Mechanisms by which Cytoplasmic Calcium Wave Propagation and Alternans Are Generated in Cardiac Atrial Myocytes Lacking T-Tubules—Insights from a Simulation Study

This study investigated the mechanisms underlying the propagation of cytoplasmic calcium waves and the genesis of systolic Ca2+ alternans in cardiac myocytes lacking transverse tubules (t-tubules). These correspond to atrial cells of either small mammals or large mammals that have lost their t-tubules due to disease-induced structural remodeling (e.g., atrial fibrillation). A mathematical model was developed for a cluster of ryanodine receptors distributed on the cross section of a cell that was divided into 13 elements with a spatial resolution of 2 μm. Due to the absence of t-tubules, L-type Ca2+ channels were only located in the peripheral elements close to the cell-membrane surface and produced Ca2+ signals that propagated toward central elements by triggering successive Ca2+-induced Ca2+ release (CICR) via Ca2+ diffusion between adjacent elements. Under control conditions, the Ca2+ signals did not fully propagate to the central region of the cell. However, with modulation of several factors responsible for Ca2+ handling, such as the L-type Ca2+ channels (Ca2+ influx), SERCA pumps (sarcoplasmic reticulum (SR) Ca2+ uptake), and ryanodine receptors (SR Ca2+ release), Ca2+ wave propagation to the center of the cell could occur. These simulation results are consistent with previous experimental data from atrial cells of small mammals. The model further reveals that spatially functional heterogeneity in Ca2+ diffusion within the cell produced a steep relationship between the SR Ca2+ content and the cytoplasmic Ca2+ concentration. This played an important role in the genesis of Ca2+ alternans that were more obvious in central than in peripheral elements. Possible association between the occurrence of Ca2+ alternans and the model parameters of Ca2+ handling was comprehensively explored in a wide range of one- and two-parameter spaces. In addition, the model revealed a spontaneous second Ca2+ release in response to a single voltage stimulus pulse with SR Ca2+ overloading and augmented Ca2+ influx. This study provides what to our knowledge are new insights into the genesis of Ca2+ alternans and spontaneous second Ca2+ release in cardiac myocytes that lack t-tubules.