Linking a novel mutation to its short QT phenotype through multiscale computational modelling

The aim of this work was to assess the link between a newly identified KCNQ1 mutation and the short QT syndrome clinically observed in the patients. We applied two human Action Potential models, the ten Tusscher - Panfilov (TTP) and the O'Hara Rudy (ORd). We also simulated the effects of adrenergic stimulation on action potential, since the basal adrenergic tone should likely affect the
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influence on QTc in vivo. Finally, we simulated the pseudo ECG taking into account the heterogeneity of the cardiac wall. Simulations predict a shortening of the action potential consistent with the patient phenotype: using the TTP model the shortening was largely more pronounced (e.g. from 397 to 297 ms in M cells) than with the ORd (e.g. from 332 to 318 ms in M cells). When simulating the β-adrenergic stimulation, the APD shortening was enhanced in ORd model. Pseudo ECG results confirm the reduction of the QT interval caused by mutation.