Sacubitril/valsartan: beyond natriuretic peptides

Jagdeep S. S. Singh, Louise M. Burrell, Myriam Cherif, Iain B. Squire, Andrew L. Clark, Chim C. Lang (Lead / Corresponding author)

Research output: Contribution to journalReview articlepeer-review

30 Citations (Scopus)
533 Downloads (Pure)

Abstract

Natriuretic peptides, especially B-type natriuretic peptide (BNP), have primarily been regarded as biomarkers in heart failure (HF). However, they are also possible therapeutic agents due to potentially beneficial physiological effects. The angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, simultaneously augments the natriuretic peptide system (NPS) by inhibiting the enzyme neprilysin (NEP) and inhibits the renin-angiotensin-aldosterone system (RAAS) by blocking the angiotensin II receptor. It has been shown to improve mortality and hospitalisation outcomes in patients with HF due to left ventricular systolic dysfunction. The key advantage of sacubitril/valsartan has been perceived to be its ability to augment BNP, while its other effects have largely been overlooked. This article highlights the important effects of sacubitril/valsartan, beyond just the augmentation of BNP. First we discuss how NPS physiology differs between healthy individuals and those with HF by looking at mechanisms like the overwhelming effects of RAAS on the NPS, natriuretic peptide receptor desensitisation and absolute natriuretic deficiency. Secondly, this review explores other hormones that are augmented by sacubitril/valsartan such as, bradykinin, substance-P and adrenomedullin that may contribute to the efficacy of sacubitril/valsartan in HF. We also discuss concerns that sacubitril/valsartan may interfere with amyloid β homeostasis with potential implications on Alzheimer’s disease and macular degeneration. Finally, we explore the concept of ‘auto-inhibition’ which is a recently described observation that humans have innate NEP inhibitory capability when natriuretic peptide levels rise above a threshold. There is speculation that auto-inhibition may provide a surge of natriuretic and other vasoactive peptides to rapidly reverse decompensation. We contend that by pre-emptively inhibiting NEP, sacubitril/valsartan is inducing this surge earlier during decompensation, resulting in the better outcomes observed.
Original languageEnglish
Pages (from-to)1569-1577
Number of pages9
JournalHeart
Volume103
Issue number20
Early online date8 Jul 2017
DOIs
Publication statusPublished - Oct 2017

Keywords

  • Sacubitril/valsartan
  • angiotension receptor-neprilysin inhibitor
  • natriuretic peptides
  • B-type natriuretic peptide
  • mechanism of action
  • bradykinin
  • Alzheimer's disease

Fingerprint Dive into the research topics of 'Sacubitril/valsartan: beyond natriuretic peptides'. Together they form a unique fingerprint.

Cite this