{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T06:10:25Z","timestamp":1788934225388,"version":"build-2803163510"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T00:00:00Z","timestamp":1579737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"},{"start":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T00:00:00Z","timestamp":1579737600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"CVie Therapeutics Limited"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Istaroxime is a first-in-class agent which acts through inhibition of the sarcolemmal Na+\/K+ pump and activation of the SERCA2a pump. This study assessed the effects of a 24\u2009h infusion of istaroxime in patients hospitalised for acute heart failure (AHF).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We included patients hospitalised for AHF with left ventricular ejection fraction \u226440% and E\/e\u2019 &amp;gt;\u200910. Patients were randomised to a 24\u2009h intravenous infusion of placebo or istaroxime at doses of 0.5\u2009\u03bcg\/kg\/min (cohort 1: placebo n = 19; istaroxime n = 41) or 1.0\u2009\u03bcg\/kg\/min (cohort 2: placebo n = 20, istaroxime n = 40). The primary endpoint of change in E\/e\u2019 ratio from baseline to 24\u2009h decreased with istaroxime vs. placebo (cohort 1: \u22124.55\u2009\u00b1\u20094.75 istaroxime 0.5\u2009\u03bcg\/kg\/min vs. \u22121.55\u2009\u00b1\u20094.11 placebo, P = 0.029; cohort 2: \u22123.16\u2009\u00b1\u20092.59 istaroxime 1.0\u2009\u03bcg\/kg\/min vs. \u22121.08\u2009\u00b1\u20092.72 placebo, P = 0.009). Both istaroxime doses significantly increased stroke volume index and decreased heart rate. Systolic blood pressure increased with istaroxime, achieving significance with the high dose. Self-reported dyspnoea and N-terminal pro-brain natriuretic peptide improved in all groups without significant differences between istaroxime and placebo. No significant differences in cardiac troponin absolute values or clinically relevant arrhythmias were observed during or after istaroxime infusion. Serious cardiac adverse events (including arrhythmias and hypotension) did not differ between placebo and istaroxime groups. The most common adverse events were injection site reactions and gastrointestinal events, the latter primarily with istaroxime 1.0\u2009\u03bcg\/kg\/min.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In patients hospitalised for AHF with reduced ejection fraction, a 24\u2009h infusion of istaroxime improved parameters of diastolic and systolic cardiac function without major cardiac adverse effects.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.1743","type":"journal-article","created":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T22:03:40Z","timestamp":1579817020000},"page":"1684-1693","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Treatment with 24\u2009Hour Istaroxime Infusion in Patients Hospitalised for Acute Heart Failure: A Randomised, Placebo-Controlled Trial"],"prefix":"10.1093","volume":"22","author":[{"given":"Valentina","family":"Carubelli","sequence":"first","affiliation":[{"name":"Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University and Civil Hospital of Brescia , Brescia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Heart Failure Center, Fuwai Hospital, National Center for Cardiovascular Diseases , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Metra","sequence":"additional","affiliation":[{"name":"Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University and Civil Hospital of Brescia , Brescia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Lombardi","sequence":"additional","affiliation":[{"name":"Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University and Civil Hospital of Brescia , Brescia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Michael","family":"Felker","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine and Duke Clinical Research Institute , Durham, NC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerasimos","family":"Filippatos","sequence":"additional","affiliation":[{"name":"National and Kapodistrian University of Athens , Athens ,","place":["Greece"]},{"name":"Medical School, University of Cyprus , Nicosia ,","place":["Cyprus"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Inova Heart and Vascular Institute , Falls Church, VA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Teerlink","sequence":"additional","affiliation":[{"name":"Section of Cardiology, San Francisco Veterans Affairs Medical Center , San Francisco, CA ,","place":["USA"]},{"name":"School of Medicine, University of California , San Francisco, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Simmons","sequence":"additional","affiliation":[{"name":"Windtree Therapeutics, Inc. , Warrington, PA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Segal","sequence":"additional","affiliation":[{"name":"Windtree Therapeutics, Inc. , Warrington, PA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Malfatto","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Auxologico Italiano, Department of Cardiovascular, Neural and Metabolic Sciences, S. Luca Hospital , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"La Rovere","sequence":"additional","affiliation":[{"name":"Istituti Clinici Scientifici Maugeri IRCCS, Department of Cardiology, Institute of Montescano , Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianfu","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial People\u2019s Hospital, First Affiliated Hospital of Nanjing Medical University , Nanjing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumin","family":"Han","sequence":"additional","affiliation":[{"name":"The General Hospital of Shenyang Military Region of Chinese People\u2019s Liberation Arm , Shenyang ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuyi","family":"Yuan","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Xi\u2019An Jiaotong University , Xi\u2019an ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Yao","sequence":"additional","affiliation":[{"name":"The First Hospital of Lanzhou University , Lanzhou ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Li","sequence":"additional","affiliation":[{"name":"Lee\u2019s Pharmaceutical Limited , Taipei ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lit Fui","family":"Lau","sequence":"additional","affiliation":[{"name":"CVie Therapeutics Limited , Taipei ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Bianchi","sequence":"additional","affiliation":[{"name":"Windtree Therapeutics, Inc. , Warrington, PA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Heart Failure Center, Fuwai Hospital, National Center for Cardiovascular Diseases , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Istaroxime ADHF Trial Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,1,23]]},"reference":[{"key":"2026011721370312500_ejhf1743-bib-0001","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":"2026011721370312500_ejhf1743-bib-0002","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1161\/CIR.0b013e31829e8807","article-title":"2013 ACCF\/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation\/American Heart Association Task Force on Practice Guidelines","volume":"128","author":"Yancy","year":"2013","journal-title":"Circulation"},{"key":"2026011721370312500_ejhf1743-bib-0003","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1002\/ejhf.289","article-title":"Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine","volume":"17","author":"Mebazaa","year":"2015","journal-title":"Eur J Heart Fail"},{"key":"2026011721370312500_ejhf1743-bib-0004","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1001\/jama.296.18.2217","article-title":"Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure","volume":"296","author":"Gheorghiade","year":"2006","journal-title":"JAMA"},{"key":"2026011721370312500_ejhf1743-bib-0005","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.pcad.2011.03.011","article-title":"Old and new intravenous inotropic agents in the treatment of advanced heart failure","volume":"54","author":"Metra","year":"2011","journal-title":"Prog Cardiovasc Dis"},{"key":"2026011721370312500_ejhf1743-bib-0006","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1093\/eurheartj\/ehr026","article-title":"Cardiac inotropes: current agents and future directions","volume":"32","author":"Hasenfuss","year":"2011","journal-title":"Eur Heart J"},{"key":"2026011721370312500_ejhf1743-bib-0007","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1016\/j.jacc.2019.02.051","article-title":"Cardiac calcitropes, myotropes, and mitotropes: JACC review topic of the week","volume":"73","author":"Psotka","year":"2019","journal-title":"J Am Coll Cardiol"},{"key":"2026011721370312500_ejhf1743-bib-0008","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/ejhf.991","article-title":"Long-term safety of intravenous cardiovascular agents in acute heart failure: results from the European Society of Cardiology Heart Failure Long-Term Registry","volume":"20","author":"Mebazaa","year":"2018","journal-title":"Eur J Heart Fail"},{"key":"2026011721370312500_ejhf1743-bib-0009","doi-asserted-by":"crossref","first-page":"3626","DOI":"10.1093\/eurheartj\/ehy600","article-title":"Treatments targeting inotropy","volume":"40","author":"Maack","year":"2019","journal-title":"Eur Heart J"},{"key":"2026011721370312500_ejhf1743-bib-0010","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1111\/bph.12278","article-title":"Istaroxime stimulates SERCA2a and accelerates calcium cycling in heart failure by relieving phospholamban inhibition","volume":"169","author":"Ferrandi","year":"2013","journal-title":"Br J Pharmacol"},{"key":"2026011721370312500_ejhf1743-bib-0011","doi-asserted-by":"crossref","first-page":"24A","DOI":"10.1016\/j.amjcard.2006.09.003","article-title":"Istaroxime, a stimulator of sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a activity, as a novel therapeutic approach to heart failure","volume":"99","author":"Micheletti","year":"2007","journal-title":"Am J Cardiol"},{"key":"2026011721370312500_ejhf1743-bib-0012","first-page":"141","article-title":"Combining SERCA2a activation and Na-K ATPase inhibition: a promising new approach to managing acute heart failure syndromes with low cardiac output","volume":"12","author":"Gheorghiade","year":"2011","journal-title":"Discov Med"},{"key":"2026011721370312500_ejhf1743-bib-0013","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1124\/jpet.104.077933","article-title":"Modulation of sarcoplasmic reticulum function by Na+\/K+ pump inhibitors with different toxicity: digoxin and PST2744 [(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride]","volume":"313","author":"Rocchetti","year":"2005","journal-title":"J Pharmacol Exp Ther"},{"key":"2026011721370312500_ejhf1743-bib-0014","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s10741-009-9153-y","article-title":"Agents with inotropic properties for the management of acute heart failure syndromes. Traditional agents and beyond","volume":"14","author":"Teerlink","year":"2009","journal-title":"Heart Fail Rev"},{"key":"2026011721370312500_ejhf1743-bib-0015","doi-asserted-by":"crossref","first-page":"2276","DOI":"10.1016\/j.jacc.2008.03.015","article-title":"Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized controlled trial in patients hospitalized with heart failure","volume":"51","author":"Gheorghiade","year":"2008","journal-title":"J Am Coll Cardiol"},{"key":"2026011721370312500_ejhf1743-bib-0016","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.ahj.2009.03.007","article-title":"Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: results from the Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized controlled trial in patients hospitalized with heart failure (HORIZON-HF) trial","volume":"157","author":"Shah","year":"2009","journal-title":"Am Heart J"},{"key":"2026011721370312500_ejhf1743-bib-0017","doi-asserted-by":"crossref","first-page":"1A","DOI":"10.1016\/j.amjcard.2006.09.001","article-title":"Istaroxime: an investigational luso-inotropic agent for acute heart failure syndromes","volume":"99","author":"Gheorghiade","year":"2007","journal-title":"Am J Cardiol"},{"key":"2026011721370312500_ejhf1743-bib-0018","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s10741-009-9136-z","article-title":"Istaroxime, a first in class new chemical entity exhibiting SERCA-2 activation and Na-K-ATPase inhibition: a new promising treatment for acute heart failure syndromes?","volume":"14","author":"Khan","year":"2009","journal-title":"Heart Fail Rev"},{"key":"2026011721370312500_ejhf1743-bib-0019","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1002\/ejhf.333","article-title":"In-hospital worsening heart failure","volume":"17","author":"Butler","year":"2015","journal-title":"Eur J Heart Fail"},{"key":"2026011721370312500_ejhf1743-bib-0020","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1093\/ejechocard\/jep007","article-title":"Recommendations for the evaluation of left ventricular diastolic function by echocardiography","volume":"10","author":"Nagueh","year":"2009","journal-title":"Eur J Echocardiogr"},{"key":"2026011721370312500_ejhf1743-bib-0021","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s10741-012-9315-1","article-title":"Current management and future directions for the treatment of patients hospitalized for heart failure with low blood pressure","volume":"18","author":"Gheorghiade","year":"2013","journal-title":"Heart Fail Rev"},{"key":"2026011721370312500_ejhf1743-bib-0022","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1002\/ejhf.890","article-title":"Clinical phenotypes and outcome of patients hospitalized for acute heart failure: the ESC Heart Failure Long-Term Registry","volume":"19","author":"Chioncel","year":"2017","journal-title":"Eur J Heart Fail"},{"key":"2026011721370312500_ejhf1743-bib-0023","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S1388-9842(02)00041-7","article-title":"The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure-a meta-regression analysis","volume":"4","author":"Thackray","year":"2002","journal-title":"Eur J Heart Fail"}],"container-title":["European Journal of Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ejhf.1743","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ejhf.1743","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/22\/9\/1684\/66111826\/eurjhf_22_9_1684.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/22\/9\/1684\/66111826\/eurjhf_22_9_1684.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T02:39:09Z","timestamp":1768703949000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eurjhf\/article\/22\/9\/1684\/8384617"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,23]]},"references-count":23,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,1,23]]},"published-print":{"date-parts":[[2020,9,1]]}},"URL":"https:\/\/doi.org\/10.1002\/ejhf.1743","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.737267548.793589940","asserted-by":"object"}]},"ISSN":["1388-9842","1879-0844"],"issn-type":[{"value":"1388-9842","type":"print"},{"value":"1879-0844","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,9]]},"published":{"date-parts":[[2020,1,23]]},"assertion":[{"value":"2019-09-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}