Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction

Endothelial dysfunction (ED) in the setting of cardiovascular risk factors such as hypercholesterolemia, hypertension, diabetes mellitus, chronic smoking as well as in patients with heart failure has been shown to be at least in part dependent on the production of reactive oxygen species (ROS) such as superoxide and the subsequent decrease in vascular bioavailability of nitric oxide (NO). Methods to quantify endothelial dysfunction include forearm plethysmography, flow-dependent dilation of the brachial artery, finger-pulse plethysmography, pulse curve analysis, and quantitative coronary angiography after intracoronary administration of the endothelium-dependent vasodilator acetylcholine. S…

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…

P6456Neopterin for risk stratification of patients with acute chest pain

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…

Homocysteine concentration in coronary artery disease: Influence of three common single nucleotide polymorphisms.

Whether single nucleotide polymorphisms (SNPs) of homocysteine metabolism enzymes influence the rate of cardiovascular (CV) events in coronary artery disease (CAD) patients remains controversial.In this analysis, 1126 subjects from the AtheroGene study with CAD and 332 control subjects without known CAD were included. The following SNPs were investigated: methylentetrahydrofolate reductase (MTHFR-C667T), methionin synthetase (MS-D919G), and cystathionin beta synthetase (CBS-I278T). The endpoint was the combination of cardiovascular death, stroke, and non-fatal myocardial infarction (N = 286). The median follow-up time was 6.4 years. Kaplan-Meier curve analysis showed an increasing event rat…

Predictors of self-reported heart failure - results from the Gutenberg Health study

Association of Serum Procalcitonin With Cardiovascular Prognosis in Coronary Artery Disease

Background: Procalcitonin (PCT) is an established biomarker for the diagnosis of sepsis. Evidence is growing that PCT concentration correlates with the extent of atherosclerosis and prognosis in patients with coronary artery disease (CAD). Methods and Results: A total of 2,131 patients with CAD were followed up for a median of 3.6 years. During follow-up, death from cardiovascular causes was registered in 95 patients and non-fatal myocardial infarction in 85 patients. Median and quartile 1 and 3 are reported for PCT concentration. Patients who died of cardiovascular causes had higher PCT concentrations [0.021 (0.012/0.036) ng/ml vs. 0.015 (0.010/0.023) ng/ml; P<0.0001]. Patients with acute …

Association between multiple biomarkers and classical risk factors with early carotid atherosclerosis

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,…

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 …

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 …

Gender-specific diagnosis of acute myocardial infarction using high-sensitivity assayed cardiac troponin I

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…

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-…

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…

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

The objectives of this study were to describe gender differences in intima-media thickness (IMT) in a community-based population study and to define normal IMT values for healthy men and women. In total, 4,814 participants (aged 35 to 74 years; 2,433 men, 2,381 women) from the Gutenberg-Heart Study (GHS) were included. IMT was measured at both common carotid arteries using an edge detection system. Median IMT was 0.62 mm (25th percentile 0.55, 75th percentile 0.70) in women and 0.65 mm (25th percentile 0.57, 75th percentile 0.75) in men and was significantly associated with age (p0.0001). On multivariate analysis, advanced age, smoking, and arterial hypertension were positively associated w…

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…

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…

History of depression but not current depression is associated with signs of atherosclerosis: data from the Gutenberg Health Study.

ObjectivesTo test the vascular depression hypothesis in the general population, we analyzed the association between current depression, medical history of depression, cognitive and somatic depressive symptom dimensions and measures of atherosclerosis [intima–media thickness (IMT) and carotid plaques].MethodWe included a representative sample of 5000 participants from the Gutenberg Health Study (GHS). Depression was assessed by the nine-item Patient Health Questionnaire (PHQ-9), and IMT and carotid plaques were measured at both common carotid arteries using an edge detection system. Regression analyses were performed separately for participants with and without cardiovascular disease, adjust…

Up-and-Coming Markers: Myeloperoxidase, a Novel Biomarker Test for Heart Failure and Acute Coronary Syndrome Application?

Myeloperoxidase (MPO) is a mammalian enzyme responsible for generation of hypochlorite. The advantage of myeloperoxidase for use as a biomarker in the setting of heart failure and acute coronary syndrome is the early increase of MPO concentration in response to the acute event. In the setting of heart failure the reported independency of coronary artery disease and general inflammation, as indicated by MPO concentration in comparison to other inflammatory markers or in subgroups of patients with ischemic and non-ischemic cardiomyopathy, has to be highlighted. In terms of ACS, inclusion of MPO into a multiple marker strategy might add to enhance diagnosis and therapy decision making. Therefo…

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…