Effects of amiodarone on short QT syndrome variant 3 in human ventricles: a simulation study

Fig. 1. Computer-based assessment flowchart for testing amiodarone actions at hierarchical levels including ion channel, cellular and tissue. The actions of amiodarone on ventricular excitation associated with SQT3 at cell and tissue levels can be characterized by analyzing their effects on a family of biomarkers

Fig. 2. Simulated current–voltage (I–V) relationships. a–c Currents traces for WT, WT-D172N and D172N I K1 elicited by 400 ms depolarizing voltage steps from −120 to +20 mV and from a holding potential of −60 mV. d–f Current–voltage relationships. The current amplitude of the WT-D172N and D172N mutant conditions is significantly larger than that of the WT condition

Fig. 3. Simulations of APs together with the corresponding time course and amplitude of I K1 in the WT, WT-D172N and D172N conditions. a, d APs and I K1 for ENDO cells. b, e APs and I K1 for MIDDLE cells. c, f APs and I K1 for EPI cells

Fig. 4. Effects of low and high doses of amiodarone on human ventricular EPI cell. a, c APs under the WT-D172N condition in the presence of amiodarone, and corresponding APD90 histogram. b, d APs under the D172N condition in the presence of amiodarone, and corresponding APD90 histogram

Fig. 5. Rate-dependent APD restitution curves and ERP restitution curves for EPI cells under the WT, WT-D172N and D172N conditions, and in the presence of amiodarone. a, b APD restitution curves under the WT-D172N and D172N conditions, respectively. c, d Measured slopes of APD restitution curves under the WT-D172N and D172N conditions, respectively. e, f ERP restitution curves under the WT-D172N and D172N conditions, respectively. g, h Measured slopes of ERP restitution curves under the WT-D172N and D172N conditions, respectively

Fig. 6. Space–time plot of AP propagation along a 1D fiber and the pseudo-ECGs. a, b Color mapping of membrane potential of cells in the WT-D172N and a low dose of amiodarone conditions, respectively. Space runs vertically from the ENDO end at the top to the EPI end at the bottom. Time runs horizontally (left to right). c, d The corresponding pseudo-ECGs derived from the propagating excitation wave for the WT-D172N and a low dose of amiodarone conditions, respectively. e, f Color mapping of membrane potential of cells in the D172N and a low dose of amiodarone conditions, respectively. g, h The corresponding pseudo-ECGs derived from the propagating excitation wave for the D172N and a low dose of amiodarone conditions, respectively. i, k Superimposed pseudo-ECGs for the WT-D172N and D172N conditions, respectively. j, l Associated QT intervals

Fig. 7. Membrane potential heterogeneity (δV) between single ENDO, MIDDLE and EPI cells and transmural APD90 distribution and its spatial gradient in 1D fiber model for the WT, WT-D172N, D172N and amiodarone-in-action conditions. a, b ENDO, MIDDLE and EPI APs in WT-D172N and WT-D172N + low amiodarone conditions. c, d Corresponding plots of δV against time for the two conditions. Horizontal dashed lines mark peak ENDO-MIDDLE and MIDDLE-EPI δV in WT-D172N condition. e, f Maximal δV observed during repolarization (ENDO-MIDDLE) under WT-D172N and D172N conditions in the presence of amiodarone, respectively. Horizontal dashed lines mark peak ENDO-MIDDLE δV in WT condition. g Spatial distribution of APD90 on 1D fiber model in WT, WT-D172N and amiodarone-in-action conditions. h Spatial gradient of APD90 on 1D fiber model in WT, WT-D172N and amiodarone-in-action conditions. i, j The maximal spatial gradient of APD90 under WT-D172N and D172N conditions in the presence of amiodarone, respectively

Fig. 8. Space–time plots of propagating conditioning excitation wave and response of the tissue to a premature stimulus in the WT condition. Membrane potentials of cells are mapped onto a color spectrum. Space runs vertically from the ENDO end at the top to the EPI end at the bottom. Time runs horizontally (left to right). a–c, g, h Premature stimulus applied at ENDO part at: a 335 ms, bidirectional block. b 341.5 ms, unidirectional block. c 350 ms, bidirectional conduction. g Vulnerability of the tissue in WT-D172N and amiodarone-in-action conditions. h Vulnerability of the tissue in D172N and amiodarone-in-action conditions. d–f, i, j Premature stimulus applied at EPI part at: d 332 ms, bidirectional block. e 340 ms, unidirectional block. f 350 ms, bidirectional conduction. i Vulnerability of the tissue in WT-D172N and amiodarone-in-action conditions. j Vulnerability of the tissue in D172N and amiodarone-in-action conditions

Fig. 9. Snapshots of initiation and conduction of re-entrant excitation wave in a 2D model of transmural ventricle tissue under the WT, WT-D172N and amiodarone-in-action conditions. a, f, k A planar wave generated by S1 stimulus at the ENDO end, which propagates towards the MIDDLE and EPI regions. Snapshots at time = 10 ms. b, g, l S2 was applied to the MIDDLE-EPI junction region during the vulnerable window of the tissue. c, h, m Developed re-entrant excitation waves. d, i, n Developed re-entrant excitation waves. Snapshots at time 650 ms. e, j, o Snapshots of the re-entrant excitation waves. Re-entry was prevented in the presence of amiodarone. Snapshots at time 1500 ms. p, q, r Evolution of the AP of an EPI cell under the WT, WT-D172N and WT-D172N + low amiodarone conditions, respectively. s, t The measured minimum spatial length of S2 that provides a sufficient substrate for the formation of a re-entrant circuit under WT-D172N and D172N conditions in the presence of amiodarone, respectively