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Pharmacol Rep. 2013;65(5):1281-93. doi: 10.1016/s1734-1140(13)71486-5.
Identified as being the primary mechanism involved in the induction of torsades de pointes (TdP), early after-depolarisation (EAD) formation is an important parameter in cardiac safety pharmacology. Easily observed experimentally at the cellular or tissue level, EAD can also be simulated by computer algorithms using animal or human models. During the last decade, confidence in these algorithms has greatly increased. We investigated the putative usefulness of EAD simulation for cardiac safety pharmacology.
EAD simulations were performed in non-failing human ventricular myocytes using the O'Hara-Rudy dynamic model. The role of each cardiac current was investigated by modifying the amplitude of its activity in the model. Prediction of EAD induction by drugs was based on the ratio of their 50% inhibitory concentration values for various cardiac ionic currents to their maximal effective free therapeutic plasma concentration (EFTPCmax).
In the ventricular endocardial myocytes, EAD was only induced by at least 85% inhibition of the rapid delayed rectifier K(+) current (IKr). The other currents can either induce or prevent EAD under sub- (80% IKr inhibition) or up-threshold conditions (87% IKr inhibition) of EAD. The study of the ability of drugs to induce EAD resulted in a classification which was in agreement with the Tdp risk classification.
Based on EAD computer simulation within the human situation, the present study identified the role of various cardiac currents in the EAD formation and suggested that prediction of EAD formation can be useful for early cardiac safety pharmacology.
早期后除极（EAD）的形成被认为是导致尖端扭转型室性心动过速（TdP）的主要机制，它是心脏安全药理学中的一个重要参数。EAD 在细胞或组织水平上很容易通过实验观察到，也可以使用动物或人类模型通过计算机算法进行模拟。在过去十年中，人们对这些算法的信心大大增强。我们研究了 EAD 模拟在心脏安全药理学中的潜在用途。
使用 O'Hara-Rudy 动力学模型在非衰竭的人心室肌细胞中进行 EAD 模拟。通过改变模型中各心脏电流的活动幅度来研究各心脏电流的作用。药物诱导 EAD 的预测基于其对各种心脏离子电流的 50%抑制浓度值与最大有效游离治疗血浆浓度（EFTPCmax）的比值。
在心室内膜心肌细胞中，只有快速延迟整流钾电流（IKr）的抑制率至少达到 85%时才会诱发 EAD。在 EAD 亚阈值（IKr 抑制率 80%）或阈上条件（IKr 抑制率 87%）下，其他电流可诱发或预防 EAD。对药物诱导 EAD 的能力的研究导致了一种分类，该分类与 Tdp 风险分类一致。
基于人类情况下的 EAD 计算机模拟，本研究确定了各种心脏电流在 EAD 形成中的作用，并表明 EAD 形成的预测可能对早期心脏安全药理学有用。
