Combined action potential- and dynamic-clamp for accurate computational modelling of the cardiac IKr current

In the present work Action-Potential clamp (APC) and Dynamic clamp (DC) were used in combination in order to optimize the Luo-Rudy (LRd) mathematical formulation of the guinea-pig rapid delayed rectifier K(+) current (IKr), and to validate the optimized model. To this end, IKr model parameters were adjusted to fit the experimental E4031-sensitive current (IE4031) recorded under APC in guinea-pig myocytes. Currents generated by LRd model (ILRd) and the optimized one (IOpt) were then compared by testing their suitability to replace IE4031 under DC. Under APC, ILRd was significantly larger than IE4031 (mean current densities 0.51±0.01 vs 0.21±0.05pA/pF; p<0.001), mainly because of different rectification. IOpt mean density (0.17±0.01pA/pF) was similar to the IE4031 one (NS); moreover, IOpt accurately reproduced IE4031 distribution along the different AP phases. Models were then compared under DC by blocking native IKr (5μM E4031) and replacing it with ILRd or IOpt. Whereas injection of ILRd overshortened AP duration (APD90) (by 25% of its pre-block value), IOpt injection restored AP morphology and duration to overlap pre-block values. This study highlights the power of APC and DC for the identification of reliable formulations of ionic current models. An optimized model of IKr has been obtained which fully reversed E4031 effects on the AP. The model strongly diverged from the widely used Luo-Rudy formulation; this can be particularly relevant to the in silico analysis of AP prolongation caused by IKr blocking or alterations.