Inhibition of cardiomyocytes late INa with ranolazine to prevent anthracyclines cardiotoxicity in experimental models in vitro and in vivo.

170 Background: Anthracyclines are first line drugs against cancer, but produce a well-known cardiomyopathy through multiple mechanisms, which also include Ca2+ overload due to reduced SERCA2a activity and inappropriate opening of the RyR2, and impaired myocardial energetics. Anthracyclines generate Reactive Oxigen and Nitrogen Species, posing the heart at increased demand for oxygen, thus setting the stage for a metabolic ischemia that also activates late INa, the target of ranolazine (RAN). Here, we aim at assessing whether RAN, diminishing intracellular Ca2+ through its inhibition of late INa, and enhancing myocardial glucose utilization (and/or reverting impairment of glucose utilization caused by chemotherapy) blunts anthracyclines cardiotoxicity. Methods: To assess for cardiotoxicity in vitro, rat H9C2 cardiomyoblasts were pretreated with RAN (0.1-1µM) for 72 hours and then treated with doxorubicin (DOX, 0.1 µM)for additional 24 hours. Cells counts were assessed by Trypan exclusion test. To evaluate...