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JACC Heart Fail. 2015 Aug;3(8):629-36. doi: 10.1016/j.jchf.2015.03.011.

Elevated Plasma B-Type Natriuretic Peptide Concentrations Directly Inhibit Circulating Neprilysin Activity in Heart Failure.

Author information

1
Inserm UMR-S 942, Paris, France; DHU FIRE, Paris, France.
2
Inserm UMR-S 942, Paris, France; Department of Cardiology, EA3920, University Hospital Jean Minjoz, Besançon, France.
3
Inserm UMR-S 942, Paris, France; Department of Emergency Medicine, Lariboisière Hospital, Paris, France.
4
Inserm UMR-S 942, Paris, France; DHU Neurovasc, Paris, France; Department of Anaesthesiology and Intensive Care, Lariboisière Hospital, Paris, France.
5
Heart and Lung Center, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
6
Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts.
7
Emergency Department and Research Unit UR06SP21, Fattouma Bourguiba University Hospital, Monastir, Tunisia.
8
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.
9
Inserm UMR-S 942, Paris, France; DHU FIRE, Paris, France; Department of Anaesthesiology and Intensive Care, Lariboisière Hospital, Paris, France.
10
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.
11
University of Otago, Christchurch, New Zealand; National University Health System, Singapore.
12
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.
13
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.

Abstract

OBJECTIVES:

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.

KEYWORDS:

BNP; BNP-mediated neprilysin inhibition; heart failure; neprilysin; substance P

PMID:
26251090
DOI:
10.1016/j.jchf.2015.03.011
[Indexed for MEDLINE]
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