The current positive inotropic interventions for the management of heart failure (HF) are all associated to an unchanged or increased long term mortality, which limit their use. Istaroxime (IST) is a novel positive inotrope able to inhibit Na+, K+ ATPase and to stimulate SERCA pump. We employed IST as a tool to assess the role of a mild SERCA stimulation as a positive inotropic intervention. In a guinea pig model of HF, where the sarcoplasmic reticulum (SR) function was deranged, IST was able to restore an optimal SR function, increase the SR Ca2+ content and to improve all the EC coupling parameters considered. The comparison if IST and digoxin, a pure inhibitor of Na+, K+ ATPase, in mouse ventricular myocytes, showed that IST was less pro-arrhythmic than digoxin, as already observed in guinea pig. Digoxin induced a rapid accumulation of cytosolic Ca2+, while IST did not, and neither compound directly affected SR Ca2+ leakage, suggesting that a better compartmentalization of the ion was achieved in the presence of IST by the stimulation of SERCA pump. We concluded that the mild stimulation of SERCA is associated to a reduced pro-arrhythmic effect, and that it might represent a promising target for a new class of positive inotropic interventions associated to a reduced long term mortality.

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