Pathophysiology and pharmacology of short QT syndrome gene mutations in the human atria: Insights from multi-scale computational modelling

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is characterised by rapid and irregular activation of the upper chambers of the heart. Many cardiac pathologies predispose to AF, including rare, congenital rhythm disorders such as the short QT syndrome (SQTS). However, mechanisms and management of AF in the context of the SQTS are poorly understood. Existing ways of investigating the pathology and pharmacology of the SQTS, such as in vitro electrophysiology experiments, are typically conducted in isolated expression systems, removed from the physiological environment of the whole cardiac cell and tissue. Multi-scale simulation platforms offer a viable way of investigating how changes at the ion channel level in the SQTS affect electrical propagation and arrhythmogenesis at the organ scale. The objective of this research was to develop biophysical computational models of human cardiac electrophysiology in order to investigate primarily the pathophysiology and pharmacology of SQTS gene mutations in the human atria, and is thus divided into two parts. (1) Novel mathematical formulations of repolarising K+ currents which are implicated in variants 1-3 of the SQTS were first developed using existing in vitro electrophysiology data, and integrated into single cell, idealised tissue, and anatomically-detailed tissue models of the human atria and ventricles in order to elucidate mechanisms of arrhythmogenesis. At the cellular level, K+ channel mutations in variants 1-3 of the SQTS accelerated the repolarisation phase of the action potential through distinct mechanisms. In tissue, this shortened the effective refractory period and excitation wavelength, which allowed higher activation frequencies and promoted sustenance of re-entrant excitations in a 3D anatomical model of the human atria. (2) Mechanistic models of the actions of clinically-available and hypothetical drugs were subsequently developed and applied in multi-scale simulations to gain insights into pharmacotherapeutic strategies in the SQTS. The efficacy of antiarrhythmic therapies in controlling the rate and rhythm of re-entrant arrhythmias was primarily determined by their ability to prolong the action potential duration and/or the effective refractory period. The work in this thesis represents a significant advance in understanding the mechanisms and management of AF in the context of the SQTS.

Date of Award	1 Aug 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Jian Lu (Supervisor) & Henggui Zhang (Supervisor)