Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease.

Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.

Increased Levels of Circulating Fatty Acids Are Associated with Protective Effects against Future Cardiovascular Events in Nondiabetics.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide, particularly in individuals with diabetes. The current study objective was to determine the circulating metabolite profiles associated with the risk of future cardiovascular events, with emphasis on diabetes status. Nontargeted metabolomics analysis was performed by LC-HRMS in combination with targeted quantification of eicosanoids and endocannabinoids. Plasma from 375 individuals from the IMPROVE pan-European cohort was included in a case-control study design. Following data processing, the three metabolite data sets were concatenated to produce a single data set of 267 identified metabolites. Factor analysis identified six factors that described 26.6% of the variability in the given set of predictors. An association with cardiovascular events was only observed for one factor following adjustment (p = 0.026). From this factor, we identified a free fatty acid signature (n = 10 lipids, including saturated, monounsaturated, and polyunsaturated fatty acids) that was associated with lower risk of future cardiovascular events in nondiabetics only (OR = 0.65, 0.27-0.80 95% CI, p = 0.030), whereas no association was observed among diabetic individuals. These observations support the hypothesis that increased levels of circulating omega-6 and omega-3 fatty acids are associated with protective effects against future cardiovascular events. However, these effects were only observed in the nondiabetic population, further highlighting the need for patient stratification in clinical investigations.

The effects of a nutraceutical combination on plasma lipids and glucose: A systematic review and meta-analysis of randomized controlled trials.

Dyslipidemia and hyperglycemia are associated with an increased risk of ischemic cardiovascular disease. Positive effects of a nutraceutical combination comprising red yeast rice, berberine, policosanol, astaxanthin, coenzyme Q10 and folic acid (NComb) on plasma lipid and glucose levels have been reported in some but not all clinical trials. To address this inconsistency, we tried to estimate the size of lipid- and glucose-lowering effects of NComb through a systematic review and meta-analysis of randomized controlled trials. A systematic literature search in PubMed-Medline, SCOPUS and Google Scholar databases was conducted to identify randomized controlled trials investigating the effects of NComb on plasma lipids and glucose levels. Inverse variance-weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for net changes in lipid and glucose levels using a random-effects model. Random-effects meta-regression was performed to assess the effect of putative confounders on plasma lipid and glucose levels. Fourteen trials (1670 subjects in the NComb arm and 1489 subjects in the control arm) met the eligibility criteria for lipid analysis and 10 trials (1014 subjects in the NComb arm and 962 subjects in the control arm) for glucose analysis. Overall, WMDs were significant for the impact of NComb supplementation on plasma levels of total cholesterol (-26.15mg/dL, p<0.001), LDL-cholesterol (-23.85mg/dL, p<0.001), HDL-cholesterol (2.53mg/dL, p<0.001), triglycerides (-13.83mg/dL, p<0.001) and glucose (-2.59mg/dL, p=0.010). NComb-induced amelioration of lipid profile was not affected by duration of supplementation nor by baseline lipid levels; conversely, a greater glucose-lowering effect of NComb was found with higher baseline glucose levels and longer durations of supplementation. In conclusion, the present results suggest that NComb supplementation is associated with improvement of lipid and glucose profile. Short-term beneficial effects of NComb supplementation appear to be maintained in the long term.

A serum 25-hydroxyvitamin D concentration-associated genetic variant in DHCR7 interacts with type 2 diabetes status to influence subclinical atherosclerosis (measured by carotid intima-media thickness).

AIMS/HYPOTHESIS: The findings of studies investigating whether or not low serum 25-hydroxyvitamin D [25(OH)D] concentration promotes development of atherosclerosis have been contradictory. The present study employed a Mendelian randomisation approach and carotid artery intima-media thickness (cIMT), a surrogate marker of coronary artery disease, to address this question. METHODS: The multicentre, longitudinal Carotid Intima-Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population (IMPROVE) cohort study, which enrolled individuals with at least three cardiovascular risk factors and no history or symptoms of cardiovascular disease, was used for the present investigation. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30. Six single nucleotide polymorphisms (SNPs) associated with serum 25(OH)D concentration in genome-wide association studies were identified and genotyped in 3,418 individuals, of whom 929 had type 2 diabetes. RESULTS: SNPs in the genes encoding vitamin D binding protein (GC; rs2282679 and rs7041) and 7-dehydrocholesterol reductase/NAD synthetase-1 (DHCR7; rs12785878 and rs3829251) were negatively associated with 25(OH)D levels. Effect sizes and significance of associations between SNPs and 25(OH)D levels differed between individuals with and without type 2 diabetes, although no significant interactions were observed. A SNP in DHCR7 interacted with type 2 diabetes to significantly influence progression of cIMT measures independent of 25(OH)D levels and established risk factors. Expression analysis demonstrated that this SNP modulates DHCR7 mRNA levels in aortic adventitia. CONCLUSIONS/INTERPRETATION: SNPs in GC and DHCR7 were associated with serum levels of 25(OH)D, but only rs3829251 (DHCR7) influenced progression of subclinical atherosclerosis, as measured by cIMT, in a manner dependent on type 2 diabetes status but independent of 25(OH)D levels.

Progression of carotid intima-media thickness as predictor of vascular events: results from the IMPROVE study.

OBJECTIVE: To investigate whether several different measures of carotid intima-media thickness (IMT) progression are associated with subsequent vascular events and whether such associations are independent of baseline carotid atherosclerotic profile and Framingham risk factors. APPROACH AND RESULTS: A longitudinal cohort study (the Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population study) was performed in 7 centers in 5 European countries (Finland, France, Italy, the Netherlands, and Sweden). Three thousand four hundred eighty-two subjects (median age 64.1 years; 47.8% men) with ≥ 3 vascular risk factors were recruited and monitored for a postprogression median follow-up of 21.5 months, during which time 129 subjects experienced a first vascular event (incidence of 20.4 per 1000 person-years). The 15th month progression of mean and maximum carotid IMT of the left and right common carotids, bifurcations, internal carotid arteries, and their composite measures, as well as the fastest IMTmax progression (Fastest-IMT(max-progr)) detected in the whole carotid tree regardless of location, were used in statistical analyses. All carotid IMT measures showed significant progression during the first 15 months (P<0.001), but only the Fastest-IMT(max-progr) was significantly associated with the risk of subsequent vascular events. The Fastest-IMT(max-progr) association persisted after Bonferroni correction for multiple comparisons and after adjustments for Framingham risk factors and pharmacological treatments (all P<0.005). The use of Framingham Risk Score in place of Framingham risk factors provided almost identical results (P=0.003). CONCLUSIONS: The Fastest-IMT(max-progr), a novel approach to assess carotid IMT progression, identifies focal increases of carotid IMT and, in contrast to other progression variables, is associated with cardiovascular risk.

Serum 25-hydroxyvitamin D concentration in subclinical carotid atherosclerosis.

OBJECTIVE: Vitamin D deficiency has been implicated in cardiovascular disease and is associated with multiple cardiovascular risk factors. We investigated the serum 25-hydroxyvitamin D (25(OH)D) concentration in relation to latitude, baseline carotid intima-media thickness (IMT), and IMT progression, the carotid IMT measures being surrogate markers of subclinical atherosclerosis and cardiovascular disease risk. APPROACH AND RESULTS: Serum 25(OH)D concentration was related to high-resolution carotid IMT measures in 3430 middle-aged and elderly subjects with high cardiovascular risk but no prevalent disease, who were recruited at 7 centers in Finland, Sweden, The Netherlands, France, and Italy. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30 after entry into the study, whereas blood samples, clinical data, and information about lifestyle were collected at baseline. Serum 25(OH)D levels were positively associated with latitude (Jonckheere-Terpstra χ=166.643; P<0.001) and, as previously reported, associated with a range of cardiovascular risk factors. There were no independent relationships between 25(OH)D and segment-specific or composite IMT measures in the entire cohort. In analyses stratified by sex, diabetes mellitus, and statin treatment, weak associations with some baseline and progression measures of carotid IMT were observed in males, diabetics, and nonstatin-treated individuals. CONCLUSIONS: Levels of 25(OH)D differed across Europe, were highest in the North, showed multiple associations with established and emerging cardiovascular risk factors but were not consistently, independently related to measures of carotid IMT. This argues against a protective role of vitamin D against subclinical atherosclerosis in high-risk individuals.

Diagnostic performance of a multiple real-time PCR assay in patients with suspected sepsis hospitalized in an internal medicine ward.

Early identification of causative pathogen in sepsis patients is pivotal to improve clinical outcome. SeptiFast (SF), a commercially available system for molecular diagnosis of sepsis based on PCR, has been mostly used in patients hospitalized in hematology and intensive care units. We evaluated the diagnostic accuracy and clinical usefulness of SF, compared to blood culture (BC), in 391 patients with suspected sepsis, hospitalized in a department of internal medicine. A causative pathogen was identified in 85 patients (22%). Sixty pathogens were detected by SF and 57 by BC. No significant differences were found between the two methods in the rates of pathogen detection (P = 0.74), even after excluding 9 pathogens which were isolated by BC and were not included in the SF master list (P = 0.096). The combination of SF and BC significantly improved the diagnostic yield in comparison to BC alone (P < 0.001). Compared to BC, SF showed a significantly lower contamination rate (0 versus 19 cases; P < 0.001) with a higher specificity for pathogen identification (1.00, 95% confidence interval [CI] of 0.99 to 1.00, versus 0.94, 95% CI of 0.90 to 0.96; P = 0.005) and a higher positive predictive value (1.00, 95% CI of 1.00 to 0.92%, versus 0.75, 95% CI of 0.63 to 0.83; P = 0.005). In the subgroup of patients (n = 191) who had been receiving antibiotic treatment for ≥24 h, SF identified more pathogens (16 versus 6; P = 0.049) compared to BC. These results suggest that, in patients with suspected sepsis, hospitalized in an internal medicine ward, SF could be a highly valuable adjunct to conventional BC, particularly in patients under antibiotic treatment.

Aortic stiffness is increased in polymyalgia rheumatica and improves after steroid treatment.

BACKGROUND: Inflammatory rheumatic diseases have been associated with increased cardiovascular risk and arterial stiffness. Polymyalgia rheumatica (PMR), a disease which affects primarily older people, is characterised by a systemic inflammatory response but little is known about aortic involvement in PMR. A study was undertaken to investigate whether aortic stiffness is increased in PMR and whether it improves after steroid treatment. METHODS: Thirty-nine patients with PMR (age 72 ± 8 years, 44% men, blood pressure (BP) 134/75 ± 16/9 mm Hg) and 39 age-, sex- and BP-matched control subjects underwent aortic pulse wave velocity (PWV) determination. Aortic augmentation as a measure of the impact of the reflection wave on central haemodynamics was also measured and corrected for heart rate. Twenty-nine of the patients were re-examined after 4 weeks of treatment with prednisone at a dose of 15 mg/day. RESULTS: Aortic PWV was higher in patients with PMR than in control subjects (12.4 ± 4 vs 10.2 ± 2 m/s, p<0.01). Treatment was followed by a reduction in heart rate (from 78 ± 12 to 70 ± 10 beats/min, p<0.001) and no significant change in BP. Aortic PWV decreased after prednisone treatment (from 11.8 ± 3 to 10.5 ± 3 m/s, p=0.015), and the difference was independent of BP and heart rate changes. The change in aortic PWV had a direct correlation with percentage change in plasma C reactive protein (r=0.40, p=0.037). Treatment was also associated with a significant reduction in aortic augmentation index (from 34 ± 7% to 29 ± 8%, p=0.012). CONCLUSIONS: Polymyalgia rheumatica is associated with increased aortic stiffness which may improve upon reduction of systemic inflammation induced by treatment with glucocorticoids.

Visceral fat positively correlates with cholesterol synthesis in dyslipidaemic patients.

BACKGROUND: Quantification of plasma noncholesterol sterols allows the study of cholesterol absorption and synthesis. A pattern of low cholesterol absorption and high synthesis has been demonstrated in patients with obesity and insulin resistance. To understand the relationship between cholesterol absorption/synthesis and visceral obesity, we investigated surrogate markers of cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) in dyslipidaemic patients with different representation of abdominal fat, estimated by ultrasonographic measurement of visceral fat area (VFA). METHODS: In 126 patients with primary hyperlipaemias, plasma sitosterol, campesterol and lathosterol were determined by gas chromatography coupled with mass spectrometry. Visceral and subcutaneous fats were evaluated by ultrasonography. The study population was divided into two groups on the basis of VFA median values, below/equal and above 154 cm(2) . RESULTS Patients with higher VFA had significantly higher lathosterol levels (median 109 vs. 76 × 10(2) µmol/mmol cholesterol P < 0·004), body mass index, waist circumference, blood pressure, triglycerides, insulin, homoeostatic model assessment (HOMA)-IR and lower high-density lipoprotein (HDL)-C. VFA was positively correlated with lathosterol (ρ = 0·35, P < 0·001) and negatively with HDL-C (ρ = -0·43, P < 0·001), campesterol (ρ = -0·23, P = 0.01) and sitosterol (ρ = -0·35, P < 0·001). VFA was an independent predictor of lathosterol values (ß = 0·389, P < 0·0001, P of the model < 0·0001);age, systolic blood pressure, BMI, waist circumference, triglycerides, HDL-C and HOMA failed to enter the final equation. CONCLUSIONS: In hyperlipidaemic patients, the amount of visceral fat correlates with cholesterol synthesis; the use of ultrasonographic detection of abdominal adiposity allows a better characterization of cholesterol pathway, potentially useful for a tailored therapeutic approach.

Transient osteoporosis of the hip: successful treatment with teriparatide.

A 62-year-old man presented with a 2-month history of increasing pain in the left hip. Magnetic resonance imaging (MRI) showed bone marrow edema (BME) of the left femur, dual energy X-ray absorptiometry (DXA) showed osteopenia at the same level, whereas pelvis X-rays failed to show any objective findings. After ruling out other possible causes of BME such as aseptic osteonecrosis, infectious arthritis, primary or metastatic malignancy, tuberculosis, osteomyelitis, rheumatoid arthritis, and seronegative spondyloarthropathies, a diagnosis of transient osteoporosis of the hip (TOH) was made, and treatment with teriparatide at a daily dose of 20 µg was started and continued for 4 weeks. Disappearance of the symptoms and normalization of MRI were obtained.

Osteoanabolic therapy: a non-surgical option of treatment for Kümmell's disease?

Kümmell's disease is the current eponym of avascular osteonecrosis (AVN) of a vertebral body leading to a delayed non-healing vertebral compression fracture (VCF) and thus pseudo-arthrosis. AVN is characterized by production of gas that outlines a radiolucent zone in the vertebral body, called vacuum cleft sign (VCS) or "Kümmell's sign". This sign has been observed in up to one-third of VCFs and is often associated with osteoporosis and never with malignant or inflammatory diseases. Generally, treatment strategies are conservative management and percutaneous vertebroplasty. Teriparatide (rhPTH [1-34]) is an osteoanabolic agent approved for treatment of osteoporosis and helpful in fracture's healing too. Here, we describe the case of an 81-year-old osteoporotic woman presented with a 1-year history of persistent low back pain onset after a trauma. A lumbar spine Computer Tomography (CT) scan performed 2 months after the injury (November 2006) showed the VCS within a VCF of the first lumbar vertebra; a control CT scan 1 year later showed persistence of the finding. After 12 months of treatment with teriparatide 20 mcg/day, symptoms disappeared and vacuum was significantly reduced. In conclusion, Kümmell's disease may be hypothesized in patients with chronic spinal symptoms, especially in the presence of osteoporosis. Moreover in this condition, osteoanabolic treatment may be used in patients with Kümmell's disease to enhance vertebral fracture's healing and contribute to back pain relief.

Plasma lecithin:cholesterol acyltransferase and carotid intima-media thickness in European individuals at high cardiovascular risk.

Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for cholesterol esterification in plasma. LCAT is a major factor in HDL remodeling and metabolism, and it has long been believed to play a critical role in macrophage reverse cholesterol transport (RCT). The effect of LCAT on human atherogenesis is still controversial. In the present study, the plasma LCAT concentration was measured in all subjects (n = 540) not on drug treatment at the time of enrollment in the multicenter, longitudinal, observational IMPROVE study. Mean and maximum intima-media thickness (IMT) of the whole carotid tree was measured by B-mode ultrasonography in all subjects. In the entire cohort, LCAT quartiles were not associated with carotid mean and maximum IMT (P for trend 0.95 and 0.18, respectively), also after adjustment for age, gender, HDL-cholesterol (HDL-C), and triglycerides. No association between carotid IMT and LCAT quartiles was observed in men (P=0.30 and P=0.99 for mean and maximum IMT, respectively), whereas carotid IMT increased with LCAT quartiles in women (P for trend 0.14 and 0.019 for mean and maximum IMT, respectively). The present findings support the concept that LCAT is not required for an efficient reverse cholesterol transport and that a low plasma LCAT concentration and activity is not associated with increased atherosclerosis.

Cross-sectional analysis of baseline data to identify the major determinants of carotid intima-media thickness in a European population: the IMPROVE study.

AIMS: The 'IMPROVE study' was designed to investigate whether cross-sectional carotid artery intima-media thickness (IMT) and overall IMT progression are predictors of new vascular events in European individuals at high risk of cardiovascular diseases. This paper reports the results of the baseline analyses aimed at identifying the major determinants of increased carotid IMT (C-IMT). METHODS AND RESULTS: IMPROVE is a prospective, multicentre, longitudinal, observational study. A total of 3711 subjects (age range 54-79 years) with at least three vascular risk factors (VRFs) were recruited in seven centres in Finland, France, Italy, the Netherlands, and Sweden. Collected variables included clinical, biochemical, genetic, socioeconomic, psychological, nutritional, and educational data, personal and family history of diseases, drug intake, and physical activity. By multiple linear regression analysis, C-IMT was positively associated with latitude, age, gender, pulse pressure, pack-years, and hypertension, and inversely with educational level (all P < 0.0001 for IMT(mean-max)). Latitude was the strongest independent determinant of C-IMT (partial r(2) for IMT(mean-max) = 0.109, P < 0.0001) and alone accounted for nearly half of the variation explained by the regression model (partial r(2) for IMT(mean-max) = 0.243, P < 0.0001). The geographical gradient for C-IMT paralleled the well-known north-to-south cardiovascular mortality gradient (r(2) for IMT(mean) = 0.96). CONCLUSION: Latitude is an important determinant of C-IMT, which is not explained by between-country differences in established VRFs. Other unknown contributory mechanisms such as heritable, nutritional, or environmental factors may be important in the genesis of this geographical gradient.

High weight or body mass index increase the risk of vertebral fractures in postmenopausal osteoporotic women.

In the general population, low body weight and body mass index (BMI) are significant risk factors for any fracture, but the specific association between body weight, BMI, and prevalence of vertebral fractures in osteoporotic women is not fully recognized. Hence, the association between body weight, BMI, and prevalent vertebral fractures was investigated in 362 women with never-treated postmenopausal osteoporosis. All participants underwent measurement of BMI, bone mineral density (BMD), and semiquantitative assessment of vertebral fractures. Thirty percent of participants had > or =1 vertebral fracture. Body weight and BMI were associated with L1-L4 BMD (R = 0.29, P < 0.001 and R = 0.17, P = 0.009, respectively). In logistic regression analysis, BMI was positively associated with the presence of vertebral fractures independent of age and other traditional risk factors for fractures. Including weight and height instead of BMI in the multivariate model, showed weight as a positive and significant covariate of the presence of vertebral fractures (OR = 1.045; P = 0.016; 95% CI 1.008-1.084). BMI was associated with the number of vertebral fractures (rho = 0.18; P = 0.001), this association being confirmed also in the multivariate analysis (beta = 0.14; P = 0.03) after correction for smoking, early menopause, family history of fragility fractures and BMD. In conclusion, among postmenopausal women with osteoporosis, body weight and BMI are associated with a higher likelihood of having a vertebral fracture, irrespective of the positive association between weight and BMD.

Diffuse muscoskeletal pain and proximal myopathy: do not forget hypovitaminosis D.

A 20-year-old vegetarian man was admitted to our hospital complaining of muscle weakness and gait disturbances of 4 years duration. For the past 5 years, he had major depression and had confined himself at home. He exhibited tenderness upon palpation of the chest, sternum and proximal muscles. Hypocalcemia, hypophosphatemia, vitamin D deficiency, increased levels of alkaline phosphatase, and intact parathyroid hormone were noted. An x-ray skeletal survey revealed generalized osteopenia, multiple vertebral and costal fractures, and a pelvis deformed into the shape of a triangle. A diagnosis of osteomalacia secondary to vitamin D deficiency from lack of exposure to sunlight and to inadequacy of the diet was made. The patient was started on a treatment with 20,000 IU of vitamin D3 once a week plus 1 g/d of calcium. Eight months later, gait disturbances have significantly improved and laboratory findings have all normalized.

Influence of short-term rosuvastatin therapy on endothelial progenitor cells and endothelial function.

Endothelial progenitor cells maintain endothelium integrity by replacing injured endothelial cells. Cholesterol-lowering promotes either endothelial progenitor cells mobilization or improves endothelial function. It is unknown whether improving endothelial function with statin is associated with a parallel increased endothelial progenitor cells availability. Thirty-two hypercholesterolemic patients were assigned to 4-week rosuvastatin (10 mg daily) and 16 hypercholesterolemic served as controls. Circulating endothelial progenitor cells, brachial artery flow-mediated vasodilatation, an index of endothelial function, and the lipid profile were measured before and after the 4-week statin therapy. At baseline, we found a correlation between circulating endothelial progenitor cells and flow-mediated vasodilatation (r = .31, P = .029). At the end of the 4-week intervention with rosuvastatin there was a 37% reduction in low-density lipoprotein cholesterol (P < .001) and a significant 72% increase in the number of endothelial progenitor cells and flow-mediated vasodilatation (4.7 + 0.7% to 8.8 + 0.4%, P < .001). Endothelial progenitor cells and flow-mediated vasodilatation were unchanged at the end of the study in patients not taking statin. A correlation emerged between endothelial progenitor cells and flow-mediated vasodilatation variations (r = .52, P < .001), this correlation being still significant after controlling for blood cholesterol reduction. In conclusion, short-term rosuvastatin therapy contributes in hyperchoelsterolemic patients to improving endothelial function by lowering cholesterol and increasing the number of circulating endothelial progenitor cells; the latter effect appears to be partly independent from reduction in plasma cholesterol.

Maraviroc Intensification Modulates Atherosclerotic Progression in HIV-Suppressed Patients at High Cardiovascular Risk. A Randomized, Crossover Pilot Study.

BACKGROUND: Experimental CCR5 antagonism with maraviroc in atherosclerosis-prone mice and preliminary data in humans suggest an anti-atherosclerotic effect of the drug. We assessed the impact of maraviroc treatment in persons living with HIV on subclinical indicators of atherosclerosis. METHODS: Persons living with HIV on effective antiretroviral therapy (ART) including only protease inhibitors were recruited if they had a Framingham risk score >20% and brachial flow-mediated dilation (bFMD) <4%, as indices of high cardiovascular risk. Maraviroc (300 mg per os for 24 weeks) was administered, in addition to ongoing ART, to all patients using a crossover design. Brachial FMD, carotid-femoral pulse wave velocity (cfPWV), and carotid intima-media thickness (cIMT) were measured as markers of atherosclerosis. Vascular competence-as expressed by the ratio of circulating endothelial microparticles (EMPs) to endothelial progenitor cells (EPCs)-and markers of systemic inflammation and monocyte and platelet activation were assessed. RESULTS: Maraviroc treatment significantly improved bFMD, cfPWV, and cIMT by 66%, 11%, and 13%, respectively (P = .002, P = .022, P = .038, respectively). We also found a beneficial effect of maraviroc on the EMP/EPC ratio (P < .001) and platelet/leucocyte aggregates (P = .013). No significant changes in markers of systemic inflammation, monocyte activation, and microbial translocation were observed. CONCLUSIONS: Maraviroc led to significant improvements in several markers for cardiovascular risk, endothelial dysfunction, arterial stiffness, and early carotid atherosclerosis, which was accompanied by an increase of vascular competence, without seeming to affect systemic inflammation. Our data support the need for larger studies to test for any effects of maraviroc on preventing atherosclerosis-driven pathologies.

A priori-defined Mediterranean-like dietary pattern predicts cardiovascular events better in north Europe than in Mediterranean countries.

BACKGROUND: The Mediterranean Diet (MD) is a model of healthy eating contributing to a favorable health status, but its clinical usefulness is still debated. The aim of this study was to relate the adherence to MD with the incidence of cardio/cerebro-vascular events (VEs) in north and south European participants of the IMPROVE study. METHODS: IMPROVE is an observational, longitudinal, prospective cohort study involving 3703 individuals from five European countries (Finland, Sweden, Netherlands, France and Italy). The study end-point was the incidence of the first combined cardio/cerebro-vascular event occurring during 36-months follow-up. At baseline, a dietary questionnaire about the usual intake during the year preceding enrollment was administered. Based on 7 nutritional items, a MD Score was constructed in which minimal adherence was 0 and maximal adherence was 7. RESULTS: Latitude was the strongest determinant of MD score (p < 0.001). VEs occurred in 215 participants. The incidence of VEs was the highest in subjects with MD score 0-1, lower in those with score 2-3 and the lowest in those with score ≥ 4. MD score remained significantly associated with subsequent VEs after adjustment for confounders (hazard ratio for one-point increment of the score = 0.75, p < 0.001) and the association was stronger in northern than in southern countries (p = 0.04 for MD Score × latitude interaction). CONCLUSIONS: The MD adherence score based on a simple dietary questionnaire detects changes of risk of VEs. According to our findings north Europeans appear to benefit most from VE-prevention when their diet is altered to the MD diet.

Data on the association between a simplified Mediterranean diet score and the incidence of combined, cardio and cerebro vascular events.

Data presented in this article are related to the research article entitled "A priori-defined Mediterranean-like dietary pattern predicts cardiovascular events better in north Europe than in Mediterranean countries" [Veglia et al., 2018]. Data contain information about the incidence of cardiovascular events in a high-risk European population (IMPROVE study) [Baldassarre et al., 2010, 2012, 2013]. Combined vascular events, as well as cardio- and cerebro-vascular events were stratified according to a priori-defined simple Mediterranean Diet (MD) score, based on just seven nutritional items (minimal adherence was 0 and maximal adherence was 7).

Preclinical vascular damage in white postmenopausal women: the relevance of osteoprotegerin.

Osteoprotegerin (OPG) has recently been implicated in human atherogenesis. Abdominal obesity represents an established risk factor for the onset and development of atherosclerotic damage. The aim of the present study was to investigate the link between OPG and abdominal fat and the relationship to precocious features of atherosclerotic disease such as brachial flow-mediated vasodilation (FMV) and the intima-media thickening (IMT) in 195 white postmenopausal women (age range, 43-75 years). The study population was divided into 2 groups: group 1-waist circumference <80 cm and group 2-waist circumference > or = 80 cm. Group 2 had higher menopausal years, body mass index, low-density lipoprotein cholesterol, triglycerides, C-reactive protein, and carotid IMT. High-density lipoprotein cholesterol was higher in group 1. Afterward, these groups were divided on the basis of a cutoff value of OPG (6.85 pmol/L) that was the median of its distribution: patients with OPG < or = 6.85 pmol/L were OPG(-), and those with OPG >6.85 pmol/L were OPG(+). The OPG(+) subjects in both had lower brachial FMV and higher carotid IMT in comparison with OPG(-) subjects. At the multivariate regression analysis, waist circumference, high-density lipoprotein cholesterol, C-reactive protein, and OPG were predictors of carotid mean IMT (beta = 0.55, P = .001; beta = -0.14, P = .001; beta = 0.16, P = .001; and beta = 0.14, P = .05, respectively) and age, OPG, low-density lipoprotein cholesterol, and brachial diameter of brachial FMV (beta = -0.13, P = .05; beta = -0.25, P = .001; beta = -0.14, P = .024; and beta = 0.48, P = .001, respectively). The conclusions are as follows: first, OPG levels did not appear to be conditioned by a risk factor such as abdominal obesity; and second, OPG levels are mainly linked to the evidence of vascular damage. On this basis, we could speculate that OPG levels may be considered not a cardiovascular risk condition but a defense against atherosclerotic progression.