The modulation of SERCA pump activity as a tool for management of hearth failure

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.