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The role of adipose tissue in arrhythmogenesis : an in silico study

Tim De Coster (UGent)
(2019)
Author
Promoter
(UGent) and Piet Claus
Organization
Abstract
Cardiovascular diseases encompass the largest percentage of mortal incidences in the industrialised world. Amongst them is sudden cardiac death, which in 90 % of cases occurs due to ventricular arrhythmias. Another important arrhythmia is atrial fibrillation (AF) as it is estimated that one in three strokes occur due to AF. It also forms an economic burden on modern health care, affecting approximately 1.5 % of the population and as much as 9 % of people above the age of 80. AF is a progressive disease and results in increased mortality, morbidity and impaired quality of life. It therefore constitutes a major problem in cardiac electrophysiology. Developing insights into the mechanism and origin of arrhythmias is of great interest to progress therapeutic strategies. The onset of irregular wave patterns in the heart depends on structural and electrophysiological properties of cardiac tissue. In this thesis, these properties are investigated by the means of mathematical and in silico modelling. One of the most important changes leading to arrhythmias is characterised by the presence of a large number of non-excitable cells in the heart, of which the most well-known example is fibrosis. Recently, adipose tissue was put forward as another similar factor contributing to cardiac arrhythmias. Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. Adipocytes infiltrate into cardiac tissue and produce in-excitable obstacles that interfere with myocardial conduction. However, adipose infiltrates have a different spatial texture than fibrosis. Over the course of time, adipose tissue also remodels into fibrotic tissue. We investigate the arrhythmogenic mechanisms resulting from the structural presence of adipose tissue in the heart. We use the TP06 model for human ventricular cells and study how the texture, and in particular the size and percentage of adipose infiltrates, affects basic properties of wave propagation and the onset of arrhythmias under high frequency pacing in a 2D model for cardiac tissue. We show that although presence of adipose infiltrates can result in the onset of cardiac arrhythmias, its impact is less significant than that of fibrosis. We quantify this process and discuss how the remodelling of adipose infiltrates affects arrhythmia onset. Electrophysiological remodelling of myocytes due to the presence of adipocytes constitutes another possibly important pathway in the pathogenesis of atrial fibrillation. We perform an in-silico study of the effect of such myocyte remodelling on the onset of atrial arrhythmias and study the dynamics of arrhythmia sources — spiral waves. We use the Courtemanche model for atrial myocytes and modify their electrophysiological properties based on published cellular electrophysiological measurements in myocytes co-cultered with adipocytes (a 69 − 87 % increase in action potential duration (APD_90) and an increase of the resting membrane potential (RMP) by 2.5 − 5.5 mV .). In a generic 2D setup we show that adipose tissue remodelling substantially affects the spiral wave dynamics resulting in complex arrhythmia and such arrhythmia can be initiated under high frequency pacing if the size of the remodelled tissue is sufficiently large. These results are confirmed in simulations with an anatomically accurate model of the human atria. Overall we show that presence of adipose tissue is a strong arrhythmogenic factor. Both structural and electrophysiological remodelling increase probability of break-up of electrical waves in the heart and onset of cardiac arrhythmias. We quantify the specific mechanisms of increased arrhythmogenicity and discuss possible clinical applications of our research.
Keywords
Arrhythmias, Atrial Fibrillation, Adipose Tissue, Spiral Waves, Biophysics

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Citation

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Chicago
De Coster, Tim. 2019. “The Role of Adipose Tissue in Arrhythmogenesis : an in Silico Study”. Ghent ; Leuven, Belgium: Ghent University. Faculty of Sciences ; KU Leuven. Faculty of Biomedical Sciences.
APA
De Coster, Tim. (2019). The role of adipose tissue in arrhythmogenesis : an in silico study. Ghent University. Faculty of Sciences ; KU Leuven. Faculty of Biomedical Sciences, Ghent ; Leuven, Belgium.
Vancouver
1.
De Coster T. The role of adipose tissue in arrhythmogenesis : an in silico study. [Ghent ; Leuven, Belgium]: Ghent University. Faculty of Sciences ; KU Leuven. Faculty of Biomedical Sciences; 2019.
MLA
De Coster, Tim. “The Role of Adipose Tissue in Arrhythmogenesis : an in Silico Study.” 2019 : n. pag. Print.
@phdthesis{8620736,
  abstract     = {Cardiovascular diseases encompass the largest percentage of mortal incidences in the industrialised world. Amongst them is sudden cardiac death, which in 90 % of cases occurs due to ventricular arrhythmias. Another important arrhythmia is atrial fibrillation (AF) as it is estimated that one in three strokes occur due to AF. It also forms an economic burden on modern health care, affecting approximately 1.5 % of the population and as much as 9 % of people above the age of 80. AF is a progressive disease and results in increased mortality, morbidity and impaired quality of life. It therefore constitutes a major problem in cardiac electrophysiology.
Developing insights into the mechanism and origin of arrhythmias is of great interest to progress therapeutic strategies. The onset of irregular wave patterns in the heart depends on structural and electrophysiological properties of cardiac tissue. In this thesis, these properties are investigated by the means of mathematical and in silico modelling.
One of the most important changes leading to arrhythmias is characterised by the presence of a large number of non-excitable cells in the heart, of which the most well-known example is fibrosis. Recently, adipose tissue was put
forward as another similar factor contributing to cardiac arrhythmias. Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. Adipocytes infiltrate into cardiac tissue and produce in-excitable
obstacles that interfere with myocardial conduction. However, adipose infiltrates have a different spatial texture than fibrosis. Over the course of time, adipose tissue also remodels into fibrotic tissue.
We investigate the arrhythmogenic mechanisms resulting from the structural presence of adipose tissue in the heart. We use the TP06 model for human ventricular cells and study how the texture, and in particular the size and percentage of adipose infiltrates, affects basic properties of wave propagation and the onset of arrhythmias under high frequency pacing in a 2D model for cardiac tissue. We show that although presence of adipose infiltrates can result in the onset of cardiac arrhythmias, its impact is less significant than that of fibrosis. We quantify this process and discuss how the remodelling of adipose infiltrates affects arrhythmia onset.
Electrophysiological remodelling of myocytes due to the presence of adipocytes constitutes another possibly important pathway in the pathogenesis of atrial fibrillation. We perform an in-silico study of the effect of such myocyte remodelling on the onset of atrial arrhythmias and study the dynamics of arrhythmia sources — spiral waves. We use the Courtemanche model for atrial myocytes and modify their electrophysiological properties based on published cellular electrophysiological measurements in myocytes co-cultered with adipocytes (a 69 − 87 % increase in action potential duration (APD_90) and an increase of the resting membrane potential (RMP) by 2.5 − 5.5 mV .). In a generic 2D setup we show that adipose tissue remodelling substantially affects the spiral wave dynamics resulting in complex arrhythmia and such arrhythmia can be initiated under high frequency pacing if the size of the remodelled tissue is sufficiently large. These results are confirmed in simulations with an anatomically accurate model of the human atria.
Overall we show that presence of adipose tissue is a strong arrhythmogenic factor. Both structural and electrophysiological remodelling increase probability of break-up of electrical waves in the heart and onset of cardiac arrhythmias. We quantify the specific mechanisms of increased arrhythmogenicity and discuss possible clinical applications of our research.},
  author       = {De Coster, Tim},
  isbn         = {9789463754217},
  keywords     = {Arrhythmias,Atrial Fibrillation,Adipose Tissue,Spiral Waves,Biophysics},
  language     = {eng},
  pages        = {XXVIII, 171},
  publisher    = {Ghent University. Faculty of Sciences ; KU Leuven. Faculty of Biomedical Sciences},
  school       = {Ghent University},
  title        = {The role of adipose tissue in arrhythmogenesis : an in silico study},
  year         = {2019},
}