41] vs 3.74 [6.00-4.67] and for Lille 4.40 [3.57-5.43] vs 3.42 [2.78-4.22]. Short-term and middle-term mortality were similar in men and women. In patients surviving an ACS, middle-term mortality was, comparatively to the corresponding population, from 2 to 3 times higher in women than in men. [ABSTRACT FROM AUTHOR]

Background Determinants of short-term mortality after acute coronary syndrome (ACS) are relatively well known. However, those for middle-term mortality aren’t clearly established. Purpose The aim of our study was to describe 28-day mortality in patients hospitalized for ACS in comparison with the middle-term mortality. Methods this study was based on data from 6812 people aged 35-74 years hospitalized for a first or a recurrent ACS, registered in the Strasbourg and Toulouse MONICA registry between 2009 and 2011. Three categories of ACS were defined: (ST+), ACS with ST elevation at ECG; (ST-Enz+), ACS with no ST elevation plus significant cardiac enzyme elevation; (ST-Enz-), ACS with no ST elevation and no enzyme elevation. Results The mean of follow up was 3.3±1.1 years with a maximum of 5 years. In all there were 2441 (35.8%) ACS with (ST+), 1548 (22.7%) ACS with (ST-Enz+) and 2823 (41.4%) patients with (ST-Enz-). The 28-day mortality rate (number of deaths =760) was 11.2% [8.9-13.4] and the middle-term mortality (number of deaths =576) rate was 9.5% [7.1-11.9]. The risk of death at 28-days was (OR [95% CI]) 0.67 [0.51-0.88] for (ST-Enz+) and 2.74 [2.29-3.28] for (STEnz-) in comparison with (ST+). After multivariate adjustments; region, gender, age, history of IHD and complications at hospital admission odds ratios remained significant; 0.70 [0.5-0.88] for (ST-Enz+) and 3.56 [2.8-4.54] for (ST-Enz-) respectively. In patients who survived after 28 days (n=6052), the middle-term risk of death was after multivariate adjustments (HR [95% CI]) 1.42 [1.15-1.77] in (ST-Enz+) in comparison to (ST+) and 1.07 [0.86-1.32] in (ST-Enz-). Conclusions For STEMI patients risk of death was higher at 28 day and lower when middle-term mortality was considered. These patterns were inverse for NSTEMI (ST+Enz-) patients. In the early years following ACS, mortality rate was around 2.9% each year. [ABSTRACT FROM AUTHOR]

Introduction The impact of dairy fats on cardiovascular risk has been debated. Circulating Pentadecanoic (15:0) and heptadecanoic (17:0) saturated fatty acids are good biomarkers of dairy product consumption as they are mainly provided by dairy fats. We described the prevalence of cardiovascular risk factors according to erythrocyte membrane phospholipid content in 15:0 and 17:0 fatty acids. Methods 402 women and men aged 45-64 were randomly selected in 2005-2007, from the general population of three French areas. Nutritional data were collected through a 3-day food record. Fatty acid content was measured in erythrocyte membrane phospholipids. Results Erythrocyte membrane contents in 15:0 and 17:0 fatty acids significantly increased with the consumption of dairy products collected during the 3-day food record. Prevalence of hypertension significantly decreased from the lowest to the highest quartile of 15:0 erythrocyte content (48.1%; 33.3%; 29.9%; 25.5%; p=0.005). A similar trend was observed for metabolic syndrome prevalence (39.4%; 28.1%; 25.2%; 21.3%; p=0.029). Prevalence of hypertension, hypertriglyceridaemia, overweight and metabolic syndrome significantly decreased from the lowest to the highest quartile of 17:0 erythrocyte content (44.1%; 36.5%; 28.1%; 25.6%; p=0.020 for hypertension; 30.3%; 15.4%; 16.9%; 16.7%; p=0.017 for hypertriglyceridaemia; 68.1%; 58.7%; 46.6%; 44.4%; p=0.002 for overweight; and 43.2%; 26.9%; 22.5%; 17.8%; p<0.001 for metabolic syndrome). All these relationships remained significant after adjustment for age and gender. The link did not reach significance level for diabetes. Conclusion Elevated erythrocyte membrane phospholipid contents in 15:0 and 17:0 saturated fatty acids are associated with a lower prevalence of the metabolic syndrome and several of its components. These results suggest that saturated fat intake should not be systematically associated with high cardiovascular risk and can be considered as part of a balanced diet. [ABSTRACT FROM AUTHOR]

Purpose The assessment of cardiovascular risk is uniformly recommended as a decision-support for therapies aimed at preventing cardiovascular diseases. The aim of this study was to assess the predictive accuracy of the ESC SCORE in French general population. Methods Our analysis was based on the Third French MONICA Cross-sectional population-based survey (from South-Western(SW), North-Eastern(NE) and Northern(N) France), on cardiovascular risk factors (1995-1996) and on subjects consecutively referred for cardiovascular check-up to a Department of Preventive Cardiology (DPC) in a SW French University Hospital since 1995. Vital status was obtained 10 years after inclusion. The 10-year predicted risk of cardiovascular (CV) death was calculated using the SCORE equation for low-risk countries and was compared to the 10-year incidence of CV death. Results SCORE equation was applied in 6915 participants aged 35-64 (56% were men) and 56 CV deaths occurred. The CV death rate was 0.67% [95% confidence interval: 0.39-1.13] in DPC and 0.81%[0.42-1.56], 1.10%[0.61-1.98] and 2.00%[1.31-3.05] in SW, NE and N MONICA sample, respectively. The median risk SCORE was 0.97% and was not significantly different to the 10-year incidence of CV death (1.05%[0.81-1.37]). The C-statistic of the SCORE equation in our sample was 79%[73-85]. The median risk SCORE according to sex, age, educational level, family history of premature CV disease, physical activity, impaired fasting glucose, smoking, systolic blood pressure, total cholesterol, LDL-cholesterol, HDL-cholesterol and risk SCORE was not different to the 10-year incidence of CV death. According to the cut-point of 5%, 6440 participants(93%) were correctly classified using the SCORE equation (i.e. subjects with risk SCORE ?65; 5% deceased during the 10-year period or subjects with risk SCORE<5% non-deceased during the 10-year period). Conclusions In French general population aged 35-64, the SCORE equation adequately predicts CV death. [ABSTRACT FROM AUTHOR]

Guidelines recommend lowering LDL-cholesterol (LDL-c) according to level of cardiovascular risk. We aimed at exploring, in the French general population, the proportion of subjects above the recommended goal, and to assess among these people, how much LDL-c should be further decreased to reach the goal. Methods We analyzed data from a multicenter cross-sectional study conducted in 2006-2007 in Lille, Strasbourg and Toulouse areas. Participants were selected from the general population by drawing on polling lists. Results The sample comprised 4609 subjects aged 35-74 (49.9% of women), among whom 35.0% had no cardiovascular risk factor (age < 50 for men, 60 for women; no family history of premature coronary heart disease; no hypertension; no diabetes, HDL-c ≥ 0.40 g/L; and no current or recent smoking). The sample was further composed of 27.1%, 16.5%, and 3.9% of subjects with 1, 2 and 3 risk factors, respectively, and 17.5% of people at high cardiovascular risk. The percentage of people not reaching LDL-c goal increased from subjects with 0 to those with 3 risk factors (1.2%; 9.7%; 28.0%; and 56.9%), and 82.2% of high risk subjects presented with LDL-c above 1 g/L. These latter people had either a documented cardiovascular disease (68.8% had LDL-c ≥ 1 g/L), or an elevated 10-year absolute risk of cardiovascular disease (86.7% ≥ 1 g/L). In high risk people above the goal, mean LDL-c was 1.49 g/L (±0.32). An average 31.2% (±13.3) decrease in LDL-c was requested to reach the goal. The average decrease requested for people with 0 to 3 risk factors who were above the goal, was 9.7% (±8.6), 8.8% (±7.8), 12.6% (±9.6), and 15.1% (±10.1), respectively. A similar analysis was conducted considering ESC instead of French guidelines. Conclusion By estimating the average decrease in LDL-c needed to reach recommended goal in different risk categories, this study provides helpful information that may guide health agencies to conceive recommendations for management strategies. [ABSTRACT FROM AUTHOR]

Purpose Death rate of acute coronary syndromes has decreased for more than 50 years. Out-of-hospital mortality remains high despite improvements in acute coronary syndrome's care. Aims To evaluate the importance of out-of-hospital mortality and the main determinants of in-hospital and one-year mortality in France. Methods Analyses were based on data from the French MONICA population-based registry including exhaustively all acute coronary syndromes occurring in people aged 35-74 during the year 2006 in 3 geographic areas. First we evaluated out-of-hospital mortality. Then analyses were performed through Cox models on incident ACS reaching the hospital alive in order to determine main factors explaining the one-year mortality. Number of attributable deaths was assessed for variables of interest. Results After a one-year follow-up, case-fatality was 29.3% for incident events (n=2547) with 70.3% of out-of-hospital deaths and 21.1% occurring in the 28 days following the event. The number of attributable deaths related to 3 situations with a strong impact identified from multivariate analyses (out-of-hospital life-and-death emergency, hospitalization before ACS occurrence, and lack of coronary angiography) was 130 (59% of deaths occurring after reaching the hospital) during the one-year follow-up. These sub-groups were corresponding to patients with an important initial state of severity and not benefiting from traditionally recommended treatments. Conclusion The major part of deaths after ACS occurs in the out-of-hospital phase. Moreover, the major part of one-year mortality is associated with a very poor prognosis before medicalization. This underlines the importance of cardiovascular prevention, population education and better out-of-hospital emergency management. [ABSTRACT FROM AUTHOR]

Purpose Statins have demonstrated their efficacy in many situations to prevent cardiovascular risk. In this work we investigated the link between chronic use of statins, type of subsequent acute coronary syndrome (ACS), namely ST-elevation myocardial infarction (STEMI) or unstable angina/non ST-elevation myocardial infarction (UA/NSTEMI), early complications and their impact on one-year mortality in real life conditions. Methods Our study was based on 2006 data from the French MONICA population-based registry which collects all cases of ACS occurring in people aged 35-74 in 3 French areas. The sample consisted of 1951 hospitalized incident ACS (72 were excluded because of missing data). Relationship between chronic use of statins and type of ACS or early complications (resuscitated cardiac arrests and shocks) were analyzed through logistic regression. Impact on one-year mortality was evaluated through Cox models. Analyses were adjusted for patients' characteristics (living area, age, gender and previous cardiovascular treatments). Results Before index event, the rate of statins treated patients was 18%. The percentage of UA/NSTEMI among all hospitalized ACS was 45%; 54.5% in patients with previous statins treatment and 42.9% in those without (p<0.0001). The adjusted odds ratio (OR) for UA/NSTEMI was 1.29 (p=0.049) for subjects with versus those without statins. There was a significant association between statins and early complications (adjusted OR 0.58; p=0.030). Statins treatment prior to event was associated with a significant decrease in one-year mortality with an adjusted HR equal to 0.62 (p=0.017). Conclusions In our registry, people already treated with statins before an incident ACS had a lower rate of one-year mortality. This may result from a lower probability to develop STEMI, or early complications. However it remains difficult to assess from these observational data what is related to the treatment and what is related to potential confounding bias. [ABSTRACT FROM AUTHOR]

Purpose Cardiovascular rehabilitation after an acute coronary syndrome (ACS) has become more prescribed; differences still remain in prescription rates. The aim of this work was to assess the prognostic influence of rehabilitation after ACS in the current medical practice. Methods Our study was based on 2006 data from the French MONICA population-based registry which collects all cases of ACS occurring in people aged 35-74 in 3 French areas. The population consisted of 1838 incident hospitalized ACS after exclusion of those who died in the first 28 days of follow-up. The relationship between prescription of rehabilitation and composite outcome (ACS-recurrence or death) was analyzed using Cox models adjusted for living area, age, number of diseased vessels, diabetes, cardiovascular treatments and delays between symptoms and the first medical care. Results There were 171 ACS-recurrences or deaths during a median follow-up of 18.1 months and 23.6% of women. The rate of rehabilitation was higher in men than in women (36 vs. 26%, p<0.0001) and decreased with age. After multivariate adjustment the risk of composite outcome occurrence was identical in men and women for STEMI but higher in women for UA/NSTEMI [adjusted HR 1.75, 95% confidence interval (1.10-2.77)]. Rehabilitation was associated with a decrease of composite outcome whatever the type of ACS [adjusted HR 0.48, (0.32-0.73)]. However a significant interaction between rehabilitation and gender has been found in UA/NSTEMI (p=0.04) but not in STEMI. A stratified analysis for gender in UA/NSTEMI showed a significant benefit of rehabilitation in women [adjusted HR 0.06, (0.01-0.44)] but not in men [adjusted HR 0.82, (0.39-1.72)]. Conclusions Whatever the definition of ACS, rehabilitation was associated with a reduction of ACS-recurrence and death in both sexes. However it seems to be more beneficial in women presenting UA/NSTEMI in whom it is less prescribed and in whom the rate of recurrence and death is higher. [ABSTRACT FROM AUTHOR]

Background: In 2008, the results of the JUPITER trial were published, showing lower rates of mortality and cardiovascular morbidity in the rosuvastatin group compared to placebo. Beyond these results, a major question often arose among health practitioners and agencies: How many “JUPITER eligible” people can we find in the real world? The aim of the present analysis was to estimate the proportion of French subjects matching the JUPITER inclusion criteria. Methods: We used data from a cross-sectional study on the prevalence of cardiovascular risk factors in the French general population aged 35–75. The study was conducted in 2006–2007 in Lille, Strasbourg and Toulouse areas. Participants were selected by drawing on polling lists and a fasting blood sample was obtained. A direct standardization on age and gender was applied to percentages, using the 2006 French population as reference. Results: The sample was restricted to 1527 men and women aged 50–75 and 60–75, respectively, without lipid-lowering therapy, as younger people and treated dyslipidemic patients were not included in the JUPITER trial. Among them, 6.8% [95% confidence interval: 5.5% – 8.1%] fulfilled the JUPITER inclusion criteria (mainly CRP 2mg/l, LDL-cholesterol < 3.4mmol/l, triglycerides < 5.6mmol/l, no diabetes or cardiovascular disease). Median body mass index, LDL-cholesterol, and CRP in these JUPITER eligible patients were 28.0kg/m2, 3.02mmol/l and 4.2mg/l, respectively. Sixty percent had hypertension, 12% had HDL-cholesterol < 1mmol/l, 18% were current smokers, 33% had a metabolic syndrome and 4% a family history of premature coronary heart disease. The median Framingham ten-year risk score reached 12%. Conclusion: Among people aged 50–75, without lipid lowering therapy, 6.8% could match the JUPITER trial inclusion criteria. These data bring valuable information to estimate the number of eligible patients if the marketing authorization of rosuvastatin were extended. [Copyright &y& Elsevier]

Purpose: Assessment of cardiovascular risk level is uniformly recommended for appropriate management of risk factors. Risk of all-cause death is seldom considered in available algorithms. We aimed to establish an updated algorithm to predict 10-year all-cause mortality in apparently healthy subjects. Methods: Our analysis was based on the Third French MONICA Cross-sectional survey on cardiovascular risk factors (1995-1996). Participants aged 35-64 were randomly recruited from French polling lists. Subjects with a history of atherosclerotic cardiovascular disease or severe chronic disease were excluded. Vital status was obtained 10 years after inclusion. Results: There were 3208 participants and 156 deaths over the 10-year period. Determinants significantly and independently associated with 10-year all-cause death were living area (Hazard Ratio=1.04 [95% confidence interval: 0.67-1.61] for East, HR=1.76 [1.21-2.58] for North, versus South-west of France), age (HR=1.64 [1.02-2.64] for 45-54, HR=3.89 [2.49-6.09] for 55-64 vs 35-44 years), male gender (HR=2.11 [1.48-3.01]), no high school completion (HR=1.57 [1.05-2.33]), smoking (HR=2.61 [1.45-4.70] for smoking < 15 packs-years, HR=2.90 [2.01-4.17] for ≥ 15 packs-years, vs non-smoking), systolic blood pressure ≥ 160mmHg (HR= 1.57 [1.03-2.39]), LDL-cholesterol ≥ 5.2mmol/l (HR=1.62 [1.01-2.61]) and diabetes (HR=1.62 [1.10-2.37]). We developed an algorithm and established score sheets to estimate absolute 10-year risk of death, for a given subject, according to baseline characteristics. For example, a non diabetic, heavy smoker, 46 year old man, living in South-west of France, who did not complete high school, with LDL-cholesterol ≥ 5.2mmol/l and systolic blood pressure < 160mmHg, has a 17% 10-year risk of death. Conclusions: This prediction algorithm is a simple tool adapted to a European population to guide practitioners towards a more or less aggressive management of risk factors in apparently healthy subjects. [Copyright &y& Elsevier]

Background: The management of dyslipidemias remains a priority of preventive cardiology. The aim of this work was to assess lipids, lipoproteins and dyslipidemias trends between 1996 and 2007 in France. Methods: Two representative surveys of the general population were carried out in Northern, in North-Eastern and in Southwestern areas of France in 1996-97 (n=3508) and in 2006-07 (n=3597). Men and women aged 35 to 64 years were included. The investigators recorded all the cardiovascular risk factors and a blood sample was drawn. Data have been rectified with the respective original populations to study a 10-year trend in the measured parameters. Results: From 1996 to 2007, a significant 5.7% decrease in LDL-cholesterol (C) levels was observed in adults aged 35-64 years (p<0.001). During this same period a significant 7.8% increase in triglycerides was observed (p<0.001). LDL-C variation was more striking in subjects treated with a lipid-lowering drug, with a 17.6% reduction (p<0.001). Lipid-lowering drug prevalence increased significantly from 10.4% to 12.5% between the two periods (p=0.004). In 1996-97, 33.7% of the dyslipidemic subjects were treated with statins and 71.8% in 2006-07. In 2006-07, atorvastatin was the most commonly prescribed statin (35.8% of all statins) whereas the most common fibrate was fenofibrate (87.2% of all fibrates). A decrease in most of dyslipidemias (LDL-C >4.1 mmol/L or triglycerides ≥2.3 mmol/L or HDL-C <1.05 mmol/L in men or <1.3 mmol/L in women) has also been observed at a 10-year interval. On the other hand, we observed a significant increase in the combination of hypertriglyceridemia with high LDL-C. Conclusion: This study shows a favorable trend in LDL-C and dyslipidemias in France. The significant decrease in LDL-C observed among all the subjects and more particularly among subjects treated with lipid-lowering drugs should be incentive for physicians to support the management of all adults. [Copyright &y& Elsevier]

Background: Discrepancies may exist between guidelines and their implementation in daily practice. The aim of this study was to analyze management of acute myocardial infarction (AMI) in three population registries. Methods: In three areas of France, we registered in 2006 all acute coronary syndromes (ACS) aged 35-74 years, without any previous history of coronary heart disease, in the 3 MONICA Registries of Lille, Strasbourg and Toulouse. We obtained data before, during and after hospitalization for all consecutive cases of ACS in all hospitals covered by the 3 registries. In order to compare with the 2008 ESC guidelines on AMI, we restricted our analysis in patients (pts) with a discharge diagnosis of incident AMI. Results: Among 2018 incident ACS hospitalized in 2006, 1212 (60%) were discharged with a diagnosis of incident AMI (mean age 57.2 ± 10.3, 79.2% men). The delay between symptom onset and first medical contact was <1 h in 25%, <2 h in 45% and <4 h in 59% of pts. The first medical contact was a physician-manned ambulance for 48% of pts. The delay between symptom onset and hospitalization was <1 h in 8%, <2 h in 26% and <4 h in 53% of pts. Pre-hospital care included pre-hospital fibrinolysis in 10.6%, aspirin in 35.5% and clopidogrel in 15.1% of pts. Among all AMI, 74% were hospitalized in a percutaneous coronary intervention (PCI)-capable hospital and 53% had a primary angioplasty. During the first 24 h of hospitalization, 60.7% had PCI, 5.0% in-hospital fibrinolysis, 89.2% aspirin, 86.2% clopidogrel, 66.0% β-blockers, 60.7% angiotensin-converting enzyme (ACE) inhibitors and 42.2% statins. Among discharged pts, 93.7% had aspirin, 86.3% clopidogrel, 87.0% β-blockers, 75.6% ACE inhibitors and 90.8% had statins. One month mortality was 6.0%. Conclusion: The management of AMI has greatly improved in France. However, the first medical contact often remains a general practitioner and about half of the pts are admitted at hospital more than 4 hours after symptom onset. [Copyright &y& Elsevier]

The association of an elevated level of lipoprotein (a) (Lp(a)) with the development of coronary heart disease (CHD) remains controversial. Lp(a) was investigated as a CHD risk factor in the PRIME Study, a prospective cohort study which included 9133 French and Northern Irish men aged 50–59 at entry, without a history of CHD and not on hypolipidaemic drugs. During a follow-up of 5 years, 288 subjects experienced at least one CHD event (myocardial infarction (MI), coronary death, angina pectoris). Lp(a) was measured by immunoassay in all subjects on fresh plasma obtained at entry. Traditional cardiovascular risk factors such as low-density lipoproteins (LDL)-cholesterol, HDL-cholesterol, triglycerides, the presence of diabetes, hypertension or smoking were determined. Logistic regression analysis was used to evaluate Lp(a) level as a CHD risk factor after controlling for the other risk factors. In addition, its possible interaction with LDL- and HDL-cholesterol levels was investigated. Lp(a) appeared a significant risk factor (P<0.0006) in the whole cohort without between-population interaction, even if the association was not statistically significant in the Belfast sample. The relative risk (RR) of CHD events in subjects with Lp(a) levels in the highest quartile was 1.5 times that of subjects in the lowest quartile (RR: 1.56; 95% confidence intervals (CIs): 1.10–2.21). A high Lp(a) level was a risk for MI, coronary death and angina pectoris. A significant interaction term between Lp(a) and LDL-cholesterol levels, however, was found. The relative CHD risk associated with a Lp(a) level &ges;33 mg/dl in comparison with Lp(a) <33 mg/dl increasing gradually from 0.82 (95% CI: 0.28–2.44) in men with LDL-cholesterol in the lowest quartile (<121 mg/dl) to 1.58 (95% CI: 1.06–2.40) in the highest quartile (>163 mg/dl). In conclusion, Lp(a) increased the risk for MI and angina pectoris, especially in men with a high LDL-cholesterol level. This study which analyzed Lp(a) level using a measurement independent of apolipoprotein (a) size on fresh plasma, has confirmed utility of Lp(a) as a predictor of CHD. [Copyright &y& Elsevier]

Background Isolated negative T waves (INTW) are considered a common and minor electrocardiographic (ECG) abnormality. However, few recent studies have associated the presence of INTW with an increased risk of all-causes and cardiovascular mortalities. The aim was to evaluate the predictive value of INTW for coronary heart disease (CHD) and all-cause mortality. Methods Between 1991 and 1994, 12-lead ECGs were recorded in a sample of 10,600 men (PRIME Study). Among them, 1284 (12.1%) were excluded because of major ECG abnormalities at entry according to Minnesota code, a history of CHD or likely ischemic chest pain on the Rose Questionnaire. INTW were found in 256 subjects (2.74%). The primary outcome was myocardial infarction and angina pectoris after a 10 year follow-up (9.6 ± 1.4). Secondary outcome was all causes of death. Results After multivariate adjustment, INTW < 1 mm in anterior or inferior leads was associated with a higher risk of angina pectoris [HR 3.04 95% CI (1.13–8.22) and HR 3.67 95% CI (1.35–9.96) respectively] and INTW ≥ 1 mm in lateral or anterior leads were associated with a higher incidence of myocardial infarction [HR 2.75, 95% CI (1.29–5.88) and HR 3.20 95% CI (1.68–6.09) respectively]. The association of INTW ≥ 1 mm in leads V1 to V5 with mortality remained highly significant [HR 3.17 95% CI (1.77–5.65)] after multivariate adjustment. Conclusions In middle-age men, INTW is associated with a 2 to 3-fold higher risk of death, myocardial infarction and angina pectoris. [ABSTRACT FROM AUTHOR]

Abstract: Background: Food frequency questionnaires (FFQs) are often used to evaluate individuals' food intakes in epidemiologic studies because of their simplicity and low cost. Objective: To assess the validity of a short (24 items), qualitative FFQ used in the MONA LISA-NUT study. Design: Cross-sectional study of a representative sample in three French counties. Participants/setting: The sample included 2,630 participants aged 35 to 65 years from the MONA LISA-NUT study. Main outcome measures: Food consumption was measured with the FFQ and via food records for 3 consecutive days. Plasma fatty acids were measured from a subset of participants. Statistical analyses performed: The FFQ items' validity was assessed by calculating crude and deattenuated Pearson correlation coefficients between frequencies reported by the FFQ and average weights reported by the food records. Furthermore, the validity of some items of the FFQ measuring the consumption of fatty foods was assessed by calculating Pearson correlation coefficients between frequencies of consumption of these foods and dosages of the corresponding plasma fatty acids: fish and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), olive oil and oleic acid, margarine and elaidic acid, and dairy products and pentadecanoic and heptadecanoic acids. Results: The mean of the deattenuated Pearson correlation coefficients for all items was 0.46, with values ranging from 0.22 (fried food) to 0.77 (breakfast cereal). The correlation coefficient was ≤0.4 for one third of the 24 items. Moderate correlations were found between fish and EPA/DHA (EPA: r=0.43, 95% CI 0.33 to 0.51; DHA: r=0.39, 95% CI 0.30 to 0.47), but not for other food items. Conclusions: One third of the 24 items in the short, qualitative FFQ evaluated here were not sufficiently valid. However, for the food groups most commonly studied in the literature, this FFQ had the same degree of validity as other questionnaires designed to classify subjects according to their level of intake. [Copyright &y& Elsevier]

Abstract: The role of plasma retinol and carotenoids in coronary heart disease (CHD) remains unclear. The PRIME Study prospectively evaluated these in France and Northern Ireland in 9758 men aged 50–59 years who were free of CHD at baseline. After five years’ follow-up 150 incident cases of CHD (non-fatal myocardial infarction and fatal CHD) were compared with 285 controls matched for age, date of blood collection and study centre. Geometric means of major carotenoids did not differ significantly between cases and controls (P >0.05), whereas the absolute and lipid-standardized plasma retinol levels were 9% lower in cases than controls in both countries (P <0.002), without correlation with carotenoids. After adjusting for risk factors, the relative risks (RRs) of CHD in the first four quintiles of retinol distribution in controls (≤601, −683, −760, and −846μg/l) were 2.65 (P =0.0009), 1.70, 1.03, and 1.12 (all P >0.05) respectively, relative to the top quintile (retinol ≥846μg/l; linear trend P =0.0001). The 10th percentile of lipid-standardized retinol (≤544μg/l) predicted an RR of 4.7 (P <0.001). The risk associated with low retinol was comparable to strong risk factors (e.g. HDL-cholesterol, Interleukin-6) and behaved additively. In conclusion, plasma retinol levels of <601μg/l in a fifth of middle-aged European men place them at an approximately threefold RR of developing CHD. Thus the intake of vitamin A might be too low in middle-aged men. These findings must be confirmed. [Copyright &y& Elsevier]

Abstract: Background: Intermittent claudication (IC) is associated with an increased cardiovascular morbidity. The goal of the present study was to assess the contribution of conventional cardiovascular risk factors (CVRFs) to this increased risk. Method: The PRIME Study is a multicenter Prospective Cohort Study of 10 602 men recruited in 1991–1993, aged 50–59 at baseline and followed over 10 years. At baseline, a questionnaire on socio demographic data was self-administered and CVRFs were measured. Composite outcome consisted of incident MI, effort angina, unstable angina and coronary death. The standardized questionnaire of the London School of hygiene was used to identify claudicants. Data were analyzed using multivariate Cox models. Results: Probable and possible cases of IC were reported by 1.4% (135) and 4.6% (442) of subjects, respectively. Compared to subjects with no claudication, the probable cases demonstrated higher rates of CVRFs. The incidence of CAD events was 7.23/1000 person-year. Compared to non claudicants, probable claudicants had an increased age and country adjusted risk of coronary events (HR (95% CI), 2.4 (1.5–3.7), p <0.0001). After further adjustments for school duration, family history of early myocardial infarction, tobacco consumption, alcohol consumption, BMI, systolic blood pressure, antihypertensive treatment, diabetes, total cholesterol, HDL-cholesterol, triglycerides and lipid-lowering treatment, participants with probable claudication had an increased risk of coronary events but this was no longer significant (HR (95% CI), 1.3 (0.8–2.1), p =0.23). Conclusion: IC is associated with an increased risk of developing coronary events. This association is largely explained by the coexistence of CVRFs. [Copyright &y& Elsevier]

Abstract: We aimed at associating common osteopontin (OPN) gene variants with cardiovascular disease phenotypes.We scanned the OPN gene in 190 chromosomes from myocardial infarction (MI) patients and identified five variants in the promoter, three synonymous and one non-synonymous variant. All variants were investigated in case–control studies for MI (ECTIM: 990 cases, 900 controls) and brain infarction (BI) (GÉNIC: 466 cases, 444 controls). Promoter variants were functionally analyzed by bandshift assays, the coding D147D [T/C] by Western blot. Allele D147D C was independently and significantly associated with lower apoB levels (P =0.044 [ECTIM] P =0.03 [GENIC]), its allele frequency was significantly lower in patients with BI compared to controls (OR [95% CI] 0.39 [0.20–0.74], P =0.004), and C allele carriers had a significantly lower frequency of presence of carotid plaques (P =0.02). Bandshifts with HepG2 and Ea.hy926 nuclear proteins did not reveal any functionality of promoter variants, whereas the OPN-441C-containing construct resulted in reduced OPN protein expression in Western blots, complying with its potential protective effect on the phenotypes studied.We here provide evidence that a portion of the OPN locus is likely to associate with cardiovascular disease-related phenotypes. However, further experiments are warranted to clarify the functional role of OPN variants. [Copyright &y& Elsevier]

Lipid-lowering drugs are one of the most prescribed drugs worldwide. The aim was to compare 10-year all-cause mortality according to initial dyslipidemia status and lipid-lowering drug exposure. The PRIME study was a multicenter population-based prospective cohort study of men recruited in 1991 to 1993, aged 50 to 59 years at baseline, and followed up for 10 years. The 4 groups compared were normolipidemic, untreated dyslipidemic, and dyslipidemic subjects on fibrate or statin therapy. Data were analyzed using multivariate Cox models. The cohort included 7,722 French men (statin group 4.0%, fibrate group 7.9%, untreated dyslipidemic subjects 19.0%, and normolipidemic subjects 69.1%). After 10 years, 4.8% of the sample was lost to follow-up and 416 deaths occurred (cancers 53.1%, cardiovascular diseases 17.1%, and other 29.8%). After adjustment for center, age, educational level, cardiovascular risk factors, lipids, alcohol intake, and history of cardiovascular and severe chronic diseases, hazard ratios (HRs) for all-cause mortality were 0.49 (95% confidence interval [CI] 0.26 to 0.94, p = 0.031) for subjects treated with a statin, 0.65 (95% CI 0.42 to 0.99, p = 0.046) for those on fibrate therapy, and 0.76 (95% CI 0.56 to 1.03, p = 0.080) for normolipidemic men compared with untreated dyslipidemic subjects. In the statin group, HRs for death from cardiovascular disease, cancer, and other causes were 0.55 (p = 0.348), 0.41 (p = 0.067), and 0.68 (p = 0.546) compared with dyslipidemic subjects, respectively. In the fibrate group, HRs were 0.76 (p = 0.499), 0.52 (p = 0.041), and 0.87 (p = 0.746). In conclusion, in this cohort study carried out in a real-life setting, all-cause mortality was significantly lower in dyslipidemic subjects on fibrate or statin therapy than in untreated dyslipidemic patients. No excess risk of noncardiovascular death was observed. [Copyright &y& Elsevier]

Abstract: Background: Reports about the relationships between insulin concentrations and CHD risk are controversial. The objective of this survey was to study the association between insulin levels and CHD risk in middle-aged male participants of the PRIME Study after 5 years of follow-up. Methods: Our study adopted a nested case-control design including 294 cases of CHD and 536 controls randomly selected among healthy participants from the PRIME cohort. Data were obtained by questionnaires (medical history, lifestyle), standardised clinical measurements (blood pressure, anthropometric measurements), and a blood sample was obtained for biological measurements. Odds-Ratios for associations of four ordered classes of insulin concentration with CHD risk after adjustment for confounding factors were estimated using conditional logistic regression. Results: In Belfast, a significant trend (p <0.03) was observed between insulin classes and CHD risk in bivariate analyses, but this association lost its significance after multiple adjustments. In the French centres, a high risk of CHD (OR=3.24 [1.80–5.85], p <0.0001) was observed only for the second class of insulin concentration (6.5 to 9.9 mIU/l), compared with the reference class (<6.5 mIU/l). After multiple adjustments, this association remained highly significant (OR=2.92 [1.44–5.92], p <0.005). Conclusions: In Belfast (high-risk population), a significant trend was observed between insulin concentration classes and CHD risk but hyperinsulinaemia lost its association with CHD risk in multivariate analyses. In the French centres (lower risk population), slightly increased insulin concentrations were associated with a high risk of CHD, independently of cardiovascular risk factors and other features of the metabolic syndrome, but very high insulin concentrations were not. [Copyright &y& Elsevier]

Abstract: The pathogenesis of ischemic coronary events involves degradation of the extracellular matrix in atherosclerotic lesions. The cysteine protease inhibitor cystatin-C may be involved in this phenomenon. The association of plasma cystatin-C with the incidence of myocardial infarction—coronary death and angina, was examined in a nested case–control (two controls per case) design within the prospective cohort study (Prospective Epidemiological Study of Myocardial Infarction (PRIME Study)) which included 9758 men aged 50–59 years who were free of coronary heart disease (CHD) on entry and followed for a 5-year period. Three hundred and thirteen participants suffered myocardial infarction or coronary death (n =159) or angina pectoris (n =154) during follow-up. Cystatin-C was positively correlated with body mass index (BMI), low-density lipoprotein (LDL)-cholesterol, triglycerides and several inflammatory markers such as fibrinogen (r =0.18), C-reactive protein (CRP) (r =0.24), interleukin-6 (=0.20), tumor necrosis factor-α (TNFα) (r =0.27) and two TNFα receptors: TNFR1A (r =0.43) and TNFR1B (r =0.41); and negatively with high-density lipoprotein (HDL)-cholesterol (r =−0.25). After adjustment for traditional risk factors (age, diabetes, smoking, hypertension, BMI, triglycerides, LDL- and HDL-cholesterol), cystatin-C was significantly associated with the occurrence of the first ischemic coronary event. However, this association was no longer significant when CRP was included in the analysis. A decrease in glomerular filtration rate did not explain higher cystatin-C in cases than in controls. Cystatin-C appears to participate in the inflammatory phenomenon observed in the atherosclerotic process. Cystatin-C is not a more predictive risk marker of CHD than CRP or interleukin-6, but could be useful in detecting moderate chronic renal disease. [Copyright &y& Elsevier]

Abstract: The prevalence of coronary heart disease is much higher in men than in women and sex hormones might play a role in these differences through their influence on the lipid profile. The aim of this cross-sectional study was to study the relationship between hormonal markers (total testosterone (TT), estradiol (E2), sex-hormone-binding globulin (SHBG)) and plasma lipids in a population-based sample. Subjects were 352 men, 50–59 years old, selected in France (Lille, Strasbourg and Toulouse) and Northern-Ireland (Belfast) who had questionnaires and a medical examination at baseline of the PRIME prospective study (1991–1993). Pearson correlation coefficients and Student''s t tests were used to identify factors associated with plasma lipids. Multiple linear regression models were used for multivariate analyses, using triglycerides (TG) (log-transformed) and high density-lipoprotein cholesterol (HDL-C) as dependent variables. SHBG and TT were negatively correlated with TG (p &#60;0.0001 and p &#60;0.05, respectively) and positively correlated with HDL-C (p &#60;0.0001 and p &#60;0.01). E2 was positively correlated with TG (p &#60;0.05). No significant association was found between sex-hormones and LDL-C. In multiple linear regression analyses, SHBG remained independently associated negatively with TG (p &#60;0.01) and positively with HDL-C (p &#60;0.0001) after adjustment for centre of recruitment, age, body mass index, systolic blood pressure, smoking, alcohol intake and physical activity. After further adjustment for insulin, the association between SHBG and HDL-C remained highly significant (p &#60;0.0001). The association between SHBG and TG was weakened but remained also significant. Our results suggest that SHBG might to be a central protein in the hormonal regulation of the lipid profile. [Copyright &y& Elsevier]

Human paraoxonase-1 is hypothesised to protect serum lipoproteins from oxidative stress. Decreased serum activity of paraoxonase-1 in animal models is associated with an increased risk of vascular disease and has been linked to the anti-oxidant capacity of the enzyme. Promoter polymorphisms of the human paraoxonase-1 gene strongly influence serum concentrations of the enzyme. The present study examined the hypothesis that promoter polymorphisms may be genetic risk factors for vascular disease in man. Genotypes arising from the promoter C(-907)G polymorphism were analysed in the ECTIM2 population. The global odds ratio for myocardial infarction, comparing the high expressor GG genotype to other genotypes, was 0.77 (0.61–0.97) (P=0.024). The association with the promoter genotype was more pronounced in the youngest age group (odds ratio 0.52 (0.31–0.87), P=0.012) and was progressively lost with age (respectively 50 years to <60 years, P=0.26; >60 years, P=0.45). There was no association between the promoter genotypes and serum lipids. The data are consistent with the high expressor promoter genotype being linked to reduced risk of myocardial infarction. The influence of the genotype may be compromised in older patients. [Copyright &y& Elsevier]

The plasma cholesteryl ester transfer protein (CETP) plays a key role in reverse cholesterol transport (RCT) by mediating the transfer of cholesteryl ester (CE) from high-density lipoprotein (HDL) to atherogenic ApoB-containing lipoproteins, including VLDL, IDL and LDL. We describe a new polymorphism located at position −971 in the human CETP gene promoter, which corresponds to a G/A substitution at a potential AvaI restriction site. The relationship between the −971G/A polymorphism, plasma lipid parameters and plasma CETP concentration was evaluated in the Etude Cas-Te´moins de l'Infarctus du Myocarde (control–myocardial infarction cases) cohort, and revealed that the −971G/A polymorphism (A allele frequency: 0.491) was significantly associated with both plasma high-density lipoprotein cholesterol (HDL-C) levels and CETP concentration (P=0.006 and 0.009, respectively). Subjects with genotype −971GG displayed both low HDL-C levels and high plasma CETP concentration, while genotype −971AA subjects displayed the inverse relationship. Evaluation of potential interactions between the −971G/A and the −629C/A or TaqIB polymorphisms demonstrated that the −971G/A polymorphism interacts significantly with the functional −629C/A site and the TaqIB polymorphism with respect to plasma HDL-C levels (P=0.0014 and 0.012, respectively), but does not affect plasma CETP concentration. These results clearly suggest that the interaction between the 971G/A polymorphism and either the −629C/A or the TaqIB polymorphism on plasma CETP concentration is different than that implicated in HDL-C levels. Transient transfection of HepG2 cells revealed that the −971G/A polymorphism did not modulate transcriptional activity of the human CETP gene promoter. The −971G/A promoter polymorphism therefore constitutes a non-functional marker. Furthermore, the observed effects of the −971G/A polymorphism on both plasma CETP concentration and HDL-C levels are due to functional variants in linkage disequilibrium with it. Our findings strongly suggest the existence of as yet unidentified functional polymorphisms in the CETP gene promoter that could explain the association between specific polymorphisms of the CETP gene and both plasma HDL-C and CETP concentrations. [Copyright &y& Elsevier]

The PRIME Study was begun in 1991 and recruited 10,600 men aged 50 to 59 years in the WHO MONICA Project centers of Belfast, Lille, Strasbourg and Toulouse. Although drinkers in France and Northern Ireland consumed almost identical amounts, the pattern of consumption was different. In Northern Ireland beer and spirits were the staple beverages, whereas in France it was predominantly red wine; in France, 90% of men drank at least one unit per week versus 61% in Northern Ireland. Frenchmen drank evenly throughout the week, whereas in Northern Ireland two thirds of the consumption took place on Friday and Saturday nights. In the 5-year follow up of PRIME in France, the usual cardiovascular protective effect of increasing consumption (up to 45 units per week) was shown and the level of significance for trend in consumption was highly significant (p = 0.006); in Northern Ireland, this pattern was less consistent and did not attain significance. It remains a matter of conjecture whether in Northern Ireland the beneficial effects of alcohol consumption were annulled by a pattern of drinking that increases blood pressure, a well-established risk factor for heart disease, or whether the protection in France resulted from the consumption of wine along with food. [Copyright &y& Elsevier]