{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T22:44:45Z","timestamp":1784328285235,"version":"3.55.0"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMW","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002996","name":"Heart Foundation","doi-asserted-by":"publisher","award":["95105003"],"award-info":[{"award-number":["95105003"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NWO-ZonMW","award":["91818602"],"award-info":[{"award-number":["91818602"]}]},{"DOI":"10.13039\/100018890","name":"Dutch Cardiovascular Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018890","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Previous studies have shown that individuals with a hypertrophic cardiomyopathy (HCM) pathogenic variant (PV) or likely pathogenic variant (LPV) without a HCM phenotype (PV\/LPV carrier) have decreased myocardial external efficiency (MEE), which is thought to be a key pathomechanism in the onset and progression of HCM. Metabolic treatments improved exercise capacity in HCM patients, but evidence that such drugs correct reduced MEE is lacking. The ENERGY trial is a double-blind, placebo-controlled randomized clinical trial to define if the metabolic drug trimetazidine (TMZ) corrects reduced MEE in PV\/LPV carriers for HCM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>51 MYBPC3 or MYH7 PV\/LPV carriers were screened after which 40 were included and randomized into a treatment group (n = 20) or placebo group (n = 20) stratified for sex. Participants were treated with TMZ 20\u2005mg or placebo three times daily during 8 weeks. The main outcome of this study was MEE as measured by [11C]-acetate positron emission tomography\/computed tomography (PET\/CT) and cardiac magnetic resonance (CMR) scan. Secondary outcomes were exercise parameters as measured by cardio-pulmonary exercise testing (CPET). Drug safety was monitored by (serious) adverse event registration. Treatment groups were comparable in terms of age, sex, body mass index, P\/LP gene variant, and echocardiographic parameters without significant differences. Baseline CMR parameters and MEE were not significantly different between treatment groups. Eight weeks of treatment with TMZ did not significantly alter MEE compared to placebo. The mean MEE changed from 30.3 \u00b1 3.8 to 29.8 \u00b1 4.3% in the placebo group and from 30.1 \u00b1 4 to 29.1 \u00b1 4% in the TMZ group. Compared to placebo, the TMZ group did not have a significantly different MEE (difference \u22120.44, 95% interaction CI, \u22122.863 to 1.986, P = 0.68). The mean V\u2032O2max as a percentage of predicted V\u2032O2max (V\u2032O2max %pred) changed from 108 \u00b1 17 to 111 \u00b1 19 (95% CI, \u22126 to 10, P = 0.84) percent in the placebo group and from 105 \u00b1 17 to 113 \u00b1 14 (95% CI, 1 to 16, P = 0.03) percent in the TMZ group. After adjustment for baseline, the TMZ group had a significantly increased V\u2032O2max %pred (difference 6.37, 95% interaction CI, \u22123 to 16, P = 0.04).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The ENERGY trial is the first proof-of-concept randomized controlled trial to test the hypothesis that TMZ improves MEE in MYBPC3 or MYH7 PV\/LPV carriers. We conclude that metabolic therapy with TMZ may not correct the P\/LP gene variant-related decrease in MEE.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>Netherlands Trial Register NL7492 (URL https:\/\/onderzoekmetmensen.nl\/nl\/trial\/25078)<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf120","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T08:03:54Z","timestamp":1751443434000},"page":"1917-1928","source":"Crossref","is-referenced-by-count":1,"title":["Effect of trimetazidine dihydrochloride therapy on myocardial external efficiency in pre-clinical individuals with a hypertrophic cardiomyopathy pathogenic variant: results of the ENERGY trial"],"prefix":"10.1093","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8287-3707","authenticated-orcid":false,"given":"Beau Olivier","family":"van Driel","sequence":"first","affiliation":[{"name":"Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Location VUmc , VUmc O2 building, De Boelelaan 1117, Room 11W53, 1081HV Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6235-016X","authenticated-orcid":false,"given":"Stephan A C","family":"Schoonvelde","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Thorax Center, Cardiovascular Institute, Erasmus Medical Center, Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9066-7401","authenticated-orcid":false,"given":"Sonia","family":"Borodzicz-Jazdzyk","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Location VUmc , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7405-8668","authenticated-orcid":false,"given":"Roy","family":"Huurman","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Thorax Center, Cardiovascular Institute, Erasmus Medical Center, Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Visch","sequence":"additional","affiliation":[{"name":"Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Location VUmc , VUmc O2 building, De Boelelaan 1117, Room 11W53, 1081HV Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8826-7628","authenticated-orcid":false,"given":"Lourens","family":"Robbers","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Location VUmc , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Harms","sequence":"additional","affiliation":[{"name":"MedTrace Pharma A\/S , Horsholm ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0340-3433","authenticated-orcid":false,"given":"Judith","family":"Verhagen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus Medical Center, Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa","family":"Vermeer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam UMC, Location AMC , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4092-1907","authenticated-orcid":false,"given":"Joost","family":"van den Aardweg","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Amsterdam UMC , Location VUmc, Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1714-4652","authenticated-orcid":false,"given":"Albert C","family":"van Rossum","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Location VUmc , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2781-0145","authenticated-orcid":false,"given":"Tjeerd","family":"Germans","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Location VUmc , Amsterdam ,","place":["The 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