Introduction

Drug-induced block of the hERG potassium channel could predispose to torsade de pointes, depending on occurrence of concomitant blocks of the calcium and/or sodium channels. Since the hERG potassium channel block affects cardiac repolarization, the aim of this study was to propose a new reliable index for non-invasive assessment of drug-induced hERG potassium channel block based on electrocardiographic T-wave features.

Methods

ERD_30% (early repolarization duration) and T_S/A (down-going T-wave slope to T-wave amplitude ratio) features were measured in 22 healthy subjects who received, in different days, doses of dofetilide, ranolazine, verapamil and quinidine (all being hERG potassium channel blockers and the latter three being also blockers of calcium and/or sodium channels) while undergoing continuous electrocardiographic acquisition from which ERD_30% and T_S/A were evaluated in fifteen time points during the 24 h following drug administration (“ECG Effects of Ranolazine, Dofetilide, Verapamil, and Quinidine in Healthy Subjects” database by Physionet). A total of 1320 pairs of ERD_30% and T_S/A measurements, divided in training (50%) and testing (50%) datasets, were obtained. Drug-induced hERG potassium channel block was modelled by the regression equation B_ECG(%) = a·ERD_30% + b·T_S/A+ c·ERD_30%∙T_S/A· + d; B_ECG(%) values were compared to plasma-based measurements, B_REF(%).

Results

Regression coefficients values, obtained on the training dataset, were: a = −561.0 s⁻¹, b = −9.7 s, c = 77.2 and d = 138.9. In the testing dataset, correlation coefficient between B_ECG(%) and B_REF(%) was 0.67 (p < 10⁻⁸¹); estimation error was −11.5 ± 16.7%.

Conclusion

B_ECG(%) is a reliable non-invasive index for the assessment of drug-induced hERG potassium channel block, independently from concomitant blocks of other ions.

中文翻译：

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用于评估药物诱导的 hERG 钾通道阻滞的心电图指数

介绍

药物诱导的 hERG 钾通道阻滞可能导致尖端扭转型室性心动过速，这取决于钙和/或钠通道的伴随阻滞的发生。由于 hERG 钾通道阻滞影响心脏复极化，本研究的目的是提出一种新的可靠指标，用于基于心电图 T 波特征对药物诱导的 hERG 钾通道阻滞进行无创评估。

方法

在 22 名健康受试者中测量了ERD _30%（早期复极持续时间）和T _S/A （下行 T 波斜率与 T 波幅度比）特征，这些受试者在不同天接受了剂量的多非利特、雷诺嗪、维拉帕米和奎尼丁（均为 hERG 钾通道阻滞剂，后三种也是钙和/或钠通道阻滞剂）同时进行连续心电图采集，在服药后 24 小时内的 15 个时间点评估ERD _30%和T _S/A管理（“雷诺嗪、多非利特、维拉帕米和奎尼丁对健康受试者的心电图影响”数据库，由 Physionet 提供）。共1320对ERD _30%获得了分为训练（50%）和测试（50%）数据集的T _S/A测量值。药物诱导的 hERG 钾通道阻滞由回归方程B _ECG (%) = a· ERD _30%  + b· T _S/A + c· ERD _30% ∙ T _S/A · + d 建模；B _ECG (%) 值与基于血浆的测量值B _REF (%) 进行比较。

结果

在训练数据集上获得的回归系数值为：a = -561.0 s ^-1，b = -9.7 s，c = 77.2 和 d = 138.9。在测试数据集中，B _ECG (%) 和B _REF (%) 之间的相关系数为 0.67 ( p  < 10 ^-81 )；估计误差为 -11.5 ± 16.7%。

结论

B _ECG (%)是一种可靠的非侵入性指标，用于评估药物诱导的 hERG 钾通道阻滞，独立于其他离子的伴随阻滞。