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 _m ) and intracellular calcium (Ca _i ) and a robust analytical method based on spatiotemporal entropy difference (E _d ) to investigate the hypothesis that early V _m /Ca _i 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 _d values for NST VT were significantly higher than E _d values for ST VT. Analysis of wave front topology during the early phase of ST VT showed the Ca _i wave front following closely V _m wave front consistent with a lower degree of E _d . In contrast, NST VT was associated with uncoupling of V _m /Ca _i 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 _m /Ca _i that destabilized wave front propagation and can explain a sustained complex reentrant excitation pattern. [ABSTRACT FROM AUTHOR]