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Schematic   illustration of approximation of local Ca dynamics in our updat...
Published: 09 August 2022
Figure 1. Schematic illustration of approximation of local Ca dynamics in our updated CRU-based SAN cell model. (A) CRUs are placed under the cell membrane. (B and C) Three layers of voxels approximate intracellular Ca dynamics (shown not in scale): in cross-section (B) and longitudinal sec... More
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Effect of Poisson clumping: Clusterization of CRUs and emergence of voids a...
Published: 09 August 2022
Figure 2. Effect of Poisson clumping: Clusterization of CRUs and emergence of voids as disorder in CRU locations increases. Left: The cell cylinder surfaces unwrapping to squares with examples of distributions of RyR clusters under the cell membrane with varying degrees of disorder used in our s... More
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Disorder in CRU position shortens CL (i.e., increases AP firing rate). (A) ...
Published: 09 August 2022
Figure 3. Disorder in CRU position shortens CL (i.e., increases AP firing rate). (A) CL intervalograms for SAN cell models with various degrees of disorder in CRU positions. Inset shows that CL correlates with the average nearest neighbor distance, that is, shortens as disorder increases. (B) ... More
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Perturbing CRU positions around their original square lattice positions inc...
Published: 09 August 2022
Figure 4. Perturbing CRU positions around their original square lattice positions increases synchronization and recruitment of CRU to release Ca via locally propagating CICR, resulting in earlier activation of I NCX and shorter AP firing cycle. (A–D) Shown are representative examples of simulations of Vm (A), number of open CRUs at a given time (B), INCX (C), and ICaL (D). The traces are synchronized at the MDP to clearly see difference in time course during diastolic depolarization. More
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Disorder in CRU positions accelerates synchronization of CRU firing and AP ...
Published: 09 August 2022
Figure 5. Disorder in CRU positions accelerates synchronization of CRU firing and AP ignition process. (A and B) Shown are representative cycles of AP firing (Vm, blue curves) for 500 ms simulation time beginning from the MDP (time = 0) for two CRU distributions: uniformly random (A) and square lattice (B). The ignition process in both cases is characterized by simultaneous activation of CRUs firing (black), INCX (red), and ICaL (green, truncated) during diastolic depolarization. However, the activation kinetics is faster in the uniformly random case so its diastolic depolarization is about twice shorter. More
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Sizes of LCRs increase during diastolic depolarization via propagating CICR...
Published: 09 August 2022
Figure 6. Sizes of LCRs increase during diastolic depolarization via propagating CICR as disorder in CRU positions increases from square lattice to uniformly random (from top to bottom). Shown are instant distributions of local [Ca]sub ([Ca] under cell membrane) at the same membrane potential of −45 mV, i.e., close to the ICaL activation threshold. [Ca]sub is coded by a color scheme shown at the bottom from 0.15 to 10 μM; open CRUs are shown by white dots. Closed CRUs in refractory period are shown by blue dots; closed reactivated CRUs (available to fire) are shown by green dots. JSR Ca level is coded by respective shade (white, blue, or green) with a saturation level set at 0.3 mM. See respective Videos 1 , 2 , 3 , 4 , and 5 . More
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Results of sensitivity analysis demonstrating failure of pacemaker function...
Published: 09 August 2022
Figure 7. Results of sensitivity analysis demonstrating failure of pacemaker function (AP firing ceased) in cell models with square lattice positions of CRUs, but not with uniformly random CRU distribution at lower, albeit physiological, I CaL densities. (A) Bridging experimentally measured ICaL densities (green circles) and our model parameter gCaL describing maximum ICaL conductance (magenta). The data points for ICaL experimental data were replotted from Monfredi et al. (2018) . Magenta band shows range of gCaL in our sensitivity analysis. (B) Results of sensitivity analyses for cell models with uniformly random CRU distribution (red) and square lattice distribution (blue). Data points are average CLs evaluated between 5 and 16.5 s after simulation onset. Red shade square shows the gCaL margin where square lattice models failed, but uniformly random model continued generating spontaneous APs. (C) An example of AP firing failure in a square lattice model, but rhythmic AP firing in uniformly random model when in both cases gCaL reduced to 70% of its basal value. See original simulation data in Fig. S2 . More