Combined Action Potential- and dynamic-clamp for accurate computational modeling of the kinetics of cardiac IKr current

The aims of this work were the optimization of the I
_Kr
model, based on the Luo-Rudy (LRd) formulation by fitting it to I
_Kr
recorded as E4031-sensitive current (I
_E4031
) under Action Potential clamp and the validation of the optimized model by testing its suitability to replace native I
_Kr
under Dynamic Clamp conditions. We found the experimental I
_E4031
very different from the I
_Kr
based on the LRd model. We therefore looked for an I
_Kr
formulation which better fit our experimental data. By solving a minimization problem we found an “optimized” formulation of the I
_Kr
model. The optimized model was validated by using the dynamic clamp technique: we considered the AP traces in control conditions, under I
_Kr
block, after injection of the modeled LRd I
_Kr
and after injection of the optimized modeled I
_Kr
. Dynamic clamp experiments showed that the LRd I
_Kr
shortens too much the action potential while our model brings back the AP closer the control AP morphology and duration.