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Development of Cellular and Tissue Models to Simulate the Effect of Fibroblast-Myocyte Coupling on Cardiac Pacemaking and Conduction

Qiao, Le

[Thesis]. Manchester, UK: The University of Manchester; 2016.

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Abstract

Constituting 90-95% of the cardiac non-myocyte cell population, cardiac fibroblasts can electrically couple to cardiac myocytes by forming gap junctions. The electrical interaction between cardiac myocytes and fibroblasts plays a vital role in cardiac fibrosis and arrhythmia related heart disease. In this thesis, cellular models of fibroblast-myocyte coupling in the rabbit sinoatrial node (SAN) and atrium were developed to explore the mechanism underlying the coupling. The effects of coupling fibroblast number and coupling strength between fibroblast and myocyte on electrical activities of the coupled myocyte were also investigated. 2D SAN-atrium tissue models with fibroblasts coupled in different ways were then developed to investigate the effects of the coupling fibroblast number and coupling strength on action potential initiation and propagation in cardiac tissue.Our simulation found that the coupling exerts significant effects on the action potential (AP) waveform of coupled myocyte in the SAN centre under weak coupling (the gap junction conductance (Ggap) is less than 0.2 nS), showing a smaller action potential amplitude (APA), a less negative maximum diastolic potential (MDP), a shortened APD90, and a decreased dV/dtmax after coupling with a larger Ggap or more fibroblasts. Moreover, the spontaneous activity in the SAN centre is abolished under strong coupling (Ggap > 1 nS). In contrast, there is no significant changes in AP characteristics of coupled myocytes in the SAN periphery and atrium under weak coupling. The APD90 increases along with the coupling fibroblast number or Ggap in atrium and SAN periphery under strong coupling. In the 2D tissue model, the conduction velocity (CV) increases in coupling regions after coupling with a larger Ggap or more fibroblasts in the attachment models. However, it increases in the SAN centre and decreases in the SAN periphery and atrium in the insertion models. Conduction blocks can be observed in both models after coupling with a certain number of fibroblasts. Therefore, fibroblasts are not only able to modulate the electrical activities of individual cells but also can modify the pacemaking activities and the AP conduction in cardiac tissue. However, the extent of changes is highly dependent on the electrophysiological properties of coupled myocytes, coupling fibroblast number and coupling strength between the myocyte and the fibroblast.

Bibliographic metadata

Type of resource:
Content type:
Form of thesis:
Type of submission:
Degree type:
Master of Philosophy
Degree programme:
MPhil Physics
Publication date:
Location:
Manchester, UK
Total pages:
100
Abstract:
Constituting 90-95% of the cardiac non-myocyte cell population, cardiac fibroblasts can electrically couple to cardiac myocytes by forming gap junctions. The electrical interaction between cardiac myocytes and fibroblasts plays a vital role in cardiac fibrosis and arrhythmia related heart disease. In this thesis, cellular models of fibroblast-myocyte coupling in the rabbit sinoatrial node (SAN) and atrium were developed to explore the mechanism underlying the coupling. The effects of coupling fibroblast number and coupling strength between fibroblast and myocyte on electrical activities of the coupled myocyte were also investigated. 2D SAN-atrium tissue models with fibroblasts coupled in different ways were then developed to investigate the effects of the coupling fibroblast number and coupling strength on action potential initiation and propagation in cardiac tissue.Our simulation found that the coupling exerts significant effects on the action potential (AP) waveform of coupled myocyte in the SAN centre under weak coupling (the gap junction conductance (Ggap) is less than 0.2 nS), showing a smaller action potential amplitude (APA), a less negative maximum diastolic potential (MDP), a shortened APD90, and a decreased dV/dtmax after coupling with a larger Ggap or more fibroblasts. Moreover, the spontaneous activity in the SAN centre is abolished under strong coupling (Ggap > 1 nS). In contrast, there is no significant changes in AP characteristics of coupled myocytes in the SAN periphery and atrium under weak coupling. The APD90 increases along with the coupling fibroblast number or Ggap in atrium and SAN periphery under strong coupling. In the 2D tissue model, the conduction velocity (CV) increases in coupling regions after coupling with a larger Ggap or more fibroblasts in the attachment models. However, it increases in the SAN centre and decreases in the SAN periphery and atrium in the insertion models. Conduction blocks can be observed in both models after coupling with a certain number of fibroblasts. Therefore, fibroblasts are not only able to modulate the electrical activities of individual cells but also can modify the pacemaking activities and the AP conduction in cardiac tissue. However, the extent of changes is highly dependent on the electrophysiological properties of coupled myocytes, coupling fibroblast number and coupling strength between the myocyte and the fibroblast.
Additional digital content not deposited electronically:
N/A
Non-digital content not deposited electronically:
N/A
Thesis main supervisor(s):
Thesis co-supervisor(s):
Language:
en

Institutional metadata

University researcher(s):

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:303516
Created by:
Qiao, Le
Created:
4th September, 2016, 23:55:47
Last modified by:
Qiao, Le
Last modified:
3rd November, 2017, 11:16:28

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