Date Published: July 8, 2019
Publisher: Public Library of Science
Author(s): Werner Bystricky, Christoph Maier, Gary Gintant, Dennis Bergau, Kent Kamradt, Patrick Welsh, David Carter, Randall Lee Rasmusson.
We 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.
We 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.
The 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].
TVV 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.
Drug effects on ion currents affecting the cardiac ventricular repolarization are well understood on the cellular level. On the ECG level, QTc prolongation is an established surrogate marker for Torsade-de-Pointes (TdP), and was introduced as an electrocardiographic biomarker standard for pro-arrhythmic risk assessment via regulatory pathways in 2005 . Since that time, no drugs have been withdrawn from the market due to unexpected induction of TdP, demonstrating that QTc shows good sensitivity in identifying potentially dangerous compounds. However, a major point of criticism relates to the well-known lack of specificity of QTc, which may result in early discontinuation of promising candidate drugs.
For Study A, Fig 3 displays the drug effects of dofetilide, quinidine, ranolazine, and verapamil in terms of an exposure-response relationship on the (double-delta) 30%, 50%, 70%, and 100% T vector trajectory quantiles. For dofetilide (Fig 3 left column) the slopes in all four graphs are positive. The remaining three compounds show a negative slope for Tr30c (Fig 3, row 1, columns 2–4). Fig 4 displays the effect profiles of all TrXc parameters using representative drug concentrations as described in section 3.4 and indicated as vertical grey lines in Fig 3. Please note that negative effect profile values relate to negative slopes in the exposure-response relation, and positive values correspond to positive slopes. Drug effects on the 10% quantile were negative for all four drugs. Dofetilide displayed a continuously increasing effect profile up to the 100% quantile. The quinidine effect profile was negative up to the 30% quantile with a stronger increase in the middle phase, and slightly reduced growth in the later repolarization phase. The ranolazine effect profile was negative up to the 40% quantile, increased in the mid repolarization phase and stayed close to constant till end of repolarization. Verapamil’s effect profile was slightly negative up to the 40% quantile and stayed close to zero up to the 100% quantile.
In this study, we present and evaluate heart rate corrected quantiles of the heart’s dipole vector trajectory along the 3-dimensional T vector loop as a new set of ECG biomarkers for assessing drug effects on the repolarization process. We define the X% T vector trajectory quantile TrX as the time after the J point when X% of the total T vector trajectory length has been reached. From a conceptual point of view, the major advancement entailed by TVV analysis is its capability to quantify drug effects as delays or accelerations quasi-continuously over the entire time range of repolarization. Thus, in contrast to QTc, drug effects can be associated with the relative phase of repolarization. This additional level of detail unveils that blocking of inward ion currents which maintain the plateau phase 2 of the cardiac action potential (late sodium and calcium) causes acceleration of the cellular repolarization process mainly during earlier repolarization. In contrast, blocking of the hERG/iKr current increasingly delays repolarization over its entire course. The method’s potential is highlighted by the fact that it clearly outperforms the current state of the art in separating multi-ion channel block from pure hERG/IKr block. But we are confident that the TVV approach can provide still more sophisticated information. We propose that systematic analysis of the TrX effect profile permits temporal disentanglement of superimposed multi-ion channel activity. It reveals information about the relative effect size of ion current blockade at the cellular level, and this information can be assessed from the surface ECG. We see an important future role for TVV analysis in characterizing a drug’s effects on ion channels in vivo and in the assessment of its pro-arrhythmic potential.
The T vector trajectory quantiles and the related effect profiles extend the discrete ECG characteristics Tpeak and QT to a quasi-continuous view on the repolarization process. Linking the effect size and direction to the relative phase of repolarization, they allow more detailed description of drug effects on the various ionic currents, and enable better differentiation of single versus multichannel block than the currently best biomarker for this purpose, J-Tpeak.