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Aim of our study was to evaluate the impact of sacubitril\/valsartan on exercise parameters and echocardiographic and biomarker changes at different drug doses.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We prospectively enrolled consecutive HFrEF outpatients eligible to start sacubitril\/valsartan. Patients underwent clinical assessment, cardiopulmonary exercise test (CPET), blood sampling, echocardiography, and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Sacubitril\/valsartan was introduced at 24\/26\u00a0mg b.i.d. dose and progressively uptitrated in a standard monthly-based fashion to 97\/103\u00a0mg b.i.d. or maximum tolerated dose. Study procedures were repeated at each titration visit and 6\u00a0months after reaching the maximum tolerated dose.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Ninety-six patients completed the study, 73 (75%) reached maximum sacubitril\/valsartan dose. We observed a significant improvement in functional capacity across all study steps: oxygen intake increased, at peak exercise (from 15.6\u2009\u00b1\u20094.5 to 16.5\u2009\u00b1\u20094.9\u00a0mL\/min\/kg; <jats:italic>p<\/jats:italic> trend\u2009=\u20090.001), while minute ventilation\/carbon dioxide production relationship reduced in patients with an abnormal value at baseline. Sacubitril\/valsartan induced positive left ventricle reverse remodeling (EF from 31\u2009\u00b1\u20095 to 37\u2009\u00b1\u20098%; <jats:italic>p<\/jats:italic> trend\u2009&lt;\u20090.001), while NT-proBNP reduced from 1179 [610\u20132757] to 780 [372\u20131344] pg\/ml (<jats:italic>p<\/jats:italic> trend\u2009&lt;\u20090.0001). NYHA functional class and the subjective perception of limitation in daily life at KCCQ-12 significantly improved. The Metabolic Exercise Cardiac Kidney Index (MECKI) score progressively improved from 4.35 [2.42\u20137.71] to 2.35% [1.24\u20134.96], <jats:italic>p<\/jats:italic>\u2009=\u20090.003.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>A holistic and progressive HF improvement was observed with sacubitril\/valsartan in parallel with quality of life. Likewise, a prognostic enhancement was observed.\n<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00228-023-03527-y","type":"journal-article","created":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T06:02:25Z","timestamp":1687845745000},"page":"1173-1184","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Effects of sacubitril\/valsartan on exercise capacity: a prognostic improvement that starts during uptitration"],"prefix":"10.1007","volume":"79","author":[{"given":"Massimo","family":"Mapelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Mattavelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Paolillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Salvioni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiano","family":"Magr\u00ec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Galotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"De Martino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Mantegazza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Vignati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Immacolata","family":"Esposito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Dell\u2019Aversana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Paolillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Capovilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Tamborini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro Alberto","family":"Nepitella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale Perrone","family":"Filardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piergiuseppe","family":"Agostoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,6,27]]},"reference":[{"key":"3527_CR1","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/S0140-6736(17)32520-5","volume":"391","author":"N Conrad","year":"2018","unstructured":"Conrad N, Judge A, Tran J, Mohseni H, Hedgecott D, Crespillo AP et al (2018) Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals. 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J Am Coll Cardiol 70:776\u2013803","journal-title":"J Am Coll Cardiol"}],"container-title":["European Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00228-023-03527-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00228-023-03527-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00228-023-03527-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T03:14:39Z","timestamp":1692155679000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00228-023-03527-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,27]]},"references-count":44,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2023,9]]}},"alternative-id":["3527"],"URL":"https:\/\/doi.org\/10.1007\/s00228-023-03527-y","relation":{},"ISSN":["0031-6970","1432-1041"],"issn-type":[{"value":"0031-6970","type":"print"},{"value":"1432-1041","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,27]]},"assertion":[{"value":"17 May 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 June 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 June 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The present research protocol complies with World Medical Association Declaration of Helsinki, and it was approved by the Centro Cardiologico Monzino Ethical Committee (CCM 898). This observational cohort study was also registered to clinicaltrials.gov with ID: NCT04434170.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Each subject provided written consent to the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no conflict of interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclaimer"}}]}}