In silico investigation of the functional effects of KCNQ1-G269S mutation in human ventricles

A recent study identified a loss-in-function mutation KCNQ1-G269S in long-QT patients who remained asymptomatic at rest but exhibited prolonged QT intervals after exercise, showing loss-of-function and blunted adrenergic activation in the slow component of delayed rectifier K+ current (IKs). The aim of this study was to evaluate the functional effects of the mutation in human ventricles through computer modelling. The O´Hara-Rudy model of human ventricular cells was modified to incorporate an updated model of IKs and an adrenergic activation model. The single cell models were then incorporated into a 1D strand model to quantify the effects of the mutation on tissue vulnerability in genesis of uni-directional conduction block. Using a 3D anatomical model of human ventricles and torso model, effects of the mutation on ventricular electrical activities and electrocardiograms (ECG) were simulated. It was shown that the mutation exerted moderate prolongations to action potential duration (APD) in the absence of adrenergic stimulation, and slightly increased the tissue vulnerability to produce unidirectional conduction block. These effects were much more pronounced after adrenergic stimulation. Simulated ECGs revealed moderate and severe QT prolongations for at rest and after exercise conditions respectively, which matched the clinical data. Our simulations provide insights into the pathological mechanisms of the KCNQ1-G269S mutation.