Atorvastatin-induced cardioprotection of human myocardium is mediated by the inhibition of mitochondrial permeability transition pore opening via tumor necrosis factor-\u3b1 and Janus kinase/signal transducers and activators of transcription pathway

BACKGROUND: The role of tumor necrosis factor-\u3b1 (TNF-\u3b1), Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and mitochondrial Permeability Transition Pore in atorvastatin-induced cardioprotection were examined in human myocardium, in vitro. METHODS: Isometric force of contraction of human right atrial trabeculae was recorded during 30-min hypoxia and 60-min reoxygenation (control) and in the presence of atorvastatin (0.1 \ub5M, 1 \ub5M, 10 \ub5M). In early reoxygenation, the TNF-\u3b1 inhibitor, AG490 (inhibitor of JAK/STAT), or atractyloside (mitochondrial Permeability Transition Pore opener), were administered. Cyclosporine A (inhibitor of mitochondrial Permeability Transition Pore opening) was administered during the first minute of reoxygenation alone or in presence of atorvastatin and TNF-\u3b1 inhibitor or AG490. The force of contraction (percentage of baseline) at the end of reoxygenation period was compared (mean \ub1 SD; n = 6 in each group). Protein expression of JAK/STAT pathway was measured using Western immunoblotting. RESULTS: Atorvastatin 0.1 \ub5M (70 \ub1 9%), 1 \ub5M (85 \ub1 5%), 10 \ub5M (89 \ub1 5%), and Cyclosporine A (87 \ub1 10%) improved the recovery of force of contraction at the end of reoxygenation, as compared with control (50 \ub1 3%). Atorvastatin 1 \ub5M (4.64 \ub1 2.90 ng \ub7 ml(-1) \ub7 g(-1) of tissue) decreased the release of troponin Ic after hypoxia-reoxygenation (control: 26.34 \ub1 19.30 ng \ub7 ml(-1) \ub7 g(-1); P < 0.001). The enhanced recovery of force of contraction after atorvastatin administration was abolished by TNF-\u3b1 inhibitor (53 \ub1 8%), AG490 (56 \ub1 7%), atractyloside (48 \ub1 8%). Cyclosporine A restored the atorvastatin-induced cardioprotection abolished by TNF-\u3b1 inhibitor (87 \ub1 6%) and AG490 (83 \ub1 9%). Atorvastatin significantly increased the phosphorylation of JAK-2 and STAT-3, TNF-\u3b1 inhibitor abolished the enhanced phosphorylation of JAK-2 and STAT-3 by atorvastatin. CONCLUSIONS: Atorvastatin-induced cardioprotection involved the inhibition of the mitochondrial Permeability Transition Pore opening via the activation of TNF-\u3b1 and the JAK/STAT pathway in early reoxygenatio

Effects of glycaemic variability on cardiac remodelling after reperfused myocardial infarction: Evaluation of streptozotocin-induced diabetic Wistar rats using cardiac magnetic resonance imaging

International audienc

Cardiovascular safety of rapidly accelerated fibrosarcoma B-type and/or mitogen-activated extracellular signal-regulated kinase inhibitors: A mixed approach combining a meta-analysis and a pharmacovigilance disproportionality analysis.

The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is not fully characterized. To evaluate the cardiovascular adverse events risks related to BRAF and/or MEK inhibitors in randomized placebo-controlled clinical trials and in the real-life setting. We used two approaches. First, we conducted a systematic review and meta-analysis of randomized placebo-controlled clinical trials reporting the incidence of cardiovascular adverse events for BRAF and/or MEK inhibitors in cancer patients. Second, we performed a disproportionality analysis, using age- and sex-adjusted reporting odds ratios (arORs) and their 95% confidence intervals (CIs) from the World Health Organization's pharmacovigilance database (VigiBase®) of anticancer drug-associated reports, to investigate real-life data. MEK inhibitors increased the risk of ejection fraction decrease (odds ratio [OR] 3.35, 95% CI 1.58-7.07), peripheral oedema (OR 2.87 95% CI 1.93-4.27) and syncope (OR 6.71, 95% CI 3.00-14.99) compared with placebo in randomized placebo-controlled clinical trials. BRAF and MEK inhibitor combination therapy further increased the risk of ejection fraction decrease. In the disproportionality analysis, we found over-reporting of ejection fraction decrease (arOR 8.42, 95% CI 7.03-10.09), peripheral oedema (arOR 1.39, 95% CI 1.17-1.66), syncope (arOR 1.56, 95% CI 1.22-1.99), torsade de pointes/QT prolongation (arOR 6.13, 95% CI 5.04-7.47) and supraventricular arrhythmias (arOR 1.50, 95% CI 1.21-1.85) for BRAF and MEK inhibitors. BRAF and MEK inhibitors were not associated with hypertension in either approach. In conclusion, MEK inhibitors increase the risk of ejection fraction decrease, peripheral oedema and syncope in randomized placebo-controlled clinical trials. Real-life data confirm these findings, and suggested additional risks of torsade de pointes/QT prolongation and supraventricular arrhythmias with BRAF/MEK inhibitors

Literary Style, Corpus stylistic and Lexico-grammatical narrative patterns. Toward the concept of litterary motifs. Chapter 1

International audienceIn this chapter we survey previous research and present the methodology employed in the present book. We begin by outlining work done in stylistics (e.g. Barthes 1966, Leech & Short 2007), corpus stylistics (Stubbs 2005, Fischer-Starcke 2010, Mahlberg 2013) and ‘textométrie’ (Brunet 1981) to characterize the style used by various authors (e.g. Flaubert, Proust, Dickens, Austen). Next, the focus shifts to the scarcity of research in fiction-specific lexico-grammatical patterns based on large corpora, which will be at the centre of the present volume. We then proceed to defining said patterns (often called ‘motifs’, e.g., by Longrée & Mellet 2013 and Legallois 2006 in the French literature on the subject), followed by differentiating them from other types of phraseological units. The chapter concludes by underscoring the contribution that introducing the notion of ‘motif’ makes to linguistics and literary studies research

Preoperative plasma aldosterone and the risk of atrial fibrillation after coronary artery bypass surgery. a prospective cohort study

Objective: Postoperative atrial fibrillation (POAF) is associated with poor outcomes after coronary artery bypass graft (CABG) surgery. We aimed to assess the additional value of preoperative plasma aldosterone levels, a biomarker promoting proarrhythmic and profibrotic pathways, for predicting POAF after CABG. Methods: We conducted a prospective cohort study involving consecutive patients with left ventricular ejection fraction (LVEF) more than 50% requiring elective CABG in our university hospital. Plasma aldosterone levels, two-dimensional echocardiography including left atrial strain analysis and galectin-3 (Gal-3) examination were assessed before cardiac surgery. The primary endpoint was the occurrence of POAF within 30 days after surgery. Results: POAF occurred in 34 (24.8%) out of the 137 included patients. Compared with controls, patients experiencing POAF were significantly older (73 years old ± 8 vs 65 ± 11, P &lt; 0.001) and had higher preoperative plasma aldosterone levels [183 pmol/l (interquartile range 138-300) vs 143 pmol/l (interquartile range 96.5-216.5), P &lt; 0.01]. Age [odds ratio (OR), 1.088; 95% confidence interval (CI) (1.038-1.140); P = 0.0004] and plasma aldosterone levels [OR, 1.007; 95% CI (1.003-1.012); P = 0.0013] were independently associated with POAF in multivariate analysis and could therefore be combined to predict the occurrence of POAF ['Aldoscore', OR, 2.7; 95% CI (1.7-4.3); P &lt; 0.0001]. Reverse transcriptase PCR analysis performed on right atrial appendage and plasma examination revealed that Gal-3 was activated in POAF patients. Conclusion: We developed the preoperative 'Aldoscore' for POAF risk stratification among patients with preserved LVEF requiring elective CABG. This new tool may be helpful to identify good responders to interventions targeting the proarrhythmic and profibrotic pathways of aldosterone

Sequencing and titrating approach of therapy in heart failure with reduced ejection fraction following the 2021 European Society of Cardiology guidelines: an international cardiology survey

Aims In symptomatic patients with heart failure and reduced ejection fraction (HFrEF), recent international guidelines recommend initiating four major therapeutic classes rather than sequential initiation. It remains unclear how this change in guidelines is perceived by practicing cardiologists versus heart failure (HF) specialists.Methods and results An independent academic web-based survey was designed by a group of HF specialists and posted by email and through various social networks to a broad community of cardiologists worldwide 1 year after the publication of the latest European HF guidelines. Overall, 615 cardiologists (38 [32-47] years old, 63% male) completed the survey, of which 58% were working in a university hospital and 26% were HF specialists. The threshold to define HFrEF was <= 40% for 61% of the physicians. Preferred drug prescription for the sequential approach was angiotensin-converting enzyme inhibitors or angiotensin receptor-neprilysin inhibitors first (74%), beta-blockers second (55%), mineralocorticoid receptor antagonists third (52%), and sodium-glucose cotransporter 2 inhibitors (53%) fourth. Eighty-four percent of participants felt that starting all four classes was feasible within the initial hospitalization, and 58% felt that titration is less important than introducing a new class. Age, status in training, and specialization in HF field were the principal characteristics that significantly impacted the answers.Conclusion In a broad international cardiology community, the 'historical approach' to HFrEF therapies remains the preferred sequencing approach. However, accelerated introduction and uptitration are also major treatment goals. Strategy trials in treatment guidance are needed to further change practices.[GRAPHICS]