Development of a biomechanical computational model of the human heart for the study of cardiac arrhythmias

Abstract

Cardiac arrhythmias are the most common cardiac disease, causing morbidity. They are characterised by irregular electrical excitation waves propagating in the heart, impairing the tissue's cardiac mechanical contraction and leading to blood circulation failure. However, the mechanism underlying arrhythmogenesis in prolonging the action potential duration (APD)/QT interval is incompletely understood, which may evolve in Torsades de Pointes (TdP), a life-threatening ventricular tachyarrhythmia. This thesis studied three scenarios causing the prolongation of the APD. In the first scenario, the medication to treat COVID-19 on a healthy ventricle was assessed. In the second scenario, the APD prolongation in the hypertrophic cardiomyopathy (HCM) condition at rest was studied. In the third scenario, the APD prolongation in the HCM condition under adrenergic stimulation was assessed. The methodology implemented to achieve the objectives of this thesis was, in the first instance, to assess the proarrhythmic effects of hydroxychloroquine (HCQ) and azithromycin (AZM) in the human ventricles following the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. Subsequently, substrates leading to prolongation of APD/QT interval in a single cell and 1D scale in undiseased ventricles were identified. Additionally, an early afterdepolarisation (EAD) screening to identify the ion channels' vulnerability to HCQ and AZM was performed. Secondly, a ventricular single-cell model was developed. This model includes mitochondrial remodelling with HCM based on human experimental data and integrates a B-adrenergic receptor stimulation (B-ARS) model (the EFME-BARS model). Finally, the resulting model from the assembly of the above was used to evaluate the APD prolongation, the energetic dysregulation, oxidative stress, and potential pharmacological treatment with selective INaL inhibitors (ranolazine and GS-967) in HCM at rest and under B-adrenergic receptor stimulation. The assessment of HCQ and AZM drugs showed that the higher doses of HCQ alone or in combination with AZM cause the largest prolongation in APD/QT interval, implying a higher likelihood of developing TdP. The EADs screening shows that applying HCQ in combination with AZM in reduced IKs current conditions leads to the highest proarrhythmic effects. The EFME-BARS model is an innovative and pioneering approach that integrates electrophysiology, mitochondrial energetics, myofilament force generation, and B-adrenergic receptor stimulation to simulate the behaviour of the human ventricle. This model convincingly emulates the experimental characteristics of the HCM disease under various conditions, including at rest, during B-adrenergic receptor stimulation, and after the administration of ranolazine and GS-967 drugs. The EFME-BARS model simulations showed an energetic dysregulation in HCM at rest and under B-adrenergic receptor stimulation as indicated by the reduced phosphocreatine to adenosine triphosphate ratio (PCr/ATP). Additionally, the simulations predicted that the mitochondrial remodelling in HCM causes increased oxidative stress and reduced antioxidant activity. The EFME-BARS model also showed that ranolazine and GS-967 positively reduced the diastolic force generated in the HCM condition at rest and under B-ARS but had no significant effect on ATP consumption.

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