Dependency of Ca2+ Alternans on Ion Channel Localization in Human Atrial Cells

Abstract

Introduction: Localization of ion channels to t-tubules (TTs) comprises a critical part of excitation-contraction coupling in cardiomyocytes. Recent studies have shown that TT organization varies greatly among atrial cells, which have different ion channel distribution than ventricular cells. Ca2+ transient (CaT) alternans are known to occur in atrial cells with fewer TTs, but the ion channels which contribute to this are unknown. Hypothesis: Decreased localization of L-type Ca2+ channels (LTCCs) and ryanodine receptors (RyRs) to TTs in atrial cells results in increased propensity for arrhythmogenic CaT alternans. Methods: Using a human atrial cell model from Grandi et al. incorporating chronic AF remodeling, the effects of ion channel redistribution were evaluated by moving 0-100% of TT ionic currents to the sub-sarcolemmal compartment (SL). Ryanodine receptor (RyR) redistribution was also tested by moving 0-100% of RyR release from the TTs to the cytosol. In 500 virtual cells, a total of 12 different ion channels were redistributed stochastically and independently. The effect of each ion channel on alternans threshold cycle length (CL) was evaluated by regression analysis. Results: The alternans threshold CL in the original model was 431 ms. Redistribution of LTCCs from TTs to the SL had the greatest effect on alternans threshold CL (regression coefficient of −0.95), with alternans occurring at slower pacing rates as the fraction of TT-localized LTCCs decreased due to steepening of the SR Ca2+ release slope. Redistribution of RyRs or Na+/Ca2+ exchangers had a smaller and opposite effect on alternans threshold CL (regression coefficients of 0.16 and 0.072, respectively), with decreased TT localization of these channels causing alternans to only occur at faster pacing rates. Conclusions: Decreased localization of LTCCs to TTs in atrial cells promotes arrhythmogenic CaT alternans at slower pacing rates.