Istaroxime, an emerging inotrope with less cardiotoxicity than digitalis

GONANO, LUIS ALBERTO; RACIOPPI, MARÍA FLORENCIA; MORELL, MALENA; BURGOS, JUAN IGNACIO

Beijing

Congreso; 2019 XXIII ISHR WORLD CONGRESS; 2019

International Society for Heart Research (ISHR)

Pharmacological inhibition of sodium/potassium ATPase (NKA) with digitalis improves cardiac contractility but also promote diastolic Ca2+ waves. We have demonstrated that acute exposure to high doses of digitalis induces CaMKII-dependent phosphorylation of RyR2 and Ca2+ related arrhythmias. In parallel, we showed that low “therapeutic” doses of digitalis activate CaMKII-dependent apoptosis in ventricular cardiomyocytes.Istaroxime has a dual effect which combines NKA inhibition with sarcoplasmic reticulum (SR)-Ca2+ uptake acceleration due to SERCA-PLB dissociation. This peculiar combination makes istaroxime an inotropic-lusitropic agent with lower arrhytmogenic potential compared to digitalis compounds. However, the impact of istaroxime on cardiomyocyte viability and apoptosis has never been addressed. Our hypothesis is that istaroxime can reach a significant inotropic response with lower induction of cardiomyocyte apoptosis.To investigate this, mouse ventricular cardiomyocytes were paced at 1 Hz and superfused with Hepes-buffer at 37 °C in the presence of ouabain 2 μM or istaroxime 10 μM, detecting that both promoted a similar increase in cell shortening. We also measured SR Ca2+ waves in Fluo-4 loaded cells to confirm if, after 1 h of incubation, istaroxime is less arrhytmogenic than ouabain. On average, 2 μM ouabain-treated cells presented a significantly higher Ca2+ waves frequency compared to 10 μM istaroxime-treated cells (0,135 ± 0,020 and 0,061 ± 0,013 waves/min respectively. n = 23 per group). Cardiomyocytes were cultured for 24 h at 37 °C and we observed a significant reduction in cell viability accompanied by an increase in caspase-3 activity in ouabain-treated cells. Interestingly, 10 μM and even 20 μM istaroxime did not significantly affect cell viability and caspase-3 activity compared to control without drugs (n = 5 cultures per group). We conclude that istaroxime is less cardiotoxic than ouabain, suggesting its potential benefit for the treatment of chronic heart failure.