Gradient-based parameter optimization method to determine membrane ionic current composition in human induced...

Premature cardiac myocytes derived from human induced pluripotent stem cells (hiPSC-CMs) show heterogeneous action potentials (APs), probably due to different expression patterns of membrane ionic currents. We developed a method for determining expression patterns of functional channels in terms of whole-cell ionic conductance (G_x) using individual spontaneous AP configurations. It has been suggested that apparently identical AP configurations can be obtained using different sets of ionic currents in mathematical models of cardiac membrane excitation. If so, the inverse problem of G_x estimation might not be solved. We computationally tested the feasibility of the gradient-based optimization method. For a realistic examination, conventional 'cell-specific models' were prepared by superimposing the model output of AP on each experimental AP recorded by conventional manual adjustment of G_xs of the baseline model. G_xs of 4-6 major ionic currents of the 'cell-specific models' were randomized within a range of ± 5-15% and used as an initial parameter set for the gradient-based automatic G_xs recovery by decreasing the mean square error (MSE) between the target and model output. Plotting all data points of the MSE-G_x relationship during optimization revealed progressive convergence of the randomized population of G_xs to the original value of the cell-specific model with decreasing MSE. The absence of any other local minimum in the global search space was confirmed by mapping the MSE by randomizing G_xs over a range of 0.1-10 times the control. No additional local minimum MSE was obvious in the whole parameter space, in addition to the global minimum of MSE at the default model parameter.