Identify drug-induced T wave morphology changes by a cell-to-electrocardiogram model and validation with clinical trial data

BackgroundIncrease of repolarization heterogeneity has been identified as a major factor for drug-induced arrhythmia event like torsade de pointes. In recent years, there have been quite a few efforts for studying T wave morphology changes, hoping to identify more sensitive proarrhythmia electrocardiogram (ECG) biomarkers than QT interval. However, the associations among ECG morphologies and the repolarization heterogeneities are still not clear.MethodA cell-to-ECG model has been built by our group to study relationship between multiple factors of ion channels on the heart tissue and ECG morphology changes measured on the torso. More specifically, we varied both transmural (from Epi to Endo myocardium layers) and apex-to-base heterogeneities by blocking rapid delayed rectifier potassium current (Ikr), slow delayed rectifier potassium current (Iks), and late sodium current (InaL) with different extents on Epi, M, and Endo myocardium. On ECG measurement part, the study was focused on some new morphology-related features including T-peak to T-end (TpTe) interval, T wave flatness, T wave symmetric, and T wave notch. Two types of transmural dispersion of repolarization (TDR) were created: global and localized heterogeneities. Vector magnitude and principal component–based composite leads were formed from multiple chest leads for robustness against large variation of individual lead due to placement and noise issues. Cross-correlation methods were used to determine the relationship of the new ECG morphology features with the heterogeneities. All the ECG morphology measurements were first analyzed with the cell-to-ECG model and then validated with previously acquired clinical trial ECG data (d-sotalol).ResultsThe results based on our cell-to-ECG model showed that the new TpTe interval of the composite signal based on V2, V3, and V4 leads has the correlation coefficients of 0.99 and 0.98 with the simulated global and localized TDR, respectively, highest among other tested ECG parameters. The combined T wave morphology score has the correlation coefficients of 0.98 and 0.92 with the simulated global and localized TDR, respectively. The validation results of d-sotalol show that new TpTe measurement has a correlation coefficient of 0.90 with plasma concentration, and the parameter's correlation with heart rate is 0.02.ConclusionsThe study provided preliminary results showing the usefulness of the cell-to-ECG model for studying relationship between multiple ion-channel factors with ECG morphology changes. The global and localized TDR generate very different T wave morphologies. The newly identified T wave morphology parameters are highly correlated with transmural dispersion and are heart rate independent.