Development of Ventricular Cell Models for the Study of Alternans, Heart Failure and Energetic Impairment.

Abstract

In this thesis the changes observed in human ventricular cells with disease are examined. As heart disease remains one of the leading causes of death in Europe computational modelling provides a powerful tool in understanding the mechanisms underlying changes observed with disease. In this project, an integrated model of a human ventricular cardiomyocyte incorporating electrophysiology, mitochondrial energetics and contraction was constructed. This model was then modified with recent data from patients with hypertrophic cardiomyopathy to allow insight into factors leading to exercise intolerance with the disease. The cell was found to be energetically impaired due to a combination of Ca2+ overload and mitochondrial dysfunction. The effect of three drugs were then tested on the model, each found to block Na+ and Ca2+ handling channels within the cell. Two of these drugs, K201 and SEA-0400 were found to improve the energetic status of the cell during exercise through a reduction in myofilament ATP consumption. Changes observed in mRNA expression were then utilised to modify a model of a previous human ventricular cell and update the regulation of RyR gating. Regulation by calsequestrin of the recovery from inactivation of the RyRs is found to mediate the production of alternans. Finally a compartmentalised model of spatial Ca2+ dynamics was updated with a recent model of mitochondrial energetics. Disruption of mitochondrial Ca2+ uptake is simulated and shown to result in mitochondrial dysfunction. Energetic impairment of localised processes within the cell due to dysfunction was investigated.

Date of Award	31 Dec 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Jian Lu (Supervisor) & Henggui Zhang (Supervisor)