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• W2013860488 abstract "HomeCirculation: Heart FailureVol. 6, No. 3Renin–Angiotensin Blockade Combined With Natriuretic Peptide System Augmentation Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBRenin–Angiotensin Blockade Combined With Natriuretic Peptide System AugmentationNovel Therapeutic Concepts to Combat Heart Failure Thomas G. von Lueder, MD, PhD, S. Jeson Sangaralingham, PhD, Bing H. Wang, PhD, Andrew R. Kompa, PhD, Dan Atar, MD, PhD, John C. BurnettJr, MD and Henry Krum, MBBS, PhD Thomas G. von LuederThomas G. von Lueder From the Department of Epidemiology and Preventive Medicine, Monash Center of Cardiovascular Research and Education in Therapeutics, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia (T.G.v.L., B.H.W., A.R.K., H.K.); Department of Cardiology B, Oslo University Hospital Ullevål, 0407 Oslo and Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (T.G.v.L., D.A.); and Division of Cardiovascular Diseases, Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN (S.J.S., J.C.B.). Search for more papers by this author , S. Jeson SangaralinghamS. Jeson Sangaralingham From the Department of Epidemiology and Preventive Medicine, Monash Center of Cardiovascular Research and Education in Therapeutics, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia (T.G.v.L., B.H.W., A.R.K., H.K.); Department of Cardiology B, Oslo University Hospital Ullevål, 0407 Oslo and Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (T.G.v.L., D.A.); and Division of Cardiovascular Diseases, Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN (S.J.S., J.C.B.). Search for more papers by this author , Bing H. WangBing H. Wang From the Department of Epidemiology and Preventive Medicine, Monash Center of Cardiovascular Research and Education in Therapeutics, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia (T.G.v.L., B.H.W., A.R.K., H.K.); Department of Cardiology B, Oslo University Hospital Ullevål, 0407 Oslo and Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (T.G.v.L., D.A.); and Division of Cardiovascular Diseases, Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN (S.J.S., J.C.B.). Search for more papers by this author , Andrew R. KompaAndrew R. Kompa From the Department of Epidemiology and Preventive Medicine, Monash Center of Cardiovascular Research and Education in Therapeutics, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia (T.G.v.L., B.H.W., A.R.K., H.K.); Department of Cardiology B, Oslo University Hospital Ullevål, 0407 Oslo and Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (T.G.v.L., D.A.); and Division of Cardiovascular Diseases, Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN (S.J.S., J.C.B.). Search for more papers by this author , Dan AtarDan Atar From the Department of Epidemiology and Preventive Medicine, Monash Center of Cardiovascular Research and Education in Therapeutics, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia (T.G.v.L., B.H.W., A.R.K., H.K.); Department of Cardiology B, Oslo University Hospital Ullevål, 0407 Oslo and Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (T.G.v.L., D.A.); and Division of Cardiovascular Diseases, Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN (S.J.S., J.C.B.). Search for more papers by this author , John C. BurnettJrJohn C. BurnettJr From the Department of Epidemiology and Preventive Medicine, Monash Center of Cardiovascular Research and Education in Therapeutics, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia (T.G.v.L., B.H.W., A.R.K., H.K.); Department of Cardiology B, Oslo University Hospital Ullevål, 0407 Oslo and Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (T.G.v.L., D.A.); and Division of Cardiovascular Diseases, Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN (S.J.S., J.C.B.). Search for more papers by this author and Henry KrumHenry Krum From the Department of Epidemiology and Preventive Medicine, Monash Center of Cardiovascular Research and Education in Therapeutics, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia (T.G.v.L., B.H.W., A.R.K., H.K.); Department of Cardiology B, Oslo University Hospital Ullevål, 0407 Oslo and Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (T.G.v.L., D.A.); and Division of Cardiovascular Diseases, Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN (S.J.S., J.C.B.). Search for more papers by this author Originally published1 May 2013https://doi.org/10.1161/CIRCHEARTFAILURE.112.000289Circulation: Heart Failure. 2013;6:594–605IntroductionCardiovascular diseases in general and heart failure (HF) in particular are major contributors to death and morbidity in the Western world, where they are also recognized as important drivers of healthcare expenditure. The health and economic burden of these disorders is projected to increase with the aging of populations around the world.1–3 On the basis of accumulating evidence that chronic overactivity of the renin–angiotensin–aldosterone system (RAAS) plays a fundamental role in HF pathophysiology, drugs inhibiting key components of the RAAS have become a cornerstone of contemporary cardiovascular drug therapy.4–6 For example, angiotensin-converting enzyme inhibitors (ACEi) reduce biosynthesis of angiotensin-II (Ang-II), 1 of the strongest vasoconstrictors, prohypertrophic and profibrotic hormones in man. Moreover, ACEi may prevent proteolysis of bradykinin, thus enhancing bradykinin-mediated vasodilatory effects that may counteract the profound vasoconstriction seen in patients with HF.7 Excessive levels of Ang-II have been implicated in many cardiovascular diseases, and in addition to ACEi, the detrimental actions of Ang-II can be abrogated by direct angiotensin-receptor blockers (ARB). However, despite encouraging results from many clinical trials, ACEi- and ARBs-based pharmacotherapy is still far from optimal. ACEi may lose their efficacy over time because of redundant Ang-II–generating pathways and the so-called aldosterone escape,8 whereas conventional ARBs do not possess the bradykinin-enhancing properties of ACEi and are considered less effective in HF compared with ACEi.4,5The natriuretic peptides (NPs), consisting of atrial NP (ANP), B-type NP (BNP), C-type NP (CNP), and urodilatin, are predominantly generated by the heart, vasculature, kidney, and central nervous system in response to wall stress and number of other stimuli. Importantly the NPs, particularly ANP and BNP, represent the body’s own blood pressure (BP)–lowering system. Besides promoting vasodilation, NPs counteract pathological growth, fibrosis, and dysfunction of heart, kidneys, brain, and the vasculature. Current NP-augmenting strategies include the design of a number of synthetic NPs and inhibition of neprilysin, the key enzyme responsible for NP breakdown. Dual-acting angiotensin-receptor neprilysin inhibitors (ARNi) are under scientific scrutiny for the treatment of hypertension and HF.This review summarizes the current knowledge on RAAS blockade and NP-augmenting drugs as single or combined strategies in HF. We will discuss challenges that have been met with some of these compounds and novel therapeutic agents currently being evaluated, which could strengthen our pharmacological armamentarium for HF.Renin–Angiotensin Aldosterone SystemThe RAAS is fundamental in the overall regulation of cardiovascular homeostasis through the actions of important hormones, which regulate vascular tone, and specifically BP through vasoconstriction and renal sodium and water retention. These hormones, specifically Ang-II and aldosterone, also possess direct actions that are important in HF by mediating cardiomyocyte hypertrophy and cardiac fibrosis with activation of collagen synthesis and fibroblast proliferation (Figure 1).9–11 RAAS is also causally involved in the pathophysiology of cardiorenal syndrome in HF, which carries a particularly poor prognosis. Thus, blockade of RAAS has become a central therapeutic strategy for HF using RAAS modulating drugs, such as ACEi, ARBs, and mineralcorticoid receptor antagonists (MRA).4Download figureDownload PowerPointFigure 1. Simplified schematic of the renin–angiotensin–aldosterone system. A multitude of stressor signals induce the angiotensin gene. The prohormone angiotensinogen is cleaved by the protease renin to the direct precursor angiotensin-I (Ang-I), and further to biologically active angiotensin-II (Ang-II). These steps can be inhibited by renin-inhibitors or ACE-inhibitors (ACEi), respectively, but important alternative Ang-II–generating pathways exist. Alternative splicing of Ang-I and prohormones Ang-(1–12) or Ang-(1–9) by neprilysin (NEP) results in generation of Ang-(1–7). Binding of mature Ang-II to the type-1 angiotensin receptor (ATR-1) activates intracellular signaling cascades that exert adverse biological effects within the cardiovascular system, such as pathological cardiac hypertrophy, vascular remodeling, and renal fibrosis.To date these agents have had a positive impact on HF with improvements in symptoms, outcomes, and survival. Indeed their use is increasingly widespread and their use is moving from symptomatic HF into earlier stages of mild and asymptomatic myocardial dysfunction to delay the progression of HF. Recently, a pivotal trial was completed with the MRA epleronone in patients with systolic HF and mild symptoms.12 Importantly, MRAs compared with placebo reduced the risk of the both death and hospitalization, thus delaying disease progression and providing further momentum to this continuously expanding therapeutic modality. In addition, the MRA spironolactone is under investigation in the ongoing TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) trial for efficacy in HF with preserved ejection fraction (HFPEF), a disease entity for which no specific treatment recommendations exist.4,13Direct renin inhibition upstream of ACE, well-known for decades as a RAAS-blocking concept, prevents the generation of Ang-I and thus, Ang-II. The first-in-class drug aliskiren is currently being evaluated in 2 clinical HF trials, the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) and the Aliskiren Trial of Minimizing Outcomes for Patients with Heart Failure (ATMOSPHERE).14–16 ASTRONAUT set out to evaluate the primary and the secondary composite end points of cardiovascular death or HF rehospitalization at 6 and 12 months, respectively, in 1782 patients recently hospitalized with HF and reduced systolic left ventricular (LV) function. The very recently published study showed that aliskiren in addition to standard therapy failed to reduce primary or secondary end points but led to significantly larger decrease from baseline in NT-proBNP levels.16 Subgroup analysis demonstrated increased all-cause mortality at 12 months for patients with a history of diabetes mellitus randomized to aliskiren, whereas patients with non–diabetes mellitus showed net benefit compared with placebo. The reason for such a bidirectional effect of aliskiren on all-cause mortality depending on the presence or on the absence of diabetes mellitus deserves further evaluation. In a similar but considerably larger HF cohort (planned enrollment, n=7000), ATMOSPHERE will compare effects on mortality and morbidity by aliskiren, enalapril, or dual aliskiren+enalapril treatment. Recent evidence suggest similar rates of angioedema with aliskiren and ACEi.17Perhaps the latest advance in RAAS blockade in HF has been the development of innovative AT1 receptor antagonists, which possess dual actions that go beyond simple antagonism of Ang-II binding. Like conventional ARBs, these molecules target the superfamily of G-protein–coupled receptors. Activation of G-protein–coupled receptors by an agonist leads to intracellular dissociation of a heterotrimeric G-protein into Ga and G13 subunits, resulting in activation of second messenger–mediated cellular responses. The 13 arrestins are a second group of proteins, which activate specific signaling pathways in a G-protein–independent manner. Studies have shown that some ligands can selectively activate either G-protein or 13 arrestin pathways.18 We recently reported the actions of a novel 13-arrestin–biased ligand for the Ang-II type 1 (AT1R), TRV120027.19 TRV120027 antagonizes G-protein signaling like an ARB, but, unlike conventional AT1 receptor antagonists, it activates 13 arrestin and downstream signals. In rodents, TRV12007 has vasodilating effects similar to a conventional ARB, but, unlike an ARB, enhanced cardiac contractility while decreasing myocardial oxygen consumption.20 In a large animal model of HF, TRV12007, in combination with furosemide, has potent renal and systemic vasodilating properties and preserved glomerular filtration rate (GFR), despite a reduction in BP.21 Currently, TRV12007 has entered early trials in acute decompensated HF (ADHF).Together, although efficient RAAS blockade can be achieved at multiple levels, ACEi and MRA remain the cornerstone of contemporary HF pharmacotherapy.4 Despite initial enthusiasm because of their greater tolerability compared with ACEi, ARBs offer little cardioprotection at least after MI, and do, therefore, no longer seem on the A-list of recommended medical therapy for HF.4,22 Novel ARBs, including contractility-enhancing compounds, seem promising. RAAS blockade afforded by direct renin-inhibitors may eliminate some of the shortcomings of current strategies but no clinical outcome data in HF are available yet. Moreover, regarding their safety profile important adverse effects do not seem to occur less frequently than with ACEi.17Natriuretic Peptide SystemThe NP system (NPS; Figure 2) has emerged as an increasingly important autocrine, paracrine, and endocrine system linked to particulate guanylyl cyclase (GC) receptors, the second messenger cGMP and its effector molecule protein kinase G.23 Originally discovered by de Bold et al,24 who reported that the heart synthesized and released a factor that both not only augmented natriuresis by the kidney, but also possessed BP-lowering properties. This cardiac factor was identified as ANP and recent studies have reported that genetic variations of the ANP gene, which increases circulating levels of ANP and protects against human hypertension.25 On the basis of these renal and vascular actions of ANP an intravenous drug, known as carperitide, has been approved for HF in Japan. Studies have also well established that ANP mediates its action via the GC-A receptor, which is widely expressed throughout a number of tissues and especially in the adrenal cortex in which ANP is a potent inhibitor of aldosterone independent of its robust renin inhibitory actions.26,27 In the kidney, alternative processing of the ANP precursor, proANP by an unknown protease generates an ANP-like peptide called urodilatin, which regulates renal sodium and water handling.28 Indeed studies evaluating the effects of synthetic ularitide in patients with ADHF (SIRIUS I29 and SIRIUS II30) have shown favorable effects on hemodynamic, neurohumoral, and symptomatic profiles without any compromise in renal function, despite a modest and dose-dependent decrease in BP. Moreover, a larger Phase III trial is currently ongoing, evaluating the efficacy and safety of ularitide in patients with ADHF (TRUE-AHF [Trial to Evaluate the Efficacy and Safety of Ularitide (Urodilatin) Intravenous Infusion in Patients Suffering From Acute Decompensated Heart Failure]).31 To complement ANP is the cardiac hormone BNP, which is approved as nesiritide in the United States and Canada for the treatment of ADHF. Like ANP, BNP is a ligand for the GC-A receptor and possesses similar pleiotropic actions, which include natriuresis, aldosterone suppression, and vasodilatation. Although the seminal VMAC (Vasodilatation in the Management of Acute CHF) clinical trial32 lead to the US Food and Drug Administration approval of nesiritide for ADHF, 2 subsequent meta-analyses suggested that nesiritide administration may be associated with increased short-term risk of death33 and worsening renal function34 in patients with ADHF. However, several other studies, including Acutely Decompensated Heart Failure Registry (ADHERE),35–39 failed to demonstrate these adverse associations with nesiritide therapy. Thus, the ASCEND-HF clinical trial was designed to address these safety and efficacy concerns that were raised since its approval. In the ASCEND trial, nesiritide improved symptoms in the European, but not in the United States patient cohort with ADHF and was not superior to conventional therapy in improving mortality in patients with ADHF.40 Notably, these neutral findings could have been related to excessive hypotension with doses that are potently vasodilating, and thus offsetting the beneficial renal actions of nesiritide. To underscore the importance of the GC-A receptor beyond the actions discussed above and relevant to HF are the antihypertrophic and antiapoptotic actions, which may contribute to long-term favorable antiremodeling actions if a GC-A agonist can be given chronically.23,41 Indeed, in a recently completed human trial in mild systolic HF, 8 weeks of BNP administered twice daily by subcutaneous injection improved symptoms and reduced LV mass as determined by MRI.42Download figureDownload PowerPointFigure 2. Simplified schematic of the natriuretic peptide system (NPS). Atrial NP (ANP), B-type NP (BNP), and urodilatin (URO) stimulate cyclic GMP (cGMP) production by binding to the guanylyl cyclase (GC) receptor A, whereas CNP generates cGMP by binding to the GC-B receptor. cGMP modulates the activity of cGMP-dependent protein kinase G (PKG) to exert its pluripotent cardiac, vascular, and renal biological actions. cGMP also regulates phosphodiesterases (PDEs) and cation channels. The cGMP signal is terminated by a variety of PDEs that hydrolyze cGMP to GMP. The NPs are removed from the circulation and inactived by the clearance receptor (NPR-C) and also degraded by a variety of peptidases, including neprilysin (NEP) and dipeptidyl peptidase IV (DPPIV). In addition to the clearance capacity of NPR-C from the circulation, evidence has promoted the concept that the NPR-C mediates non–cGMP-regulated biological actions.CNP is the third member of the NP family and is produced in endothelial cells43,44 and renal epithelial cells.45,46 CNP mediates its biological action through the activation of the GC-B receptor and potentially the non–cGMP-mediated receptor, NPR-C.26,47–50 Although having an important action to promote bone growth, evidence has supported that CNP has important CV actions as well. These include hyperpolarization of vascular smooth muscle,49 antithrombotic actions,50 promotion of re-endothelialization,51 and potent antifibrotic properties.48,52,53 The use of CNP as a HF therapeutic has been limited by both its rapid enzymatic degradation and lack of renal-enhancing actions. A designer CNP-based NP has been engineered, which is now in clinical trials for HF and this will be discussed below.A key component of the NPS is the ectoenzyme neutral endopeptidase (neprilysin), which is also known as neprilysin. This membrane-bound enzyme is widely expressed, but is most abundant in the kidney. Neprilysin serves as the principal mechanism for enzymatic removal of the native NPs with susceptibility to degradation greatest for CNP>ANP>BNP.54 Furthermore, many other substrates for neprilysin exist, some of them with opposing physiological actions. These include endothelin-1, kinin peptides, opioid peptides, Substance P, amyloid beta protein, and gastrin.55–57 Importantly, neprilysin hydrolyzes Ang-I to Ang-(1–7),58 and because Ang-(1–7) opposes the action of Ang-II, the hydrolysis of Ang-I to Ang-(1–7) by neprilysin potentially has beneficial CV effects. Inhibition of NEP (NEPi) has been advanced as a therapeutic modality. If neprilysin only targeted NPs, NEPi would augment the vasodilating and natriuretic actions afforded by increased levels of these peptides. However, neprilysin’s ability to catabolize numerous substrates also means that sole NEPi yields broader effects than anticipated, and explains why NEPi is best combined with the inhibition of other vasoactive peptides. Candoxatril was the first potent, orally available neprilysin inhibitor. Candoxatril mediated not only a dose-dependent increase in plasma ANP, natriuresis, and cGMP in humans, but also increased circulating Ang-II.59 Importantly, Candoxatril’s effects on BP in patients with hypertension were not clinically meaningful. Candoxatril was also investigated in HF. In a canine model of severe HF, which is characterized by both NP elevation and RAAS activation, candoxatril was natriuretic and suppressed aldosterone.60 In human HF, candoxatril increased ANP and BNP levels, promoted natriuresis, and decreased clearance of exogenously administered ANP.61 However, systemic and pulmonary vascular resistances were not altered.Early strategies to enhance the salutary actions of the NPS have clearly met challenges. Clinical efficacy of recombinant drugs, such as nesiritide, carperitide, or ularitide has been limited by hypotension and their short bioavailability. For the class of single-acting NEPi, as discussed below, their effectiveness to promote the endogenous NPs and to improve overall cardiorenal function was only finally realized when combined with RAAS modulators.Designer Natriuretic PeptidesTherapeutic use of the native NPs has been highly attractive, given their diverse intrinsic protective properties, which include natriuresis, diuresis, RAAS suppressing, inhibition of fibrosis, vasodilatation, and angiogenesis. In an effort to overcome the shortcomings of recombinant NPs outlined above, the concept of designer NPs has emerged as an innovative advancement in drug discovery for the treatment of various CV diseases. Designer NPs are novel peptides that have been engineered through modifications in their amino acid (AA) structures or through use of genetically altered forms of native NPs. The rationale behind this concept is to produce chimeric NPs whose pharmacological and beneficial biological profiles go beyond those of the native NPs while minimizing undesirable effects.CD-NP (Cenderitide)The most advanced designer NP to date was designed by investigators in the Cardiorenal Research Laboratory at Mayo Clinic and first reported in 2008.62 This novel 37 AA hybrid NP named CD-NP (Figure 3), which is now known as cenderitide, consists of the mature form of native human CNP fused with the15 AA C terminus of dendroaspis NP, which was first isolated from the venom of the green mamba.63 This unique first-generation designer NP62 retains the antifibrotic,48,52,53 antiproliferative,64 and antihypertrophic65,66 effects and venodilatation67 of CNP, as well as natriuretic and diuretic effects of dendroaspis NP,68 which are very desirable properties for drugs to combat a number of CV diseases, including HF. Importantly, CD-NP also has antiproliferative actions in cultured human cardiac fibroblasts and stimulates cGMP production in these same cells to a greater extent than equimolar concentrations of BNP.62 In vitro studies have demonstrated CD-NP is the first NP to activate both the GC-A and the GC-B receptor at physiological doses69 and is more resistant to proteolytic degradation than ANP, BNP, and CNP.70 In normal canines, intravenous infusion of CD-NP activates plasma cGMP and had natriuretic, diuretic, RAAS-suppressing actions, and unloaded the heart with minimal effects on mean atrial pressure.62 Furthermore, when compared with conventional recombinant BNP (nesiritide) therapy, an equimolar dose of CD-NP significantly increased GFR and was less hypotensive than BNP.62 Moreover, infusion of CD-NP in experimental HF induced by rapid ventricular pacing also had significant cardiac-unloading effects, increases in GFR, renal perfusion, diuresis and natriuresis, and reductions in plasma renin activity together with a modest reduction in mean atrial pressure.62 In healthy human subjects, CD-NP infusion increased urinary and plasma cGMP levels, suppressed plasma aldosterone, induced a significant diuretic and natriuretic responses and a minimal, yet significant reduction in mean atrial pressure.71 In March 2011, cenderitide received a fast-track designation from the Food and Drug Administration and currently is in Phase II clinical trials targeting postacute patients with HF using chronic subcutaneous infusion technology.72Download figureDownload PowerPointFigure 3. Amino acid structures of designer natriuretic peptides (NP). CD-NP (cenderitide) consists of amino acids from native human C-type NP (CNP; green) and dendroaspis NP (light blue). CU-NP consists of amino acids from native human CNP (green) and urodilatin (pink). ANX-042 consists of amino acids from native human B-type NP (BNP; red) and 16 amino acids (yellow) from the C terminus of the alternative spliced transcript of BNP.CU-Natriuretic PeptideBuilding on the encouraging findings of cenderitide in both experimental and human studies and designer NP technology, a humanized version of cenderitide, called CU-natriuretic peptide (CU-NP) was created. CU-NP is an engineered NP (Figure 3), consisting of the 17 AA ring of native human CNP linked to both the C and N termini of urodilatin, which is a 32 AA cleavage product of intrarenal processed proANP.73 Although CU-NP is in the early stages of drug development, initial experimental studies have demonstrated that intravenous infusion of CU-NP activates cGMP in canine HF and exerts renal-enhancing, cardiac-unloading, and RAAS-suppressing actions without excessive hypotension.74 CU-NP has also direct antihypertrophic effects through the inhibition of the sodium–hydrogen exchanger 1(NHE-1)/calcineurin pathway.75Designer NP ANX-042Another strategy for drug discovery is the biology of alternative RNA splicing which may provide unique opportunities to identify drug targets and therapeutics. We recently reported an alternative spliced transcript for BNP (AS-BNP).76 This alternative spliced BNP transcript is present in failing human hearts and is reduced after mechanical unloading. The transcript would generate a unique 34 AA C terminus although maintaining the remaining structure of native mature BNP. Importantly, unlike BNP, this novel peptide failed to stimulate cGMP in vascular cells or to vasorelax preconstricted arterial rings. From this structure, we designed a shortened 42-AA peptide from AS-BNP, which is currently known as ANX-042 (Figure 3), and demonstrated its ability to stimulate cGMP, like BNP, in canine glomerular isolates and cultured human mesangial cells but lacking similar effects in vascular cells. In a canine-pacing model of HF, systemic infusion of ANX-042 did not alter mean atrial pressure but increased GFR, suppressed plasma renin and Ang-II, while inducing natriuresis and diuresis. Importantly in 2012, ANX-042 was approved as an investigational new drug from the Food and Drug Administration and now has begun a first-in-human clinical trial as a designer renal-enhancing and nonhypotensive NP, which could make ANX-042 a potential novel renal-selective agent for HF.In summary, the NPs represent the most important endogenous counterpart to RAAS by conferring cardiac, renal, and vascular protection. Therapeutic augmentation of the NPS in HF has been attempted directly using a broad range of recombinant and engineered NPs, or indirectly by preventing NP degradation (through NEPi). In particular, degradation-resistant NPs, including designer NPs, have shown encouraging early results and are now under evaluation in clinical trials. NEPi as monotherapy to augment NPs has largely produced neutral effects in clinical studies, and, therefore, its greatest potential presumably lies in the combination with blockers of the RAAS and other neurohormonal systems that are causally inflicted in HF.RAAS Blockade Combined With NPS AugmentationDual ACE/Neprilysin (Vasopeptidase) Inhibition in HFAs previously described, the RAAS and NPS have a yin/yang relationship with each system, serving as a counter-regulatory constraint on the activity of the other.77 This physiological relationship provides the potential to achieve greater benefits with modulation of both systems than manipulation of individual systems. Specifically, the beneficial effects of inhibition of the RAAS may potentially be augmented by enhancement of NP activity. Conversely, the disappointing clinical effects of neprilysin inhibitors as monotherapy78 may be overcome by combination with RAAS blockade.Single molecular entities have been developed combining NEP inhibition (NEPi) with both ACEi and ARBs as single molecules (Table).Table. Important Clinical and Preclinical Studies of Combined NEP Inhibitors in Cardiovascular DiseaseDrugStudy or Model CharacteristicsStudy End PointsKey Results (NEPi Drugs vs Comparator)ACEi+NEPi (vasopeptidase inhibitors)Sampatrilat79Patients with hypertensionBP, plasma renin activity, urinary cGMP excretionGood antihypertensive effect. No increase of plasma renin activitySampatrilat80Patients with resistant hypertensionBP, plasma renin activity at 8 wkSustained antihypertensive effect superior to ACEi. No increase of plasma renin activitySampatrilat81Preclinical. Rats with HF post-MILV hemodynamic" @default.
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• W2013860488 date "2013-05-01" @default.
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• W2013860488 title "Renin–Angiotensin Blockade Combined With Natriuretic Peptide System Augmentation" @default.
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