{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:35:35Z","timestamp":1791318935582,"version":"4.3.1"},"reference-count":30,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T00:00:00Z","timestamp":1667865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Merck Sharpe &amp; Dohme"},{"name":"Novartis"},{"name":"Abbott"},{"name":"Medtronic"},{"name":"Daiichi Sankyo"},{"name":"Servier"},{"name":"Vifor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Pharmacotherapy of chronic heart failure with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF) remains challenging. We aimed to assess whether combined neuro-humoral modulation (NHM) (renin\u2013angiotensin system inhibitors, betablockers, mineralocorticoid receptor antagonists) was differentially associated with outcome according to phenotype and age groups. Between 1999 and 2018 we recruited in a nationwide cardiology registry 4707 patients (HFmrEF n = 2298, HFpEF n = 2409) from three age groups: &lt;65, 65\u201379 and 80+ years old. We analyzed clinical characteristics and 1 year all-cause mortality\/cardiovascular hospitalization according to none\/single, any double, or triple NHM. Prescription rates of no\/single and triple NHM were 25.1% and 26.7% for HFmrEF; 36.5% and 17.9% for HFpEF patients, respectively. Older age was associated with higher prescription of no\/single NHM in HFmrEF (ptrend = 0.001); the reverse was observed among HFpEF (ptrend = 0.005). Triple NHM increased over time in both phenotypes (all p for trend &lt; 0.0001). Compared to no\/single NHM, triple, but not double, NHM was associated with better outcomes in both HFmrEF (HR 0.700, 95%CI 0.505\u20130.969, p = 0.032) and HFpEF (HR 0.700, 95%CI 0.499\u20130.983, p = 0.039), with no interaction between NHM treatment and age groups (p = 0.58, p = 0.80, respectively). In a cardiology setting, among HF outpatients with EF &gt; 40%, triple NHM treatment increased over time and was associated with better patient outcomes.<\/jats:p>","DOI":"10.3390\/jcm11226627","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T02:44:32Z","timestamp":1667961872000},"page":"6627","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Combined Neuro-Humoral Modulation and Outcomes in Patients with Chronic Heart Failure and Mildly Reduced or Preserved Ejection Fraction"],"prefix":"10.3390","volume":"11","author":[{"given":"Mauro","family":"Gori","sequence":"first","affiliation":[{"name":"Heart Failure Working Group, Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), 50121 Florence, Italy"},{"name":"Cardiology Division, Cardiovascular Department, Papa Giovanni XXIII Hospital, 24127 Bergamo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Marini","sequence":"additional","affiliation":[{"name":"Heart Failure Working Group, Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), 50121 Florence, Italy"},{"name":"Department of Cardiovascular Sciences Cardiology, Ospedali Riuniti, 60122 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3847-7149","authenticated-orcid":false,"given":"Lucio","family":"Gonzini","sequence":"additional","affiliation":[{"name":"ANMCO Research Center, Heart Care Foundation, 50121 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2429-1135","authenticated-orcid":false,"given":"Samuela","family":"Carigi","sequence":"additional","affiliation":[{"name":"Heart Failure Working Group, Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), 50121 Florence, Italy"},{"name":"Cardiology Unit, Infermi Hospital, 47900 Rimini, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"De Gennaro","sequence":"additional","affiliation":[{"name":"Heart Failure Working Group, Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), 50121 Florence, Italy"},{"name":"Cardiology Department, San Paolo Hospital, 70123 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piero","family":"Gentile","sequence":"additional","affiliation":[{"name":"Heart Failure Working Group, Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), 50121 Florence, Italy"},{"name":"De Gasperis Cardio ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Leonardi","sequence":"additional","affiliation":[{"name":"Heart Failure Working Group, Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), 50121 Florence, Italy"},{"name":"SSD Severe Heart Failure, PO \u201cG. Rodolico\u201d, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Orso","sequence":"additional","affiliation":[{"name":"Heart Failure Working Group, Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), 50121 Florence, Italy"},{"name":"Heart Failure Unit, Division of Geriatric Medicine and Intensive Care Unit, Department of Medicine and Geriatrics, Careggi University Hospital, 50141 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denitza","family":"Tinti","sequence":"additional","affiliation":[{"name":"Heart Failure Working Group, Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), 50121 Florence, Italy"},{"name":"Unit of Cardiology, San Camillo Hospital, 00152 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8614-785X","authenticated-orcid":false,"given":"Donata","family":"Lucci","sequence":"additional","affiliation":[{"name":"ANMCO Research Center, Heart Care Foundation, 50121 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9613-5062","authenticated-orcid":false,"given":"Massimo","family":"Iacoviello","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Department of Medical and Surgical Sciences, University Hospital Policlinico Riuniti, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8417-7783","authenticated-orcid":false,"given":"Alessandro","family":"Navazio","sequence":"additional","affiliation":[{"name":"Cardiology Division, Arcispedale S. Maria Nuova, Azienda USL di Reggio Emilia\u2014IRCCS, 71013 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Ammirati","sequence":"additional","affiliation":[{"name":"De Gasperis Cardio Center, and Transplant Center, Niguarda Hospital, 20162 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Municin\u00f2","sequence":"additional","affiliation":[{"name":"Department of Cardiology, A. Gallino Hospital, ASL3, 16164 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Benvenuto","sequence":"additional","affiliation":[{"name":"ICU Cardiology and Hemodynamics, G. Mazzini Hospital, 64100 Teramo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonarda","family":"Cassaniti","sequence":"additional","affiliation":[{"name":"Cardiology Division, A.O. of National Importance and High Specialization \u201cGaribaldi\u201d, \u201cGaribaldi-Nesima\u201d Hospital, 95122 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Tavazzi","sequence":"additional","affiliation":[{"name":"Maria Cecilia Hospital, GVM Care and Research, 48033 Cotignola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2764-6779","authenticated-orcid":false,"given":"Aldo Pietro","family":"Maggioni","sequence":"additional","affiliation":[{"name":"ANMCO Research Center, Heart Care Foundation, 50121 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8474-7923","authenticated-orcid":false,"given":"Renata","family":"De Maria","sequence":"additional","affiliation":[{"name":"Heart Failure Working Group, Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), 50121 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/S0140-6736(17)32520-5","article-title":"Temporal trends and patterns in heart failure incidence: A population-based study of 4 million individuals","volume":"391","author":"Conrad","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1056\/NEJMoa2107038","article-title":"EMPEROR-Preserved Trial Investigators. 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