CHF prevalence is continuously increasing worldwide and maintains one of the poorest prognoses of any major disease. Abundant evidence points to derangement of Ca(2+) cycling as the primary biochemical mark of the failing myocyte. Istaroxime is a novel compound with a dual mechanism of action: inhibition of Na(+), K(+)-ATPase and stimulation of SERCA2a. The increase in cytoplasmic Ca(2+) due to Na(+), K(+)-ATPase inhibition together with greater sarcoplasmic reticulum reloading result in both increased inotropy and lusitropy. This effect is seen in normal and failing in vitro and in vivo models. Istaroxime improvement of the contraction-relaxation cycle constitutes a novel therapeutic approach to the treatment of heart failure.