Feasibility of Estimating Maximum Ion Conductance Parameters from the Shape of the Action Potential. A Simulation Study

Abstract

Simultaneous measurement of ion currents and transmembrane potential (V(t)) is difficult. We verified whether the V(t) of a myocardial action potential (AP) is sufficient to estimate the cell's ion currents densities. We built a database of 45000 simulated APs by running the Luo-Rudy dynamic model simulator (LRd) on uniform randomly generated parameter sets comprising the maximum conductances for 12 major ion current components in the range of 0.5--2.0 times the default. A ‘data’ action potential (V_d(t)) was generated randomly in the same parameter interval and we tried to estimate its parameters. Each AP in the database was assigned the same prior probability at step 0. Then, at each of 50 steps spaced at 5 ms, a posterior probability was computed that was used as the prior probabily for the next step. We considered for each step t(j) the difference DV(i,j) between the i'th action potential in the database and the ‘data’ action potential. Using a normal noise model we calculated the non-conditional probability of DV(i,j), then the post-probability for step j given the prior obtained in step j-1. The highest posterior probability finally obtained identified our estimated parameters in the database.RESULTS. In 100 such simulated experiments we found a RMSD of 4.14±1.15 mV (mean±SD) between estimate V(t) and data, corresponding to a very close resemblance. However, the absolute differences in parameters were large, ranging from 0.30±0.31 for I_Kr to 0.9±0.5 for I_Na.CONCLUSION. There appears to be insufficient information in the single AP recording to simultaneously estimate the maximum conductances for 12 ion currents, as the same AP can be reconstructed from quite different parameters. Further progress will need taking into account other measurable experimental data.