Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart

Anh Tuan Ton,Andre Ghetti,Tamara Cotta,Ky Truong,Yannick Miron,Najah Abi-Gerges,Lana Rasoul,Ana Espinoza,William Nguyen,Guy Page,Andrew Macias,Tiara Wong,Eduardo Hernandez,Alexa Stafford,Christina Mai,Paul E Miller,Katrina Sweat,Valentyna Geft,Tim Indersmitten

doi:10.1038/s41598-021-91528-1

Abstract

Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues from donor hearts. Potentiation of late INa with ATX-II (anemonia sulcata toxin II) and E-4031 (selective blocker of the hERG channel) slowed the kinetics of action potential repolarization, impaired Ca2+ homeostasis, increased contractility, and increased the manifestation of arrhythmia markers. These effects could be reversed by late INa inhibitors, ranolazine and GS-967. We also report that atrial tissues from donor hearts affected by atrial fibrillation exhibit arrhythmia markers in the absence of drug treatment and inhibition of late INa with GS-967 leads to a significant reduction in arrhythmic behaviour. These findings reveal a critical role for the late INa in cardiac arrhythmias and suggest that inhibition of this conductance could provide an effective therapeutic strategy. Finally, this study highlights the utility of human ex-vivo heart models for advancing cardiac translational sciences.

Highlights

In current clamp recording of action potentials induced by current injection in isolated adult human ventricular cardiomyocytes, we found that the application of 0.1 μM GS-967 decreased the action potential duration and reduced the temporal variability in action potential duration at 90% repolarization (APD90) between consecutive beats, a biomarker for pro-arrhythmia[52], quantified as short-term variability in APD90 (STV(APD90)) (Fig. 2a–d)
Late INa; (2) late INa contributes to the normal human ventricular action potential plateau conductances; (3) enhancement of late INa can mimic LQTS3 and LQTS2 conditions and result in prolongation of ventricular action potential, with concomitant increase in the instability of action potential duration; (4) enhanced late INa generates abnormal ventricular Ca2+ dynamics; (5) treatments that enhance late INa and inhibit IKr increase ventricular and atrial contractility and cause arrhythmic contractions; (6) atrial tissues from donor hearts affected by atrial fibrillation exhibit spontaneous arrhythmic markers in the absence of drug treatment and inhibition of late INa led to a significant reduction of arrhythmia markers, indicating a possible direct contribution of late INa to atrial fibrillation and a therapeutic approach targeting this conductance
We found that, compared to cel lines stably expressing human Nav1.5 c hannels[56, 57] and rabbit ventricular myocytes[51], human primary cardiomyocytes and trabeculae are 2.5- to fivefold more sensitive to these gating modilators

Summary

Introduction

The increase in short-term variability of action potential duration measured in the presence of ATX-II suggests that enhancement of late INa could have a pro-arrhythmic effect in human adult cardiomyocytes. We assessed the effects of inhibition of late INa on repolarization abnormalities induced by inhibition of IKr. In isolated adult human cardiomyocytes, 1 μM E-4031 increased action potential duration and STV(APD90) (Fig. 4; Supplementary Fig. 2c).

Results

Conclusion