A Novel Computational Model of the Rabbit Atrial Cardiomyocyte With Spatial Calcium Dynamics

Abstract

Models of cardiac electrophysiology are widely used to supplement experimental results and to provide insight into mechanisms of cardiac function and pathology. The rabbit has been a particularly important animal model for studying mechanisms of atrial pathophysiology and atrial fibrillation, which has motivated the development of models for the rabbit atrial cardiomyocyte electrophysiology. Previously developed models include detailed representations of membrane currents and intracellular ionic concentrations, but these so-called “common-pool” models lack a spatially distributed description of the calcium handling system, which reflects the detailed ultrastructure likely found in cells in vivo . Because of the less well-developed T-tubular system in atrial compared to ventricular cardiomyocytes, spatial gradients in intracellular calcium concentrations may play a more significant role in atrial cardiomyocyte pathophysiology, rendering common-pool models less suitable for investigating underlying electrophysiological mechanisms. In this study, we developed a novel computational model of the rabbit atrial cardiomyocyte incorporating detailed compartmentalization of intracellular calcium dynamics, in addition to a description of membrane currents and intracellular processes. The spatial representation of calcium was based on dividing the intracellular space into eighteen different compartments in the transversal direction, each with separate systems for internal calcium storage and release, and tracking ionic fluxes between compartments in addition to the dynamics driven by membrane currents and calcium release. The model was parameterized employing a population-of-models approach using experimental data from different sources. The parameterization of this novel model resulted in a reduced population of models with inherent variability in calcium dynamics and electrophysiological properties, all of which fall within the range of observed experimental values. As such, the population of models may represent natural variability in cardiomyocyte electrophysiology or inherent uncertainty in the underlying experimental data. The ionic model population was also able to reproduce the U-shaped waveform observed in line-scans of triggered calcium waves in atrial cardiomyocytes, characteristic of the absence of T-tubules, resulting in a centripetal calcium wave due to subcellular calcium diffusion. This novel spatial model of the rabbit atrial cardiomyocyte can be used to integrate experimental findings, offering the potential to enhance our understanding of the pathophysiological role of calcium-handling abnormalities under diseased conditions, such as atrial fibrillation.

A Computational Study of the Effects of Tachycardia-Induced Remodeling on Calcium Wave Propagation in Rabbit Atrial Myocytes

“…We used the previously published model of the rabbit atrial cardiomyocyte with spatial description of the calcium handling system, which allows for the simulation of intracellular calcium wave propagation. A complete description of the model development and structure is provided in Vagos et al (2020). In brief, the model was based on the rabbit atrial myocyte model by Aslanidi et al (2009), and the human atrial myocyte model by Voigt et al (2014).…”

“…Conceptually, the model is based on segmenting the cardiomyocyte into transversal slices, which are further sub-divided into domains in the transversal direction, as illustrated in Figure 1. As described in detail in Vagos et al (2020), the model distinguishes between the domains close to the membrane and the interior domains. The inner domains contain the cytosol, sarcoplasmic reticulum (SR), a sub-SR space (SRS), and calcium release units (CRU), while the membrane domains also include the sub-sarcolemmal (SL) space, junctional space (j), and associated sarcolemmal currents.…”

“…The membrane currents include calcium currents I CaL and I CaT ; the fast sodium current I Na ; repolarizing K + currents I to1 , I Kr , I Ks , and I K1 , three background currents I Cab , I Nab , and I Clb , as well as the Na + -Ca 2+ exchanger I NCX , the Na + -K + pump I NaK , and the plasmalemmal Ca 2+ pump I CaP . The formulation of the I NCX current was adopted from Voigt et al (2014), while all other ionic current formulations were taken from Aslanidi et al (2009), and reparameterized in Vagos et al (2020). Flux of Ca 2+ between neighboring domains is described by a linear diffusion model adopted from Voigt et al (2014).…”

“…In the present paper we elucidate the underlying mechanisms of calcium silencing by comparing computational model results with experimental observations. We have previously developed a model of the rabbit atrial myocyte with spatial calcium description (Vagos et al, 2020), which was parameterized to match experimentally observed rabbit-specific electrophysiology using a population of models approach. The parameterization resulted in 16 different models of the rabbit atrial cell, each with a unique combination of ion channel maximum conductances, but all closely matching experimentally observed electrophysiological characteristics.…”

“…The purpose of the present study is to assess the role of different cellular parameters that are believed to change as a result of rapid atrial pacing (RAP) induced remodeling. By changing their values in the model in one-at-a-time fashion, and applying these changes to all of the 16 models obtained from our previous study (Vagos et al, 2020). We changed the maximum conductances of I CaL , I NCX , and I NaK , RyR open probability parameters, RyR density, Serca2a density, as well as calcium buffering strength.…”