Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study
- PMID: 30520545
- DOI: 10.1002/ejhf.1342
Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study
Abstract
Aim: This study aimed at evaluating the effects of sacubitril/valsartan on neprilysin (NEP), and the metabolism of natriuretic peptides in heart failure (HF) and providing additional mechanistic information on the mode of action of the drug.
Methods and results: We enrolled 73 chronic HF patients who were switched from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to sacubitril/valsartan. In addition to clinical and echocardiographic assessment, plasma biomarkers were measured at baseline, day 30 and day 90 after initiation of treatment. Sacubitril/valsartan led to decrease in New York Heart Association class and improvement of echocardiographic parameters, as well as a dose-dependent decrease in soluble NEP (sNEP) activity, while sNEP concentration remained unchanged. Neprilysin inhibition translated into an increase in its substrates such as atrial natriuretic peptide (ANP), substance P, and glucagon-like peptide 1, the latter translating into a decrease in fructosamine. Cardiac troponin and soluble ST2 levels, biomarkers of HF severity unrelated to NEP metabolism also decreased. While there was a ∼4-fold increase in ANP, we observed no change in plasma brain natriuretic peptide (BNP) and plasma BNP activity, and a mild decrease in N-terminal proBNP (NT-proBNP) concentrations. Finally, we found a progressive increase in the relationship between BNP and NT-proBNP, which strongly correlated with an increase in T71 proBNP glycosylation (R2 = 0.94).
Conclusion: Sacubitril/valsartan rapidly and strongly reduced sNEP activity, leading to an increase in levels of NEP substrates. These data suggest a pleiotropic favourable impact of sacubitril/valsartan on the metabolism of HF patients with ANP rather than BNP as major effectors amongst natriuretic peptides.
Keywords: Atrial natriuretic peptide; Brain natriuretic peptide; Heart failure with reduced ejection fraction; Neprilysin; Sacubitril/valsartan.
© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.
Comment in
-
Beneficial effects of sacubitril/valsartan in heart failure with reduced ejection fraction: pas à cause du BNP?Eur J Heart Fail. 2019 May;21(5):609-612. doi: 10.1002/ejhf.1451. Epub 2019 Mar 4. Eur J Heart Fail. 2019. PMID: 30834697 Free PMC article. No abstract available.
-
How does neprilysin inhibition in heart failure work?Eur J Heart Fail. 2019 May;21(5):606-608. doi: 10.1002/ejhf.1454. Epub 2019 Mar 18. Eur J Heart Fail. 2019. PMID: 30884077 No abstract available.
Similar articles
-
B-Type Natriuretic Peptide During Treatment With Sacubitril/Valsartan: The PARADIGM-HF Trial.J Am Coll Cardiol. 2019 Mar 26;73(11):1264-1272. doi: 10.1016/j.jacc.2019.01.018. Epub 2019 Mar 4. J Am Coll Cardiol. 2019. PMID: 30846338 Free PMC article. Clinical Trial.
-
Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure: Secondary Analysis of the Open-label Extension of the PIONEER-HF Trial.JAMA Cardiol. 2020 Feb 1;5(2):202-207. doi: 10.1001/jamacardio.2019.4665. JAMA Cardiol. 2020. PMID: 31825471 Free PMC article. Clinical Trial.
-
Effect of Neprilysin Inhibition on Various Natriuretic Peptide Assays.J Am Coll Cardiol. 2019 Mar 26;73(11):1273-1284. doi: 10.1016/j.jacc.2018.12.063. J Am Coll Cardiol. 2019. PMID: 30898202
-
Pharmacokinetic, pharmacodynamic, and antihypertensive effects of the neprilysin inhibitor LCZ-696: sacubitril/valsartan.J Am Soc Hypertens. 2017 Jul;11(7):461-468. doi: 10.1016/j.jash.2017.04.012. Epub 2017 May 25. J Am Soc Hypertens. 2017. PMID: 28652105 Review.
-
Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.Circulation. 2016 Mar 15;133(11):1115-24. doi: 10.1161/CIRCULATIONAHA.115.018622. Circulation. 2016. PMID: 26976916 Free PMC article. Review.
Cited by
-
Does Speckle Tracking Transthoracic Echocardiography Indicate Subtle Changes in Left Ventricular Function in Heart Failure Patients with Reduced Ejection Fraction Treated by Sacubitril-valsartan?J Cardiovasc Echogr. 2024 Jan-Mar;34(1):19-24. doi: 10.4103/jcecho.jcecho_5_24. Epub 2024 Apr 26. J Cardiovasc Echogr. 2024. PMID: 38818314 Free PMC article.
-
Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction.Circ Heart Fail. 2024 Feb;17(2):e011146. doi: 10.1161/CIRCHEARTFAILURE.123.011146. Epub 2024 Feb 1. Circ Heart Fail. 2024. PMID: 38299345 Free PMC article.
-
Impact of sacubitril/valsartan on cardiac and systemic hypoxia in chronic heart failure.iScience. 2023 Nov 23;27(1):108520. doi: 10.1016/j.isci.2023.108520. eCollection 2024 Jan 19. iScience. 2023. PMID: 38161412 Free PMC article.
-
Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy.iScience. 2023 Oct 12;26(11):108190. doi: 10.1016/j.isci.2023.108190. eCollection 2023 Nov 17. iScience. 2023. PMID: 37953952 Free PMC article.
-
Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective.J Cell Mol Med. 2024 Jan;28(2):e17993. doi: 10.1111/jcmm.17993. Epub 2023 Oct 17. J Cell Mol Med. 2024. PMID: 37847125 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous