Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y.

Pigmentation is a polygenic trait encompassing some of the most visible phenotypic variation observed in humans. Here we present direct estimates of selection acting on functional alleles in three key genes known to be involved in human pigmentation pathways--HERC2, SLC45A2, and TYR--using allele frequency estimates from Eneolithic, Bronze Age, and modern Eastern European samples and forward simulations. Neutrality was overwhelmingly rejected for all alleles studied, with point estimates of selection ranging from around 2-10% per generation. Our results provide direct evidence that strong selection favoring lighter skin, hair, and eye pigmentation has been operating in European populations over the last 5,000 y.

Kidney injury and mortality after transcatheter aortic valve implantation in a routine clinical cohort.

OBJECTIVES: We aimed at identifying predictors of renal impairment and its impact on long-term outcome after transcatheter aortic valve implantation (TAVI). BACKGROUND: Renal impairment is common in mostly elderly, multimorbid patients undergoing TAVI. The risk of periprocedural renal function impairment and its association with outcome is incompletely understood. METHODS: In 458 consecutive patients (mean age, 80.6 ± 7.0 years, 52.2% women) who underwent routine TAVI procedures, we assessed estimated glomerular filtration rate (eGFR) at baseline, during 72-hr postprocedure and at discharge. Over a median follow-up of 0.96 years, we observed 142 deaths. RESULTS: In multivariable-adjusted models, predictors of renal function deterioration within 72 hr were baseline eGFR (ß = 0.83, 95% confidence interval [CI] = 0.76/0.91; P < 0.0001), body mass index (ß = -1.20, 95% CI = 1.77/-0.62; P < 0.0001), and major access site complications (ß = -14.82, 95% CI = -26.52/-3.11; P = 0.013) including bleeding (ß = -11.97, 95% CI = -21.05/-2.89; P = 0.0099). Strongest renal function predictor of 1-year mortality in risk factor adjusted analyses was the change of eGFR within 72 hr (odds ratio, 0.97; 95% CI = 0.96/0.98; P < 0.0001). The addition of information on the change of eGFR increased the C-statistic of the logistic EuroSCORE (P = 0.021). CONCLUSIONS: In our routine TAVI sample, baseline eGFR, body mass index, and major access site complications mainly owing to bleeding were correlates of acute kidney injury after TAVI. Acute renal impairment was a risk factor for mortality and adverse cardiovascular events which provided risk information beyond the EuroSCORE.

Blood transfusion is associated with impaired outcome after transcatheter aortic valve implantation.

OBJECTIVES: We sought to evaluate the relationship of blood transfusion after transcatheter aortic valve implantation (TAVI) and mid-term outcome to improve patient selection and periprocedural treatment. BACKGROUND: Increasing evidence suggests a negative influence of blood transfusion on outcomes of patients with cardiovascular diseases. While the adverse impact of bleeding events on survival has been documented after TAVI, data on the impact of postoperative blood transfusions are scarce. METHODS: TAVI was performed in 700 consecutive patients; 14.7% of TAVI patients suffered from bleeding or access site complications and were excluded from analysis to minimize confounding. Outcomes were analyzed with emphasis on blood transfusions and according to the Valve Academic Research Consortium definitions. Median follow-up duration was 364 days. Multivariable analyses were performed to identify predictors for transfusion and 1-year mortality. RESULTS: 33.0% of patients received blood transfusions after TAVI, irrespective of access choice. Blood transfusions were associated with a higher baseline risk profile (median logistic EuroSCORE 21.0 vs. 17.0%), increased rates of postoperative complications and impaired survival (21.2 vs. 36.1% all-cause 1-year mortality). Transfusion was an independent predictor of mortality at 1 year (OR 2.78 [CI 1.59-4.86]). Low body mass index (OR 0.94 [0.89-1.0]), low baseline hemoglobin (OR 0.39 [0.33-0.47]) and combined anticoagulation/antiplatelet therapy were identified as independent predictors of blood transfusion after TAVI. CONCLUSIONS: Blood transfusions were frequently required after TAVI even in the absence of overt bleeding or access site complications and were identified as an independent predictor of impaired mid-term outcome. Optimization of baseline factors, strict blood conservation strategies, and individualized antiplatelet or anticoagulant regimens may improve outcome after TAVI.

Predictors and outcomes after transcatheter aortic valve implantation using different approaches according to the valve academic research consortium definitions.

OBJECTIVES: We report the results of a large single-center study evaluating predictors and outcomes after transcatheter aortic valve implantation (TAVI) with different devices and access routes according to the Valve Academic Research Consortium (VARC). BACKGROUND: The widespread adoption of TAVI warrants a systematic analysis of outcomes. Only few comprehensive data exist comparing different approaches as selected by a heart team. METHODS: TAVI was performed in 326 consecutive patients (mean age 80.6 ± 7.1 years, 55.5% female) at high risk for surgery with balloon-expandable and self-expanding devices through transfemoral or transapical access. Data were analyzed according to VARC endpoints; predictors of mortality were identified. RESULTS: All-cause mortality was 10.1% (30 days) and 29.9% (1 year) overall and comparable with regard to valve or access choice (P = 0.295) despite different risk profiles at baseline. Device success and 30-day safety endpoints were achieved in 87.1 and 21.2%. Myocardial infarction [hazard ratio (HR) 6.52], stage-2 and -3 acute kidney injury (HR 2.52 and 6.80) and major access site complications (HR 1.96) were independent predictors of 1-year all-cause mortality. Device success had a protective effect (HR 0.58). Baseline predictors included body mass index <20 kg/m(2) (HR 3.20), NYHA class IV (HR 1.87), left ventricular ejection-fraction <30% (HR 2.30), higher STS-PROM scores (HR 1.05 per percent), and age (group 75-85 years, HR 0.47). CONCLUSIONS: Comparable results were achieved with different devices and access routes in a heart team approach. Baseline and perioperative predictors of all-cause mortality were identified, contributing to the refinement of patient and device selection criteria for TAVI.

Patient gender does not affect outcome after transcatheter aortic valve implantation (TAVI).

BACKGROUND AND AIM OF THE STUDY: Female gender has recently been suggested to predict a beneficial outcome and lower mortality following transcatheter aortic valve implantation (TAVI). The study aim was to address gender differences in outcome following TAVI and potentially to replicate these findings. METHODS: The present single-center prospective registry of 326 patients with severe aortic stenosis treated by TAVI between 2008 and 2011 consisted of 181 women and 145 men. RESULTS: The procedural risk was not significantly different between men and women at baseline. For all-cause mortality no difference was observed at 30 days and at 12 months after TAVI. CONCLUSION: While several baseline characteristics between men and women treated by TAVI were shown to be different among the study population, no difference was observed in survival between both genders.

Distinct profiles of REST interactions with its target genes at different stages of neuronal development.

Differentiation of pluripotent embryonic stem (ES) cells through multipotent neural stem (NS) cells into differentiated neurons is accompanied by wholesale changes in transcriptional programs. One factor that is present at all three stages and a key to neuronal differentiation is the RE1-silencing transcription factor (REST/NRSF). Here, we have used a novel chromatin immunoprecipitation-based cloning strategy (SACHI) to identify 89 REST target genes in ES cells, embryonic hippocampal NS cells and mature hippocampus. The gene products are involved in all aspects of neuronal function, especially neuronal differentiation, axonal growth, vesicular transport and release, and ionic conductance. Most target genes are silent or expressed at low levels in ES and NS cells, but are expressed at much higher levels in hippocampus. These data indicate that the REST regulon is specific to each developmental stage and support the notion that REST plays distinct roles in regulating gene expression in pluripotent ES cells, multipotent NS cells, and mature neurons.

Ancestry and demography and descendants of Iron Age nomads of the Eurasian Steppe.

During the 1st millennium before the Common Era (BCE), nomadic tribes associated with the Iron Age Scythian culture spread over the Eurasian Steppe, covering a territory of more than 3,500 km in breadth. To understand the demographic processes behind the spread of the Scythian culture, we analysed genomic data from eight individuals and a mitochondrial dataset of 96 individuals originating in eastern and western parts of the Eurasian Steppe. Genomic inference reveals that Scythians in the east and the west of the steppe zone can best be described as a mixture of Yamnaya-related ancestry and an East Asian component. Demographic modelling suggests independent origins for eastern and western groups with ongoing gene-flow between them, plausibly explaining the striking uniformity of their material culture. We also find evidence that significant gene-flow from east to west Eurasia must have occurred early during the Iron Age.

ß-Lactoglobulin as nanotransporter--Part I: Binding of organosulfur compounds.

The binding reaction of allicin and diallyl disulfide with ß-lactoglobulin and the influence of pH value and protein denaturation on this reaction have been examined in the present study. Regardless of the structural similarity of both the organosulfur compounds, their binding behavior was significantly different. Both ligands were covalently bound by the free thiol group of the protein, whereas the affinity for allicin was significantly higher. In addition, diallyl disulfide was non-covalently bound. The binding reaction of both ligands was very sensitive to the pH value during incubation. The optimal pH range was between pH 8.0 and 9.0. Protein denaturation increased the reaction rate and reduced the number of binding sites for allicin, whereas the number of non-covalent binding sites increased for diallyl disulfide. Based on these findings, it can be proposed that the covalent modification of ß-lactoglobulin functions as a specific transporter stabilizing allicin or diallyl disulfide.

ß-Lactoglobulin as nanotransporter for allicin: Sensory properties and applicability in food.

The thiosulfinate allicin is a labile, bioactive compound of garlic. In order to enrich allicin in a functional food, a delivery system which stabilises the compound and masks its intense flavour is necessary. In the present study allicin was covalently bound to the whey protein ß-lactoglobulin and the incorporation of this transporter in a food matrix was tested. The sensory properties of the pure functional ingredient as well as of an enriched beverage were characterised by quantitative descriptive analysis. The concentration of volatile compounds was analysed by headspace gas chromatography-mass spectrometry. The garlic-related organoleptic properties of garlic powder were significantly improved by the binding of allicin in combination with spray drying. After purification of the modified ß-lactoglobulin the garlic taste and smell were barely perceptible. ß-Lactoglobulin modified with allicin provided a stable functional ingredient that can be used to enrich a broad range of food products.

ß-Lactoglobulin as nanotransporter--Part II: Characterization of the covalent protein modification by allicin and diallyl disulfide.

The whey protein ß-lactoglobulin has been proposed as a transporter for covalent bound bioactive compounds in order to enhance their stability and reduce their sensory perception. The garlic derived compounds allicin and diallyl disulfide were bound covalently to the native and heat denatured protein. The binding site and the influence of the modification on the digestibility were determined by mass spectrometric analysis of the modified ß-lactoglobulin. Further, the conformation of the modified protein was assessed by circular dichroism and dynamic light scattering. The free thiol group of Cys(121) turned out to be the major binding site. After proteolysis with trypsin at pH 7 but not with pepsin at pH 2, a limited transfer to other cysteinyl residues was observed. The covalently bound ligands did not mask any proteolytic cleavage sites of pepsin, trypsin or chymotrypsin. The modified ß-lactoglobulin showed a native like conformation, besides a moderate loosening of protein folding. The covalent binding of organosulfur compounds to ß-lactoglobulin provides a bioactive ingredient without impairing the digestibility and functional properties of the protein.

Multiple biomarkers and atrial fibrillation in the general population.

BACKGROUND: Different biological pathways have been related to atrial fibrillation (AF). Novel biomarkers capturing inflammation, oxidative stress, and neurohumoral activation have not been investigated comprehensively in AF. METHODS AND RESULTS: In the population-based Gutenberg Health Study (n = 5000), mean age 56 ± 11 years, 51% males, we measured ten biomarkers representing inflammation (C-reactive protein, fibrinogen), cardiac and vascular function (midregional pro adrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro-B-type natriuretic peptide [Nt-proBNP], sensitive troponin I ultra [TnI ultra], copeptin, and C-terminal pro endothelin-1), and oxidative stress (glutathioneperoxidase-1, myeloperoxidase) in relation to manifest AF (n = 161 cases). Individuals with AF were older, mean age 64.9 ± 8.3, and more often males, 71.4%. In Bonferroni-adjusted multivariable regression analyses strongest associations per standard deviation increase in biomarker concentrations were observed for the natriuretic peptides Nt-proBNP (odds ratio [OR] 2.89, 99.5% confidence interval [CI] 2.14-3.90; P<0.0001), MR-proANP (OR 2.45, 99.5% CI 1.91-3.14; P<0.0001), the vascular function marker MR-proADM (OR 1.54, 99.5% CI 1.20-1.99; P<0.0001), TnI ultra (OR 1.50, 99.5% CI 1.19-1.90; P<0.0001) and. fibrinogen (OR 1.44, 99.5% CI 1.19-1.75; P<0.0001). Based on a model comprising known clinical risk factors for AF, all biomarkers combined resulted in a net reclassification improvement of 0.665 (99.3% CI 0.441-0.888) and an integrated discrimination improvement of >13%. CONCLUSIONS: In conclusion, in our large, population-based study, we identified novel biomarkers reflecting vascular function, MR-proADM, inflammation, and myocardial damage, TnI ultra, as related to AF; the strong association of natriuretic peptides was confirmed. Prospective studies need to examine whether risk prediction of AF can be enhanced beyond clinical risk factors using these biomarkers.

Development of a risk score for outcome after transcatheter aortic valve implantation.

AIMS: Transcatheter aortic valve implantation (TAVI) is an increasingly common procedure in elderly and multimorbid patients with aortic stenosis. We aimed at developing a pre-procedural risk evaluation scheme beyond current surgical risk scores. METHODS: We developed a risk algorithm for 1-year mortality in two cohorts consisting of 845 patients undergoing routine TAVI procedures by commercially available devices, mean age 80.9 ± 6.5, 51 % women. Clinical variables were determined at baseline. Multivariable Cox regression related clinical data to mortality (n = 207 deaths). RESULTS: To account for variability related to age and sex and by enrolment site we forced age, sex, and cohort into the score model. Body mass index, estimated glomerular filtration rate, hemoglobin, pulmonary hypertension, mean transvalvular gradient and left ventricular ejection fraction at baseline were most strongly associated with mortality and entered the risk prediction algorithm [C-statistic 0.66, 95 % confidence interval (CI) 0.61-0.70, calibration χ (2)-statistic = 6.51; P = 0.69]. Net reclassification improvement compared to existing surgical risk predication schemes was positive. The score showed reasonable model fit and calibration in external validation in 333 patients, N = 55 deaths (C-statistic 0.60, 95 % CI 0.52-0.68; calibration χ (2)-statistic = 16.2; P = 0.06). Additional measurement of B-type natriuretic peptide and troponin I did not improve the C-statistic. Frailty increased the C-statistic to 0.71, 95 % CI 0.65-0.76. CONCLUSIONS: We present a new risk evaluation tool derived and validated in routine TAVI cohorts that predicts 1-year mortality. Biomarkers only marginally improved risk prediction. Frailty increased the discriminatory ability of the score and needs to be considered. Risk algorithms specific for TAVI may help to guide decision-making when patients are evaluated for TAVI.

Depression in atrial fibrillation in the general population.

BACKGROUND: Initial evidence suggests that depressive symptoms are more frequent in patients with atrial fibrillation. Data from the general population are limited. METHODS AND RESULTS: In 10,000 individuals (mean age 56±11 years, 49.4% women) of the population-based Gutenberg Health Study we assessed depression by the Patient Health Questionnaire (PHQ-9) and a history of depression in relation to manifest atrial fibrillation (n = 309 cases). The median (25th/75th percentile) PHQ-9 score of depressive symptoms was 4 (2/6) in atrial fibrillation individuals versus 3 (2/6) individuals without atrial fibrillation, P(X2-Test) = 0.32. Multivariable regression analyses of the severity of depressive symptoms in relation to atrial fibrillation in cardiovascular risk factor adjusted models revealed a relation of PHQ-9 values and atrial fibrillation (odds ratio (OR) 1.04, 95% confidence interval (CI) 1.01-1.08; P = 0.023). The association was stronger for the somatic symptom dimension of depression (OR 1.08, 95% CI 1.02-1.15; P = 0.0085) than for cognitive symptoms (OR 1.05, 95% CI 0.98-1.11; P = 0.15). Results did not change markedly after additional adjustment for heart failure, partnership status or the inflammatory biomarker C-reactive protein. Both, self-reported physical health status, very good/good versus fair/bad, (OR 0.54, 95% CI 0.41-0.70; P<0.001) and mental health status (OR 0.61 (0.46-0.82); P = 0.0012) were associated with atrial fibrillation in multivariable-adjusted models. CONCLUSIONS: In a population-based sample we observed a higher burden of depressive symptoms driven by somatic symptom dimensions in individuals with atrial fibrillation. Depression was associated with a worse perception of physical or mental health status. Whether screening and treatment of depressive symptoms modulates disease progression and outcome needs to be shown.

Association of MR-proadrenomedullin with cardiovascular risk factors and subclinical cardiovascular disease.

AIMS AND BACKGROUND: Midregional proadrenomedullin (MR-proADM) is a protein, which exerts various effects on the cardiovascular system. Recent studies underscored its prognostic implications in patients with acute dyspnea and cardiovascular diseases. Therefore, we aimed to determine the distribution of MR-proADM in the general population and to reveal potential associations of MR-proADM with cardiovascular risk factors and measures of subclinical cardiovascular disease. METHODS AND RESULTS: MR-proADM plasma concentrations were determined in individuals of the population-based cohort of the Gutenberg Health Study (N = 5000) using a commercially available fluoroimmunoassay. Individuals were enrolled between April 2007 and October 2008. Subclinical cardiovascular disease was assessed using echocardiographic and functional measures of myocardial and vascular function. The mean age of the study population was 55.5 ± 10.9 years. In the overall population we determined a median MR-proADM plasma concentration of 0.44 nmol/L in men and women. MR-proADM concentrations were elevated in individuals with hypertension, diabetes, dyslipidemia, known cardiovascular disease, heart failure, peripheral artery disease, atrial fibrillation, and history of myocardial infarction and stroke. In men, we observed a positive association of MR-proADM with reduced ejection fraction, intraventricular septal diameter, wall thickness, and echocardiographic measures of diastolic dysfunction. CONCLUSIONS: In this study, we present age-dependent reference values for MR-proADM in a representative population sample. Elevated MR-proADM plasma concentrations were strongly associated with classical cardiovascular risk factors and manifest cardiovascular diseases. Furthermore, we revealed a gender-specific association with echocardiographic measures of hypertension. MR-proADM seems to be a promising prognostic biomarker for subclinical and manifest cardiovascular disease.

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.

Atrial fibrillation: its prevalence and risk factor profile in the German general population.

BACKGROUND: Atrial fibrillation (AF) is an increasingly common problem in primary care, but little is known about its prevalence and the distribution of AF risk factors in the general population. METHODS: We determined the prevalence of AF and the distribution of known AF risk factors among persons participating in the population-based Gutenberg Health Study. To this end, we used interview data about the medical diagnosis of AF and electrocardiograms (ECGs) that were performed for the study in 5000 persons aged 35 to 74. The response rate was 60.4%. RESULTS: There were 5000 persons in the study sample (age 52.2 ± 11 years; 50.6% were women). The prevalence of AF, weighted for the age and sex distribution of the general population, was 2.5%. AF was found to be more common in older persons, with a more pronounced increase in men: whereas its prevalence was 0.7% in 35- to 44-year-old men, the corresponding figure for the age group 65- to 74 was as high as 10.6%. Twenty five participants (15.5% of AF cases) received their initial diagnosis of AF on the basis of the study ECG. Compared to persons without AF, persons with AF were older and more commonly male, and they had a higher burden of cardiovascular risk factors. 14.3% of persons with AF had none of the well-established risk factors for AF (systolic blood pressure, antihypertensive medication, increased body-mass-index, heart failure). 42.7% of persons with AF were not taking either anticoagulants or platelet inhibitors. CONCLUSION: These data indicate that the prevalence of AF in the middle-aged general population is 2.5% overall, and higher in the elderly. AF is thus a significant public health problem, and greater awareness of it is needed.

Multiple endothelial biomarkers and noninvasive vascular function in the general population: the Gutenberg Health Study.

Vascular reactivity is reflected by blood biomarkers and noninvasive vascular function measurement. The relation of biomarkers to flow-mediated dilation and peripheral arterial tonometry in the general population is little understood. In 5000 individuals (mean age, 56±11 years; age range, 35-74 years; 49% women) of the population-based Gutenberg Health Study we simultaneously assessed 6 biomarkers of cardiovascular function (midregional proadrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro B-type natriuretic peptide, copeptin, C-terminal proendothelin 1, and neopterin) in relation to flow-mediated dilation and peripheral arterial tonometry. Strongest partial correlations (adjusted for age and sex) were observed for baseline pulse amplitude with MR-proADM (r=0.13) and MR-proANP (r=-0.13); hyperemic response variables showed the highest correlation for MR-proADM and peripheral arterial tonometry ratio (r=-0.14). In multivariable linear regression models, strongest associations with baseline vascular function were observed for MR-proANP with baseline pulse amplitude (ß per SD increase [99.17%], -0.080 [-0.115 to -0.044]; P<0.0001 after Bonferroni correction for multiple testing) and MR-proADM (-0.044 [-0.070 to -0.017]; P<0.0001), as well as MR-proANP (-0.033 [-0.057 to -0.009]; P=0.0017) and N-terminal pro B-type natriuretic peptide (-0.027 [-0.051 to -0.003]; P=0.015) with brachial artery diameter. For hyperemic response variables, highest associations were seen for peripheral arterial tonometry ratio with MR-proADM (-0.022 [-0.043 to -0.004]; P=0.043), MR-proANP (0.016 [-0.0034 to 0.035]; P=0.18), and C-terminal proendothelin 1 (-0.025 [-0.043 to -0.008]; P=0.00094]. In our large, population-based study, we identified MR-proADM and MR-proANP as circulating biomarkers of vascular function most strongly related to noninvasive measures of conduit artery and peripheral arterial performance. Whether determination of blood biomarkers helps to better understand vascular pathology and may provide prognostic information needs to be investigated in future studies.

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.

Sex differences in early carotid atherosclerosis (from the community-based Gutenberg-Heart Study).

The objectives of this study were to describe gender differences in intima-media thickness (IMT) in a community-based population study and to define normal IMT values for healthy men and women. In total, 4,814 participants (aged 35 to 74 years; 2,433 men, 2,381 women) from the Gutenberg-Heart Study (GHS) were included. IMT was measured at both common carotid arteries using an edge detection system. Median IMT was 0.62 mm (25th percentile 0.55, 75th percentile 0.70) in women and 0.65 mm (25th percentile 0.57, 75th percentile 0.75) in men and was significantly associated with age (p <0.0001). On multivariate analysis, advanced age, smoking, and arterial hypertension were positively associated with higher IMT in men and women. A subgroup of 1,025 subjects without cardiovascular risk factors or previous cardiovascular disease was analyzed to define normal IMT values. Nomograms were calculated according to age and gender. For each age group, IMT >95th percentile was defined as abnormal. In this subgroup, gender differences in IMT became nonsignificant at older ages. At the age of 35 years, IMT was 0.71 mm in men and 0.61 mm in women at the 95th percentile. In comparison, at the age of 74 years, IMT at the 95th percentile was 0.90 mm in men and 0.89 mm in women. In conclusion, men had higher carotid IMT than women, but predictors of early carotid atherosclerosis were similar across genders. In young subjects without cardiovascular risk factors, normal values for IMT were lower in women compared with men. In contrast, in older subjects, gender differences in IMT became nonsignificant.

A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease.

BACKGROUND: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). METHODS AND RESULTS: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-3)). CONCLUSIONS: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.