Modelling the effects of chloroquine onKCNJ2-linked short QT syndrome

Figures

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  Figure 1. Simulated action potential clamp experiments CQ blocks IK1 current through the WT and mutant WT-D172N and D172N Kir2.1 channels. (A) IK1 current traces for the WT (i) and WT + 3 µM CQ (ii) conditions elicited by a 400 ms pulses from –120 to 20 mV, applied in 10 increments, and I-V relationships for the peak current in the WT condition and the presence of CQ at 0.3, 1 and 3 µM (iii). (B) IK1 current traces for the WT-D172N (i) and WT-D172N + 3 µM CQ (ii) conditions and I-V relationships for the peak current in the WT-D172N condition and the presence of CQ at 0.3, 1 and 3 µM (iii). (C) IK1 current traces for the D172N (i) and D172N + 3 µM CQ (ii) conditions and I-V relationships for the peak current in the WT condition and the presence of CQ at 0.3, 1 and 3 µM (iii).

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  Figure 2. Simulated transmembrane voltages of ventricular myocyte together with the corresponding IK1 current profile and a peak density for the WT, WT-D172N, and D172N conditions Gain-of-function of IK1 abbreviated the AP. (A) ENDO simulations of AP waveforms (i), corresponding APD90 histogram (ii), IK1 current profile (iii) and peak density (iv) in the WT, WT-D172N, and D172N conditions. (B) MIDDLE simulations of AP waveforms (i), corresponding APD90 histogram (ii), IK1 current profile (iii), and peak density (iv) in the WT, WT-D172N, and D172N conditions. (C) EPI simulations of AP waveforms (i), corresponding APD90 histogram (ii), IK1 current profile (iii), and peak density (iv) in the WT, WT-D172N and D172N conditions.

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  Figure 3. Transmembrane voltages of an EPI myocyte together with the corresponding IK1 current profile and peak density for the WT, WT-D172N, and D172N simulations at the indicated CQ concentrations (0.3, 1 and 3 µM) (A) AP waveforms (i), corresponding APD90 histogram (ii), IK1 current profile (iii), and peak density (iv) for the WT simulations at the indicated CQ concentrations. (B) AP waveforms (i), corresponding APD90 histogram (ii), IK1 current profile (iii), and peak density (iv) for the WT-D172N simulations at the indicated CQ concentrations. (C) AP waveforms (i), corresponding APD90 histogram (ii), IK1 current profile (iii), and peak density (iv) for the D172N simulations at the indicated CQ concentrations.

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  Figure 4. Rate-dependent APD restitution curves and ERP restitution curves for an EPI myocyte for the WT, WT-D172N, and D172N simulations at the indicated CQ concentrations (0.3, 1, and 3 µM) (A) APD restitution curves for the WT, WT-D172N (i), and D172N (ii) simulations at 3 µM concentration of CQ. (B) Measured slopes of APD restitution curves for the WT (i), WT-D172N (ii), and D172N (iii) simulations at the indicated CQ concentrations. (C) ERP restitution curves for the WT, WT-D172N (i), and D172N (ii) simulations at 3 µM concentration of CQ. (D) Measured slopes of ERP restitution curves for the WT (i), WT-D172N (ii), and D172N (iii) simulations at the indicated CQ concentrations.

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  Figure 5. Dose-dependent effects of CQ on the pseudo-ECG of a 1D transmural strand in the WT, WT-D172N and D172N conditions (A) Excitation prolongation across a 1D transmural strand model for the WT-D172N (i) simulations at 3 µM concentration of CQ (ii). Space runs from the top (ENDO, 0 mm) to the bottom (EPI, 15 mm). Time runs from the left (0 ms) to the right (800 ms). The corresponding pseudo-ECGs derived from the propagating electrical excitation wave. (B) Superimposed pseudo-ECGs (i) for the WT simulations at the indicated concentrations and the corresponding QT interval histogram (ii). (C) Superimposed pseudo-ECGs (i) for the WT-D172N simulations at the indicated concentrations and the corresponding QT interval histogram (ii). (D) Superimposed pseudo-ECGs (i) for the WT simulations at the indicated concentrations and the corresponding QT interval histogram (ii).

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  Figure 6. Membrane voltage heterogeneity (δV) between ENDO, MIDDLE, and EPI cells and transmural APD90 distribution and its spatial gradient in the 1D transmural strand (A) ENDO, MIDDLE, and EPI APs for the WT-D172N simulations (i) at 3 µM concentration of CQ (ii). (B) Plots of δV against time for the WT-D172N simulations (i) at 3 µM concentration of CQ (ii). (C) Maximal δV observed during repolarization (MIDDLE-EPI) for the WT (i), WT-D172N (ii) and D172N (iii) simulations at the indicated CQ concentrations.

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  Figure 7. Spatial distribution of APD90 and its spatial gradient in a 1D transmural strand for the WT, WT-D172N, and D172N simulations at the indicated CQ concentrations (A) The spatial gradient of APD90 (i) and its spatial gradient (ii) in a 1D transmural strand. Space runs from the left (ENDO, 0 mm) to the right (EPI, 15 mm) on the x-axis. (B) The maximal spatial gradient of APD90 in a 1D transmural strand for the WT (i), WT-D172N, (ii) and D172N (iii) simulations at the indicated CQ concentrations.

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  Figure 8. Simulated vulnerable window by using a 1D transmural strand model for the WT, WT-D172N, and D172N simulations at the indicated CQ concentrations (A) Space-time plot of excitation propagation and response of a 1D transmural strand to a test stimulus. APs are mapped into a colour spectrum ranging from –85 ms to 45 mV. Space runs from top (ENDO) to bottom (EPI). Time runs from left (0 ms) to the right (400 ms). The premature stimulus applied at EPI part at 320 ms, bi-directional block (i); 340 ms, unidirectional conduction block (ii); and 350 ms, bi-directional conduction (iii). (B) The vulnerability of the tissue for the WT (i), WT-D172N (ii), and D172N (iii) simulations at the indicated CQ concentrations.

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  Figure 9. Snapshots of initiation and conduction of re-entry in a 2D idealized model of transmural ventricle for the WT, WT-D172N, and D172N simulations at the indicated CQ concentrations (A) In the WT condition, a planar conditioning wave generated by S1 stimulus at the ENDO end, which propagates through MIDDLE then towards the EPI end. An S2 stimulus applied to the MIDDLE-EPI junction during the vulnerable window of the local tissue. Space runs from the left (ENDO, 0 mm) to the right (EPI, 15 mm) on the x-axis. Space runs from the bottom (0 mm) to the top (150 mm) on the y-axis. Snapshots at time=2 ms (i), 340 ms (ii), 750 ms (iii), 2000 ms (iv) and the corresponding evolution of an EPI cell AP (v). (B) In the WT-D172N condition, a re-entry was initiated and maintained. Snapshots at time=2 ms (i), 314 ms (ii), 750 ms (iii), 2000 ms (iv) and the corresponding evolution of an EPI cell AP (v). (C) In the WT-D172N + 3 µM CQ condition, a re-entry was initiated and maintained. Snapshots at time=2 ms (i), 340 ms (ii), 750 ms (iii), 2000 ms (iv) and the corresponding evolution of an EPI cell AP (v). Spiral wave self-terminated in the WT condition before this recording point, but persisted in the…

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  Figure 10. Snapshots of initiation and conduction of re-entry in the 2D slice model of human ventricles (A) In the WT condition, a conditioning wave generated by an S1 stimulus. Application of a premature S2 stimulus into the refractory and partially recovered region of an excitation wave after a delay of 340 ms. Snapshots at time = 2 ms (i), 170 ms (ii), 340 ms (iii), 850 ms (iv), and 1800 ms (v). (B) In the WT-D172N condition, a re-entry was initiated and maintained. Snapshots at time = 2 ms (i), 170 ms (ii), 310 ms (iii), 850 ms (iv), and 1800 ms (v). (C) In the WT-D172N + 3 µM CQ condition, a re-entry terminated. Snapshots at time = 2 ms (i), 170 ms (ii), 340 ms (iii), 850 ms (iv), and 1800 ms (v). Re-entrant wave self-terminated in the WT condition before this recording point but persisted in the WT-D172N condition. CQ eliminated the wavelets and terminated the re-entrant wave.

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  Figure 11. Snapshots of initiation and conduction of re-entry in the 3D model of human ventricles (A) A conditioning wave generated by an S1 stimulus. Scroll wave was initiated by using the cut-wavefront protocol after a delay of 210 ms for the WT condition from the initial wave stimulus. Snapshots at time = 2 ms (i), 170 ms (ii), 210 ms (iii), 650 ms (iv), and 1000 ms (v). (B) Scroll wave was initiated by using the cut-wavefront protocol after a delay of 190 ms for WT condition from the initial wave stimulus. Snapshots at time = 2 ms (i), 170 ms (ii), 190 ms (iii), 800 ms (iv), and 1000 ms (v). (C) Scroll wave was initiated by using the cut-wavefront protocol after a delay of 210 ms for the WT condition from the initial wave stimulus. Snapshots at time = 2 ms (i), 170 ms (ii), 210 ms (iii), 650 ms (iv), and 1000 ms (v). Scroll wave self-terminated in the WT condition before this recording point, but persisted in the WT-D172N condition. CQ terminated the scroll wave.