FIGURE 5.

Baseline FF and KO computational models. (A) I_CaL in the KO model was parameterized to permit the markedly slowed I_CaL inactivation accompanying loss of SR calcium release (left panel) and moderately increased peak current observed in KO myocytes (right panel). (B) Conductances for the slower activating component of I_Kslow (Kv2.1, I_Kslow,2) and the steady state K⁺ current (I_Kss) were both reduced by 25% to fit end-pulse “pedestal” total I_K (main left panel). Simulated currents were assessed as the sum of all end-pulse K⁺ currents as for the experimental measurements shown in Figure 2, where this compound current is referred to as I_Kp. To simultaneously fit the pedestal and peak components of the compound I_K, as well as differences in I_CaL and steady state APD, it was necessary to implement the slower activation kinetics of Kv2.1/I_Kslow,2 (inset left). Peak I_K was straightforwardly fit through scaling the conductance of I_to,f in both the FF and KO models (right panel). (C) Together, these alterations resulted in slowed intermediate repolarization (APD₅₀ and APD₇₀) similar to that observed for KO myocytes. However, the slower early repolarization and rapid late repolarization in KO cells were much more difficult to capture with models that remained faithful to the voltage-clamp measurements. See Supplementary Table 1 for complete details of differences between these two baseline models.