Abstract
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 Ca2+-induced Ca2+ release, have also been identified in atrial myocytes. AT and TT remodeling and changes in distribution, composition, and phosphorylation status of Ca2+ release units are thought to underlie Ca2+ 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 Ca2+ signaling in the rabbit ventricular myocyte to develop an analogous model in the human atrium. We also coupled the Ca2+ 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 Ca2+ spark and wave properties. When TT density is low, as shown in isolated atrial myocytes, the model recapitulates the typical U-shaped Ca2+ wave seen experimentally in transverse confocal line-scan images. Introduction of ATs resulted in W-shaped Ca2+ waves, reflecting more synchronous Ca2+ release. The frequency and amplitude of Ca2+ 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 Ca2+ abnormalities seen in AF.
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