{"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":1793945859714,"version":"4.8.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"19","license":[{"start":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T00:00:00Z","timestamp":1715040000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2024,5,7]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              We included 24 patients with heart failure with reduced ejection fraction (17 men; 65\u00b19 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2\u00b11.1 L\/min versus 5.0\u00b11.1 L\/min; difference, 0.3 L\/min [95% CI, 0.1\u20130.5), and pulmonary capillary wedge pressure was lower (8\u00b13 mm\u2009Hg versus 11\u00b13 mm\u2009Hg; difference, \u22122 mm\u2009Hg [95% CI, \u22124 to \u22121]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (\u22123 mm\u2009Hg [95% CI, \u22125 to \u22121] ) and higher mean CO (0.5 L\/min [95% CI, 0.1\u20130.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, \u221298 ng\/L [95% CI, \u2212185 to \u221223]), higher left ventricular ejection fraction (37\u00b15 versus 34\u00b15%;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.01), and lower left atrial and ventricular volumes.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>REGISTRATION:<\/jats:title>\n            <jats:p>\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              ; Unique identifier: NCT05161650.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.123.067971","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T09:02:23Z","timestamp":1711530143000},"page":"1474-1489","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":86,"title":["Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial"],"prefix":"10.1161","volume":"149","clinical-trial-number":[{"clinical-trial-number":"nct05161650","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5110-0656","authenticated-orcid":true,"given":"Kristoffer","family":"Berg-Hansen","sequence":"first","affiliation":[{"name":"Department of Cardiology (K.B.-H., N.G., K.H.C., B.L., M.J.A., S.H.P., R.N., H.W.), Aarhus University Hospital, Denmark."},{"name":"Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark (K.B.-H., N.G., K.H.C., B.L., S.H.P., N.M., H.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6363-7406","authenticated-orcid":true,"given":"Nigopan","family":"Gopalasingam","sequence":"additional","affiliation":[{"name":"Department of Cardiology (K.B.-H., N.G., K.H.C., B.L., M.J.A., S.H.P., R.N., H.W.), Aarhus University Hospital, Denmark."},{"name":"Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark (K.B.-H., N.G., K.H.C., B.L., S.H.P., N.M., H.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian Hylleberg","family":"Christensen","sequence":"additional","affiliation":[{"name":"Department of Cardiology (K.B.-H., N.G., K.H.C., B.L., M.J.A., S.H.P., R.N., H.W.), Aarhus University Hospital, Denmark."},{"name":"Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark (K.B.-H., N.G., K.H.C., B.L., S.H.P., N.M., H.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3749-6789","authenticated-orcid":true,"given":"Bertil","family":"Ladefoged","sequence":"additional","affiliation":[{"name":"Department of Cardiology (K.B.-H., N.G., K.H.C., B.L., M.J.A., S.H.P., R.N., H.W.), Aarhus University Hospital, Denmark."},{"name":"Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark 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