Figure 5: Effects of opposing mechanisms on modelled action potentials.

(a) The LRd model was used to gauge TS mutation effects on cardiac ventricular APs. Model activation curves (black curve) fit well the tail-current data (black circles). G406R (red) and G402S (blue) curves shifted to match experiments (circles). Inactivation parameters were similarly adjusted. (b) A single WT AP generated by the model. (c) Modelled WT APs displayed on an expanded timebase during 1-Hz pacing to show stability. (d) Severe effects of G406R channels. Variable G406R expression modelled by including a variable fraction of mutant versus WT channels. At first, APD increased monotonically, then become patently unstable before reaching TS2 levels. (e) Significant APD prolongation at ∼15% G406R. Asterisk indicates corresponding data in d. (f) Profound AP prolongation due to arrhythmogenic early after depolarizations at ∼20% G406R. Double asterisk indicates corresponding data point in d. (g) Milder G402S mutation (blue) effects. Significant APD prolongation does not arise until mutant channels reach the anticipated mean of TS2 patients. The G406R curve is reproduced for comparison (dashed red). (h) APD prolongation at ∼40% G402S. Asterisk indicates corresponding data in g. (i) Slight further increase of G402S (∼44%) induces alternans. Double asterisk indicates corresponding data point in g.