{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T17:23:37Z","timestamp":1768757017762,"version":"3.49.0"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2019,6,6]],"date-time":"2019-06-06T00:00:00Z","timestamp":1559779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"},{"start":{"date-parts":[[2019,6,6]],"date-time":"2019-06-06T00:00:00Z","timestamp":1559779200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100002491","name":"Bristol-Myers Squibb","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002491","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hospitalisation for acute heart failure remains a major public health problem with high prevalence, morbidity, mortality, and cost. Prior attempts to develop new therapies for this condition have not been successful. Nitroxyl (HNO) plays a unique role in cardiovascular physiology by direct post-translational modification of thiol residues on target proteins, specifically SERCA2a, phospholamban, the ryanodine receptor and myofilament proteins in cardiomyocytes. In animal models, these biological effects lead to vasodilatation, increased inotropy and lusitropy, but without tachyphylaxis, pro-arrhythmia or evidence of increased myocardial oxygen demand. BMS-986231 is an HNO donor being developed as a therapy for heart failure, and initial studies in patients with heart failure support the potential clinical value of these physiological effects. In this manuscript, we describe the ongoing phase II development programme for BMS-986231, which consists of three related randomised placebo-controlled clinical trials, StandUP-AHF, StandUP-Imaging and StandUP-Kidney, which are designed to provide evidence of tolerability and efficacy as well as confirm the anticipated physiological effects in patients with heart failure with reduced ejection fraction. These studies will set the stage for the further study of BMS-986231 in future phase III clinical trials.<\/jats:p>","DOI":"10.1002\/ejhf.1504","type":"journal-article","created":{"date-parts":[[2019,6,6]],"date-time":"2019-06-06T03:14:47Z","timestamp":1559790887000},"page":"1022-1031","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Rationale and Design for the Development of a Novel Nitroxyl Donor in Patients with Acute Heart Failure"],"prefix":"10.1093","volume":"21","author":[{"given":"G. Michael","family":"Felker","sequence":"first","affiliation":[{"name":"Duke Clinical Research Institute (DCRI), Duke University School of Medicine , Durham, NC ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Borentain","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb , Princeton, NJ ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John G.","family":"Cleland","sequence":"additional","affiliation":[{"name":"Robertson Centre for Biostatistics & Clinical Trials, University of Glasgow , Glasgow ,","place":["UK"]},{"name":"National Heart & Lung Institute, Royal Brompton & Harefield Hospitals, Imperial College , London ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary M.","family":"DeSouza","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb , Princeton, NJ ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul D.","family":"Kessler","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb , Princeton, NJ ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher M.","family":"O'Connor","sequence":"additional","affiliation":[{"name":"Inova Heart & Vascular Institute , Falls Church, VA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dietmar","family":"Seiffert","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb , Princeton, NJ ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John R.","family":"Teerlink","sequence":"additional","affiliation":[{"name":"San Francisco Veterans Affairs Medical Center and School of Medicine, University of California, San Francisco , San Francisco, CA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriaan A.","family":"Voors","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Centre Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John J.V.","family":"McMurray","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular & Medical Sciences, University of Glasgow , Glasgow ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,6,6]]},"reference":[{"key":"2026011721313281500_ejhf1504-bib-0001","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nrcardio.2012.181","article-title":"The disconnect between phase II and phase III trials of drugs for heart failure","volume":"10","author":"Vaduganathan","year":"2013","journal-title":"Nat Rev Cardiol"},{"key":"2026011721313281500_ejhf1504-bib-0002","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1002\/ejhf.153","article-title":"Breathlessness at rest is not the dominant presentation of patients admitted with heart failure","volume":"16","author":"Shoaib","year":"2014","journal-title":"Eur J Heart Fail"},{"key":"2026011721313281500_ejhf1504-bib-0003","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1056\/NEJMoa1005419","article-title":"Diuretic strategies in patients with acute decompensated heart failure","volume":"364","author":"Felker","year":"2011","journal-title":"N Engl J Med"},{"key":"2026011721313281500_ejhf1504-bib-0004","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.jacc.2017.04.025","article-title":"2017 ACC\/AHA\/HFSA Focused update of the 2013 ACCF\/AHA guideline for the management of heart failure: a report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America","volume":"70","author":"Yancy","year":"2017","journal-title":"J Am Coll Cardiol"},{"key":"2026011721313281500_ejhf1504-bib-0005","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). 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