Empagliflozin and ROS-CaMKII-late sodium current signaling in heart failure with preserved ejection fraction.

Abstract

Empagliflozin has been shown to improve cardiovascular outcomes in patients with heart failure and preserved ejection fraction (HFpEF), independent of diabetes status. Preclinical studies showed that empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, can directly affect heart cells. SGLT2 expression is virtually absent in cardiomyocytes, suggesting off-target beneficial effects; however, exact signaling mechanisms remain elusive. Reductions in reactive oxygen species (ROS) production, Ca/calmodulin-dependent kinase II (CaMKII) activity, and late Na+ current (INaL) have been implicated in empagliflozin's action. We tested for empagliflozin effects on INaL and consequent action potential duration (APD) changes in two complementary translational murine HFpEF models that exhibit different pathophysiology. Both HFpEF models combine metabolic and hemodynamic stresses, and exhibit diastolic dysfunction, but one has much more marked hyperglycemia. Empagliflozin pretreatment of isolated myocytes, but not its acute application, reduced the INaL, and attenuated APD prolongation and delayed afterdepolarizations in both HFpEF models. CaMKII inhibition closely mimicked these effects. Moreover, myocytes with oxidation-resistant mutations in CaMKII (MM281/282VV) prevented both H2O2-induced increase in INaL and suppression by empagliflozin. Our data suggest that empagliflozin likely regulates INaL in HFpEF by an indirect mechanism, which could include limiting ROS and its ability to activate CaMKII. In conclusion, suppression of INaL and CaMKII by empagliflozin reverses proarrhythmic APD changes and Ca handling impairments, thus may exert antiarrhythmic properties and improve diastolic function in HFpEF.