In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome

Figure 1. Propafenone 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 0.5 μM propafenone (PROPAF) of IhERG during pulse protocol (shown inset) (Bi), and dose-response curve under WT (blue) and SQT1 mutant N588K (red) conditions (Bii), where IC50 values are 390 nM and 936 nM (2.4-fold increase), respectively. (Ci) Simulated and (Cii) experimental current traces in response to a 10,000 ms depolarising voltage step to 0 mV from a holding potential of −80 mV (Di,Dii) under control conditions and with application of 0.5 μM PROPAF – these data were used to validate and not to further train the model. Experimental data at 37°C are taken from Paul et al. (2002) and McPate et al. (2008).

Figure 2. Propafenone interactions with sodium channels. (Ai) Simulated (solid lines) and experimental (points) use-dependent block of sodium channels by propafenone (PROPAF) elicited using a series of 8 pulses from −90 mV to 0 mV at 3 Hz for three different test concentrations. (Aii) Steady state block of sodium channels using pulses from −90 mV to 0 mV at 3 Hz until a steady state was achieved. Experimental data are taken from Harmer et al. (2008), where the steady state block IC50 value is given as 1.4 μM. (B) Simulated and (C) experimentally-measured PROPAF-induced reduction in maximum upstroke velocity (V°max) upon application of 0.3 and 1.5 μM PROPAF at a cycle length (CL) of (i) 500 ms and (ii) 300 ms. All V°max reductions are relative to the control (C) value at a CL of 500 ms. Experimental data, recorded from canine atrial myocytes, are taken from Burashnikov et al. (2012).

Figure 3. Effects of the N588K-hERG mutation at the single cell and whole human atria level. (Ai) Single cell action potential profiles under WT (blue), WT-N588K (green), and N588K (red) conditions at a pacing frequency of 1 Hz, with corresponding current traces for (Aii) IKr, (Aiii) IK1, (Aiv) IKs, and (Av) ICaL, and (Avi) a summary of the measured APD90. (B) Activation-recovery interval (ARI) maps under (i) WT, (ii) WT-N588K, and (iii) N588K conditions. (Ci) View looking into the cavities of the 3D anatomical human atria model, with the following regions highlighted: crista terminalis (CT), left atrium (LA), pectinate muscles (PM), pulmonary veins (PV), and right atrium (RA). (Cii) Measured dispersion of activation-recovery interval, ΔARI, between different atrial regions under WT and SQT1 mutation conditions.

Figure 4. Scroll waves under WT and SQT1 mutation conditions in the 3D anatomical human atria model. (i) Evolution of scroll waves following initiation of re-entry in a clockwise configuration (from a RA posterior wall aspect) at times t = 100 ms, t = 1,000 ms, t = 5,000 ms, and t = 10,000 ms under (A) WT, (B) WT-N588K, and (C) N588K conditions, with (ii) corresponding pseudo ECGs taken from the first 5.0 s of re-entry simulations.

Figure 5. Effects of class I drugs on human atrial electrophysiology in SQT1. Effects of (A) disopyramide (DISO), (B) quinidine (QUIN), and (C) propafenone (PROPAF) on (i) single human atrial cell action potentials (APs) under wild type (WT) conditions (blue, dashed line), drug-free WT-N588K (SQT1) conditions (green, solid line), and SQT1 + varying drug concentrations (purple, orange, and red solid lines). Corresponding fractional block of (ii) IKr and (iii) INa, and (iv) increase in APD90 (red) and effective refractory period (ERP; blue). (D) Activation sequences in the 3D anatomical human atria model under (i) drug-free SQT1 (control – C), (ii) SQT1 + 2 μM DISO, (iii) SQT1 + 2 μM QUIN, and (iv) SQT1 + 0.5 μM PROPAF conditions, with corresponding (E) activation (ACT) time summarized as a barchart. All simulations performed at a basic cycle length of 1,000 ms.

Figure 6. Re-entry dynamics in homogeneous 2D sheets upon application of disopyramide, propafenone, and quinidine in SQT1 mutation conditions. (A) Representative snapshots of re-entrant spiral waves under (i) drug-free SQT1 and (ii) SQT1 + 5 μM disopyramide (DISO) conditions at times, t = 250, 500, 750, and 1,000 ms following re-entry initiation, with spiral wave core trajectories superimposed onto membrane potentials in black. Spiral wave core trajectories over a 5,000 ms period under (Bi, Ci, Di) drug-free SQT1 conditions, and upon application of (Bii) 1 μM, (Biii) 2 μM, and (Biv) 5 μM DISO, (Cii) 1 μM, (Ciii) 2 μM, and (Civ) 5 μM quinidine (QUIN), and (Dii) 0.2 μM, (Diii) 0.5 μM, and (Div) 0.8 μM propafenone (PROPAF).

Figure 7. Arrhythmia termination in 3D anatomical human atria by representative concentrations of disopyramide, propafenone, and quinidine under SQT1 mutation conditions. (A) Snapshots of re-entrant scroll waves in a clockwise configuration (viewed from RA posterior wall) at various time points after initiation of a scroll wave in the 3D anatomical human atrial model under (i) drug-free WT-N588K conditions, and upon application of (ii) 5 μM disopyramide (DISO), (iii) 0.5 μM propafenone (PROPAF), and (iv) 2 μM quinidine (QUIN) conditions, with (B) corresponding pseudo ECG recorded during the final 5.0 s. In pharmacological simulation drugs were applied at t = 2,500 ms. (C) Barcharts summarizing DF upon application of various concentrations of (i) DISO, (ii) PROPAF, and (iii) QUIN for clockwise and anti-clockwise initial conditions (ICs 1 and ICs 2, respectively). * denotes simulations in which DF was not calculated due to occurrence of re-entry termination.

Figure 8. A schematic summary of pro-arrhythmic effects of the N588K-hERG mutation in human atria and anti-arrhythmic effects of class I drugs. At the ion channel level, the N588K mutation impairs hERG channel inactivation, increasing IKr which shortens the action potential duration (APD) at the cellular level, and increases its dispersion, ΔAPD, between certain regions of the human atria. In tissue, shortened APD corresponds to shortened effective refractory period (ERP) and excitation wavelength (WL), promoting sustenance of arrhythmias at the organ scale through higher dominant frequency (DF) and lifespan (LS) of re-entry. Class I drugs disopyramide (DISO), quinidine (QUIN), and propafenone (PROPAF) exert effects at the ion channel level by blocking IKr and INa, in addition to secondary actions. This prolongs APD and ERP, and reduces maximum upstroke velocity (MUV) and conduction velocity (CV) at the cellular and tissue levels, respectively. At the organ scale these pharmacological actions promote arrhythmia rate and rhythm control through reduced DF and LS of re-entry.