Neprilysin Inhibitors in Heart Failure: The Science, Mechanism of Action, Clinical Studies, and Unanswered Questions

Abstract

This article provides a contemporary review and a new perspective on the role of neprilysin inhibition in heart failure (HF) in the context of recent clinical trials and addresses potential mechanisms and unanswered questions in certain HF patient populations. Neprilysin is an endopeptidase that cleaves a variety of peptides such as natriuretic peptides, bradykinin, adrenomedullin, substance P, angiotensin I and II, and endothelin. It has a broad role in cardiovascular, renal, pulmonary, gastrointestinal, endocrine, and neurologic functions. The combined angiotensin receptor and neprilysin inhibitor (ARNi) has been developed with an intent to increase vasodilatory natriuretic peptides and prevent counterregulatory activation of the angiotensin system. ARNi therapy is very effective in reducing the risks of death and hospitalization for HF in patients with HF and New York Heart Association functional class II to III symptoms, but studies failed to show any benefits with ARNi when compared with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker in patients with advanced HF with reduced ejection fraction or in patients following myocardial infarction with left ventricular dysfunction but without HF. These raise the questions about whether the enzymatic breakdown of natriuretic peptides may not be a very effective solution in advanced HF patients when there is downstream blunting of the response to natriuretic peptides or among post-myocardial infarction patients in the absence of HF when there may not be a need for increased natriuretic peptide availability. Furthermore, there is a need for additional studies to determine the long-term effects of ARNi on albuminuria, obesity, glycemic control and lipid profile, blood pressure, and cognitive function in patients with HF.

Keywords: ACE, angiotensin-converting enzyme; ANP, atrial natriuretic peptide; ARB, angiotensin receptor blocker; ARN, angiotensin receptor–neprilysin; ARNi; Aβ, amyloid beta; BNP, brain natriuretic peptide; BP, blood pressure; CSF, cerebrospinal fluid; EF, ejection fraction; FDA, U.S. Food and Drug Administration; GFR, glomerular filtration rate; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LV, left ventricular; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NEP inhibitor; NT-proBNP, N-terminal pro–brain natriuretic peptide; NYHA, New York Heart Association; PDE, phosphodiesterase; RAAS, renin-angiotensin-aldosterone system; UACR, urinary albumin/creatine ratio; angiotensin receptor–neprilysin inhibitor; cGMP, cyclic guanosine monophosphate; eGFR, estimated glomerular filtration rate; heart failure; neprilysin; neprilysin inhibitor; sacubitril; sacubitril/valsartan.

Graphical abstract

Central Illustration

Peptide Substrates for Neprilysin, a Zinc-Dependent Membrane Endopeptidase That Cleaves Peptides Peptides that are important for cardiovascular and other systems are included. These include vasodilatory peptides (listed on the left) such as natriuretic peptides, bradykinin, adrenomedullin, and substance P; vasoconstrictor peptides (listed on the right) such as angiotensin I and II, endothelin, and neurotensin; and other peptides (listed at the bottom) implicated in pathways related to amyloid deposition, pain sensorium, mood, gastrointestinal processes, and metabolism such as amyloid beta peptide, enkephalins, endomorphins, corticotropin, neuropeptide Y, gastrin, cholecystokinin 8, somatostatin, glucagon, vasoactive intestinal peptide, and oxytocin.

Figure 1

Tissue and Organ Distribution of Neprilysin Neprilysin is widely distributed in most mammalian tissues but with varying expression. For example, neprilysin levels tend to be lower in brain than in kidney, where they are mostly expressed in renal tubules. NEP = neprilysin.

Figure 2

Balance of Neprilysin Inhibition Neprilysin inhibition can result in prevention of the degradation of peptides with potential beneficial effects (benefits, shown at the right) vs adverse effects (risks, shown at the left) in patients with heart failure. The significance of the reduced breakdown of certain peptides remains uncertain (shown at the bottom). ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide; cGMP = cyclic guanosine monophosphate; CNP = C-type natriuretic peptide; VIP = vasoactive intestinal peptide.