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Background Elevated BNP and the N-terminal fragment of the proBNP (NT-proBNP) are hallmarks of heart failure (HF). Generally, both biomarkers parallel each other. In patients receiving sacubitril/valsartan, BNP remained stable while NT-proBNP decreased. As BNP and NT-proBNP assays have limited specificity due to cross-reactivity, we quantified by mass spectrometry (MS) the contributing molecular species. Methods We included 356 healthy volunteers, 100 patients with acute dyspnoea (49 acute decompensated HF; 51 dyspnoea of non-cardiac origin), and 73 patients with chronic HF and reduced ejection fraction treated with sacubitril/valsartan. BNP and NT-proBNP immunoreactivities (BNPir and NT-proBNPir) were measured by immunoassays (Abbott ARCHITECT and Roche Diagnostics proBNPII) and proBNP-derived peptides and glycosylation at serine 44 by MS on plasma samples. Results BNPir corresponded to the sum of proBNP1–108, BNP1–32, BNP3–32, and BNP5–32 (R2 = 0.9995), while NT-proBNPir corresponded to proBNP1–108 and NT-proBNP1–76 not glycosylated at serine 44 (R2 = 0.992). NT-proBNPir was better correlated (R2 = 0.9597) than BNPir (R2 = 0.7643) with proBNP signal peptide (a surrogate of proBNP production). In patients receiving sacubitril/valsartan, non-glycosylated NT-proBNP1–76 remained constant (P = 0.84) despite an increase in NT-proBNP1–76 and its glycosylation (P < 0.0001). ProBNP1–108 remained constant (P = 0.12) while its glycosylation increased (P < 0.0001), resulting in a decrease in non-glycosylated proBNP1–108 (P < 0.0001), and in NT-proBNPir. Conclusions Glycosylation interfered with NT-proBNPir measurement, explaining the discrepant evolution of these 2 biomarkers in patients receiving sacubitril/valsartan. Both BNPir and NT-proBNPir are surrogates of proBNP1–108 production, NT-proBNPir being more robust in the clinical contexts studied.

Background: Sacubitril/valsartan (S/V) treatment is beneficial in patients with heart failure with reduced ejection fraction (HFrEF), but its mode of action remains elusive, although it involves the increase in ANP (atrial natriuretic peptide). Methods: Combining mass spectrometry and enzymatic assay in the plasma of 73 HFrEF patients treated with S/V and controls, we deciphered proANP processing that converts proANP into 4 vasoactive peptides. Results: We found that proANP processing is sequential and involved meprin B, ECE (endothelin-converting enzyme) 1, and ANPEP (aminopeptidase N). This processing is limited in HFrEF patients via the downregulation of proANP production, corin, and meprin B activities by miR-425 and miR1-3p. S/V restored or compensated proANP processing by downregulating miR-425 and miR1-3p, hence increasing levels of proANP-derived bioactive peptides. In contrast, S/V directly and indirectly partially inhibited ECE1 and ANPEP. ECE1 partial inhibition resulted in a lower-than-expected increase in ET1 (endothelin 1), tilting the vasoactive balance toward vasodilation, and possibly hypotension. Furthermore, proANP glycosylation interferes with the midregional proANP assay –a clinical surrogate for proANP production, preventing any pathophysiological interpretation of the results. The analysis of S/V dose escalation with respect to baseline treatments suggests S/V-specific effects. Conclusions: These findings offer mechanistic evidence to the natriuretic peptide -defective state in HFrEF, which is improved by S/V. These data also strongly suggests that S/V increases plasma ANP by multiple mechanisms that involve 2 microRNAs, besides its protection from NEP (neprilysin) cleavage. Altogether, these data provide new insights on HFrEF pathophysiology and the mode of action of S/V.

The physiology of venous and tissue CO2 monitoring has a long and well-established physiological background, leading to the technological development of different tissue capnometric devices, such as transcutaneous capnometry monitoring (TCM). To outline briefly, measuring transcutaneous PCO2 (tcPCO2) depends on at least three main phenomena: (I) the production of CO2 by tissues (VCO2), (II) the removal of CO2 from the tissues by perfusion (wash-out phenomenon), and (III) the reference value of CO2 at tissue inlet represented by arterial CO2 content (approximated by arterial PCO2, or artPCO2). For this reason, there are, at present, roughly two clinical uses for tcPCO2 measurement: a respiratory approach where tcPCO2 is likely to estimate and non-invasively track artPCO2; and a hemodynamic under-estimate use where tcPCO2 can reflect tissue perfusion, summarized by a so-called "tc-art PCO2 gap". Recent research shows that these two uses are not incompatible and could be combined. The spectrum of indications and validation studies in ICUs is summarized in this review to give a survey of the potential applications of TCM in critically ill patients, focusing mainly on its potential (micro)circulatory monitoring contribution. We strongly believe that the greatest benefit of measuring tcPCO2 is not to only to estimate artPCO2, but also to quantify the gap between these two values, which can then help clinicians continuously and noninvasively assess both respiratory and hemodynamic failures in critically ill patients.

Aim This study aimed at evaluating the effects of sacubitril/valsartan on neprilysin (NEP), and the metabolism of natriuretic peptides in heart failure (HF) and providing additional mechanistic information on the mode of action of the drug. Methods and results We enrolled 73 chronic HF patients who were switched from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to sacubitril/valsartan. In addition to clinical and echocardiographic assessment, plasma biomarkers were measured at baseline, day 30 and day 90 after initiation of treatment. Sacubitril/valsartan led to decrease in New York Heart Association class and improvement of echocardiographic parameters, as well as a dose-dependent decrease in soluble NEP (sNEP) activity, while sNEP concentration remained unchanged. Neprilysin inhibition translated into an increase in its substrates such as atrial natriuretic peptide (ANP), substance P, and glucagon-like peptide 1, the latter translating into a decrease in fructosamine. Cardiac troponin and soluble ST2 levels, biomarkers of HF severity unrelated to NEP metabolism also decreased. While there was a ∼4-fold increase in ANP, we observed no change in plasma brain natriuretic peptide (BNP) and plasma BNP activity, and a mild decrease in N-terminal proBNP (NT-proBNP) concentrations. Finally, we found a progressive increase in the relationship between BNP and NT-proBNP, which strongly correlated with an increase in T71 proBNP glycosylation (R2 = 0.94). Conclusion Sacubitril/valsartan rapidly and strongly reduced sNEP activity, leading to an increase in levels of NEP substrates. These data suggest a pleiotropic favourable impact of sacubitril/valsartan on the metabolism of HF patients with ANP rather than BNP as major effectors amongst natriuretic peptides.

Background Since the introduction of sacubitril/valsartan in clinical cardiology, neprilysin has become a major target for heart failure treatment. Plasma neprilysin concentration has been discussed as a novel biomarker that predicts cardiac events. Natriuretic peptides may inhibit plasma neprilysin. As they accumulate in chronic kidney disease (CKD), we hypothesized that high plasma neprilysin loses its predictive role in CKD patients. Methods We measured plasma levels of neprilysin concentration, neprilysin activity and brain natriuretic peptide (BNP) in 542 CKD G2-G4 patients within the CARE FOR HOMe study. Patients were followed for predefined endpoints of hospitalization for acute decompensated heart failure and incident atherosclerotic cardiovascular events. Results During 5.1 ± 2.1 years, 63 patients had acute decompensated heart failure and 125 patients had incident atherosclerotic cardiovascular events. In both Kaplan-Meier and multivariate Cox regression analyses, high plasma BNP and low, rather than elevated, neprilysin activity predicted future hospitalization for acute decompensated heart failure; neprilysin concentration was not predictive. Furthermore, only BNP was an independent predictor of incident atherosclerotic cardiovascular events. Conclusions In line with experimental studies, high natriuretic peptides may inhibit neprilysin activity in CKD. Therefore, high neprilysin activity and concentrations are not predictors of adverse cardiovascular outcome in CKD patients. Thus neprilysin inhibitors should be implemented with caution in patients with advanced CKD.

Background B-type natriuretic peptide (BNP) and the N-terminal proBNP (NT-proBNP) exhibit different evolution in chronic heart failure patients with reduced ejection fraction treated with Sacubitril/Valsartan; BNP increasing or remaining stable, while NT-proBNP decreases. However, how this difference translates upon acute decompensation is unknown. Case summary Herein, we described in a 78-year-old woman with chronic heart failure with reduced ejection fraction treated with Sacubitril/Valsartan who had acute decompensated heart failure (ADHF). BNP and NT-proBNP were markedly high during ADHF and showed parallel return to baseline level after clinical improvement. Discussion BNP and NT-proBNP retained similar value for the diagnosis of ADHF in patient treated with Sacubitril/Valsartan. These findings strongly suggest that either BNP or NT-proBNP can be used indifferently in this context, while their relative use is debated in chronic heart failure.

Background During general anaesthesia, intraoperative hypotension (IOH), defined as a mean arterial pressure (MAP) reduction of > 20%, is frequent and may lead to complications. Pulse oximetry is mandatory in the operating room, making the photoplethysmographic signal and parameters, such as relative dicrotic notch height (Dicpleth) or perfusion index (PI), readily available. The purpose of this study was to investigate whether relative variations of Dicpleth and PI could detect IOH during anaesthesia induction, and to follow their variations during vasopressor boluses. Methods MAP, Dicpleth, and PI were monitored at 1-min intervals during target control induction of anaesthesia with propofol and remifentanil in 61 subjects. Vasopressor infusion (norepinephrine or phenylephrine) was performed when hypotension occurred according to the decision of the physician. Results The delta in Dicpleth and PI accurately detected IOH, with areas under the receiver operating characteristic curves (AUC) of 0.86 and 0.83, respectively. The optimal thresholds were –19% (sensitivity 79%; specificity 84%) and 51% (sensitivity 82%; specificity 74%) for ΔDicpleth and ΔPI, respectively. There was no difference between the ROC of ΔDicpleth and ΔPI (P=0.22). Combining both ΔDicpleth and ΔPI further improved the hypotension detection power (AUC=0.91) with a sensitivity and specificity of 84%. MAP variations were correlated with ΔDicpleth and ΔPI during vasopressor infusion (r=0.73 and –0.62, respectively; P Conclusions The relative variation in Dicpleth and PI derived from the photoplethysmographic signal can be used as a non invasive, continuous, and simple tool to detect intraoperative hypotension, and to track the vascular response to vasoconstrictor drugs during induction of general anaesthesia. Clinical trial registration NCT03756935 .

In shock, the increase in cutaneous-to-arterial carbon dioxide partial pressure (Pc-aCO2) and the decrease in the perfusion index (PI) are related to macrovascular or microvascular alterations. We hypothesized that inducing cutaneous vasodilation and local perfusion with heat could provide a noninvasive tool to monitor microvascular reactivity.This study aimed to develop a noninvasive approach, the heating challenge (HC), to monitor the microvascular reactivity of patients with shock and to evaluate the potential relationship with outcome.After ethics committee agreement was obtained, 59 shock patients, including 37 septic shock, 22 non-septic shock (14 cardiogenic and eight hemorrhagic), 10 intensive care unit (ICU)-controls and 12 healthy volunteers, were included in this study. The HC consisted of heating the ear lobe PcCO2 sensor from 37° to 45° over 5 min and recording PcCO2 and PI variations (ΔPcCO2 and PImax/min). HC was performed on admission and during the first 48 h of hospitalization.Pc-aCO2 was significantly higher in shock patients than ICU-controls at baseline (P 0.05). HC led to a decrease in PcCO2 and an increase in PI in the healthy volunteers (ΔPcCO2 = -9.0 ± 4.6% and PImax/min = 5.5 ± 1.9). On admission, non-septic shock patients (cardiogenic and hemorrhagic shocks) had an HC response profile identical to that of healthy volunteers and ICU-controls. In contrast, septic shock patients had a lower ΔPcCO 2 and PImax/min compared to healthy volunteers and all other groups (P 0.05). After the first day, the combination of a Pc-aCO217 mm Hg with a positive ΔPcCO2 could predict mortality with a specificity of 82% and a sensitivity of 93%.HC appears to be a dynamic test to classify vascular reactivity alterations in shock. At baseline, HC results were impaired in septic patients and conserved in non-septic patients. After the first day, the association between Pc-aCO2 and ΔPcCO2 was strongly related to prognosis in shock patients.

Aims Heart failure (HF) is accompanied by major neuroendocrine changes including the activation of the natriuretic peptide (NP) pathway. Using the unique model of patients undergoing implantation of the CARMAT total artificial heart and investigating regional differences in soluble neprilysin (sNEP) in patients with reduced or preserved systolic function, we studied the regulation of the NP pathway in HF. Methods and results Venous blood samples from two patients undergoing replacement of the failing ventricles with a total artificial heart were collected before implantation and weekly thereafter until post-operative week 6. The ventricular removal was associated with an immediate drop in circulating NPs, a nearly total disappearance of circulating glycosylated proBNP and furin activity and a marked decrease in sNEP. From post-operative week 1 onwards, NP concentrations remained overall unchanged. In contrast, partial recoveries in glycosylated proBNP, furin activity, and sNEP were observed. Furthermore, while in patients with preserved systolic function (n = 6), sNEP concentrations in the coronary sinus and systemic vessels were similar (all P > 0.05), in patients with reduced left-ventricular systolic function, sNEP concentration, and activity were ∼three-fold higher in coronary sinus compared to systemic vessels (n = 21, all P Conclusion The heart plays a pivotal role as a regulator of the endocrine response in systolic dysfunction, not only by directly releasing NPs but also by contributing to circulating sNEP, which in turn determines the bioavailability of other numerous vasoactive peptides.

Introduction Sacubitril/valsartan that combines a neprilysin (NEP) inhibitor and an angiotensin receptor blocker (ARB) was shown superior to enalapril for the treatment of heart failure with reduced ejection fraction (HFrEF) (1). The inhibition of sNEP by Sacubitril on the processing of proBNP remains unclear. Objective The aim was to evaluate the evolution of cardiovascular biomarkers in patients who were switched from angiotensin converting enzyme inhibitor or ARB to sacubitril/valsartan and to evaluate the possible implication of the T71 proBNP glycosylation. Method We included 90 consecutive HFrEF patients who were treated with sacubitril/valsartan according to the current ESC guidelines in two university hospital. Plasma samples were collected before the first intake of sacubitril/valsartan, at day 30 (D30) and at day 90 (D90) for 60 patients who were selected for further paired analysis. Results sNEP activity decreased from D30 onward and being the lowest at D90. In contrast, there was no change in sNEP concentration. BNP and NT-proBNP plasma levels remained unchanged while high-sensitive troponin I decrease and GLP-1 increase from D90. We observed a gradual increase in T71 proBNP glycosylation. To assess the effect of T71 proBNP glycosylation on the processing of proBNP, we plotted the slope of the linear regression between BNP and NT-proBNP versus the median values of T71 proBNP glycosylation at each time points; the direct correlation observed (R2 = 0.99) strongly suggest that the independent evolution of BNP and NT-proBNP plasma levels in patients receiving sacubitril/valsartan results directly from the increase in T71 proBNP glycosylation. Conclusion The results showed that while sacubitril/valsartan decreased sNEP activity without no effect on the mNEP release. The increase in T71 proBNP glycosylation being responsible for the discrepancies between BNP and NT-proBNP plasma levels.

Cervical necrotizing fasciitis (CNF) is a severe and debilitating disease that requires intensive care unit (ICU) management and prompt surgical treatment to reduce morbidity and mortality. The aim of this study was to estimate the incidence and factors associated with severe complications of CNF. We reviewed the medical records of consecutive patients hospitalized in an ICU from 2007 to 2012. The data were collected retrospectively; initial cervical and thoracic computed tomography (CT) scans, performed on admission, were reviewed by an experienced and blinded radiologist to determine CNF complications. A cohort of 160 patients admitted for CNF was included. The following complications of CNF were found: bilateral extension of CNF (28 %), internal jugular vein thrombosis (21 %), descending necrotic effusion (14 %), mediastinitis (24 %), and mortality (4 %); 53 % had at least one complication, and 48 % had at least one cervical complication. On the basis of a univariate analysis, the significant independent factors are odynophagia, dyspnea, oral glucocorticoids intake before admission, and pharyngeal source. Oral nonsteroidal anti-inflammatory drug intake before admission does not have any impact. The initial CNF complications increased both the duration of mechanical ventilation and the length of stay in the ICU. On the basis of a multivariate analysis, the independent factors for severe complications are pharyngeal CNF and oral glucocorticoid intake before admission. Our study demonstrated that an initial cervico-thoracic CT scan revealed a high incidence of cervical and mediastinal CNF complications that all needed immediate management. Those severe complications might be avoidable as they were associated, at least partially, with prehospital oral glucocorticoid intake.

Introduction La cellulite est une maladie grave et delabrante, d’autant plus la cellulite cervico-faciale. Elle met en jeu le pronostic vital en l’absence de prise en charge rapide et multidisciplinaire, de par sa diffusion rapide le long des espaces aponevrotiques de la face et du cou, possible jusqu’au mediastin. D’autres complications sont decrites (thrombose jugulaire ou bilateralisation) mais leur incidence n’est pas connue. De plus, l’effet des traitements pris avant l’admission (AINS, corticoides, antibiotiques) pourrait etre associe a une augmentation des complications [1] . L’objectif de cette etude est d’evaluer l’incidence et les facteurs lies aux complications des cellulites cervico-faciales, dont le traitement avant admission. L’examen cle pour rechercher les complications a la phase initiale est le scanner injecte cervico-thoracique. Materiel et methodes Nous avons analyse retrospectivement tous les patients hospitalises en reanimation de 2007 a 2012 a l’hopital Lariboisiere apres accord du CEERB (n o 428-08). Les donnees ont ete recueillies retrospectivement et les tomodensitometries (CT) initiales ont ete relues en aveugle par un radiologue experimente, pour determiner l’origine de la cellulite et la presence de complications. Resultats Nous avons etudie les complications a la phase initiale de 160 patients admis pour cellulite cervico-faciale : bilateralite de la cellulite (28 %), thrombose de la veine jugulaire interne (21 %), coulees de necrose (14 %), mediastinite (24 %) et mortalite (4 %). Cinquante et un pour cent presentent au moins une complication dont 48 % de complications cervicales. En analyse univariee, les facteurs significatifs sont l’odynophagie, la dyspnee, la prise orale de glucocorticoides avant l’admission et l’origine pharyngee. On ne retrouve pas d’impact de la prise d’AINS dans l’incidence des complications. Les complications ont un impact significatif sur la duree de ventilation mecanique et de sejour en reanimation et la survenue d’autres infections. Les facteurs independants de complications en analyse multivariee sont l’origine pharyngee et la prise orale de glucocorticoides avant l’admission ( Tableau 1 ). Discussion Les complications doivent etre recherchees systematiquement. Le scanner en est l’examen cle. La prise orale de glucocorticoides avant l’admission a un impact important sur l’evolution des complications des cellulites cervico-faciales.

Introduction QSOX1 a ete identifie comme un marqueur diagnostic de l’insuffisance cardiaque aigue (ICA), plus performant que le BNP dans sa zone de grise chez l’homme. Des modeles murins ont permis de montrer que l’expression de QSOX1 est specifiquement induite dans le cœur au cours de l’ICA. De plus un stress cardiaque aigu par injection d’isoproterenol (ISO) associe a un « knock-down » de QSOX1 aggrave la dysfonction cardiaque des animaux traites. Nous avons voulu investiguer le role de QSOX1 au cours du developpement et analyser la reponse de QSOX1 dans un modele cellulaire HL-1 apres differents stress. Materiel et methodes Des souris knock-out pour QSOX1 et porteur de gene LacZ en aval du promoteur de QSOX1 ont ete utilises. Les animaux ont ete preleves a E12, E15 et E18, J1, J10, J21 et adultes. Le marquage par β-galactosidase a ete etudie au niveau macroscopique et cellulaire. Les ARNm intra-cardiaques de ces animaux ont ete etudies. Le modele cellulaire utilise une lignee de cardiomyocytes auriculaires immortalises. Les cellules ont ete soumises a plusieurs stress, tels que l’isoproterenol, la deprivation, l’hypoxie et le stress oxydant. Les ARNm en reponse a ces stress ont ete analyses par PCR quantitative ( QSOX1 , ANP , BNP , QSOX2 , et CTGF ). Resultats Au cours du developpement, QSOX1 est exprime de maniere stable au niveau de la jonction atrio-ventriculaire, de l’aorte, de l’artere pulmonaire, de l’arbre respiratoire et de l’uretere. L’absence de QSOX1 n’entraine pas de modification de l’expression des transcrits testes. Les experiences in vitro montre que le traitement des cellules HL-1 par l’ISO recapitule le phenotype in vivo, mais que le stress oxydant et l’hypoxie decouple l’induction de QSOX1 de celle des peptides natriuretiques ; la deprivation ayant un effet intermediaire ( Fig. 1 ). Discussion QSOX1 est exprime de maniere constante au cours du developpement dans le cœur et son absence n’entraine pas de phenotype cardiaque macroscopique ni moleculaire. Dans un modele in vitro, QSOX1 est regule de maniere independante des peptides natriuretiques.