Figure 5. Computational screening for dofetilide and moxifloxacin induced arrhythmia vulnerability.

(A) Predicted temporal APD dispersion of 1000 simulated O’Hara-Rudy human ventricular action potentials generated after incorporating physiological noise to induce beat-to-beat (bTb) variability at 1 Hz in the drug-free control case and following simulated application of dofetilide (2.72 ng/mL), and moxifloxacin (2.5 mg/L). Dispersion of APD was quantified as the difference between the maximum and minimum of 1000 individual cells (Control = 47 ms; Moxifloxacin 2.5 mg/L = 50 ms; Dofetilide 2.72 ng/mL = 78 ms). (B) Action potential triangulation as a function of APD prolongation for individual cells for control (slope = 0.25), Moxifloxacin 2.5 mg/L (slope = 0.34), and Dofetilide 2.72 ng/mL (slope = 0.66) conditions (C) Simulated bTb instability of action potentials to small perturbations before and after application of drugs. Poincaré plots of sequential APD pairs indicating bTb instability are shown. (D) Action potential adaptation curves show APD₉₀ at various pacing frequencies with or without dofetilide or moxifloxacin, demonstrating drug reverse use dependence. (E) Pseudo ECGs after a long pause (5000 ms) are shown for control, moxifloxacin 2.5 mg/L, and dofetilide 2.72 ng/mL conditions. (F) Relative increased T-wave area by 79% with dofetilide 2.72 ng/mL, and 9.4% with moxifloxacin 2.5 mg/L. (G) The Pearson’s correlation coefficients between paired TRIaD parameters. Pearson’s coefficient value indicated by the color gradient, where 1 is highly correlated (black). (H) bTb instability emerged as the most important feature from the TRIaD parameters. (I) Classified regions for control (n = 1000), dofetilide 1 ng/mL (n = 1000), dofetilide 2.72 ng/mL (n = 1000), Moxifloxacin 2.5 mg/L (n = 1000), and Moxifloxacin 4.73 mg/L (n = 1000) using bTb instability and T-wave area.