Nicolas Vodovar1, Marie-France Séronde2, Said Laribi3, Etienne Gayat4, Johan Lassus5, James L Januzzi6, Riadh Boukef7, Semir Nouira7, Philippe Manivet8, Jane-Lise Samuel9, Damien Logeart10, Alain Cohen-Solal10, A Mark Richards11, Jean-Marie Launay12, Alexandre Mebazaa13. 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.
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, humanBNP 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: Michaela Auer-Grumbach; Stefan Toegel; Maria Schabhüttl; Daniela Weinmann; Catharina Chiari; David L H Bennett; Christian Beetz; Dennis Klein; Peter M Andersen; Ilka Böhme; Regina Fink-Puches; Michael Gonzalez; Matthew B Harms; William Motley; Mary M Reilly; Wilfried Renner; Sabine Rudnik-Schöneborn; Beate Schlotter-Weigel; Andreas C Themistocleous; Jochen H Weishaupt; Albert C Ludolph; Thomas Wieland; Feifei Tao; Lisa Abreu; Reinhard Windhager; Manuela Zitzelsberger; Tim M Strom; Thomas Walther; Steven S Scherer; Stephan Züchner; Rudolf Martini; Jan Senderek Journal: Am J Hum Genet Date: 2016-09-01 Impact factor: 11.025
Authors: Melissa A Lyle; Seethalakshmi R Iyer; Margaret M Redfield; Yogesh N V Reddy; G Michael Felker; Thomas P Cappola; Adrian F Hernandez; Christopher G Scott; John C Burnett; Naveen L Pereira Journal: JACC Heart Fail Date: 2019-08-07 Impact factor: 12.035
Authors: Mattia Arrigo; Nicolas Vodovar; Hélène Nougué; Malha Sadoune; Chris J Pemberton; Pamela Ballan; Pierre-Olivier Ludes; Nicolas Gendron; Alain Carpentier; Bernard Cholley; Philippe Bizouarn; Alain Cohen-Solal; Jagmeet P Singh; Jackie Szymonifka; Christian Latremouille; Jane-Lise Samuel; Jean-Marie Launay; Julien Pottecher; A Mark Richards; Quynh A Truong; David M Smadja; Alexandre Mebazaa Journal: Eur Heart J Date: 2018-05-21 Impact factor: 29.983