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BACKGROUND:: Epidemiologic evidence for work stress as a risk factor for coronary heart disease is mostly based on a single measure of stressful work known as job strain, a combination of high demands and low job control. We examined whether a complementary stress measure that assesses an imbalance between efforts spent at work and rewards received predicted coronary heart disease. METHODS:: This multi-cohort study (the ‘IPD-Work’ consortium) was based on harmonized individual-level data from 11 European prospective cohort studies. Stressful weappork in 90,164 men and women without coronary heart disease at baseline was assessed by validated effort–reward imbalance and job strain questionnaires. We defined incident coronary heart disease as the first non-fatal myocardial infarction or coronary death. Study-specific estimates were pooled by random-effects meta-analysis. RESULTS:: At baseline, 31.7% of study members reported effort–reward imbalance at work and 15.9% reported job strain. During a mean follow-up of 9.8 years, 1078 coronary events were recorded. After adjustment for potential confounders, a hazard ratio of 1.16 (95% confidence interval 1.00-1.35) was observed for effort–reward imbalance compared to no imbalance. The hazard ratio was 1.16 (1.01-1.34) for having either effort–reward imbalance or job strain, and 1.41 (1.12-1.76) for having both these stressors compared to having neither effort–reward imbalance nor job strain. CONCLUSIONS:: Individuals with effort–reward imbalance at work have an increased risk of coronary heart disease, and this appears to be independent of job strain experienced. These findings support expanding focus beyond just job strain in future research on work stress.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Kararigas G.,Charite University Hospital | Bito V.,Catholic University of Leuven | Tinel H.,Bayer AG | Becher E.,Charite University Hospital | And 5 more authors.
Journal of the American College of Cardiology | Year: 2012

Objectives: This study investigated the effects of 17β-estradiol (E2) on gene regulation in human cardiac tissues. We hypothesized that a candidate E2 effect is cardiomyocyte (CM)- and sex-specific, conserved between humans and mice, and that E2 impairs contractile function in male CMs only. Background: Both men and women produce E2 locally from androgenic precursors. E2 regulates cardiovascular function, but specific mechanisms, protective or harmful, are not fully understood. Methods: We performed genome-wide expression profiling of E2-treated cardiac tissues from men and women, and studied gene expression and function in CMs from hearts of male and female E2-treated mice. Results: We found 36 E2-dependent genes regulated in a sex-specific manner. Of these, after E2 exposure, the myosin regulatory light chain interacting protein (MYLIP) gene was induced in tissues of men only. Focusing on Mylip and employing isolated mouse CMs, we confirmed our hypotheses that the E2 effect is CM- and sex-specific and conserved between humans and mice. The E2-treatment led to impaired contractile function in male CMs only, which was characterized by increased Mylip mRNA and protein levels, and decreased myosin regulatory light chain (Mrlc) protein. Our report is the first to our knowledge to show that cardiac Mrlc is an in vivo substrate for Mylip, leading to augmented Mrlc ubiquitination. Of relevance, we found that MYLIP expression levels rise with increasing age in hearts of men. Conclusions: E2 directly influences cardiac gene regulation, and E2 actions may be different between the sexes. Since E2 levels rise in older and/or obese men, pharmacological targeting of MYLIP in men with elevated E2 levels could possibly decrease their risk for the development or progression of cardiovascular disease. © 2012 American College of Cardiology Foundation.

Wessel D.L.,Childrens National Medical Center | Berger F.,German Heart Institute Berlin | Li J.S.,Duke Clinical Research Institute | Dahnert I.,University of Leipzig | And 4 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Infants with cyanotic congenital heart disease palliated with placement of a systemic-to-pulmonary-artery shunt are at risk for shunt thrombosis and death. We investigated whether the addition of clopidogrel to conventional therapy reduces mortality from any cause and morbidity related to the shunt. METHODS: In a multicenter, double-blind, event-driven trial, we randomly assigned infants 92 days of age or younger with cyanotic congenital heart disease and a systemic-to-pul-monary-artery shunt to receive clopidogrel at a dose of 0.2 mg per kilogram of body weight per day (467 infants) or placebo (439 infants), in addition to conventional therapy (including aspirin in 87.9% of infants). The primary efficacy end point was a composite of death or heart transplantation, shunt thrombosis, or performance of a cardiac procedure due to an event considered to be thrombotic in nature before 120 days of age. RESULTS: The rate of the composite primary end point did not differ significantly between the clopidogrel group (19.1%) and the placebo group (20.5%) (absolute risk difference, 1.4 percentage points; relative risk reduction with clopidogrel, 11.1%; 95% confidence interval, -19.2 to 33.6; P = 0.43), nor did the rates of the three components of the composite primary end point. There was no significant benefit of clopidogrel treatment in any subgroup, including subgroups defined by shunt type. Clopidogrel recipients and placebo recipients had similar rates of overall bleeding (18.8% and 20.2%, respectively) and severe bleeding (4.1% and 3.4%, respectively). CONCLUSIONS: Clopidogrel therapy in infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary-artery shunt, most of whom received concomitant aspirin therapy, did not reduce either mortality from any cause or shunt-related morbidity. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00396877.) Copyright © 2013 Massachusetts Medical Society.

Kuebler W.M.,Li Ka Shing Knowledge Institute | Kuebler W.M.,University of Toronto | Kuebler W.M.,Charité - Medical University of Berlin | Kuebler W.M.,German Heart Institute Berlin
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2011

FOLLOWING ITS IDENTIFICATION as the long-searched-for endothelial-derived relaxing factor and the subsequent recognition of its additional anti-inflammatory and antiaggregatory properties, nitric oxide (NO) was initially hailed as the new universal therapeutic weapon in pathologies associated with hypertension, inflammation, and/or coagulation. Hopes were particularly high for the treatment of acute lung injury (ALI), which characteristically displays all of these pathological features. Yet, although clinical trials showed initial improvement of oxygenation with inhalation of NO, these effects were not sustained and did not reduce mortality (8). These and other studies led to the realization that the role of NO in ALI and permeability-type lung edema is much more complex, in that NO, based on its site of action and interaction partners, may have both protective and detrimental effects. In the past, the beneficial effects of NO have at large been attributed to activation of its molecular target soluble guanylyl cyclase (sGC) and the formation of the second messenger 3′,5′-cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), whereas barrier-disruptive effects were ascribed to the formation of peroxynitrite (ONOO-) in the presence of superoxide (O2-) or conjecturally to S-nitrosylation of junctional proteins (15). Recent evidence, however, demonstrates that cGMP signaling by itself may play an ambivalent role in vascular barrier regulation, a recognition that not only incites new scientific perspectives and challenges but may be of considerable clinical relevance given the pending introduction of sGC activators as novel therapeutic strategy in cardiopulmonary disease (18). © 2011 the American Physiological Society.

Shakibaei M.,Ludwig Maximilians University of Munich | Mobasheri A.,University of Nottingham | Lueders C.,German Heart Institute Berlin | Busch F.,Ludwig Maximilians University of Munich | And 2 more authors.
PLoS ONE | Year: 2013

Objective: Development of treatment resistance and adverse toxicity associated with classical chemotherapeutic agents highlights the need for safer and effective therapeutic approaches. Herein, we examined the effectiveness of a combination treatment regimen of 5-fluorouracil (5-FU) and curcumin in colorectal cancer (CRC) cells. Methods: Wild type HCT116 cells and HCT116+ch3 cells (complemented with chromosome 3) were treated with curcumin and 5-FU in a time- and dose-dependent manner and evaluated by cell proliferation assays, DAPI staining, transmission electron microscopy, cell cycle analysis and immunoblotting for key signaling proteins. Results: The individual IC50 of curcumin and 5-FU were approximately 20 μM and 5 μM in HCT116 cells and 5 μM and 1 μM in HCT116+ch3 cells, respectively (p<0.05). Pretreatment with curcumin significantly reduced survival in both cells; HCT116+ch3 cells were considerably more sensitive to treatment with curcumin and/or 5-FU than wild-type HCT116 cells. The IC50 values for combination treatment were approximately 5 μM and 1 μM in HCT116 and 5 μM and 0.1 μM in HCT116+ch3, respectively (p<0.05). Curcumin induced apoptosis in both cells by inducing mitochondrial degeneration and cytochrome c release. Cell cycle analysis revealed that the anti-proliferative effect of curcumin and/or 5-FU was preceded by accumulation of CRC cells in the S cell cycle phase and induction of apoptosis. Curcumin potentiated 5-FU-induced expression or cleavage of pro-apoptotic proteins (caspase-8, -9, -3, PARP and Bax), and down-regulated anti-apoptotic (Bcl-xL) and proliferative (cyclin D1) proteins. Although 5-FU activated NF-κB/PI-3K/Src pathway in CRC cells, this was down-regulated by curcumin treatment through inhibition of IκBα kinase activation and IκBα phosphorylation. Conclusions: Combining curcumin with conventional chemotherapeutic agents such as 5-FU could provide more effective treatment strategies against chemoresistant colon cancer cells. The mechanisms involved may be mediated via NF-κB/PI-3K/Src pathways and NF-κB regulated gene products. © 2013 Shakibaei et al.

Prsa M.,German Heart Institute Berlin | Ewert P.,German Heart Institute Berlin
Catheterization and Cardiovascular Interventions | Year: 2011

Rapid advances in paediatric interventional cardiology allow transcatheter closure of patent ductus arteriosus (PDA) in increasingly smaller patients. We describe a successful transcatheter closure of a large tubular PDA in a symptomatic preterm infant of 2,210 g using an Amplatzer Vascular Plug IV device. Copyright © 2010 Wiley-Liss, Inc.

Manka R.,German Heart Institute Berlin
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance | Year: 2010

The purpose of this study was to determine the ability of blood oxygen level dependent (BOLD) cardiovascular magnetic resonance (CMR) to detect stress-inducible myocardial ischemic reactions in the presence of angiographically significant coronary artery disease (CAD). Forty-six patients (34 men; age 65 ± 9 years,) with suspected or known coronary artery disease underwent CMR at 3Tesla prior to clinically indicated invasive coronary angiography. BOLD CMR was performed in 3 short axis slices of the heart at rest and during adenosine stress (140 μg/kg/min) followed by late gadolinium enhancement (LGE) imaging. In all 16 standard myocardial segments, T2* values were derived at rest and under adenosine stress. Quantitative coronary angiography served as the standard of reference and defined normal myocardial segments (i.e. all 16 segments in patients without any CAD), ischemic segments (i.e. supplied by a coronary artery with ≥50% luminal narrowing) and non-ischemic segments (i.e. supplied by a non-significantly stenosed coronary artery in patients with significant CAD). Coronary angiography demonstrated significant CAD in 23 patients. BOLD CMR at rest revealed significantly lower T2* values for ischemic segments (26.7 ± 11.6 ms) compared to normal (31.9 ± 11.9 ms; p < 0.0001) and non-ischemic segments (31.2 ± 12.2 ms; p = 0.0003). Under adenosine stress T2* values increased significantly in normal segments only (37.2 ± 14.7 ms; p < 0.0001). Rest and stress BOLD CMR at 3Tesla proved feasible and differentiated between ischemic, non-ischemic, and normal myocardial segments in a clinical patient population. BOLD CMR during vasodilator stress identified patients with significant CAD.

Ricken T.,University of Duisburg - Essen | Dahmen U.,University of Duisburg - Essen | Dirsch O.,German Heart Institute Berlin
Biomechanics and Modeling in Mechanobiology | Year: 2010

Liver resection can lead to focal outflow obstruction due to transection of hepatic veins. Outflow obstruction may cause additional damage to the small remnant liver. Drainage of the obstructed territories is reestablished via dilatation of sinusoids. Subsequently, sinusoidal canals are formed draining the blood from the obstructed territory to the neighboring unobstructed territories. We raised the phenomenological hypothesis that the blood pressure gradient is the main driving force for the formation of sinusoidal vascular canals. We generated a biphasic mechanical model to describe this vascular remodeling process in relation to the variable pressure gradient. Therefore, we introduced a transverse isotropic permeability relation aswell as an evolutional optimization rule to describe the relationship between pressure gradient and the direction of the sinusoidal blood flow in the fluid phase. As a next step, we developed a framework for the calculation concept including the representation of the governing weak formulations. Then, we examined a representative numerical example with simulation of the blood flow under both conditions, the physiological situation as well as after outflow obstruction. Doing so, we were able to reproduce numerically the experimentally observed process of reestablishing hepatic venous drainage via redirection of blood flow and formation of new vascular structures in respect to the fluid flow. The calculated results support the hypothesis that the reorientation of blood flow mainly depends on the pressure gradient. Further investigations are needed to determine the micromechanical influences on the reorientation of the sinusoids. © Springer-Verlag 2010.

Regitz-Zagrosek V.,Charité - Medical University of Berlin | Oertelt-Prigione S.,Charité - Medical University of Berlin | Seeland U.,Charité - Medical University of Berlin | Hetzer R.,German Heart Institute Berlin
Circulation Journal | Year: 2010

Heart failure (HF) is a leading cause of cardiovascular mortality and morbidity in the Western world. It affects men at younger age than women. Women have more frequently diastolic HF, associated with the major risk factors of diabetes and hypertension and men have more frequently systolic HF because of coronary artery disease. Under stress, male hearts develop more easily pathological hypertrophy with dilatation and poor systolic function than female hearts. Women with aortic stenosis have more concentric hypertrophy with better systolic function, less upregulation of extracellular matrix genes and better reversibility after unloading. Stressed female hearts maintain energy metabolism better than male hearts and are better protected against calcium overload. Estrogens and androgens and their receptors are present in the myocardium and lead to coordinated regulation of functionally relevant pathways. Atrial fibrillation (AF) is a more ominous sign in women than in men. Men with end-stage cardiomyopathy more frequently have auto-antibodies than women. Women receive less guideline-based diagnostics and therapy. Expensive and invasive therapies such as advanced pacemakers and transplantation are underused in women. Drug studies point at sex differences in efficacy. Despite worse diagnostics and therapy, prognosis is better in women than in men.

Stawowy P.,German Heart Institute Berlin | Just I.A.,German Heart Institute Berlin | Kaschina E.,Charité - Medical University of Berlin
Coronary Artery Disease | Year: 2014

Hypercholesterolemia is a key risk factor for atherosclerosis. Because of its role in controlling serum levels of low-density lipoprotein (LDL) through the regulation of hepatic LDL-receptors, the recently discovered proprotein convertase subtilisin/kexin-type 9 (PCSK9) is a promising pharmacological target. This review aims to discuss the impact of natural mutations in the PCSK9 gene on cholesterol metabolism and thus coronary artery disease, as well as molecular mechanisms and therapeutic strategies for PCSK9 inhibition. We summarize data from recent clinical trials using fully humanized monoclonal antibodies, showing that PCSK9 inhibition results in a significant reduction in LDL-cholesterol in high-risk cardiovascular patients. Future studies will have to address the long-term safety and efficacy as well as the impact of PCSK9-targeting therapies on cardiovascular outcomes.© 2014 Wolters Kluwer Health.

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