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

Abstract

16We present a new family TrX of ECG biomarkers based on the T vector velocity (TVV) for assessing 17 drug effects on ventricular repolarization. Assuming a link between the TVV and the instantaneous 18 change of the cellular action potentials, drugs accelerating repolarization by blocking inward 19 (depolarizing) ion currents cause a relative increase of the TVV, while drugs delaying repolarization by 20 blocking outward ion currents cause a relative decrease of the TVV. 21 Evaluating the published data from two FDA funded studies, the TrX effect profiles indicate 22 increasingly delayed electrical activity over the entire repolarization process for drugs solely reducing 23 outward potassium current (dofetilide, moxifloxacin). For drugs eliciting block of the inward sodium or 24 calcium currents (mexiletine, lidocaine), the TrX effect profiles were consistent with accelerated 25 electrical activity in the initial repolarization phase. For multichannel blocking drugs (ranolazine) or 26 drug combinations blocking multiple ion currents (dofetilide + mexiletine, dofetilide + lidocaine), the 27 overall TrX effect profiles indicate a superposition of the individual TrX effect profiles. 28 The parameter Tr40c allows separating pure potassium channel blocking drugs from multichannel 29 blocking drugs with an area under the ROC curve (AUC) value of 0.90, CI = [0.88 to 0.92]. This is 30 significantly larger than the performance of J-T peak c (0.81, CI = [0.78 to 0.84]) using the published data 31 from the second FDA study. Further performance improvement was achieved by combining the ten 32 parameters Tr10c to Tr100c in a logistic regression model, resulting in an AUC value of 0.94. 33 The TVV based approach substantially improves assessment of drug effects on cardiac repolarization, 34 providing a plausible and improved mechanistic link between drug effects on ionic currents and overall 35 ventricular repolarization reflected in the body surface ECG. TVV may contribute to a better 36 assessment of the proarrhythmic risk of drugs beyond QTc prolongation and JT peak c. 37 3 38

Identification of Drug-Induced Multichannel Block and Proarrhythmic Risk in Humans Using Continuous T Vector Velocity Effect Profiles Derived From Surface Electrocardiograms

“…A threshold value of p zero = 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 of 0.97. This is superior to the separation performance reported for J-T peak c ( Vicente et al, 2016 ) or for the 40% T vector trajectory duration quantile Tr40c ( Bystricky et al, 2019 ). Tr40c describes the drug-induced change of time to reach 40% of the T vector trajectory length.…”

“…These observations indicate consistency between the TVV analysis and the J-T peak c analyses observed in studies A, B, and C. However, we think that the major information characterizing balanced ion channel-blocking drugs is represented over the entire repolarization phase captured in the effect profile, but which is missed to some extent by looking at only one point in time (T peak ). From a method perspective, providing the effect profile in a continuous fashion constitutes a substantial extension to our previous work ( Bystricky et al, 2019 ). The latter described the effect profile using 10 separate mixed-effects models each associated with a fixed relative trajectory position.…”

“…The T peak was typically observed to be between 50 and 60% of the T vector trajectory length ( Bystricky et al, 2019 ). This means that the T vector trajectory path up to the point with largest distance from the origin is slightly longer than the trajectory path back to depolarization (visible in Figure 1 ).…”

“…In order to exclude possible late depolarization effects, the beginning of the T vector trajectory was determined as the J-point plus 20 ms. The T vector trajectory was determined as described in Bystricky et al (2019) . The trajectory quantiles for an ECG were, individually for each p, calculated as average of the beat related Tr(p) values.…”

“…Approaches to identify the T-wave peak in a more reproducible and stable way have been suggested ( Hnatkova et al, 2019 ). Recently, we presented a TVV-based analysis approach as a new method for electrocardiographic repolarization assessment and demonstrated that it outperforms J-T peak c as a biomarker for identification of multi-channel blocking drugs ( Bystricky et al, 2019 ).…”