br Natriuretic peptides and neprilysin Left ventricular syst

Natriuretic peptides and neprilysin Left ventricular systolic function, most commonly due to myocardial damage as a consequence of coronary artery disease, hypertension or both, and leading to sustained, pathological activation of the renin angiotensin Cy3 carboxylic acid (non-sulfonated) system (RAAS) and sympathetic nervous system (SNS), results in the syndrome of HFrEF (Fig. 1). In an effort to ameliorate the deleterious effects of this dysfunctional activation of the RAAS and SNS, the body releases a group of vasoactive peptides known as the natriuretic peptides (NP) in response to distension of the atria and ventricles. The first of these, atrial natriuretic peptide (ANP) was discovered by de Bold and colleagues in 1981 following the observation that the intravenous administration of atrial extracts in rats resulted in a potent natriuretic and diuretic response [21]. Additional beneficial vasodilatory, anti-fibrotic and anti-hypertrophic properties have also been described in ANP, B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) [22]. The potential to augment endogenous levels of NPs to harness their protective properties was therefore identified as a potential therapeutic strategy in HFrEF. Despite favourable haemodynamic and natriuretic effects, the administration of exogenous NPs has not been shown to reduce mortality or HF hospitalisation in patients with acutely decompensated HFrEF in a series of RCTs [[23], [24], [25], [26]]. The alternative method to augment endogenous levels of NP is to prevent their clearance which occurs through 2 pathways; elimination via the NP clearance receptor (NPRC or NPRC3) or enzymatic degradation by neprilysin (also known as neutral endopeptidase 24.11 [NEP], enkephalinase, vasopeptidase and atriopeptidase) [27]. Neprilysin is a membrane bound endopeptidase found in various tissues, but predominantly in the kidney [28]. Along with the degradation of NPs, neprilysin plays a role in the degradation of a number of other vasodilatory peptides including adrenomedullin, bradykinin, substance-P, vasoactive intestinal peptide (VIP), calcitonin gene related peptide (CGRP), glucagon-like peptide 1 (GLP-1) and apelin, all of which may be beneficial in the vasoconstrictive state of HFrEF (Fig. 1) [[29], [30], [31], [32]]. Pharmacological inhibition of neprilysin activity, was therefore proposed as a potential therapeutic avenue to maximise the benefits of the body's own protective NP system. The question was, how best to achieve it?
Neprilysin inhibitors The first neprilysin inhibitor, thiorphan, was reported in 1980 by Roques and colleagues, with subsequent formulations demonstrating favourable haemodynamic and hormonal responses in animal models [[33], [34], [35]]. Initial investigations in humans were promising; both oral (racecodotril and ecadotril) and intravenous (candoxatrilat) preparations were reported to stimulate natriuresis and diuresis along with increases in circulating plasma levels of ANP [[36], [37], [38]]. Unlike loop diuretics, this effect was not accompanied by a deleterious activation of the RAAS [39]. Furthermore, ecadotril and candoxatrilat resulted in reductions in pulmonary wedge pressure in patients with HFrEF [36, 38]. However, the development of neprilysin inhibitors as monotherapy for both HFrEF and hypertension was halted after extended treatment with the oral prodrug candoxatril in patients with hypertension did not result in a sustained blood-pressure lowering effect [40]. It later transpired that the lack of any anti-hypertensive effect with neprilysin inhibitors when administered as monotherapy was secondary to the inhibition of breakdown, and therefore increased levels of, the vasoconstrictors angiotensin II and endothelin 1, thereby neutralising the augmentation of vasodilatory peptides by neprilysin inhibition [[41], [42], [43]].
Combined neprilysin and ACE inhibition On the basis of the results of the CONSENSUS and SOLVD-Treatment trials, ACE inhibitors had cemented their role as first-line disease-modifying therapy for patients with HFrEF. The addition of a neprilysin inhibitor to an ACE inhibitor (i.e. combined neprilysin and RAAS blockade) was felt to be the logical answer to the issues with neprilysin inhibitor monotherapy and this gave rise to a class of medications known as vasopeptidase inhibitors [44, 45]. Of these, omapatrilat was the most extensively investigated [46]. The IMPRESS (Inhibition of Metalloprotease by Omapatrilat in a Randomized Exercise and Symptoms Study in Heart Failure) trial in 573 patients with HFrEF reported a trend towards improved survival and reduced risk of admission for worsening HF with omapatrilat compared to the ACE inhibitor, lisinopril [47]. A subsequent large phase 3 RCT, the Omapatrilat versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE), was conducted but showed that treatment with omapatrilat did not result in a significant reduction in the primary endpoint of all-cause mortality or HF hospitalisation when compared with enalapril 10 mg twice daily [48]. However, potential benefit of vasopeptidase inhibitors was not excluded, with a significant 9% reduction observed in the secondary endpoint of all-cause mortality and cardiovascular (CV) hospitalisation. Unfortunately, the incidence of angioedema was more common with omapatrilat compared to enalapril, and this finding was replicated in a trial of omapatrilat in patients with hypertension [49]. Each of ACE and neprilysin catabolise bradykinin, and enzyme inhibition results in reduced breakdown of bradykinin. Later it was also found that omapatrilat inhibits aminopeptidase p, the third key enzyme involved in bradykinin degradation [50]. As well as having potent vasodilatory properties, bradykinin increases tissue permeability and fluid extravasation through increased prostaglandin concentrations. The risk of potentially life-threatening angioedema when the two (or three) enzymes were inhibited together, along with the lack of any significant benefit compared to ACE inhibitors, halted the further development of vasopeptidase inhibitors.