{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:25:00Z","timestamp":1785803100154,"version":"3.56.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":163,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/14\/77\/30913"],"award-info":[{"award-number":["FS\/14\/77\/30913"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/14\/77\/30913"],"award-info":[{"award-number":["FS\/14\/77\/30913"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Skeletal muscle energetic augmentation might be a mechanism via which intravenous iron improves symptoms in heart failure, but no direct measurement of intrinsic mitochondrial function has been performed to support this notion. This molecular substudy of the FERRIC-HF II trial tested the hypothesis that ferric derisomaltose (FDI) would improve electron transport chain activity, given its high dependence on iron\u2013sulfur clusters which facilitate electron transfer during oxidative phosphorylation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Vastus lateralis skeletal muscle biopsies were taken before and 2\u2009weeks after randomization. Mitochondrial complex I, II, and I&amp;II respiration were quantified with respirometry of permeabilized fresh skeletal muscle biopsies. Net respiratory capacities, reflecting respiration that is truly available for adenosine triphosphate generation, were calculated by subtracting non-phosphorylating LEAK respiration. Complex I\u2013V and myoglobin protein levels, and skeletal muscle fibre type composition were assayed. Patients randomised to FDI (n\u2009=\u200921) or placebo (n\u2009=\u200919) were similar (age 66\u2009\u00b1\u200913\u2009years, 73% men, left ventricular ejection fraction 37\u2009\u00b1\u20098%, 48% New York Heart Association class III, 50% diabetic). After 2\u2009weeks, total complex I-linked respiration (0.33 [interquartile range 0.24\u20130.37] vs. 0.19 [0.06\u20130.27] nmol\/min\/mg, p\u2009=\u20090.03) and net complex I-linked respiration (0.21 [0.16\u20130.24] vs. 0.11 [0.04\u20130.16] nmol\/min\/mg, p\u2009=\u20090.01) were higher in patients allocated to FDI. There was no intergroup difference in other respiratory states, in mitochondrial abundance as reflected by complex I\u2013V protein levels, and in skeletal muscle myoglobin and oxidative fibre type content.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Iron repletion induces an early, selective, and potentially direct enhancement of mitochondrial complex I-dependent respiration in the skeletal muscle of heart failure patients. This could be harnessed to optimize repletion protocols to maximize patient benefits.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.70028","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T08:14:54Z","timestamp":1757319294000},"page":"2343-2351","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ferric Derisomaltose Augments Intrinsic Skeletal Muscle Electron Transport Chain Activity in Heart Failure: A FERRIC-HF II Molecular Substudy"],"prefix":"10.1093","volume":"27","author":[{"given":"Mohamad F.","family":"Barakat","sequence":"first","affiliation":[{"name":"School of Cardiovascular & Metabolic Medicine and Science, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson","family":"Amaral","sequence":"additional","affiliation":[{"name":"School of Cardiovascular & Metabolic Medicine and Science, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Brayson","sequence":"additional","affiliation":[{"name":"School of Cardiovascular & Metabolic Medicine and Science, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London ,","place":["UK"]},{"name":"School of Life Sciences, University of Westminster"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Amin-Youssef","sequence":"additional","affiliation":[{"name":"King's College Hospital NHS Foundation Trust , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huda","family":"Abu-Own","sequence":"additional","affiliation":[{"name":"School of Cardiovascular & Metabolic Medicine and Science, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London ,","place":["UK"]},{"name":"King's College Hospital NHS Foundation Trust , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma","family":"Ayis","sequence":"additional","affiliation":[{"name":"School of Population Health and Environmental Sciences, King's College , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Papalia","sequence":"additional","affiliation":[{"name":"School of Cardiovascular & Metabolic Medicine and Science, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadi","family":"Jouhra","sequence":"additional","affiliation":[{"name":"School of Cardiovascular & Metabolic Medicine and Science, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Nabeebaccus","sequence":"additional","affiliation":[{"name":"School of Cardiovascular & Metabolic Medicine and Science, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Monaghan","sequence":"additional","affiliation":[{"name":"School of Cardiovascular & Metabolic Medicine and Science, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London ,","place":["UK"]},{"name":"King's College Hospital NHS Foundation Trust , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerry","family":"Carr-White","sequence":"additional","affiliation":[{"name":"School of Cardiovascular & Metabolic Medicine and Science, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London ,","place":["UK"]},{"name":"Guy's and St Thomas' NHS Foundation Trust , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Sleigh","sequence":"additional","affiliation":[{"name":"Wolfson Brain Imaging Centre, University of Cambridge School of Clinical Medicine , Cambridge ,","place":["UK"]},{"name":"Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Cambridge ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey","family":"Charles-Edwards","sequence":"additional","affiliation":[{"name":"School of Imaging Sciences and Biomedical Engineering, King's College , London ,","place":["UK"]},{"name":"Medical Physics, Division of Imaging Sciences and Biomedical Engineering, Guy's and St Thomas'-NHS Foundation Trust , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay M.","family":"Shah","sequence":"additional","affiliation":[{"name":"School of Cardiovascular & Metabolic Medicine and Science, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham J.","family":"Kemp","sequence":"additional","affiliation":[{"name":"Liverpool Magnetic Resonance Imaging Centre and Institute of Life Course and Medical Sciences, University of Liverpool , Liverpool ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience, University of Cambridge , Cambridge ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darlington O.","family":"Okonko","sequence":"additional","affiliation":[{"name":"School of Cardiovascular & Metabolic Medicine and Science, James Black Centre, King's College London British Heart Foundation Centre of Excellence , London ,","place":["UK"]},{"name":"King's College Hospital NHS Foundation Trust , London ,","place":["UK"]},{"name":"School of Population Health and Environmental Sciences, King's College , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"key":"2026021721495941800_ejhf70028-bib-0001","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jacc.2007.09.036","article-title":"Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency: FERRIC-HF: A randomized, controlled, observer-blinded trial","volume":"51","author":"Okonko","year":"2008","journal-title":"J Am Coll Cardiol"},{"key":"2026021721495941800_ejhf70028-bib-0002","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1056\/NEJMoa0908355","article-title":"FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency","volume":"361","author":"Anker","year":"2009","journal-title":"N Engl J Med"},{"key":"2026021721495941800_ejhf70028-bib-0003","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1161\/CIRCULATIONAHA.118.038516","article-title":"Effect of iron isomaltoside on skeletal muscle energetics in patients with chronic heart failure and iron deficiency","volume":"139","author":"Charles-Edwards","year":"2019","journal-title":"Circulation"},{"key":"2026021721495941800_ejhf70028-bib-0004","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1038\/s41598-021-03968-4","article-title":"Abnormal whole-body energy metabolism in iron-deficient humans despite preserved skeletal muscle oxidative phosphorylation","volume":"12","author":"Frise","year":"2022","journal-title":"Sci Rep"},{"key":"2026021721495941800_ejhf70028-bib-0005","doi-asserted-by":"crossref","first-page":"7023","DOI":"10.1113\/JP273839","article-title":"Oxidative phosphorylation: Regulation and role in cellular and tissue metabolism","volume":"595","author":"Wilson","year":"2017","journal-title":"J Physiol"},{"key":"2026021721495941800_ejhf70028-bib-0006","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/nature11871","article-title":"Crystal structure of the entire respiratory complex I","volume":"494","author":"Baradaran","year":"2013","journal-title":"Nature"},{"key":"2026021721495941800_ejhf70028-bib-0007","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.bbabio.2016.02.018","article-title":"The multitude of iron-sulfur clusters in respiratory complex I","volume":"1857","author":"Gnandt","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"2026021721495941800_ejhf70028-bib-0008","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.celrep.2015.09.023","article-title":"Lethal cardiomyopathy in mice lacking transferrin receptor in the heart","volume":"13","author":"Xu","year":"2015","journal-title":"Cell Rep"},{"key":"2026021721495941800_ejhf70028-bib-0009","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1016\/j.ebiom.2015.09.041","article-title":"Metabolic catastrophe in mice lacking transferrin receptor in muscle","volume":"2","author":"Barrientos","year":"2015","journal-title":"EBioMedicine"},{"key":"2026021721495941800_ejhf70028-bib-0010","first-page":"E535","article-title":"Distinguishing effects of anemia and muscle iron deficiency on exercise bioenergetics in the rat","volume":"246","author":"Davies","year":"1984","journal-title":"Am J Physiol"},{"key":"2026021721495941800_ejhf70028-bib-0011","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1111\/j.1365-2958.2006.05028.x","article-title":"Iron-sulphur clusters and the problem with oxygen","volume":"59","author":"Imlay","year":"2006","journal-title":"Mol Microbiol"},{"key":"2026021721495941800_ejhf70028-bib-0012","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1146\/annurev.biochem.74.082803.133518","article-title":"Structure, function, and formation of biological iron-sulfur clusters","volume":"74","author":"Johnson","year":"2005","journal-title":"Annu Rev Biochem"},{"key":"2026021721495941800_ejhf70028-bib-0013","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1016\/j.biocel.2009.03.013","article-title":"Capacity of oxidative phosphorylation in human skeletal muscle: New perspectives of mitochondrial physiology","volume":"41","author":"Gnaiger","year":"2009","journal-title":"Int J Biochem Cell Biol"},{"key":"2026021721495941800_ejhf70028-bib-0014","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1038\/nprot.2008.61","article-title":"Analaysis of mitochondrial function in situ in permeabilized muscle fibers, tissues and cells","volume":"3","author":"Kuznetsov","year":"2008","journal-title":"Nat Protoc"},{"key":"2026021721495941800_ejhf70028-bib-0015","first-page":"1","article-title":"Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis","volume":"2","author":"Gnaiger","year":"2020","journal-title":"Bioenerg Commun"},{"key":"2026021721495941800_ejhf70028-bib-0016","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.120.017091","article-title":"Unique transcriptome signature distinguishes patients with heart failure with myopathy","volume":"9","author":"Caspi","year":"2020","journal-title":"J Am Heart Assoc"},{"key":"2026021721495941800_ejhf70028-bib-0017","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1093\/gerona\/glac164","article-title":"Impact of aging and lifelong exercise training on mitochondrial function and network connectivity in human skeletal muscle","volume":"78","author":"Ringholm","year":"2023","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"2026021721495941800_ejhf70028-bib-0018","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1113\/JP284142","article-title":"Exercise and ageing impact the kynurenine\/tryptophan pathway and acylcarnitine metabolite pools in skeletal muscle of older adults","volume":"601","author":"Hinkley","year":"2023","journal-title":"J Physiol"},{"key":"2026021721495941800_ejhf70028-bib-0019","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1001\/jamacardio.2023.0957","article-title":"Skeletal muscle mitochondrial respiration and exercise intolerance in patients with heart failure with preserved ejection fraction","volume":"8","author":"Scandalis","year":"2023","journal-title":"JAMA Cardiol"},{"key":"2026021721495941800_ejhf70028-bib-0020","doi-asserted-by":"crossref","DOI":"10.3390\/nu13041056","article-title":"Iron deficiency without anemia decreases physical endurance and mitochondrial complex I activity of oxidative skeletal muscle in the mouse","volume":"13","author":"Rineau","year":"2021","journal-title":"Nutrients"},{"key":"2026021721495941800_ejhf70028-bib-0021","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1093\/cvr\/cvad092","article-title":"Preemptive iron supplementation prevents myocardial iron deficiency and attenuates adverse remodelling after myocardial infarction","volume":"119","author":"Chung","year":"2023","journal-title":"Cardiovasc Res"},{"key":"2026021721495941800_ejhf70028-bib-0022","doi-asserted-by":"crossref","DOI":"10.1155\/2017\/3647657","article-title":"Fe-S clusters emerging as targets of therapeutic drugs","volume":"2017","author":"Vernis","year":"2017","journal-title":"Oxid Med Cell Longev"},{"key":"2026021721495941800_ejhf70028-bib-0023","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/0005-2728(82)90292-4","article-title":"Effects of dietary iron deficiency of iron-sulfur proteins and bioenergetic functions of skeletal muscle mitochondria","volume":"679","author":"Maguire","year":"1982","journal-title":"Biochim Biophys Acta"},{"key":"2026021721495941800_ejhf70028-bib-0024","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.jchf.2014.06.008","article-title":"The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: Results from Q-SYMBIO: A randomized double-blind trial","volume":"2","author":"Mortensen","year":"2014","journal-title":"JACC Heart Fail"},{"key":"2026021721495941800_ejhf70028-bib-0025","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.exger.2017.01.013","article-title":"Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice","volume":"90","author":"Gusdon","year":"2017","journal-title":"Exp Gerontol"},{"key":"2026021721495941800_ejhf70028-bib-0026","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1093\/gerona\/glac238","article-title":"Mitochondrial energetics in skeletal muscle are associated with leg power and cardiorespiratory fitness in the study of muscle, mobility and aging","volume":"78","author":"Mau","year":"2023","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"2026021721495941800_ejhf70028-bib-0027","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.133289","article-title":"Impaired skeletal muscle mitochondrial bioenergetics and physical performance in chronic kidney disease","volume":"5","author":"Kestenbaum","year":"2020","journal-title":"JCI Insight"},{"key":"2026021721495941800_ejhf70028-bib-0028","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1113\/EP092337","article-title":"Development of a standardized single-session cardiopulmonary exercise test for combined assessment of peak oxygen uptake and on\/off-kinetics","volume":"110","author":"Santana","year":"2025","journal-title":"Exp Physiol"},{"key":"2026021721495941800_ejhf70028-bib-0029","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.1161\/01.CIR.91.12.2924","article-title":"Prolonged kinetics of recovery of oxygen consumption after maximal graded exercise in patients with chronic heart failure. Analysis with gas exchange measurements and NMR spectroscopy","volume":"91","author":"Cohen-Solal","year":"1995","journal-title":"Circulation"}],"container-title":["European Journal of Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/27\/11\/2343\/66833981\/eurjhf_27_11_2343.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/27\/11\/2343\/66833981\/eurjhf_27_11_2343.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T02:50:04Z","timestamp":1771383004000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eurjhf\/article\/27\/11\/2343\/8470318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,8]]},"references-count":29,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,9,8]]},"published-print":{"date-parts":[[2025,11,1]]}},"URL":"https:\/\/doi.org\/10.1002\/ejhf.70028","relation":{},"ISSN":["1388-9842","1879-0844"],"issn-type":[{"value":"1388-9842","type":"print"},{"value":"1879-0844","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,11]]},"published":{"date-parts":[[2025,9,8]]},"assertion":[{"value":"2025-02-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}