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.