Abstract
To understand how excitable tissues give rise to arrhythmias, it is crucially necessary to understand the electrical dynamics of cells in the context of their environment. Multicellular monolayer cultures have proven useful for investigating arrhythmias and other conduction anomalies, and because of their relatively simple structure, these constructs lend themselves to paired computational studies that often help elucidate mechanisms of the observed behavior. However, tissue cultures of cardiomyocyte monolayers currently require the use of neonatal cells with ionic properties that change rapidly during development and have thus been poorly characterized and modeled to date. Recently, Kirkton and Bursac demonstrated the ability to create biosynthetic excitable tissues from genetically engineered and immortalized HEK293 cells with well-characterized electrical properties and the ability to propagate action potentials. In this study, we developed and validated a computational model of these excitable HEK293 cells (called “Ex293” cells) using existing electrophysiological data and a genetic search algorithm. In order to reproduce not only the mean but also the variability of experimental observations, we examined what sources of variation were required in the computational model. Random cell-to-cell and inter-monolayer variation in both ionic conductances and tissue conductivity was necessary to explain the experimentally observed variability in action potential shape and macroscopic conduction, and the spatial organization of cell-to-cell conductance variation was found to not impact macroscopic behavior; the resulting model accurately reproduces both normal and drug-modified conduction behavior. The development of a computational Ex293 cell and tissue model provides a novel framework to perform paired computational-experimental studies to study normal and abnormal conduction in multidimensional excitable tissue, and the methodology of modeling variation can be applied to models of any excitable cell.
Highlights
One of the major challenges in the field of cardiac electrophysiology is quantifying the electrical dynamics of myocytes in the context of their environment
The Ex293 membrane model includes four constitutive currents: the inward rectifying potassium current (IK1, carried by the Kir2.1 channel) and the fast voltage-gated sodium current (INa, carried by the Nav1.5 channel), both of which are transfected into HEK293 cells to create the Ex293 line; as well as two endogenous HEK293 currents, a voltage gated sodium current [16] and a delayed-rectifier potassium current [17,18,19]
For each trial parameter set, conduction was simulated in a two dimensional continuous monodomain (Fig 2A) using the Cardiowave system [20], and two error functions: (1) the root mean square error of the simulated action potential compared to a representative experimental action potential, and (2) the absolute error in simulated conduction velocity (CV) were calculated
Summary
One of the major challenges in the field of cardiac electrophysiology is quantifying the electrical dynamics of myocytes in the context of their environment. Walmsley et al conducted a more comprehensive examination of the effects of beatto-beat variability and cell-to-cell variability in two dimensional tissue simulations and found that while the effects of both are muted in well-coupled tissues, the effect of cell-to-cell variability predominates as tissue coupling is reduced [12] It is well-known that electrophysiological properties vary between subjects, and models have been developed to capture this variability by recreating experimental action potentials from different subjects [13,43,51], but no models known to us have used the combination of inter-subject and within-subject variation to explain experimentally recorded variability
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