Effects of Varying Transverse and Axial Tubules in a Three-Dimensional Model of Calcium Signaling in the Human Atrial Myocyte

T-tubules are invaginations of the sarcolemma that play a key role in excitation-contraction coupling in ventricular myocytes. Atrial myocytes are generally thought to possess sparse irregular transverse-tubular (TT) components, as opposed to the highly dense and regular ventricular TT system. Axial tubules (ATs) with extensive junctions to the sarcoplasmic reticulum that include ryanodine receptor (RyR) clusters, characterized by rapid activation of Ca 2+-induced Ca 2+ release, have also been identified in atrial myocytes. AT and TT remodeling and changes in distribution, composition, and phosphorylation status of Ca 2+ release units are thought to underlie Ca 2+ abnormalities in atrial fibrillation (AF), the most common cardiac arrhythmia. Here, we performed a computational analysis to investigate how changes in the tubular network affect human atrial electrophysiology. We modified our well-established three-dimensional model of Ca 2+ signaling in the rabbit ventricular myocyte to develop an analogous model in the human atrium. We also coupled the Ca 2+ signaling model to our well-established model of membrane electrophysiology in the human atrial myocyte. We systematically varied TT and AT density and RyR distribution and assessed the effect on Ca 2+ spark and wave properties. When TT density is low, as shown in isolated atrial myocytes, the model recapitulates the typical U-shaped Ca 2+ wave seen experimentally in transverse confocal line-scan images. Introduction of ATs resulted in W-shaped Ca 2+ waves, reflecting more synchronous Ca 2+ release. The frequency and amplitude of Ca 2+ release events were affected by both density of TT and AT, as well as RyR distribution. Our newly developed three-dimensional model of the human atrial myocyte will be employed to investigate whether and how AF-induced cellular electrical and structural remodeling effects collectively contribute to the membrane potential and Ca 2+ abnormalities seen in AF