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 IKr model, based on the Luo-Rudy (LRd) formulation by fitting it to IKr recorded as E4031-sensitive current (IE4031) under Action Potential clamp and the validation of the optimized model by testing its suitability to replace native IKr under Dynamic Clamp conditions. We found the experimental IE4031 very different from the IKr based on the LRd model. We therefore looked for an IKr formulation which better fit our experimental data. By solving a minimization problem we found an 'optimized' formulation of the IKr model. The optimized model was validated by using the dynamic clamp technique: we considered the AP traces in control conditions, under IKr block, after injection of the modeled LRd IKr and after injection of the optimized modeled IKr. Dynamic clamp experiments showed that the LRd IKr shortens too much the action potential while our model brings back the AP closer the control AP morphology and duration. © 2013 CCAL.