A novel approach for the acute treatment of heart failure

Hani N. Sabbah, Carlo Gabriele Tocchetti, Mengjun Wang, Samantapudi Daya, Ramesh C. Gupta, Richard S. Tunin, Reza Mazhari, Eiki Takimoto, Nazareno Paolocci, Douglas Cowart, Wilson S. Colucci, David A Kass

Research output: Contribution to journalArticle

Abstract

Background.The nitroxyl (HNO) donor, Angeli fs salt, exerts positive inotropic, lusitropic, and vasodilator effects in vivo that are cAMP independent. Its clinical usefulness is limited by chemical instability and cogeneration of nitrite which itself has vascular effects. Here, we report on effects of a novel, stable, pure HNO donor (CXL-1020) in isolated myoctyes and intact hearts in experimental models and in patients with heart failure (HF). Methods and Results.CXL-1020 converts solely to HNO and inactive CXL-1051 with a t1/2 of 2 minutes. In adult mouse ventricular myocytes, it dose dependently increased sarcomere shortening by 75% to 210% (50.500 Êmol/L), with a .30% rise in the peak Ca2+ transient only at higher doses. Neither inhibition of protein kinase A nor soluble guanylate cyclase altered this contractile response. Unlike isoproterenol, CXL-1020 was equally effective in myocytes from normal or failing hearts. In anesthetized dogs with coronary microembolization-induced HF, CXL-1020 reduced left ventricular enddiastolic pressure and myocardial oxygen consumption while increasing ejection fraction from 27% to 40% and maximal ventricular power index by 42% (both P

Original languageEnglish (US)
Pages (from-to)1250-1258
Number of pages9
JournalCirculation: Heart Failure
Volume6
Issue number6
DOIs
StatePublished - 2013

Fingerprint

Treatment Failure
Muscle Cells
Heart Failure
Tissue Donors
Sarcomeres
Ventricular Pressure
Nitrites
Cyclic AMP-Dependent Protein Kinases
Vasodilator Agents
Isoproterenol
Oxygen Consumption
Blood Vessels
Theoretical Models
Dogs
oxyhyponitrite
Soluble Guanylyl Cyclase
nitroxyl

Keywords

  • Cardiomyopathies
  • Heart contractility
  • Humans
  • Muscle cells
  • Nitroxyl
  • Pharmacology
  • Vasodilator drugs

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Sabbah, H. N., Tocchetti, C. G., Wang, M., Daya, S., Gupta, R. C., Tunin, R. S., ... Kass, D. A. (2013). A novel approach for the acute treatment of heart failure. Circulation: Heart Failure, 6(6), 1250-1258. https://doi.org/10.1161/CIRCHEARTFAILURE.113.000632

A novel approach for the acute treatment of heart failure. / Sabbah, Hani N.; Tocchetti, Carlo Gabriele; Wang, Mengjun; Daya, Samantapudi; Gupta, Ramesh C.; Tunin, Richard S.; Mazhari, Reza; Takimoto, Eiki; Paolocci, Nazareno; Cowart, Douglas; Colucci, Wilson S.; Kass, David A.

In: Circulation: Heart Failure, Vol. 6, No. 6, 2013, p. 1250-1258.

Research output: Contribution to journalArticle

Sabbah, HN, Tocchetti, CG, Wang, M, Daya, S, Gupta, RC, Tunin, RS, Mazhari, R, Takimoto, E, Paolocci, N, Cowart, D, Colucci, WS & Kass, DA 2013, 'A novel approach for the acute treatment of heart failure', Circulation: Heart Failure, vol. 6, no. 6, pp. 1250-1258. https://doi.org/10.1161/CIRCHEARTFAILURE.113.000632
Sabbah HN, Tocchetti CG, Wang M, Daya S, Gupta RC, Tunin RS et al. A novel approach for the acute treatment of heart failure. Circulation: Heart Failure. 2013;6(6):1250-1258. https://doi.org/10.1161/CIRCHEARTFAILURE.113.000632
Sabbah, Hani N. ; Tocchetti, Carlo Gabriele ; Wang, Mengjun ; Daya, Samantapudi ; Gupta, Ramesh C. ; Tunin, Richard S. ; Mazhari, Reza ; Takimoto, Eiki ; Paolocci, Nazareno ; Cowart, Douglas ; Colucci, Wilson S. ; Kass, David A. / A novel approach for the acute treatment of heart failure. In: Circulation: Heart Failure. 2013 ; Vol. 6, No. 6. pp. 1250-1258.
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