title: Elevated Plasma B-Type Natriuretic Peptide Concentrations Directly Inhibit Circulating Neprilysin Activity in Heart Failure.
abstract: OBJECTIVE
  This study sought to hypothesize that elevated B-type natriuretic peptide (BNP) could act as an endogenous neprilysin inhibitor.
  
  
  BACKGROUND
  A hallmark of acute decompensated heart failure (ADHF) is the overproduction of natriuretic peptides (NPs) by stretched cardiomyocytes. Various strategies have been developed to potentiate the beneficial effect of the NPs, including the recent use of neprilysin angiotensin receptor inhibitors. Contrary to rodents, human BNP is poorly sensitive to neprilysin degradation while retaining affinity to neprilysin.
  
  
  METHODS
  We enrolled 638 patients presenting to the emergency department with acute dyspnea of which 468 had ADHF and 169 had dyspnea of noncardiac origin. We also included 46 patients with stable chronic heart failure (HF) and 10 age-matched healthy subjects. Plasma samples were collected within 4 h after emergency department admission. BNP, neprilysin concentration and activity, and the neprilysin substrate substance P concentration were measured.
  
  
  RESULTS
  We found that when plasma BNP rose above 916 pg/ml, neprilysin activity was markedly reduced (p < 0.0001) and stratified 95% of the population into 2 groups: BNP <916 pg/ml/neprilysin activity ≥ 0.21 nmol/ml/min and BNP ≥916 pg/ml/neprilysin activity <0.21 nmol/ml/min with very different prognoses. In vitro, BNP was responsible for neprilysin inhibition. Neprilysin activity was inversely correlated with the concentration of substance P (ρ = -0.80; p < 0.0001).
  
  
  CONCLUSIONS
  Besides being an effector of the cardiac response to cardiomyocyte stretching in ADHF, elevated plasma BNP is also an endogenous neprilysin inhibitor. A biologically relevant BNP threshold discriminates 2 populations of HF patients with different vasoactive peptide profiles and outcome. If confirmed, this may identify an important threshold for managing HF patients.
authors.affiliation: Inserm UMR-S 942, Paris, France; DHU FIRE, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vodovar
authors.affiliation: Inserm UMR-S 942, Paris, France; Department of Cardiology, EA3920, University Hospital Jean Minjoz, Besançon, France.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Séronde
authors.affiliation: Inserm UMR-S 942, Paris, France; Department of Emergency Medicine, Lariboisière Hospital, Paris, France.
authors.forename: Said
authors.initials: S
authors.lastname: Laribi
authors.affiliation: Inserm UMR-S 942, Paris, France; DHU Neurovasc, Paris, France; Department of Anaesthesiology and Intensive Care, Lariboisière Hospital, Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Gayat
authors.affiliation: Heart and Lung Center, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Johan
authors.initials: J
authors.lastname: Lassus
authors.affiliation: Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: James L
authors.initials: JL
authors.lastname: Januzzi
authors.affiliation: Emergency Department and Research Unit UR06SP21, Fattouma Bourguiba University Hospital, Monastir, Tunisia.
authors.forename: Riadh
authors.initials: R
authors.lastname: Boukef
authors.affiliation: Emergency Department and Research Unit UR06SP21, Fattouma Bourguiba University Hospital, Monastir, Tunisia.
authors.forename: Semir
authors.initials: S
authors.lastname: Nouira
authors.affiliation: Inserm UMR-S 942, Paris, France; DHU FIRE, Paris, France; Department of Biochemistry, Lariboisière Hospital, Paris, France; Centre for Biological Resources BB-0033-00064, Lariboisière Hospital, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Manivet
authors.affiliation: Inserm UMR-S 942, Paris, France; DHU FIRE, Paris, France; Department of Anaesthesiology and Intensive Care, Lariboisière Hospital, Paris, France.
authors.forename: Jane-Lise
authors.initials: JL
authors.lastname: Samuel
authors.affiliation: Inserm UMR-S 942, Paris, France; DHU FIRE, Paris, France; Department of Cardiology, Lariboisière Hospital, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Logeart
authors.affiliation: Inserm UMR-S 942, Paris, France; DHU FIRE, Paris, France; Department of Cardiology, Lariboisière Hospital, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Cohen-Solal
authors.affiliation: University of Otago, Christchurch, New Zealand; National University Health System, Singapore.
authors.forename: A Mark
authors.initials: AM
authors.lastname: Richards
authors.affiliation: Inserm UMR-S 942, Paris, France; DHU FIRE, Paris, France; Department of Biochemistry, Lariboisière Hospital, Paris, France; Centre for Biological Resources BB-0033-00064, Lariboisière Hospital, Paris, France. Electronic address: jean-marie.launay@lrb.aphp.fr.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.affiliation: Inserm UMR-S 942, Paris, France; DHU Neurovasc, Paris, France; Department of Anaesthesiology and Intensive Care, Lariboisière Hospital, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France. Electronic address: alexandre.mebazaa@lrb.aphp.fr.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mebazaa
mesh_terms: D015415:Biomarkers / Q000097:blood*; D006333:Heart Failure / Q000097:blood* / Q000401:mortality; D006801:Humans; D066298:In Vitro Techniques; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000097:blood; D010446:Peptide Fragments / Q000097:blood*; D011379:Prognosis; D012016:Reference Values; D015996:Survival Rate
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D015260:Neprilysin
keywords: BNP; BNP-mediated neprilysin inhibition; heart failure; neprilysin; substance P