Author + information
- Received December 3, 2014
- Revision received February 23, 2015
- Accepted March 6, 2015
- Published online August 1, 2015.
- Nicolas Vodovar, PhD∗,†,
- Marie-France Séronde, MD, PhD∗,‡,
- Said Laribi, MD, PhD∗,§,
- Etienne Gayat, MD, PhD∗,‖,¶,
- Johan Lassus, MD, PhD#,
- James L. Januzzi Jr., MD∗∗,
- Riadh Boukef, MD††,
- Semir Nouira, MD††,
- Philippe Manivet, PharmD, PhD∗,†,‡‡,§§,
- Jane-Lise Samuel, MD, PhD∗,†,¶,
- Damien Logeart, MD, PhD∗,†,‖‖,¶¶,
- Alain Cohen-Solal, MD, PhD∗,†,‖‖,¶¶,
- A. Mark Richards, MD∗∗∗,†††,
- Jean-Marie Launay, PharmD, PhD∗,†,‡‡,§§∗∗ (, )
- Alexandre Mebazaa, MD, PhD∗,‖,¶,¶¶∗ (, )
- GREAT Network
- ∗Inserm UMR-S 942, Paris, France
- †DHU FIRE, Paris, France
- ‡Department of Cardiology, EA3920, University Hospital Jean Minjoz, Besançon, France
- §Department of Emergency Medicine, Lariboisière Hospital, Paris, France
- ‖DHU Neurovasc, Paris, France
- ¶Department of Anaesthesiology and Intensive Care, Lariboisière Hospital, Paris, France
- #Heart and Lung Center, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland
- ∗∗Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
- ††Emergency Department and Research Unit UR06SP21, Fattouma Bourguiba University Hospital, Monastir, Tunisia
- ‡‡Department of Biochemistry, Lariboisière Hospital, Paris, France
- §§Centre for Biological Resources BB-0033-00064, Lariboisière Hospital, Paris, France
- ‖‖Department of Cardiology, Lariboisière Hospital, Paris, France
- ¶¶Paris Diderot University, Sorbonne Paris Cité, Paris, France
- ∗∗∗University of Otago, Christchurch, New Zealand
- †††National University Health System, Singapore
- ↵∗Reprint requests and correspondence:
Dr. Alexandre Mebazaa, Department of Anesthesiology and Intensive Care, Lariboisière Hospital, 2, Rue A. Paré, 75475 Paris, Cedex 10, France.
- ↵∗∗Dr. Jean-Marie Launay, Department of Biochemistry, Lariboisière Hospital, 2, Rue A. Paré, 75475 Paris, Cedex 10, France.
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.
This work was financed by Inserm and research grants received from Roche, Thermo Fisher, the Fondation Cœur et Recherche, the National University of Singapore–University Sorbonne Paris Cité (NUS-USPC) Alliance, and the DHU FIRE. Dr. Vodovar is supported by a post-doctoral fellowship from the European Commission’s Seventh Framework program under grant agreement No. 305507 (HOMAGE). Dr. Gayat has received travel fees from Servier; and has received lecture fees from Bristol-Myers Squibb. Dr. Lassus has received honoraria from Roche Diagnostics, Novartis, Vifor Pharma, Bayer, Orion Pharma, and Pfizer. Dr. Januzzi has received research grants from Siemens, Singulex, and Thermo Fisher; and has received consulting fees from Roche, Critical Diagnostics, Sphingotc, Amgen, and Novartis. Dr. Logeart has received honorarium from Biotronic, Boston Scientific, Cordis, Roche Diagnostics, Novartis, Pfizer, and Servier. Dr. Solal has received speaker and consulting fees from Actelion, Ipsen, Sorin, Abbott, Novartis, Thermo Fisher, Alere, Pfizer, Vifor, Amgen, Servier, Bayer, Sanofi, and Boehringer Ingelheim. Dr. Richards has received research grants, speaker fees, and travel support from Roche Diagnostics and Alere. Dr. Mebazaa has received speaker honoraria from Cardiorentis, The Medicines Company, Critical Diagnostics, Vifor, Orion, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Vodovar and Séronde contributed equally to this work.
- Received December 3, 2014.
- Revision received February 23, 2015.
- Accepted March 6, 2015.
- American College of Cardiology Foundation