Subcellular calcium patterns in ventricular myocytes

Veasy, Joshua (2018) Subcellular calcium patterns in ventricular myocytes. PhD thesis, University of Nottingham.

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Abstract

Understanding the biology and mechanisms as to how the heart contracts has long been a point of interest for biologists and mathematicians alike. Since inconsistent beating of the heart has been linked to multiple pathological conditions, research into this area has been extensive but we still only have some of the answers. One of the key findings over the last century has been the role of calcium in activating the machinery within the heart that drives contraction. Further studies have shown that when calcium is mishandled by the heart's myocytes, it can lead to some of these pathological conditions. Since such discoveries a major point of research into the heart has focused on the possible avenues that calcium mishandling can occur.

This thesis explores some of these avenues using a mathematical model of the ventricular myocyte developed by Thul and Coombes in their 2010 paper 'Understanding cardiac alternans: A piecewise linear modeling framework'. The chosen model contains key components involved in the movement of calcium within the myocyte. Moreover, the model used is piecewise linear and the stability of some important behaviours can be studied exactly without the need for approximations and reductions. This is often an issue in many other models used to study the calcium dynamics within a ventricular myocyte.

The avenue towards calcium mishandling that this thesis predominantly focuses on is that of intracellular calcium diffusion between the building blocks of ventricular myocytes known as sarcomeres. Our research extends previous research into how strong diffusion between sarcomeres can cause unwanted calcium dynamics. Further to this, we explore how the balance in the strength of different forms of calcium diffusion between sarcomeres can drive a variety of spatial patterns in terms of how the calcium is distributed throughout the cell. Throughout these studies we also investigate the role of other parts of the myocyte, particularly the sarcoplasmic reticulum Calcium-ATPase pumps and sarcoplasmic reticulum release in relation to diffusion driven instabilities.

As well as intracellular diffusion of calcium, this thesis considers the role of intercellular diffusion of calcium through gap junctions. This form of diffusion has historically been considered to a lesser extent than intracellular diffusion. As such this thesis introduces new ideas concerning gap junctions. These include a role in driving the mishandling of calcium as well as altering behaviours driven by intracellular diffusion. An important message is that calcium diffusion within the myocyte is far more important in terms of how unwanted behaviours can appear than previous studies suggest.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Thul, Ruediger
Coombes, Stephen
Keywords: Calcium; Myocetes; Intercellular diffusion; Intracellular diffusion
Subjects: Q Science > QA Mathematics > QA299 Analysis
Q Science > QP Physiology > QP501 Animal biochemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Mathematical Sciences
Item ID: 55014
Depositing User: Veasy, Joshua
Date Deposited: 25 Jan 2019 14:00
Last Modified: 07 Feb 2019 18:15
URI: http://eprints.nottingham.ac.uk/id/eprint/55014

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