Impact of Structure Modification on Cardiomyocyte Functionality

by Filippo Giovanni Cosi
Doctoral thesis
Date of Examination:2020-02-27
Date of issue:2020-05-28
Advisor: Prof. Dr. Apl. Ulrich Apl. Parlitz
Referee: Prof. Dr. Apl. Ulrich Apl. Parlitz
Referee:Prof. Dr. Stefan Klumpp
Persistent Address: http://dx.doi.org/10.53846/goediss-7998

 

 

Files in this item

Name:thesis-filippo-cosi.pdf
Size:11.3Mb
Format:PDF

The following license files are associated with this item:

Abstract

English

Cardiac diseases are often related to defects in subcellular components of the heart’s main constituents, the heart muscle cells also called cardiac myocytes. These biological cells periodically contract due to excitation-contraction coupling, i.e. an interplay of intracellular ion dynamics and membrane potential which is centered around calcium release units (CRUs). Especially alterations of the functions and the geometry of CRUs may lead to distorted intracellular ion and voltage dynamics resulting in a malfunctioning cell. While the functions of CRUs are well studied, the knowledge about their geometry is still incomplete. However, recently the ryanodine receptors 2 (RyRs), i.e. calcium handling channels in CRUs, have been found to form elongated clusters rather than being densely packed into lattice-like configurations, as was previously assumed. This experimental observation represents a good reason to investigate the influence of the geometrical arrangement of ionic channels on the dynamics of cardiomyocytes. In this thesis a multiscale mathematical model is employed to quantify the impact different RyR arrangements in CRUs have on the ion dynamics and voltage dynamics of cardiac myocytes. The model describes the microscopic and stochastic processes of calcium release as well as the intracellular mesoscopic ion diffusion and action potential dynamics. Using this model we show that not only the shape of the RyR cluster, but also the density and the arrangement of the channels are found to be relevant for the cell dynamics. The numerical simulations proved changes in the microscopic structure and geometry of cell components to significantly affect observed quantities like the action potential duration or the average peak calcium concentration and thus the whole cardiomyocyte functionality. Moreover, since the employed mathematical model is computationally expensive, a method for the generation and validation of a cheaper numerical model is applied. Using this approach a meta model is generated based on the results from only a few hundred simulation runs of the complex original model. Computationally faster regressions based on the meta model can thus now accompany the multiscale mathematical model improving the efficiency, with which descriptive and relevant predictions can be made.
Keywords: PhD Thesis; Physics; Multiscale Mathematical Model; Cardiomyocytes; Calcium Release Units; Calcium Dynamics; Ryanodine Receptors; Structure Modification; Surrogate/Meta Model
 
Statistik