{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T21:41:24Z","timestamp":1794433284891,"version":"4.9.1"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":205,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018890","name":"Dutch Cardiovascular Alliance","doi-asserted-by":"publisher","award":["2020B008 RECONNEXT"],"award-info":[{"award-number":["2020B008 RECONNEXT"]}],"id":[{"id":"10.13039\/100018890","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018890","name":"Dutch Cardiovascular Alliance","doi-asserted-by":"publisher","award":["2020B008 RECONNEXT"],"award-info":[{"award-number":["2020B008 RECONNEXT"]}],"id":[{"id":"10.13039\/100018890","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Heart failure with preserved ejection fraction (HFpEF) is a major healthcare burden with limited treatment options. Geranylgeranylacetone (GGA) has been shown to improve myocardial compliance and endothelial function in preclinical models. Given the mechanistic profile of GGA and established safety as an over-the-counter drug in Asia, we performed a phase 2 clinical trial in patients with HFpEF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>GLADIATOR-HFpEF (NCT05672134, EudraCT2022-000655-36-NL) is a phase 2, double-blind, randomized, placebo-controlled, crossover trial. Patients were randomized 1:1 to GGA or placebo and treated for 3\u2009months with a washout-period of 6\u2009weeks. The dual primary endpoints were diastolic function (E\/e\u2032) and reactive hyperaemia index (RHI). Secondary endpoints were renal haemodynamic measurements; measured glomerular filtration rate and effective renal plasma flow, New York Heart Association class and 6-min walking test distance, cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP], high-sensitivity C-reactive protein), quality of life and laser speckle contrast analysis. Between March 2023 and December 2023, 43 patients were randomized and 39 were included in the per-protocol analysis. The cohort consisted of 28 women (72%), mean left ventricular ejection fraction was 59% and median NT-proBNP was 238\u2009ng\/L. There were no significant differences in the primary outcomes; E\/e\u2032 (\u22120.24 [\u22120.90\u20130.41], p\u2009=\u20090.46) and RHI (\u22120.02 [\u22120.36\u20130.33], p\u2009=\u20090.92). We found a decrease in BSA-adjusted ERPF (\u221229.62[\u221257.52;1.71], p\u2009=\u20090.038) and BSA-adjusted RBF (\u221250.20 [\u221295.80; \u22124.61], p\u2009=\u20090.032). There were no significant differences in safety outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Geranylgeranylacetone, a drug that showed promising effects on myocardial relaxation and endothelial function in preclinical studies, had no effects on diastolic function, endothelial function and exercise capacity in patients with HFpEF. GGA reduced effective renal plasma flow and renal blood flow. There were no differences in safety outcomes between GGA and placebo.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.3711","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T13:09:14Z","timestamp":1753708154000},"page":"3304-3311","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effects of Geranylgeranylacetone on Diastolic and Microvascular Function in Patients with Heart Failure with a Preserved Ejection Fraction: A Phase 2, Randomized, Placebo-Controlled, Crossover Trial"],"prefix":"10.1093","volume":"27","author":[{"given":"Soufiane","family":"Nassiri","sequence":"first","affiliation":[{"name":"Department of Cardiology, Amsterdam University Medical Center, Amsterdam Cardiovascular Sciences , Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Cardiovascular Sciences Heart Failure and Arrhythmias , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8403-0562","authenticated-orcid":false,"given":"Geert H.D.","family":"Voordes","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Centre Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loek","family":"van Heerebeek","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Onze Lieve Vrouw Gasthuis , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dani\u00ebl H.","family":"van Raalte","sequence":"additional","affiliation":[{"name":"Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne C.","family":"Verhaar","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, University Medical Center Utrecht , Utrecht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daan J.","family":"Touw","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merle M.","family":"Krebber","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, University Medical Center Utrecht , Utrecht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk J.","family":"Duncker","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Erasmus University Medical Center , Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etto C.","family":"Eringa","sequence":"additional","affiliation":[{"name":"Department of Physiology, Amsterdam University Medical Center, Amsterdam Cardiovascular Sciences , Amsterdam ,","place":["The Netherlands"]},{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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