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Tang L.,Huazhong University of Science and Technology | Wu Y.-Y.,Huazhong University of Science and Technology | Lip G.Y.H.,Center for Cardiovascular science | Yin P.,Huazhong University of Science and Technology | Hu Y.,Huazhong University of Science and Technology
The Lancet Haematology | Year: 2015

Background: Venous thromboembolism is a major global health problem that is often secondary to other clinical situations. Many studies have investigated the association between venous thromboembolism and heart failure, but have yielded inconsistent findings. We aimed to quantify the absolute and relative risks (RR) for venous thromboembolism in patients with heart failure after hospital admission. We also assessed rates of venous thromboembolism in patients in different settings. Methods: In this systematic review and meta-analysis, we searched for studies investigating the risk of venous thromboembolism in patients in hospital with heart failure. We searched for studies published between Jan 1, 1955, and March 31, 2015, in PubMed, Embase, Evidence-Based Medicine Reviews, Allied and Complementary Medicine Database, Ovid HealthSTAR, Global Health, Ovid Nursing Database, Web of Science, CINAHL Plus, ProQuest Central, Conference Papers Index, BIOSIS Previews, and ClinicalTrials.gov. All cohort studies and subgroup analyses of randomised controlled trials (RCTs) were eligible for inclusion if they reported venous thromboembolism rates (number of events per follow-up period) or RR estimates. We extracted data from published reports and contacted the corresponding authors of records with insufficient quantitative data. RRs and 95% CIs were pooled using a random-effects model. This study is registered with PROSPERO, number CRD42014015504. Findings: Of 8673 records identified, we included 71 studies with data from 88 cohorts in our analysis, with 59 cohorts included in the assessment of venous thromboembolism rates and 46 cohorts included in the meta-analysis of heart failure and risk of venous thromboembolism. Venous thromboembolism rates varied widely in patients in hospital with heart failure from different settings. The overall median symptomatic venous thromboembolism rate was 2·48% (IQR 0·84-5·61); rates was were 3·73% (1·05-7·31) for patients who did not receive thromboprophylaxis and 1·47% (0·64-3·54) for those who did. Overall, patients with heart failure in hospital had an RR of 1·51 (1·36-1·68) for venous thromboembolism. The overall I 2 statistic was 96·1% and there was no evidence of publication bias (Egger's test, p=0·46). Interpretation: Heart failure is a common independent risk factor for venous thromboembolism. Thromoboprophylaxis should be considered in clinical practice for high-risk patients. Funding: National Natural Science Foundation. © 2015 Elsevier Ltd. Source

Dias I.H.K.,Aston University | Mistry J.,Aston University | Fell S.,Aston University | Reis A.,Aston University | And 4 more authors.
Free Radical Biology and Medicine | Year: 2014

Elevated total cholesterol in midlife has been associated with increased risk of dementia in later life. We have previously shown that low-density lipoprotein (LDL) is more oxidized in the plasma of dementia patients, although total cholesterol levels are not different from those of age-matched controls. β-Amyloid (Aβ) peptide, which accumulates in Alzheimer disease (AD), arises from the initial cleavage of amyloid precursor protein by β-secretase-1 (BACE1). BACE1 activity is regulated by membrane lipids and raft formation. Given the evidence for altered lipid metabolism in AD, we have investigated a mechanism for enhanced Aβ production by SH-SY5Y neuronal-like cells exposed to oxidized LDL (oxLDL). The viability of SH-SY5Y cells exposed to 4 μg oxLDL and 25 μM 27-hydroxycholesterol (27OH-C) was decreased significantly. Lipids, but not proteins, extracted from oxLDL were more cytotoxic than oxLDL. In parallel, the ratio of reduced glutathione (GSH) to oxidized glutathione was decreased at sublethal concentrations of lipids extracted from native and oxLDL. GSH loss was associated with an increase in acid sphingomyelinase (ASMase) activity and lipid raft formation, which could be inhibited by the ASMase inhibitor desipramine. 27OH-C and total lipids from LDL and oxLDL independently increased Aβ production by SH-SY5Y cells, and Aβ accumulation could be inhibited by desipramine and by N-acetylcysteine. These data suggest a mechanism whereby oxLDL lipids and 27OH-C can drive Aβ production by GSH depletion, ASMase-driven membrane remodeling, and BACE1 activation in neuronal cells. © 2014 The Authors. Source

Dias H.K.I.,Aston University | Brown C.L.R.,Aston University | Polidori M.C.,University of Cologne | Lip G.Y.H.,Center for Cardiovascular science | Griffiths H.R.,Aston University
Clinical Science | Year: 2015

Elevated low-density lipoprotein (LDL) concentration in mid-life increases the risk of developing Alzheimer's disease (AD) in later life. Increased oxidized LDL (oxLDL) modification and nitration is observed during dementia and hypercholesterolaemia. We investigated the hypothesis that statin intervention in mid-life mitigates the inflammatory effects of oxLDL on the microvasculature. Human microvascular endothelial cells (HMVECs) were maintained in transwells to mimic the microvasculature and exposed to patient and control LDL. Blood was obtained from statin-naive, normo- and hyper-lipidaemic subjects, AD with vascular dementia (AD-plus) and AD subjects (n=10/group) at baseline. Only hyperlipidaemic subjects with normal cognitive function received 40 mg of simvastatin intervention/day for 3 months. Blood was re-analysed from normo- and hyper-lipidaemic subjects after 3 months. LDL isolated from statin-naive hyperlipidaemic, AD and AD-plus subjects was more oxidized (agarose gel electrophoretic mobility, protein carbonyl content and 8-isoprostane F2α) compared with control subjects. Statin intervention decreased protein carbonyls (2.5± 0.4 compared with 3.95± 0.2 nmol/mg; P < 0.001) and 8-isoprostane F2α (30.4± 4.0 pg/ml compared with 43.5± 8.42 pg/ml; P < 0.05). HMVEC treatment with LDL-lipids (LDL-L) from hyperlipidaemic, AD and AD-plus subjects impaired endothelial tight junction expression and decreased total glutathione levels (AD; 18.61± 1.3, AD-plus; 16.5± 0.7 nmol/mg of protein) compared with untreated cells (23.8± 1.2 compared with nmol/mg of protein). Basolateral interleukin (IL)-6 secretion was increased by LDL-L from hyperlipidaemic (78.4± 1.9 pg/ml), AD (63.2± 5.9 pg/ml) and AD-plus (80.8± 0.9 pg/ml) groups compared with healthy subject lipids (18.6± 3.6 pg/ml). LDL-L isolated after statin intervention did not affect endothelial function. In summary, LDL-L from hypercholesterolaemic, AD and AD-plus patients are inflammatory to HMVECs. In vivo intervention with statins reduces the damaging effects of LDL-L on HMVECs. © 2015 Authors. Source

Crijns H.J.,Maastricht University | Pisters R.,Center for Cardiovascular science
Stroke Prevention in Atrial Fibrillation | Year: 2012

Atrial fibrillation (AF) is extremely common, affecting one in every four people aged more than 55 years, and is associated with significantly increased risk of stroke. It should therefore be a top priority to reduce the number of AF-related strokes to an absolute minimum. This book, from a team of international experts, provides the essential information on stroke risk and associated mechanisms in AF and the appropriate antithrombotic management. It highlights the importance of assessing the individual risk for thromboembolic events, explores which classical, unsuspected and future (non-)pharmacological strategies can be used according to the latest international guidelines, and draws attention to the associated hurdles and solutions that may be encountered. © 2012 Future Medicine Ltd. All rights reserved. Source

Zhang J.,Center for Cardiovascular science | O'Donnell J.J.,Rush University Medical Center | Holian O.,Rush University Medical Center | Vincent P.A.,Center for Cardiovascular science | And 2 more authors.
Microvascular Research | Year: 2010

P120 catenin (p120ctn) belongs to the family of Armadillo repeat-containing proteins, which are believed to have dual functions of cell-cell adhesion and transcriptional regulation. In vascular endothelium, p120ctn is mostly recognized for its cell-cell adhesion function through its ability to regulate VE-cadherin. The current study investigated whether p120ctn in endothelial cells also has the capability to signal transcription events. Examination of several endothelial cell types indicated that Kaiso, a p120ctn-binding transcription factor, was abundantly expressed, with a predominant localization to the perinuclear region. Immunoprecipitation of endothelial cell lysates with a p120ctn antibody resulted in p120ctn-Kaiso complex formation, confirming the interactions of the two proteins. Transfection of the KBS (Kaiso-binding sequence) luciferase reporter plasmid into endothelial cells resulted in a 40% lower reporter activity compared to the mutant Kaiso-insensitive construct or empty vector pGL3, indicating that the suppressed reporter activity was attributed to endogenous Kaiso. The knock-down of p120ctn increased the KBS reporter activity 2-fold over control, but had no effects on the mutant KBS reporter activity. Furthermore, p120ctn knock-down also reduced Kaiso expression, suggesting that p120ctn functioned to stabilize Kaiso. Overall, the findings provide evidence that in endothelial cells, p120ctn has a transcription repression function through regulation of Kaiso, possibly as a cofactor with the transcription factor. © 2010 Elsevier Inc. Source

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