{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T22:31:04Z","timestamp":1777501864785,"version":"3.51.4"},"reference-count":53,"publisher":"Wiley","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"Abstract<\/jats:title>Heart failure with preserved ejection fraction (HFpEF) remains a major health concern with limited therapeutic options. Growing evidence supports the multiple benefits of ketones in heart disease, but their impact on HFpEF remains unknown. We investigated whether increasing ketones can help to manage HFpEF. Using the ZSF1 rat model of HFpEF, 16\u2010week\u2010old rats were randomly assigned to one of three subgroups: (i) control diet; (ii) ketogenic diet (KD); or (iii) control diet with added exogenous ketone salts (KS) in their drinking water for 10 weeks. We found that both KD and KS ameliorated the HFpEF phenotype by improving structural echocardiographic parameters, lowering glycaemia and lipid profiles, and reducing HFpEF\u2010related fibrosis and hypertrophy without impacting in vivo<\/jats:italic> diastolic function. Nevertheless, ex vivo<\/jats:italic> cardiomyocyte preparations showed improved calcium handling and myofilament relaxation, suggesting benefits at the cellular level. Interestingly, KD still proved effective, despite the potentially adverse increase in fat mass. There was decreased myofilament Ca2+<\/jats:sup> sensitivity and normalized active and passive tension in both groups, especially KS. These results suggest that providing ketone through the diet or supplements could be a valuable strategy to complement HFpEF treatment. Given the well\u2010known challenges of implementing dietary changes, exogenous KS offer a more practical and effective option to achieve these benefits.\nimage<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>Key points<\/jats:title>\nKetogenic diet and ketone salts effectively reversed the cardiac structural impairments associated with the ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype by ameliorating left ventricular mass.<\/jats:p><\/jats:list-item>\nBoth treatments reduced fibrosis and hypertrophy, leading to improved or, in the case of ketone salts, even reversed cardiomyocyte contractile and relaxation performance.<\/jats:p><\/jats:list-item>\nKetone salts also reversed HFpEF\u2010related cardiomyocyte stiffness and prevented a reduction in the development of maximum force.<\/jats:p><\/jats:list-item>\nBoth treatments improved myofilament Ca2+<\/jats:sup> sensitivity.<\/jats:p><\/jats:list-item>\nBoth treatments also improved the metabolic profile, reducing hyperglycaemia, blood triglycerides and levels of NT\u2010proBNP, a well\u2010known biomarker of worsening heart failure.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp288229","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T08:51:54Z","timestamp":1743843114000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Ketogenic diet and ketone salts differentially improve cardiometabolic complications in an HFpEF rat model"],"prefix":"10.1113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5386-8378","authenticated-orcid":false,"given":"Alexandre","family":"Gon\u00e7alves","sequence":"first","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine University of Porto Porto Portugal"},{"name":"RISE\u2010Health, Faculty of Medicine University of Porto Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8329-3758","authenticated-orcid":false,"given":"In\u00eas N.","family":"Alves","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine University of Porto Porto Portugal"},{"name":"RISE\u2010Health, Faculty of Medicine University of Porto Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4452-6149","authenticated-orcid":false,"given":"Cl\u00e1udia","family":"Mendes","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine University of Porto Porto Portugal"},{"name":"RISE\u2010Health, Faculty of Medicine University of Porto Porto Portugal"}]},{"given":"Daniela","family":"Miranda","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine University of Porto Porto Portugal"},{"name":"RISE\u2010Health, Faculty of Medicine University of Porto Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7986-2425","authenticated-orcid":false,"given":"Gl\u00f3ria","family":"Concei\u00e7\u00e3o","sequence":"additional","affiliation":[{"name":"RISE\u2010Health, Faculty of Medicine University of Porto Porto Portugal"},{"name":"Cardiovascular Regeneration Program Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3769-8962","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Almeida\u2010Coelho","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine University of Porto Porto Portugal"},{"name":"RISE\u2010Health, Faculty of Medicine University of Porto Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4536-2315","authenticated-orcid":false,"given":"Diana","family":"Martins","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine University of Porto Porto Portugal"},{"name":"RISE\u2010Health, Faculty of Medicine University of Porto Porto Portugal"}]},{"given":"Isabel","family":"Miranda","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine University of Porto Porto Portugal"},{"name":"RISE\u2010Health, Faculty of Medicine University of Porto Porto Portugal"}]},{"given":"Alexandre","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine University of Porto Porto Portugal"},{"name":"RISE\u2010Health, Faculty of Medicine University of Porto Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0442-3947","authenticated-orcid":false,"given":"Carolina","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine University of Porto Porto Portugal"},{"name":"RISE\u2010Health, Faculty of Medicine University of Porto Porto Portugal"}]},{"given":"Sandra Marisa","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine University of Porto Porto Portugal"},{"name":"RISE\u2010Health, Faculty of Medicine University of Porto Porto Portugal"}]},{"given":"Jos\u00e9","family":"Sereno","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Coimbra Coimbra Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8952-8618","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Coimbra Coimbra Portugal"}]},{"given":"Ulrich","family":"Dischinger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Diabetes University Hospital W\u00fcrzburg W\u00fcrzburg Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5786-8447","authenticated-orcid":false,"given":"Henrique","family":"Gir\u00e3o","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Coimbra Coimbra Portugal"}]},{"given":"Adelino F.","family":"Leite\u2010Moreira","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, Faculty of Medicine University of Porto Porto Portugal"},{"name":"RISE\u2010Health, Faculty of Medicine University of Porto Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9192-7674","authenticated-orcid":false,"given":"Vasco","family":"Sequeira","sequence":"additional","affiliation":[{"name":"Department of Translational Science, DZHI Universit\u00e4tsklinikum W\u00fcrzburg W\u00fcrzburg Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1937-3782","authenticated-orcid":false,"given":"In\u00eas","family":"Falc\u00e3o\u2010Pires","sequence":"additional","affiliation":[{"name":"Department of Surgery 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