The Role of CaMKII Overexpression and Oxidation in Atrial Fibrillation—A Simulation Study

Figures

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  Figure 1. The schematic diagram of the Markov chain model of CaMKII activation model and oxidation model. (A) 6-state Markov chain model of CaMKII activation model. (B) 4-state Markov chain model of CaMKII oxidation model.

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  Figure 2. Fitted model data (line) to experimental data (dot) of normalized kinase activity of CaMKII by oxidative activation.

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  Figure 3. Comparison of the action potential (AP) and main membrane currents between CaMKII-OE and WT model. (A,B) Action potential, (C) late-sodium current (INaL), (D) transient outward potassium current (Ito), (E) inward rectifier potassium current (IK1), (F) Na+-Ca2+ exchanger current (INCX).

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  Figure 4. Effects of overexpression and oxidation of CaMKII on the characters of action potential (AP) and the calcium cycling process. Figure shows the superimposed AP (A), recorded APD25, APD50 and APD90 (B), AP amplitude (C), dV/dtmax (D) and resting potential (E), intracellular Ca2+ concentration (F), sarcoplasmic reticulum (SR) Ca2+ concentration (G), the SR Ca2+ release current (H), the SR Ca2+ reuptake current (I) of the WT model and the CaMKII-OE model with and without additional ROS.

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  Figure 5. Simulation results of the WT model [a(i)–i(i)] and the CaMKII-OE model [a(ii)–i(ii)] under the burst pacing protocol. (a) recorded AP during the whole simulation time; (b) enlarged AP record after burst pacing (from time point 13.5–17.5 s); (c) the concentration of activated CaMKII in cell junctional area; (d–f) the phosphorylation level of LTCC (d), PLB (e) and RyR (f); (g) intracellular Ca2+ concentration; (h) sarcoplasmic reticulum (SR) Ca2+ concentration; (i) intracellular Na+ concentration. Generated DADs are marked by “*”.

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  Figure 6. Simulation results of the WT model [a(i)–i(i)] and the CaMKII-OE model [a(ii)–i(ii)] with the application of ROS under the burst pacing protocol. (a) Recorded AP during the whole simulation time; (b) enlarged AP record after burst pacing (from time point 13.5–17.5 s); (c) the concentration of activated CaMKII in cell junctional area; (d–f) the phosphorylation level of LTCC (d), PLB (e) and RyR (f); (g) intracellular Ca2+ concentration; (h) sarcoplasmic reticulum (SR) Ca2+ concentration; (i) intracellular Na+ concentration. Generated DADs are marked by “*”.

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  Figure 7. Simulation results of the CaMKII-OE model with the application of ROS under the burst pacing protocol, the [Na+]i [a(i)–i(i)] or the level of RyR phosphorylation [a(ii)–i(ii)] in the model was clamped. (a) Recorded AP during the whole simulation time; (b) enlarged AP record after burst pacing (from time point 13.5–17.5 s); (c) the concentration of activated CaMKII in cell junctional area; (d–f) the phosphorylation level of LTCC (d), PLB (e) and RyR (f); (g) intracellular Ca2+ concentration; (h) sarcoplasmic reticulum (SR) Ca2+ concentration; (i) intracellular Na+ concentration. Generated DADs are marked by “*”.

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  Figure 8. Simulation results of RyR phosphorylation level and [Ca2+]SR clamping. (a,b) The RyR channel activation threshold map (a) and the amplitude of the first RyR release current map (b) under corresponding RyR phosphorylation level and [Ca2+]SR, the top right area shown as the white color means the RyR channel kept open without any stimulus. A, B, C are three representative conditions, which are condition clamping at 20, 40, 60% RyR phosphorylation level and 300, 450, 600 μM [Ca2+]SR, respectively. Arrows in (b) show the condition movement direction after [Ca2+]SR unclamped; (c,d) The current traces (i) and their maximum values for each beat (ii) of the RyR release current (c) and [Ca2+]SR (d) for the three representative condition marked as A, B, C in (a); (e,f) The value of the RyR release current (e) and [Ca2+]SR (f) for the three representative condition for the 1st, 20th, 60th beat; (g) The time period for the model to reach a stable RyR release current from the three representative initial conditions.

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  Figure 9. The schematic diagram for the mechanism role of CaMKII overexpression and oxidation in DAD generation.