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.