Biphasic effects on human atrial arrhythmogenicity of L-type calcium channel mutations associated with a Brugada/Short QT overlap syndrome - insights from a multiscale simulation study

Figures

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  Fig 1. Simulated 𝐈CaL traces during voltage-clamp for WT and CACNA1C A39V and CACNA1C G490R mutations by using the simple approach of gCaL reduction for the mutation conditions. (A) Simulation data. (B) Experimental data reproduced from Antzelevitch et al. [5]. The patch-clamp protocol (inset) used in simulations is the same as used in Antzelevitch et al. [5]. It had a holding potential of -90 mV, and testing potentials ranging from -50 mV to 50 mV with an increment of 10 mV. In the panel, (i), (ii) and (iii) denote WT, CACNA1C A39V and CACNA1C G490R mutations respectively. (C) Normalized peak 𝐈CaL amplitudes and their relative reduction as compared to the WT condition. Simulated (dark bars) and experimental (pale bars) I-V relationship peaks for WT (black), A39V (red), G490R (blue). The amplitude of ICaL in mutation conditions was normalized to the WT condition for both experimental and simulation settings.

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  Fig 2. Computed APs and related ion channel currents in WT, G490R mutation (f = 1) and intermediate 𝐈CaL deficiency (f = 0.2, 0.4, 0.5, 0.6 and 0.8) conditions. (i) APs. (ii) 𝐈CaL. (iii) 𝐈Na. (iv) 𝐈Kr. (v) 𝐈NaCa. (vi) 𝐈K1.

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  Fig 3. Simulations at the single cell level: (i) APD restitution (APDr) curve. (ii) The maximal slope of the APDr curves. (iii) ERP restitution (ERPr) curves. (iv) APD and ERP versus various f in G490R mutations.

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  Fig 4. Restitution curves of CV, ERP, WL and excitation threshold (EXT) in WT, heterozygous (f = 0.5), homozygous (f = 1) CACNA1C G490R mutation and intermediate 𝐈CaL deficiency (f = 0.2, 0.4, 0.6 and 0.8) conditions. (A) Rate-dependency of CV. Bifurcation of the CVr curve at WT and low degrees of ICaL deficiency (f ≤ 0.2) was observed, indicating conduction alternans of electrical excitation waves. The bifurcation disappeared at a high degree of ICaL deficiency (f > 0.2). (B) Rate-dependency of ERP. Bifurcation in the ERPr curves with low degrees of ICaL deficiency was observed and disappeared at high degrees of ICaL deficiency. (C) Rate-dependency of WL. Bifurcation in the WLr curves with low degrees of ICaL deficiency was observed and disappeared at high degrees of ICaL deficiency. (D) Tissue excitation threshold against S1-S2 intervals (SI).

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  Fig 5. Computed excitation threshold at the critical SI (corresponding typical EXT) when significant alterations of tissue excitability were observed. The typical EXT at critical SIs: 282, 267, 248, 233, 206, 130 and 99 ms for WT and deficient 𝐈CaL with f equal to 0.2, 0.4, 0.5, 0.6, 0.8 and 1 (CACNA1C G490R mutation) respectively.

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  Fig 6. Computed temporal vulnerability of atrial tissue for WT, G490R and corresponding 𝐈CaL deficient conditions at the CT/PM (A) and LA/PV (B) junctions. Biphasic variations in the measured width of VW at the CT/PM (C). At the LA/PV (D) junction, the VW width was increased with the increase of deficient coefficient f.

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  Fig 7. Dynamic behaviours of reentrant spiral waves in two-dimensional atrial tissue in WT (A), heterozygous (D; f = 0.5), homozygous CACNA1C G490R mutation (G; f = 1) and intermediate 𝐈CaL deficiency (B, C, E &F) conditions. In each case, snapshots of reentry (e.g., Ai to Aiii), and tip trajectory pattern (e.g., Aiv), time series of integrated transmembrane potential across the entire 2D tissue (e.g., Av) and its power spectrum (e.g., Avi) are shown. The lifespan (H) of reentries and the meandering area of tip traces for WT, G490R and intermediate 𝐈CaL deficient conditions (I).

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  Fig 8. (A) Bar charts of 𝐀𝐏𝐃90 range across the whole 3D human atrial tissue in all types. (B) Lifespan of re-entrant scroll waves in WT, G490R mutation and deficient 𝐈CaL conditions. (C) Normalized APD dispersion: ΔAPD90 (normalized by the midrange of spatial APD90 across the 3D atria) versus scaling factor f. (D) The lifespan of 3D re-entrant scroll waves with dashed lines.

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  Fig 9. Characterisation of scroll wave dynamics and action potential properties in 3D human atrial simulations. (A) Temporal evolution of re-entrant scroll waves at representative time points (indicated above each panel) obtained from 3D computational simulations. The action potential distribution is represented using a colour gradient map ranging from -100 mV (blue) to +20 mV (dark red), with the corresponding colour scale provided below the panel. (B) Spatial distribution of APD heterogeneity across the 3D human atrial tissue. APD dispersion is visualised using a color-coded map ranging from 55 ms (blue) to 269 ms (dark red), with the colour scale displayed below the panel. (C) Temporal integration of the total membrane potential, calculated as the spatial integration of action potentials across the entire 3D human atrial tissue.