Sex differences in noninvasive vascular function in the community.

OBJECTIVE: The relation of noninvasive vascular function to sex, sex hormones, and reproductive history in the general population is little understood. METHODS: We simultaneously assessed flow-mediated dilation (FMD) and peripheral arterial tonometry in 454 women (mean age 40.4±16.1 years, age range 19-78 years) and 100 men (mean age 44.7±15.3 years) in a community-based cohort. Plasma estradiol, progesterone, luteinizing hormone, and follicle stimulating hormones were measured, and menstrual cycle and reproductive history were recorded. RESULTS: Vascular function was blunted in men as compared to women irrespective of menopausal status and adjustment for classical cardiovascular risk factors and hormones. Vascular reactivity changed during the menstrual cycle and correlated with estradiol concentrations for FMD, r=0.13 and inversely with progesterone for pulse amplitude, r=-0.14, and brachial artery diameter, r=-0.10. Multivariable-adjusted regressions showed a relation of estradiol with FMD, ß 0.658, 95% confidence interval (CI) 0.084/1.232, P=0.025 in women. Age at menarche (ß 0.070, 95% CI 0.039/0.101, P<0.0001) and breastfeeding duration (ß -0.006, 95% CI -0.011/-0.001, P=0.036) were related to brachial artery diameter, age at menarche also to FMD (ß -0.455, 95% CI -0.886/-0.023, P=0.039). CONCLUSION: Sex differences in noninvasive conduit and peripheral arterial function with better vascular reactivity in women were not fully explained by female sex hormones and menopausal status. Age at menarche and duration of breastfeeding were also related to vascular function and need further investigation.

Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.

One major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitative trait loci (eQTLs) have been reliably related to disease susceptibility. Trans-regulating mechanisms may play a more prominent role in disease susceptibility. We analyzed 12,808 genes detected in at least 5% of circulating monocyte samples from a population-based sample of 1,490 European unrelated subjects. We applied a method of extraction of expression patterns-independent component analysis-to identify sets of co-regulated genes. These patterns were then related to 675,350 SNPs to identify major trans-acting regulators. We detected three genomic regions significantly associated with co-regulated gene modules. Association of these loci with multiple expression traits was replicated in Cardiogenics, an independent study in which expression profiles of monocytes were available in 758 subjects. The locus 12q13 (lead SNP rs11171739), previously identified as a type 1 diabetes locus, was associated with a pattern including two cis eQTLs, RPS26 and SUOX, and 5 trans eQTLs, one of which (MADCAM1) is a potential candidate for mediating T1D susceptibility. The locus 12q24 (lead SNP rs653178), which has demonstrated extensive disease pleiotropy, including type 1 diabetes, hypertension, and celiac disease, was associated to a pattern strongly correlating to blood pressure level. The strongest trans eQTL in this pattern was CRIP1, a known marker of cellular proliferation in cancer. The locus 12q15 (lead SNP rs11177644) was associated with a pattern driven by two cis eQTLs, LYZ and YEATS4, and including 34 trans eQTLs, several of them tumor-related genes. This study shows that a method exploiting the structure of co-expressions among genes can help identify genomic regions involved in trans regulation of sets of genes and can provide clues for understanding the mechanisms linking genome-wide association loci to disease.

Noninvasive vascular function measurement in the community: cross-sectional relations and comparison of methods.

BACKGROUND: Several methods of noninvasive vascular function testing have been suggested for cardiovascular risk screening in the community. A direct comparison of the different methods and their relation to classical cardiovascular risk factors in a large cohort is missing. METHODS AND RESULTS: In 5000 individuals (mean age, 55.5 ± 10.9 years; age range, 35 to 74 years; women, 49.2%) of the population-based Gutenberg Heart Study, we performed simultaneous measurement of flow-mediated dilation (FMD) and peripheral arterial volume pulse determined by infrared photo (reflection index) and pneumatic plethysmography (PAT) and explored their associations. All function measures were recorded at baseline and after reactive hyperemia induced by 5-minute brachial artery occlusion. Correlations between different measures of vascular function were statistically significant but moderate. The strongest association for hyperemic response variables was observed for PAT ratio and FMD (Spearman r = 0.17; age- and sex-adjusted partial correlation, 0.068). Classical risk factors explained between 15.8% (baseline reflection index) and 58.4% (brachial artery diameter) of the baseline values but only accounted for 3.2% (reflection index), 15.4% (FMD), and 13.9% (PAT ratio) of the variability of reflective hyperemic response. Regression models varied in their relations to classical risk factors for the individual vascular function measures. Consistently associated with different vascular function methods were age, sex, body mass index, and indicators of hypertension. Peripheral tonometry also showed a relation to fasting glucose concentrations. CONCLUSIONS: Noninvasive measures of conduit artery and peripheral arterial function are modestly correlated, differ in their relation to classical cardiovascular risk factors, and may thus reflect different pathologies.

Multiple marker approach to risk stratification in patients with stable coronary artery disease.

AIMS: multimarker approaches for risk prediction in coronary artery disease have remained inconsistent. We assessed multiple biomarkers representing distinct pathophysiological pathways in relation to cardiovascular events in stable angina. METHODS AND RESULTS: we investigated 12 biomarkers reflecting inflammation [C-reactive protein, growth-differentiation factor (GDF)-15, neopterin], lipid metabolism (apolipoproteins AI, B100), renal function (cystatin C, serum creatinine), and cardiovascular function and remodelling [copeptin, C-terminal-pro-endothelin-1, mid-regional-pro-adrenomedullin (MR-proADM), mid-regional-pro-atrial natriuretic peptide (MR-proANP), N-terminal-pro-B-type natriuretic peptide (Nt-proBNP)] in 1781 stable angina patients in relation to non-fatal myocardial infarction and cardiovascular death (n = 137) over 3.6 years. Using Cox proportional hazards models and C-indices, the strongest association with outcome for log-transformed biomarkers in multivariable-adjusted analyses was observed for Nt-proBNP [hazard ratio (HR) for one standard deviation increase 1.65, 95% confidence interval (CI) 1.28-2.13, C-index 0.686], GDF-15 (HR 1.59, 95% CI 1.25-2.02, C-index 0.681), MR-proANP (HR 1.46, 95% CI 1.14-1.87, C-index 0.673), cystatin C (HR 1.39, 95% CI 1.10-1.75, C-index 0.671), and MR-proADM (HR 1.63, 95% CI 1.21-2.20, C-index 0.668). Each of these top single markers and their combination (C-index 0.690) added predictive information beyond the baseline model consisting of the classical risk factors assessed by C-index and led to substantial reclassification (P-integrated discrimination improvement <0.05). CONCLUSION: comparative analysis of 12 biomarkers revealed Nt-proBNP, GDF-15, MR-proANP, cystatin C, and MR-proADM as the strongest predictors of cardiovascular outcome in stable angina. All five biomarkers taken separately offered incremental predictive ability over established risk factors. Combination of the single markers slightly improved model fit but did not enhance risk prediction from a clinical perspective.

Genetics and beyond--the transcriptome of human monocytes and disease susceptibility.

BACKGROUND: Variability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits and have a critical role in physiological and disease processes. METHODOLOGY/PRINCIPAL FINDINGS: To get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors. Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected (P<5.78x10(-12)), most of them (90%) being cis-modulated. Extensive analyses showed that associations identified by genome-wide association studies of lipids, body mass index or blood pressure were rarely compatible with a mediation by monocyte expression level at the locus. At a study-wide level (P<3.9x10(-7)), 1,662 expression traits (13.0%) were significantly associated with at least one risk factor. Genome-wide interaction analyses suggested that genetic variability and risk factors mostly acted additively on gene expression. Because of the structure of correlation among expression traits, the variability of risk factors could be characterized by a limited set of independent gene expressions which may have biological and clinical relevance. For example expression traits associated with cigarette smoking were more strongly associated with carotid atherosclerosis than smoking itself. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that the monocyte transcriptome is a potent integrator of genetic and non-genetic influences of relevance for disease pathophysiology and risk assessment.

Selenium supplementation improves antioxidant capacity in vitro and in vivo in patients with coronary artery disease The SElenium Therapy in Coronary Artery disease Patients (SETCAP) Study.

BACKGROUND: Selenium is a central determinant of antioxidative glutathione peroxidase 1 (GPx-1) expression and activity. The relevance of selenium supplementation on GPx-1 in coronary artery disease (CAD) needs to be established. We assessed the effect of selenium supplementation on GPx-1 in cell culture and on endothelial function in a prospective clinical trial. METHODS: Human coronary artery endothelial cells were incubated with 5.78 to 578 nmol/L sodium selenite, Se-methyl-selenocysteine hydrochloride, or seleno-l-methionine. Glutathione peroxidase 1 mRNA and protein expression and activity were measured. Coronary artery disease patients (n = 465) with impaired endothelial function (flow-mediated dilation [FMD] <8%) were randomly assigned to receive 200 or 500 microg sodium selenite daily or matching placebo during a 12-week period. We tested the effect on red blood cell GPx-1 activity and brachial artery FMD. Furthermore, differences in biomarkers of oxidative stress and inflammation were measured. RESULTS: Sodium selenite and Se-methyl-selenocysteine hydrochloride increased GPx-1 protein and activity in a dose-dependent manner (P < .0001). The intention-to-treat groups comprised 433 CAD patients. Glutathione peroxidase 1 activity increased from 37.0 U/gHb (31.3-41.7) to 41.1 U/gHb (35.2-48.4) (P < .0001) in the 200 microg and from 38.1 U/gHb (33.2-43.8) to 42.6 U/gHb (35.0-49.1) (P < .0001) in the 500 microg sodium selenite group treated for 12-weeks. No relevant changes were observed for FMD or biomarkers of oxidative stress and inflammation. CONCLUSIONS: Sodium selenite supplementation increases GPx-1 activity in endothelial cells and in CAD patients. Future studies have to demonstrate whether long-term CAD outcome can be improved.