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      Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy

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          Abstract

          Natriuretic peptides ( NPs) promote diuresis, natriuresis and vasodilation in early chronic heart failure ( CHF), countering renin–angiotensin–aldosterone system ( RAAS) and sympathetic nervous system ( SNS) overstimulation. Despite dramatic increases in circulating NP concentrations as CHF progresses, their effects become blunted. Increases in diuresis, natriuresis, and vasodilation after administration of exogenous atrial ( ANP) or brain ( BNP) natriuretic peptides are attenuated in patients with advanced CHF compared with controls. Several major factors may account for the reduced effectiveness of the natriuretic peptide system ( NPS) in CHF. First, there is reduced availability of active forms of NPs, namely BNP. Second, target organ responsiveness becomes diminished. Third, the counter‐regulatory hormones of the RAAS and SNS, and endothelin‐1 become over‐activated. Therefore, pharmacological approaches to enhance the functional effectiveness of the NPS in CHF have been explored in recent years. In terms of clinical outcomes, studies of synthetic BNP, or of neprilysin inhibitors alone or associated with an angiotensin converting enzyme inhibitor, have been controversial for several reasons. Recently, however, encouraging results have been obtained with the angiotensin receptor neprilysin inhibitor sacubitril/valsartan. The available data show that treatment with sacubitril/valsartan is associated with increased levels of NPs and their intracellular mediator cyclic guanosine monophosphate, suggesting improved functional effectiveness of the NPS, in addition to beneficial effects on mortality and morbidity outcomes. Therefore, combined targeting of the NPS and RAAS with sacubitril/valsartan emerges as the current optimal approach for redressing the neurohormonal imbalance in CHF.

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          Most cited references63

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          Natriuretic peptides.

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            Natriuretic peptide metabolism, clearance and degradation.

            Atrial natriuretic peptide, B-type natriuretic peptide and C-type natriuretic peptide constitute a family of three structurally related, but genetically distinct, signaling molecules that regulate the cardiovascular, skeletal, nervous, reproductive and other systems by activating transmembrane guanylyl cyclases and elevating intracellular cGMP concentrations. This review broadly discusses the general characteristics of natriuretic peptides and their cognate signaling receptors, and then specifically discusses the tissue-specific metabolism of natriuretic peptides and their degradation by neprilysin, insulin-degrading enzyme, and natriuretic peptide receptor-C. © 2011 The Author Journal compilation © 2011 FEBS.
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              Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE).

              Combined inhibition of the angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may produce greater benefits in heart failure than ACE inhibition alone. We randomly assigned 5770 patients with New York Heart Association class II to IV heart failure to double-blind treatment with either the ACE inhibitor enalapril (10 mg BID, n=2884) or to the ACE-NEP inhibitor omapatrilat (40 mg once daily, n=2886) for a mean of 14.5 months. The primary end point-the combined risk of death or hospitalization for heart failure requiring intravenous treatment--was used prospectively to test both a superiority and noninferiority hypothesis (based on the effect of enalapril in the Studies of Left Ventricular Dysfunction [SOLVD] Treatment Trial). A primary end point was achieved in 973 patients in the enalapril group and in 914 patients in the omapatrilat group (hazard ratio 0.94; 95% CI: 0.86 to 1.03, P=0.187)--a result that fulfilled prespecified criteria for noninferiority but not for superiority. The omapatrilat group also had a 9% lower risk of cardiovascular death or hospitalization (P=0.024) and a 6% lower risk of death (P=0.339). Post hoc analysis of the primary end point with the definition used in the SOLVD Treatment Trial (which included all hospitalizations for heart failure) showed an 11% lower risk in patients treated with omapatrilat (nominal P=0.012). Omapatrilat reduces the risk of death and hospitalization in chronic heart failure but was not more effective than ACE inhibition alone in reducing the risk of a primary clinical event. Between-group differences in favor of omapatrilat observed in secondary and post hoc analyses warrant further study.
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                Author and article information

                Contributors
                jadimar@unav.es
                Journal
                Eur J Heart Fail
                Eur. J. Heart Fail
                10.1002/(ISSN)1879-0844
                EJHF
                European Journal of Heart Failure
                John Wiley & Sons, Ltd (Oxford, UK )
                1388-9842
                1879-0844
                21 October 2016
                February 2017
                : 19
                : 2 ( doiID: 10.1002/ejhf.2017.19.issue-2 )
                : 167-176
                Affiliations
                [ 1 ] Program of Cardiovascular Diseases, Centre for Applied Medical Research, and Department of Cardiology and Cardiac Surgery University of Navarra Clinic, University of Navarra PamplonaSpain
                Author notes
                [*] [* ] Corresponding author. Centre for Applied Medical Research, Pio XII, 55, E–31008 Pamplona, Spain. Tel: +34 948 194 700, Fax: +34 948 194716, Email: jadimar@ 123456unav.es
                Article
                EJHF656
                10.1002/ejhf.656
                5297869
                27766748
                208f4bde-ee02-4cb0-9528-43536f5961e2
                © 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 18 April 2016
                : 16 August 2016
                : 18 August 2016
                Page count
                Figures: 6, Tables: 3, Pages: 10, Words: 6796
                Funding
                Funded by: Novartis
                Funded by: AbbVie
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                ejhf656
                February 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.5 mode:remove_FC converted:08.02.2017

                Cardiovascular Medicine
                natriuretic peptide,atrial natriuretic peptide,brain natriuretic peptide,heart failure,neprilysin

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