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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 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.

BackgroundCardiac rehabilitation (CR) improves the symptoms, exercise capacity and quality of life of chronic heart failure (CHF) patients. Its effects on new plasma biomarkers of prognostic importance are unknown. The present study aimed at analysing the effects of a structured CR programme on plasma cardiac biomarkers in a large population of patients with CHF and reduced left ventricular ejection fraction (LVEF).MethodsWe enrolled 107 consecutive CHF patients with LVEF ≤ 45% in an ambulatory CR programme. Peak VO2 and plasma levels of Galectin-3, mid-regional proANP (MR-proADM), soluble suppressor of tumorigenicity 2 (sST2) and mid-regional pro-adrenomedullin (MR-proANP) were assessed at inclusion and at the end of CR. Twenty-four unenrolled patients were managed with standard medical care and evaluated over the same period (no-CR group).ResultsGalectin-3, sST2, MR-proADM and MR-proANP plasma levels decreased after CR, with respective median reductions of 6.3% for Galectin 3 (p

Background Acute myocardial infarction (MI) is associated with a strong inflammatory response resulting from the cardiac insult. On the other hand, such an inflammation may lead and/or worsen adverse left ventricular (LV) remodeling after MI. Among the markers of inflammation is Indoleamine 2,3-dioxygenase (IDO), which production is induced upon inflammation. IDO catalyzes the transformation of tryptophane into kynurenine. Purpose We tested plasma IDO activity as a predictor of LV remodeling post-MI. Methods The PREGICA cohort recruited prospectively patients who were admitted because of first acute myocardial infarction. Blood samples were collected on admission, at day 4 and at day 6. Echocardiography and cardiac MRI were obtained at day 4 and at 6 months. To be included, the number of akinetic LV wall segments had to be ≥3 on 17 at day 4. IDO activity was the ratio between kynurenine and tryptophane measured by high pressure liquid chromatography coupled with fluorimetric detection. Remodelers were identified as patients with a variation of end-diastolic left ventricular volume (EDLVV) between day 4 and 6 months post-MI >20%. Results Among the 292 patients studied (mean age 57y, mean necrosis size 26% on MRI), the median increase in EDLVV was 16.7% and 137 (47%) were classified as remodelers. On admission as well as at day 4, IDO activity was significantly higher in remodelers (8.2±4.2% vs 5.3±2.5% and 8.7±5.7% vs 5.6±4.4%, p Conclusions IDO activity appears as a promising biomarker for the prediction of LV remodeling after MI. Its specific role in postMI remodeling pathways requires further investigation. Acknowledgement/Funding PHRC national

Neprilysin (also known as the neutral endopeptidase, EC 3.4.24.11) is a ubiquitous transmembrane and circulating protease with a broad range of substrates. Those include natriuretic peptides (NPs), vasoactive peptides (e.g. endothelin-1, bradykinins), neuropeptides (e.g. substance P, enkephalins), and the β-amyloid (Aβ) peptide amongst others.1,2 Given the central role played by neprilysin in the metabolism of cardiovascular peptides and the Aβ peptide, neprilysin has emerged as a pharmaceutical target of interest, both in the fields of cardiovascular disease (CVD) and Alzheimer's disease (AD). However, the strategies deployed in each field are completely opposite and one may wonder the rationale of neprilysin as a practical pharmaceutical target after all, since the populations suffering from CVD and AD are overlapping. In cardiovascular diseases, neprilysin gained interest as responsible for the degradation of NPs and other cardiovascular peptides.2 The development of neprilysin inhibitors (NEPi) have aimed at prolonging and potentiating the beneficial effects of vasoactive/NPs. However, since neprilysin has a broad range of substrates with antagonist effects (vasoconstrictor and vasodilator), the use of sole NEPi (candoxatrilat) was ineffective for the treatment of hypertension due to an aldosterone-independent increase in Angiotensin II.3 To overcome this limitation, NEPi were combined either with an inhibitor of angiotensin-converting enzyme (ACEi, e.g. omapatrilat4) or an angiotensin-receptor blocker (ARB, LCZ6965). Both omapatrilat6 and LCZ6967 were found, respectively, superior to enalapril (ACEi) and valsartan (ARB), for the treatment of hypertension. In the recent PARADIGM-HF trial, chronic administration of LCZ696 was found superior to enalapril for improving outcome in the treatment of chronic heart failure with reduced ejection fraction ( Figure 1 ).5 Recently, this beneficial effect on …

Background Increases in plasma B-type natriuretic peptide (BNP) concentrations in those with acutely decompensated heart failure (ADHF) has been mainly attributed to an increase in NPPB gene transcription. Recently, proBNP glycosylation has emerged as a potential regulatory mechanism in the production of amino-terminal (NT)-proBNP and BNP. The aim of the present study was to investigate proBNP glycosylation, and corin and furin activities in ADHF patients. Methods and results Plasma levels of proBNP, NT-proBNP, BNP, as well as corin and furin concentration and activity were measured in a large cohort of 683 patients presenting with ADHF ( n = 468), non-cardiac dyspnoea (non-ADHF: n = 169) and 46 patients with stable chronic heart failure (CHF); the degree of plasma proBNP glycosylation was assessed in a subset of these patients (ADHF: n = 49, non-ADHF: n = 50, CHF: n = 46). Our results showed a decrease in proBNP glycosylation in ADHF patients that paralleled NT-proBNP overproduction ( ρ = −0.62, P 0.88), and negatively related to the degree of proBNP glycosylation (ρ = −0.62, P < 0.001). Conclusion These comprehensive results provide a paradigm for the post-translational modification of natriuretic peptides in ADHF: as proBNP glycosylation decreases, furin activity increases. This synergistically amplifies the processing of proBNP into BNP and NT-proBNP. Clinical Trial Registration . Identifier: [NCT01374880][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01374880&atom=%2Fehj%2Fearly%2F2014%2F10%2F06%2Feurheartj.ehu314.atom

The interest in heart failure (HF)5 care, and particularly the use of biomarkers such as B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), has been stimulated of late by the concept that novel compounds such as angiotensin receptor neprisylin inhibitor (ARNi) LCZ696 (valsartan/Sacubitril) can markedly improve the treatment of patients with HF (1). Although many questions remain, the recent Paradigm-HF trial demonstrated improvement in all HF outcomes with this compound, which is a combination of an angiotensin receptor blocker (valsartan) and a neprilysin inhibitor (Sacubitril). It has been suggested that the mechanism by which this drug works is by inhibiting the neutral endopeptidases that degrade active BNP1–32. The trial data suggest that such compounds increase BNP values but diminish NT-proBNP values (2). However, this is no doubt overly simplistic given ( a ) the complexity of the natriuretic peptide system; ( b ) that neprilysin inhibits the breakdown of multiple potentially important peptides that participate in the pathogenesis of congestive HF, including adrenomedullin, substance P, atrial natriuretic peptide, bradykinin, endothelin 1, and angiotensin II; and ( c ) that neprilysin has only modest documented effects directly on human BNP (3). These advances demand that we begin to bring additional insights into our understanding of the natriuretic peptide system and clarify what is being measured in blood by commercial assays for BNP and NT-proBNP. Much of the focus about what is being measured has been on BNP, and we know that BNP assays are heterogeneous and measure both proBNP and the breakdown products of BNP1–32. It has been suggested by some that proBNP is the major form detected by BNP assays (4). However, a mass spectrometry study showed that BNP immunoassay data measurements in patients with HF correlated not with proBNP or BNP1–32, which was detectable in only 56% …

Purpose: Studies have shown that aldosterone would have angiogenic effects, and therefore would be beneficial in the context of cardiovascular diseases. We thus investigated the potential involvement of aldosterone in triggering a cardiac angiogenic response in the context of type-2 diabetes, and the molecular pathways involved. Procedure: 3 week-old male mice, overexpressing aldosterone-synthase (AS), and their controls littermates (WT) were fed with a standard or high fat, high sucrose (HFHS) diet. After 6 months of diet, mice were sacrificed and cardiac samples were assayed by RT-PCR, immuno-blotting and -histology. Findings: HFHS-diet induced type-2 diabetes (D) in WT and AS mice. VEGFa mRNAs were decreased in WT-D (-43%, P

QSOX1 was identified as a new biomarker of acute heart failure (AHF). Using a proteomics strategy on plasma, QSOX1, which exists in 2 isoforms (short S and long L form), emerged as a promising marker to differentiate dyspnea caused by AHF from other syndromes. Preliminary results from our group suggested a protective role of OSOX1 cardiac induction in AHF. We developed an AHF murine model by isoproterenol injections. To further study the role of QSOX1 during AHF, we used antisense oligonucleotides (AOs) and we generated a knock-out (KO) mouse for QSOX1. AHF was provoked by two daily injections of 150 mg/kg of Isoproterenol (ISO) for two days; control mice (C) received NaCl 0.09‰ injections. Mice were sacrificed the third day, after cardiac function has been assessed by echocardiography. To silence QSOX1 expression, mice were treated by intraperitoneal injection of antisense oligonucleotides (AOs) for QSOX1. QSOX1 cardiac expression was analyzed by RT-qPCR, immunoblotting and immonofluorescence. In parallel, embryonic stem cell clone QSOX1tm1a (KOMP), in which the QSOX1 gene is invalidated, were injected into mouse blastocysts (SEAT platform, France). The KO constructs contain a promoter-less lacZ gene that is under the control of the QSOX1 regulatory sequences. QSOX1+/- heterozygotes mice were obtained from chimeric mice. The ISO mice exhibited a decrease in shortening fraction (C = 35.0 ± 0.4 %; ISO = 27.2 ± 3.3 %; p