Comparison of in silico predictions of action potential duration in response to inhibition of IKr and ICaL with new human ex vivo recordings

Figures

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  Fig 1. Experimental ΔAPD90 measured ex vivo under various drug conditions in human ventricular trabeculae, as a function of IKr and ICaL inhibition and cubic surface approximating the trabeculae data points in the background. IKr and ICaL inhibition were computed using the Hill equation (Eq 1), with the CiPA (left) and Pharm (right) datasets. The bottom panels report the inter-trabeculae variability observed experimentally. The marker type indicates the drug used to apply the IKr and ICaL inhibition.

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  Fig 2. Left: Surfaces fitted through experimental data points. Right: 2-D maps of predicted APD90 change from baseline after ICaL and IKr inhibition. The colour scale indicates shortening of APD90 (i.e., ΔAPD90 < 0 ms) for colours towards dark blue, and APD90 prolongation (i.e., ΔAPD90 > 0 ms) for colours towards red. ΔAPD90 values below –50 ms and above + 320 ms were set to dark blue and red, respectively, for better visualisation. For IKr and ICaL inhibition leading to −1 ms<ΔAPD90<+1 ms, the pixel is coloured in white.

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  Fig 3. Comparison of in-silico prediction of ΔAPD90 response to IKr and/or ICaL inhibition with ex vivo data. CiPA (triangle) and Pharm (circle) datasets for IC50 values were used to compute drug perturbation. σM denotes here the experimental standard error of the mean ΔAPD90 response to each drug perturbation.

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  Fig 4. Comparison of the abilities of human ventricular AP models to reproduce the APD90 response to IKr and ICaL inhibition observed ex vivo. The lower the error measure (Eq 2), the more accurate the model predictions. A: The error measure was summed over all the drugs used in this study, when using the CiPA and Pharm protocols to compute the reduction of ionic currents by drugs. For each model, two bar plots were plotted, to compare the predictive power of models with the Pharm (left bar) and the CiPA (right bar) datasets. B and C: Detail of the error measures associated with each of the drugs using the CiPA and Pharm datasets, respectively, for each model. The log10 of the error measure is plotted along the radial-axis.

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  Fig 5. Protocol for sharp electrode recordings of the electrophysiological activity in isolated left- and right-ventricular human trabeculae. After baseline conditions, the response to three conditions with drug was recorded. At the end of the experiments, 100 nM Dofetilide was added as a positive control for APD90 prolongation with IKr block.

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  Fig 6. Steady-state 1 Hz AP simulated with the AP models included in this study. External concentrations were set to experimental values (dashed line) or left at the values in the original CellML model (solid line).

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  Fig 7. Schematic of methods used to plot ΔAPD90 2-D maps. Simulated ΔAPD90 was computed from the in silico AP model run for 1500 paces, using IKr and/or ICaL inhibition as input for the model. The corresponding point was then added to the 2-D map, with ΔAPD90 reported with the colour-map.