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

Abstract

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.

The Effects of Sacubitril/Valsartan on Clinical, Biochemical and Echocardiographic Parameters in Patients with Heart Failure with Reduced Ejection Fraction: The “Hemodynamic Recovery”

“…Coherently with echocardiographic measurements, neprilysin inhibition mediated by sacubitril acutely amplified the hemodynamic effects of natriuretic peptides determining natriuresis and vasodilation [11,12] which resulted in decreased neurohormonal activation as our data have demonstrated by NT-proBNP concentrations abatement at follow-up.…”

June 2017 at a glance: biomarkers and medical treatment

“…A paradigm shift has occurred after the demonstration of its superiority over enalapril in patients with HFrEF . Neprilysin inhibition causes an increase of many different peptides, including atrial, brain, C‐type natriuretic peptides (ANP, BNP, CNP), bradykinin, substance P, adrenomedullin, whose effects on the cardiovascular system and their role as biomarkers are nicely summarized in this issue of our journal …”

“…D'Elia et al review the neurohormonal changes induced by the administration of an angiotensin receptor‐neprilysin inhibitor (ARNI), sacubitril/valsartan . A paradigm shift has occurred after the demonstration of its superiority over enalapril in patients with HFrEF .…”

Neprilysin Inhibitors as a New Approach in the Treatment of Right Heart Failure in the Course of Chronic Obstructive Pulmonary Disease. Response to the Letter of Siniorakis et al.

“…The PARADIGM-HF study showed that the number of confirmed angioedema cases for sacubitril/ /valsartan as compared to enalapril during a double-blind trial was 19 (0.45%) vs 10 (0.24%) (the relative risk was 1.9 [95%CI 0.8-4.5], thus the risk of occurrence of this adverse reaction was assessed as low. It is worth mentioning that no increased risk of angioedema was observed in current smokers administered sacubitril/valsartan or enalapril [8].…”