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

A modeled heart and an intersection of the ventricle wall. On the right, 3 types of myocardium cells are shown: Epi-, M, and Endo cells, where M cell has the maximum APD, and Epi cell has the shortest APD.

Transmural dispersion of repolarization is created by different Ikr block factors for Endo-, M, and Epi cell layers, where endocardial cells have the most Ikr block, and the epicardial cells have the least Ikr block.

T wave morphology parameters: asymmetry, notch, and flatness. The combination score (MCS) is formed by summing them together.

Comparing QTpeak and TpTe changes when TDR increases. On the left are QTpeak and TpTe changes for global TDR cases; on the right are changes for localized TDR cases. Both QTpeak and TpTe increased for global TDR cases, whereas only TpTe increased for localized TDR cases.

Comparing ECG morphology changes on global and localized TDR cases with Ikr block by 70% on Endo and M cell layers and 40% on epicardial layer. Row 1 is AP profiles of whole ventricle: earliest to latest AP endings; row 2 is the AP profile of anterior area: earliest Epi ending to latest M and Endo layer endings; row 3 is the VM_ant; row 4 is the VM of 12 leads; and row 5 is ECG of V3. Both global and localized Ikr blocks result in APD prolongation and triangularization. A, The case without Ikr block. B, Global TDR created block Ikr across all ventricle, and both QTpeak and TpTe prolonged and T wave notch appear before the major T peak. C, A case of localized TDR created by only applying Ikr block on anterior wall and TpTe change much more than QTpeak change, and T wave notch appears after the major T peak as indicated with the arrow sign.

Correlation of TDR and TpTe of VM_ant. T-peak to T-end interval of VM_ant is correlated with both global and localized TDR cases well, although it shows even higher correlation with global TDR changes.

The correlation of TDR and the T wave MCS. The morphology score is correlated with both global and localized TDR cases well, although it shows higher correlation with global TDR changes than localized cases.

Change TDR by increasing late sodium current (InaL) on different layers. The right side shows when InaL increases 50% on Endo and M cells and 20% on Epi cells and shows how AP profile and ECG morphology change. The left side shows the QTpeak and TpTe changes and the correlation of TDR versus TpTe, with r² = 0.99.

Measurements of TpTe of VM in d-sotalol clinical trail cases with 24-hour tracking. There are high-dose (320 mg) and low-dose (160 mg) cases. The upper traces are mean compound concentration curves, and the lower traces are TpTe curves. The correlation coefficients between the concentration and TpTe are 0.9 and 0.91 for low and high doses, respectively.

Measurements of the T wave morphology of the PCA vector in d-sotalol clinical trail cases with 24-hour tracking. There are high-dose (320 mg) and low-dose (160 mg) cases. The upper traces are combination score (MCS) curves on the left and QTcF curve on the right, and the lower traces are curves of flatness, asymmetry, and notches of T wave. New T wave morphologies follow the concentration curve shown in Fig. 10 very well.