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Intra- and Inter-Individual Cardiomy...

Pullinger, Taylor Kelsey,

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Intra- and Inter-Individual Cardiomyocyte Heterogeneity Impacts Arrhythmia Risk /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Intra- and Inter-Individual Cardiomyocyte Heterogeneity Impacts Arrhythmia Risk // Taylor Kelsey Pullinger.
Author:	Pullinger, Taylor Kelsey,
Description:	1 electronic resource (174 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-07, Section: B.
Contained By:	Dissertations Abstracts International85-07B.
Subject:	Biophysics. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30989394
ISBN:	9798381403114

Intra- and Inter-Individual Cardiomyocyte Heterogeneity Impacts Arrhythmia Risk /
Pullinger, Taylor Kelsey,

Intra- and Inter-Individual Cardiomyocyte Heterogeneity Impacts Arrhythmia Risk /Taylor Kelsey Pullinger. - 1 electronic resource (174 pages)

Source: Dissertations Abstracts International, Volume: 85-07, Section: B.

Heterogeneity has been shown to impact resilience in a range of complex systems, including the heart. Cardiac heterogeneity takes many forms including structural heterogeneity, variation among individuals, and cell-to-cell heterogeneity. In this dissertation I use mathematical modeling techniques to explore questions of how cardiac heterogeneity impacts resilience to arrhythmia. I begin by exploring how cell-to-cell heterogeneity in ion channel conductance affects substrate vulnerability-the tendency for an ectopic depolarization to develop into a tissue-wide arrhythmia instead of resolving harmlessly. In Chapter 2, I characterize one aspect of substrate vulnerability, the generation of unidirectional block, using a population of uniform 1-dimensional cardiomyocyte cable models. Parameter sensitivity analysis and other regression techniques enabled by the population-based approach reveal ion channel conductances that influence this phenomenon, as well as correlation with underlying electrophysiological patterns. Chapter 3 brings this knowledge to heterogeneous cardiomyocyte cable models where it becomes clear that the generation of unidirectional block is highly localized and variable at different tissue locations. While unidirectional block can still be manipulated by global perturbations, like exposure to channel blocking drugs or modified gap junctional coupling strength, it cannot be simply predicted as in uniform cables. In Chapter 4 I shift to exploring regional heterogeneity in the context of disease. This collaborative project aims to use a genetic algorithm to fit cell-specific cardiomyocyte models to electrophysiological experimental data collected from pigs that have experienced myocardial infarction or a sham procedure. As a result, we gain understanding about differences in post-myocardial infarction ion channel remodeling between the 'border zone' region adjacent to the fibrotic scar and more remote tissue regions. Chapter 5 employs similar methods with stem cell-derived cardiomyocytes. In this collaborative project we developed and evaluated a pipeline to efficiently and robustly calibrate cell-specific computational models to induced pluripotent stem cell-derived cardiomyocyte experimental data using a genetic algorithm. Overall, this work deepens our understanding of the impact of heterogeneity between individual cardiomyocytes on resilience to arrhythmia, when these cells are coupled in tissue or in isolation.

English

ISBN: 9798381403114Subjects--Topical Terms:

518360
Biophysics.
Subjects--Index Terms:

Cardiac arrhythmia

Intra- and Inter-Individual Cardiomyocyte Heterogeneity Impacts Arrhythmia Risk /
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520 $a Heterogeneity has been shown to impact resilience in a range of complex systems, including the heart. Cardiac heterogeneity takes many forms including structural heterogeneity, variation among individuals, and cell-to-cell heterogeneity. In this dissertation I use mathematical modeling techniques to explore questions of how cardiac heterogeneity impacts resilience to arrhythmia. I begin by exploring how cell-to-cell heterogeneity in ion channel conductance affects substrate vulnerability-the tendency for an ectopic depolarization to develop into a tissue-wide arrhythmia instead of resolving harmlessly. In Chapter 2, I characterize one aspect of substrate vulnerability, the generation of unidirectional block, using a population of uniform 1-dimensional cardiomyocyte cable models. Parameter sensitivity analysis and other regression techniques enabled by the population-based approach reveal ion channel conductances that influence this phenomenon, as well as correlation with underlying electrophysiological patterns. Chapter 3 brings this knowledge to heterogeneous cardiomyocyte cable models where it becomes clear that the generation of unidirectional block is highly localized and variable at different tissue locations. While unidirectional block can still be manipulated by global perturbations, like exposure to channel blocking drugs or modified gap junctional coupling strength, it cannot be simply predicted as in uniform cables. In Chapter 4 I shift to exploring regional heterogeneity in the context of disease. This collaborative project aims to use a genetic algorithm to fit cell-specific cardiomyocyte models to electrophysiological experimental data collected from pigs that have experienced myocardial infarction or a sham procedure. As a result, we gain understanding about differences in post-myocardial infarction ion channel remodeling between the 'border zone' region adjacent to the fibrotic scar and more remote tissue regions. Chapter 5 employs similar methods with stem cell-derived cardiomyocytes. In this collaborative project we developed and evaluated a pipeline to efficiently and robustly calibrate cell-specific computational models to induced pluripotent stem cell-derived cardiomyocyte experimental data using a genetic algorithm. Overall, this work deepens our understanding of the impact of heterogeneity between individual cardiomyocytes on resilience to arrhythmia, when these cells are coupled in tissue or in isolation.
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