Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research

Risk Factors, Subsequent Disease Onset, and Prognostic Impact of Myocardial Infarction and Atrial Fibrillation

BACKGROUND: Although myocardial infarction (MI) and atrial fibrillation (AF) are frequent comorbidities and share common cardiovascular risk factors, the direction and strength of the association of the risk factors with disease onset, subsequent disease incidence, and mortality are not completely understood. METHODS AND RESULTS: In pooled multivariable Cox regression analyses, we examined temporal relations of disease onset and identified predictors of MI, AF, and all-cause mortality in 108 363 individuals (median age, 46.0 years; 48.2% men) free of MI and AF at baseline from 6 European population-based cohorts. During a maximum follow-up of 10.0 years, 3558 (3.3%) individuals were diagnosed exclusively with MI, 1922 (1.8%) with AF but no MI, and 491 (0.5%) individuals developed both MI and AF. Association of sex, systolic blood pressure, antihypertensive treatment, and diabetes appeared to be stronger with incident MI than with AF, whereas increasing age and body mass index showed a higher risk for incident AF. Total cholesterol and daily smoking were significantly related to incident MI but not AF. Combined population attributable fraction of cardiovascular risk factors was &gt;70% for incident MI, whereas it was only 27% for AF. Subsequent MI after AF (hazard ratio [HR], 1.68; 95% CI, 1.03–2.74) and subsequent AF after MI (HR, 1.75; 95% CI, 1.31–2.34) both significantly increased overall mortality risk. CONCLUSIONS: We observed different associations of cardiovascular risk factors with both diseases indicating distinct pathophysiological pathways. Subsequent diagnoses of MI and AF significantly increased mortality risk

ENPP1 Affects Insulin Action and Secretion: Evidences from In Vitro Studies

The aim of this study was to deeper investigate the mechanisms through which ENPP1, a negative modulator of insulin receptor (IR) activation, plays a role on insulin signaling, insulin secretion and eventually glucose metabolism. ENPP1 cDNA (carrying either K121 or Q121 variant) was transfected in HepG2 liver-, L6 skeletal muscle- and INS1E beta-cells. Insulin-induced IR-autophosphorylation (HepG2, L6, INS1E), Akt-Ser473, ERK1/2-Thr202/Tyr204 and GSK3-beta Ser9 phosphorylation (HepG2, L6), PEPCK mRNA levels (HepG2) and 2-deoxy-D-glucose uptake (L6) was studied. GLUT 4 mRNA (L6), insulin secretion and caspase-3 activation (INS1E) were also investigated. Insulin-induced IR-autophosphorylation was decreased in HepG2-K, L6-K, INS1E-K (20%, 52% and 11% reduction vs. untransfected cells) and twice as much in HepG2-Q, L6-Q, INS1E-Q (44%, 92% and 30%). Similar data were obtained with Akt-Ser473, ERK1/2-Thr202/Tyr204 and GSK3-beta Ser9 in HepG2 and L6. Insulin-induced reduction of PEPCK mRNA was progressively lower in untransfected, HepG2-K and HepG2-Q cells (65%, 54%, 23%). Insulin-induced glucose uptake in untransfected L6 (60% increase over basal), was totally abolished in L6-K and L6-Q cells. GLUT 4 mRNA was slightly reduced in L6-K and twice as much in L6-Q (13% and 25% reduction vs. untransfected cells). Glucose-induced insulin secretion was 60% reduced in INS1E-K and almost abolished in INS1E-Q. Serum deficiency activated caspase-3 by two, three and four folds in untransfected INS1E, INS1E-K and INS1E-Q. Glyburide-induced insulin secretion was reduced by 50% in isolated human islets from homozygous QQ donors as compared to those from KK and KQ individuals. Our data clearly indicate that ENPP1, especially when the Q121 variant is operating, affects insulin signaling and glucose metabolism in skeletal muscle- and liver-cells and both function and survival of insulin secreting beta-cells, thus representing a strong pathogenic factor predisposing to insulin resistance, defective insulin secretion and glucose metabolism abnormalities

Splenic trauma : WSES classification and guidelines for adult and pediatric patients

Spleen injuries are among the most frequent trauma-related injuries. At present, they are classified according to the anatomy of the injury. The optimal treatment strategy, however, should keep into consideration the hemodynamic status, the anatomic derangement, and the associated injuries. The management of splenic trauma patients aims to restore the homeostasis and the normal physiopathology especially considering the modern tools for bleeding management. Thus, the management of splenic trauma should be ultimately multidisciplinary and based on the physiology of the patient, the anatomy of the injury, and the associated lesions. Lastly, as the management of adults and children must be different, children should always be treated in dedicated pediatric trauma centers. In fact, the vast majority of pediatric patients with blunt splenic trauma can be managed non-operatively. This paper presents the World Society of Emergency Surgery (WSES) classification of splenic trauma and the management guidelines.Peer reviewe

Search for high-mass diphoton resonances in pp collisions at √s = 8 TeV with the ATLAS detector

This article describes a search for high-mass resonances decaying to a pair of photons using a sample of 20.3  fb−¹ of pp collisions at √s = 8 TeV recorded with the ATLAS detector at the Large Hadron Collider. The data are found to be in agreement with the Standard Model prediction, and limits are reported in the framework of the Randall-Sundrum model. This theory leads to the prediction of graviton states, the lightest of which could be observed at the Large Hadron Collider. A lower limit of 2.66 (1.41) TeV at 95% confidence level is set on the mass of the lightest graviton for couplings of k/M̄Pl=0.1(0.01)