{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T06:17:39Z","timestamp":1793945859849,"version":"4.8.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Accumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Two independent rodent heart failure models were used for the studies: transverse aortic constriction\/myocardial infarction (MI) in mice and post-MI remodeling in rats. Seventy-five mice underwent a prevention treatment strategy with a KE comprised of hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) diet, and 77 rats were treated in either a prevention or treatment regimen using a commercially available \u03b2-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              The KE-1 diet in mice elevated \u03b2-hydroxybutyrate levels during nocturnal feeding, whereas the KE-2 diet in rats induced ketonemia throughout a 24-hour period. The KE-1 diet preventive strategy attenuated development of left ventricular dysfunction and remodeling post-transverse aortic constriction\/MI (left ventricular ejection fraction\u00b1SD, 36\u00b18 in vehicle versus 45\u00b111 in KE-1;\n              <jats:italic>P<\/jats:italic>\n              =0.016). The KE-2 diet therapeutic approach also attenuated left ventricular dysfunction and remodeling post-MI (left ventricular ejection fraction, 41\u00b111 in MI-vehicle versus 61\u00b17 in MI-KE-2;\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001). In addition, ventricular weight, cardiomyocyte cross-sectional area, and the expression of ANP (atrial natriuretic peptide) were significantly attenuated in the KE-2\u2013treated MI group. However, treatment with KE-2 did not influence cardiac fibrosis post-MI. The myocardial expression of the ketone transporter and 2 ketolytic enzymes was significantly increased in rats fed KE-2 diet along with normalization of myocardial ATP levels to sham values.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Chronic oral supplementation with KE was effective in both prevention and treatment of heart failure in 2 preclinical animal models. In addition, our results indicate that treatment with KE reprogrammed the expression of genes involved in ketone body utilization and normalized myocardial ATP production following MI, consistent with provision of an auxiliary fuel. These findings provide rationale for the assessment of KEs as a treatment for patients with heart failure.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circheartfailure.120.007684","type":"journal-article","created":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T10:00:17Z","timestamp":1609149617000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":145,"title":["Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9126-739X","authenticated-orcid":true,"given":"Salva R.","family":"Yurista","sequence":"first","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands (S.R.Y., H.H.W.S., K.T.N., D.J.v.V., R.A.d.B., B.D.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy R.","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (T.R.M., K.S.M., S.V.S., T.C.L., D.P.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herman H.W.","family":"Sillj\u00e9","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands (S.R.Y., H.H.W.S., K.T.N., D.J.v.V., R.A.d.B., B.D.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4979-5698","authenticated-orcid":true,"given":"Kirsten T.","family":"Nijholt","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands (S.R.Y., H.H.W.S., K.T.N., D.J.v.V., R.A.d.B., B.D.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendra S.","family":"McDaid","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (T.R.M., K.S.M., S.V.S., T.C.L., D.P.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swapnil V.","family":"Shewale","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (T.R.M., K.S.M., S.V.S., T.C.L., D.P.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa C.","family":"Leone","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (T.R.M., K.S.M., S.V.S., T.C.L., D.P.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8455-0100","authenticated-orcid":true,"given":"John C.","family":"Newman","sequence":"additional","affiliation":[{"name":"Division of Geriatrics, Buck Institute for Research on Aging, University of California, San Francisco (J.C.N., E.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Verdin","sequence":"additional","affiliation":[{"name":"Division of Geriatrics, Buck Institute for Research on Aging, University of California, San Francisco (J.C.N., E.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk J.","family":"van Veldhuisen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands (S.R.Y., H.H.W.S., K.T.N., D.J.v.V., R.A.d.B., B.D.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4775-9140","authenticated-orcid":true,"given":"Rudolf A.","family":"de Boer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands (S.R.Y., H.H.W.S., K.T.N., D.J.v.V., R.A.d.B., B.D.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3811-9491","authenticated-orcid":true,"given":"Daniel P.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (T.R.M., K.S.M., S.V.S., T.C.L., D.P.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1362-7019","authenticated-orcid":true,"given":"B. 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