Figures & data
Figure 1 Schematic of natriuretic peptides and bradykinin and their physiological effects.
Abbreviations: ACE, angiotensin-converting enzyme; NEP, neprilysin; RAAS, renin–angiotensin–aldosterone system.
Figure 2 Schematic of action mechanism of NEP and ACE inhibitors (omapatrilat).
Abbreviations: NEP, neprilysin; NPs, natriuretic peptides; Angio II, angiotensin II; ACE, angiotensin-converting enzyme.
Figure 3 Schematic of action mechanism of NEP (sacubitril) and ARB (valsartan) inhibitors in heart failure.
Abbreviations: ARB, angiotensin-receptor blocker; NEP, neprilysin; NPs, natriuretic peptides; Angio II, angiotensin II.
Figure 4 The central role of LCZ696 in the dual inhibition of the RAAS and of neprilysin.
Notes: Heart failure with reduced ejection fraction (HFrEF) activates both the SNS and the RAAS, which act in the release of renin. Renin acts on angiotensinogen to produce Angio I. ACE catalyzes the formation of Angio II, which acts on the AT1 receptor, whose physiological actions include the release of aldosterone, besides vasoconstriction and sodium retention. The HFrEF also activates the NPS with release of ANP and BNP, whose physiological actions result in vasodilation, natriuresis, diuresis, and fibrosis inhibition. ANP also blocks the release of renin. On the other hand, neprilysin breaks down ANP. The LCZ696 has two components: an angiotensin-receptor blocker (valsartan), which blocks activation of RAAS; and a neprilysin inhibitor (sacubitril), which preserves ANP. These actions produce beneficial effects on vasodilation, natriuresis, diuresis, and fibrosis inhibition.
Abbreviations: SNS, sympathetic nervous system; RAAS, renin–angiotensin–aldosterone system; NPS, natriuretic peptide system; Angio I, angiotensin I; Angio II, angiotensin II; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide.
Abbreviations: SNS, sympathetic nervous system; RAAS, renin–angiotensin–aldosterone system; NPS, natriuretic peptide system; Angio I, angiotensin I; Angio II, angiotensin II; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide.
Figure 5 Additional benefit of an angiotensin–neprilysin inhibitor on cardiovascular death compared to an angiotensin-receptor blocker and an ACE inhibitor.
Notes: The CHARM (candesartan in heart failure – assessment of mortality and morbidity) alternative trial compared an angiotensin-receptor blocker with placebo,Citation110 the SOLVD (effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure) treatment trial compared an ACE inhibitor with placebo,Citation15 and the PARADIGM-HF (prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure) trial compared an angiotensin–neprilysin inhibitor with an ACE inhibitor.Citation29 Adapted with permission of Portland Press Ltd, from The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment, Volpe M, Carnovali M, Mastromarino V, Clin Sci (Lond), 130(2), © 2016; permission conveyed through Copyright Clearance Center, Inc.Citation36
Abbreviation: ACE, angiotensin-converting enzyme.
Abbreviation: ACE, angiotensin-converting enzyme.
