Abstract
Spontaneous Ca2+-release events (SCaEs) from the sarcoplasmic reticulum play crucial roles in the initiation of cardiac arrhythmias by promoting triggered activity. However, the subcellular determinants of these SCaEs remain incompletely understood. Structural differences between atrial and ventricular cardiomyocytes, e.g., regarding the density of T-tubular membrane invaginations, may influence cardiomyocyte Ca2+-handling and the distribution of cardiac ryanodine receptors (RyR2) has recently been shown to undergo remodeling in atrial fibrillation. These data suggest that the subcellular distribution of Ca2+-handling proteins influences proarrhythmic Ca2+-handling abnormalities. Here, we employ computational modeling to provide an in-depth analysis of the impact of variations in subcellular RyR2 and L-type Ca2+-channel distributions on Ca2+-transient properties and SCaEs in a human atrial cardiomyocyte model. We incorporate experimentally observed RyR2 expression patterns and various configurations of axial tubules in a previously published model of the human atrial cardiomyocyte. We identify an increased SCaE incidence for larger heterogeneity in RyR2 expression, in which SCaEs preferentially arise from regions of high local RyR2 expression. Furthermore, we show that the propagation of Ca2+ waves is modulated by the distance between RyR2 bands, as well as the presence of experimentally observed RyR2 clusters between bands near the lateral membranes. We also show that incorporation of axial tubules in various amounts and locations reduces Ca2+-transient time to peak. Furthermore, selective hyperphosphorylation of RyR2 around axial tubules increases the number of spontaneous waves. Finally, we present a novel model of the human atrial cardiomyocyte with physiological RyR2 and L-type Ca2+-channel distributions that reproduces experimentally observed Ca2+-handling properties. Taken together, these results significantly enhance our understanding of the structure-function relationship in cardiomyocytes, identifying that RyR2 and L-type Ca2+-channel distributions have a major impact on systolic Ca2+ transients and SCaEs.
Highlights
Despite the significant advances in the treatment of cardiovascular diseases during the past 50 years, the frequency of cardiac arrhythmias, atrial fibrillation (AF), is projected to increase, placing a significant burden on modern healthcare systems (Chugh et al, 2014; Roth et al, 2015; Morillo et al, 2017)
With σ = 0.4, the incidence of SCaEs was 14× larger (3.31 ± 0.51 s−1 vs. 0.23 ± 0.04 s−1, n = 6, p < 0.05) and the average size of a Ca2+ wave as fraction of cardiomyocyte volume was 5x smaller than with σ = 0.0 (0.18 ± 0.02 vs. 0.91 ± 0.11, n = 6, p < 0.05)
We compared the magnitude of the effect of altered ryanodine receptor type-2 (RyR2) distribution to a 25% change in total RyR2 expression
Summary
Despite the significant advances in the treatment of cardiovascular diseases during the past 50 years, the frequency of cardiac arrhythmias, atrial fibrillation (AF), is projected to increase, placing a significant burden on modern healthcare systems (Chugh et al, 2014; Roth et al, 2015; Morillo et al, 2017). Axial tubules promote a faster Ca2+ release from the SR in the center of the cell, which is partly mediated by coupling of LTCC to hyperphosphorylated RyR2 surrounding axial tubules (Brandenburg et al, 2016). This axial tubular system undergoes extensive remodeling during cardiovascular disease, e.g., proliferating in the presence of atrial hypertrophy (Brandenburg et al, 2016) or disappearing in mice with atrialspecific knock-out of NCX1 (Yue et al, 2017). It is currently experimentally challenging to study both (sub)cellular structure and functional Ca2+-handling in human atrial cardiomyocytes, as the former usually requires fixation of the cardiomyocyte
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