The Sodium/Glucose Cotransporter 2 Inhibitor Empagliflozin Inhibits Long QT 3 Late Sodium Currents in a Mutation Specific Manner
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Background
Sodium/glucose cotransporter 2 inhibitors (SGLT2is) such as empagliflozin have demonstrated substantial cardioprotective effects in patients with or without diabetes. The SGLT2is have been shown to selectively inhibit the late component of cardiac sodium current (late I Na ). Induction of late I Na is also the primary mechanism involved in the pathophysiology of congenital long QT syndrome type 3 (LQT3) gain-of-function mutations in the SCN5A gene that encodes the major cardiac sodium channel isoform Nav1.5. Therefore, we investigated the effect of empagliflozin on late I Na in thirteen known LQT3 mutations located in distinct regions of the channel structure.
Methods
The whole-cell patch-clamp technique was used to investigate the effect of empagliflozin (10 µM) 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 residing in the inactivation gate region of Nav1.5, with no effect on either peak current or channel kinetics. In contrast, empagliflozin caused inhibition of both peak and late I Na in mutations in the S4 voltage-sensing regions as well as changes in activation and inactivation kinetics and a slowing of recovery from inactivation. Empagliflozin had no effect on late/peak I Na or channel kinetics in channels containing LQT3 mutations located in the putative empagliflozin binding region. Simulation of our experimental findings in a mathematical model of human ventricular myocytes predicts that empagliflozin may have a desirable therapeutic effect in LQT3 mutations located in the inactivation gate region.
Conclusions
Our results show that empagliflozin selectively inhibits late I Na , without affecting gating kinetics, in LQT3 mutations residing in the inactivation gate region. Patients with mutations in voltage-sensing regions are less suitable candidates as empagliflozin may prevent action potential firing. The SGLT2is may therefore be a promising novel precision medicine approach for patients with certain LQT3 mutations.
