T vector velocity: A new ECG biomarker for identifying drug effects on cardiac ventricular repolarization

BackgroundWe present a new family of ECG biomarkers for assessing drug effects on ventricular repolarization. We show that drugs blocking inward (depolarizing) ion currents cause a relative increase of the T vector velocity (TVV) and accelerate repolarization, while drugs blocking outward ion currents cause a relative decrease of the TVV and delay repolarization. The results suggest a link between the TVV and the instantaneous change of the cellular action potentials that may contribute to bridge the gap between the surface ECG and myocardial cellular processes.MethodsWe measure TVV as the time required to reach X% of the total Trajectory length of the T vector loop, denoted as TrX. Applied to data from two FDA funded studies (22+22 subjects, 5232+4208 ECGs) which target ECG effects of various ion-channel blocking drugs, the TrX effect profiles indicate increasingly delayed electrical activity over the entire repolarization process for drugs solely reducing outward potassium current (dofetilide, moxifloxacin). For drugs eliciting block of the inward sodium or calcium currents (mexiletine, lidocaine), the TrX effect profiles were consistent with accelerated electrical activity in the initial repolarization phase. For multichannel blocking drugs (ranolazine) or drug combinations blocking multiple ion currents (dofetilide + mexiletine, dofetilide + lidocaine), the overall TrX effect profiles indicate a superposition of the individual TrX effect profiles.ResultsThe parameter Tr40c differentiates pure potassium channel blocking drugs from multichannel blocking drugs with an area under the ROC curve (AUC) of 0.90, CI = [0.88 to 0.92]. This is significantly better than the performance of J-Tpeakc (0.81, CI = [0.78 to 0.84]) identified as the best parameter in the second FDA study. Combining the ten parameters Tr10c to Tr100c in a logistic regression model further improved the AUC to 0.94, CI = [0.92 to 0.96].ConclusionsTVV analysis substantially improves assessment of drug effects on cardiac repolarization, providing a plausible and improved mechanistic link between drug effects on ionic currents and overall ventricular repolarization reflected in the body surface ECG. TVV contributes to an enhanced appraisal of the proarrhythmic risk of drugs beyond QTc prolongation and J-Tpeakc.

研究背景：本研究提出一套全新的心电图（electrocardiogram, ECG）生物标志物体系，用于评估药物对心室复极过程的影响。研究发现，阻断内向（去极化）离子电流的药物会使T波向量速度（T vector velocity, TVV）相对升高，并加快复极进程；而阻断外向离子电流的药物则会使TVV相对降低，并延缓复极。本研究结果表明，TVV与细胞动作电位的瞬时变化存在关联，这有望填补体表心电图与心肌细胞生理过程之间的研究空白。

研究方法：本研究将TVV定义为达到T向量环总轨迹长度X%所需的时间，记为TrX。将该方法应用于两项由美国食品药品监督管理局（Food and Drug Administration, FDA）资助的研究数据（受试对象共22+22例，心电图样本共5232+4208份），这些研究旨在评估各类离子通道阻断剂类药物的心电图效应。结果显示，仅阻断外向钾电流的药物（多非利特、莫西沙星）的TrX效应曲线表明，其在整个复极过程中会逐渐延缓心肌电活动。对于阻断内向钠电流或钙电流的药物（美西律、利多卡因），其TrX效应曲线与复极早期心肌电活动加快的现象一致。对于多通道阻断剂类药物（雷诺嗪）或联合阻断多种离子电流的药物组合（多非利特+美西律、多非利特+利多卡因），整体TrX效应曲线显示出各单一药物TrX效应曲线的叠加效应。

研究结果：参数Tr40c可区分纯钾离子通道阻断剂与多通道阻断剂，其受试者工作特征曲线（Receiver Operating Characteristic curve, ROC）下面积（Area Under the Curve, AUC）为0.90，置信区间（Confidence Interval, CI）为[0.88, 0.92]。该性能显著优于第二项FDA研究中被认定为最优参数的J-T峰校正间期（J-Tpeakc，AUC=0.81，CI=[0.78, 0.84]）。将Tr10c至Tr100c共10个参数纳入逻辑回归模型后，AUC进一步提升至0.94，CI=[0.92, 0.96]。

研究结论：TVV分析可显著提升药物对心脏复极过程影响的评估效能，为药物对离子电流的作用与体表心电图所反映的整体心室复极状态之间搭建了合理且更完善的机制关联。相较于校正QT间期（QTc）延长与J-Tpeakc指标，TVV有助于更精准地评估药物的致心律失常风险。