[Show abstract][Hide abstract] ABSTRACT: Background:
Low circulating homoarginine has been associated with adverse cardiovascular (CV) outcome and mortality in patients at risk and in the general population. The present study aimed to define plasma homoarginine reference intervals from a representative population sample to improve risk stratification between healthy individuals and individuals at risk.
We determined age- and sex-specific reference intervals for circulating plasma homoarginine in a subgroup of 786 healthy participants (no CV disease or risk factors) of the Gutenberg Health Study. Homoarginine concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method.
Median EDTA plasma homoarginine concentration was 1.88 [25th; 75th percentile, 1.47; 2.41] μmol/L, with lower concentrations in women (1.77 [1.38; 2.26] μmol/L) than in men (2.01 [1.61; 2.56] μmol/L; p<0.001). Sex-specific 2.5th and 97.5th percentiles of reference intervals were 0.84 and 3.89 μmol/L in women and 0.98 and 4.10 μmol/L in men, respectively. Homoarginine concentrations also depended on age and single nucleotide polymorphisms related to the L-arginine:glycine amidinotransferase gene.
We provide plasma homoarginine reference intervals in men and women of the general population. The determination of homoarginine levels might be favorable for individual risk stratification.
Clinical Chemistry and Laboratory Medicine 11/2015; DOI:10.1515/cclm-2015-0785 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mean Platelet Volume (MPV), a measure of platelet size, is a potential biological marker of platelet function. To date, a comprehensive, combined analysis including known genetic and non-genetic factors determining MPV is still lacking. The purpose of this study is to evaluate the role of genetic and non-genetic factors for MPV variability in males and females from a large population-based cohort. MPV has been evaluated in 15,010 individuals from the population-based Gutenberg Health Study. Genetic information was available in 4,175 individuals where a full multivariable linear regression model was applied. Our results showed that age [β=0.0346, 95%CI: 0.0255;0.0436], cardiovascular risk factors (CVRFs) as smoking [β=0.178 (0.128;0.229)] and hypertension [β=0.05 (0.00289; 0.0981)] and high glucose level [β=0.00179 (0.0006;0.00299)] were linked with higher MPV in males only. Intake of oral contraceptives [β=0.150 (0.0649;0.236)] and menstruation [β=0.123 (0.0231;0.224)] were strongly associated with higher MPV in females. The linear regression analysis revealed 7 Single Nucleotide Polymorphisms (SNPs) for females and 4 SNPs for males associated with higher MPV. The full model including age, CVRFs, laboratory parameters, medications and genetic variation explained 20.4% of females and 18.6% of males MPV variance. The curves of cumulative mortality, stratified for sex, showed worse survival for males only with MPV > 9.96fL vs MPV≤ 9.96fL (p<0.0001). This study gives evidence for heterogeneity in the profile of determinants for MPV between sexes. The observed interactions between genetic variability, CVRFs and MPV and its association to the development of cardiovascular disease or thrombotic risk need to be further investigated.
[Show abstract][Hide abstract] ABSTRACT: Aims:
Heme oxygenase-1 (HO-1) confers protection to the vasculature and suppresses inflammatory properties of monocytes and macrophages. It is unclear how HO-1 determines the extent of vascular dysfunction in mice and humans.
Methods and results:
Decreased HO-1 activity and expression was paralleled by increased aortic expression and activity of the nicotinamide dinucleotide phosphate oxidase Nox2 in HO-1 deficient Hmox1(-/-) and Hmox1(+/-) compared with Hmox1(+/+) mice. When subjected to angiotensin II-infusion, streptozotocin-induced diabetes mellitus and aging, HO-1 deficient mice showed increased vascular dysfunction inversely correlated with HO activity. In a primary prevention population-based cohort, we assessed length polymorphisms of the HMOX1 promoter region and established a bipolar frequency pattern of allele length (long vs. short repeats) in 4937 individuals. Monocytic HMOX1 mRNA expression was positively correlated with flow-mediated dilation and inversely with CD14 mRNA expression indicating pro-inflammatory monocytes in 733 hypertensive individuals of this cohort. Hmox1(-/-) mice showed drastically increased expression of the chemokine receptor CCR2 in monocytes and the aorta. Angiotensin II-infused Hmox1(-/-) mice had amplified endothelial inflammation in vivo, significantly increased aortic infiltration of pro-inflammatory CD11b(+)Ly6C(hi) monocytes and Ly6G(+) neutrophils and were marked by Ly6C(hi) monocytosis in the circulation and an increased blood pressure response. Finally, individuals with unfavourable HMOX1 gene promoter length had increased prevalence of arterial hypertension and reduced cumulative survival after a median follow-up of 7.23 years.
Heme oxygenase-1 is a regulator of vascular function in hypertension via determining the phenotype of inflammatory circulating and infiltrating monocytes with possible implications for all-cause mortality.
European Heart Journal 10/2015; DOI:10.1093/eurheartj/ehv544 · 15.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims:
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 heart-type fatty acid binding protein, having area under the curve >0.70. Measured biomarkers showed comparable discriminatory ability in atrial fibrillation and non-atrial fibrillation patients. The combination of hsTnI on admission with additional biomarkers did not clinically significantly improve diagnostic performance. In atrial fibrillation patients, hsTnI concentrations ⩽21.7 ng/L (99th percentile in a healthy German cohort) on admission gave a negative predictive value of ~100% (95% confidence interval 97-100%). The combination of hsTnI on admission and absolute change of hsTnI concentration after three hours of ⩾40 ng/L resulted in a positive predictive value of 81.2% and sensitivity of 88.6%. Diagnostic accuracy was validated in an independent cohort (N=1076).
The diagnostic accuracy of hsTnI in patients with acute chest pain and atrial fibrillation is high and comparable to those without atrial fibrillation. Absolute change in hsTnI concentration enhanced diagnostic performance. No clinically relevant improvement was achieved by adding other biomarkers.
[Show abstract][Hide abstract] ABSTRACT: Background:
-Interleukin-18 (IL-18) is a pleiotropic cytokine centrally involved in the cytokine cascade with complex immunomodulatory functions in innate and acquired immunity. Circulating IL-18 concentrations are associated with type 2 diabetes, cardiovascular events and diverse inflammatory and autoimmune disorders.
Methods and results:
-To identify causal variants affecting circulating IL-18 concentrations, we applied various omics and molecular biology approaches. By GWAS, we confirmed association of IL-18 levels with a SNP in the untranslated exon 2 of the inflammasome component NLRC4 (NLR family, CARD domain containing 4) gene on chromosome 2 (rs385076, P=2.4×10(-45)). Subsequent molecular analyses by gene expression analysis and reporter gene assays indicated an effect of rs385076 on NLRC4 expression and differential isoform usage by modulating binding of the transcription factor PU.1.
-Our study provides evidence for the functional causality of SNP rs385076 within the NLRC4 gene in relation to IL-18 activation.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies have identified and repeatedly confirmed the association of rs3197999 in MST1 with inflammatory bowel disease (IBD). However, the underlying pathophysiology remains unclear. rs3197999 is a non-synonymous single-nucleotide polymorphism which modifies the function of macrophage stimulating protein-1 (MST1). We show by haplotyping that rs3197999 is in linkage disequilibrium with rs1050450 in GPX1, with almost complete cosegregation of the minor alleles. As shown by immunoassay, rs3197999 influences the MST-1 level in serum. But also rs1050450 causes an amino acid exchange in glutathione peroxidase 1 (GPx-1) and reduced activity of this antioxidant enzyme. The association of GPx deficiency and IBD in mice was already shown. We propose that GPx-1 is a better candidate than MST1 for the pathophysiologic link between IBD locus 12 and IBD.Genes and Immunity advance online publication, 10 September 2015; doi:10.1038/gene.2015.35.
Genes and immunity 09/2015; DOI:10.1038/gene.2015.35 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The antiphospholipid syndrome (APS) has been the subject of intensive research since its initial description as a disease entity more than 30 years ago. While significant progress in our understanding of the pathophysiology of APS has been made, many unsolved questions remain. Already in the 1990s clear evidence proved that the antiphospholipid antibodies (aPL) associated with APS cause the major clinical symptoms of the disorder, i.e. thrombotic events and abortions. This finding prompted further research into the molecular events elicited by aPL. Research focused initially on the plasmatic coagulation system. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 08/2015; 13(10):n/a-n/a. DOI:10.1111/jth.13119 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The introduction of modern troponin assays has facilitated diagnosis of acute myocardial infarction due to improved sensitivity with corresponding loss of specificity. Atrial fibrillation (AF) is associated with elevated levels of troponin. The aim of the present study was to evaluate the diagnostic performance of troponin I in patients with suspected acute coronary syndrome and chronic AF.
Contemporary sensitive troponin I was assayed in a derivation cohort of 90 patients with suspected acute coronary syndrome and chronic AF to establish diagnostic cut-offs. These thresholds were validated in an independent cohort of 314 patients with suspected myocardial infarction and AF upon presentation. Additionally, changes in troponin I concentration within 3 hours were used.
In the derivation cohort, optimized thresholds with respect to a rule-out strategy with high sensitivity and a rule-in strategy with high specificity were established. In the validation cohort, application of the rule-out cut-off led to a negative predictive value of 97 %. The rule-in cut-off was associated with a positive predictive value of 88 % compared with 71 % if using the 99th percentile cut-off. In patients with troponin I levels above the specificity-optimized threshold, additional use of the 3-hour change in absolute/relative concentration resulted in a further improved positive predictive value of 96 %/100 %.
Troponin I concentration and the 3-hour change in its concentration provide valid diagnostic information in patients with suspected myocardial infarction and chronic AF. With regard to AF-associated elevation of troponin levels, application of diagnostic cut-offs other than the 99th percentile might be beneficial.
BMC Medicine 07/2015; 13(1):169. DOI:10.1186/s12916-015-0410-8 · 7.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Venous thromboembolism (VTE) with its two manifestations deep vein thrombosis (DVT) and pulmonary embolism (PE) is a major public health problem. The VTEval Project aims to investigate numerous research questions on diagnosis, clinical management, treatment and prognosis of VTE, which have remained uncertain to date.
The VTEval Project consists of three observational, prospective cohort studies on VTE comprising cohorts of individuals with a clinical suspicion of acute PE (with or without DVT), with a clinical suspicion of acute DVT (without symptomatic PE) and with an incidental diagnosis of VTE (PE or DVT). The VTEval Project expects to enrol a total of approximately 2000 individuals with subsequent active and passive follow-up investigations over a time period of 5 years per participant. Time points for active follow-up investigations are at months 3, 6, 12, 24 and 36 after diagnosis (depending on the disease cohort); passive follow-up investigations via registry offices and the cancer registry are performed 48 and 60 months after diagnosis for all participants. Primary short-term outcome is defined by overall mortality (PE-related death and all other causes of death), primary long-term outcome by symptomatic VTE (PE-related death, recurrence of non-fatal PE or DVT). The VTEval Project includes three 'all-comer' studies and involves the standardised acquisition of high-quality data, covering the systematic assessment of VTE including symptoms, risk profile, psychosocial, environmental and lifestyle factors as well as clinical and subclinical disease, and it builds up a large state-of-the-art biorepository containing various materials from serial blood samplings.
The VTEval Project has been approved by the local data safety commissioner and the responsible ethics committee (reference no. 837.320.12 (8421-F)). Trial results will be published in peer-reviewed journals and presented at national and international scientific meetings.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BMJ Open 07/2015; 5(7):e008157. DOI:10.1136/bmjopen-2015-008157 · 2.27 Impact Factor
[Show abstract][Hide abstract] 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.
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.
Individuals with AF (N=161), 71% men, were older, mean age 64.9±8.3years. In Bonferroni-corrected multivariable-adjusted regression analyses we observed moderate inverse associations for l-arginine, SDMA, and l-arginine/ADMA ratio with ventricular heart rate, and for l-arginine and l-arginine/ADMA ratio with QTc interval. l-arginine was correlated with QRS duration. In echocardiographic analyses, SDMA was related to left atrial diameter and deceleration time, ADMA and NMMA were correlated with left ventricular mass. ADMA (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.11-1-32; p=0.013) and NMMA (OR 1.17, 95% CI 1.09-1.26, p=0.014) were related to prevalent AF. l-arginine/ADMA ratio was inversely associated (OR 0.8, 95% CI 0.71-0.90, p=0.0082). Results were similar after adjustment for creatinine.
In our large, population-based cohort, we observed moderate associations of l-arginine metabolites and intermediate electrocardiographic and echocardiographic variables and AF. Our findings support further investigations to define the role of l-arginine derivatives in AF and their clinical utility.
International Journal of Cardiology 05/2015; 203. DOI:10.1016/j.ijcard.2015.05.102 · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the age- and sex-specific prevalence and determinants of Retinal vein occlusions (RVO) in a large populations-based German cohort.
The investigation comprised 15,010 participants (35-74 years) from the Gutenberg Health Study (GHS). We determined the prevalence of RVO (central retinal vein occlusion, CRVO; branch retinal vein occlusion, BRVO) for the local population by assessing fundus photographs of 12,954 (86.3%; 49.8% females, 50.2% males) participants. Furthermore, we analyzed the associations of RVO with cardiovascular, anthropometric, and ophthalmic parameters.
The weighted prevalences of RVO, CRVO, and BRVO were 0.40%, 0.8%, and 0.32%, respectively. Males were 1.7 times more frequently affected by RVO than females. Prevalence of RVO was 0.2% in participants aged 35-44 and 45-54 years, respectively, 0.48% from 55-64 and 0.92% in participants between 65-74 years. 91.5% of persons with RVO had one or more cardiovascular risk factors or diseases versus 75.9% of persons without RVO. BRVO was associated with arterial hypertension (OR: 2.69; 95%CI: 1.27-5.70) and atrial fibrillation (3.37; 1.24-9.12) and CRVO with higher age (7.02, 1.63-30.19) and a family history of stroke (4.64; 1.18-18.25). Median visual acuity (base 10 logarithm of minimum angle of resolution; logMAR) was 0.2 in persons with RVO versus 0.05 in those without.
The prevalence of RVO in this German population was 0.4% and males were 1.7 times more frequently affected than females. CRVO was associated with higher age and a family history of stroke, and BRVO with arterial hypertension and atrial fibrillation. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 04/2015; 13(7). DOI:10.1111/jth.12982 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 were determined in a subcohort.
In total, 7,584 men and 7,426 women were analyzed (range 35-74 years), with 1,425 and 1,299 having prediabetes and diabetes, respectively. Biomarkers showed varying dynamics from normoglycemic via subjects with prediabetes to subjects with diabetes: 1) gradual increase (WBCs, granulocytes, monocytes, IL-1RA, IL-18, and fibrinogen), 2) increase with subclinical disease only (lymphocytes and CRP), 3) increase from prediabetes to diabetes only (neopterin), and 4) no variation with glucose status (hematocrit). The strongest relative differences were found for CRP, IL-1RA, and fibrinogen concentrations. Several inflammatory and immune markers were associated with the glucose status independent from cardiovascular risk factors and comorbidities, varied with disease severity and the presence of disease-specific complications in the diabetes subcohort.
The inflammatory and immune biomarker profile varies with the development and progression of type 2 diabetes. Markers of inflammation and immunity enable differentiation between the early preclinical and clinical phases of the disease, disease complications, and progression.
Diabetes care 04/2015; 38(7). DOI:10.2337/dc14-3008 · 8.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
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 m2), 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 decrease of the 99th percentile URL for hs-cTnI from 23.7 to 14.1 ng/L and from 11.2 to 7.1 ng/L, when using the non-parametric percentile and robust methods, respectively; a further reduction after exclusion of individuals with dyslipidemia was noted. Male gender, BNP, HbA1c and smoking status were independently associated with hs-cTnI concentration in the presumably healthy population, while the impact of age, present in the univariate analysis, decreased after adjustments for gender and surrogate biomarkers. The BNP-based inclusion criterion had the most pronounced effect on the 99th percentile URL, excluding 21% of the study participants and decreasing its value to 11.0 (7.1) ng/L according to the non-parametric (robust) method. Gender, but not age-specific, differences at 99th percentile URL have been identified.
The selection of a reference population has a critical impact on the 99th percentile value for hs-cTnI. A uniform protocol for the selection of the healthy reference population is needed.
International Journal of Cardiology 03/2015; 187(1). DOI:10.1016/j.ijcard.2015.03.282 · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This paper describes the study design, methodology, cohort profile and self-reported diseases in the ophthalmological branch of the Gutenberg Health Study (GHS).
The GHS is an ongoing, prospective, interdisciplinary, single-center, population-based cohort study in Germany. The main goals of the ophthalmological section are to assess the prevalence and incidence of ocular diseases and to explore risk factors, genetic determinants and associations with systemic diseases and conditions. The eye examination at baseline included a medical history, self-reported eye diseases, visual acuity, refractive errors, intraocular pressure, visual field, pachymetry, keratometry, fundus photography and tear sampling. The 5-year follow-up visit additionally encompassed optical coherence tomography, anterior segment imaging and optical biometry. The general examination included anthropometry; blood pressure measurement; carotid artery ultrasound; electrocardiogram; echocardiography; spirometry; cognitive tests; questionnaires; assessment of mental conditions; and DNA, RNA, blood and urine sampling.
Of 15,010 participants (aged 35-74 years at the time of inclusion), ocular data are available for 14,700 subjects (97.9%). The mean visual acuity (standard deviation), mean spherical equivalent, median decimal visual acuity, and mean intraocular pressure were 0.08 (0.17) logMar, -0.42 (2.43) diopters, 0.9 and 14.24 (2.79) mm Hg, respectively. The frequencies of self-reported strabismus, glaucoma, surgery for retinal detachment and retinal vascular occlusions were 2.7%, 2.3%, 0.2% and 0.4%, respectively.
The GHS is the most extensive dataset of ophthalmic diseases and conditions and their risk factors in Germany and one of the largest cohorts worldwide. This dataset will provide new insight in the epidemiology of ophthalmic diseases and related medical specialties.
PLoS ONE 03/2015; 10(3):e0120476. DOI:10.1371/journal.pone.0120476 · 3.23 Impact Factor