{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T12:48:02Z","timestamp":1769086082157,"version":"3.49.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"vor","delay-in-days":2305,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2019,9,28]],"date-time":"2019-09-28T00:00:00Z","timestamp":1569628800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Research Foundation\u2014Flanders","award":["1127917N"],"award-info":[{"award-number":["1127917N"]}]},{"name":"Research Foundation-Flanders","award":["1127917N"],"award-info":[{"award-number":["1127917N"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Iron deficiency is common in heart failure with reduced ejection fraction (HFrEF). In patients with cardiac resynchronization therapy (CRT), it is associated with a diminished reverse remodelling response and poor functional improvement. The latter is partially related to a loss in contractile force at higher heart rates (negative force\u2013frequency relationship).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>The effect of intravenous ferric carboxymaltose on reverse remodelling following cardiac resynchronization therapy (IRON-CRT) trial is a multicentre, prospective, randomized, double-blind controlled trial in HFrEF patients who experienced incomplete reverse remodelling (defined as a left ventricular ejection fraction below &amp;lt;45%) at least 6 months after CRT. Additionally, patients need to have iron deficiency defined as a ferritin below 100 \u03bcg\/L irrespective of transferrin saturation or a ferritin between 100 and 300 \u03bcg\/L with a transferrin saturation &amp;lt;20%. Patients will be randomized to either intravenous ferric carboxymaltose (dose based according to Summary of Product Characteristics) or intravenous placebo. The primary objective is to evaluate the effect of ferric carboxymaltose on metrics of cardiac reverse remodelling and contractility, measured by the primary endpoint, change in left ventricular ejection fraction assessed by three-dimensional (3D) echo from baseline to 3 month follow-up and the secondary endpoints change in left ventricular end-systolic and end-diastolic volume. The secondary objective is to determine if ferric carboxymaltose is capable of improving cardiac contractility in vivo, by assessing the force\u2013frequency relationship through incremental biventricular pacing. A total of 100 patients will be randomized in a 1:1 fashion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The IRON-CRT trial will determine the effect of ferric carboxymaltose on cardiac reverse remodelling and rate-dependent cardiac contractility in HFrEF patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ehf2.12503","type":"journal-article","created":{"date-parts":[[2019,9,28]],"date-time":"2019-09-28T05:09:47Z","timestamp":1569647387000},"page":"1208-1215","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Rationale and Design of the IRON-CRT Trial: Effect of Intravenous Ferric Carboxymaltose on Reverse Remodelling Following Cardiac Resynchronization Therapy"],"prefix":"10.1093","volume":"6","author":[{"given":"Pieter","family":"Martens","sequence":"first","affiliation":[{"name":"Department of Cardiology, Ziekenhuis Oost-Limburg , Genk ,","place":["Belgium"]},{"name":"Doctoral School for Medicine and Life Sciences, Hasselt University , Diepenbeek ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Dupont","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Ziekenhuis Oost-Limburg , Genk ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeroen","family":"Dauw","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Ziekenhuis Oost-Limburg , Genk ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frauke","family":"Somers","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Ziekenhuis Oost-Limburg , Genk ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lieven","family":"Herbots","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Jessa Ziekenhuis , Hasselt ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Timmermans","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Jessa Ziekenhuis , Hasselt ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Verwerft","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Jessa Ziekenhuis , Hasselt ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wilfried","family":"Mullens","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Ziekenhuis Oost-Limburg , Genk ,","place":["Belgium"]},{"name":"Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University , Diepenbeek ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,9,28]]},"reference":[{"key":"2026012115083352300_ehf212503-bib-0001","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.ahj.2013.01.017","article-title":"Iron deficiency in chronic heart failure: an international pooled analysis","volume":"165","author":"Klip","year":"2013","journal-title":"Am Heart J"},{"key":"2026012115083352300_ehf212503-bib-0002","first-page":"1","article-title":"Impact of iron deficiency on exercise capacity and outcome in heart failure with reduced, mid-range and preserved ejection fraction","volume":"73","author":"Martens","year":"2017","journal-title":"Acta Cardiol"},{"key":"2026012115083352300_ehf212503-bib-0003","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/ejhf.823","article-title":"Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis","volume":"20","author":"Anker","year":"2018","journal-title":"Eur J Heart Fail"},{"key":"2026012115083352300_ehf212503-bib-0004","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.cardfail.2011.08.003","article-title":"Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure","volume":"17","author":"Jankowska","year":"2011","journal-title":"J Card Fail"},{"key":"2026012115083352300_ehf212503-bib-0005","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1002\/ejhf.1154","article-title":"Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function","volume":"20","author":"Hoes","year":"2018","journal-title":"Eur J Heart Fail"},{"key":"2026012115083352300_ehf212503-bib-0006","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1002\/ejhf.1174","article-title":"Cardiac iron deficiency\u2014how to refuel the engine out of fuel","volume":"20","author":"Martens","year":"2018","journal-title":"Eur J Heart Fail"},{"key":"2026012115083352300_ehf212503-bib-0007","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.amjcard.2016.09.017","article-title":"Impact of iron deficiency on response to and remodeling after cardiac resynchronization therapy","volume":"119","author":"Martens","year":"2017","journal-title":"Am J Cardiol"},{"key":"2026012115083352300_ehf212503-bib-0008","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1161\/CIRCGENETICS.109.871236","article-title":"Modulation of mitochondrial proteome and improved mitochondrial function by biventricular pacing of dyssynchronous failing hearts","volume":"3","author":"Agnetti","year":"2010","journal-title":"Circ Cardiovasc Genet"},{"key":"2026012115083352300_ehf212503-bib-0009","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1161\/CIRCEP.113.000400","article-title":"Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure","volume":"6","author":"Aiba","year":"2013","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"2026012115083352300_ehf212503-bib-0010","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3001909","article-title":"G\u03b1s-biased \u03b22-adrenergic receptor signaling from restoring synchronous contraction in the failing heart","volume":"3","author":"Chakir","year":"2011","journal-title":"Sci Transl Med"},{"key":"2026012115083352300_ehf212503-bib-0011","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1161\/CIRCRESAHA.116.305268","article-title":"Cardiac resynchronization therapy restores sympathovagal balance in the failing heart by differential remodeling of cholinergic signaling","volume":"116","author":"DeMazumder","year":"2015","journal-title":"Circ Res"},{"key":"2026012115083352300_ehf212503-bib-0012","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.yjmcc.2014.03.012","article-title":"Remodeling of the sarcomeric cytoskeleton in cardiac ventricular myocytes during heart failure and after cardiac resynchronization therapy","volume":"72","author":"Lichter","year":"2014","journal-title":"J Mol Cell Cardiol"},{"key":"2026012115083352300_ehf212503-bib-0013","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jacc.2007.07.087","article-title":"Myocardial gene expression in heart failure patients treated with cardiac resynchronization therapy responders versus nonresponders","volume":"51","author":"Vanderheyden","year":"2008","journal-title":"J Am Coll Cardiol"},{"key":"2026012115083352300_ehf212503-bib-0014","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1161\/CIRCRESAHA.111.246124","article-title":"Redox regulation of mitochondrial ATP synthase: implications for cardiac resynchronization therapy","volume":"109","author":"Wang","year":"2011","journal-title":"Circ Res"},{"key":"2026012115083352300_ehf212503-bib-0015","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1002\/ejhf.938","article-title":"Limited contractile reserve contributes to poor peak exercise capacity in iron-deficient heart failure","volume":"20","author":"Martens","year":"2018","journal-title":"Eur J Heart Fail"},{"key":"2026012115083352300_ehf212503-bib-0016","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.hrthm.2007.09.009","article-title":"Early and late effects of cardiac resynchronization therapy on force\u2013frequency relation and contractility regulating gene expression in heart failure patients","volume":"5","author":"Mullens","year":"2008","journal-title":"Heart Rhythm"},{"key":"2026012115083352300_ehf212503-bib-0017","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1056\/NEJMra063052","article-title":"The failing hear\u2014an engine out of fuel","volume":"356","author":"Neubauer","year":"2007","journal-title":"N Engl J Med"},{"key":"2026012115083352300_ehf212503-bib-0018","first-page":"362","article-title":"Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure","volume":"38","author":"Haddad","year":"2017","journal-title":"Eur Heart J"},{"key":"2026012115083352300_ehf212503-bib-0019","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.jacc.2008.11.024","article-title":"Insights from a cardiac resynchronization optimization clinic as part of a heart failure disease management program","volume":"53","author":"Mullens","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"2026012115083352300_ehf212503-bib-0020","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1056\/NEJMoa0908355","article-title":"Ferric carboxymaltose in patients with heart failure and iron deficiency","volume":"361","author":"Anker","year":"2009","journal-title":"N Engl J Med"},{"key":"2026012115083352300_ehf212503-bib-0021","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/ehf2.12006","article-title":"Rationale and design of the CONFIRM-HF study: a double-blind, randomized, placebo-controlled study to assess the effects of intravenous ferric carboxymaltose on functional capacity in patients with chronic heart failure and iron deficiency","volume":"1","author":"Ponikowski","year":"2014","journal-title":"ESC Heart Fail"},{"key":"2026012115083352300_ehf212503-bib-0022","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1002\/ejhf.592","article-title":"2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"18","author":"Ponikowski","year":"2016","journal-title":"Eur J Heart Fail"},{"key":"2026012115083352300_ehf212503-bib-0023","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1161\/CIRCULATIONAHA.117.027497","article-title":"Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency","volume":"136","author":"van Veldhuisen","year":"2017","journal-title":"Circulation"},{"key":"2026012115083352300_ehf212503-bib-0024","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/ehjci\/jer316","article-title":"EAE\/ASE recommendations for image acquisition and display using three-dimensional echocardiography","volume":"13","author":"Lang","year":"2012","journal-title":"Eur Heart J Cardiovasc Imaging"},{"key":"2026012115083352300_ehf212503-bib-0025","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/S0894-7317(03)00221-9","article-title":"Force\u2013frequency relationship in the echocardiography laboratory: a noninvasive assessment of Bowditch treppe?","volume":"16","author":"Bombardini","year":"2003","journal-title":"J Am Soc Echocardiogr"},{"key":"2026012115083352300_ehf212503-bib-0026","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1016\/j.jacc.2007.07.029","article-title":"Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency","volume":"50","author":"Toblli","year":"2007","journal-title":"J Am Coll Cardiol"},{"key":"2026012115083352300_ehf212503-bib-0027","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.pcad.2017.05.009","article-title":"Heart Failure with Myocardial Recovery - The Patient Whose Heart Failure Has Improved: What Next?","volume":"60","author":"Nijst","year":"2017","journal-title":"Prog Cardiovasc Dis"},{"key":"2026012115083352300_ehf212503-bib-0028","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/ehf2.12101","article-title":"Left ventricular ejection fraction recovery in patients with heart failure treated with intravenous iron: a pilot study","volume":"3","author":"Nunez","year":"2016","journal-title":"ESC Heart Fail"}],"container-title":["ESC Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fehf2.12503","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ehf2.12503","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ehf2.12503","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/eschf\/article-pdf\/6\/6\/1208\/66135935\/eschf_6_6_1208.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eschf\/article-pdf\/6\/6\/1208\/66135935\/eschf_6_6_1208.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T20:10:45Z","timestamp":1769026245000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eschf\/article\/6\/6\/1208\/8403485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,28]]},"references-count":28,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,9,28]]},"published-print":{"date-parts":[[2019,12,1]]}},"URL":"https:\/\/doi.org\/10.1002\/ehf2.12503","relation":{},"ISSN":["2055-5822"],"issn-type":[{"value":"2055-5822","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,12]]},"published":{"date-parts":[[2019,9,28]]},"assertion":[{"value":"2019-05-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}