Effects of fibroblast‐myocyte coupling on the sinoatrial node activity: A computational study

Abstract

While the sinoatrial node (SAN) is structurally heterogeneous, most computer simulations of electrical activity take into account SAN pacemaker cells only. Our aim was to investigate how fibroblasts affect the SAN activity. We simulated the rabbit sinoatrial node accounting for differences between central and peripheral pacemaker cells, and for fibroblast-myocyte electrical coupling. We have observed that only if fibroblast-myocyte coupling is taken into account, (1) action potential is initiated in the central part of the SAN (within 1.2 mm of the center of simulated tissue); otherwise, leading centers are located on the periphery; (2) few (1 to 6) leading centers initiate action potential in the SAN; otherwise, we observed more than 8 leading centers; (3) acetylcholine superfusion results in a shift of leading centers toward the SAN periphery; and (4) sinus pauses up to 1.9 second follow acetylcholine superfusion. We observed negligible effect of fibroblast-myocyte coupling on the period of SAN activation. We conclude that fibroblast-myocyte coupling may explain action potential initiation and propagation from the center of the SAN observed in experimental studies, while atrial load on the peripheral SAN fails to explain this fact.

Functional Heterogeneity of Cell Populations Increases Robustness of Pacemaker Function in a Numerical Model of the Sinoatrial Node Tissue

“…A plethora of numerical models of SAN tissue function have been developed previously, including models in one dimension ( Zhang et al, 2001 ; Huang et al, 2011 ; Glynn et al, 2014 ; Li et al, 2018 ), two dimensions ( Michaels et al, 1987 ; Oren and Clancy, 2010 ; Campana, 2015 ; Gratz et al, 2018 ; Karpaev et al, 2018 ), and full-scale SAN models in three dimensions ( Munoz et al, 2011 ; Li et al, 2013 ; Li et al, 2014 ; Kharche et al, 2017 ; Mata et al, 2019 ). These models examined effects of cell-to-cell coupling ( Li et al, 2013 ; Campana, 2015 ; Gratz et al, 2018 ; Mata et al, 2019 ), inter-cellular variability ( Campana, 2015 ; Mata et al, 2019 ), coupling to other cell types (fibroblasts) ( Oren and Clancy, 2010 ; Karpaev et al, 2018 ), and normal and abnormal impulse propagation in three dimensions ( Munoz et al, 2011 ; Li et al, 2014 ; Kharche et al, 2017 ).…”

Parallel simulation of the synchronization of heterogeneous cells in the sinoatrial node

“…The Euler method was used iterating 5000 times per second of simulation. A more recent work dealing with the simulation of the SAN in parallel systems is the work of Karpaev et al They implemented the model of Aliev and Chailakhyan for the SAN. The simulation of a maximum number of 4000 cells took around 12 hours for each simulation second, using the MPI programming tool.…”

“…Depending on the selected SAN model the computational effort increases, and the numerical method used to solve the ordinary differential equations (ODE) also impacts the execution time. Previous works used the explicit Euler method to integrate the systems of ordinary differential equations; however, limitations of this method related to stability, accuracy, convergence rate, and computational cost are well known …”

“…In addition, random values for the conductances, obtained from a normal distribution, are also used to evaluate the possible effects on the electrical activity of the SAN. It is worth noting that other modeling works have considered some of the aspects included in the model here presented, although not all of them simultaneously, as we do in the present work. Moreover, previous theoretical studies of the electrical connectivity of cells of the SAN have been either limited to 2D configurations, performed with a reduced number of cells or, instead, considering a large number of cells with the drawback of sacrificing the numerical methods used to solve the underlying equations.…”

“…Furthermore, due to the importance of intracellular Ca 2+ for a myriad of cellular processes (including electrical activity itself), it is usually needed to include the intracellular distribution of Ca 2+ in the models, thus increasing considerably the number of differential equations . Fortunately, as a consequence of the technological advances of recent years, both in hardware and software, models of multicellular arrays (ie, at the tissue level) have been developed more and more frequently . The sinoatrial node (SAN) serves as the pacemaker where the electrical signals determining the heart frequency spread throughout the heart.…”