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

Abstract

AbstractWe present a new family TrX of ECG biomarkers based on the T vector velocity (TVV) for assessing drug effects on ventricular repolarization. Assuming a link between the TVV and the instantaneous change of the cellular action potentials, drugs accelerating repolarization by blocking inward (depolarizing) ion currents cause a relative increase of the TVV, while drugs delaying repolarization by blocking outward ion currents cause a relative decrease of the TVV.Evaluating the published data from two FDA funded studies, 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.The parameter Tr40c allows separating pure potassium channel blocking drugs from multichannel blocking drugs with an area under the ROC curve (AUC) value of 0.90, CI = [0.88 to 0.92]. This is significantly larger than the performance of J-Tpeakc (0.81, CI = [0.78 to 0.84]) using the published data from the second FDA study. Further performance improvement was achieved by combining the ten parameters Tr10c to Tr100c in a logistic regression model, resulting in an AUC value of 0.94.The TVV based approach 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 may contribute to a better assessment of the proarrhythmic risk of drugs beyond QTc prolongation and JTpeakc.