Data_Sheet_1_Voltage/Calcium Uncoupling Underlies Sustained Torsade de Pointes Ventricular Tachyarrhythmia in an Experimental Model of Long QT Syndrome.PDF

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.

背景 临床经验表明，长QT综合征（long QT syndrome, LQTS）患者中，绝大多数尖端扭转型室性心动过速（Torsade de Pointes, TdP）相关室性快速性心律失常（ventricular tachyarrhythmia, VT）呈自限性（self-terminating, ST），但少数非自限性（non-self-terminating, NST）病例具有潜在致命性。临床心律失常学领域的核心议题之一，是阐明自限性与非自限性尖端扭转型室性心动过速的电生理机制差异。
方法 本研究以豚鼠海葵素A（Anthopleurin-A）诱导的长QT综合征实验模型——该模型是先天性LQT3型的精准替代模型——为研究对象，同步采集膜电压（Vm）与细胞内钙（Cai）的光学信号，并采用基于时空熵差（spatiotemporal entropy difference, Ed）的严谨分析方法，验证如下假说：尖端扭转型室性心动过速发作早期出现的Vm/Cai解偶联，可在室性快速性心律失常的持续发作中发挥核心作用。
结果 本研究共分析了来自14个豚鼠长QT综合征替代模型的35次尖端扭转型室性心动过速发作，其中23次为自限性发作，12次为非自限性发作。非自限性室性快速性心律失常的时空熵差（Ed）值显著高于自限性发作组。对自限性室性快速性心律失常早期阶段的波前拓扑结构分析显示，细胞内钙波前紧随膜电压波前传播，对应较低的Ed值；与之相反，非自限性室性快速性心律失常在发作最初2~3个周期即出现Vm/Cai波前解偶联，并伴随早期波裂传播模式。
结论 本研究通过严谨的分析方法证实，与自限性尖端扭转型室性心动过速相比，非自限性发作始终伴随早期Vm/Cai解偶联现象，该现象可破坏波前传播稳定性，并可解释持续性复杂折返激动的形成机制。