Fig. 7.

In silico pharmacological results suggesting that GS-458967 can reduce all proarrhythmia-linked parameters set out in the TRIaD approach: Triangulation, reverse use dependence, beat-to-beat instability of action potential duration, as well as temporal and spatial action potential duration dispersion. Predicted temporal action potential duration dispersion of 1000 simulated myocyte action potentials generated after incorporating physiological noise to induce beat-to-beat variability at 1 Hz in (A) the drug-free control case, (B) effects of simulated application of the I_Kr blocker Dofetilide (16 nM) and (C) predicted effects of 0.3 μM GS-458967 with Dofetilide 16 nM. Action potential triangulation as a function of APD prolongation for individual myocytes for (D) control (slope = 0.37), (E) Dofetilide 16 nM (slope = 0.52) and (F) Dofetilide 16 nM + GS-458967 0.3 μM (slope = 0.35). (G) Instability of APD was quantified as the difference between the maximum and minimum of 1000 individual myocytes in the presence of physiological noise current as a function of prolongation of APD (shown in panels A–C). (H) Simulated beat-to-beat instability of rabbit ventricular myocyte action potentials to small perturbations before and after application of drugs. Poincaré plots of sequential APD pairs indicating beat-to-beat instability are shown for each case. (I) GS-458967 improved dofetilide induced reverse use dependence: Action potential adaptation curves show APD₉₀ at various pacing frequencies in the presence or absence of drugs.