Increased SERCA2a sub-cellular heterogeneity in right-ventricular heart failure inhibits excitation-contraction coupling and modulates arrhythmogenic dynamics

Figures

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  Figure 1.. Image processing and experimental-simulation framework. (a) Original microscopy images are semi-automatically processed into a form suitable for a variogram fitting protocol, rotating the longitudinal axis to match the x-axis, cropping and down-sampling. Scale bar illustrates 10 µm for all panels. (b) The spatial variation across pairs of points in the integrated two-dimensional dataset is plotted as a function of distance (a variogram) to measure the length-scale of correlation in the spatial data. Outputs are a statistical summary of greater than 50 successful fits. (c) Examples of two-dimensional Gaussian random field (GRF) maps produced at different length-scales (left) and an illustration of a full three-dimensional GRF map (right). (d) Fundamental structure of the three-dimensional spatio-temporal Ca2+ handling model in the multi-scale cardiac simulation framework (MSCSF) [27], illustrating the compartments for each calcium release unit (CRU) of the dyadic cleft (DS), reduced-buffering subspace (RBSS), bulk cytoplasmic space (CYTO) and junctional and network SR (JSR and NSR, respectively), as well as the primary Ca2+ fluxes. The GRF map determines the local scale factor for…

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  Figure 2.. SERCA2a heterogeneity in control and RV-HF cardiomyocytes. (a) The comparison of cell-average correlation length-scales, λ, in control (saline-treated) (i) cells and monocrotaline (MCT)-treated cells (ii). Horizontal lines represent overall mean (full line) and s.d. (dotted line) for control and MCT cells, respectively. Vertical error lines are 95% confidence intervals. (b) Comparison of mean λ in control and MCT-treated rat ventricular myocytes (i) and in left ventricular (LV) and right ventricular (RV) cells (ii). (Online version in colour.)

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  Figure 3.. Ca2+ transient variability as a consequence of SERCA2a heterogeneity. (a) Illustration of the GRF maps, describing the local Jupmax scale factor, produced at different length-scales (upper). The value of the scale factor along a longitudinal linescan through the centre of the cell is shown for clarity (lower). Maps shown correspond to ‘map 1’ of the three independent GRF maps used at each length-scale. (b) Whole-cell Ca2+ transients (i) and SR-Ca2+ (ii) during normal pacing, for homogeneous control (white) and heterogeneous SERCA2a maps at each length-scale (1 µm—red; 3 µm—blue; 5 µm—orange; 10 µm—yellow); three maps at each length-scale were used (solid, dashed and dotted lines). Summary of the CaT magnitude (iii) and diastolic SR-Ca2+ (iv) at each length-scale and for each map. (c) Space–time images of the Ca2+ transient in the longitudinal axis (through the centre of the cell) in the homogeneous and all heterogeneous map conditions, corresponding to the same normal pacing excitations as shown in (b). Normalized whole-cell-average CaTs are overlaid in white for context. Plots to the left of each space–time image show the SERCA2a scale factor along the same longitudinal linescan…

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  Figure 4.. Mechanisms of heterogeneous and reduced SR-Ca2+. (a) Cartoon illustration of the mechanisms by which low-SERCA2a regions may exhibit the highest peak diastolic SR-Ca2+ during regular pacing. (b) The relationship between the time-constant of intra-SR diffusion (τnSR-nSR, shown on a log-scale) in a single heterogeneous map and diastolic peak SR-Ca2+, normalized to the value in the homogeneous cell model under control conditions. (c) The relationship between global Jup scale factor (SERCA2a expression) in homogeneous cell models and diastolic peak SR-Ca2+, normalized to the value in the homogeneous cell model under control conditions. The red marker indicates the mean across the scale factors. (Online version in colour.)

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  Figure 5.. Summary of alternans behaviour in control to pro-arrhythmic conditions. (a) Colourmaps detailing the mean beat-to-beat difference in cytosolic Ca2+ (left) and percentage difference (right) in a range of conditions from control (a) to pro-arrhythmic (b–h) at 120 bpm. Conditions are described by scaling factors applied to each of Jupmax (whole-cell SERCA2a flux), NLTCC (L-type-Ca2+ channel density) and LTCCPo (channel opening transition rate). Maps are organized left to right. (b) Space–time plots showing CaT alternans in two different conditions (upper). Whole-cell CaT is overlaid in white for context. Circled regions illustrate those which show either different behaviour on a beat-to-beat basis for the small beat (homogeneous, (i)) or broadly the same behaviour for the small beat (heterogeneous, (ii)). Lower panels show the local CaT at three selected CRUs for the same two conditions; coloured triangular markers indicate the location of each CRU selected for the plot. In the heterogeneous condition, each CRU has its own corresponding Jupmax scale factor, indicated by the colour key. The dotted square highlights the same diastolic Ca2+ in the homogeneous condition and different…

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  Figure 6.. Impact of SERCA2a heterogeneity on spontaneous calcium release events. Statistical summary of SCRE behaviour for condition 1 (a) and condition 2 (b), showing triggered AP count (i) and mean peak SCRE CaT magnitude across all simulations (ii) and for each individual map (iii). (c) The comparison of mean SCRE count (i), TA count (ii) and SCRE magnitude (iii) for different combinations of heterogeneous/homogeneous SERCA2a maps and SR-Ca2+ load. (Online version in colour.)