IKs computational modeling to enforce the investigation of D242N, a KV7.1 LQTS mutation

Abstract

A KCNQ1 mutation, D242N, was found in a pair of twins and characterized at the cellular level. To investigate whether and how the mutation causes the clinically observed lost adaptation to fast heart rate, we performed a computational study. Firstly, we identified a new IKs model based on voltage clamp experimental data. Then we included this formulation in the human action potential model of O'Hara Rudy (ORd) and simulated the effects of the mutation. We also included adrenergic stimulation to the action potential, since the basal adrenergic tone is likely to affect the influence of IKs on QTc in vivo. Finally, we simulated the pseudo-ECG, taking into account the heterogeneity of the cardiac wall. At the basal rate (60bpm), the mutation had negligible effects for all cell types, whereas at the high rate (180bpm), with concomitant β-adrenergic stimulation (mimicking exercise conditions), the mutant AP failed to adapt its duration to the same extent as the wild-type AP (e.g. 281ms vs. 267ms in M cells), due to a smaller amount of IKs current. Pseudo-ECG results show only a slight rate adaptation, and the simulated QTc was significantly prolonged from 387ms to 493ms, similar to experimental recordings.