Sensitivity analysis of the QT and JTpeak intervals from a high-resolution human left-ventricular wedge model

Abstract

There is an interest in looking at sub-intervals of the QT in the Comprehensive in-vitro Proarrhythmia Assay (CiPA) initiative. Here, we performed a sensitivity analysis of JTpeak and T-wave morphology (TWM) parameters computed on transmural ECGs, generated by a highresolution human left-ventricular wedge model, with a modified version of the ten Tusscher 2006 cardiac cell model, with respect to the block of the slow and rapid potassium channels (IKs and IKr), and the late sodium channel (NaL), from 0% to 90%. Moreover, we simulated the effects of Dofitilide and Ranolazine. TWM parameters were QT interval (QT), T-peak to T-end (TpTe), T amplitude (Tamp), J to T-peak (JTpeak), Flatness Score (FS), Asymmetry Score (AS), average APD90 (APD90avg), APD Dispersion (APD90Disp) and standard deviation of the re-polarization times (sρ). Sensitivities were computed as the percentage variation normalized at 50% block and they varied across ion channels and amount of block. QT interval, JTpeak and APD90avg performed similarly across channels (0.29). TpTe and sρ provided similar sensitivities (0.80 for both IKr and NaL, and 0.13 for IKs). AS resulted with the highest sensitivity to NaL block (8.35). Morover, the wedge model was capable to simulate the effects of the drugs. In conclusion, TWM parameters reflected ion channel alterations with different proportions.