Computational Modeling of Electrical Cell-to-cell Interactions in Cardiac Tissue: Applications to Model Parameter Selection and Pacemaker Function
Abstract
Cell-to-cell interactions are important in determining the electrophysiological behavior of cardiac tissue. In this research, computer modeling is used to investigate the importance of these interactions in two different contexts: 1) how to adjust parameters in single cell models to accurately reproduce tissue behavior, and 2) determining requirements for successful conduction at the interface between different tissue types, specifically from the sinoatrial node (SAN) to the atrium.
Membrane resistance (Rm), the inverse of the slope of the current-voltage (I/V) relationship for a cardiac myocyte, is an important
determinant of electrical cell-to-cell interactions. Experimentally, Rm can be measured by applying a small current and measuring the resulting change in membrane voltage. To investigate the importance of Rm, a multi-objective genetic algorithm approach was developed for enhancing the fitting of action potentials (APs) in single cell models. Rm was fit at several points during the AP along with AP morphology. The results demonstrate that including Rm as a fitting criterion yields improved convergence, reduced variability in parameter estimates,
and improved robustness, while specifically improving the ability of the model to
reproduce tissue behavior.
Bioengineered pacemakers are cellular constructs intended to replace the SAN pacemaker function. The interface between the SAN and atrium appears to have features designed to facilitate conduction. Depending on the species, these features involve gradual transitions (gradients) in ion channel densities and coupling conductance, or insulating boundaries with
conduction at discrete exit points only. We used simulations to determine the importance of each of these features, with the aim to provide guidance to future development of bioengineered pacemakers. We found that gradients in ionic conductance (specifically ICaL) are required in rabbit SAN. There is narrow range of coupling for which the SAN is able to propagate towards atrium without coupling gradients. In canine SAN, these gradients support conduction. However, gradients are not required, provided conduction from SAN to atrium is restricted to discrete exit points. This suggests two possible strategies for successful conduction at the interface between a bioengineered pacemaker and the atrium: 1) engineer the construct to have appropriate ionic current and intercellular coupling gradients, or 2) functionally insulate a homogeneous construct from the atrium with conduction only at discrete points.
Description
Keywords
Computer Science, Engineering--Biomedical, Engineering--Electronics and Electrical
Citation
Kaur, J. (2017). Computational Modeling of Electrical Cell-to-cell Interactions in Cardiac Tissue: Applications to Model Parameter Selection and Pacemaker Function (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/25394