Biophysically Detailed Modelling of The Functional Impact Of L-Type Calcium Channel Gene Mutations Associated with the ‘Short QT Syndrome’

Abstract

The cardiac L-type calcium channel is an oligomeric complex consisting of α1, β, and α2δ subunits. The CaV1.2 α-1C, the pore-forming subunit is encoded by CACNA1C gene, while the CaV β2 and CaV α2δ-1 subunits encoded by CACNB2b and CACNA2D1 respectively, control the biophysical properties and trafficking of CaV channels. In human ventricular cells, CaV1.2 channel regulates the inward movement of the calcium ions. The dome profile of the ventricular action potential is the result of inward calcium movement which also triggers Ca2+ release from the sarcoplasmic reticulum (SR) that regulates the excitation-contraction coupling. Genetic mutations in Cav subunits can be responsible for several phenotypes including the early repolarisation syndrome, the Brugada syndrome and the short QT syndrome. Short QT syndrome associated with L-type calcium channels are relatively new and rare clinical entity, manifested by an elevated ST segment and a shorter than normal QT interval. A short QT interval with an elevated ST segment can contribute to cardiac arrhythmia, ventricular fibrillation and sudden cardiac death (SCD). The work presented in this thesis is the development of a computational model to explain the functional behaviour of gene mutations associated with the SQT syndromes, initiation and maintenance of ventricular arrhythmias, and impairment of ventricular contraction. Three different mathematical models for SQT4, SQT5, and SQT6 were developed by using extant biophysical experimental data. The LTCC Hodgkin-Huxley formulation of the O’Hara & Rudy human ventricular single cell model (ORd) was reformed to integrate the kinetic properties of WT, SQT4 (A39V and G490R), SQT5 (S481L) and SQT6 (S755T) mutations. The validated formulations were then incorporated into the O’Hara & Rudy ventricular single cell and anatomically detailed tissue models (1D and 2D) to demonstrate how these variants advance to ventricular arrhythmias. The ORd electrophysiological short QT models were coupled with the myofilament model to investigate the functional impact of mutation on the mechanical coupling in single cell models. Simulated results showed that each mutation uniquely increased the temporal vulnerability of tissue to arrhythmogenesis in response to the premature excitation stimulus, indicating an increased risk of arrhythmia. Electromechanical single and 3D models illustrate a reduction of contractility in all three short QT models. These results provide better understanding into the mechanisms by which genetic variants of SQT4 (A39V and G490R), SQT5 (S481L) and SQT6 (S755T) mutations are pro-arrhythmic.

Date of Award	1 Aug 2019
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Henggui Zhang (Supervisor) & Ming Lei (Supervisor)