060 Plasma aldosterone levels predict long-term clinical outcome after percutaneous coronary revascularization

The renin-angiotensin-aldosterone system is a major therapeutic target in coronary artery disease (CAD). Recent data suggest that plasma aldosterone has a high prognostic value in acute coronary syndrome (ACS). We tested whether plasma aldosterone could predict clinical outcome in patients undergoing scheduled percutaneous coronary revascularization (PCR).MethodsFrom June 2001 to September 2002, we included all consecutive patients referred to Lille's University Hospital for scheduled PCR. Blood samples were taken during the PCR. The primary endpoint was cardiac death throughout at least 12 months of follow-up.Results807 patients were included, with a mean age of 61 years. Most were men (78%), smokers (71%). 32% were diabetics, mean LVEF was 58±15% and 93% received stents. 50% had stable angina. The mean plasma aldosterone level was 25(13-45)pg/mL. BMI (p=0.003), NYHA class>1 (p=0.0001) and elevated baseline troponine (p=0.01) were associated with increased aldosterone level. Old age (p=0.0001), normal GFR (p=0.01) and betablockers (p=0.01) were associated with decreased aldosterone level. The mean follow-up was 14.9 months and there were 40 cardiac deaths during this period. In multivariate analysis, old age (HR=1.42, p=0.04), low LVEF (HR=1.58, p=0.001), diabetes mellitus (HR=2.2, p=0.04), a recent history of ACS (HR=3.23, p=0.02), high usCRP (HR=2.59, p=0.004) and high plasma aldosterone (HR=3.48, p=0.004) were independent predictors of cardiac mortality.ConclusionPlasma aldosterone level seems to have an independent prognostic value in patients referred for PCR and could be useful in determining the individual cardiovascular risk. Whether this is the result of direct deleterious effects (promotion of endothelial dysfunction, pro-fibrotic, pro-inflammatory and pro-thrombotic effects) or the marker of a global activation of the neuroendocrine system remains to be determined. However plasma aldosterone appears to be an attractive risk marker in CAD

Nouveaux mécanismes de protection des cardiomyocytes contre les lésions d'ischémie / reperfusion

Cardiovascular diseases are a major problem of public health management. Ischemic and pharmacological pre and postconditioning should significantly improve the prognosis of patients suffering from myocardial ischemia/reperfusion. However, the morbi-mortality of these patients is still high and research must remain active. The first results of myocardial stem cell therapy show that we cannot regenerate myocardium but a recent meta-analysis reported positive effects that can be explained through a paracrine mechanism. Mesenchymal stem cells protect ischemic cardiomyocytes from reperfusion injury through a paracrine activation of the PI3kinase/Akt pathway in a similar way to ischemic postconditioning. The mediators of this protection could be growth factors such as VEGF or IGF-1 though we couldn’t demonstrate a direct effect of one or the other. Modulating the activity of the ATP synthase during ischemia is another promising therapeutic target. This enzyme reverses its activity and hydrolyses ATP when the supply in oxygen is impaired. This leads to the reduction of the cellular pool of ATP and accelerates cell death. We identified new small molecules with a similar effect to IF1 that can selectively inhibit the reverse activity of the ATP synthase, preserve ATP and thus increase cell survival in a preconditioning-like effect. These two different techniques could be part of the therapeutic arsenal against ischemia/reperfusion in the next decades.Les maladies cardiovasculaires constituent un problème de santé publique. Les pré et postconditionnement ischémiques mais aussi pharmacologiques constituent autant d‘avancées qui permettront l‘amélioration de la prise en charge des malades en situation d‘ischémie/reperfusion myocardique. Néanmoins, la morbi-mortalité des maladies cardiovasculaires reste importante et nécessite le développement de nouvelles techniques. Les premiers résultats de la thérapie cellulaire myocardique ont été décevants, et s‘il est désormais établi que l‘on ne peut régénérer le myocarde, les effets bénéfiques observés, notamment avec les cellules souches mésenchymateuses semblent en rapport avec un effet paracrine qui passe par l‘activation de la voie de signalisation PI3kinase/Akt sur un mécanisme comparable à celui du postconditionnement ischémique. Les médiateurs de cet effet sont vraisemblablement des facteurs de croissance comme le VEGF ou l‘IGF-1 même si un effet individuel direct de l‘une ou l‘autre de ces molécules n‘a pu être mis en évidence. La modulation de l‘activité de l‘ATP synthase mitochondriale est également une cible thérapeutique prometteuse. Cette enzyme inverse son activité et hydrolyse l‘ATP durant l‘ischémie, conduisant à dépléter le pool d‘ATP intracellulaire et accélérer la survenue de la mort cellulaire. De nouvelles molécules ayant un effet similaire à l‘IF1 permettent de bloquer cette inversion d‘activité de l‘ATP synthase, de préserver l‘ATP et donc d‘améliorer la survie cellulaire par un effet de type préconditionnement ischémique. Ces 2 techniques, très différentes mais non antinomiques, pourraient faire partie de l‘arsenal thérapeutique dans les années à veni

New mechanisms of protection of cardiomyocytes from ischemia / reperfusion injury

Les maladies cardiovasculaires constituent un problème de santé publique. Les pré et postconditionnement ischémiques mais aussi pharmacologiques constituent autant d‘avancées qui permettront l‘amélioration de la prise en charge des malades en situation d‘ischémie/reperfusion myocardique. Néanmoins, la morbi-mortalité des maladies cardiovasculaires reste importante et nécessite le développement de nouvelles techniques. Les premiers résultats de la thérapie cellulaire myocardique ont été décevants, et s‘il est désormais établi que l‘on ne peut régénérer le myocarde, les effets bénéfiques observés, notamment avec les cellules souches mésenchymateuses semblent en rapport avec un effet paracrine qui passe par l‘activation de la voie de signalisation PI3kinase/Akt sur un mécanisme comparable à celui du postconditionnement ischémique. Les médiateurs de cet effet sont vraisemblablement des facteurs de croissance comme le VEGF ou l‘IGF-1 même si un effet individuel direct de l‘une ou l‘autre de ces molécules n‘a pu être mis en évidence. La modulation de l‘activité de l‘ATP synthase mitochondriale est également une cible thérapeutique prometteuse. Cette enzyme inverse son activité et hydrolyse l‘ATP durant l‘ischémie, conduisant à dépléter le pool d‘ATP intracellulaire et accélérer la survenue de la mort cellulaire. De nouvelles molécules ayant un effet similaire à l‘IF1 permettent de bloquer cette inversion d‘activité de l‘ATP synthase, de préserver l‘ATP et donc d‘améliorer la survie cellulaire par un effet de type préconditionnement ischémique. Ces 2 techniques, très différentes mais non antinomiques, pourraient faire partie de l‘arsenal thérapeutique dans les années à venirCardiovascular diseases are a major problem of public health management. Ischemic and pharmacological pre and postconditioning should significantly improve the prognosis of patients suffering from myocardial ischemia/reperfusion. However, the morbi-mortality of these patients is still high and research must remain active. The first results of myocardial stem cell therapy show that we cannot regenerate myocardium but a recent meta-analysis reported positive effects that can be explained through a paracrine mechanism. Mesenchymal stem cells protect ischemic cardiomyocytes from reperfusion injury through a paracrine activation of the PI3kinase/Akt pathway in a similar way to ischemic postconditioning. The mediators of this protection could be growth factors such as VEGF or IGF-1 though we couldn’t demonstrate a direct effect of one or the other. Modulating the activity of the ATP synthase during ischemia is another promising therapeutic target. This enzyme reverses its activity and hydrolyses ATP when the supply in oxygen is impaired. This leads to the reduction of the cellular pool of ATP and accelerates cell death. We identified new small molecules with a similar effect to IF1 that can selectively inhibit the reverse activity of the ATP synthase, preserve ATP and thus increase cell survival in a preconditioning-like effect. These two different techniques could be part of the therapeutic arsenal against ischemia/reperfusion in the next decades

Rôle pronostique à long terme de l'aldostérone plasmatique dans l'angioplastie programmée

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation

Tocilizumab, a humanized anti-IL-6 receptor α (IL-6Rα) is widely used in the treatment of a panel of pathologies such as adult and juvenile rheumatoid arthritis (RA) and the systemic form of juvenile idiopathic arthritis in children. Its indications are expected to be largely extended to other inflammatory diseases in close future. Dendritic cells (DCs) appear to be deeply involved in the immunopathology of these diseases, yet the effects of tocilizumab on these cells were poorly studied. In this study, we explored the effect of tocilizumab on the regulation of IL-6R subunits [gp130, soluble form of IL-6Rα (sIL-6Rα), and mIL-6Rα] in human monocyte-derived DCs. Human DCs were derived from CD14+ monocytes purified with beads with IL-4 and granulocyte macrophage colony-stimulating factor. Ex vivo cultures of DCs were performed in the presence of tocilizumab. Using lipopolysaccharide (LPS) maturation of DCs, we demonstrated that tocilizumab did not inhibit IL-6 secretion, enhanced mIL-6Rα expression, and largely increased sIL-6Rα secretion. MAPK modulated STAT3 phosphorylation and surface expression of IL-6Rα in LPS-DCs. Tocilizumab had no impact on STAT3 phosphorylation in LPS-DCs while both LPS and IL-6 increased its activation. Tocilizumab modulated the regulation of IL-6R subunits leading to an inflammatory status of DCs and a massive secretion of IL-6Rα. Our results demonstrate that DCs acquire a pro-inflammatory profile following tocilizumab treatment, becoming a major source of IL-6 trans-signaling activation that might explain the poor clinical benefit in some RA patients

Revisiting myocardial necrosis biomarkers: assessment of the effect of conditioning therapies on infarct size by kinetic modelling

Abstract Infarct size is a major predictor of subsequent cardiovascular events following ST-segment elevation myocardial infarction (STEMI) and is frequently used in clinical trials focused on cardioprotection. Approximately assessed through serial blood sampling, it can be accurately measured by imaging techniques, e.g. cardiac magnetic resonance imaging, which is the actual gold standard for infarct size determination but with limited availability in daily practice. We developed a mathematical biomarker kinetic model based on pharmacokinetic compartment models to easily and accurately estimate infarct size using individual data from five clinical trials evaluating the impact of conditioning therapies in STEMI between 2005 and 2013. Serial blood sampling was available in all studies with data regarding creatine kinase (CK), CK specific of cardiomyocytes (CK-MB) and cardiac troponin I. Our model allowed an accurate estimation of biomarker release as a surrogate marker of infarct size and a powerful assessment of conditioning treatments. This biomarker kinetic modelling approach identified CK-MB as the most accurate biomarker in determining infarct size and supports the development of limited sampling strategies that estimate total biomarker amount released with a lower number of samples. It will certainly be a useful add-on to future studies in the field of STEMI and cardioprotection

Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation

International audienceTocilizumab, a humanized anti-IL-6 receptor α (IL-6Rα) is widely used in the treatment of a panel of pathologies such as adult and juvenile rheumatoid arthritis (RA) and the systemic form of juvenile idiopathic arthritis in children. Its indications are expected to be largely extended to other inflammatory diseases in close future. Dendritic cells (DCs) appear to be deeply involved in the immunopathology of these diseases, yet the effects of tocilizumab on these cells were poorly studied. In this study, we explored the effect of tocilizumab on the regulation of IL-6R subunits [gp130, soluble form of IL-6Rα (sIL-6Rα), and mIL-6Rα] in human monocyte-derived DCs. Human DCs were derived from CD14 + monocytes purified with beads with IL-4 and granulocyte macrophage colony-stimulating factor. Ex vivo cultures of DCs were performed in the presence of tocilizumab. Using lipopolysaccharide (LPS) maturation of DCs, we demonstrated that tocilizumab did not inhibit IL-6 secretion, enhanced mIL-6Rα expression, and largely increased sIL-6Rα secretion. MAPK modulated STAT3 phosphorylation and surface expression of IL-6Rα in LPS-DCs. Tocilizumab had no impact on STAT3 phosphorylation in LPS-DCs while both LPS and IL-6 increased its activation. Tocilizumab modulated the regulation of IL-6R subunits leading to an inflammatory status of DCs and a massive secretion of IL-6Rα. Our results demonstrate that DCs acquire a pro-inflammatory profile following tocilizumab treatment, becoming a major source of IL-6 trans-signaling activation that might explain the poor clinical benefit in some RA patients

Should Atrial Fibrillation Patients With Only 1 Nongender-Related CHA 2 DS 2 -VASc Risk Factor Be Anticoagulated?

International audienceBackground and Purpose— There is some uncertainty about treating patients with atrial fibrillation (AF) with 1 nongender-related (NGR) stroke risk factor (CHA 2 DS 2 -VASc [ie, congestive heart failure, hypertension, age (≥75 years; 2 points), diabetes, stroke/transient ischemic attack (2 points), vascular disease, age (65–74 years), sex (female)] score of 1 in males and 2 in females) with oral anticoagulation (OAC). Methods— We investigated adverse outcomes and calculated the net clinical benefit of OAC use in a community-based cohort of unselected AF patients with 0 compared with 1 NGR stroke risk factor (CHA 2 DS 2 -VASc 0 versus 1 in males; and 1 versus 2 in females). Among 8962 patients with AF, 2208 (25%) had 0 or 1 NGR stroke risk factors, of which 45% were not prescribed OAC. Results— During a follow-up of 1028±1189 days (median, 495; interquartile range, 5–1882 days), the yearly rate of the combined end point of stroke/systemic embolism in nonanticoagulated AF patients with 1 NGR stroke risk factor was 2.09% (95% confidence interval, 1.37–3.18). This corresponded to an adjusted hazard ratio of 2.82 (95% confidence interval, 1.32–6.04) relative to the group with 0 NGR stroke risk factor. When the benefit of ischemic stroke reduction was balanced against the increased risk of intracranial hemorrhage among patients with 1 NGR stroke risk factor, the net clinical benefit was positive in favor of OAC use versus no antithrombotic therapy or antiplatelet therapy use. The net clinical benefit was negative for antiplatelet therapy use versus no antithrombotic therapy. Conclusions— Among AF patients with 1 NGR stroke risk factor (ie, CHA 2 DS 2 -VASc 1 in males or 2 in females), OAC use as indicated according to the guidelines was associated with a positive net clinical benefit for the prevention of stroke and thromboembolic events

Evaluation of the efficacy of a self-training programme in focus cardiac ultrasound with simulator

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Stimulation of murine P2Y11-like purinoreceptor protects against hypoxia/reoxygenation injury and decreases heart graft rejection lesions

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