The sodium/glucose cotransporter 2 inhibitor Empagliflozin inhibits long QT 3 late sodium currents in a mutation specific manner

Sodium/glucose cotransporter 2 inhibitors (SGLT2is) like empagliflozin have demonstrated cardioprotective effects in patients with or without diabetes. SGLT2is have been shown to selectively inhibit the late component of cardiac sodium current (late INa). Induction of late INa is the primary mechanism in the pathophysiology of congenital long QT syndrome type 3 (LQT3) gain-of-function mutations in the SCN5A gene encoding Nav1.5. We investigated empagliflozin's effect on late INa in thirteen known LQT3 mutations located in distinct regions of the channel. The whole-cell patch-clamp technique was used to investigate the effect of empagliflozin on late INa in recombinantly expressed Nav1.5 channels containing different LQT3 mutations. Molecular modeling of human Nav1.5 and simulations in a mathematical model of human ventricular myocytes were used to extrapolate our experimental results to excitation-contraction coupling. Empagliflozin selectively inhibited late INa in LQT3 mutations in the inactivation gate region of Nav1.5, without affecting peak current or channel kinetics. In contrast, empagliflozin inhibited both peak and late INa in mutations in the S4 voltage-sensing regions, altered channel gating, and slowed recovery from inactivation. Empagliflozin had no effect on late/peak INa or channel kinetics in channels with mutations in the putative empagliflozin binding region. Simulation results predict that empagliflozin may have a desirable therapeutic effect in LQT3 mutations in the inactivation gate region. Empagliflozin selectively inhibits late INa, without affecting channel kinetics, in LQT3 mutations in the inactivation gate region. Empagliflozin may thus be a promising precision medicine approach for patients with specific LQT3 mutations. [Display omitted] •Long QT syndrome type 3 is a heart rhythm disorder with limited treatment options.•Late sodium current is the primary driver of long QT syndrome type 3.•Empagliflozin selectively inhibits late sodium current.•Empagliflozin may be effective in certain long QT syndrome type 3 mutations.