Computational analysis of long QT syndrome type 2 and the therapeutic effects of KCNQ1 antibodies

Abstract

Objective Long QT interval syndrome (LQTS) is a highly dangerous cardiac disease that can lead to sudden cardiac death; however, its underlying mechanism remains largely unknown. This study is conceived to investigate the impact of two general genotypes of LQTS type 2, and also the therapeutic effects of an emerging immunology-based treatment named KCNQ1 antibody. Methods A multiscale virtual heart is developed, which contains multiple biological levels ranging from ion channels to a three-dimensional cardiac structure with realistic geometry. Critical biomarkers at different biological levels are monitored to investigate the remodeling of cardiac electrophysiology induced by mutations. Results Simulations revealed multiple important mechanisms that are hard to capture via conventional clinical techniques, including the augmented dispersion of repolarization, the increased vulnerability to arrhythmias, the impaired adaptability in tissue to high heart rates, and so on. An emerging KCNQ1 antibody-based therapy could rescue the prolonged QT interval but did not reduce the vulnerable window. Conclusions Tiny molecular alterations can lead to cardiac electrophysiological remodeling at multiple biological levels, which in turn contributes to higher susceptibility to lethal arrhythmias in long QT syndrome type 2 patients. The KCNQ1 antibody-based therapy has proarrhythmic risks notwithstanding its QT-rescuing effects.