CD14+CD16+ monocytes in coronary artery disease and their relationship to serum TNF-α levels

SummaryMonocytes play a central role in the inflammatory disease atherosclerosis. CD14+CD16+ monocytes are considered proinflammatory monocytes, as they have an increased capacity to produce proinflammatory cytokines, such as TNF-α, and are elevated in various inflammatory diseases. We hypothesized that patients with coronary artery disease (CAD) have increased levels of CD14+CD16+ monocytes, and that CD14+CD16+ monocytes are associated with inflammation markers. We investigated CD14+CD16+ monocytes in 247 patients with CAD and 61 control subjects using flow cytometry. In addition serum concentrations of TNF-α, IL-6, and Hs-CRP were assessed. Patients with CAD had higher levels of CD14+CD16…

Domains of Physical Activity in Relation to Stiffness Index in the General Population.

Background Regular exercise training represents an important modifier of arterial stiffness (AS). Therefore, sex‐specific relations between domains of physical activity (PA; commuting, domestic, and leisure‐time PA, including active sport and occupational PA) with AS were investigated. Methods and Results Stiffness index by digital photoplethysmography was investigated in 12 650 subjects from the GHS (Gutenberg Health Study). Self‐reported PA was evaluated by the “Short Questionnaire to Assess Health‐Enhancing Physical Activity” and reported as activity score peer week, being a combined measure of duration, frequency, and intensity of PA. Multivariable linear regression analysis demonstrat…

Cardio‐Renal Biomarker Soluble Urokinase‐Type Plasminogen Activator Receptor Is Associated With Cardiovascular Death and Myocardial Infarction in Patients With Coronary Artery Disease Independent of Troponin, C‐Reactive Protein, and Renal Function

Background Risk stratification among patients with coronary artery disease ( CAD ) is of considerable interest due to the potential to guide secondary preventive therapies. Thus, we evaluated the predictive value of soluble urokinase‐type plasminogen activator receptor (su PAR ) levels for cardiovascular mortality and nonfatal myocardial infarction in patients with CAD . Methods and Results Plasma levels of su PAR were measured in a cohort of 1703 patients with documented CAD as evidenced by coronary angiography—including 626 patients with acute coronary syndrome and 1077 patients with stable angina pectoris. Cardiovascular death and/or nonfatal myocardial infarction were defined as main o…

Biosensor Analysis of β2-Glycoprotein I–Reactive Autoantibodies: Evidence for Isotype-Specific Binding and Differentiation of Pathogenic from Infection-Induced Antibodies

Abstract Background: For the laboratory diagnosis of the antiphospholipid syndrome (APS) we developed a biosensor with the ability to distinguish between disease-relevant anti-β2-glycoprotein I (β2GPI) autoantibodies (anti-β2GPI) and pathogen-specific β2GPI cross-reactive antibodies that occur transiently during infections. Methods: We used a surface plasmon resonance (SPR) biosensor device. For the detection of anti-β2GPI in serum samples, affinity-purified human β2GPI was covalently attached to a functionalized n-alkanethiol self-assembling monolayer on the biosensor chip. After verifying the specificity of the biosensor system with a panel of monoclonal antibodies to β2GPI, we analyzed s…

Tissue factor pathway inhibitor primes monocytes for antiphospholipid antibody-induced thrombosis

Antiphospholipid antibodies (aPLs) with complex lipid and/or protein reactivities cause complement-dependent thrombosis and pregnancy complications. Although cross-reactivities with coagulation regulatory proteins contribute to the risk for developing thrombosis in patients with antiphospholipid syndrome, the majority of pathogenic aPLs retain reactivity with membrane lipid components and rapidly induce reactive oxygen species-dependent proinflammatory signaling and tissue factor (TF) procoagulant activation. Here, we show that lipid-reactive aPLs activate a common species-conserved TF signaling pathway. aPLs dissociate an inhibited TF coagulation initiation complex on the cell surface of m…

Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus

The author manuscript of this article is open access and is freely available online at PubMed Central

Telemedicine-Based Specialized Care Improves the Outcome of Anticoagulated Individuals with Venous Thromboembolism-Results from the thrombEVAL Study.

Venous thromboembolism (VTE) is a life-threatening disease with risk of recurrence. Oral anticoagulation (OAC) with vitamin K antagonists (VKA) is effective to prevent thromboembolic recurrence. We aimed to investigate the quality of OAC of VTE patients in regular medical care (RMC) compared to a telemedicine-based coagulation service (CS). The thrombEVAL study (NCT01809015) is a prospective, multi-center study to investigate OAC treatment (recruitment: January 2011&ndash

Determinants of arterial stiffness in pre- and postmenopausal women

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 x 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 x 10(-11) for rs2472493 near ABCA1 and P = 6.39 x 10(-11) for rs8176693…

Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in fabry disease.

Fabry disease (FD) is an X-linked hereditary defect of glycosphingolipid storage caused by mutations in the gene encoding the lysosomal hydrolase α-galactosidase A (GLA, α-gal A). To date, over 400 mutations causing amino acid substitutions have been described. Most of these mutations are related to the classical Fabry phenotype. Generally in lysosomal storage disorders a reliable genotype/phenotype correlation is difficult to achieve, especially in FD with its X-linked mode of inheritance. In order to predict the metabolic consequence of a given mutation, we combined in vitro enzyme activity with in vivo biomarker data. Furthermore, we used the pharmacological chaperone (PC) 1-deoxygalacto…

Prevalence of Strabismus and Its Impact on Vision-Related Quality of Life

Purpose This study investigates the prevalence of manifest strabismus and its subtypes in adulthood and analyzes the risk factors and its impact on vision-related quality of life (VRQoL). Design The Gutenberg Health Study (GHS) is a population-based, observational cohort study. A cross-sectional analysis of the baseline examination was conducted. Participants Participants aged 35 to 74 years were included (n = 15  010). Methods All participants were examined with a comprehensive ophthalmologic and general examination including the Hirschberg corneal reflex test to detect manifest strabismus. The following risk factors were analyzed: age, sex, socioeconomic status, birth weight, maternal age…

Platelet-localized FXI promotes a vascular coagulation-inflammatory circuit in arterial hypertension

Multicellular interactions of platelets, leukocytes, and the blood vessel wall support coagulation and precipitate arterial and venous thrombosis. High levels of angiotensin II cause arterial hypertension by a complex vascular inflammatory pathway that requires leukocyte recruitment and reactive oxygen species production and is followed by vascular dysfunction. We delineate a previously undescribed, proinflammatory coagulation-vascular circuit that is a major regulator of vascular tone, blood pressure, and endothelial function. In mice with angiotensin II-induced hypertension, tissue factor was up-regulated, as was thrombin-dependent endothelial cell vascular cellular adhesion molecule 1 ex…

A novel in vitro model for the study of plaque development in atherosclerosis

SummaryFor the study of atherogenesis in vitro, coculture systems have been devised, in which two or more cell types can be cultured in close contact to each other. Herein, we describe a novel in vitro model that aims at the simulation of the morphology ofa normal muscular artery allowing for the study of the initial events in atherosclerosis. Usinga modified fibrin gel as a scaffold for the coculture of endothelial cells (ECs) and smooth muscle cells (SMCs), we generated an autologous in vitro model with a multilayer growth of SMCs (intima-like structure) covered by an endothelium. The production of extracellular matrix (ECM) could be visualized histologically and verified by (i) ascorbic-…

Different calculations of ankle-brachial index and their impact on cardiovascular risk prediction.

Background— An ankle-brachial index (ABI; ratio of ankle and brachial systolic blood pressure) <0.9 indicates peripheral arterial disease (PAD) and is a strong predictor of cardiovascular events. The aim of the present study was to address the prognostic value of different methods of ABI calculation. Methods and Results— In 831 patients admitted with chest pain for diagnostic heart catheterization, blood pressure of both anterior and posterior tibial arteries was measured. ABI was calculated for each leg with the higher of the 2 ankle pressures (current definition of the American Heart Association) or with the lower of the 2 ankle pressures (modified definition) in relation to the highe…

Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2−/− mice

Background and purpose: Mitochondrial aldehyde dehydrogenase (ALDH-2) has been shown to provide a pathway for bioactivation of organic nitrates and to be prone to desensitization in response to highly potent, but not to less potent, nitrates. We therefore sought to support the hypothesis that bioactivation by ALDH-2 critically depends on the number of nitrate groups within the nitrovasodilator. Experimental approach: Nitrates with one (PEMN), two (PEDN; GDN), three (PETriN; glyceryl trinitrate, GTN) and four (pentaerithrityl tetranitrate, PETN) nitrate groups were investigated. Vasodilatory potency was measured in isometric tension studies using isolated aortic segments of wild type (WT) an…

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Item does not contain fulltext Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic ne…

Birthweight and its association with retinal vessel equivalents – Results from the population‐based German Gutenberg Health Study

Refined atrial fibrillation screening and cost-effectiveness in the German population

ObjectiveLittle is known on optimal screening population for detecting new atrial fibrillation (AF) in the community. We describe characteristics and estimate cost-effectiveness for a single timepoint electrocardiographic screening.MethodsWe performed a 12-lead ECG in the German population-based Gutenberg Health Study between 2007 and 2012 (n=15 010), mean age 55±11 years, 51% men and collected more than 120 clinical and biomarker variables, including N-terminal pro B-type natriuretic peptide (Nt-proBNP), risk factors, disease symptoms and echocardiographic variables.ResultsOf 15 010 individuals, 466 (3.1%) had AF. New AF was found in 32 individuals, 0.2% of the total sample, 0.5% of indivi…

Identification and prevention of genotyping errors caused by G-quadruplex- and i-motif-like sequences.

Abstract Background: Reliable PCR amplification of DNA fragments is the prerequisite for most genetic assays. We investigated the impact of G-quadruplex– or i-motif–like sequences on the reliability of PCR-based genetic analyses. Methods: We found the sequence context of a common intronic polymorphism in the MEN1 gene (multiple endocrine neoplasia I) to be the cause of systematic genotyping errors by inducing preferential amplification of one allelic variant [allele dropout (ADO)]. Bioinformatic analyses and pyrosequencing-based allele quantification enabled the identification of the underlying DNA structures. Results: We showed that G-quadruplex– or i-motif–like sequences can reproducibly …

KCND3 is a novel susceptibility locus for early repolarization

AbstractThe presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. We assessed the ERP in 12-lead ECGs of 39,456 individuals and conducted a two-stage meta-analysis of genome-wide association studies (GWAS). In the discovery phase, we included 2,181 cases and 23,641 controls from eight European ancestry studies and identified 19 genome-wide significant (p<5E-8) variants in the KCND3 (potassium voltage gated channel subfamily D member 3) gene with a p-value of 4.6E-10. …

B-Type Natriuretic Peptide and the Risk of Cardiovascular Events and Death in Patients With Stable Angina Results From the AtheroGeneStudy

ObjectivesThe aim of this study was to assess the predictive value of the cardiac hormone B-type natriuretic peptide (BNP) for long-term outcome in a large cohort of stable angina patients.BackgroundRecent data suggest a role of BNP in stable ischemic heart disease beyond its known value in heart failure and acute coronary syndromes.MethodsIn 1,085 patients with coronary artery disease (CAD) baseline levels of BNP were prospectively associated with cardiovascular (CV) events during a mean follow-up of 2.5 years.ResultsBNP concentrations were significantly elevated in patients with future CV events (median [25th/75th interquartile range] 119.2 [43.6/300.4] pg/ml vs. 36.2 [11.3/94.6] pg/ml; p…

Relations of Sex to Diagnosis and Outcomes in Acute Coronary Syndrome

Background The atypical presentation of women with acute coronary syndrome ( ACS ) has been related to delayed diagnosis and treatment, which may explain worse outcome compared with men. Methods and Results We analyzed pooled data of 2520 patients of 2 prospective cohorts in terms of differences in presentation and management of women and men suggestive of ACS . Using logistic regression, we established 2 diagnostic models and tested their diagnostic performance in both sexes separately. Sex‐specific differences in management of patients with ACS were ascertained and a 2‐year follow‐up was performed. Women were older than men (median 67 versus 61 years, P =0.001), had more often dyspnea (2…

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), a…

Head-to-Head Comparison of the Incremental Predictive Value of The Three Established Risk Markers, Hs-troponin I, C-Reactive Protein, and NT-proBNP, in Coronary Artery Disease

Risk stratification among patients with coronary artery disease (CAD) is of considerable interest to potentially guide secondary preventive therapies. Cardiac troponins as well as C-reactive protein (hsCRP) and natriuretic peptides have emerged as biomarkers for risk stratification. The question remains if one of these biomarkers is superior in predicting adverse outcomes. Thus, we perform a head-to-head comparison between high-sensitivity troponin I (hsTnI), hsCRP, and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with CAD. Plasma levels were measured in a cohort of 2193 patients with documented CAD. The main outcome measures were cardiovascular (CV) death and/or nonfata…

Removing Batch Effects from Longitudinal Gene Expression - Quantile Normalization Plus ComBat as Best Approach for Microarray Transcriptome Data

International audience; Technical variation plays an important role in microarray-based gene expression studies, and batch effects explain a large proportion of this noise. It is therefore mandatory to eliminate technical variation while maintaining biological variability. Several strategies have been proposed for the removal of batch effects, although they have not been evaluated in large-scale longitudinal gene expression data. In this study, we aimed at identifying a suitable method for batch effect removal in a large study of microarray-based longitudinal gene expression. Monocytic gene expression was measured in 1092 participants of the Gutenberg Health Study at baseline and 5-year fol…

Iron Metabolism Contributes to Prognosis in Coronary Artery Disease: Prognostic Value of the Soluble Transferrin Receptor Within the AtheroGene Study

Background Coronary heart disease is a leading cause of mortality worldwide. Iron deficiency, a frequent comorbidity of coronary heart disease, causes an increased expression of transferrin receptor and soluble transferrin receptor levels (sTfR) levels, while iron repletion returns sTfR levels to the normal physiological range. Recently, sTfR levels were proposed as a potential new marker of iron metabolism in cardiovascular diseases. Therefore, we aimed to evaluate the prognostic value of circulating sTfR levels in a large cohort of patients with coronary heart disease. Methods and Results The disease cohort comprised 3423 subjects who had angiographically documented coronary heart diseas…

Assessment of microRNAs in patients with unstable angina pectoris.

Aims While cardiac troponin measurements have significantly improved the early diagnosis of myocardial infarction, the timely biomarker-based diagnosis of unstable angina pectoris (UAP) remains a major unmet clinical challenge. The aim of this study was to assess levels of circulating microRNAs (miRNAs) as possible novel biomarkers in patients with UAP. Methods and results A three-phase approach was conducted, comprising (i) profiling of miRNAs in patients with UAP and controls groups; (ii) replication of significant miRNAs in an independent patient cohort, (iii) validation of a multi-miRNAs panel in a third cohort. Out of 25 miRNAs selected for replication, 8 miRNAs remained significantly …

Complement C5 but not C3 is expendable for tissue factor activation by cofactor-independent antiphospholipid antibodies

The complement and coagulation cascades interact at multiple levels in thrombosis and inflammatory diseases. In venous thrombosis, complement factor 3 (C3) is crucial for platelet and tissue factor (TF) procoagulant activation dependent on protein disulfide isomerase (PDI). Furthermore, C5 selectively contributes to the exposure of leukocyte procoagulant phosphatidylserine (PS), which is a prerequisite for rapid activation of monocyte TF and fibrin formation in thrombosis. Here, we show that monoclonal cofactor-independent antiphospholipid antibodies (aPLs) rapidly activate TF on myelomonocytic cells. TF activation is blocked by PDI inhibitor and an anti-TF antibody interfering with PDI bin…

Inflammation, atherosclerotic burden and cardiovascular prognosis.

The aim of this study was to evaluate the impact of various inflammatory markers on atherosclerotic burden and cardiovascular prognosis.In a prospective study 720 patients preceding coronary angiography were enrolled. In all patients carotid and leg arteries were examined using sonographic methods and C-reactive protein, fibrinogen, interleukin-18 (IL-18) and interleukin-6 have been determined. Patients were compared with regard to atherosclerotic burden: no clinically significant stenosis (N=57, 7.9%), coronary artery disease only (N=362, 50.3%), coronary artery disease with peripheral atherosclerosis (=multi-vascular atherosclerosis, N=301, 41.8%).Follow-up data after a median of 6.5 year…

Reduced In Vivo Aortic Uptake of Radiolabeled Oxidation-Specific Antibodies Reflects Changes in Plaque Composition Consistent With Plaque Stabilization

Objective— Labeled oxidation-specific antibodies (Ox-AB) detect, quantify, and noninvasively image lipid-rich atherosclerotic lesions. However, it is unknown whether Ox-AB detect plaque stabilization. Methods and Results— The aortic uptake of intravenously injected 125 I-MDA2 (Ox-AB to malondialdehyde [MDA]–low-density lipoprotein [LDL]) was quantitated in: (1) LDL receptor−/− mice with established atherosclerosis continued on Western diet (Progression) or switched to chow (Regression) or chow+vitamins E and C (Regression-VIT) for 6 months; and (2) Watanabe rabbits (3- to 57-months old) with naturally evolved atherosclerotic lesions. In mice, the Progression group had more extensive athero…

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

Abstract 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. Individua…

c.451dupT in KLKB1 is common in Nigerians, confirming a higher prevalence of severe prekallikrein deficiency in Africans compared to Europeans

Essentials Prekallikrein (PK) deficiency is a recessive trait with isolated aPTT prolongation. KLKB1 c.451dupT is common in Nigerians (7/600 alleles) and absent in a European group (0/600). To date, all genotyped PK-deficient patients of African ancestry were homozygous for 451dupT. Diagnostics of isolated aPTT prolongation in African descendants should include PK testing. ABSTRACT: Background Severe prekallikrein deficiency (PK deficiency) is an autosomal-recessive condition thought to be very rare. Recently we reported that the previously unnoticed variant c.451dupT, p.Ser151Phefs*34 in KLKB1, which is listed in databases aggregating genome data, causes PK deficiency and is common in Afri…

Antiphospholipid antibodies in pediatric patients with prolonged activated partial thromboplastin time during infection.

Abstract Objective To investigate the close association between different antiphospholipid antibodies (aPL) caused by infection and their appearance together with a prolonged activated partial thromboplastin time (aPTT). Methods Sera from 122 children were evaluated in this study. Thirty-seven children with mild to medium prolonged aPTT (>37.2 s) and elevated C-reactive protein (CRP) levels during various forms of infections (group 2), 18 children without infections (group 3) but with mild to medium prolonged aPTT and 13 children with infections (group 4) and with elevated CRP-level as well as a control group (group 1) of 54 patients without any infection and normal aPTT and negative CRP le…

ADMA and arginine derivatives in relation to non-invasive vascular function in the general population.

Nitric oxide produced from l-arginine is central to vascular homeostasis. Little is known about the relationship between arginine derivatives including asymmetric dimethylarginine (ADMA) and non-invasive vascular function measures in the general population.In 5000 individuals (median age 56; 25th/75th percentile: 46, 65; 49% women) taking part in the population-based Gutenberg Health Study (Mainz area, Germany), we measured the relationship between the arginine derivatives asymmetric dimethylarginine (ADMA), N-monomethyl l-arginine (NMMA), symmetric dimethylarginine (SDMA) and l-arginine with flow-mediated dilation (FMD) and peripheral arterial tonometry (PAT). Weak bivariate correlations w…

Association of Low Birth Weight With Altered Corneal Geometry and Axial Length in Adulthood in the German Gutenberg Health Study

IMPORTANCE: Low birth weight is associated with altered ocular organ development in childhood, including the morphology of the eye. However, no population-based data exist about this association in adulthood. OBJECTIVE: To evaluate whether low birth weight has a long-term association with anterior segment anatomy and axial length in adulthood. DESIGN, SETTING, AND PARTICIPANTS: The Gutenberg Health Study is a population-based, observational cohort study in Germany. All participants underwent ocular biometry. Among the participants with follow-up and self-reported birth weight available, associations were assessed between low birth weight and anterior segment anatomy and axial length using m…

Initiation and progression of atherosclerosis – enzymatic or oxidative modification of low-density lipoprotein?

AbstractAtherosclerosis is widely regarded as a chronic inflammatory disease that develops as a consequence of entrapment of low-density lipoprotein (LDL) in the arterial intima. Native LDL lacks inflammatory properties, so the lipoprotein must undergo biochemical alterations to become atherogenic. Among several other candidates, two different concepts of lipoprotein modification are propagated, the widespread oxidation hypothesis and the less common E-LDL hypothesis, which proposes that modification of LDL occurs through the action of ubiquitous hydrolytic enzymes (enzymatically modified LDL or E-LDL) rather than oxidation. By clearly distinguishing between the initiation and progression o…

Association of ocular, cardiovascular, morphometric and lifestyle parameters with retinal nerve fibre layer thickness.

BACKGROUND Glaucoma is a neurodegenerative disease, leading to thinning of the retinal nerve fibre layer (RNFL). The exact influence of ocular, cardiovascular, morphometric, lifestyle and cognitive factors on RNFL thickness (RNFLT) is unknown and was analysed in a subgroup of the Gutenberg Health Study (GHS). METHODS Global peripapillary RNFLT was measured in 3224 eyes of 1973 subjects (49% female) using spectral-domain optical coherence tomography (SD-OCT). The association of age, sex, ocular, cardiovascular, morphometric, lifestyle and cognitive factors on RNFLT was analysed using Pearson correlation coefficient and fitting a linear mixed model. RESULTS In the univariable analysis highest…

Isolated Pulmonary Embolism Is Associated With a High Risk of Arterial Thrombotic Disease

Background Isolated PE is associated with a higher burden of atherosclerotic disease than other manifestations of VTE. Research Question We hypothesized that the presence of isolated PE may signal a chronically elevated risk of arterial thrombotic disease. Study Design and Methods Data from the VTEval Study, a prospective cohort study enrolling individuals with clinical suspicion and imaging-based diagnosis or exclusion of VTE, were analyzed. Patients with PE received whole-leg ultrasonography to assess presence of DVT. Regularized logistic regression identified features that discriminate between isolated PE and other VTE phenotypes at clinical presentation. Survival analyses were performed…

Assessing Planning Ability Across the Adult Life Span in a Large Population-Representative Sample: Reliability Estimates and Normative Data for the Tower of London (TOL-F) Task

AbstractObjectives:The Tower of London (TOL) test has probably become the most often used task to assess planning ability in clinical and experimental settings. Since its implementation, efforts were made to provide a task version with adequate psychometric properties, but extensive normative data are not publicly available until now. The computerized TOL-Freiburg Version (TOL-F) was developed based on theory-grounded task analyses, and its psychometric adequacy has been repeatedly demonstrated in several studies but often with small and selective samples.Method:In the present study, we now report reliability estimates and normative data for the TOL-F stratified for age, sex, and education …

Pathogenic lipid‐binding antiphospholipid antibodies are associated with severity of COVID‐19

Abstract Background Coronavirus disease 19 (COVID‐19)–associated coagulopathy is a hallmark of disease severity and poor prognosis. The key manifestations of this prothrombotic syndrome—microvascular thrombosis, stroke, and venous and pulmonary clots—are also observed in severe and catastrophic antiphospholipid syndrome. Antiphospholipid antibodies (aPL) are detectable in COVID‐19 patients, but their association with the clinical course of COVID‐19 remains unproven. Objectives To analyze the presence and relevance of lipid‐binding aPL in hospitalized COVID‐19 patients. Methods Two cohorts of 53 and 121 patients from a single center hospitalized for PCR‐proven severe acute respiratory syndro…

GDF-15 predicts cardiovascular events in acute chest pain patients

Background Treatment of patients presenting with possible acute myocardial infarction (AMI) is based on timely diagnosis and proper risk stratification aided by biomarkers. We aimed at evaluating the predictive value of GDF-15 in patients presenting with symptoms suggestive of AMI. Methods Consecutive patients presenting with suspected AMI were enrolled in three study centers. Cardiovascular events were assessed during a follow-up period of 6 months with a combined endpoint of death or MI. Results From the 1818 enrolled patients (m/f = 1208/610), 413 (22.7%) had an acute MI and 63 patients reached the combined endpoint. Patients with MI and patients with adverse outcome had higher GDF-15 le…

ADMA, subclinical changes and atrial fibrillation in the general population.

Abstract Background Pathways of oxidative stress, nitric oxide bioavailability and l-arginine derivatives are hypothesized to be related to atrial fibrillation (AF). Circulating methylated l-arginine metabolites can be assessed in the general population and may show an association with AF. Methods We determined l-arginine and its metabolites asymmetric dimethylarginine (ADMA), l-N ω -monomethylarginine (NMMA) and symmetric dimethylarginine (SDMA) in the population-based Gutenberg Health Study (n=5000), mean age 55±11years, 51% men, in association with clinical variables of AF such as electrocardiographic and echocardiographic measures and manifest AF. Results Individuals with AF (N=161), 71…

Low Homoarginine Levels in the Prognosis of Patients With Acute Chest Pain.

Background The endogenous amino acid homoarginine predicts mortality in cerebro‐ and cardiovascular disease. The objective was to explore whether homoarginine is associated with atrial fibrillation ( AF ) and outcome in patients with acute chest pain. Methods and Results One thousand six hundred forty‐nine patients with acute chest pain were consecutively enrolled in this study, of whom 589 were diagnosed acute coronary syndrome ( ACS ). On admission, plasma concentrations of homoarginine as well as brain natriuretic peptide ( BNP ), and high‐sensitivity assayed troponin I (hsTnI) were determined along with electrocardiography ( ECG ) variables. During a median follow‐up of 183 days, 60 ma…

Resistin, acute coronary syndrome and prognosis results from the AtheroGene study

Resistin, an adipocyte and macrophage derived cytokine, causes insulin resistance and glucose intolerance. We investigated the impact of resistin as a diagnostic marker in patients with acute coronary syndrome and its prognostic value for future cardiovascular events.Resistin levels were determined in 1153 patients with stable angina (SAP), 380 patients with unstable angina, 278 patients with non-ST-elevation myocardial infarction (NSTEMI) and 111 patients with ST-elevation myocardial infarction (STEMI). All patients have been followed up for a median follow-up of 2.6 years. During follow-up, 70 patients died from cardiovascular causes.Compared to SAP, resistin levels (5.1 ng/mL in SAP) wer…

Mean Platelet Volume and Arterial Stiffness - Clinical Relationship and Common Genetic Variability

AbstractVessel wall stiffening is an important clinical parameter, but it is unknown whether platelets, key elements in the pathogenesis of arterial thrombosis, are associated with arterial stiffness. The present studies sought to determine whether mean platelet volume (MPV), a potential marker of platelet activation, is linked to vascular elasticity as assessed by the augmentation index (AIx), in 15,010 individuals from the population-based Gutenberg Health Study. Multivariable analysis showed that MPV in both males (β 0.776; 95thCI [0.250;1.16]; p = 0.0024) and females (β 0.881[0.328;1.43]; p = 0.0018) is strongly associated with AIx. Individuals with MPV and AIx above the sex-specific me…

Inhibition of Rac1 signaling by lovastatin protects against anthracycline-induced cardiac toxicity

Normal tissue damage limits the efficacy of anticancer therapy. For anthracyclines, the clinically most relevant adverse effect is cardiotoxicity. The mechanisms involved are poorly understood and putative cardioprotectants are controversially discussed. Here, we show that the lipid-lowering drug lovastatin protects rat H9c2 cardiomyoblasts from doxorubicin in vitro. Protection by lovastatin is related to inhibition of the Ras-homologous GTPase Rac1. It rests on a reduced formation of DNA double-strand breaks, resulting from the inhibition of topoisomerase II by doxorubicin. Doxorubicin transport and reactive oxygen species are not involved. Protection by lovastatin was confirmed in vivo. I…

Cardiac biomarkers and arterial stiffening: data from the Gutenberg Health study

Disturbed Glucose Metabolism and Left Ventricular Geometry in the General Population

Background: This study sought to investigate the prevalence and clinical outcome of left ventricular (LV) geometry in prediabetes and type 2 diabetes mellitus (T2DM) and the impact of glucose metabolism on the incidence of left ventricular hypertrophy (LVH). Methods: 15,010 subjects (35–74 years) of the population-based Gutenberg Health Study were categorized into euglycemia, prediabetes, and T2DM according to clinical and metabolic (HbA1c) information. Clinical outcome was assessed via structured follow-up. Results: The study comprised 12,121 individuals with euglycemia (81.6%), 1415 with prediabetes (9.5%), and 1316 with T2DM (8.9%). Prevalence of LVH increased from euglycemia (10.2%) ove…

Glutathione Peroxidase-1 Deficiency Potentiates Dysregulatory Modifications of Endothelial Nitric Oxide Synthase and Vascular Dysfunction in Aging

Recently, we demonstrated that gene ablation of mitochondrial manganese superoxide dismutase and aldehyde dehydrogenase-2 markedly contributed to age-related vascular dysfunction and mitochondrial oxidative stress. The present study has sought to investigate the extent of vascular dysfunction and oxidant formation in glutathione peroxidase-1–deficient ( GPx-1 −/− ) mice during the aging process with special emphasis on dysregulation (uncoupling) of the endothelial NO synthase. GPx-1 −/− mice on a C57 black 6 (C57BL/6) background at 2, 6, and 12 months of age were used. Vascular function was significantly impaired in 12-month-old GPx-1 −/− -mice as compared with age-matched controls. Oxidan…

Troponin I Assay for Identification of a Significant Coronary Stenosis in Patients with Suspected Acute Myocardial Infarction and Wide QRS Complex

Background Common ECG criteria such as ST-segment changes are of limited value in patients with suspected acute myocardial infarction (AMI) and bundle branch block or wide QRS complex. A large proportion of these patients do not suffer from an AMI, whereas those with ST-elevation myocardial infarction (STEMI) equivalent AMI benefit from an aggressive treatment. Aim of the present study was to evaluate the diagnostic information of cardiac troponin I (cTnI) in hemodynamically stable patients with wide QRS complex and suspected AMI. Methods In 417 out of 1818 patients presenting consecutively between 01/2007 and 12/2008 in a prospective multicenter observational study with suspected AMI a pro…

The relationship of ocular geometry with refractive error in normal and low birth weight adults

Purpose Low birth weight (BW) individuals have an increased risk for myopic refractive error. However, it is unclear which ocular geometric alterations lead to an increase in myopic refractive error. This study aims to evaluate the impact of ocular biometry in interaction with BW on refractive error. Methods Participants of the prospective, observational, population-based Gutenberg Health Study (GHS) with self-reported BW aged 40–80 years and objective refraction and optical biometry were included. Linear regression analyses were conducted to evaluate associations between spherical equivalent with corneal power, anterior chamber depth, lens thickness and axial length and its interaction wit…

Homoarginine Levels are Regulated by L-Arginine: Glycine Amidinotransferase and Affect Stroke Outcome: Results from Human and Murine Studies

Background— Endogenous arginine homologues, including homoarginine, have been identified as novel biomarkers for cardiovascular disease and outcomes. Our studies of human cohorts and a confirmatory murine model associated the arginine homologue homoarginine and its metabolism with stroke pathology and outcome. Methods and Results— Increasing homoarginine levels were independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years of follow-up; hazard ratio for 1-SD homoarginine, 0.79 [95% confidence interval, 0.64–0.96]; P =0.019; n=389). Homoarginine was also independently associated with the National Institutes of Health Stroke Scale+age score …

Comparison of HapMap and 1000 genomes reference panels in a large-scale genome-wide association study

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were ass…

No effect of C-reactive protein on early atherosclerosis in LDLR-/- / human C-reactive protein transgenic mice

summaryThe association between increased concentrations of C-reactive protein (CRP) and future cardiovascular events is well established. However, it is currently unclear whether this clinical observation represents an epiphenomenon or whether the pentraxin may actively promote the development of atherosclerosis. Experimental studies with knockout mice with a defect in apolipoprotein E (ApoE-/-) have been used to investigate the role of CRP in atherogenesis, but the results obtained have been contradictory so far. Since knockout mice with a defect in low density lipoprotein receptor (LDLR-/-) may represent a better model of atherogenesis compared to ApoE-/- animals, we undertook experiments…

Glycogen phosphorylase BB in acute coronary syndromes

AbstractThe diagnosis of myocardial damage is preferably based on measurement of the cardiac-specific troponins. However, there is an emerging need for early, specific cardiac markers. One potential candidate is the glycogen phosphorylase BB isoenzyme (GPBB). We investigated the use of a new, commercially available GPBB ELISA assay in 61 patients presenting with an acute coronary syndrome (37 acute myocardial infarction, 24 unstable angina pectoris) in comparison to established cardiac markers such as troponin T, creatine kinase isoenzyme MB (CKMB) mass, and myoglobin. Blood samples were obtained on arrival, as well as 1, 2, 3, 4, 8, 12 and 24h later. GPBB plasma concentrations were elevate…

Cystatin C and cardiovascular mortality in patients with coronary artery disease and normal or mildly reduced kidney function: results from the AtheroGene study

Aims Chronic kidney disease is associated with increased risk of cardiovascular disease. Cystatin C is a promising marker to reliably mirror renal function. The role of cystatin C in patients with coronary artery disease (CAD) and normal or mildly reduced kidney function is the subject of current investigation. Methods and results In 2162 patients, over the whole spectrum of CAD, baseline cystatin C concentrations were measured. Patients with an estimated glomerular filtration rate of ≤60 mL/min per 1.73 m2 ( n = 295) were excluded. In patients with complete follow-up information ( n = 1827), 66 cardiovascular deaths were registered during a median follow-up of 3.65 years. Logarithmically t…

Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse …

Prevalence of corneal arcus and associated factors in a German population-Results from the Gutenberg Health Study.

Purpose We aimed to determine the prevalence of corneal arcus and to identify associated factors in the general population of Germany. Methods The Gutenberg Health Study (GHS) is a population-based cohort study in Germany, which includes an ophthalmological assessment. Refraction, distance-corrected visual acuity, non-contact tonometry and anterior segment imaging were performed for the five-year follow-up examination. Anterior segment photographs were graded for the presence of corneal arcus. Prevalence estimates were computed, and multivariable logistic regression analysis was applied to determine associated factors for corneal arcus including sex, age, spherical equivalent, central corn…

Management of Oral Anti-Coagulation in Patients with Heart Failure-Insights from the ThrombEVAL Study

AbstractPatients with heart failure (HF) are frequently anti-coagulated with vitamin K-antagonists (VKAs). The use of long-acting VKA may be preferable for HF patients due to higher stability of plasma concentrations. However, evidence on phenprocoumon-based oral anti-coagulation (OAC) therapy in HF is scarce. The aim of this study was to assess the impact of the presence of HF on quality of phenprocoumon-based OAC and the subsequent clinical outcome. Quality of OAC therapy and the incidence of adverse events were analysed in a cohort of regular care (n = 2,011) from the multi-centre thrombEVAL study program (NCT01809015) stratified by the presence of HF. To assess the modifiability of outc…

Estimation of Values below the Limit of Detection of a Contemporary Sensitive Troponin I Assay Improves Diagnosis of Acute Myocardial Infarction

Abstract BACKGROUND The limit of detection (LoD) is the minimal amount of a substance that can be consistently detected. In the diagnosis of acute myocardial infarction (AMI) many patients present with troponin concentrations below the LoD of contemporary sensitive cardiac troponin I (cs-cTnI) assays. These censored values below the LoD influence the diagnostic performance of these assays compared to highly sensitive cTnI (hs-cTnI) assays. Therefore we assessed the impact of a new approach for interpolation of the left-censored data of a cs-cTnI assay in the evaluation of patients with suspected AMI. METHODS Our posthoc analysis used a real world cohort of 1818 patients with suspected MI. D…

Prognostic information of glycogen phosphorylase isoenzyme BB in patients with suspected acute coronary syndrome.

Early and adequate risk stratification is essential in patients with suspected acute coronary syndrome (ACS). The aim of the present study was to investigate whether glycogen phosphorylase BB (GPBB) could add prognostic information in the context of contemporary sensitive troponin I determination and B-type natriuretic peptide (BNP). Patients with suspected ACS were consecutively enrolled at 3 German study centers from January 2007 through December 2008. Troponin I, GPBB, and BNP were determined at admission. Follow-up information on the combined end point of death, myocardial infarction, revascularization, and hospitalization owing to a cardiovascular cause was obtained 6 months after enro…

Response to Letter Regarding Article, “Different Calculations of Ankle Brachial Index and Their Impact on Cardiovascular Risk Prediction”

We thank Jaquinandi et al for their interest in our publication. We want to stress that the patient population of the AtheroGene study is not comparable with the patient populations reported in the articles from Lee et al and Kreitner et al, which included only patients with known advanced peripheral arterial disease.1,2 The AtheroGene study includes primarily patients with coronary artery disease, no patient had rest pain or peripheral ulcers and only 52 patients (6.3%) had intermittent claudication.3 In addition, …

Heparin–polynitroxides: Synthesis and preliminary evaluation as cardiovascular EPR/MR imaging probes and extracellular space-targeted antioxidants

We report here the synthesis of heparin-polynitroxide derivatives (HPNs) in which nitroxide moieties are linked either to uronic acid or glycosamine residues of the heparin macromolecule. HPNs have low anticoagulant activity, possess superoxide scavenging properties, bind to the vascular endothelium/extra-cellular matrix and can be detected by EPR and MRI techniques. As the vascular wall-targeted redox-active paramagnetic compounds, HPNs may have both diagnostic (molecular MRI) and therapeutic (ecSOD mimics) applications.

Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.

Context Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. Objective To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. Design, Setting, and Participants Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nuc…

Comprehensive exploration of the effects of miRNA SNPs on monocyte gene expression.

We aimed to assess whether pri-miRNA SNPs (miSNPs) could influence monocyte gene expression, either through marginal association or by interacting with polymorphisms located in 3'UTR regions (3utrSNPs). We then conducted a genome-wide search for marginal miSNPs effects and pairwise miSNPs × 3utrSNPs interactions in a sample of 1,467 individuals for which genome-wide monocyte expression and genotype data were available. Statistical associations that survived multiple testing correction were tested for replication in an independent sample of 758 individuals with both monocyte gene expression and genotype data. In both studies, the hsa-mir-1279 rs1463335 was found to modulate in cis the expres…

Chronic Diarrhea in a 5-Year-Old Girl: Pitfall in Routine Laboratory Testing with Potentially Severe Consequences

A 5-year-old girl was referred because of recurrent watery diarrhea, abdominal pain, and flatulence. She was the second of 3 children. Her 10-year-old sister was normally developed and healthy. Her younger brother has meningomyelocele and hydrocephalus. At 1 year of age, the patient was admitted to the hospital for recurrent bronchitis, otitis media, food refusal, mild diarrhea, and abdominal distension since weaning. A sweat chloride analysis excluded cystic fibrosis. At that time, the patient’s laboratory results showed increased C-reactive protein (139 mg/L; reference interval, <5 mg/L) and moderate leukocytosis (14.6 × 109/L; reference interval, 4.5–13.5 × 109/L). Values for all other v…

Cardiac Troponins for the Diagnosis of Acute Myocardial Infarction in Chronic Kidney Disease

Background Patients with chronic kidney disease ( CKD ) are at high risk of myocardial infarction. Cardiac troponins are the biomarkers of choice for the diagnosis of acute myocardial infarction ( AMI ) without ST ‐segment elevation ( NSTE ). In patients with CKD , troponin levels are often chronically elevated, which reduces their diagnostic utility when NSTE ‐ AMI is suspected. The aim of this study was to derive a diagnostic algorithm for serial troponin measurements in patients with CKD and suspected NSTE ‐ AMI . Methods and Results Two cohorts, 1494 patients from a prospective cohort study with high‐sensitivity troponin I (hs‐ cTnI ) measurements and 7059 cases from a clinical registr…

Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: Results of the randomized, double-blind, placebo-controlled INEF study

High-density-lipoproteins-cholesterol (HDL-C) is invertedly related to the incidence of cardiovascular events. Recent studies suggest that HDL-C directly improves endothelial function. Nicotinic acid (niacin) effectively raises serum HDL-C. We therefore hypothesized that treatment with niacin improves endothelial dysfunction in patients with coronary artery disease (CAD). One hundred seven patients with CAD were randomly assigned to double-blinded treatment for 12 weeks with extended-release (ER)-niacin 1000 mg/day (N) or placebo (C), respectively. Flow-mediated dilation (FMD) of the brachial artery, nitroglycerin-mediated endothelium-independent dilation (NMD) and serum lipid concentration…

The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats

Hyperglycemia associated with inflammation and oxidative stress is a major cause of vascular dysfunction and cardiovascular disease in diabetes. Recent data reports that a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin (Jardiance®), ameliorates glucotoxicity via excretion of excess glucose in urine (glucosuria) and significantly improves cardiovascular mortality in type 2 diabetes mellitus (T2DM). The overarching hypothesis is that hyperglycemia and glucotoxicity are upstream of all other complications seen in diabetes. The aim of this study was to investigate effects of empagliflozin on glucotoxicity, β-cell function, inflammation, oxidative stress and endothel…

Evaluation of a new pooling strategy based on leukocyte count for rapid quantification of allele frequencies.

Abstract Background: Allele frequencies of single-nucleotide polymorphisms (SNPs) can be quantified from DNA pools. The conventional preparation of DNA pools requires DNA isolation and quantification for each blood sample. We hypothesized that pooling of whole blood samples according to their leukocyte count, which determines DNA content, would be as reliable as the conventional pooling method but much less tedious to perform. Methods: We collected 100 whole blood samples and measured the leukocyte count. Samples were frozen until further use. After thawing, pools were generated by combining aliquots containing an equal number of leukocytes. In parallel, DNA was extracted from another aliqu…

Determination of globotriaosylceramide in plasma and urine by mass spectrometry

Abstract Background: Fabry disease is an X-chromosomally inherited lysosomal storage disorder leading to accumulation of glycosphingolipids, mainly globotriaosylceramide (ceramide-trihexoside, Gb3). Concentrations of Gb3 in plasma and urine have been used to diagnose Fabry disease and to monitor enzyme replacement therapy with recombinant α-galactosidase. Methods: Gb3 was purified from plasma or urine by combined liquid extraction/protein precipitation and solid-phase extraction, and was detected by flow-injection analysis electrospray mass spectrometry (MS) using multi-reaction-monitoring. Calibration was performed via standard addition using C17-Gb3 as internal standard. The most abundant…

Myopia and Cognitive Performance: Results From the Gutenberg Health Study.

Purpose To analyze the association between myopia and cognitive performance. Methods A cohort of the population-based Gutenberg Health Study included 3819 eligible enrollees between 40 and 79 years. We used the Tower of London (TOL) test to assess cognitive performance. Myopia was defined as a spherical equivalent (SE) ≤ -0.5 diopters (D) via noncycloplegic autorefractometry. We conducted linear mixed models with the SE as the dependent variable and the age, sex, duration of education, and TOL score as covariates. Results Complete data were available for 3452 participants (90.4%). The mean TOL score was 14.0 ± 3.9 in the myopes versus 12.9 ± 4.0 in the nonmyopes (P < 0.001). The mean TOL sc…

Overexpression of TGF-ß1 in macrophages reduces and stabilizes atherosclerotic plaques in ApoE-deficient mice.

Although macrophages represent the hallmark of both human and murine atherosclerotic lesions and have been shown to express TGF-ß1 (transforming growth factor β1) and its receptors, it has so far not been experimentally addressed whether the pleiotropic cytokine TGF-ß1 may influence atherogenesis by a macrophage specific mechanism. We developed transgenic mice with macrophage specific TGF-ß1 overexpression, crossed the transgenics to the atherosclerotic ApoE (apolipoprotein E) knock-out strain and quantitatively analyzed both atherosclerotic lesion development and composition of the resulting double mutants. Compared with control ApoE(-/-) mice, animals with macrophage specific TGF-ß1 overe…

Prognostic use of soluble fms-like tyrosine kinase-1 and placental growth factor in patients with coronary artery disease.

Background: Intention of the study is to assess the cardiovascular mortality of patients with coronary artery disease (CAD) with the biomarkers of angiogenesis PlGF and its endogenous inhibitor sFlt-1. Methods: The cohort included n = 1848 patients with CAD and 282 subjects without CAD. In 85 patients cardiovascular mortality, as combination of fatal myocardial infarction or any cardiac death, during a median follow-up duration of 3.9 years was reported. Results: In Kaplan–Meier curve analysis PlGF in rising thirds was not predictive regarding outcome (p = 0.54), the same was shown for sFlt-1 (p = 0.44). Cox regression for the fully adjusted model provided a hazard ratio (HR) of 0.8 (p = 0…

Epidemiologic Analysis of Asteroid Hyalosis and Associations: The Gutenberg Health Study

Thrombin generation in cardiovascular disease and mortality – results from the Gutenberg Health Study

Thrombin generation may be a potential tool to improve risk stratification for cardiovascular diseases. The aim of this study was to explore the relation between thrombin generation and cardiovascular risk factors, cardiovascular diseases, and total mortality. For this study, 5,000 subjects from the population-based Gutenberg Health Study were analyzed in a highly standardized setting. Thrombin generation was assessed by the Calibrated Automated Thrombogram method at 1 and 5 pM tissue factor triggers in platelet-poor plasma. Lag time, endogenous thrombin potential, and peak height were derived from the thrombin generation curve. Sex-specific multivariable linear regression analysis adjusted…

Abstract 13257: FEV1 and FVC predict Mortality in Individuals Without Manifest Lung Disease Independent of Cardiac Performance - Results From the Population-based Gutenberg Health Study

Background: Pulmonary disease has consistently been related to increased mortality. We investigated central spirometry variables in relation to total mortality in individuals from the general population without diagnosed lung disease also accounting for cardiac function. Methods: In 15,010 individuals from the general population (mean age 55±11 years, age range 35-74 years, 50.5% men) in the Gutenberg Health Study we performed spirometry and multimodal transthoracic echocardiography. The biomarkers N-terminal pro-B-type natriuretic peptide (Nt-proBNP) and high-sensitive troponin I (TnI) were measured in the first 5000 individuals using commercially available assays. Multivariable Cox regre…

A role for Toll-like receptor mediated signals in neutrophils in the pathogenesis of the anti-phospholipid syndrome.

The anti-phospholipid syndrome (APS) is characterized by recurrent thrombosis and occurrence of anti-phospholipid antibodies (aPL). aPL are necessary, but not sufficient for the clinical manifestations of APS. Growing evidence suggests a role of innate immune cells, in particular polymorphonuclear neutrophils (PMN) and Toll-like receptors (TLR) to be additionally involved. aPL activate endothelial cells and monocytes through a TLR4-dependent signalling pathway. Whether this is also relevant for PMN in a similar way is currently not known. To address this issue, we used purified PMN from healthy donors and stimulated them in the presence or absence of human monoclonal aPL and the TLR4 agonis…

Subendothelial infiltration of neutrophil granulocytes and liberation of matrix-destabilizing enzymes in an experimental model of human neo-intima.

SummaryIt was the objective of this study to examine the role of human neutrophil granulocytes (PMN) in an in-vitro model of human neo-intima developed for the study of atherosclerosis. Human granulocytes were subjected to a co-culture model of human endothelial and smooth muscle cells. Subendothelial lipid accumulation was achieved by addition of native LDL to the culture medium. Tissue samples were analyzed by immunohistochemistry and scanning/transmission electron microscopy, and culture supernatants were examined for the presence of interleukin- 8 (IL-8), MCP-1, GRO-α, elastase and matrixmetalloproteinase-8 (MMP-8). Following addition of 2 mg/ml LDL, adherence, transmigration and infilt…

Urinary ethyl glucuronide (uEtG) as a marker for alcohol consumption in liver transplant candidates: a real-world cohort

 In order to reduce alcohol relapse after liver transplantation (LT), the German national guidelines for waiting-list maintenance and organ allocation demand a minimum 6-month period of alcohol abstinence pre-LT, confirmed by measuring urinary ethyl glucuronide (uEtG). Between January 2015 and June 2016, uEtG was measured at least once in 339 cirrhotic patients with an indication for LT at the University Medical Center Mainz. uEtG was measured with an enzyme-linked immunosorbent assay (ELISA) screening test (cutoff value: 500 µg/L). For uEtG values ≥ 500 µg/L, liquid chromatography-mass spectrometry (LC-MS/MS) was performed as a confirmatory assay. Data were collected prospectively in a tra…

Genetic and environmental influences on the fibrinolytic system: a twin study.

SummaryThe determination of heritability is a key issue to assess the predictive power of polymorphisms for disease in clinical studies. The aim of this study was to determine the heritability of proteins and activation markers of the fibrinolytic system in a large cohort of healthy twins. Heritability was calculated as 0.76 for thrombin activatable fibrinolysis inhibitor (TAFI), 0.44 for plasminogen activator inhibitor-1 (PAI-1), and 0.43 for tissue plasminogen activator. No significant genetic influence was observed for α2-antiplasmin-plasmin-complex and D-dimer. Heritability explained by single gene polymorphisms was 25.2% for TAFI 505G&gt;A, 31.5% for 1542C&gt;G, and 50.0% for combinati…

Serum autoantibodies to alpha-fodrin are present in glaucoma patients from Germany and the United States.

PURPOSE Glaucoma is characterized by a progressive loss of retinal ganglion cells that results in a characteristic optic neuropathy associated with visual field loss. In previous studies, changes in the antibody profiles have been shown in the sera of patients with glaucoma, and these findings suggest a role for autoimmune involvement in the pathogenesis of glaucoma in some patients. The purpose of this study was to compare the antibody profiles against optic nerve antigens in patients with glaucoma in two different study populations from Germany and the United States. METHODS One hundred twenty patients were included in the study, 60 from Germany and 60 from the United States: a control gr…

Predictors of leptin concentration and association with cardiovascular risk in patients with coronary artery disease: results from the AtheroGene study

AbstractContext: Leptin is produced in white adipose tissue, but also in human coronary atherosclerotic lesions.Objective: The aim of this study is to assess the prognostic value of leptin in patients with proven coronary artery disease (CAD) (N = 1907).Methods: AtheroGene is a contemporary CAD cohort study (N = 3229). Median follow-up time was 3.8 (Quartile 1/3 with 2.8/4.9) years.Results: Leptin concentration was associated with a hazard ratio (HR) for the fully adjusted model of HR = 1.32 in women but was not significant in men. The endpoint cardiovascular death and non-fatal myocardial infarction was observed in 167 patients.Conclusion: In women with known CAD, increased leptin concentr…

Birth weight and its association with optic nerve head morphology - results from the population-based German Gutenberg Health Study.

Enhanced Age-Dependent ENOS Dysfunction and - Uncoupling in Glutathione Peroxidase-1-Deficient Mice

Depression and cognitive deficits as long-term consequences of thrombotic thrombocytopenic purpura

BACKGROUND Thrombotic thrombocytopenic purpura (TTP) is an acute life-threatening microangiopathy with a tendency of relapse characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, and spontaneous von Willebrand factor–induced platelet clumping leading to microthrombi. The brain is frequently affected by microthrombi leading to neurologic abnormalities of varying severity. STUDY DESIGN AND METHODS The aim of this observational cohort study was to investigate the prevalence of depression and cognitive deficits in 104 patients having survived acute TTP. TTP survivors were repeatedly assessed by means of different standardized questionnaires to evaluate depression (ID…

A novel approach to CFTR mutation testing by pyrosequencing-based assay panels adapted to ethnicities.

Abstract Background: Cystic fibrosis (CF) is a common autosomal recessive genetic disorder caused by a variety of sequence alterations in the CFTR gene [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)]. Because the relative prevalence of mutations strongly depends on the ethnic background, first-level testing of CF as defined by recent consensus recommendations ought to be adaptable to the ethnicity of patients. Methods: We therefore developed and implemented a diagnostic approach to first-level testing for CF based on published mutation frequencies and Pyrosequencing (PSQ) technology that we complemented with standard procedures of mutation…

Defining normality in a European multinational cohort: Critical factors influencing the 99th percentile upper reference limit for high sensitivity cardiac troponin I

To establish and critically evaluate the 99th percentile upper reference limit (URL) for high-sensitivity cardiac troponin I (hs-cTnI) in a large healthy European cohort using different selection criteria.1368 presumably healthy individuals from 9 countries were evaluated with surrogate biomarkers for diabetes (glycated hemoglobin [HbA1c]48 mmol/mol), myocardial (B-type natriuretic peptide [BNP]35 pg/mL) and renal dysfunction (estimated glomerular filtration rate [eGFR]60 mL/min/1.73 m(2)), and dyslipidemia to refine the healthy cohort. The 99th percentile URLs were independently determined by the non-parametric and robust methods.The use of biomarker selection criteria resulted in a decrea…

Birth Weight and Diabetic Retinopathy: Results From the Population-Based Gutenberg Health Study (GHS).

Purpose: This study investigates the relationship between diabetic retinopathy (DR) and birth weight (BW) in diabetic subjects sampled from the general population. Methods: The Gutenberg Health Study (GHS) is a population-based, observational cohort study in participants aged from 35 to 74 years. Criteria for diabetes diagnosis were HbA1c ≥6.5% at study entry, a doctor-diagnosis of diabetes, or diabetes medication. The presence of DR was determined by evaluating fundus photographs. BW was assessed by self-reports. GHS participants were divided into three different BW groups (low: &lt;2500 g; normal: 2500–4000 g; high:&gt;4000 g). Logistic regression analysis was conducted as uni- and multiv…

Multicenter validation study for the certification of a CFTR gene scanning method using next generation sequencing technology.

AbstractBackground:Many European laboratories offer molecular genetic analysis of theCFTRgene using a wide range of methods to identify mutations causative of cystic fibrosis (CF) and CFTR-related disorders (CFTR-RDs). Next-generation sequencing (NGS) strategies are widely used in diagnostic practice, and CE marking is now required for most in vitro diagnostic (IVD) tests in Europe. The aim of this multicenter study, which involved three European laboratories specialized in CF molecular analysis, was to evaluate the performance of Multiplicom’s CFTR MASTR Dx kit to obtain CE-IVD certification.Methods:A total of 164 samples, previously analyzed with well-established “reference” methods for t…

KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern

BACKGROUND: The presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown. METHODS: To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry. RESULTS: We identified a genome-wide significant (P < 5 × 10(–8)) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discov…

Glutathione Peroxidase 1 Activity and Cardiovascular Events in Patients With Coronary Artery Disease

Along with superoxide dismutase, glutathione peroxidase 1 is one of the cellular antioxidant enzymes that have a key role in controlling reactive oxygen species. It uses glutathione to reduce hydrogen peroxide to water and lipid peroxides to their respective alcohols. There are suggestions from in vitro and animal studies that these enzymes could protect against atherosclerosis. This prospective study examined the possibility that relatively high activity of antioxidant enzymes protects against cardiovascular events. The study population included 636 patients suspected of having coronary artery disease who were followed for a median period of 4.7 years. Stable angina was present in 510 pati…

Effects of clopidogrel vs. prasugrel vs. ticagrelor on endothelial function, inflammatory parameters, and platelet function in patients with acute coronary syndrome undergoing coronary artery stenting: a randomized, blinded, parallel study

Abstract Aims In a randomized, parallel, blinded study, we investigate the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome. Methods and results The primary endpoint of the study was the change in endothelium-dependent flow-mediated dilation (FMD) following stenting. A total of 90 patients (age 62 ± 9 years, 81 males, 22 diabetics, 49 non-ST elevation myocardial infarctions) were enrolled. There were no significant differences among groups in any clinical parameter. Acutely before stenting, all three drugs improved FMD without differences between groups (P = 0.73). Stenting blunted FMD in the cl…

Noise annoyance is associated with depression and anxiety in the general population : the contribution of aircraft noise

BACKGROUND: While noise annoyance has become recognized as an important environmental stressor, its association to mental health has hardly been studied. We therefore determined the association of noise annoyance to anxiety and depression and explored the contribution of diverse environmental sources to overall noise annoyance. PATIENTS AND METHODS: We investigated cross-sectional data of n = 15.010 participants of the Gutenberg Health Study (GHS), a population-based, prospective, single-center cohort study in Mid-Germany (age 35 to 74 years). Noise annoyance was assessed separately for road traffic, aircraft, railways, industrial, neighborhood indoor and outdoor noise ("during the day"; "i…

Subclinical impairment of lung function is related to mild cardiac dysfunction and manifest heart failure in the general population.

Lung function impairment has previously been related to heart failure, although no overt cardiovascular or structural heart disease is present. The extent to which pulmonary function is related to subclinical left ventricular impairment in the general population remains to be investigated.15010 individuals from the general population (mean age 55±11years, 50.5% men) in the Gutenberg Health Study underwent spirometry, transthoracic echocardiography and biomarker measurement. Forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) in percent of the predicted value and FEV1/FVC ratio were associated with echocardiographic measures of cardiac structure, systolic and diastolic func…

Subclinical levels of anxiety but not depression are associated with planning performance in a large population-based sample

BackgroundMajor depression and anxiety disorders are known to negatively influence cognitive performance. Moreover, there is evidence for greater cognitive decline in older adults with generalized anxiety disorder. Except for clinical studies, complex executive planning functions and subclinical levels of anxiety have not been examined in a population-based sample with a broad age range.MethodsPlanning performance was assessed using the Tower of London task in a population-based sample of 4240 participants aged 40–80 years from the Gutenberg Health Study (GHS) and related to self-reported anxiety and depression by means of multiple linear regression analysis.ResultsHigher anxiety ratings we…

Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium.

Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on …

Multi-site analytical evaluation of a chemiluminescent magnetic microparticle immunoassay (CMIA) for sirolimus on the Abbott ARCHITECT analyzer.

Objective This study evaluated a new chemiluminescent magnetic microparticle immunoassay (CMIA) for sirolimus on the ARCHITECT analyzer. Design and methods Patient and laboratory proficiency samples were tested at three European sites and one site in the United States. Results The CMIA total %CV's were all < 8% and the Limit of Quantification (LOQ) was < 1.52 ng/mL across the four sites. It cross-reacts to sirolimus metabolites F4 and F5 and showed no hematocrit interference over a range of 25% to 55%. Patient specimen correlations to three LC/MS/MS methods gave R ≥ 0.91 at three sites and mean biases of 14%, 25% and 39%. CMIA patient specimen correlations to the Abbott IMx gave R ≥ 0.94 at…

Abstract 13812: Pulmonary Function Predicts Cardiac Function, Structure &amp; Clinical Outcome in Chronic Heart Failure: Results From the Myovasc Study

Introduction: A growing body of evidence suggests a relevance of pulmonary function in the pathophysiology of heart failure (HF). Comprehensive data on the role of forced expiratory volume in 1 second (FEV1) in the development &amp; progression of HF is limited. Hypothesis: Given this background, we hypothesized, that (FEV1) is associated with deteriorated left ventricular (LV) functional as well as structural status, &amp; predicts specific clinical outcome in HF. Methods: Data from the MyoVasc Study (n=3,289) were analysed. Comprehensive clinical phenotyping including body plethysmography for the evaluation of FEV1 &amp; standardized echocardiography were performed during a five-hour inv…

Release kinetics of early ischaemic biomarkers in a clinical model of acute myocardial infarction

ObjectiveTo determine the release kinetics of different biomarkers with potential as novel early ischaemic biomarkers in patients with acute coronary syndrome (ACS); it is difficult to establish the detailed release kinetics in patients with acute myocardial infarction (AMI).MethodsWe analysed the release kinetics of soluble fms-like tyrosine kinase (sFlt-1), ischaemia modified albumin (IMA), and heart-type fatty acid binding protein (hFABP) in patients with hypertrophic obstructive cardiomyopathy who were undergoing transcoronary ablation of septal hypertrophy (TASH), a procedure mimicking AMI. Consecutive patients (n=21) undergoing TASH were included. Blood samples were collected before T…

Myopia and Level of Education

Purpose To analyze the association between myopia and educational level in an adult European cohort. Design Population-based cross-sectional study. Participants A cohort of the Gutenberg Health Study, including 4658 eligible enrollees between 35 and 74 years of age. Methods We applied a standardized protocol entailing a comprehensive questionnaire; thorough ophthalmic, general, cardiovascular, and psychological examinations; and laboratory tests, including genetic analyses. We documented achievement levels in school education and post-school professional education. The spherical equivalent (SE) was determined by noncycloplegic autorefractometry. We fitted mixed linear models including age, …

Abstract 18540: Heme Oxygenase 1 Activity and Expression Suppresses a Proinflammatory Phenotype in Monocytes and Correlates With Endothelial Function in Mice and Humans

Background: Heme oxygenase-1 (HO-1) confers protection to the vasculature and suppresses inflammatory properties of monocytes and macrophages. It is unclear how HO-1 activity and expression determine the extent of vascular dysfunction in mice and humans. Methods and results: Decreasing HO activity was parallelled by decreasing aortic HO-1, eNOS and phospho-eNOS (ser1177) protein expression in HO-1 deficient mice, whereas aortic expression of nox2 showed a stepwise increase in HO-1+/- and HO-1-/- mice as compared to HO-1+/+ controls. Aortic superoxide formation increased depending on the extent of HO-1 deficiency and was blunted by the PKC inhibitor chelerythrine, indicating activation of t…

Human antiphospholipid antibodies induce TNFα in monocytes via Toll-like receptor 8

The antiphospholipid syndrome (APS) is characterized by recurrent arterial and/or venous thromboses, pregnancy loss and the presence of antiphospholipid antibodies (aPL). One of the discussed mechanisms of this thrombotic activity in APS patients is attributed to TNFalpha secretion in monocytes after aPL stimulation. To investigate this mechanism in detail, we employed a monoclonal aPL and IgG fractions of APS patients for stimulation of human peripheral monocytes. Stimulation with this monoclonal aPL resulted in an increased expression and secretion of TNFalpha, caused by specific upregulation of TLR8 mRNA and protein expression levels. To confirm the specificity of this finding we could d…

Head and neck paragangliomas: Report of 175 patients (1989-2010)

Attention of the otorhinolaryngologist needs to be drawn to the versatile aspects of head and neck paragangliomas (PGLs).This study is a retrospective, nonrandomized clinical study of all 175 individuals with PGLs treated in our department between 1989 and 2010. A genetic analysis was performed on 86 patients.The 175 patients presented 224 head and neck PGLs as well as 2 thyroid papillary carcinomas. Genetic analysis resulted in 1 patient positive for a von Hippel-Lindau (VHL) gene mutation and 34 for succinate dehydrogenase (SDH) gene mutations (22 SDHD, 7 SDHC, and 5 SDHB), 12 of the latter carrying a novel mutation. Thirty-three patients (18.9%) had multiple PGLs and 11 patients (6.3%) h…

Investigation of Sudan IV staining areas in aortas of infants and children: Possible prelesional stages of atherogenesis

Although atherosclerosis in infants and children is generally acknowledged, the temporal and spatial sequence of LDL insudation, modification and intimal monocyte accumulation has not been systematically studied. We have investigated herein very early stages of lesion formation in human aortas of individuals up to the age of 15 years. Aortic specimens from 61 cases (37 male, 24 female) were examined. 34 cases were1 year old, 16 cases were between 1 and 5 years old, and 11 cases were between 6 and 15 years old. Areas preselected under a dissection microscope after Sudan IV staining were investigated in depth by immunohistochemical staining for apolipoprotein B, monocytes/macrophages, smooth …

SELDI-TOF-MS ProteinChip array profiling of tears from patients with dry eye.

Protein and peptides in tears play an important role in ocular surface diseases. In previous studies, changes have been demonstrated in the electrophoretic protein profiles of patients with dry eye. The purpose of this work was to determine the usefulness of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) ProteinChip Array (Ciphergen Biosystems, Inc., Fremont, CA) technology for the automated analysis of proteins and peptides in tear fluid.Patients with dry eye (DRY, n = 88) and healthy subjects (CTRL, n = 71) were examined. Their tear proteins were analyzed using SELDI-TOF-MS ProteinChip Arrays with three different chromatographic surfaces (CM10…

Non-invasive peripheral vascular function, incident cardiovascular disease, and mortality in the general population

AIMS Evidence suggests that peripheral vascular function is related to cardiovascular disease (CVD) and mortality. We evaluated the associations of noninvasive measures of flow-mediated dilatation and peripheral arterial tonometry with incident CVD and mortality. METHODS AND RESULTS In a post-hoc analysis of the community-based Gutenberg Health Study, median age 55 years (25th/75th percentile 46/65) and 49.5% women, we measured brachial artery flow-mediated dilatation (N = 12,599) and fingertip peripheral arterial tonometry (N = 11,125). After a follow-up of up to 11.7 years, we observed 595 incident CVD events, 106 cardiac deaths, and 860 deaths in total. Survival curves showed decreased e…

Severe High Molecular Weight Kininogen (HK) Deficiency: Clinical Characteristics, Deficiency-Causing KNG1 Variants in Reported and New Cases, and Estimated Prevalence

Abstract Background: Severe high molecular weight kininogen (HK) deficiency is an autosomal recessive defect of the contact system caused by mutations in KNG1. Limited scientific interest in HK deficiency due to the rarity of the seemingly asymptomatic condition may increase, as HK, the precursor of bradykinin, is now discussed as a therapeutic target e.g. in hereditary angioedema. Aims: We provide a comprehensive analysis of the diagnostic, clinical, and genetic features of HK deficiency and estimate its frequency. Methods: We identified a new case of HK deficiency, systematically review the literature, conduct new genetic studies of reported cases, and comprehensively analyze the clinical…

Copeptin Improves Early Diagnosis of Acute Myocardial Infarction

ObjectivesEarly identification of myocardial infarction in chest pain patients is crucial to identify patients at risk and to maintain a fast treatment initiation.BackgroundThe aim of the current investigation is to test whether determination of copeptin, an indirect marker for arginin-vasopressin, adds diagnostic information to cardiac troponin in early evaluation of patients with suspected myocardial infarction.MethodsBetween January 2007 and July 2008, patients with suspected acute coronary syndrome were consecutively enrolled in this multicenter study. Copeptin, troponin T (TnT), myoglobin, and creatine kinase-myocardial band were determined at admission and after 3 and 6 h.ResultsOf 1,…

No evidence for an association of plasma homocysteine levels and refractive error – Results from the population-based Gutenberg Health Study (GHS)

Purpose There is a strong association between severe hyperhomocysteinemia and myopia. Thus we studied the hypothesis that even moderately increased levels of homocysteine (Hcy) might be a potentially treatable risk factor for myopia. Methods The Gutenberg Health Study (GHS) is a population-based, prospective, observational cohort study in Germany, including 15,010 participants aged between 35 and 74 at recruitment. The baseline examination was conducted from 2007–2012. Refraction was measured using autorefraction (HARK 599, Carl Zeiss AG, Jena, Germany). Hcy was measured by an immunoassay. We included only phakic participants without a history of corneal surgery or corneal laser treatment. …

Combined B, T and NK Cell Deficiency Accelerates Atherosclerosis in BALB/c Mice.

This study focused on the unique properties of both the Ldlr knockout defect (closely mimicking the human situation) and the BALB/c (C) inbred mouse strain (Th-2 slanted immune response). We generated two immunodeficient strains with severe combined B- and T-cell immunodeficiency with or without a complete lack of natural killer cells to revisit the role of adaptive immune responses on atherogenesis. C-Ldlr-/- Rag1-/- mice, which show severe combined B- and T-cell immunodeficiency and C-Ldlr-/- Rag1-/- Il2rg-/- mice, which combine the T- and B-cell defect with a complete lack of natural killer cells and inactivation of multiple cytokine signalling pathways were fed an atherogenic Western ty…

Sensitive Troponin I Assay in Early Diagnosis of Acute Myocardial Infarction

BACKGROUND Cardiac troponin testing is central to the diagnosis of acute myocardial infarction. We evaluated a sensitive troponin I assay for the early diagnosis and risk stratification of myocardial infarction. METHODS In a multicenter study, we determined levels of troponin I as assessed by a sensitive assay, troponin T, and traditional myocardial necrosis markers in 1818 consecutive patients with suspected acute myocardial infarction, on admission and 3 hours and 6 hours after admission. RESULTS For samples obtained on admission, the diagnostic accuracy was highest with the sensitive troponin I assay (area under the receiver-operating-characteristic curve [AUC], 0.96), as compared with t…

Noise annoyance predicts symptoms of depression, anxiety and sleep disturbance 5 years later. Findings from the Gutenberg Health Study

Abstract Background Cross-sectional studies have shown that noise annoyance is strongly associated with mental distress, however, its long-term effects on mental health is unknown. We therefore investigated whether noise annoyance predicts depression, anxiety and sleep disturbance in a large, representative sample 5 years later. Methods We investigated longitudinal data of N = 11 905 participants of the Gutenberg Health Study, a population-based, prospective, single-centre cohort study in mid-Germany (age at baseline 35–74 years). Noise annoyance was assessed at baseline and 5-year follow-up (sources: road traffic, aircraft, railways, industrial, neighbourhood indoor and outdoor noise; and …

Comprehensive platelet phenotyping supports the role of platelets in the pathogenesis of acute venous thromboembolism - results from clinical observation studies

Background: The pathogenesis of arterial and venous thrombosis is in large part interlaced. How much platelet phenotype relates to acute venous thromboembolism (VTE) independent of the underlying cardiovascular profile is presently poorly investigated.Methods: Platelet count and mean platelet volume (MPV), platelet aggregation in whole blood and platelet rich plasma (PRP), platelet-dependent thrombin generation (TG) and platelet surface activation markers were measured under standardized conditions. Machine learning was applied to identify the most relevant characteristics associated with VTE from a large array (N = 58) of clinical and plateletrelated variables.Findings: VTE cases (N = 159)…

Early Diagnosis of Acanthamoeba Infection during Routine Cytological Examination of Cerebrospinal Fluid

ABSTRACT Early identification of Acanthamoeba in cerebrospinal fluid is mandatory to prevent fatal granulomatous amebic encephalitis. In the case presented here amebic trophozoites were detected in a routine cerebrospinal fluid sample. The antibiotic treatment and the apparently low virulence of this isolate were responsible for the benign progression of the infection.

Gut Microbiota Restricts NETosis in Acute Mesenteric Ischemia-Reperfusion Injury.

Objective: Recruitment of neutrophils and formation of neutrophil extracellular traps (NETs) contribute to lethality in acute mesenteric infarction. To study the impact of the gut microbiota in acute mesenteric infarction, we used gnotobiotic mouse models to investigate whether gut commensals prime the reactivity of neutrophils towards formation of neutrophil extracellular traps (NETosis). Approach and Results: We applied a mesenteric ischemia-reperfusion (I/R) injury model to germ-free (GF) and colonized C57BL/6J mice. By intravital imaging, we quantified leukocyte adherence and NET formation in I/R-injured mesenteric venules. Colonization with gut microbiota or monocolonization with Esch…

Severe plasma prekallikrein deficiency : clinical characteristics, novel KLKB1 mutations, and estimated prevalence

BACKGROUND Severe plasma prekallikrein (PK) deficiency is an autosomal-recessive defect characterized by isolated activated partial thromboplastin time prolongation. To date, no comprehensive methodologically firm analysis has investigated the diagnostic, clinical, and genetic characteristics of PK deficiency, and its prevalence remains unknown. PATIENTS/METHODS We described new families with PK deficiency, retrieved clinical and laboratory information of cases systematically searched in the (gray) literature, and collected blood of these cases for complementary analyses. The Genome Aggregation Database (gnomAD) and the population-based Gutenberg Health Study served to study the prevalence …

Impact of inflammatory markers on cardiovascular mortality in patients with metabolic syndrome.

Recent investigations suggest the inclusion of inflammatory markers in the definition of the metabolic syndrome (MS). The aim of this study was to address the role of C-reactive protein, fibrinogen, interleukin-6 (IL-6) and IL-18 (IL-18) on cardiovascular prognosis in accordance to MS.A total of 1263 patients with documented coronary artery disease were prospectively included. We defined MS (MS yes: N=533, 42.2%) as the presence of at least three of the following criteria: triglyceridesor=150 mg/dl; low high-density lipoprotein cholesterol (men:40 mg/dl women:50 mg/dl); body mass index greater than 30 kg/m; blood pressureor=130/85 mmHg; fasting glucoseor=100 mg/dl. In addition, we determine…

Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies

Background— Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts. Methods and Results— Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fi…

Kappa free light chains in cerebrospinal fluid as markers of intrathecal immunoglobulin synthesis.

Abstract Background: Intrathecal immunoglobulin synthesis is observed in several inflammatory disorders of the central nervous system, but its detection by current laboratory tests is either tedious or relatively insensitive. We assessed the diagnostic accuracy of an assay for κ free light chains (κFLC) in cerebrospinal fluid (CSF) and serum, and compared it with traditional tests for intrathecal immunoglobulin synthesis. Methods: κFLCs were measured by nephelometry in CSF/serum pairs from 112 patients. Samples were excluded if blood contamination of CSF as a result of traumatic lumbar puncture (n = 12) or monoclonal bands in both CSF and serum (n = 5) were present. The remaining sample pai…

The combination of different antiphospholipid antibody subgroups in the sera of patients with autoimmune diseases is a strong predictor for thrombosis

Summary Objective: To determine the distribution of different antiphospholipid antibodies (APL-Ab) and their association with thrombosis in patients with autoimmune diseases. Methods: Clinical data and laboratory features of 30 patients with different autoimmune diseases with positive APL-Ab were retrospectively studied for a period of more than two years. Anti-cardiolipin (aCL), anti-phosphatidylserine (aPS) and anti-β2-glycoprotein I (aβ2-GPI) antibodies were determined by ELISA. Results: Autoantibodies that target only PS were detected in 53.3% (n=16) patients, aCL antibodies only were found in one patient (3,3%). In 43.3% (n=13), aPS were associated with elevated levels of aCL and/or aβ…

Midregional Proadrenomedullin for Prediction of Cardiovascular Events in Coronary Artery Disease: Results from the AtheroGene Study

Abstract BACKGROUND Midregional proadrenomedullin (MR-proADM) is a newly identified prognostic marker in heart failure. We evaluated the prognostic impact of MR-proADM in a cohort of patients with symptomatic coronary artery disease according to their clinical presentation. METHODS We measured baseline MR-proADM concentrations in 2240 individuals from the prospective AtheroGene study and evaluated the prognostic impact on future fatal and nonfatal cardiovascular events during a follow-up period of 3.6 (1.6) years. RESULTS The sample comprised 1355 individuals with stable angina pectoris (SAP) and 885 with acute coronary syndrome (ACS). A cardiovascular event occurred in 192 people. Individu…

Psychosomatische Medizin in der Gutenberg- Gesundheitsstudie (GHS) – Fragestellungen, Messverfahren, ausgewählte Ergebnisse

Psychosomatic medicine in the Gutenberg Health Study (GHS) - research questions, measurement instruments, selected results Goal: Main questions from the Gutenberg Health Study (GHS) related to psychosomatic medicine are presented: (1) Prevalence and incidence of mental illnesses, (2) Sex-specific risk- and protective factors for mental health, (3) Interplay between psychological and somatic diseases and (4) methodical-psychometric developments. Methods: The GHS is an ongoing, prospective and interdisciplinary cohort study in Mainz. The comprehensive examinations include psychological characteristics and clinical and laboratory tests. 15010 respondents were selected in the baseline study fro…

Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium

To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for …

Quantification of the Fabry marker lysoGb3 in human plasma by tandem mass spectrometry

Morbus Fabry is a hereditary metabolic disorder with low prevalence and late clinical manifestation. A defect in the α-galactosidase gene leads to lysosomal accumulation of the glycolipid globotriaosylceramide (Gb3). Gb3 may be used for monitoring of enzyme replacement therapy (ERT), but diagnostic sensitivity is limited. Recently, globotriaosylsphingosine (lysoGb3) was introduced as a promising new marker with significantly better sensitivity. For Fabry diagnosis, clinical studies and possible therapy monitoring, we established a fast and reliable LC-MS/MS assay for quantification of lysoGb3 in human plasma. Protein precipitation and glycolipid extraction from EDTA plasma was performed usi…

COVID-19 as a Potential Trigger for Immune Thrombotic Thrombocytopenic Purpura and Reason for an Unusual Treatment: A Case Report

AbstractImmune thrombotic thrombocytopenic purpura (iTTP) is a rare autoimmune disorder characterized by severely reduced activity of the von Willebrand factor (VWF)-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) due to autoantibodies. This leads to the development of pathogenic multimers of VWF, causing a thrombotic microangiopathy with decreased number of platelets, hemolysis, and life-threatening tissue ischemia of mostly brain, heart, and kidneys. Standard treatment of iTTP involves daily plasma exchange to remove ultra large multimers of VWF, inhibitors, substituting ADAMTS13, and the accompaniment of an immunosuppressive …

FEV1 Predicts Cardiac Status and Outcome in Chronic Heart Failure

Background COPD is an established predictor of clinical outcome in patients with chronic heart failure (HF). However, little evidence is available about the predictive value of FEV1 in chronic HF. Research Question Is pulmonary function related to the progression of chronic HF? Study Design and Methods The MyoVasc study ( ClinicalTrials.gov Identifier: NCT04064450) is a prospective cohort study of HF. Information on pulmonary and cardiac functional and structural status was obtained by body plethysmography and echocardiography. The primary study end point was worsening of HF. Results Overall 2,998 participants (age range, 35-84 years) with available FEV1 data were eligible for analysis. Lin…

The diagnostic performance of renal function-adjusted D-dimer testing in individuals suspected of having venous thromboembolism

Renal impairment, a source of chronic hypercoagulability[1][1] and inflammation,[2][2] is known to reduce the specificity of the D-dimer test in the diagnosis of venous thromboembolism (VTE).[3][3] This leads to many false positives in such patients and consequently to additional costs, as well as

Alterations in Lipid and Carbohydrate Metabolism in Patients with Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

&lt;i&gt;Background:&lt;/i&gt; Classic 21-hydroxylase deficiency (21HD) presents some traits of the metabolic syndrome. &lt;i&gt;Aim:&lt;/i&gt; To characterize discrete alterations of lipid and carbohydrate metabolism in children and young adults with classic 21HD, which could predict early atherogenesis. &lt;i&gt;Patients and Methods:&lt;/i&gt; Twenty-seven Caucasian patients with classic 21HD (4–31 years); 27 sex-, age- and BMI-matched controls. Clinical parameters, hormonal status and genotype were assessed in all patients. Lipid parameters, including relative (%) and absolute (mg/dl) small-dense low-density lipoproteins subfractions (sd-LDL) were measured in patients and controls. Oral …

Prediction of Acute Kidney Injury after TAVI by New Biomarkers

Distribution of HOMA-IR in a population-based cohort and proposal for reference intervals

Abstract Objectives Insulin resistance (IR) is a hallmark of type 2 diabetes mellitus (DM). The homeostatic model assessment of insulin resistance (HOMA-IR) provides an estimate for IR from fasting glucose and insulin serum concentrations. The aim of this study was to obtain a reference interval for HOMA-IR for a specific insulin immunoassay. Methods The Gutenberg Health Study (GHS) is a population-based, prospective, single-center cohort study in Germany with 15,030 participants aged 35–74 years. Fasting glucose, insulin, and C-peptide were available in 10,340 participants. HOMA-IR was calculated in this group and three reference subgroups with increasingly more stringent inclusion criteri…

Cross-Sectional Associations between Homoarginine, Intermediate Phenotypes, and Atrial Fibrillation in the Community—The Gutenberg Health Study

Homoarginine has come into the focus of interest as a biomarker for cardiovascular disease. Atrial fibrillation (AF) causes a substantial increase in morbidity and mortality. Whether circulating homoarginine is associated with occurrence or persistence of AF and may serve as a new predictive biomarker remains unknown. We measured plasma levels of homoarginine in the population-based Gutenberg health study (3761 patients included, of them 51.7% males), mean age 55.6 &plusmn

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 …

Transcriptome-Wide Analysis Identifies Novel Associations With Blood Pressure.

Hypertension represents a major cardiovascular risk factor. The pathophysiology of increased blood pressure (BP) is not yet completely understood. Transcriptome profiling offers possibilities to uncover genetics effects on BP. Based on 2 populations including 2549 individuals, a meta-analyses of monocytic transcriptome-wide profiles were performed to identify transcripts associated with BP. Replication was performed in 2 independent studies of whole-blood transcriptome data including 1990 individuals. For identified candidate genes, a direct link between long-term changes in BP and gene expression over time and by treatment with BP-lowering therapy was assessed. The predictive value of pro…

Automated Flow Cytometric Analysis of Blood Cells in Cerebrospinal Fluid

We compared the performance of an automated method for obtaining RBC and WBC counts and WBC differential counts in cerebrospinal fluid (CSF) samples with the reference manual method. Results from 325 samples from 10 worldwide clinical sites were used to demonstrate the accuracy, precision, and linearity of the method. Accuracy statistics for absolute cell counts showed a high correlation between methods, with correlation coefficients for all reportable absolute counts greater than 0.9. Linearity results demonstrated that the method provides accurate results throughout the reportable ranges, including clinical decision points for WBCs of 0 to 10/μL. Interassay precision and intra-assay preci…

Relapse Rate in Survivors of Acute Autoimmune Thrombotic Thrombocytopenic Purpura Treated with or without Rituximab.

Background Autoimmune thrombotic thrombocytopenic purpura (iTTP) is caused by autoantibody-mediated severe a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13) deficiency leading to micro-angiopathic haemolytic anaemia (MAHA) and thrombocytopenia with organ damage. Patients survive with plasma exchange (PEX), fresh frozen plasma replacement and corticosteroid treatment. Anti-CD20 monoclonal antibody rituximab is increasingly used in patients resistant to conventional PEX or relapsing after an acute bout. Objective This retrospective observational study focused on the relapse rate and possible influencing factors including treatment with rituximab first…

Analytical Performance and Validation of a Bioassay for Thyroid-Blocking Antibodies

A cell-based bioassay for the measurement of thyroid blocking autoantibodies (TBAb) has been recently reported. The analytical performance and validation of this bioassay is assessed and described.Chinese hamster ovary cells expressing a chimeric thyrotropin receptor were treated with bovine (b) TSH and different concentrations of an immunoglobulin G (IgG) monoclonal human TBAb (K1-70). TBAb was measured as a function of luciferase activity relative to bTSH alone and expressed as percent inhibition. Results obtained in the chimeric cell line were compared with those of a wild-type cell line. Analytical performance studies were subsequently performed with the chimeric cell line only.Immunode…

Comment on “Worldwide Distribution of PK Deficiency: the Defect Seems Mainly Concentrated in West African Countries and the United States.”

Distribution and categorization of left ventricular measurements in the general population: results from the population-based Gutenberg Heart Study.

Background— Echocardiography, the dominant imaging modality for quantification of left ventricular metrics, has undergone continuing development in the past few decades. However, given the lack of population-based data, current guidelines are still based on restricted and small data sets analyzed with methods including expert opinion. This work presents empirically derived reference values from a large-scale, epidemiologic study conducted with state-of-the-art imaging technology and methods. Methods and Results— The distribution of echocardiographic measurements of the left ventricle was analyzed in a population-based sample of 5000 mid-Europeans from the Gutenberg Heart Study in Germany. …

Cholesteryl ester transfer protein activity and cardiovascular events in patients with chronic kidney disease stage V.

Background Patients with chronic kidney disease (CKD) have an increased risk for cardiovascular events (CVE). Uraemic dyslipidaemia, which is characterized by low HDL-cholesterol (HDL-C) and elevated triglycerides' levels, may contribute to this elevated cardiovascular risk. Cholesteryl ester transfer protein (CETP) lowers HDL-C by transferring cholesterol esters to LDL and VLDL particles. We tested the hypothesis that CETP activity is associated with CVE in patients with CKD stage V. Methods We measured CETP activity and cholesterol levels in 69 haemodialysis patients. CVE and death were prospectively assessed over a follow-up period of 48 months. Results CETP activity was negatively corre…

Characteristics and pathologies of the vitreo‐macular interface—results from the Gutenberg Health Study

Purpose We aimed to determine the prevalence of characteristics and pathologies of the vitreo-macular interface within the general population. Methods The Gutenberg Health Study is a population-based study in Germany, including an ophthalmological examination with refraction, biometry and optical coherence tomography (OCT) imaging. Characteristics of the vitreo-macular interface were graded on volume scans including visibility of an epiretinal membrane, full-thickness macular hole, lamellar hole and pseudohole. Overall and age-specific prevalences including 95% confidence intervals [95%-CI] were calculated. Association analyses were conducted to determine systemic and ocular factors that ar…

Pathogenesis of antiphospholipid syndrome: recent insights and emerging concepts

Introduction: Even though our understanding of the antiphospholipid syndrome (APS) has improved tremendously over the last decades, we are still not in a position to replace symptomatic anticoagulation by pathogenesis based causal treatments. Areas covered: Recent years have provided further insights into pathogenetically relevant mechanisms. These include a differentiation of pathogenic subtypes of antiphospholipid antibodies (aPL), novel mechanisms modulating disease activity, for example, extracellular vesicles and microRNA, and novel players in pathogenesis, for example, neutrophils and neutrophil extracellular traps (NETs). Expert commentary: It is evident that aPL induce a proinflamma…

Endotoxin accelerates atherosclerosis independent of complement activation

a Central Laboratory Animal Facility b Institute of Clinical Chemistry and Laboratory Medicine c Institute of Medical Microbiology and Hygiene, Johannes Gutenberg University, Mainz, Germany d Klinik fur Gefaschirurgie und Nierentransplantation, Heinrich Heine Universitatsklinik, Dusseldorf, Germany e Zentrum fur Medizin und Biowissenschaften, Forschungszentrum, Borstel, Germany f Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland g Department of Molecular Pathology, Graduate School of Medicine and Engineering, University of Yamanashi, Japan

Glutathione Peroxidase-1 and Homocysteine for Cardiovascular Risk Prediction

Objectives This prospective study was designed to evaluate the effect of joint determination of two important contrary biomarkers—homocysteine and glutathione peroxidase (GPx)-1—on cardiovascular risk stratification. Background Homocysteine plasma levels have been associated with cardiovascular risk. Experimental data suggest that antioxidative GPx-1 activity modulates cardiovascular risk associated with homocysteine. Methods In 643 patients with coronary artery disease, we performed a prospective study to assess the risk of homocysteine plasma levels and GPx-1 activity on long-term cardiovascular risk with a median follow-up of 7.1 years. Results Both homocysteine and GPx-1 were among the …

The Prevalence of Visual Impairment in the Adult Population

Background The distribution of visual impairment is an indicator of the health status of the population and for the frequency of diseases of the eye. Methods The Gutenberg Health Study (GHS) is a population-based cohort study in Germany concerning adults aged 35 to 74. 15 010 subjects from the Mainz-Bingen region underwent general medical and ophthalmological examination, with measurement of the distance-corrected visual acuity in each eye separately. As per the World Health Organization criteria, visual impairment was defined as an acuity below 0.3 in the better eye, and blindness as an acuity below 0.05. All patients who were found to be visually impaired or blind underwent further indivi…

Subtherapeutic Anticoagulation Control under Treatment with Vitamin K-Antagonists—Data from a Specialized Coagulation Service

AbstractIn contrast to overanticoagulation, evidence on risk factors and outcome of subtherapeutic oral anticoagulation (OAC) with vitamin K-antagonists (VKAs) under optimum care is limited. We investigated the clinical phenotype, anticoagulation control, and clinical outcome of 760 VKA patients who received OAC therapy by a specialized coagulation service in the thrombEVAL study (NCT01809015). During 281,934 treatment days, 278 patients experience ≥ 1 episode of subtherapeutic anticoagulation control and had lower quality of OAC therapy compared to 482 patients without subtherapeutic international normalized ratio: 67.6%, interquartile range (IQR) 54.9%/76.8% versus 81.0%, IQR 68.5%/90.4%;…

The CFTR associated protein CAP70 interacts with the apical Cl-/HCO3- exchanger DRA in rabbit small intestinal mucosa.

DRA (down regulated in adenoma) is an intestinal anion exchanger, acting in parallel with NHE3 to facilitate ileal and colonic NaCl absorption. Furthermore it is involved in small intestinal bicarbonate secretion. Because DRA has a PDZ interaction motif, which may influence its properties, we searched for DRA-interacting PDZ adapter proteins in the small intestine. Using an overlay assay with the recombinant DRA C-terminus as a ligand, a 70 kDa protein was labeled, which was restricted to the brush border membrane in rabbit duodenal and ileal mucosa and was not detected in the colon. Destruction of the C-terminal PDZ interaction motif abolished this band, suggesting a specific protein-prote…

Sex-Specific Relationship Between Parathyroid Hormone and Platelet Indices in Phenotypes of Heart Failure—Results From the MyoVasc Study

Background: Heart failure (HF) is a multifactorial syndrome with pathophysiological complexities still not fully understood. Higher mean platelet volume (MPV), a potential marker of platelet activation, and high concentrations of parathyroid hormone (PTH) have been implicated in the pathogenesis of HF.Aim: This study aims to investigate sex-specifically the association between PTH concentrations and platelet indices in phenotypes of HF.Methods and Results: PTH and platelet indices (MPV and platelet count) were available in 1,896 participants from the MyoVasc study in Mainz, Germany. Multivariable linear regression models, adjusted for age, sex, season, vitamin D status, cardiovascular risk …

Atrial Fibrillation Manifestations Risk Factors and Sex Differences in a Population-Based Cohort (From the Gutenberg Health Study)

Sex differences in cardiovascular risk factors, cardiac structure and function, and disease and symptom burden in the common arrhythmia atrial fibrillation (AF) have not been investigated systematically at the population level. Cross-sectional data of 14,796 subjects (age range 35 to 74 years, 50.5% men) from the population-based Gutenberg Health Study were examined to show the distribution of cardiovascular risk factors by AF status and sex, and to determine sex-specific predictors for AF. The prevalence of AF was higher in men (4.3%) than in women (1.9%). Men had a worse cardiovascular risk factor profile, a higher prevalence of cardiovascular disease, but fewer symptoms than women. Age-a…

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 …

Clinical relevance of antiphospholipid antibodies in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies (AMAs), but also with reactivities to other autoantigens. Recent studies showed that antibodies to phospholipids (APAs) represent an important group of autoantibodies identified in patients with PBC. In this study different types of APAs were identified in the sera of patients with PBC and autoimmune hepatitis (AIH) and control subjects. Sera from patients with PBC and AIH were tested for the presence of antibodies directed against cardiolipin (CL), phosphatidylserine (PS), and to beta(2)-glycoprotein I (beta(2)-GPI). Furthermore, an in-house test for antithrombop…

Linking cancer and mental health in men and women in a representative community sample

Abstract Objective In aging populations, a growing number of individuals are affected by cancer. However, the relevance of the disease for mental health is still controversial, especially after treatment. We drew from a representative community sample to explore the link of cancer with mental health assessing different dimensions and different periods of time. Methods A cohort of 14,375 men and women (35–74 years) underwent medical assessments and was queried about cancer history, previous diagnoses of mental disorders, current mental distress symptoms, and current subjective health appraisal. Results 1066 participants (7.4%) reported a diagnosis of cancer (survival time M = 9.79 (SD = 9.07…

High-sensitivity troponin and novel biomarkers for the early diagnosis of non-ST-segment elevation myocardial infarction in patients with atrial fibrillation.

To evaluate the diagnostic performance of high-sensitivity troponin I (hsTnI) and other novel biomarkers for diagnosing non-ST-segment elevation myocardial infarction (NSTEMI) in patients with atrial fibrillation.In an acute chest pain cohort (N=1673), mean age 61.4±13.6 (34% female), we measured hsTnI and 13 established and novel biomarkers reflecting ischaemia, necrosis, inflammation, myocardial stress, angiogenesis on admission and after three hours in order to investigate their diagnostic accuracy for NSTEMI.In atrial fibrillation patients (N=299) hsTnI on admission had the best discriminatory ability for NSTEMI (area under the curve 0.97) with only two novel biomarkers, copeptin and he…

Role of C-reactive protein in atherogenesis: can the apolipoprotein E knockout mouse provide the answer?

Objective—Human C-reactive protein (CRP) was reported to accelerate atherosclerotic lesion development in male but not in female apolipoprotein E (apoE) knockout mice. Here, mice expressing rabbit CRP (rbCRP) were crossbred onto apoE knockout animals, and the effect on atherogenesis was studied.Methods and Results—Hemolytic complement activity could not be detected in apoE knockout mice. Furthermore, in contrast to human complement, neither rabbit nor human CRP complexed to modified low-density lipoprotein–activated murine complement. At 52 weeks, rbCRP levels were similar in male and female transgenic animals. Serum cholesterol levels were equivalent in female animals irrespective of rbCRP…

Sex-specific differences in genetic and nongenetic determinants of mean platelet volume: results from the Gutenberg Health Study.

Mean platelet volume (MPV), a measure of platelet size, is a potential biological marker of platelet function. To date, a comprehensive analysis including known genetic and nongenetic factors that determine MPV is still lacking. MPV has been evaluated in 15 010 individuals from the population-based Gutenberg Health Study. Genetic information was available for 4175 individuals. Our results showed that age (β, 0.0346; 95% confidence interval [CI], 0.0255 to 0.0436), cardiovascular risk factors (CVRFs) such as smoking (β, 0.178; 95% CI, 0.128 to 0.229), hypertension (β, 0.05; 95% CI, 0.00289 to .0981), and high glucose level (β, 0.00179; 95% CI, 0.0006 to 0.00299) were linked with higher MPV i…

Lipid presentation by the protein C receptor links coagulation with autoimmunity.

A lipid-protein autoimmunity target Several autoimmune diseases, including systemic lupus erythematosus and primary antiphospholipid syndrome, are characterized by the presence of antiphospholipid antibodies (aPLs). These molecules can activate the complement and coagulation cascades, which contributes to pathologies such as thrombosis, stroke, and pregnancy complications. Müller-Calleja et al. found that endothelial protein C receptor (EPCR) in complex with lysobisphosphatidic acid (LBPA) is the cell-surface target for aPL and mediates its internalization (see the Perspective by Kaplan). aPL binding to EPCR-LBPA resulted in the activation of tissue factor–mediated coagulation and interfero…

Further evaluation of plasma sphingomyelin levels as a risk factor for coronary artery disease

Abstract Background Sphingomyelin (SM) is the major phospholipid in cell membranes and in lipoproteins. In human plasma, SM is mainly found in atherogenic lipoproteins; thus, high levels of SM may promote atherogenesis. Methods We investigated in a median follow up of 6.0 years the association of SM with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) in stable and unstable patients, and its relation to other marker of atherosclerosis in 1,102 patients with angiographically documented CAD and 444 healthy controls. Results and discussion Logistic regression analysis showed that SM categorized by median was associated with an elevated risk for CAD (HR 3.2…

Schirmer test results: are they associated with topical or systemic medication?

To test whether Schirmer test (ST) results are associated with topical or systemic medication and to evaluate the distribution of tear fluid quantity in a 3-min and 5-min ST.The Gutenberg Health Study is a population-based, prospective, observational cohort study in Germany. ST was assessed in a sub-cohort of 1,999 participants. ST was performed under topical anesthesia for 5 min (ST-5) or of 3 min (ST-3). Anthropometric factors, systemic diseases, use of systemic and eye medications were recorded. We used multivariable quantile regression analysis to assess the influence on ST measurements.The length of wetting of the Schirmer strips for ST-5 was 23.2 ± 9.31 mm for right and 22.9 ± 9.0 mm …

Serum selenium and prognosis in cardiovascular disease: results from the AtheroGene study

Experimental data suggest a protective role of the essential trace element selenium against cardiovascular disease (CVD), whereas epidemiological data remains controversial. We aimed to investigate the impact of serum selenium concentration in patients presenting with stable angina pectoris (SAP) or acute coronary syndrome (ACS) on long term prognosis.Baseline selenium concentration was measured in 1731 individuals (852 with SAP, and 879 with ACS). During a median follow-up of 6.1 years, 190 individuals died from cardiovascular causes.In those ACS patients who subsequently died of cardiac causes, selenium levels were lower compared to survivors (61.0microg/L versus 71.5microg/L; P0.0001). I…

Structural and functional characterization of a human IgG monoclonal antiphospholipid antibody

Antiphospholipid antibodies (aPL) are likely involved in the pathogenesis of the antiphospholipid syndrome (APS). This study analyzes the structural and functional characteristics of a human monoclonal aPL (HL7G) from the IgG2 subtype with λ light chains generated from a patient with primary APS and recurrent cerebral microemboli. DNA encoding the variable region of heavy and light chains of the antibody was sequenced, analyzed, and compared to HL5B a previously described monoclonal aPL from the same patient. Both antibodies are derived from the same germline genes. HL7G had similar but more extensive somatic mutations in the CDR1 and 2 regions than HL5B, indicating that both antibodies are…

Resveratrol Reverses Endothelial Nitric-Oxide Synthase Uncoupling in Apolipoprotein E Knockout Mice

A crucial cause of the decreased bioactivity of nitric oxide (NO) in cardiovascular diseases is the uncoupling of the endothelial NO synthase (eNOS) caused by the oxidative stress-mediated deficiency of the NOS cofactor tetrahydrobiopterin (BH(4)). The reversal of eNOS uncoupling might represent a novel therapeutic approach. The treatment of apolipoprotein E knockout (ApoE-KO) mice with resveratrol resulted in the up-regulation of superoxide dismutase (SOD) isoforms (SOD1-SOD3), glutathione peroxidase 1 (GPx1), and catalase and the down-regulation of NADPH oxidases NOX2 and NOX4 in the hearts of ApoE-KO mice. This was associated with reductions in superoxide, 3-nitrotyrosine, and malondiald…

Lipid-Mediated Relation between Tissue Factor Pathway Inhibitor Activity and Cardiovascular Risk Factors and Diseases in a Large Population Sample

Abstract Background: Tissue factor pathway inhibitor (TFPI), a Kunitz-type serine protease, is a potent anticoagulant protein in the extrinsic coagulation pathway and acts by inhibiting both the FXa and the Tissue Factor-FVIIa complex. In contrast to total and free TFPI antigen levels, the reference values and clinical determinants of total TFPI activity have not yet been studied in detail in the general population. In the present study, we aim to identify the cardiovascular determinants for total TFPI activity and investigate its association with cardiovascular disease (CVD) and total mortality, in a population at large. Methods: For this study, the first 4779 subjects of the population-ba…

Selenium supplementation improves antioxidant capacity in vitro and in vivo in patients with coronary artery disease

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-…

Late onset and pregnancy-induced congenital thrombotic thrombocytopenic purpura

SummaryWe report on our patient (case 2) who experienced a first acute episode of thrombotic thrombocytopenic purpura (TTP) at the age of 19 years during her first pregnancy in 1976 which ended in a spontaneous abortion in the 30th gestational week. Treatment with red blood cell concentrates was implemented and splenectomy was performed. After having suffered from several TTP episodes in 1977, possibly mitigated by acetylsalicylic acid therapy, an interruption and sterilization were performed in 1980 in her second pregnancy thereby avoiding another disease flare-up. Her elder sister (case 1) had been diagnosed with TTP in 1974, also during her first pregnancy. She died in 1977 during her se…

Molecular Mechanisms of the Crosstalk Between Mitochondrial and NADPH Oxidase Derived Reactive Oxygen Species in White Blood Cells - Implications for Cardiovascular Diseases

The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity.

Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress respo…

Possible protective role for C-reactive protein in atherogenesis: complement activation by modified lipoproteins halts before detrimental terminal sequence.

Background—Previous work indicated that enzymatically remodeled LDL (E-LDL) might activate complement in atherosclerotic lesions via a C-reactive protein (CRP)–dependent and CRP-independent pathway. We sought to substantiate this contention and determine whether both pathways drive the sequence to completion.Methods and Results—E-LDL was prepared by sequential treatment of LDL with a protease and cholesteryl esterase. Trypsin, proteinase K, cathepsin H, or plasmin was used with similar results. Functional tests were used to assess total complement hemolytic activity, and immunoassays were used to demonstrate C3 cleavage and to quantify C3a, C4a, C5a, and C5b-9. E-LDL preparations activated …

A genome-wide association study of corneal astigmatism: The CREAM Consortium

Contains fulltext : 191261.pdf (Publisher’s version ) (Open Access) Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for …

Acute deep vein thrombosis suppresses peripheral T cell effector function

Relation between Tissue Factor Pathway Inhibitor Activity and Cardiovascular Risk Factors and Diseases in a Large Population Sample.

Abstract Objective Tissue factor pathway inhibitor (TFPI) is a potent anticoagulant protein in the extrinsic coagulation pathway. In the present study, we aim to identify the cardiovascular determinants for total TFPI activity and its association with cardiovascular disease (CVD) and total mortality. Methods Total TFPI activity was assessed in a selection of the population-based Gutenberg Health Study (n = 5,000). Statistical analysis was performed to identify the determinants for total TFPI activity as well as the associations with CVD and mortality. Results Multivariable linear regression analysis identified smoking (β 0.095 [0.054–0.136]) as a positive determinant for total TFPI activity…

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 maj…

Impact of glucuronide interferences on therapeutic drug monitoring of posaconazole by tandem mass spectrometry.

Abstract Background: Posaconazole is a novel antifungal drug for oral application intended especially for therapy of invasive mycoses. Due to variable gastrointestinal absorption, adverse side effects, and suspected drug-drug interactions, therapeutic drug monitoring (TDM) of posaconazole is recommended. Method: A fast ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification of posaconazole with a run-time &lt;3 min was developed and compared to a LC-MS/MS method and HPLC method with fluorescence detection. Results: During evaluation of UPLC-MS/MS, two earlier eluting peaks were observed in the MRM trace of posaconazole. This was only seen in p…

TLR7 and TLR8 ligands and antiphospholipid antibodies show synergistic effects on the induction of IL-1beta and caspase-1 in monocytes and dendritic cells.

TLRs represent the first line of defense against invading pathogens in the innate immune system. Certain cytokines are important mediators and essentially necessary to assure an appropriately regulated immune response. Recent data gave initial evidence that IL-1beta is one of the most relevant members of these regulating cytokines. We investigated the induction of IL-1beta production in monocytes and pDCs stimulated with ligands for TLR7 and TLR8 and with antiphospholipid antibodies (aPL). Using human monocytes and pDCs for stimulation with specific TLR7 and TLR8 ligands such as resiquimod (R848) and single stranded RNA (RNA42) as well as with a human monoclonal aPL HL5B resulted in a speci…

Identification of a peptide mimicking the binding pattern of an antiphospholipid antibody

Our objective was to characterize monoclonal antiphospholipid antibodies (APL) and identify disease-associated antigens in patients with the antiphospholipid syndrome (APS). We used the monoclonal antibody HL-5B, derived from a patient with APS suffering from multiple ischemic events, to screen a 12-mer peptide phage display library (New England Biolabs, London, England). The identified phage clones were sequenced and the derived consensus peptide was synthesized. The peptide was used to perform competitive inhibition experiments for their ability to inhibit the binding of the monoclonal antibody and of serum antibodies to cardiolipin and phosphatidylserine. Additionally patients and contro…

Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p −8 ) for serum albumin ( HPN-SCN1B , GCKR-FNDC4 , SERPINF2-WDR81 , TNFRSF11A-ZCCHC2 , FRMD5-WDR76 , and RPS11-FCGRT , in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein ( TNFRS13B , 6q21.3, and ELL2 , in …

Formation of 2-nitrophenol from salicylaldehyde as a suitable test for low peroxynitrite fluxes

There has been some dispute regarding reaction products formed at physiological peroxynitrite fluxes in the nanomolar range with phenolic molecules, when used to predict the behavior of protein-bound aromatic amino acids like tyrosine. Previous data showed that at nanomolar fluxes of peroxynitrite, nitration of these phenolic compounds was outcompeted by dimerization (e.g. biphenols or dityrosine). Using 3-morpholino sydnonimine (Sin-1), we created low fluxes of peroxynitrite in our reaction set-up to demonstrate that salicylaldehyde displays unique features in the detection of physiological fluxes of peroxynitrite, yielding detectable nitration but only minor dimerization products. By mean…

B-Type Natriuretic Peptide and the Risk of Cardiovascular Events and Death in Patients With Stable Angina

B-Type Natriuretic Peptide and the Risk of Cardiovascular Events and Death in Patients With Stable Angina: Results From the AtheroGeneStudyRenate Schnabel, Edith Lubos, Hans J. Rupprecht, Christine...

Rationale, design and baseline characteristics of the MyoVasc study: A prospective cohort study investigating development and progression of heart failure.

Abstract Background Heart failure (HF) is a poly-aetiological syndrome with large heterogeneity regarding clinical presentation, pathophysiology, clinical outcome and response to therapy. The MyoVasc study (NCT04064450) is an epidemiological cohort study investigating the development and progression of HF. Methods The primary objective of the study is (a) to improve the understanding of the pathomechanisms of HF across the full spectrum of clinical presentation, (b) to investigate the current clinical classifications of HF, and (c) to identify and characterize homogeneous subgroups regarding disease development using a systems-oriented approach. Worsening of HF, that is, the composite of tr…

Broad spectrum of Fabry disease manifestation in an extended Spanish family with a new deletion in the GLA gene

Background. Fabry disease (FD) is an X-linked inherited disease based on the absence or reduction of lysosomal-galactosidase (Gla) activity. The enzymatic defect results in progressive impairment of cerebrovascular, renal and cardiac function. Normally, female heterozygote mutation carriers are less strongly affected than male hemizygotes aggravating disease diagnosis. Method. Close examination of the patients by renal biopsy, echo- and electrocardiography and MRI. Blood work and subsequent DNA analysis were carried out utilizing approved protocols for PCR and Sequencing. MLPA analysis was done to unveil deletions within the GLA gene locus. Quantitative detection of Glycolipids in patient p…

A case of Waldenstroem's disease with a monoclonal IgM antiphospholipid antibody

The antiphospholipid syndrome (APS) was described in 1983 as a clinical entity characterized by venous and arterial thrombosis, thrombocytopenia, and recurrent fetal loss. The serological markers of APS are antiphospholipid antibodies (APLA) directed mainly against anionic phospholipids, usually cardiolipin but also phosphatidylserine. Some APLA exhibit lupus anticoagulant activity. Monoclonal gammopathy sometimes occurs with the presence of autoantibodies. In this paper, we describe a patient with the diagnosis of immunocytoma with an IgM, kappa paraprotein with apparent specificity against anionic phospholipids, and lupus anticoagulant activity, but no clinical signs of APS. We describe i…

Missing value imputation in proximity extension assay-based targeted proteomics data

Targeted proteomics utilizing antibody-based proximity extension assays provides sensitive and highly specific quantifications of plasma protein levels. Multivariate analysis of this data is hampered by frequent missing values (random or left censored), calling for imputation approaches. While appropriate missing-value imputation methods exist, benchmarks of their performance in targeted proteomics data are lacking. Here, we assessed the performance of two methods for imputation of values missing completely at random, the previously top-benchmarked ‘missForest’ and the recently published ‘GSimp’ method. Evaluation was accomplished by comparing imputed with remeasured relative concentrations…

Malignant paraganglioma caused by a novel germline mutation of the succinate dehydrogenase D-gene--a case report.

Background Paragangliomas of the head and neck are rare, mostly benign tumors. Approximately 10% to 15% of paragangliomas are caused by mutations in the succinate dehydrogenase (SDH) genes B, C, or D. These are often multifocal as part of paraganglioma syndromes and hormone secreting, and malignant particularly associated with mutations in SDHB. Methods and Results A 29-year-old man was seen with recurrent paraganglioma. The patient's father reportedly suffered from bilateral carotid body tumors. Imaging studies showed metastases in both lungs and the liver. There was no increased hormone production by the tumor. Sequence analysis of the SDH genes revealed a novel C to T nonsense mutation i…

Analysis of N-terminal-pro-brain natriuretic peptide and C-reactive protein for risk stratification in stable and unstable coronary artery disease: results from the AtheroGene study

Aims N-terminal-pro-brain natriuretic peptide (Nt-proBNP) is a reliable risk predictor in acute coronary artery disease (CAD). Little is known about patients with stable angina pectoris (SAP). We aimed to investigate the prognostic impact of Nt-proBNP in a population with CAD especially focussing on patients with SAP. Methods and results We obtained baseline samples from a prospective cohort of 904 consecutive patients with CAD. Cardiovascular events were registered during followup (median 2 years; maximum 3.7 years). Baseline Nt-proBNP was significantly higher among individuals with cardiovascular events compared with those without (711.5 vs. 238.8 pg/mL; P , 0.0001). A similar association…

Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease

OBJECTIVES We sought to evaluate the association between cholesteryl ester transfer protein (CETP) genotypes and the risk of future cardiovascular mortality in patients with coronary artery disease (CAD). BACKGROUND Polymorphisms of the CETP gene influence CETP activity and high-density lipoprotein (HDL) cholesterol concentration and might affect the long-term prognosis and response to statin therapy in patients with CAD. METHODS We used serum samples and deoxyribonucleic acid collected at baseline from a prospective cohort of 1,211 patients with CAD prospectively followed up (median follow-up of 4.1 years), 82 of whom experienced a fatal cardiovascular event. The CETP/C-629A and I405V poly…

Anti-prothrombin autoantibodies enriched after infection with SARS-CoV-2 and influenced by strength of antibody response against SARS-CoV-2 proteins

Antiphospholipid antibodies (aPL), assumed to cause antiphospholipid syndrome (APS), are notorious for their heterogeneity in targeting phospholipids and phospholipid-binding proteins. The persistent presence of Lupus anticoagulant and/or aPL against cardiolipin and/or β2-glycoprotein I have been shown to be independent risk factors for vascular thrombosis and pregnancy morbidity in APS. aPL production is thought to be triggered by–among other factors–viral infections, though infection-associated aPL have mostly been considered non-pathogenic. Recently, the potential pathogenicity of infection-associated aPL has gained momentum since an increasing number of patients infected with Severe Acu…

Chronic venous insufficiency, cardiovascular disease, and mortality: a population study

Abstract Aims  Evidence regarding the health burden of chronic venous insufficiency (CVI), its clinical determinants, and impact on outcome is scarce. Methods and results  Systematic phenotyping of CVI according to established CEAP (Clinical-Etiologic-Anatomic-Pathophysiologic) classification was performed in 12 423 participants (age range: 40–80 years) of the Gutenberg Health Study from April 2012 to April 2017. Prevalence was calculated age- and sex-specifically. Multivariable Poisson regression models were calculated to evaluate the relation of CVI with cardiovascular comorbidities. Survival analyses were carried out to assess the CVI-associated risk of death. Replication of findings was…

Cigarette Smoking Is Related to Endothelial Dysfunction of Resistance, but Not Conduit Arteries in the General Population—Results From the Gutenberg Health Study

Aims: Cigarette smoking is one of the most complex and least understood cardiovascular risk factors. Importantly, differences in the tobacco-related pathophysiology of endothelial dysfunction, an early event in atherogenesis, between circulatory beds remain elusive. Therefore, this study evaluated how smoking impacts endothelial function of conduit and resistance arteries in a large population-based cohort.Methods and results: 15,010 participants (aged 35–74 years) of the Gutenberg Health Study were examined at baseline from 2007 to 2012. Smoking status, pack-years of smoking, and years since quitting smoking were assessed by a computer-assisted interview. Endothelial function of conduit an…

Jillian Russyll (AKA Jill) Tate

FEV1 and FVC predict all-cause mortality independent of cardiac function - Results from the population-based Gutenberg Health Study.

Abstract Background Lung function has previously been related to increased mortality. Whether pulmonary impairment is associated with an increased mortality independent of cardiac dysfunction remains unclear. Methods In 15010 individuals from the general population (age range 35–74years, 51% men) in the Gutenberg Health Study we performed spirometry and transthoracic echocardiography. N-terminal pro-B-type natriuretic peptide (Nt-proBNP) and high-sensitive troponin I (hsTnI) were measured in all individuals. 1819 individuals with pulmonary diseases were excluded from further analysis. Results The median for forced expiratory volume in 1s (FEV1) was 94.2% and for forced vital capacity (FVC) …

Is assessment of depression equivalent for migrants of different cultural backgrounds? Results from the German population-based Gutenberg Health Study (GHS)

BACKGROUND Bearing in mind the multicultural background of a national population, little is known about the measurement invariance across different cultures or ethnicities of frequently used screeners for depression. For this reason, the main objective of the current study is to assess the measurement invariance of the Patient Health Questionnaire (PHQ-9) across groups with different migration backgrounds. METHODS We provided psychometric analyses (descriptive statistics at item and scale level, reliability analysis, exploratory [EFA] and confirmatory factor analyses [CFA]) comparing a native population with first- and second-generation migrants of the German population-based Gutenberg Heal…

Circulating microRNAs strongly predict cardiovascular death in patients with coronary artery disease—results from the large AtheroGene study

Introduction Stratification for subsequent coronary events among patients with coronary artery disease (CAD) is of considerable interest because of the potential to guide secondary preventive therapies. Recently, we identified eight microRNAs (miRNAs), which facilitated acute coronary syndrome (ACS) diagnosis. In this study, we aimed to evaluate their potential role as prognostic biomarkers for cardiovascular disease. Methods The serum concentrations of eight candidate miRNAs -miR-19a, miR-19b, miR-132, miR-140-3p, miR-142-5p, miR-150, miR-186, and miR-210 were measured in a cohort of 1112 patients with documented CAD—including 430 patients with ACS and 682 patients with stable angina pecto…

Five-year change in refractive error and its risk factors: results from the Gutenberg Health Study.

Background/AimsTo examine the 5-year change in refractive error in phakic eyes and its risk factors in the general population.MethodsThe Gutenberg Health Study (GHS) is a population-based cohort study including 15 010 participants from Germany aged 35–74 years at baseline examination (2007–2012). After 5 years, a follow-up examination was carried out (83% participation). 5-year change of spherical equivalent (SE) was computed as difference between follow-up and baseline objective refraction. Linear and logistic regression analysis were conducted analysing potential risk factors. Only phakic eyes at follow-up examination were included.ResultsRight eyes of 10 175 subjects were included. An ag…

Generation and characterization of three monoclonal IgM antiphospholipid antibodies recognizing different phospholipid antigens.

Antiphospholipid antibodies (APLs) might be involved in the pathogenesis of the antiphospholipid syndrome (APS). This study analyzes the structural characteristics of monoclonal APLs derived from patients with this disease. Patient-derived B cells were immortalized using Epstein-Barr virus transformation and subsequent fusion to the myeloma cell line CB-F7. APL-producing hybridomas were cloned to obtain cell lines producing monoclonal APL. DNA encoding the variable region of heavy and light chains of the antibodies was sequenced and analyzed regarding their usage within the V-gene family and the existence of somatic hypermutation. Binding patterns of APL to various phospholipids and beta-2-…

Annoyance to different noise sources is associated with atrial fibrillation in the Gutenberg Health Study

Abstract Background Annoyance is a common reaction in populations exposed to environmental noise and is associated with cardiovascular diseases. We investigated for the first time the existence of an association between noise annoyance and atrial fibrillation (AF). Methods and results Cross-sectional data from 14,639 participants of the Gutenberg Health Study were collected between 2007 and 2012. Annoyance from road traffic, aircraft, railways, industrial/construction and neighbourhood noise during daytime and sleep were collected from all participants through questionnaires using a 5-point scale. AF was assessed via self-reported medical history and/or documentation of AF on the study elec…

The distribution of whole blood viscosity, its determinants and relationship with arterial blood pressure in the community: cross-sectional analysis from the Gutenberg Health Study.

Background: Blood viscosity has a role in modulating cardiovascular homeostasis; changes in this parameter have been associated with cardiovascular mortality and morbidity. However, it remains unclear whether these changes are (1) involved in the pathophysiology of disease, (2) an epiphenomenon, or (3) the expression of counterregulatory mechanisms. We report data on the normal values of blood viscosity and its association with cardiovascular risk factors, prevalent cardiovascular disease, and blood pressure in a large population-based cohort study. Methods and results: Viscosity was calculated using validated formulae and its associations were explored in 15,010 participants (mean 55.0, mi…

Association of adiponectin with adverse outcome in coronary artery disease patients: results from the AtheroGene study

In primary prevention, the adipocytokine adiponectin seems to be protective against diabetes mellitus and cardiovascular disease. Data in patients with manifest coronary artery disease (CAD) are scant stimulating the investigation of the association of adiponectin concentrations and cardiovascular outcome in a prospective CAD cohort.In 1890 consecutive patients with documented CAD [1130 with stable angina (SAP) and 760 with acute coronary syndrome (ACS)] baseline concentrations of adiponectin were measured by enzyme-linked immuno assay. During a median follow-up of 2.5 years cardiovascular events were registered (cardiovascular deaths 70; non-fatal myocardial infarction 46). Baseline adipon…

Nitrate tolerance as a model of vascular dysfunction: Roles for mitochondrial aldehyde dehydrogenase and mitochondrial oxidative stress

Organic nitrates are a group of very effective anti-ischemic drugs. They are used for the treatment of patients with stable angina, acute myocardial infarction and chronic congestive heart failure. A major therapeutic limitation inherent to organic nitrates is the development of tolerance, which occurs during chronic treatment with these agents. The mechanisms underlying nitrate tolerance remain incompletely defined and are likely multifactorial. One mechanism seems to be a diminished bioconversion of nitroglycerin, another seems to be the induction of vascular oxidative stress, and a third may include neurohumoral adaptations. Recent studies have revealed that mitochondrial reactive oxygen…

Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, …

Identification of acute myocardial infarction in elderly patients using optimized highly sensitive troponin I thresholds

Purpose: Established diagnostic thresholds for high-sensitivity cardiac troponins (hs-cTn) might not apply for elderly patients as they are elevated irrespective of the presence of an acute myocardial infarction (AMI). Aim of the present study was to investigate hs-cTnI in elderly patients with suspected AMI and to calculate optimized diagnostic cutoffs. Material and methods: Data from a prospective multi-centre study and from a second independent prospective single-centre cohort study were analysed. A number of 2903 patients were eligible for further analysis. Patients &gt; 70 years were classified as elderly. hs-cTnI was measured upon admission. Results: Around 34.7% of 2903 patients were…

Impact of C-reactive protein and fibrinogen on cardiovascular prognosis in patients with stable angina pectoris: the AtheroGene study.

Aims C-reactive protein and fibrinogen have been extensively studied and shown to be predictive for a first cardiovascular event in healthy individuals. We evaluated the potential clinical use of C-reactive protein and fibrinogen in patients already suffering from coronary artery disease (CAD). Methods and results In a substudy of the prospective Athero Gene registry, we assessed in 1806 patients with documented CAD and stable angina pectoris, the risk of cardiovascular death and non-fatal myocardial infarction ( n =183) over a median follow-up of 3.5 (maximum 7.7) years according to baseline levels of C-reactive protein and fibrinogen. C-reactive protein and fibrinogen were associated with…

Are antiphospholipid antibodies an essential requirement for an effective immune response to infections?

Antiphospholipid antibodies show a close association to a variety of infections. Recent data implicate that parvovirus B19 may be used as a model-system for studying the interaction of viral infection and the development of these autoantibodies. B19-related diseases commonly associated with the acute infection show flu-like symptoms, transient arthralgias, leukopenia and thrombocytopenia, and, in pregnant women, spontaneous abortion and hydrops fetalis. Hepatitis, myocarditis, meningitis, encephalitis, as well as pure red cell anemia may occur occasionally. In addition, parvovirus B19 infections have been frequently described as the cause or trigger of various forms of autoimmune diseases a…

Association of Global Longitudinal Strain With Clinical Status and Mortality in Patients With Chronic Heart Failure.

IMPORTANCE: Global longitudinal strain (GLS) is an emerging echocardiographic biomarker of cardiac function in heart failure (HF). Evidence from large-scale studies comprehensively investigating GLS for its association with clinical phenotypes and mortality in asymptomatic and symptomatic chronic HF is limited. OBJECTIVE: To assess the factors associated with GLS and its prognostic value in patients with chronic HF. DESIGN, SETTING, AND PARTICIPANTS: The observational, prospective MyoVasc cohort study enrolled 3289 individuals with asymptomatic to symptomatic HF between January 17, 2013, and April 27, 2018. The median follow-up was 3.2 years (interquartile range, 2.0-4.0 years). Participant…

Enzymatic modification of low-density lipoprotein in the arterial wall: a new role for plasmin and matrix metalloproteinases in atherogenesis.

Objective— Functionally interactive proteases of the plasminogen/plasmin and the matrix metalloproteinase (MMP) system degrade and reorganize the extracellular matrix of the vessel wall in atherosclerosis. Here we investigated whether such proteases are able to confer atherogenic properties onto low density lipoprotein by nonoxidative modification. Methods and Results— Similar to the recently described enzymatically-modified low-density lipoprotein (E-LDL), native LDL exposed to plasmin or matrix MMP-2 or MMP-9 and cholesterylester-hydrolase (CEH) showed extensive deesterification, with ratios of free cholesterol to total cholesterol rising to 0.8 compared with 0.2 in native LDL. When the …

Serum sphingomyelin levels are related to the clearance of postprandial remnant-like particles.

It is known that sphingomyelin (SM) content is higher in apolipoprotein B-containing particles (BLps) than in high density lipoproteins and that BLp levels, including chylomicrons and their remnant particles, are positively related to atherosclerosis. To evaluate the relationship between serum SM and postprandial remnant particle levels, we determined SM, triglyceride (TG), and cholesterol levels in serum and in remnant-like particles (RLPs) before and 3, 5, 7, and 10 h after a high-fat meal in 31 healthy subjects. We found that serum SM, like serum TG, was increased to its maximum 3 h after fat loading and then gradually decreased to basal levels after 10 h. More important, we determined t…

PCF11 links alternative polyadenylation to formation and spontaneous regression of neuroblastoma

AbstractDiversification at the transcriptome 3’end is an important and evolutionarily conserved layer of gene regulation associated with differentiation and dedifferentiation processes. However the underlying mechanisms and functional consequences are poorly defined. Here, we identify extensive transcriptome-3’end-alterations in neuroblastoma, a tumour entity with a paucity of recurrent somatic mutations and an unusually high frequency of spontaneous regression. Utilising extensive RNAi-screening we reveal the landscape and drivers of transcriptome-3’end-diversification, discovering PCF11 as critical regulator, directing alternative polyadenylation (APA) of hundreds of transcripts including…

Noninvasive peripheral vascular function and atrial fibrillation in the general population.

Background Arterial stiffness is a strong predictor of atrial fibrillation in the community. Whether noninvasively measured conduit artery function and peripheral vascular reactivity are related to atrial fibrillation remains unknown. Methods and results In 15 010 individuals of the population-based Gutenberg Health Study, mean age 55 ± 11 years, 50.5% men, we determined noninvasive vascular function by flow-mediated dilation (FMD) and peripheral arterial tonometry (PAT) in relation to manifest atrial fibrillation (N = 466). Patients with atrial fibrillation exhibited a higher mean brachial artery diameter [4.81 mm (4.17, 5.33) in atrial fibrillation vs. 4.31 mm (3.67, 4.93)] and baseline p…

Incidence of Retinal Detachment in Germany: Results from the Gutenberg Health Study

&lt;b&gt;&lt;i&gt;Purpose:&lt;/i&gt;&lt;/b&gt; To investigate the incidence of retinal detachment in the German population and to assess potential risk factors. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; The Gutenberg Health Study is a population-based cohort study in Mainz, Germany, including subjects (&lt;i&gt;n&lt;/i&gt; = 15,010) with an age range from 35 to 74 years at baseline examination. Study participants underwent a comprehensive ophthalmological examination including distant-corrected visual acuity, refraction and slit-lamp examination at baseline examination. A computer-assisted telephone interview was conducted after 2.5 and 5 years, and health events were recorded. The 5-y…

Profile of the Immune and Inflammatory Response in Individuals With Prediabetes and Type 2 Diabetes.

OBJECTIVE The inflammatory and immune systems are altered in type 2 diabetes. Here, the aim was to profile the immune and inflammatory response in subjects with prediabetes and diabetes in a large population-representative sample. RESEARCH DESIGN AND METHODS In total, 15,010 individuals were analyzed from the population-based Gutenberg Health Study. Glucose status was classified according to HbA1c concentration and history of diagnosis. All samples were analyzed for white blood cells (WBCs), granulocytes, lymphocytes, monocytes, platelets, C-reactive protein (CRP), albumin, fibrinogen, and hematocrit. Interleukin-18 (IL-18), IL-1 receptor antagonist (IL-1RA), and neopterin concentrations w…

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication …

Relative Telomere Length and Cardiovascular Risk Factors

(1) Background: Telomeres are repetitive DNA sequences located at the extremities of chromosomes that maintain genetic stability. Telomere biology is relevant to several human disorders and diseases, specifically cardiovascular disease. To better understand the link between cardiovascular disease and telomere length, we studied the effect of relative telomere length (RTL) on cardiovascular risk factors in a large population-based sample. (2) Methods: RTL was measured by a real-time quantitative polymerase chain reaction in subjects of the population-based Gutenberg Health Study (n = 4944). We then performed an association study of RTL with known cardiovascular risk factors of smoking status…

Impact of Glutathione Peroxidase-1 Deficiency on Macrophage Foam Cell Formation and Proliferation: Implications for Atherogenesis

Clinical and experimental evidence suggests a protective role for the antioxidant enzyme glutathione peroxidase-1 (GPx-1) in the atherogenic process. GPx-1 deficiency accelerates atherosclerosis and increases lesion cellularity in ApoE(-/-) mice. However, the distribution of GPx-1 within the atherosclerotic lesion as well as the mechanisms leading to increased macrophage numbers in lesions is still unknown. Accordingly, the aims of the present study were (1) to analyze which cells express GPx-1 within atherosclerotic lesions and (2) to determine whether a lack of GPx-1 affects macrophage foam cell formation and cellular proliferation. Both in situ-hybridization and immunohistochemistry of l…

6-18F-Fluoro-l-Dihydroxyphenylalanine Positron Emission Tomography Is Superior to123I-Metaiodobenzyl-Guanidine Scintigraphy in the Detection of Extraadrenal and Hereditary Pheochromocytomas and Paragangliomas: Correlation with Vesicular Monoamine Transporter Expression

Context: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) may be better detected by 18F-fluorodihydroxyphenylalanine-positron emission tomography (FDOPA-PET) than 123I-metaiodobenzyl-guanidine (123-I-MIBG) scintigraphy. Objective: The objective of the study was to correlate functional imaging results with immunohistochemical, molecular-genetic, and biochemical findings. Design and Setting: Thirty consecutive patients with suspected PHEO/PGL presenting at a tertiary referral centre were investigated in a prospective study. Patients: Twenty-five patients had confirmed PHEO/PGL. Thirteen of 25 patients had a hereditary PHEO/PGL syndrome (two multiple endocrine neoplasia II, six succinate de…

Abstract 147: The Role of Thrombin Generation in Cardiovascular Disease and Mortality - Results from the Population-based Gutenberg Health Study

Background: Thrombin formation is one of the key enzymatic processes that direct the activity of the hemostatic system. Thrombin generation (TG), a method addressing the overall potential of a given plasma sample to form thrombin, may be a potential tool to improve risk stratification for cardiovascular diseases (CVD). This study aims to explore the relation between TG and cardiovascular risk factors (CVRFs), CVD, and total mortality. Methods: For this study, N=5000 subjects from the population-based Gutenberg Health Study were analyzed in a highly standardized setting. TG was measured by the Calibrated Automated Thrombogram method at 1 and 5 pM tissue factor (TF) trigger in platelet poor …

Novel DNA Methylation Sites Influence GPR15 Expression in Relation to Smoking

Smoking is a major risk factor for cardiovascular diseases and has been implicated in the regulation of the G protein-coupled receptor 15 (GPR15) by affecting CpG methylation. The G protein-coupled receptor 15 is involved in angiogenesis and inflammation. An effect on GPR15 gene regulation has been shown for the CpG site CpG3.98251294. We aimed to analyze the effect of smoking on GPR15 expression and methylation sites spanning the GPR15 locus. DNA methylation of nine GPR15 CpG sites was measured in leukocytes from 1291 population-based individuals using the EpiTYPER. Monocytic GPR15 expression was measured by qPCR at baseline and five-years follow up. GPR15 gene expression was upregulated i…

Gender-specific diagnostic performance of a new high-sensitivity cardiac troponin I assay for detection of acute myocardial infarction.

The determination of cardiac troponin is essential for diagnosing myocardial infarction. A troponin I assay has recently been developed that provides the highest analytical sensitivity to date.The analysis included 1560 patients with chest pain, of whom 1098 were diagnosed with non-coronary chest pain, 189 with unstable angina pectoris and 273 with non-ST-segment elevation myocardial infarction. The troponin I concentration was determined on admission (0 hours) and 3 hours later. The diagnostic algorithm incorporated troponin I elevation above the gender-specific 99th percentile as well as predefined relative or absolute 3-hour changes in the troponin I concentration (delta).The diagnostic …

CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.

SUMMARY Background: Venlafaxine (V) is a mixed serotoninand noradrenaline reuptake inhibitor used as afirst-line treatment of depressive disorders. It ismetabolized primarily by the highly polymorphiccytochrome P450 (CYP) enzyme CYP2D6 to yielda pharmacologically active metabolite, O-des-methylvenlafaxine (ODV), and to a lesser extentby CYP3A4, to yield N-desmethylvenlafaxine(NDV).Objectives: The aim of this study was to assesswhether the O-demethylation phenotype of V hasan impact on the pharmacokinetics and clinicaloutcome.Method: In 100 patients treated with V, serumconcentrations of V, ODV and NDV and theratios of concentrations ODV/V as a measure ofO-demethylation were determined. Indiv…

Deficiency of glutathione peroxidase-1 accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice.

Background— We have recently demonstrated that activity of red blood cell glutathione peroxidase-1 is inversely associated with the risk of cardiovascular events in patients with coronary artery disease. The present study analyzed the effect of glutathione peroxidase-1 deficiency on atherogenesis in the apolipoprotein E-deficient mouse. Methods and Results— Female apolipoprotein E-deficient mice with and without glutathione peroxidase-1 deficiency were placed on a Western-type diet for another 6, 12, or 24 weeks. After 24 weeks on Western-type diet, double-knockout mice (GPx-1 −/− ApoE −/− ) developed significantly more atherosclerosis than control apolipoprotein E-deficient mice. Moreover…

New onset of depression in aging women and men: contributions of social, psychological, behavioral, and somatic predictors in the community.

AbstractBackgroundBased on the vulnerability–stress model, we aimed to (1) determine new onset of depression in individuals who had not shown evidence of depression at baseline (5 years earlier) and (2) identify social, psychological, behavioral, and somatic predictors.MethodsLongitudinal data ofN= 10 036 participants (40–79 years) were evaluated who had no evidence of depression at baseline based on Patient Health Questionnaire (PHQ-9), no history of depression, or intake of antidepressants. Multivariate logistic regression models were used to predict the onset of depression.ResultsPrevalence of new cases of depression was 4.4%. Higher rates of women (5.1%) than men (3.8%) were due to thei…

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation o…

A targeted proteomics investigation of the obesity paradox in venous thromboembolism

Abstract The obesity paradox, the controversial finding that obesity promotes disease development but protects against sequelae in patients, has been observed in venous thromboembolism (VTE). The aim of this investigation was to identify a body mass–related proteomic signature in VTE patients and to evaluate whether this signature mediates the obesity paradox in VTE patients. Data from the Genotyping and Molecular Phenotyping in Venous ThromboEmbolism Project, a prospective cohort study of 693 VTE patients, were analyzed. A combined end point of recurrent VTE or all-cause death was used. Relative quantification of 444 proteins was performed using high-throughput targeted proteomics technolo…

Generation of multifunctional murine monoclonal antibodies specifically directed to the VP1unique region protein of human parvovirus B19.

Little is known about the VP1unique region (VP1u), a part of one major capsid protein of human parvovirus B19 (B19), concerning its involvement in viral replication and infection cycle. Showing a phospholipase A2 (PLA2)-like activity, which is discussed to be necessary for viral release from host cell, its precise function remains unclear. The purpose of this study was to generate multifunctional monoclonal antibodies (mabs) for different applications that may be useful in investigating VP1u's relevance. To establish antiVP1u antibodies, spleen cells from Balb/c mice immunized with purified recombinant viral protein were used for generating antibody-producing hybridoma cell lines. Usability…

Protein expression profiling suggests relevance of noncanonical pathways in isolated pulmonary embolism

Abstract Patients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism Project, a multicenter prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE pa…

Frequency of Fabry disease in patients with small-fibre neuropathy of unknown aetiology: a pilot study

Background:  Early occurrence of small-fibre neuropathy (SFN) is a common feature of Fabry disease (FD) – an X-linked storage disorder caused by reduced activity of the α-galactosidase A (α-GAL). Although SFN may result from different disorders, the cause is often unclear. Therefore, we investigated the frequency of FD in patients with SFN of unknown aetiology. Methods:  Patients with idiopathic SFN, established by sensory quantitative testing and/or skin biopsy, were examined for mutations in the α-GAL gene. Where mutations in the α-GAL gene were identified, levels of globotriaosylceramide (Gb3) were measured in urine and blood and the α-GAL activity was evaluated. When new mutations were …

Adrenomedullin and arterial stiffness: integrative approach combining monocyte ADM expression, plasma MR-Pro-ADM, and genome-wide association study.

Background— Adrenomedullin (ADM) is a circulating vasoactive peptide involved in vascular homeostasis and endothelial function. Single nucleotide polymorphisms of the ADM gene are associated with blood pressure variability, and elevated levels of plasma midregional proadrenomedullin (MR-pro-ADM) are associated with cardiovascular diseases. Methods and Results— We investigated the sources of variability of ADM gene expression and plasma MR-pro-ADM concentrations in the general population, and their relationship with markers of atherosclerosis. MR-pro-ADM levels were assessed in 4155 individuals who underwent evaluation of carotid intima-media thickness and arterial rigidity (reflection inde…

CD40L controls obesity-associated vascular inflammation, oxidative stress, and endothelial dysfunction in high fat diet-treated and db/db mice

Abstract Aims CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in angiotensin-II-induced arterial hypertension by regulating vascular immune cell recruitment and platelet activation. Here we investigated the role of CD40L in experimental hyperlipidemia. Methods and results Male wild type and CD40L−/− mice (C57BL/6 background) were subjected to high fat diet for sixteen weeks. Weight, cholesterol, HDL, and LDL levels, endothelial function (isometric tension recording), oxidative stress (NADPH oxidase expression, dihydroethidium fluorescence) and inflammatory parameters (inducible nitric oxide synthase, interleukin-6 expression) were assessed. CD40L exp…

No Evidence for Classic Thrombotic Microangiopathy in COVID-19

Background: Coronavirus disease-2019 (COVID-19) triggers systemic infection with involvement of the respiratory tract. There are some patients developing haemostatic abnormalities during their infection with a considerably increased risk of death. Materials and Methods: Patients (n = 85) with SARS-CoV-2 infection attending the University Medical Center, Mainz, from 3 March to 15 May 2020 were retrospectively included in this study. Data regarding demography, clinical features, treatment and laboratory parameters were analyzed. Twenty patients were excluded for assessment of disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) due to lack of laboratory data. Resu…

Glutathione Peroxidase-1 Activity, Atherosclerotic Burden, and Cardiovascular Prognosis

Recent findings suggest that erythrocyte intracellular glutathione peroxidase-1 (GPX-1) activity is related inversely to future cardiovascular events. The aim of this study is to evaluate the association of GPX-1 activity to extent of atherosclerosis, as well as its long-term prognosis in context with atherosclerotic burden. In a prospective study, we included 508 patients before coronary angiography. Atherosclerosis of carotid and leg arteries was documented using sonographic methods. Blood samples were drawn after an overnight fasting period, and GPX-1 activity was determined in washed erythrocytes. GPX-1 activity tended to decrease with increasing numbers of atherosclerotic vascular beds…

Detection and Differential Diagnosis of Prekallikrein Deficiency: Genetic Study of New Families and Systematic Review of the Literature

Abstract Introduction. Prekallikrein (PK) and high-molecular-weight kininogen (HK) deficiencies are ultra-rare, autosomal-recessive defects of the contact system caused by biallelic mutations in the KLKB1 and KNG1 genes, respectively. Since affected subjects do not manifest a bleeding phenotype, a correct diagnosis is essential to prevent the administration of prohemostatic agents or plasma and to avoid delay of surgery. We describe a new case of PK deficiency identified at UMC Mainz. In addition, we performed a systematic review of the literature in order to i) collect blood material for genetic studies of reported PK deficient cases lacking this information, and ii) perform a comprehensiv…

Defining a reference population to determine the 99th percentile of a contemporary sensitive cardiac troponin I assay

Abstract Background Diagnosis of acute myocardial infarction (AMI) according to the universal definition is based on ischemic symptoms, imaging findings and elevated myocardial necrosis markers, preferably cardiac troponin I/T with diagnostic threshold representing the 99th percentile of a reference population. It is not clearly defined if this should be an unselected population-based or a healthy cohort with respect to cardiac diseases. Aim of the current study was to describe the distribution of troponin I using a sensitive assay and to evaluate the impact of cardiac diseases and cardiovascular risk factors in apparently healthy individuals. Methods Troponin I was determined using a conte…

Asymmetric Dimethylarginine and the Risk of Cardiovascular Events and Death in Patients With Coronary Artery Disease

As a competitive inhibitor of endothelial nitric oxide synthase, asymmetric dimethylarginine (ADMA) has been related to atherosclerotic disease. Little is known about the prognostic impact of baseline ADMA determination. In a prospective cohort of 1908 patients with coronary artery disease, we assessed baseline serum concentration of ADMA in 1874 consecutive patients with coronary artery disease. One hundred fourteen individuals developed the primary end point of death from cardiovascular causes or nonfatal myocardial infarction during a mean follow-up of 2.6±1.2 years. Median concentrations of ADMA levels were higher among individuals who subsequently developed the primary end point than …

Association of Birth Weight with Central and Peripheral Corneal Thickness in Adulthood-Results from the Population-Based German Gutenberg Health Study.

Low birth weight (BW) is associated with altered ocular geometry such as a steeper corneal shape in adulthood. However, it is unclear whether low birth weight affects corneal thickness development in the center or periphery in adulthood which may contribute to ocular disease. The purpose of this study was to investigate corneal thickness in former low birth weight individuals in adulthood. Methods: The German Gutenberg Health Study is a prospective, population-based study in which every participant (age range 40–80 years) was measured with Scheimpflug imaging (Pentacam HR, Oculus Optikgeräte GmbH, Wetzlar, Germany). BW was collected by self-reports. The relationship between birth weight and…

Prevalence of myopic maculopathy in the German population: results from the Gutenberg health study.

AimsTo determine the prevalence of myopic maculopathy in the general population in Germany and to analyse potential associations with ocular and systemic factors.DesignThe Gutenberg Health Study is a population-based study, including 15 010 participants aged 35–74 years.MethodsMyopic maculopathy was graded in phakic eyes with spherical equivalent ≤−6 D by assessing fundus photographs according to a recent international photographic classification system (META-PM). 801 eyes of 519 participants (mean age 51.0±0.77 years) met the conditions and had gradable fundus photographs. Age-specific prevalence estimates were computed. Multivariable logistic regression analysis was used to assess associa…

Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE consortium

AIMS: Our aims were to evaluate the distribution of troponin I concentrations in population cohorts across Europe, to characterize the association with cardiovascular outcomes, to determine the predictive value beyond the variables used in the ESC SCORE, to test a potentially clinically relevant cut-off value, and to evaluate the improved eligibility for statin therapy based on elevated troponin I concentrations retrospectively.METHODS AND RESULTS: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, we analysed individual level data from 10 prospective population-based studies including 74 738 participants. We investigated the value of adding troponin …

Antibodies to alpha B-crystallin, vimentin, and heat shock protein 70 in aqueous humor of patients with normal tension glaucoma and IgG antibody patterns against retinal antigen in aqueous humor.

To show the existence of IgG antibodies against retinal antigens in aqueous humor of normal tension glaucoma patients.Forty-two patients were included in this study. Aqueous humor was collected from control subjects (CO; n = 21) and patients with normal tension glaucoma (NTG; n = 21). Western blot methods against bovine retinal antigens were used to detect the IgG antibody patterns. The complex antibody repertoires were analyzed by multivariate statistical techniques. Mass spectrometry was used to identify the most important antigens.Very complex IgG antibody patterns against retinal antigens were found in all analyzed aqueous humor samples. Our multivariate approach could quantify differen…

Clinical Determinants of Thrombin Generation Measured in Presence and Absence of Platelets-Results from the Gutenberg Health Study.

AbstractThe tendency of a plasma sample to generate thrombin, a central enzyme in blood coagulation, might be an important indicator of prothrombotic risk linked to cardiovascular disease (CVD), but the presence of platelets may be a critical determinant. Clinical data, laboratory markers and thrombin generation (TG), investigated in both platelet-rich plasma (PRP) and platelet-free plasma (PFP) at 1 pM TF, were available in 407 individuals from the Gutenberg Health Study. Given the well-known effect of anticoagulants on TG, subjects taking anticoagulants (n = 15) have been excluded resulting in 392 subjects for further analysis. Lag time, endogenous thrombin potential (ETP) and peak height…

Association of Birth Weight With Foveolar Thickness in Adulthood: Results From a Population-Based Study

Purpose Low birth weight (BW) is associated with alterations of foveal shape development in childhood—leading to an increased retinal thickness of the fovea. The aim of the present study was to assess whether BW has a long-term effect on foveal retinal thickness (RT) and is still present in adulthood. Methods In the German population-based Gutenberg Health Study (GHS), participants were examined with spectral-domain optical coherence tomography. The association between self-reported BW and RT in the foveolar and perifoveal locations was assessed. Multivariable linear regression analyses with adjustment for potential confounders and grading of foveal hypoplasia were performed. Results Overal…

Distribution, genetic and cardiovascular determinants of FVIII:c - Data from the population-based Gutenberg Health Study

Background: Elevated levels of FVIII:c are associated with risk for both venous and arterial thromboembolism. However, no population-based study on the sex-specific distribution and reference ranges of plasma FVIII: c and its cardiovascular determinants is available. Methods: FVIII:c was analyzed in a randomly selected sample of 2533 males and 2440 females from the Gutenberg Health Study in Germany. Multivariable regression analyses for FVIII:c were performed under adjustment for genetic determinants, cardiovascular risk factors and cardiovascular disease. Results and conclusions: Females (126.6% (95% CI: 125.2/128)) showed higher FVIII:c levels than males (121.2% (119.8/122.7)). FVIII:c le…

T Cell-Specific Overexpression of TGFß1 Fails to Influence Atherosclerosis in ApoE-Deficient Mice

Clinical data have indicated a negative correlation between plasma TGFß1 concentrations and the extent of atherosclerosis and have thus led to the hypothesis that the pleiotropic cytokine may have anti-atherogenic properties. T-cells are currently discussed to significantly participate in atherogenesis, but the precise role of adaptive immunity in atherogenesis remains to be elucidated. TGFß1 is known to strongly modulate the function of T-cells, however, inhibition of TGFß1 signalling in T-cells of atherosclerosis-prone knock-out mice failed to unequivocally clarify the role of the cytokine for the development of atherosclerosis. In the present study, we thus tried to specify the role of T…

Urinary neutrophil gelatinase-associated lipocalin and cystatin C compared to the estimated glomerular filtration rate to predict risk in patients with suspected acute myocardial infarction.

Abstract Introduction Impaired renal function, reflected by estimated glomerular filtration rate (eGFR) or cystatin C, is a strong risk predictor in the presence of acute myocardial infarction (AMI). Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is an early marker of acute kidney injury. uNGAL might also be a good predictor of outcome in patients with cardiovascular disease. Aim of the present study was to evaluate the prognostic value of uNGAL compared to eGFR and cystatin C in patients with suspected AMI. Methods 1818 patients were enrolled with suspected AMI. Follow-up information on the combined endpoint of death or non-fatal myocardial infarction was obtained 6months after…

TCT-34 Prediction of acute kidney injury after TAVR by new biomarkers

Acute kidney injury (AKI) is a common complication after transcatheter aortic valve replacement (TAVR) and is associated with increased morbidity and mortality. Routinely used biomarkers such as creatinine show a diagnostic gap in the first hours after kidney injury. Thus, new biomarkers for earlier

Peripheral corneal thickness and associated factors - results from the population-based German Gutenberg Health Study.

PURPOSE Changes in peripheral corneal thickness are described in various corneal diseases such as corneal ectasia. However, few data exist describing the increase in corneal thickness from central to peripheral and reporting the normal distribution of corneal thickness in rings around the corneal centre. The aim of this study was to report these cornea characteristics and investigate associated factors in a population-based setting. METHODS The Gutenberg Health Study is a prospective, population-based study examining participants in a 5-year follow-up (age range 40-80 years) using Scheimpflug imaging. Corneal thickness was assessed in each participant at the apex, as well as in the corneal …

Recalled parental rearing behavior in adult women and men with depressive and anxiety symptoms: Findings from a community study.

Objectives: Addressing the lack of population-based data, the purpose of this representative study was to assess sex- and age-specific associations of maternal and paternal rearing behavior with depressiveness and anxiety controlling for sociodemographic and somatic variables. Methods: 8,175 subjects participating in a population-based study completed standardized questionnaires measuring Recalled Parental Rearing Behavior and distress. Results: Women recalled their fathers as more controlling and warmer, and their mothers as more rejecting than men. Comparisons between age groups (≤ 60 vs. > 60 years) revealed that younger participants recalled more parental control and emotional warmth. I…

Prevalence of pterygium and identification of associated factors in a German population - results from the Gutenberg Health Study.

Lovastatin attenuates ionizing radiation-induced normal tissue damage in vivo.

Abstract Background and purpose HMG-CoA-reductase inhibitors (statins) are widely used lipid-lowering drugs. Moreover, they have pleiotropic effects on cellular stress responses, proliferation and apoptosis in vitro . Here, we investigated whether lovastatin attenuates acute and subchronic ionizing radiation-induced normal tissue toxicity in vivo . Materials and methods Four hours to 24h after total body irradiation (6Gy) of Balb/c mice, acute pro-inflammatory and pro-fibrotic responses were analyzed. To comprise subchronic radiation toxicity, mice were irradiated twice with 2.5Gy and analyses were performed 3weeks after the first radiation treatment. Molecular markers of inflammation and f…

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Background Preclinical data have indicated a link between use of vitamin K antagonists ( VKA ) and detrimental effects on vascular structure and function. The objective of the present study was to determine the relationship between VKA intake and different phenotypes of subclinical cardiovascular disease in the population. Methods and Results Clinical and laboratory data, as well as medical–technical examinations were assessed from 15 010 individuals aged 35 to 74 years during a highly standardized 5‐hour visit at the study center of the population‐based Gutenberg Health Study. In total, the study sample comprised 287 VKA users and 14 564 VKA nonusers. Multivariable analysis revealed an in…

Impact of Metabolic Syndrome on Atherosclerotic Burden and Cardiovascular Prognosis

Patients with metabolic syndrome (MS) are at increased risk of cardiovascular atherosclerosis. The aim of this study was to evaluate the impact of MS on cardiovascular prognosis in context with atherosclerotic burden. A total of 811 patients with coronary heart disease (CHD) were included and carotid and leg arteries were examined using sonographic methods. Patients with low (CHD only, n = 428, 52.8%) or high atherosclerotic burden (CHD and peripheral atherosclerosis, n=383, 47.2%) were compared. Patients withor=3 of the following criteria: triglyceridesor=150 mg/dl, high-density lipoprotein cholesterol40 mg/dl (men) and50 mg/dl (women), body mass index30 kg/m2, blood pressureor=130/85 mm H…

Variation of platelet function in clinical phenotypes of acute venous thromboembolism – Results from the GMP‐VTE project

Background The role of platelets in the pathogenesis of venous thromboembolism (VTE) is receiving increasing attention; however, limited information is available on platelet function in the acute phase of the disease. Objective To characterize platelet function according to VTE phenotypes. Patients/Methods In total, 154 subjects (isolated pulmonary embolism [iPE], n = 28; isolated deep vein thrombosis [iDVT], n = 35; DVT+PE, n = 91) were included. In this study platelet function analyzer (PFA)-200, light transmission aggregometry (LTA), thrombin generation (TG) in presence (PRP) and absence (PFP) of platelets and platelet flow cytometry were investigated. LASSO regression was used to select…

PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene study.

Phospholipid transferprotein (PLTP) mediates both net transfer and exchange of phospholipids between different lipoproteins. Although many studies have investigated the role of PLTP in atherogenesis, the role of PLTP in atherosclerotic diseases is unclear. We investigated the association of serum PLTP activity with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) and its relation to other markers of atherosclerosis in 1,085 patients with angiographically documented coronary artery disease (CAD). In the median follow-up of 5.1 years, 156 patients had suffered from the combined endpoint of myocardial infarction or cardiovascular death including 47 of 395 p…