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Its benefits are achieved through the inhibition of neprilysin (NEP) and the specific blockade of the angiotensin receptor AT1. The many peptides metabolized by NEP suggest multifaceted potential consequences of its inhibition. We sought to evaluate the short-term changes in serum endorphin (EP) values and their relation with patients' physical functioning after initiation of sacubitril\/valsartan treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>A total of 105 patients with heart failure with reduced ejection fraction, who were candidates for sacubitril\/valsartan treatment, were included in this prospective, observational, multicentre, and international study. In a first visit, and in agreement with current guidelines, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker was replaced by sacubitril\/valsartan because of clinical indication by the responsible physician. By protocol, patients were reevaluated at 30 days after the start of sacubitril\/valsartan. Serum levels of \u03b1- (\u03b1-EP), \u03b3-Endorphin (\u03b3-EP), and soluble NEP (sNEP) were measured using enzyme-linked immunoassays. New York Heart Association (NYHA) functional class was used as an indicator of patient's functional status. Baseline median levels of circulating \u03b1-EP, \u03b3-EP, and sNEP were 582 (160\u2013772), 101 (37\u2013287), and 222 pg\/mL (124\u2013820), respectively. There was not a significant increase in \u03b1-EP nor \u03b3-EP serum values after sacubitril\/valsartan treatment (P value = 0.194 and 0.102, respectively). There were no significant differences in sNEP values between 30 days and baseline (P value = 0.103). Medians (IQR) of \u0394\u03b1-EP, \u0394\u03b3-EP, and \u0394sNEP between 30 days and baseline were 9.3 (\u221234 \u2212 44), \u22123.0 (\u221246.0 \u2212 18.9), and 0 units (\u221216.4 \u2212 157.0), respectively. In a pre\u2013post sacubitril\/valsartan treatment comparison, there was a significant improvement in NYHA class, with 36 (34.3%) patients experiencing improvement by at least one NYHA class category. \u0394\u03b1-EP and \u0394sNEP showed to be significantly associated with NYHA class after 30 days of treatment (P = 0.014 and P &amp;lt; 0.001, respectively). \u0394\u03b1-EP was linear and significantly associated with NYHA class improvement after 30 days of sacubitril\/valsartan treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These preliminary data suggest that beyond the haemodynamic benefits achieved with sacubitril\/valsartan, the altered cleavage of endorphin peptides by NEP inhibition may participate in patients' symptoms improvement.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ehf2.12607","type":"journal-article","created":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T09:50:45Z","timestamp":1581414645000},"page":"559-566","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Neprilysin Inhibition, Endorphin Dynamics, and Early Symptomatic Improvement in Heart Failure: A Pilot Study"],"prefix":"10.1093","volume":"7","author":[{"given":"Elena","family":"Revuelta-L\u00f3pez","sequence":"first","affiliation":[{"name":"Heart Failure and Cardiac Regeneration (ICREC) Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP) , Badalona ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovaculares, (CIBERCV,) , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"N\u00fa\u00f1ez","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovaculares, (CIBERCV,) , Madrid ,","place":["Spain"]},{"name":"Cardiology Department, Hospital Cl\u00ednico Universitario, Universitat de Val\u00e8ncia, INCLIVA , Valencia, Spain; INCLIVA; Universitat de Val\u00e8ncia, Valencia ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma","family":"Gastelurrutia","sequence":"additional","affiliation":[{"name":"Heart Failure and Cardiac Regeneration (ICREC) Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP) , Badalona ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovaculares, (CIBERCV,) , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Germ\u00e1n","family":"Cediel","sequence":"additional","affiliation":[{"name":"Cardiology Service and Heart Failure Unit, Hospital Universitari Germans Trias i Pujol , Badalona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James L.","family":"Januzzi","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Massachusetts General Hospital and Cardiometabolic Trials, Baim Institute for Clinical Research , Boston, Massachusetts, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasrien E.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Massachusetts General Hospital and Cardiometabolic Trials, Baim Institute for Clinical Research , Boston, Massachusetts, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Emdin","sequence":"additional","affiliation":[{"name":"Institute of Life Sciences, Scuola Superiore Sant'Anna, Fondazione Toscana Gabriele Monasterio , Pisa, Italy; 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