Nitroxyl (HNO) a Novel Approach for the Acute Treatment of Heart Failure.
Circ Heart Fail. 2013 Oct 9;
Authors: Sabbah HN, Tocchetti CG, Wang M, Daya S, Gupta RC, Tunin RS, Mazhari R, Takimoto E, Paolocci N, Cowart D, Colucci WS, Kass DA
Abstract
BACKGROUND: -The nitroxyl (HNO) donor, Angeli's salt (AS), exerts positive inotropic, lusitropic, and vasodilator effects in vivo that are cyclic AMP-independent. Its clinical utility is limited by chemical instability and co-generation of nitrite that 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 75-210% (50-500 μM), with a ~30% rise in the peak Ca(2+) transient only at higher doses. Neither protein-kinase-A or soluble guanylate-cyclase inhibition 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 LV end-diastolic pressure and myocardial oxygen-consumption while increasing ejection fraction from 27 to 40% and maximal ventricular power index by 42% (both p<0.05). In conscious dogs with tachypacing-induced HF, CXL-1020 increased contractility assessed by end-systolic elastance, and provided veno-arterial dilation. Heart rate was minimally altered. In patients with systolic HF, CXL-1020 reduced both left and right heart filling pressures and systemic vascular resistance, while increasing cardiac and stroke volume index. Heart rate was unchanged, and arterial pressure declined modestly.
CONCLUSIONS: -These data show the functional efficacy of a novel pure HNO donor to enhance myocardial function, and show first-in-man evidence for potential utility in heart failure. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01096043, NCT01092325.
PMID: 24107588 [PubMed - as supplied by publisher]