Aims Long QT syndrome (LQTS) carries a risk of life-threatening polymorphic ventricular tachycardia (Torsades de Pointes, TdP) and is a major cause of premature sudden cardiac death. TdP is induced by R-on-T premature ventricular complexes (PVCs), thought to be generated by cellular early-afterdepolarisations (EADs). However, EADs in tissue require cellular synchronisation, and their role in TdP induction remains unclear. We aimed to determine the mechanism of TdP induction in rabbit hearts with acquired LQTS (aLQTS). Methods and Results Optical mapping of action potentials (APs) and intracellular Ca2+ was performed in Langendorff-perfused rabbit hearts (n = 17). TdP induced by R-on-T PVCs was observed during aLQTS (50% K+/Mg++ & E4031) conditions in all hearts (p < 0.0001 vs control). Islands of AP prolongation bounded by steep voltage gradients (VGs) were consistently observed before arrhythmia and was more closely related to the PVC upstroke than EADs, both temporally (7 ± 5 ms vs 44 ± 27 ms, p < 0.0001) and spatially (1.0 ± 0.7 vs 3.6 ± 0.9 mm, p < 0.0001). PVCs were initiated at estimated voltages of approx. -40 mV and had upstroke dF/dtmax and Vm-Ca2+ dynamics compatible with ICaL activation. Computational simulations demonstrated that PVCs could arise directly from VGs, through electrotonic triggering of ICaL. In experiments and the model, sub-maximal L-type Ca2+ channel (LTCC) block (200 nM nifedipine and 90% gCaL respectively) abolished both PVCs and TdP in the continued presence of aLQTS. Conclusion These data demonstrate that ICaL activation at sites displaying steep VGs generates the PVCs which induce TdP, providing a mechanism and rationale for LTCC blockers as a novel therapeutic approach in LQTS.

中文翻译：

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获得性长 QT 综合征引发室性心律失常


目的 长 QT 综合征 (LQTS) 具有危及生命的多形性室性心动过速（Torsades de Pointes，TdP）的风险，是过早心源性猝死的主要原因。 TdP 是由 R-on-T 室性早搏复合波 (PVC) 引起的，被认为是由细胞早期后除极 (EAD) 产生的。然而，组织中的 EAD 需要细胞同步，它​​们在 TdP 诱导中的作用仍不清楚。我们的目的是确定获得性 LQTS (aLQTS) 兔心脏 TdP 诱导的机制。方法和结果 在 Langendorff 灌注的兔心脏 (n = 17) 中进行动作电位 (AP) 和细胞内 Ca2+ 的光学测绘。在所有心脏的 aLQTS（50% K+/Mg++ 和 E4031）条件下观察到由 R-on-T PVC 诱导的 TdP（p < 0.0001 与对照相比）。在心律失常之前一致观察到以陡峭电压梯度 (VG) 为界的 AP 延长岛，并且与 PVC 上冲的相关性比 EAD 更密切，无论是时间上 (7 ± 5 ms vs 44 ± 27 ms, p < 0.0001) 还是空间上 ( 1.0 ± 0.7 与 3.6 ± 0.9 毫米，p < 0.0001）。 PVC 在大约的估计电压下启动。 -40 mV，并具有与 ICaL 激活兼容的上冲程 dF/dtmax 和 Vm-Ca2+ 动力学。计算模拟表明 PVC 可以通过 ICaL 的电紧张触发直接从 VG 产生。在实验和模型中，在 aLQTS 持续存在的情况下，次最大 L 型 Ca2+ 通道 (LTCC) 阻断（分别为 200 nM 硝苯地平和 90% gCaL）消除了 PVC 和 TdP。结论 这些数据表明，在显示陡峭 VG 的位点处的 ICaL 激活会产生诱导 TdP 的 PVC，为 LTCC 阻滞剂作为 LQTS 的新型治疗方法提供了机制和原理。