Nitroxyl (HNO) a Novel Approach for the Acute Treatment of Heart Failure

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 Ca2+ 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][1], [NCT01092325][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01096043&atom=%2Fcirchf%2Fearly%2F2013%2F10%2F09%2FCIRCHEARTFAILURE.113.000632.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01092325&atom=%2Fcirchf%2Fearly%2F2013%2F10%2F09%2FCIRCHEARTFAILURE.113.000632.atom