Computational Analysis of the Mode of Action of Disopyramide and Quinidine on hERG-Linked Short QT Syndrome in Human Ventricles

Figure 1. Disopyramide and quinidine interactions with hERG channels. (Ai) Drug-free and (Aii) drug-bound (additional states shown in green) Markov chain models of IKr/hERG. Simulated (solid line) and experimental (points) mean fractional block by disopyramide (DISO) of IhERG tail currents following pulse protocol (shown inset) (Bi), and dose-response curve under WT (blue) and SQT1 mutant N588K (red) conditions (Bii), where IC50 values are 10.77 and 15.77 μM, respectively. Simulated (solid line) and experimental (points) mean fractional block by quinidine (QUIN) of IhERG during pulse protocol (shown inset) (Ci), and dose-response curve under WT (blue) and SQT1 mutant N588K (red) conditions (Cii), where IC50 values are 620 nm and 2.16 μM, respectively. Experimental data at 37°C are taken from Paul et al. (2001, 2002) and McPate et al. (2008). The light blue shaded area shown for reference in panels (Bii,Cii) corresponds to the concentration range of 1–10 μM.

Figure 2. Disopyramide and quinidine interactions with sodium channels. (A) Simulated (solid lines) and experimental (points) tonic block of sodium channels by disopyramide (DISO) and quinidine (QUIN), and (B) use-dependent block of sodium channels elicited using pulse protocol (n = 30 pulses) shown inset. Experimental data are taken from Koumi et al. (1992), where tonic block IC50 values are 36 and 17 μM for disopyramide and quinidine, respectively. The light blue shaded area shown for reference in panel (A) corresponds to the concentration range of 1–10 μM.

Figure 3. Single cell action potentials and current traces. (Ai) Endocardial action potential (AP) at 1 Hz under WT (silver, dashed line), SQT1 (red, solid line), SQT1 + 5μM disopyramide (DISO) (blue, solid line), and SQT1 + 2μM quinidine (QUIN) (green, solid line) conditions. Corresponding current traces are shown for IKr (Aii), INa (Aiii), and ICaL (Aiv). The degree of fractional block of IKr and INa is shown in (Av,Avi), respectively. The concentration dependence of the single cell AP duration at 90% repolarization (APD90) and maximum upstroke velocity (MUV) is shown in (Bi,Bii), respectively.

Figure 4. 1D transmural ventricular strand simulations. (A) Endocardial (solid line), mid-myocardial (dashed line), and epicardial (dotted line) action potentials (APs) at 1 Hz under WT, SQT1, SQT1 + 5 μM disopyramide (DISO), and SQT1 + 2 μM quinidine (QUIN) conditions (A). Corresponding pseudo ECGs (pECGs) are shown in (B), with the WT pECG (shown in gray) superimposed under that of the SQT1 condition for comparison. The QT interval, effective refractory period (ERP), and maximal transmural dispersion of repolarization (TDR) for WT, SQT1, and SQT1 + varying concentrations of disopyramide (DISO) and quinidine (QUIN) is shown in (Ci,Cii), respectively. Note that the y axis scale for QT interval and ERP is different to that of TDR.

Figure 5. Individual ionic contributions of IKr and INa to QT interval and ERP prolongation by disopyramide and quinidine. The dose-dependent increase in the QT interval (Ai,Bi) and effective refractory period (ERP) (Aii,Bii) is shown for disopyramide (DISO) (A) and quinidine (QUIN) (B) for the following scenarios: all combined actions (blue), actions on INa only (red), actions on IKr only (purple), and combined actions on INa and IKr only (green). Simulations conducted at 1 Hz.

Figure 6. Representative snapshots of re-entry under SQT1 and pharmacological modulation conditions. The evolution of scroll waves following initiation of re-entry for time t = 100, 200, 500, 1,000, 3,000, and 5,000 ms is shown for SQT1 (Ai), SQT1 + 2 μM disopyramide (DISO) (Bi), and SQT1 + 2 μM quinidine (QUIN) (Ci) conditions from an epicardial aspect. In each case, localized AP excitations (Aii,Bii,Cii), corresponding fractional block of INa (red) and IKr (blue) (Aiii,Biii,Ciii), and pseudo ECG traces (Aiv,Biv,Civ) are shown.

Figure 7. Schematic representation of anti-arrhythmic effects of disopyramide and quinidine in the setting of SQT1. The upper panel shows inhibition of INa and IKr as the principal mode of action of disopyramide and quinidine. At the cellular level, this corresponds to reduced maximum upstroke velocity (MUV), increased effective refractory period (ERP), action potential duration (APD), and rate adaptation, which is summarized in the middle panel. The lower panel shows consequent effects at the tissue level; reduced excitability and therefore reduced conduction velocity (CV), and prolonged QT interval, which translates to a reduction in the dominant frequency (DF) of re-entrant excitation waves and favors transition from multiple wavelet ventricular fibrillation (VF)- like wave patterns to single scroll wave re-entry and/or arrhythmia termination.