Neprilysin inhibition in heart failure: mechanisms and substrates beyond modulating natriuretic peptides

Emilia D'Elia, Attilio Iacovoni, Muthiah Vaduganathan, Ferdinando L. Lorini, Stefano Perlini, Michele Senni

Research output: Contribution to journalReview articlepeer-review


The autonomic nervous system, the renin–angiotensin–aldosterone system, and the natriuretic peptide system represent critical regulatory pathways in heart failure and as such have been the major targets of pharmacological development. The introduction and approval of angiotensin receptor neprilysin inhibitors (ARNi) have broadened the available drug treatments of patients with chronic heart failure with reduced ejection fraction. Neprilysin catalyses the degradation of a number of vasodilator peptides, including the natriuretic peptides, bradykinin, substance P, and adrenomedullin, as well as vasoconstrictor peptides, including endothelin-1 and angiotensin I and II. We review the multiple, potentially competing, substrates for neprilysin inhibition, and the resultant composite clinical effects of ARNi therapy. A mechanistic understanding of this novel therapeutic class may provide important insights into the expected on-target and off-target effects when this agent is more widely prescribed.

Original languageEnglish
Pages (from-to)710-717
Number of pages8
JournalEuropean Journal of Heart Failure
Issue number6
Publication statusPublished - Jun 1 2017


  • Biomarkers
  • Heart failure
  • Neprilysin
  • Neurohormonal activation
  • Pharmacology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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