Biophysical modelling of the functional impacts of gender differences on human ventricles with abnormal repolarisation

Abstract

Ventricular arrhythmia (VA) is a cardiac disorder in which an irregular heart rhythm that originates in ventricles is manifested. Numerous pathologies predispose to VA, including the repolarisation abnormalities such as long QT syndrome (LQTS) and short QT syndrome (SQTS). Gender differences in susceptibility to VA are also evident in clinical studies. However, the mechanisms underlying arrhythmogenesis are poorly understood. In this thesis, multi-scale biophysically-detailed computational models were developed to elucidate the ionic mechanisms by which these pathologies modulate ventricular electrophysiology and susceptibility to VA. Firstly, actions of a macrolide antibiotic associated with acquired LQTS azithromycin (AZM) were evaluated. At the cellular level, AZM increased the the action potential duration (APD) and action potential (AP) triangulation in a dose-dependent manner. At tissue level, the transmural APD dispersion of the tissue and lifespan of re-entry were augmented. These findings indicate that the pro-arrhythmic risk was markedly increased at high concentrations of AZM. Secondly, the effects of a SQTS mutation I560T and quinidine were investigated. The I560T mutation shortened APD and QT intervals, augmented the transmural heterogeneity and prolonged the lifespan of re-entry, whilst quinidine restored these alterations dose-dependently. The pro-arrhythmic effects of the I560T mutation and the anti-arrhythmic effects of quinidine were confirmed, proposing quinidine to be a potential drug to treat the I560T variant of SQTS. Finally, gender differences in susceptibility to VA were studied under both non-diseased heart condition and diseased heart conditions with abnormal repolarisations. Females were shown to have longer APDs and QT intervals, especially at fast pacing rates. At 3D tissue level, males showed a slightly higher sustainability of re-entry in normal cases and cases of diseased hearts with QT-shortening, but females exhibited a significantly higher susceptibility to VA in cases of diseased hearts with QT-prolongation, suggesting taking gender into account in the treatments.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Henggui Zhang (Supervisor)