Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

Abstract

Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future. (J Cardiac Fail 2015;21:741e750)

Global left atrial failure in heart failure

“…Neprilysin is a neutral endopeptidase widely expressed in the kidneys, lungs, and vascular endothelial cells, that degrades several endogenous vasoactive peptides, including NPs, bradykinin, and adrenomedullin. Neprilysin can be released from the cell surface yielding soluble neprilysin with catalytic activity, which can be inhibited by marked elevated BNP . Neprilysin cleaves ANP and CNP at the cysteine–phenylalanine bond and breaks the ring structure, which eliminates receptor binding.…”

Cardiac remodelling and RAS inhibition

“…Valsartan/sacubitril (previously known as LCZ696) is an example of an angiotensin receptor neprilysin inhibitor containing an ARB as well as a neprilysin inhibitor that acts to increase circulating levels of natriuretic peptides [Segura et al 2013]. Another dual inhibitor, omapatrilat, combined ACE and neprilysin inhibition, but use of this combination has been associated with increased levels of angioedema [Buggey et al 2015]. …”

Sacubitril/Valsartan and Ivabradine: Two Compounds for Heart Failure with Low Ejection Fraction (EFrEF), Acting by Innovative Mechanisms

“…In turn, that decreases vascular smooth muscle tone [27] . On the other hand, when vascular smooth tone decreases, peripheral vascular resistance also decreases, and the net effect is decreased capillary hydrostatic pressure and improved cardiac output by decreasing after-load [28] .…”