In silico assessment of pharmacotherapy for carbon monoxide induced arrhythmias in healthy and failing human hearts

Figures

• 

  FIGURE 1. Dose dependent effects of ranolazine and HW-0168 on ionic currents. (A) Effects of ranolazine on I Na, I NaL, I NaCa, I CaL and I Kr. (B) Effects of HW-0168 on I Kr. Green boxes indicate therapeutic ranges of ranolazine (5–10 μM) and HW-0168 (0.5–1 μM).

• 

  FIGURE 2. Schematic of 1D homogenous ventricular strand model with CO-affected regions. The tissue is 15 mm in length and contains 100 cells. The red part in the middle indicates the susceptible region where the number of cells varies from 0 to 100.

• 

  FIGURE 3. Schematic diagram of the QT interval measuring method.

• 

  FIGURE 4. Actions of ranolazine (RAN) on CO-affected myocardial cells and tissues. (A) The comparison of action potentials of three cell types under ‘healthy’, ‘healthy + CO’, and ‘healthy + CO + RAN’ conditions. (B) Spatial-temporal plots under the ‘healthy + CO + RAN’ condition (Bi), and the corresponding pseudo-ECG (Bii).

• 

  FIGURE 5. Effects of six multi-channel blockers at three doses on ECG morphology under healthy conditions. (A) amiodarone, (B) quinidine, (C) nifedipine, (D) verapamil, (E) vanoxerine and (F) bepridil. Blue ‘↓’ indicates the magnification of the rectangular area; red ‘↓’ indicates the failed depolarization in ECG.

• 

  FIGURE 6. Simulation results of ranolazine single-channel analysis and Vulnerable Window (VW) in a 1D transmural ventricular strand model. (A) Pseudo-ECG under the single-channel effect of ranolazine. (B) Simulation results for VW. (Bi) Distribution of VWs across the strand. Black and red belts stand for the ‘CO’ and ‘CO + ranolazine’ conditions, respectively. (Bii) Comparisons of the average width of VWs in the two conditions.

• 

  FIGURE 7. Simulated CV restitution curves in different conditions. (A) CV restitution curves under ‘healthy’, ‘CO’, and ‘CO + drug’ conditions. The magnified view inside the blue rectangle was shown in (B).

• 

  FIGURE 8. Actions of ranolazine (RAN) on CO-affected myocardial cells and tissues accompanied by heart failure (HF). (A) The comparison of action potentials of three cell types under ‘HF’, ‘HF + CO’, and ‘HF + CO + RAN’ conditions. (B) Spatial-temporal plots under the ‘HF + CO + RAN’ condition (Bi), and the corresponding pseudo-ECGs (Bii).

• 

  FIGURE 9. Effects of six multi-channel blockers on CO-affected ECG morphology by heart failure (HF). ECG morphology of (A) amiodarone (0.0005 μM), (B) quinidine (1 μM), (C) nifedipine (0.005 μM), (D) verapamil (0.03 μM), (E) vanoxerine (0.005 μM) and (F) bepridil (0.01 μM).

• 

  FIGURE 10. The critical size for initiating ectopic beats in failing 1D homogenous ventricular strands. (A) Simulated effects of CO on the failing 1D tissue: (Ai) Schematic of the model infected by CO region, the red region represents CO-affected cells, whereas the yellow regions at both ends represent cells that were not affected by CO; (Aii) Schematic of the 1D excitation wave conduction in the CO-affected tissue model (left) and the corresponding APs of the cells marked ‘*’ or ‘**’ (right). The red arrows (‘↑’) represent the location of ectopic beats and the corresponding EADs. (B) Simulation results under CO + ranolazine conditions.

• 

  FIGURE 11. Actions of HW-0168 (HW) on CO-affected myocardial cells and tissues. (A) The comparison of action potentials of three cell types under ‘healthy’, ‘healthy + CO’, and ‘healthy + CO + HW’ conditions. (B) Spatial-temporal plots under the ‘healthy + CO + HW’ condition (Bi), and the corresponding pseudo-ECGs (Bii). Noted that the HW-0168 restored the QT interval almost to the control level.

• 

  FIGURE 12. Actions of HW-0168 (HW) on CO-affected myocardial cells and tissues accompanied by heart failure. (A) The comparison of action potentials of three cell types under ‘HF’, ‘HF + CO’, and ‘HF + CO + HW’ conditions. (B) Spatial-temporal plots under the ‘HF + CO + HW’ condition (Bi), and the corresponding pseudo-ECGs (Bii).