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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.

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.