Multi-scale Cardiac Modelling Reveal Tachyarrhythmias Induced by Abrupt Rate Accelerations in Long QT Syndrome

Motivation: Long QT syndromes (LQTS) are characterized by early afterdepolarizations (EADs), repolarization dispersion and tachyarrhythmias. However, mechanisms by which these substrates promote tachyarrhythmias remain to be fully elucidated. This study sought to test the hypothesis that EADs induced by abrupt rate accelerations can occur and investigate how this abrupt rate accelerations is related to the mechanisms of reentrant excitations. Methods: The TP06 model for human ventricular cell was modified to model experimental conditions in LQTS. Then, the normal and EADs cell models were incorporated into homogeneous multicellular ID and 2D tissue models to study the mechanism underlying the generation of reentrant events. Results and conclusions: In single cell simulations, abrupt accelerations in the heart rate prolonged action potential duration and favored to the genesis of EADs. In the ID simulations, an EADs region increased tissue's vulnerability to unidirectional conduction block in response to abrupt rate accelerations. In the 2D idealized tissue simulations, abrupt rate accelerations induced initiation of spiral waves due to an increase in repolarization gradients caused by an EADs region. These computer simulations suggest that abrupt rate accelerations can favor to the genesis of EADs and an EADs region can enhance the susceptibility of arrhythmias by increasing dispersion of repolarization. Thus, the increased regional repolarization dispersion caused by abrupt rate accelerations is a primary factor that may primarily contribute to the genesis of tachyarrhythmias in LQTS.