Atrial Natriuretic Peptide and Treatment With Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction

Abstract

Objectives: This study sought to assess associations between longitudinal change in atrial natriuretic peptide (ANP) and reverse cardiac remodeling following initiation of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF).

Background: Neprilysin inhibition results in an increase of several vasoactive peptides that may mediate the beneficial effects of sacubitril/valsartan, including ANP.

Methods: In a prospective study of initiation and titration of sacubitril/valsartan in patients with HFrEF, blood was collected at scheduled time points into tubes containing protease inhibitors. This pre-specified exploratory analysis included patients in whom ANP was measured at baseline and serially through 12 months of treatment.

Results: Among 144 participants (mean age: 64.5 years; left ventricular ejection fraction: 30.8%), following initiation of sacubitril/valsartan, there was an early and significant increase in ANP, with the majority of rise from 99 pg/ml at baseline to 156 pg/ml at day 14 (p < 0.001). There was a further trend toward a second increase from day 30 to day 45 (p = 0.07). At maximal rise, ANP had doubled. In longitudinal analyses, early rise in ANP was followed by a subsequent increase in urinary cycle guanosine monophosphate. Larger early increase in ANP was associated with larger later improvements in left ventricular ejection fraction and left atrial volume index (p < 0.001 for both).

Conclusions: Concentrations of ANP doubled after initiation of sacubitril/valsartan in patients with HFrEF. Larger early increases in ANP were associated with a greater magnitude of subsequent reverse cardiac remodeling. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

Keywords: ANP; HFrEF; cardiac remodeling; sacubitril/valsartan.

Conflict of interest statement

Funding Support and Author disclosures This work was supported by Novartis Pharmaceuticals, Inc. Dr. Januzzi is supported in part by the Hutter Family Professorship. Dr. Prescott is an employee of Novartis Pharmaceuticals, Inc. Dr. Maisel has received consulting income from Abbott Vascular, Ortho Clinical Diagnostics, and Novartis. Dr. Felker has received research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Merck, Cytokinetics, and Roche Diagnostics and has acted as a consultant to Novartis, Amgen, Bristol Myers Squibb, Medtronic, Cardionomic, Relypsa, V-Wave, Myokardia, Innolife, EBR Systems, Arena, Abbott, Sphingotec, Roche Diagnostics, Alnylam, LivaNova, and SC Pharma. Dr. Butler has received research support from the National Institutes of Health, Patient-Centered Outcomes Research Institute, and the European Union; and serves as a consultant for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Innolife, Janssen, LinaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, V-Wave Limited, and Vifor. Dr. Piña has received consulting income from Relypsa and Novartis. Dr. Ibrahim has received honoraria from Novartis Pharmaceuticals and Roche Diagnostics. Dr. Abbas is an employee of Novartis Pharmaceuticals, Inc. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institute of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. Dr. Januzzi is a Trustee of the American College of Cardiology; has received grant support from Novartis Pharmaceuticals and Abbott Diagnostics and consulting income from Abbott Diagnostics, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/Data Safety Monitoring Boards for Abbott, AbbVie, Amgen, Bayer, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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