Combination In Vitro and in Silico Methodology for Risk Assessment of Long QT Type 1 Patients

Abstract

There is a long history of simulating the effects of channelopathies on the cardiac action potential (AP) in diseases like Long QT (LQT) Syndrome. While an important proof of concept, studies have been limited because the number of mutants considered was small and correlation with the phenotype was anecdotal. This study seeks to address such limitations by including 17 Long QT type 1 (LQT 1) mutations for which both in vitro characterizations have been performed and detailed clinical outcome data are known. The IKs channel (KCNQ1 and KCNE1 subunits) were expressed in both Xenopus oocytes and HEK-293T cells, and Gmax, Vhalf and the τ of activation and deactivation were measured. The properties were then incorporated into a humanized version of the Flaim-Giles-McCulloch reconstruction of canine cardiomyocytes. The model also included beta-adrenergic stimulation that is known to modulate IKs and is thought to contribute to exercise-induced sudden death in some LQT patients. Both single cell and 1-D cable models were investigated. The simulated QT prolongation in the cable model correlated well with the QTc in patients carrying the 17 mutations studied. The cable model including beta-adrenergic stimulation showed early after-depolarizations (EADs) and T-wave alternans for mutants. The presence of T-wave alternans correlated with cardiac risk for these patients. Correlation of electrophysiology and clinical phenotype showed that slow activation rates for LQT1 mutations are risk factors for these patients independent from QT prolongation. Incorporation of slow IKs activation into the model produced a more severe to response to β-adrenergic-mediated EADs as compared to responses with reduced IKs conductance only. Our results suggest that cellular electrophysiology in combination with 1-D cable models is a good methodology to predict cardiac risk associated with Long QT1 mutations.