The long-lasting istaroxime metabolite PST3093 stimulates SERCA2a and reverses disease-induced changes in cardiac function

Background: and Purpose. Heart failure (HF) therapeutic toolkit would strongly benefit from the availability of ino-lusitropic agents with a favorable pharmacodynamics and safety profile. Istaroxime is an agent, combining Na+/K+ pump inhibition and SERCA2a stimulation, shown by phase 2 trials to be promising in the acute setting. As PST3093 is an istaroxime metabolite reaching plasma concentration and duration greater than those of istaroxime, its evaluation is indispensable to establish its contribution to the istaroxime clinical efficacy. Experimental Approach. We studied PST3093 for its effects on SERCA2a and Na+/K+ ATPase activities, Ca2+ dynamics in intact myocytes and hemodynamic effects in an in-vivo rat model of diabetic (streptozotocin (STZ)-induced) cardiomyopathy. Key Results. The results converge to identify PST3093 as a “selective” (i.e. devoid of Na+/K+ pump inhibition) SERCA2a activator, thus differentiating it from its parent compound istaroxime. In in-vivo echocardiographic assessment, PST3093 improved overall cardiac performance (stroke volume and cardiac output) without decreasing heart rate, thus reversing many of STZ-induced abnormalities. Modulation of both systolic and diastolic indexes contributed to the improvement. For i.v. administration, PST3093 toxicity was considerably lower than that of istaroxime and its evaluation against a panel of 50 targets commonly involved in cardiac and extracardiac side-effects, failed to reveal significant interactions. Conclusion and Implication. PST3093 is a “selective” SERCA2a activator, the prototype of a novel pharmacodynamic category with a potential in the ino-lusitropic approach to HF therapy that may contribute to the clinical efficacy of istaroxime infusion.