Bystricky Werner, Maier Christoph, Gintant Gary, Bergau Dennis, Carter David
Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., North Chicago, IL, United States.
Department of Medical Informatics, Heilbronn University, Heilbronn, Germany.
Front Physiol. 2020 Sep 18;11:567383. doi: 10.3389/fphys.2020.567383. eCollection 2020.
We present continuous T vector velocity (TVV) effect profiles as a new method for identifying drug effects on cardiac ventricular repolarization. TVV measures the temporal change in the myocardial action potential distribution during repolarization. The T vector dynamics were measured as the time required to reach p percent of the total T vector trajectory length, denoted as Tr(p), with p in {1, …, 100%}. The Tr(p) values were individually corrected for heart rate at each trajectory length percentage p. Drug effects were measured by evaluating the placebo corrected changes from baseline of Tr(p)c jointly for all p using functional mixed effects models. The p-dependent model parameters were implemented as cubic splines, providing continuous drug effect profiles along the entire ventricular repolarization process. The effect profile distributions were approximated by bootstrap simulations. We applied this TVV-based analysis approach to ECGs available from three published studies that were conducted in the CiPA context. These studies assessed the effect of 10 drugs and drug combinations with different ion channel blocking properties on myocardial repolarization in a total of 104 healthy volunteers. TVV analysis revealed that blockade of outward potassium currents alone presents an effect profile signature of continuous accumulation of delay throughout the entire repolarization interval. In contrast, block of inward sodium or calcium currents involves acceleration, which accumulates during early repolarization. The balance of blocking inward versus outward currents was reflected in the percentage p of the T vector trajectory length where accelerated repolarization transitioned to delayed repolarization. Binary classification using a threshold p = 43% separated predominant hERG channel blocking drugs with potentially higher proarrhythmic risk (moxifloxacin, dofetilide, quinidine, chloroquine) from multichannel blocking drugs with low proarrhythmic risk (ranolazine, verapamil, lopinavir/ritonavir) with sensitivity 0.99 and specificity 0.97. The TVV-based effect profile provides a detailed view of drug effects throughout the entire ventricular repolarization interval. It enables the evaluation of drug-induced blocks of multiple cardiac repolarization currents from clinical ECGs. The proposed p parameter enhances identification of the proarrhythmic risk of a drug beyond QT prolongation, and therefore constitutes an important tool for cardiac arrhythmia risk assessment.
我们提出连续T向量速度（TVV）效应曲线，作为一种识别药物对心室复极化影响的新方法。TVV测量复极化期间心肌动作电位分布的时间变化。T向量动力学通过达到总T向量轨迹长度的p百分比所需的时间来测量，记为Tr(p)，其中p取值范围为{1, …, 100%}。在每个轨迹长度百分比p处，Tr(p)值会针对心率进行单独校正。使用功能混合效应模型，通过评估所有p的Tr(p)c相对于基线的安慰剂校正变化来测量药物效应。与p相关的模型参数通过三次样条实现，从而在整个心室复极化过程中提供连续的药物效应曲线。效应曲线分布通过自助模拟进行近似。我们将这种基于TVV的分析方法应用于在CiPA背景下开展的三项已发表研究中的心电图数据。这些研究总共评估了104名健康志愿者中10种具有不同离子通道阻断特性的药物及药物组合对心肌复极化的影响。TVV分析表明，单独阻断外向钾电流会在整个复极化间期呈现出延迟持续累积的效应曲线特征。相反，阻断内向钠电流或钙电流则涉及加速，这种加速在早期复极化期间累积。内向电流与外向电流阻断的平衡反映在T向量轨迹长度的百分比p上，此时加速复极化转变为延迟复极化。使用阈值p = 43%进行二元分类，可将具有潜在更高致心律失常风险的主要hERG通道阻断药物（莫西沙星、多非利特、奎尼丁、氯喹）与具有低致心律失常风险的多通道阻断药物（雷诺嗪、维拉帕米、洛匹那韦/利托那韦）区分开来，灵敏度为0.99，特异性为0.97。基于TVV的效应曲线提供了整个心室复极化间期药物效应的详细视图。它能够从临床心电图评估药物诱导的多种心脏复极化电流的阻断情况。所提出的p参数增强了对超出QT延长的药物致心律失常风险的识别，因此构成了心律失常风险评估的重要工具。
