Table 1.
A summary of trabeculae recordings for average at baseline and drug-induced
change from baseline (
). SEM: Standard error of the mean. SD: Standard deviation.
Fig 1.
Experimental measured ex vivo under various drug conditions in human ventricular trabeculae, as a function of
and
inhibition and cubic surface approximating the trabeculae data points in the background.
and
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
and
inhibition.
Fig 2.
Left: Surfaces fitted through experimental data points.
Right: 2-D maps of predicted change from baseline after
and
inhibition. The colour scale indicates shortening of
(i.e.,
< 0 ms) for colours towards dark blue, and
prolongation (i.e.,
> 0 ms) for colours towards red.
values below –50 ms and above + 320 ms were set to dark blue and red, respectively, for better visualisation. For
and
inhibition leading to
ms, the pixel is coloured in white.
Fig 3.
Comparison of in-silico prediction of response to
and/or
inhibition with ex vivo data.
CiPA (triangle) and Pharm (circle) datasets for values were used to compute drug perturbation.
denotes here the experimental standard error of the mean
response to each drug perturbation.
Fig 4.
Comparison of the abilities of human ventricular AP models to reproduce the response to
and
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.
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 prolongation with
block.
Table 2.
Drugs tested in ex vivo experiments and corresponding nominal concentrations.
Table 3.
Potency of inhibition of and hERG channels for drugs tested ex vivo. The half-inhibitory concentration (
) is reported in microMolar (
M), and the Hill coefficient h is in brackets. “Pharm” and “CiPA” refer to two different patch-clamp protocols used to characterise
and
inhibition (S1 Appendix).
Table 4.
Selected AP models. The * symbol indicates when the endocardial version of the model was selected among different versions developed by the authors of the model.
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).
Fig 7.
Schematic of methods used to plot 2-D maps.
Simulated was computed from the in silico AP model run for 1500 paces, using
and/or
inhibition as input for the model. The corresponding point was then added to the 2-D map, with
reported with the colour-map.