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Le Touquet – Paris-Plage, France

Ramkhelawon B.,Paris Cardiovascular Research Center | Rivas D.,Lady Davis Institute for Medical Research | Lehoux S.,Lady Davis Institute for Medical Research
FASEB Journal | Year: 2013

Mechanical factors such as strain, pressure, and shear stress are key regulators of cell function, but the molecular mechanisms underlying the detection and responses to such stimuli are poorly understood. Whether the angiotensin II (AngII) AT1 receptor (AT1R) transduces shear stress in endothelial cells (ECs) is unknown. We exposed human umbilical cord endothelial cells (HUVECs) to a shear stress of 0 (control) or 15 dyn/cm2 for 5 or 10 min. The colocalization of AT1R with caveolin-1 (Cav1), endosomal markers Rab5, EEA1, and Rab7, and lysosomal marker Lamp-1 increased in shear stimulated cells, detected by immunocytochemistry. Shear stress reduced labeling of wild-type mouse ECs (18±3% of unsheared control, P<0.01) but not Cav1±/± ECs (90±10%) with fluorescent AngII, confirming that internalization of AT1R requires Cav1. Shear stress activated ERK1/2 2-fold (P<0.01), which was prevented by the AT1R blocker losartan. NADPH oxidase inhibition with apocynin prevented both the colocalization of AT1R with Cav1 and the induction of ERK1/2 by shear stress. Moreover, shear-dependent ERK1/2 activation was minimal in CHO cells expressing an AT1Ra mutant that does not internalize, compared with cells expressing wild-type AT1Ra (P<0.05). Hence, AT1R may be an important transducer of shear stress-dependent activation of ERK1/2. © FASEB. Source

Marijon E.,Paris Cardiovascular Research Center | Marijon E.,University of Paris Descartes | Le Heuzey J.-Y.,University of Paris Descartes | Connolly S.,Hamilton Health Sciences | And 8 more authors.
Circulation | Year: 2013

BACKGROUND -: Atrial fibrillation is associated with increased mortality, but the specific causes of death and their predictors have not been described among patients on effective anticoagulant therapy. METHODS AND RESULTS -: The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial randomized 18 113 patients (age, 71.5±9 years; male, 64%; CHADS2 score, 2.1±1) to receive dabigatran or warfarin. Median follow-up was 2 years, and complete follow-up was achieved in 99.9% of patients. All deaths were categorized by the investigators using prespecified definitions followed by central adjudication. Overall, 1371 deaths occurred (annual mortality rate, 3.84%; 95% confidence interval [CI], 3.64-4.05). Cardiac deaths (sudden cardiac death and progressive heart failure) accounted for 37.4% of all deaths, whereas stroke-and hemorrhage-related deaths represented 9.8% of the total mortality. An examination of the causes of death according to dabigatran or warfarin showed that dabigatran significantly reduced vascular (embolism and hemorrhage-related) mortality (relative risk, 0.63; 95% CI, 0.45-0.88; P=0.007), whereas other causes of death were similar between treatments, including cardiac mortality (relative risk, 0.96; 95% CI, 0.80-1.15; P=0.638). The two strongest independent predictors of cardiac death in this population were heart failure (hazard ratio, 3.02; 95% CI, 2.45-3.73; P<0.0001), and prior myocardial infarction (hazard ratio, 2.05; 95% CI, 1.61-2.62; P<0.0001). CONCLUSIONS -: The majority of deaths are not related to stroke in a contemporary anticoagulated atrial fibrillation population. These results emphasize the need to identify interventions beyond effective anticoagulation to further reduce mortality in atrial fibrillation. CLINICAL TRIAL REGISTRATION -: URL: http://www. clinicaltrials.gov. Unique identifier: NCT00262600. © 2013 American Heart Association, Inc. Source

Reinier K.,Cedars Sinai Medical Center | Marijon E.,Cedars Sinai Medical Center | Marijon E.,Paris Cardiovascular Research Center | Uy-Evanado A.,Cedars Sinai Medical Center | And 6 more authors.
JACC: Heart Failure | Year: 2014

Objectives: The purpose of this study was to evaluate the role of congestive heart failure (CHF) in the association between atrial fibrillation (AF) and sudden cardiac death (SCD). Background: Recent studies have reported the possibility of an independent association between AF and SCD. We hypothesized that a history of CHF is a significant confounder of this association. Methods: In a prospective case-control analysis from the community (The Oregon-SUDS [Sudden Unexpected Death Study], 2002 to 2012), SCD cases (n = 652) with clinical records available (including electrocardiography and/or echocardiography) were compared with age- and sex-matched control patients with coronary artery disease. The association between AF and SCD was analyzed using multivariable logistic regression and propensity score matching. Results: Cases (age 67.3 ± 11.7 years, 65% male) were more likely than control patients (age 67.2 ± 11.4 years, 65% male) to have a history of AF (p = 0.0001), myocardial infarction (p = 0.007), CHF (p < 0.0001), stroke (p < 0.0001), and diabetes (p < 0.0001). In multivariate analysis without considering CHF, AF was a significant predictor of SCD (odds ratio [OR]: 1.6; 95% confidence interval [CI]: 1.2 to 2.0; p = 0.002). However, in a model that included CHF, the AF-SCD association was no longer significant (OR: 1.1; 95% CI: 0.8 to 1.5; p = 0.45), whereas CHF was a significant predictor of SCD (OR: 3.1; 95% CI: 2.4 to 4.1; p < 0.0001). Results on the basis of propensity score matching were consistent. Conclusions: Our findings suggest that a history of CHF, including both systolic and diastolic symptomatic dysfunction, may partially explain the AF-SCD association. © 2014 American College of Cardiology Foundation. Source

Celermajer D.S.,University of Sydney | Chow C.K.,University of Sydney | Chow C.K.,George Institute for Global Health | Marijon E.,Paris Cardiovascular Research Center | And 2 more authors.
Journal of the American College of Cardiology | Year: 2012

Over the past decade or more, the prevalence of traditional risk factors for atherosclerotic cardiovascular diseases has been increasing in the major populous countries of the developing world, including China and India, with consequent increases in the rates of coronary and cerebrovascular events. Indeed, by 2020, cardiovascular diseases are predicted to be the major causes of morbidity and mortality in most developing nations around the world. Techniques for the early detection of arterial damage have provided important insights into disease patterns and pathogenesis and especially the effects of progressive urbanization on cardiovascular risk in these populations. Furthermore, certain other diseases affecting the cardiovascular system remain prevalent and important causes of cardiovascular morbidity and mortality in developing countries, including the cardiac effects of rheumatic heart disease and the vascular effects of malaria. Imaging and functional studies of early cardiovascular changes in those disease processes have also recently been published by various groups, allowing consideration of screening and early treatment opportunities. In this report, the authors review the prevalences and patterns of major cardiovascular diseases in the developing world, as well as potential opportunities provided by early disease detection. © 2012 American College of Cardiology Foundation. Source

Providencia R.,University Paul Sabatier | Providencia R.,University of Coimbra | Albenque J.-P.,University Paul Sabatier | Combes S.,University Paul Sabatier | And 7 more authors.
Heart | Year: 2014

Background Dabigatran etexilate, a new thrombin inhibitor, has been shown to be comparable to warfarin in patients with atrial fibrillation (AF). However, there is a limited body of evidence on the efficacy and safety of using dabigatran among patients undergoing AF catheter ablation. Objective A random effects meta-analysis was performed of controlled trials comparing dabigatran and warfarin in paroxysmal/persistent AF patients undergoing catheter ablation. Methods Data sources included Medline, Embase, and Cochrane (from inception to April 2013). Three independent reviewers selected studies comparing warfarin to dabigatran. Descriptive and quantitative information was extracted from each selected study, regarding periprocedural all cause mortality, thromboembolic events and major bleeding, as well as modalities of periprocedural anticoagulation bridging. Results After a detailed screening of 228 search results, 14 studies were identified enrolling a total of 4782 patients (1823 treated with dabigatran and 2959 with warfarin). No deaths were reported. No significant differences were found between patients treated with dabigatran and warfarin as regards thromboembolic events (0.55% dabigatran vs 0.17% warfarin; risk ratios (RR)=1.78, 95% CI 0.66 to 4.80; p=0.26) and major bleeding (1.48% dabigatran vs 1.35% warfarin; RR=1.07, 95% CI 0.51 to 2.26; p=0.86). No difference was found between the 110 mg twice daily and 150 mg twice daily dabigatran dosages concerning major bleeding (0% vs 1.62%, respectively; RR=0.19, 95% CI 0.01 to 3.18; p=0.25) and thromboembolism (0% vs 0.40%, respectively; RR=0.72, 95% CI 0.04 to 12.98; p=0.82). Conclusions In the specific setting of AF catheter ablation, this first pooled analysis suggests that patients treated with dabigatran have a similar incidence of thromboembolic events and major bleeding compared to warfarin, with low event rates overall. Source

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