PMID- 32045114 OWN - NLM STAT- MEDLINE DCOM- 20210621 LR - 20210621 IS - 2055-5822 (Electronic) IS - 2055-5822 (Linking) VI - 7 IP - 2 DP - 2020 Apr TI - Neprilysin inhibition, endorphin dynamics, and early symptomatic improvement in heart failure: a pilot study. PG - 559-566 LID - 10.1002/ehf2.12607 [doi] AB - AIM: Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor developed for the treatment of heart failure with reduced ejection fraction. 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. METHODS AND RESULTS: 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 alpha- (alpha-EP), gamma-Endorphin (gamma-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 alpha-EP, gamma-EP, and sNEP were 582 (160-772), 101 (37-287), and 222 pg/mL (124-820), respectively. There was not a significant increase in alpha-EP nor gamma-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 Deltaalpha-EP, Deltagamma-EP, and DeltasNEP between 30 days and baseline were 9.3 (-34 - 44), -3.0 (-46.0 - 18.9), and 0 units (-16.4 - 157.0), respectively. In a pre-post 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. Deltaalpha-EP and DeltasNEP showed to be significantly associated with NYHA class after 30 days of treatment (P = 0.014 and P < 0.001, respectively). Deltaalpha-EP was linear and significantly associated with NYHA class improvement after 30 days of sacubitril/valsartan treatment. CONCLUSIONS: 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. CI - (c) 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology. FAU - Revuelta-Lopez, Elena AU - Revuelta-Lopez E AD - Heart Failure and Cardiac Regeneration (ICREC) Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain. AD - Centro de Investigacion Biomedica en Red Enfermedades Cardiovaculares, (CIBERCV,), Madrid, Spain. FAU - Nunez, Julio AU - Nunez J AD - Centro de Investigacion Biomedica en Red Enfermedades Cardiovaculares, (CIBERCV,), Madrid, Spain. AD - Cardiology Department, Hospital Clinico Universitario, Universitat de Valencia, INCLIVA, Valencia, Spain; INCLIVA; Universitat de Valencia, Valencia, Spain. FAU - Gastelurrutia, Paloma AU - Gastelurrutia P AD - Heart Failure and Cardiac Regeneration (ICREC) Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain. AD - Centro de Investigacion Biomedica en Red Enfermedades Cardiovaculares, (CIBERCV,), Madrid, Spain. FAU - Cediel, German AU - Cediel G AD - Cardiology Service and Heart Failure Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. FAU - Januzzi, James L AU - Januzzi JL AD - Division of Cardiology, Massachusetts General Hospital and Cardiometabolic Trials, Baim Institute for Clinical Research, Boston, Massachusetts, MA, USA. FAU - Ibrahim, Nasrien E AU - Ibrahim NE AD - Division of Cardiology, Massachusetts General Hospital and Cardiometabolic Trials, Baim Institute for Clinical Research, Boston, Massachusetts, MA, USA. FAU - Emdin, Michele AU - Emdin M AD - Institute of Life Sciences, Scuola Superiore Sant'Anna, Fondazione Toscana Gabriele Monasterio, Pisa, Italy; Fondazione Toscana Gabriele Monasterio, Pisa, Italy. FAU - VanKimmenade, Roland AU - VanKimmenade R AD - Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands. FAU - Pascual-Figal, Domingo AU - Pascual-Figal D AD - Centro de Investigacion Biomedica en Red Enfermedades Cardiovaculares, (CIBERCV,), Madrid, Spain. AD - Cardiology Department, Hospital Virgen de la Arrixaca, Universidad de Murcia, Murcia, Spain. FAU - Nunez, Eduardo AU - Nunez E AD - Cardiology Department, Hospital Clinico Universitario, Universitat de Valencia, INCLIVA, Valencia, Spain; INCLIVA; Universitat de Valencia, Valencia, Spain. FAU - Gommans, Frank AU - Gommans F AD - Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands. FAU - Lupon, Josep AU - Lupon J AD - Centro de Investigacion Biomedica en Red Enfermedades Cardiovaculares, (CIBERCV,), Madrid, Spain. AD - Cardiology Service and Heart Failure Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. AD - Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain. FAU - Bayes-Genis, Antoni AU - Bayes-Genis A AD - Centro de Investigacion Biomedica en Red Enfermedades Cardiovaculares, (CIBERCV,), Madrid, Spain. AD - Cardiology Service and Heart Failure Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. AD - Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain. LA - eng GR - CB16/11/00403/CIBER Cardiovascular/International GR - 201502-30/Fundacio la Marato de TV3/International GR - 201516-10/Fundacio la Marato de TV3/International GR - PI17/01487/Instituto de Salud Carlos III/International GR - SAF2017-84324-C2-1-R/Spanish Ministry of Economy and Competitiveness-MINECO/International GR - SLT002/16/00234/PERIS Accio Instrumental de Programes de Recerca Orientats/International GR - RD16/00111/0006/Red de Terapia Celular-TerCel/International GR - 2017-SGR-483/AGAUR/International GR - PI18/00256/Instituto de Salud Carlos III/International GR - PIC18/00014/Instituto de Salud Carlos III/International PT - Journal Article PT - Multicenter Study PT - Observational Study PT - Research Support, Non-U.S. Gov't DEP - 20200211 PL - England TA - ESC Heart Fail JT - ESC heart failure JID - 101669191 RN - 0 (Endorphins) RN - EC 3.4.24.11 (Neprilysin) SB - IM MH - *Endorphins MH - *Heart Failure/drug therapy MH - Humans MH - Neprilysin MH - Pilot Projects MH - Prospective Studies MH - Stroke Volume PMC - PMC7160502 OTO - NOTNLM OT - Endorphins OT - Heart failure OT - Neprilysin OT - Sacubitril/valsartan OT - alpha-Endorphin OT - gamma-Endorphin COIS- The authors have no other funding, financial relationships, or conflicts of interest to disclose. EDAT- 2020/02/12 06:00 MHDA- 2021/06/22 06:00 PMCR- 2020/02/11 CRDT- 2020/02/12 06:00 PHST- 2019/07/11 00:00 [received] PHST- 2019/11/26 00:00 [revised] PHST- 2019/12/09 00:00 [accepted] PHST- 2020/02/12 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/02/12 06:00 [entrez] PHST- 2020/02/11 00:00 [pmc-release] AID - EHF212607 [pii] AID - 10.1002/ehf2.12607 [doi] PST - ppublish SO - ESC Heart Fail. 2020 Apr;7(2):559-566. doi: 10.1002/ehf2.12607. Epub 2020 Feb 11.