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Aims: The prognosis of patients with infective endocarditis (IE) remains poor despite the great advances in the last decades. One of the factors closely related to mortality is the development of septic shock (SS). The aim of our study was to describe the profile of patients with IE complicated with SS, and to identify prognostic factors of new-onset SS during hospitalization. Methods and results: We conducted a prospective study including 894 episodes of IE diagnosed at three tertiary centres. A backward logistic regression analysis was undertaken to determine prognostic factors associated with SS development. Multivariable analysis identified the following as predictive of SS development: diabetes mellitus [odds ratio (OR) 2.06; confidence interval (CI) 1.16-3.68], Staphylococcus aureus infection (OR: 2.97; CI: 1.72-5.15), acute renal insufficiency (OR: 3.22; CI: 1.28-8.07), supraventricular tachycardia (OR: 3.29; CI: 1.14-9.44), vegetation size ≥15 mm (OR: 1.21; CI: 0.65-2.25), and signs of persistent infection (OR: 9.8; CI: 5.48-17.52). Risk of SS development could be stratified when combining the first five variables: one variable present: 3.8% (CI: 2-7%); two variables present: 6.3% (CI: 3.2-12.1%); three variables present: 14.6% (CI: 6.8-27.6%); four variables present: 29.1% (CI: 11.7-56.1%); and five variables present: 45.4% (95% CI: 17.5-76.6%). When adding signs of persistent infection, the risk dramatically increased, reaching 85.7% (95% CI: 61.2-95.9%) of risk. Conclusions: In patients with IE, the presence of diabetes, acute renal insufficiency, Staphylococcus aureus infection, supraventricular tachycardia, vegetation size ≥15 mm, and signs of persistent infection are associated with the development of SS., Depto. de Medicina, Fac. de Medicina, TRUE, pub

Objectives: Acute onset of infective endocarditis has been previously linked to the development of septic shock and a worse prognosis. The purpose of this study was to analyse the clinical features and in-hospital evolution of patients with acute-onset endocarditis as well as the potential role of early surgery in the treatment of these patients. Methods: From 1996 to 2014, 1053 consecutive patients with left-sided endocarditis were prospectively included. Patients were classified into 2 groups according to the clinical presentation: patients with acute-onset endocarditis (n = 491) and patients with non-acute endocarditis (n = 562). Acute-onset endocarditis was considered when the time between the appearance of symptoms and diagnosis was <15 days. Results: At admission, acute renal failure, septic shock and cerebral embolism predominated among patients with acute-onset endocarditis. Staphylococcus aureus was more frequently isolated in patients with an acute onset (27.7% vs 7.8% P < 0.001). During hospitalization, patients with acute onset developed systemic embolism and septic shock more frequently. Death was much more common in this group (42.7 vs 30.1%, P < 0.001). Paravalvular complications, nosocomial infection, heart failure, S. aureus and septic shock were predictors of mortality. Acute-onset presentation of endocarditis was strongly associated with increased mortality. Among patients with acute-onset endocarditis, early surgery, performed within the first 2 days after diagnosis, was associated with a 64% of reduction in mortality. Conclusions: Patients with endocarditis and acute onset of symptoms are at high risk of septic in-hospital complications and mortality. Early surgery, performed within the first 2 days after diagnosis, plays a central role in the treatment of these patients., Depto. de Medicina, Fac. de Medicina, TRUE, pub

[Introduction]: Inflammation has been linked to metabolic reprogramming in several diseases and cellular models. Calcific aortic valve disease (CAVD) is an increasingly prevalent valvulopathy characterized by dysregulated inflammation and metabolic changes. At the cellular level, we have shown that innate immunity pathways cooperate to promote calcification of aortic valve interstitial cells (VIC) via stabilization of hypoxia-inducible factor (HIF)-1¿, which suggests that inflammatory and metabolic pathways work in an interconnected manner in CAVD., [Objective]: Elucidating the metabolic reprogramming induced by inflammatory agents in human VIC and its impact on CAVD pathogenesis., [Methods]: Metabolic analysis of VIC treated with the pro-inflammatory agents cytokines and Toll-like receptor ligands was performed by Seahorse extracellular flux assays and glucose labeling and tracing by liquid chromatography/mass spectrometry. Metabolic and inflammatory mediator profiles were assayed by Western blot, q-PCR and metabolite kits. Mineralization was quantitated in in vitro calcification assays. Results: A quick metabolic reprogramming of VIC by inflammatory agents was observed. Metabolic rewiring included enhancement of glycolysis, extracellular acidification, ATP and oxygen reactive species production, as well as increased reliance on glucose for energy production and metabolite accumulation. Blockade of glucose catabolism and glucose deprivation blunted inflammation-induced calcification, osteoblast-like differentiation, and cytokine production. Mechanisms mediating this reprogramming include the Janus kinase (JAK)-STAT/HIF-1¿ system and nuclear factor (NF)-kB pathways., [Conclusion]: A metabolic shift to increased glycolysis is necessary for inflammation-induced calcification and osteogenic differentiation of VIC. Metabolic reprogramming is dependent on JAK/STAT-HIF-1¿ and NF-¿B pathways. Changes in metabolic phenotypes may play a relevant pathogenetic role in inflammatory stages driving to severe CAVD.

Supplemental material that contains; - method for the characterization of valvular endothelial cells by immunostaining. - Supplemental Figure S1. Characterization of aortic valve endothelial cells. - Supplemental Figure S2. Cell counting corresponding to Fig 7 of the manuscript. - Supplemental Table S1. Clinical features of patients used in the study of mixed VEC population. - Supplemental Table S2. Clinical characteristics of patients used in the study of aortic- and ventricular-sided endothelial cells.

Secreted phospholipase A2-IIA (sPLA2-IIA) is a pro-inflammatory protein associated with cardiovascular disorders, whose functions and underlying mechanisms in cardiac remodelling are still under investigation. We herein study the role of sPLA2-IIA in cardiac fibroblast (CFs)-to-myofibroblast differentiation and fibrosis, two major features involved in cardiac remodelling, and also explore potential mechanisms involved. In a mice model of dilated cardiomyopathy (DCM) after autoimmune myocarditis, serum and cardiac sPLA2-IIA protein expression were found to be increased, together with elevated cardiac levels of the cross-linking enzyme lysyl oxidase (LOX) and reactive oxygen species (ROS) accumulation. Exogenous sPLA2-IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA2-IIA promoted Src phosphorylation, shedding of the membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) ectodomain and EGFR phosphorylation, which triggered phosphorylation of ERK, P70S6K and rS6. This was also accompanied by an up-regulated expression of the bone morphogenic protein (BMP)-1, LOX and collagen I. ROS accumulation were also found to be increased in sPLA2-IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA2-IIA. In conclusion, sPLA2-IIA may promote myofibroblast differentiation through its ability to modulate EGFR transactivation and signalling as key mechanisms that underlie its biological and pro-fibrotic effects.