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

Background

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 I_Na). Induction of late I_Na 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 I_Na in thirteen known LQT3 mutations located in distinct regions of the channel.

Methods

The whole-cell patch-clamp technique was used to investigate the effect of empagliflozin on late I_Na 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.

Results

Empagliflozin selectively inhibited late I_Na 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 I_Na in mutations in the S4 voltage-sensing regions, altered channel gating, and slowed recovery from inactivation. Empagliflozin had no effect on late/peak I_Na 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.

Conclusions

Empagliflozin selectively inhibits late I_Na, 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.