Investigation of ion channel mechanisms underlying cardiac arrhythmias by multi-scale computer models of the heart

Abstract

Cardiac arrhythmia (CA) is a heart disease characterized by disruptions in the heart's rhythm, resulting in abnormal excitation or conduction of cardiac electrical signals, which in turn triggers irregular mechanical contractions of the heart chambers. Serious CA can even lead to cardiac tamponade and significantly impact the normal lives of patients worldwide. However, research into this disease has been limited due to high research costs, the complex nature of its pathogenic mechanisms, and medical ethics. Therefore, this thesis aims to construct computational cardiac models to address these limitations by providing a comprehensive analysis of three arrhythmia-causing diseases associated with the functional loss or gain of potassium channels across multiple scales, from the level of channel proteins to the three-dimensional organization of the cardiac organ. Through the utilization of experimental data and computational cardiac modeling, this research uncovers potential mechanisms contributing to arrhythmias. The first section investigates the significant contributions of slow delayed rectifier potassium currents (IKs) and rapid delayed rectifier potassium currents (IKr) to the electrical activity of the human ventricle and examines the physiological mechanisms by which associated mutations contribute to the triggering of Long QT syndromes (LQTS). Markov chain models of IKs and IKr were formulated based on experimental data of KCNQ1-D242N and KCNH2-T634S under mutant conditions. Subsequently, these channel models were incorporated into various human ventricular cell models (1D, 2D, and 3D) to assess the functional impact of mutations on transmembrane action potential (AP) heterogeneity, AP duration restitution curves (APDr), and the QT interval. The second section focuses on investigating the physiological link between atrial fibrillation (AF), the most prevalent arrhythmia, and the abnormally augmented hyperpolarization-activated channel current (If). Multiple regional models of the If channel in the human atrium were reconstructed from experimental data. The capacities for regional heterogeneity of atrial cell models generating spontaneous action potentials were assessed using enhanced If. Subsequently, cells from multiple regions were incorporated into the 3D atrial geometry to assess the interference of abnormal augmentation of If in isolated atrial regions with excitation waves under normal rhythm. The results demonstrate that abnormally augmented If evokes spontaneous electrical activity in various atrial cells, disrupting the normal depolarization process and intracellular calcium homeostasis. Observations exploring AF on the updated model suggest that AF causes negative effects on varying regional cells by inhibiting the normal electrical activity of atrial cells and shortening action potential duration (APD). This study reveals the intricate relationships between potassium channel currents, cellular electrophysiology, and the development of arrhythmias. The integration of various modeling approaches, from single-cell to tissue and organ models, enables a comprehensive assessment of electrical behavior and the exploration of CA-related alterations at multiple scales. Overall, these investigations provide valuable insights into the mechanisms that probe the effects of potassium channel dynamics-related arrhythmias on the electrical activity of the heart.

Date of Award	31 Dec 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Henggui Zhang (Supervisor)