This article refers to 'Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study' by H. Nougué et al., published in this issue on pages 598-605.A compellingly positive, large randomized controlled therapeutic trial, augmented by many ancillary studies and sub-analyses, indicates therapy based on combined angiotensin II type 1 receptor blockade and neprilysin inhibition (ARNI) confers an approximate 20% benefit for all major clinical endpoints in chronic heart failure (HF) compared to treatment based on angiotensin-converting enzyme inhibition (ACEI). 1 Patients across a broad range of age, co-morbidities and concurrent treatments enjoy net benefit from ARNI over periods of at least 1-2 years, which seemingly constitutes the greatest advance in the pharmacotherapy of HF made in the last 25 years. The treatment has received full endorsement from authoritative international clinical guidelines and will eventually be prescribed to millions of patients worldwide in expectation of major benefit. 2,3 Neprilysin cleaves cardiac natriuretic peptides and it is generally assumed augmentation of intact bioactive natriuretic peptides in plasma and tissues underlies the beneficial effects of neprilysin inhibition (NEPi). It is important we understand the mechanisms underpinning the biological effects of ARNI in order to anticipate both advantageous and adverse effects and to potentially improve on the current ARNI options and garner further benefits from later drug modifications. The B-type cardiac peptides, B-type natriuretic peptide (BNP) and N-terminal pro BNP (NT-proBNP), are the best known natriuretic peptides in the clinical community having had long-term exposure as well-established diagnostic and prognostic biomarkers and as therapy in the form of human recombinant BNP (nesiritide). Subsequently BNP has been invoked as mediating important effects in ARNI and early neurohormonal sub-studies in ARNI therapy have focused upon these peptides. 4 However, as emphasized by Nougué et al. 5 in the current issue of the Journal, BNP is not the key natriuretic peptide affected by, or mediating the effects of, NEPi and natriuretic peptides are not the sole set of potentially important neprilysin substrates involved.The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Heart Failure or of the European Society of Cardiology.Nougué et al. 5 studied 73 patients with chronic HF undergoing conversion from ACEI-based to ARNI-based treatment with sacubitril/valsartan. Reduction in New York Heart Association class and improved echocardiographic findings observed over 90 days reflected clinical benefit from the new treatment. A dose-dependent fall in plasma neprilysin activity was associated with increased plasma concentrations of substance P, atrial natriuretic peptide (ANP), and glucagon-like peptide-1 (GLP-1) and decreased fructosamine. Soluble ST2 and cardiac troponin also fell. Whilst ANP r...