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Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure.

Publication ,  Journal Article
Felker, GM; Borentain, M; Cleland, JG; DeSouza, MM; Kessler, PD; O'Connor, CM; Seiffert, D; Teerlink, JR; Voors, AA; McMurray, JJV
Published in: Eur J Heart Fail
August 2019

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.

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Published In

Eur J Heart Fail

DOI

EISSN

1879-0844

Publication Date

August 2019

Volume

21

Issue

8

Start / End Page

1022 / 1031

Location

England

Related Subject Headings

  • Stroke Volume
  • Nitrogen Oxides
  • Humans
  • Heart Failure
  • Drug Development
  • Cardiovascular System & Hematology
  • Antioxidants
  • Acute Disease
  • 3201 Cardiovascular medicine and haematology
  • 1102 Cardiorespiratory Medicine and Haematology
 

Citation

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Felker, G. M., Borentain, M., Cleland, J. G., DeSouza, M. M., Kessler, P. D., O’Connor, C. M., … McMurray, J. J. V. (2019). Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure. Eur J Heart Fail, 21(8), 1022–1031. https://doi.org/10.1002/ejhf.1504
Felker, G Michael, Maria Borentain, John G. Cleland, Mary M. DeSouza, Paul D. Kessler, Christopher M. O’Connor, Dietmar Seiffert, John R. Teerlink, Adriaan A. Voors, and John J. V. McMurray. “Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure.Eur J Heart Fail 21, no. 8 (August 2019): 1022–31. https://doi.org/10.1002/ejhf.1504.
Felker GM, Borentain M, Cleland JG, DeSouza MM, Kessler PD, O’Connor CM, et al. Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure. Eur J Heart Fail. 2019 Aug;21(8):1022–31.
Felker, G. Michael, et al. “Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure.Eur J Heart Fail, vol. 21, no. 8, Aug. 2019, pp. 1022–31. Pubmed, doi:10.1002/ejhf.1504.
Felker GM, Borentain M, Cleland JG, DeSouza MM, Kessler PD, O’Connor CM, Seiffert D, Teerlink JR, Voors AA, McMurray JJV. Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure. Eur J Heart Fail. 2019 Aug;21(8):1022–1031.
Journal cover image

Published In

Eur J Heart Fail

DOI

EISSN

1879-0844

Publication Date

August 2019

Volume

21

Issue

8

Start / End Page

1022 / 1031

Location

England

Related Subject Headings

  • Stroke Volume
  • Nitrogen Oxides
  • Humans
  • Heart Failure
  • Drug Development
  • Cardiovascular System & Hematology
  • Antioxidants
  • Acute Disease
  • 3201 Cardiovascular medicine and haematology
  • 1102 Cardiorespiratory Medicine and Haematology