QT prolongation, due to lengthening of the action potential duration in the ventricles, is a major risk factor of lethal ventricular arrhythmias. A widely known consequence of QT prolongation is the genesis of early afterdepolarizations (EADs), which are associated with arrhythmias through the generation of premature ventricular complexes (PVCs). However, the vast majority of the EADs observed experimentally in isolated ventricular myocytes are phase-2 EADs, and whether phase-2 EADs are mechanistically linked to PVCs in cardiac tissue remains an unanswered question. In this study, we investigate the genesis of PVCs using computer simulations with 8 different ventricular action potential models of various species. Based on our results, we classify PVCs as arising from two distinct mechanisms: repolarization gradient (RG)-induced PVCs and phase-2 EAD-induced PVCs. The RG-induced PVCs are promoted by increasing RG and L-type calcium current, and insensitive to gap junction coupling. EADs are not required for this PVC mechanism. In a paced beat, a single or multiple PVCs can occur depending on the properties of the RG. In contrast, phase-2 EAD-induced PVCs occur only when the RG is small and are suppressed by increasing RG and more sensitive to gap junction coupling. Unlike with RG-induced PVCs, in each paced beat, only a single EAD-induced PVC can occur no matter how many EADs in an AP. In the wide parameter ranges we explore, RG-induced PVCs can be observed in all models, but the EAD-induced PVCs can only be observed in 5 of the 8 models. The links between these two distinct PVC mechanisms and arrhythmogenesis in animal experiments and clinical settings are discussed.

中文翻译：

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QT间期延长引起室性早搏的机制

由于心室内动作电位持续时间的延长，QT 间期延长是致命性室性心律失常的主要危险因素。QT 延长的一个广为人知的后果是早期后除极 (EAD) 的发生，它通过室性早搏 (PVC) 的产生与心律失常相关。然而，在分离的心室肌细胞中通过实验观察到的绝大多数 EAD 都是 2 相 EAD，而 2 相 EAD 是否与心脏组织中的 PVC 在机械上相关仍然是一个悬而未决的问题。在这项研究中，我们使用不同物种的 8 种不同心室动作电位模型的计算机模拟来研究 PVC 的起源。根据我们的结果，我们将 PVC 归类为两种不同的机制：复极化梯度 (RG) 诱导的 PVC 和相 2 EAD 诱导的 PVC。RG 诱导的 PVC 通过增加 RG 和 L 型钙电流来促进，并且对间隙连接耦合不敏感。此 PVC 机制不需要 EAD。在有节奏的节拍中，根据 RG 的属性，可能会出现单个或多个 PVC。相反，阶段 2 EAD 诱导的 PVC 仅在 RG 较小时发生，并且通过增加 RG 和对间隙连接耦合更敏感来抑制。与 RG 诱发的 PVC 不同，在每个起搏节拍中，无论 AP 中有多少 EAD，都只能发生一次 EAD 诱发的 PVC。在我们探索的广泛参数范围内，RG 诱导的 PVC 可以在所有模型中观察到，但 EAD 诱导的 PVC 只能在 8 个模型中的 5 个中观察到。