Identification of circulating apolipoprotein M as a new determinant of insulin sensitivity and relationship with adiponectin.

BACKGROUND: The adiponectin is one of the rare adipokines down-regulated with obesity and protects against obesity-related disorders. Similarly, the apolipoprotein M (apoM) is expressed in adipocytes and its expression in adipose tissue is associated with metabolic health. We compared circulating apoM with adiponectin regarding their relationship with metabolic parameters and insulin sensitivity and examined their gene expression patterns in adipocytes and in the adipose tissue. METHODS: Circulating apoM and adiponectin were examined in 169 men with overweight in a cross-sectional study, and 13 patients with obesity during a surgery-induced slimming program. Correlations with clinical parameters including the insulin resistance index (HOMA-IR) were analyzed. Multiple regression analyses were performed on HOMA-IR. The APOM and ADIPOQ gene expression were measured in the adipose tissue from 267 individuals with obesity and a human adipocyte cell line. RESULTS: Participants with type 2 diabetes had lower circulating adiponectin and apoM, while apoM was higher in individuals with dyslipidemia. Similar to adiponectin, apoM showed negative associations with HOMA-IR and hs-CRP (r < -0.2), and positive correlations with HDL markers (HDL-C and apoA-I, r > 0.3). Unlike adiponectin, apoM was positively associated with LDL markers (LDL-C and apoB100, r < 0.20) and negatively correlated with insulin and age (r < -0.2). The apoM was the sole negative determinant of HOMA-IR in multiple regression models, while adiponectin not contributing significantly. After surgery, the change in HOMA-IR was negatively associated with the change in circulating apoM (r = -0.71), but not with the change in adiponectin. The APOM and ADIPOQ gene expression positively correlated in adipose tissue (r > 0.44) as well as in adipocytes (r > 0.81). In adipocytes, APOM was downregulated by inflammatory factors and upregulated by adiponectin. CONCLUSIONS: The apoM rises as a new partner of adiponectin regarding insulin sensitivity. At the adipose tissue level, the adiponectin may be supported by apoM to promote a healthy adipose tissue. TRIAL REGISTRATION: NCT01277068, registered 13 January 2011; NCT02332434, registered 5 January 2015; and NCT00390637, registered 20 October 2006.

Association of Circulating Autophagy Proteins ATG5 and Beclin 1 with Acute Myocardial Infarction in a Case-Control Study.

INTRODUCTION: Acute myocardial infarction (AMI) is a main contributor of sudden cardiac death worldwide. The discovery of new biomarkers that can improve AMI risk prediction meets a major clinical need for the identification of high-risk patients and the tailoring of medical treatment. Previously, we reported that autophagy a highly conserved catabolic mechanism for intracellular degradation of cellular components is involved in atherosclerotic plaque phenotype and cardiac pathological remodeling. The crucial role of autophagy in the normal and diseased heart has been well described, and its activation functions as a pro-survival process in response to myocardial ischemia. However, autophagy is dysregulated in ischemia/reperfusion injury, thus promoting necrotic or apoptotic cardiac cell death. Very few studies have focused on the plasma levels of autophagy markers in cardiovascular disease patients, even though they could be companion biomarkers of AMI injury. The aims of the present study were to evaluate (1) whether variations in plasma levels of two key autophagy regulators autophagy-related gene 5 (ATG5) and Beclin 1 (the mammalian yeast ortholog Atg6/Vps30) are associated with AMI and (2) their potential for predicting AMI risk. METHODS: The case-control study population included AMI patients (n = 100) and control subjects (n = 99) at high cardiovascular risk but without known coronary disease. Plasma levels of ATG5 and Beclin 1 were measured in the whole population study by enzyme-linked immunosorbent assay. RESULTS: Multivariate analyses adjusted on common cardiovascular factors and medical treatments, and receiver operating characteristic curves demonstrated that ATG5 and Beclin 1 levels were inversely associated with AMI and provided original biomarkers for AMI risk prediction. CONCLUSION: Plasma levels of autophagy regulators ATG5 and Beclin 1 represent relevant candidate biomarkers associated with AMI.

Neuromelanin Locus Coeruleus MRI Contrast in Migraine With Aura.

INTRODUCTION: The locus coeruleus (LC) is one of the brainstem nuclei that may be activated during migraine attack. As LC contains neuromelanin, a by-product of norepinephrine synthesis, it can be delineated in vivo using neuromelanin sensitive magnetic resonance imaging (MRI). The neuromelanin content in LC has been suggested to reflect previous LC activation. We investigated LC MRI contrast in patients with migraine with aura (MWA) and its correlation with migraine features. METHODS: This matched cohort study compared 23 MWA patients aged 30-55 and without comorbidity, to 23 sex- and age-matched healthy controls. The study was conducted in a University Hospital. LC contrast was measured with T1 neuromelanin-sensitive-weighted 3T MRI. Voxels were manually selected by 2 independent researchers and comparison was made twice using intersection and union of the voxels selected by the 2 observers. RESULTS: No difference was found in neuromelanin LC contrast between MWA patients and controls with both the INTER method (0.224 ± 0.042 vs 0.228 ± 0.048; difference: 0.0001 (95%CI: -0.032 to 0.026), P = .799) and UNION method (0.218 ± 0.043 vs 0.222 ± 0.047; difference: -0.0012 (95%CI: -0.031 to 0.026), P = .775). Global LC volume was also similar between the 2 groups with INTER method (15.087 ± 3.965 vs 13.739 ± 3.583; difference: 2 (95%CI: -1 to 4), P = .233) and UNION method (17.522 ± 4.440 vs 16.087 ± 4.274; difference: 1 (95%CI: -2 to 4), P = .270). Moreover, no correlations were found between neuromelanin LC contrast and migraine features (duration of migraine and frequency of attacks). CONCLUSION: These negative findings do not support the use of neuromelanin LC contrast as a biomarker of MA.

Subarachnoid and Subdural Hemorrhages in Lobar Intracerebral Hemorrhage Associated With Cerebral Amyloid Angiopathy.

Background and Purpose- Identifying underlying cerebral amyloid angiopathy (CAA) in patients with intracerebral hemorrhage (ICH) has important clinical implication. Convexity subarachnoid hemorrhage (cSAH) and subdural hemorrhage (SDH) are computed tomography features of CAA-related ICH. We explored whether cSAH and SDH could be additional magnetic resonance imaging markers of CAA in lobar ICH survivors. Methods- We analyzed data from consecutive patients with acute lobar ICH associated with CAA (CAA-ICH) or not attributed to CAA (non-CAA-ICH). Magnetic resonance imaging scans were analyzed for cSAH, SDH, and markers of small vessel disease. The associations of cSAH and SDH with the diagnosis of probable CAA based on the modified Boston criteria were explored using multivariable models. Results- We included 165 patients with acute lobar ICH (mean age 70±13 years): 72 patients with CAA-ICH and 93 with non-CAA-ICH. Patients with CAA-ICH had a higher prevalence of cSAH (73.6% versus 39.8%; P<0.001) and SDH (37.5% versus 21.5%; P=0.02) than non-CAA-ICH. In multivariate logistic regression analysis, the presence of cSAH was independently associated with CAA-ICH (odds ratio, 2.97; 95% CI, 1.26-6.99; P=0.013), whereas there was no association between SDH and CAA-ICH. Conclusions- Among survivors of acute lobar ICH, the presence of cSAH is associated with the magnetic resonance imaging-based diagnosis of CAA. Further studies should investigate whether cSAH help improve the sensitivity of magnetic resonance imaging for in vivo diagnosis of CAA.

Prevalence and long-term prognosis of patients with 'narrower than normal' QRS complexes.

Aims: Very narrow QRS have been reported in sudden death survivors but prevalence and prognosis role of narrow QRS is unknown. Methods and results: 546 healthy men between 50 and 60 years (group 1) and 373 similar patients with coronary artery disease (368 men, group 2) underwent signal averaged ECG (SA-ECG) allowing precise measurement of QRS duration. All cause-mortality was determined after 18 ± 3 years follow-up. Mean QRS duration was 97 ± 13 ms in group 1 and 103 ± 16 ms in group 2. Tenth percentile was 84 ms in group 1 and 85 ms in group 2. All cause-mortality in group 1 was 10.4% (57/546): 6/85 in case of QRS <85 ms (7%) and 2/23 (9%) in case of QRS >120 ms (ns). HR for all-cause mortality was 0.75 (95% CI 0.32-1.76, P = 0.52) for QRS <85 ms and 0.86 (95% CI 0.21-3.53, P = 0.84) for QRS >120 ms. All cause mortality in group 2 was 29% (109/373): 7/44 in case of QRS <85 ms (16%) and 22/44 (50%) in case of QRS >120 ms (P = 0.002). HR for all-cause mortality was 0.65 (95% CI 0.29-1.45, P = 0.29) for QRS <85 ms and 1.73 (95% CI 1.02-2.94, P = 0.05) for QRS >120 ms. Conclusion: QRS duration <80-85 ms can be observed in a significant proportion of middle-aged healthy males and in similar patients with ischemic heart disease. Narrow QRS were not linked to prognosis in any group.

Impact of occupational environmental stressors on blood pressure changes and on incident cases of hypertension: a 5-year follow-up from the VISAT study.

BACKGROUND: The role of occupational stressors (OS) on blood pressure (BP) is often suspected, but asserting its impact remains uncertain. Our goal was to evaluate their impact on BP increase and on incident cases of hypertension over a 5-year period. METHODS: One thousand, one hundred and fifty-six men and women from the French prospective VISAT study were followed up over five-years (T1 to T2). Exposures to a large panel of OS (physical, organizational, psychosocial and employment categories) were collected. Linear and logistic regressions were used to assess associations between OS and T2-T1 SBP difference and incident cases of hypertension. They were performed to determine the role of OS first considered separately, then in combination, in crude and adjusted models for main cardiovascular risk factors (gender, age, education, BMI, lifestyle habits and medical history). RESULTS: For initial SBP level < 130 mmHg, carrying loads, intense noise exposure, working more than 48 h/week, active and high strain tended to be associated with an SBP difference increase, while job recognition was associated with a decrease. After adjustment, only significant associations with job strain and job recognition persisted. For initial SBP level ≥ 130 mmHg, being exposed to an active job strain was positively associated with T2-T1 SBP difference only in unadjusted model. Considering all the OS, the recognition of completed tasks had a major protective role. No impact of OS on incident cases of hypertension was observed. CONCLUSION: Associations between OS and SBP were observed mainly when initial SBP is within the normal range, and are mainly explained by cardiovascular factors, requiring physician's particular attention to people exposed to these OS. VISAT study is registered in "LE PORTAIL EPIDEMIOLOGIE - FRANCE- AVIESAN -ID 3666".

Central obesity is associated with non-cirrhotic portal vein thrombosis.

BACKGROUND & AIMS: 30-40% of portal vein thrombosis (PVT) remains of unknown origin. An association between metabolic syndrome (MetS) and peripheral vein thrombosis has been reported but not with PVT, to date. The aim of this study was to investigate the association between MetS and PVT. METHODS: Between 2003 and 2014, all consecutive patients with non-cirrhotic PVT were prospectively included. Patient's characteristics and risks factors were recorded at the time of inclusion. Controls were selected by random in the general population and were matched 1/1 according to age and sex. RESULTS: Seventy-nine patients with PVT were included: 40 present with at least one risk factor for PVT (SPVT) and 39 were found to be idiopathic (IPVT). The prevalence of MetS was 25.6% in SPVT group vs. 47.4% in IPVT group and 17.9% in controls from the general population (C-IPVT: p=0.01). The waist circumference and body mass index were higher in the IPVT group than in the SPVT group (105 vs. 93cm, p=0.004 and 29.4 vs. 25.0kg/m(2), p=0.004) and in the C-IPVT group (105 vs. 92cm, p=0.001 and 29.4 vs. 25.8kg/m(2), p=0.003). Overweight was observed in 82.0% of patients in the IPVT group vs. 44% in the SPVT group (p=0.002) and 51% in the C-IPVT group (p=0.01). The mean visceral fat area was higher in IPVT than in SPVT (18,223mm(2)vs. 12,690mm(2), p=0.02). In multivariate analyses, an increase in waist circumference was the strongest parameter associated with idiopathic PVT. CONCLUSION: Central obesity is associated with PVT and could become one of the main risk factors for digestive thromboses.

Serum levels of mitochondrial inhibitory factor 1 are independently associated with long-term prognosis in coronary artery disease: the GENES Study.

BACKGROUND: Epidemiological and observational studies have established that high-density lipoprotein cholesterol (HDL-C) is an independent negative cardiovascular risk factor. However, simple measurement of HDL-C levels is no longer sufficient for cardiovascular risk assessment. Therefore, there is a critical need for novel non-invasive biomarkers that would display prognostic superiority over HDL-C. Cell surface ecto-F1-ATPase contributes to several athero-protective properties of HDL, including reverse cholesterol transport and vascular endothelial protection. Serum inhibitory factor 1 (IF1), an endogenous inhibitor of ecto-F1-ATPase, is an independent determinant of HDL-C associated with low risk of coronary artery disease (CAD). This work aimed to examine the predictive value of serum IF1 for long-term mortality in CAD patients. Its informative value was compared to that of HDL-C. METHOD: Serum IF1 levels were measured in 577 male participants with stable CAD (age 45-74 years) from the GENES (Genetique et ENvironnement en Europe du Sud) study. Vital status was yearly assessed, with a median follow-up of 11 years and a 29.5 % mortality rate. Cardiovascular mortality accounted for the majority (62.4 %) of deaths. RESULTS: IF1 levels were positively correlated with HDL-C (r s = 0.40; P < 0.001) and negatively with triglycerides (r s = -0.21, P < 0.001) and CAD severity documented by the Gensini score (r s = -0.13; P < 0.01). Total and cardiovascular mortality were lower at the highest quartiles of IF1 (HR = 0.55; 95 % CI, 0.38-0.89 and 0.50 (0.28-0.89), respectively) but not according to HDL-C. Inverse associations of IF1 with mortality remained significant, after multivariate adjustments for classical cardiovascular risk factors (age, smoking, physical activity, waist circumference, HDL-C, dyslipidemia, hypertension, and diabetes) and for powerful biological and clinical variables of prognosis, including heart rate, ankle-brachial index and biomarkers of cardiac diseases. The 10-year mortality was 28.5 % in patients with low IF1 (<0.42 mg/L) and 21.4 % in those with high IF1 (≥0.42 mg/L, P < 0.02). CONCLUSIONS: We investigated for the first time the relation between IF1 levels and long-term prognosis in CAD patients, and found an independent negative association. IF1 measurement might be used as a novel HDL-related biomarker to better stratify risk in populations at high risk or in the setting of pharmacotherapy.

All-Cause Mortality up to and After Coronary Heart Disease and Stroke Events in European Middle-Aged Men: The PRIME Study.

BACKGROUND AND PURPOSE: The aim was to investigate prospectively the all-cause mortality risk up to and after coronary heart disease (CHD) and stroke events in European middle-aged men. METHODS: The study population comprised 10 424 men 50 to 59 years of age recruited between 1991 and 1994 in France (N=7855) and Northern Ireland (N=2747) within the Prospective Epidemiological Study of Myocardial Infarction. Incident CHD and stroke events and deaths from all causes were prospectively registered during the 10-year follow-up. In Cox's proportional hazards regression analysis, CHD and stroke events during follow-up were used as time-dependent covariates. RESULTS: A total of 769 CHD and 132 stroke events were adjudicated, and 569 deaths up to and 66 after CHD or stroke occurred during follow-up. After adjustment for study country and cardiovascular risk factors, the hazard ratios of all-cause mortality were 1.58 (95% confidence interval 1.18-2.12) after CHD and 3.13 (95% confidence interval 1.98-4.92) after stroke. CONCLUSIONS: These findings support continuous efforts to promote both primary and secondary prevention of cardiovascular disease.

RNY-derived small RNAs as a signature of coronary artery disease.

BACKGROUND: Data from next generation sequencing technologies uncovered the existence of many classes of small RNAs. Recent studies reported that small RNAs are released by cells and can be detected in the blood. In this report, we aimed to discover the occurrence of novel circulating small RNAs in coronary artery disease (CAD). METHODS: We used high-throughput sequencing of small RNAs from human and mouse apoptotic primary macrophages, and analyzed the data by empirical Bayes moderated t-statistics to assess differential expression and the Benjamini and Hochberg method to control the false discovery rate. Results were then confirmed by Northern blot and RT-qPCR in foam cells and in two animal models for atherosclerosis, namely ApoE(-/-) and Ldlr(-/-) mouse lines. Quantitative RT-PCR to detect identified small RNAs, the RNY-derived small RNAs, was performed using sera of 263 patients with CAD compared to 514 matched healthy controls; the Student t-test was applied to statistically assess differences. Associations of small RNAs with clinical characteristics and biological markers were tested using Spearman's rank correlations, while multivariate logistic regressions were performed to test the statistical association of small RNA levels with CAD. RESULTS: Here, we report that, in macrophages stimulated with pro-apoptotic or pro-atherogenic stimuli, the Ro-associated non-coding RNAs, called RNYs or Y-RNAs, are processed into small RNAs (~24-34 nt) referred to as small-RNYs (s-RNYs), including s-RNY1-5p processed from RNY1. A significant upregulation of s-RNY expression was found in aortic arches and blood plasma from ApoE(-/-) and Ldlr(-/-) mice and in serum from CAD patients (P <0.001). Biostatistical analysis revealed a positive association of s-RNY1-5p with hs-CRP and ApoB levels; however, no statistical interaction was found between either of these two markers and s-RNY1-5p in relation to the CAD status. Levels of s-RNY1-5p were also independent from statin and fibrate therapies. CONCLUSION: Our results position the s-RNY1-5p as a relevant novel independent diagnostic biomarker for atherosclerosis-related diseases. Measurement of circulating s-RNY expression would be a valuable companion diagnostic to monitor foam cell apoptosis during atherosclerosis pathogenesis and to evaluate patient's responsiveness to future therapeutic strategies aiming to attenuate apoptosis in foam cells in advanced atherosclerotic lesions.

Expired-air carbon monoxide as a predictor of 16-year risk of all-cause, cardiovascular and cancer mortality.

BACKGROUND: Measurement of expired-air carbon monoxide (EACO) is commonly used to ascertain non-smoking status, although it can also reflect exposures not related to smoking. Our aim was to assess 16-year mortality according to EACO measured at baseline, in a general population. METHODS: Our analysis was based on the Third French MONICA population survey (1994-1997). Causes of death were obtained 16 years after inclusion, and assessment of determinants of mortality was based on Cox modeling. RESULTS: EACO was measured in 2232 apparently healthy participants aged 35-64. During follow-up, 195 deaths occurred (19% were due to cardio-vascular (CV) causes and 49% to cancer). At baseline, the mean EACO was 11.8 (±7.4)ppm, 4.6 (±2.5)ppm, 4.3 (±2.2)ppm for current, former and never smokers, respectively (P<0.001). After adjustment for main mortality risk factors and smoking, the hazard ratio (HR) for total mortality was 1.03[95% confidence interval: 1.01-1.06] per 1-unit increase in EACO, and it was 1.04[1.01-1.07] for cancer mortality. Adjusted HR for CV mortality was 1.05[1.01-1.10] but did not remain significant after additional adjustment for smoking (0.98[0.91-1.04]). Interactions between EACO and smoking were not significant. CONCLUSIONS: In a general population, baseline EACO is an independent predictor of 16-year all-cause and cancer mortality, after adjustment for confounders including smoking. Given that the effect of EACO is similar among smokers and non-smokers, EACO is probably not solely related to smoking but could also be a marker of inhaled ambient carbon monoxide and/or endogenous production. Besides, smoking better predicts CV mortality than EACO.

Tobacco Use and Cryptogenic Stroke in Young Adults.

OBJECTIVE: Cryptogenic stroke is the leading subtype of ischemic stroke in the young. We sought to evaluate the association between traditional cardiovascular risk factors and cryptogenic stroke by using a case-control study. METHODS: Patients aged 18-54 years, consecutively treated for first-ever cryptogenic ischemic stroke in an academic stroke unit, were compared with subjects from the general population living in the same geographic area. Control subjects were matched for age and sex with patients. We further evaluated the association between significant risk factors and nonobstructive (<50% stenosis) carotid plaque and thrombus among patients with cryptogenic stroke. Odds ratios [OR] were calculated using logistic regression analysis. RESULTS: A total of 155 patients with cryptogenic stroke (66.4% men, mean age 43.5 years [SD 8.4]) were included in the study. Cryptogenic stroke was associated with current tobacco use (42.6% in patients versus 23.9% in control subjects; OR = 2.38, 95% confidence interval [CI] 1.40-4.05, P = .002). Current tobacco use was associated with nonobstructive carotid plaque (OR = 6.22; 95% CI, 2.43-15.9; P = .001) and nonobstructive carotid thrombus (OR = 13.7; 95% CI, 1.42-132.7; P = .03) among the patients. CONCLUSION: Our case-control study showed a strong link between current tobacco use and cryptogenic stroke in young adults.

Adiponectin and long-term mortality in coronary artery disease participants and controls.

OBJECTIVE: Despite cardioprotective properties, studies investigating adiponectin as a cardiovascular disease marker led to conflicting results. We investigated in participants with stable coronary artery disease (CAD) and controls whether serum adiponectin was associated with long-term mortality, considering varying degrees of CAD severity. METHODS AND RESULTS: A case-control design with prospective median follow-up of 8.1 years was used. Survival rates among 715 CAD men (aged 45-74 years) in increasing quartiles of serum adiponectin values were 87.5%, 85.6%, 76.4%, and 67.6%, respectively (P<0.001). Survival rates in 782 controls with adiponectin <9.1 µg/mL and ≥9.1 µg/mL (third quartile) were 95.3% and 91.0%, respectively (P=0.035). Adiponectin concentration above the highest quartile was associated with an increased risk of total and cardiovascular disease mortality in CAD patients (P=0.001 and P=0.001) and controls (P=0.02 and P=0.004). The associations among high adiponectin, total mortality, and cardiovascular disease mortality remained significant after multivariate adjustments for metabolic, cardiac, and CAD severity variables. No significant interaction was found among CAD patients, controls, and the relationship of adiponectin with mortality. CONCLUSIONS: High serum adiponectin is a predictor of mortality, particularly from cardiovascular disease. This prognostic value remains significant whatever the severity of the CAD and the metabolic status and is not different among people with and without CAD.

Serum IF1 concentration is independently associated to HDL levels and to coronary heart disease: the GENES study.

HDL is strongly inversely related to cardiovascular risk. Hepatic HDL uptake is controlled by ecto-F1-ATPase activity, and potentially inhibited by mitochondrial inhibitor factor 1 (IF1). We recently found that IF1 is present in serum and correlates with HDL-cholesterol (HDL-C). Here, we have evaluated the relationship between circulating IF1 and plasma lipoproteins, and we determined whether IF1 concentration is associated with the risk of coronary heart disease (CHD). Serum IF1 was measured in 648 coronary patients ages 45-74 and in 669 matched male controls, in the context of a cross-sectional study on CHD. Cardiovascular risk factors were documented for each participant, including life-style habits and biological and clinical markers. In controls, multivariate analysis demonstrated that IF1 was independently positively associated with HDL-C and apoA-I (r = 0.27 and 0.28, respectively, P < 0.001) and negatively with triglycerides (r = -0.23, P < 0.001). Mean IF1 concentration was lower in CHD patients than in controls (0.43 mg/l and 0.53 mg/l, respectively, P < 0.001). In multivariate analyses, following adjustments on cardiovascular risk factors or markers, IF1 was negatively related to CHD (P < 0.001). This relationship was maintained after adjustment for HDL-C or apoA-I. This study identifies IF1 as a new determinant of HDL-C that is inversely associated with CHD.

Adipocytokines and the risk of ischemic stroke: the PRIME Study.

OBJECTIVE: Adipocytokines are hormones secreted from adipose tissue that possibly link adiposity and the risk of cardiovascular disease, but limited prospective data exist on plasma adipocytokines and ischemic stroke risk. We investigated associations and predictive properties of 4 plasma adipocytokines, namely resistin, adipsin, leptin, and total adiponectin, with regard to incident ischemic stroke in the PRIME Study. METHODS: A cohort of 9,771 healthy men 50 to 59 years of age at baseline was followed up over a period of 10 years. In a nested case-control study, 95 ischemic stroke cases were matched with 190 controls on age, study center, and date of examination. Hazard ratios (HRs) per standard deviation increase in plasma adipocytokine levels were estimated using conditional logistic regression analysis. The additive value of adipocytokines in stroke risk prediction was evaluated by discrimination and reclassification metrics. RESULTS: Resistin (HR, 1.88; 95% confidence interval [CI], 1.16-3.03), adipsin (HR, 2.01; 95% CI, 1.33-3.04), and total adiponectin (HR, 1.53; 95% CI, 1.01-2.34), but not leptin, were independent predictors of ischemic stroke. The performance of a traditional risk factor model predicting ischemic stroke was significantly improved by the simultaneous inclusion of resistin, adipsin, and total adiponectin (c-statistic: 0.673 [95% CI, 0.631-0.766] vs 0.826 [95% CI, 0.792-0.892], p < 0.001; net reclassification improvement: 38.1%, p < 0.001). INTERPRETATION: Higher plasma levels of resistin, adipsin, and total adiponectin were associated with an increased 10-year risk of ischemic stroke among healthy middle-aged men. Resistin, adipsin, and total adiponectin provided incremental value over traditional risk factors for the prediction of ischemic stroke risk.

External validation of the 2008 Framingham cardiovascular risk equation for CHD and stroke events in a European population of middle-aged men. The PRIME study.

OBJECTIVE: To test the applicability of the sex-specific 2008 Framingham general cardiovascular risk equation for coronary heart disease (CHD) and stroke in European middle-aged men from Ireland and France. METHODS: In the PRIME study, 9638 healthy middle-aged men recruited in France and Ireland were surveyed for 10 years for the occurrence of first CHD and stroke events. The original Framingham equation, the partially calibrated Framingham equation (using the PRIME baseline survival at 10 years), and the completely calibrated Framingham equation (additionally using risk factor means calculated in PRIME) were assessed. Model fit (expected versus observed events) and discrimination ability were assessed using a modified Hosmer-Lemeshow Chi-square statistic and Harrell's c-index respectively. RESULTS: The original (uncalibrated) Framingham equation overestimated by 1.94-fold the risk of CHD and stroke combined in PRIME, and by 2.23 and 1.42-fold in PRIME-France and PRIME-Ireland respectively. Adequate fit was found after complete calibration. However, discrimination ability of the Framingham equation was poor as shown by Harrell's c-index lower than 0.70. CONCLUSION: The (completely) calibrated 2008 Framingham equation predicted accurate number of CHD and stroke events but discriminated poorly individuals at higher from those at lower event risk in a European population of middle-aged men.

Early loss of bone mineral density is correlated with a gain of fat mass in patients starting a protease inhibitor containing regimen: the prospective Lipotrip study.

BACKGROUND: HIV-infected patients starting antiretroviral treatment (ART) experience deep and early disorders in fat and bone metabolism, leading to concomitant changes in fat mass and bone mineral density. METHODS: We conducted a prospective study in treatment-naive HIV-infected patients randomized to receive two nucleoside reverse transcriptase inhibitors in combination with either a protease inhibitor (PI) or a non-nucleosidic reverse transcriptase inhibitor (NNRTI), to evaluate early changes in body composition, bone mineral density and metabolic markers as differentially induced by antiretroviral therapies. We measured changes in markers of carbohydrate, of fat and bone metabolism, and, using dual-emission X-ray absorptiometry (DXA), body composition and bone mineral density (BMD). Complete data on changes between baseline and after 21 months treatment were available for 35 patients (16 in the PI group and 19 in the NNRTI group). RESULTS: A significant gain in BMI and in total and lower limb fat mass was recorded only in patients receiving PI. A loss of lumbar BMD was observed in both groups, being higher with PI. Plasma markers of bone metabolism (alkaline phosphatase, osteocalcin, collagen crosslaps) and levels of parathormone and of 1,25diOH-vitamin D3 significantly increased in both groups, concomitant with a decline in 25OH-vitamin D3. Lipids and glucose levels increased in both groups but rise in triglyceride was more pronounced with PI. A correlation between loss of BMD and gain of fat mass is observed in patients starting PI. CONCLUSIONS: We evidenced an early effect of ART on lipid and bone metabolisms. PI lead to a significant gain in fat mass correlated with a sharp drop in BMD but active bone remodelling is evident with all antiretroviral treatments, associated with low vitamin D levels and hyperparathyroidism. In parallel, signs of metabolic restoration are evident. However, early increases in lean and fat mass, triglycerides, waist circumference and leptin are much more pronounced with PI.

Plasma levels of autophagy regulator Rubicon are inversely associated with acute coronary syndrome.

Background: The discovery of novel biomarkers that improve current cardiovascular risk prediction models of acute coronary syndrome (ACS) is needed for the identification of very high-risk patients and therapeutic decision-making. Autophagy is a highly conserved catabolic mechanism for intracellular degradation of cellular components through lysosomes. The autophagy process helps maintain cardiac homeostasis and dysregulated autophagy has been described in cardiovascular conditions. Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein) is a key regulator of autophagy with a potential role in cardiac stress. Objectives: The aims of the present study were to assess whether changes in circulating Rubicon levels are associated with ACS and to evaluate the added value of Rubicon to a clinical predictive risk model. Methods and results: The study population included ACS patients (n = 100) and control subjects (n = 99) at high to very high cardiovascular risk but without known coronary event. Plasma Rubicon levels were measured in the whole study population by enzyme-linked immunosorbent assay. Multivariate logistic regression analyses established that Rubicon levels were inversely associated with ACS. A receiver operating characteristic curve analysis demonstrated that the addition of Rubicon improved the predictive performance of the model with an increased area under the curve from 0.868 to 0.896 (p = 0.038). Conclusions: Plasma levels of the autophagy regulator Rubicon are associated with ACS and provide added value to classical risk markers for ACS.

Depressive symptoms, a time-dependent risk factor for coronary heart disease and stroke in middle-aged men: the PRIME Study.

BACKGROUND AND PURPOSE: To date, the association between depressive symptoms and the risk of cardiovascular diseases remains controversial. We investigated prospectively, within the same population, the time course of the association between baseline depressive symptoms and first stroke or coronary heart disease event. METHODS: In the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study, a multicenter, observational, prospective cohort, 9601 men from France and Northern Ireland were surveyed for the occurrence of first coronary heart disease (n=647) and stroke events (n=136) over 10 years. At baseline, the fourth quartile of a 13-item modified Center for Epidemiological Studies questionnaire was used to define the presence of depressive symptoms. We sought the best time-dependent function to assess the association between depressive symptoms and outcomes. Thus, the hazard ratios were estimated by a Cox proportional hazard model after splitting the follow-up before and after 5 years of follow-up time periods. RESULTS: Depressive symptoms at baseline were associated with coronary heart disease in the first 5 years of follow-up (hazard ratio, 1.43; 1.10-1.87) and with stroke in the second 5 years of follow up (hazard ratio, 1.96; 1.21-3.19) after adjustment for age, study centers, baseline socioeconomic factors, traditional vascular risk factors, and antidepressant treatment. The association was even stronger for ischemic stroke (n=108; hazard ratio, 2.48; 1.45-4.25). CONCLUSIONS: The current study suggests that in healthy, European, middle-aged men, baseline depressive symptoms are associated with an increased risk of coronary heart disease in the short-term, and for stroke in the long-term.

MiR-223 and MiR-186 Are Associated with Long-Term Mortality after Myocardial Infarction.

Background-The identification and stratification of patients at risk of fatal outcomes after myocardial infarction (MI) is of considerable interest to guide secondary prevention therapies. Currently, no accurate biomarkers are available to identify subjects who are at risk of suffering acute manifestations of coronary heart disease as well as to predict adverse events after MI. Non-coding circulating microRNAs (miRNAs) have been proposed as novel diagnostic and prognostic biomarkers in cardiovascular diseases. The aims of the study were to investigate the clinical value of a panel of circulating miRNAs as accurate biomarkers associated with MI and mortality risk prediction in patients with documented MI. Methods and Results-seven circulating plasma miRNAs were analyzed in 67 MI patients and 80 control subjects at a high cardiovascular risk but without known coronary diseases. Multivariate logistic regression analyses demonstrated that six miRNAs were independently associated with MI occurrence. Among them, miR-223 and miR-186 reliably predicted long-term mortality in MI patients, in particular miR-223 (HR 1.57 per one-unit increase, p = 0.02), after left ventricular ejection fraction (LVEF) adjustment. Kaplan-Meier survival analyses provided a predictive threshold value of miR-223 expression (p = 0.028) for long-term mortality. Conclusions-Circulating miR-223 and miR-186 are promising predictive biomarkers for long-term mortality after MI.