Voltage/Calcium Uncoupling Underlies Sustained Torsade de Pointes Ventricular Tachyarrhythmia in an Experimental Model of Long QT Syndrome.

Herman D Himel,Nabil El-Sherif,Mohamed Boutjdir,Michael Cupelli

doi:10.3389/fphys.2021.617847

Abstract

BackgroundClinical experience showed that the majority of Torsade de Pointes (TdP) ventricular tachyarrhythmia (VT) in patients with long QT syndrome (LQTS) are self-terminating (ST), but the few that are non-self-terminating (NST) are potentially fatal. A paramount issue in clinical arrhythmology is to understand the electrophysiological mechanism of ST vs. NST TdP VT.MethodsWe investigated the electrophysiological mechanism of ST vs. NST TdP VT in the guinea pig Anthopleurin-A experimental model of LQTS, a close surrogate model of congenital LQT3. We utilized simultaneous optical recordings of membrane voltage (Vm) and intracellular calcium (Cai) and a robust analytical method based on spatiotemporal entropy difference (Ed) to investigate the hypothesis that early Vm/Cai uncoupling during TdP VT can play a primary role in perpetuation of VT episodes.ResultsWe analyzed a total of 35 episodes of TdP VT from 14 guinea pig surrogate models of LQTS, including 23 ST and 12 NST VTs. Ed values for NST VT were significantly higher than Ed values for ST VT. Analysis of wave front topology during the early phase of ST VT showed the Cai wave front following closely Vm wave front consistent with a lower degree of Ed. In contrast, NST VT was associated with uncoupling of Vm/Cai wave fronts during the first 2 or 3 cycles of VT associated with early wave break propagation pattern.ConclusionsUtilizing a robust analytical method we showed that, in comparison to ST TdP VT, NST VT was consistently predated by early uncoupling of Vm/Cai that destabilized wave front propagation and can explain a sustained complex reentrant excitation pattern.

Highlights

Patients with both congenital and acquired long QT syndrome (LQTS) are under the risk of developing ventricular tachyarrhythmia (VT), sometimes referred to as Torsade de Pointes (TdP) VT (El-Sherif and Turitto, 1999)
We analyzed the average cycle length (CL) of ST/VT and NST/VTs separately
While NST/VTs have slightly shorter CLs of 149 ± 49 ms compared to 161 ± 38 ms for ST/VTs, the difference was not statistically significant

Summary

Introduction

Patients with both congenital and acquired long QT syndrome (LQTS) are under the risk of developing ventricular tachyarrhythmia (VT), sometimes referred to as Torsade de Pointes (TdP) VT (El-Sherif and Turitto, 1999). A paramount issue in clinical arrhythmology is to understand the electrophysiological mechanism of ST vs NST TdP This is complicated, on one hand, by the different experimental models of LQTS that do not completely recapitulate all aspects of electrophysiology of the human syndrome. A case in point, a recent experimental study in a canine model of acquired LQTS that utilized tridimensional mapping techniques suggested that short-lasting ST TdP VT had a focal mechanism while long lasting NST TdP VT were maintained by reentrant excitation (Vandersickel et al, 2017). Clinical experience showed that the majority of Torsade de Pointes (TdP) ventricular tachyarrhythmia (VT) in patients with long QT syndrome (LQTS) are selfterminating (ST), but the few that are non-self-terminating (NST) are potentially fatal. A paramount issue in clinical arrhythmology is to understand the electrophysiological mechanism of ST vs. NST TdP VT

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Discussion

Conclusion