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

Background: Clinical 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.

Methods: We 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 (V ) and intracellular calcium (Ca ) and a robust analytical method based on spatiotemporal entropy difference (E ) to investigate the hypothesis that early V /Ca uncoupling during TdP VT can play a primary role in perpetuation of VT episodes.

Results: We analyzed a total of 35 episodes of TdP VT from 14 guinea pig surrogate models of LQTS, including 23 ST and 12 NST VTs. E values for NST VT were significantly higher than E values for ST VT. Analysis of wave front topology during the early phase of ST VT showed the Ca wave front following closely V wave front consistent with a lower degree of E . In contrast, NST VT was associated with uncoupling of V /Ca wave fronts during the first 2 or 3 cycles of VT associated with early wave break propagation pattern.

Conclusions: Utilizing a robust analytical method we showed that, in comparison to ST TdP VT, NST VT was consistently predated by early uncoupling of V /Ca that destabilized wave front propagation and can explain a sustained complex reentrant excitation pattern.