Linking Disrupted Cellular Ultrastructure to Human Atrial Myocyte Calcium and Voltage Instabilities: A Modeling Study
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Linking Disrupted Cellular Ultrastructure to Human Atrial Myocyte Calcium and Voltage Instabilities: A Modeling Study


Intracellular Ca2+ is an important regulator in cardiac electrophysiology and contraction under both physiology and pathophysiology. The regular excitation and effective contraction in healthy atrial myocytes are achieved by the well-organized transversal and axial tubular system (TATS, i.e., invaginations of cell membrane) that facilitate the coupling of key Ca2+-handling proteins, such as L-type Ca2+ channel (LCC) and Na+-Ca2+ exchanger (NCX) on the cell surface with ryanodine receptors (RyRs) on the sarcoplasmic reticulum (SR, intracellular Ca2+ storage). In atrial fibrillation (AF), the most common arrhythmia disease in the clinic, both ionic and ultrastructural remodeling have been associated with deranged Ca2+ signaling and electrophysiological instabilities through the altered channel and transporter expression and function, reduced density and regularity of the TATS, and subcellular re-distribution of Ca2+- handling proteins. However, due to the concurrent changes in TATS and Ca2+-handling protein expression and localization that occur in the disease, it is difficult to distinguish their individual contributions to the arrhythmogenic state.To address this, we developed a novel 3D human atrial myocyte model that couples electrophysiology and Ca2+ handling with variable TATS organization and density. We illustrate the construction of the model, which was extensively parameterized and validated against experimental data, and its use in examining TATS regulation of subcellular Ca2+ release. We then demonstrate the application of the model to investigate the isolated and interactive effects of changes in expression and localization of key Ca2+-handling proteins (i.e., NCX, RyR, and Calsequestrin, CSQ) and variable TATS density on Ca2+ abnormalities and Ca2+-driven membrane instabilities. We found that TATS loss, as seen in the disease, impairs NCX-mediated Ca2+ removal that increases intracellular Ca2+ concentration and thus elevated RyR open probability (PO). Consequentially, these changes increase arrhythmogenic spontaneous Ca2+ releases (SCRs), especially in the inner area of the cell, and subsequent voltage instabilities (i.e., delayed afterdepolarizations, DADs). Furthermore, varying the expression and distribution of NCX, RyR, and CSQ have pro- or anti-arrhythmic effects depending on the balance of opposing influences on SR Ca2+ leak-load and Ca2+-voltage relationships. Interestingly, the effects of Ca2+-handling protein changes have the most impact in cells with intermediate tubules compared to detubulated and densely tubulated myocytes. In summary, this study demonstrates a mechanistic link between TATS remodeling and Ca2+-driven proarrhythmic behavior that likely reflects AF arrhythmogenesis. We provide novel insight into the distinct and interactive consequences of TATS and Ca2+-handling protein remodeling that underlie Ca2+ dysfunction and abnormal electrophysiology in disease. These novel model-based findings may help guide future therapeutic anti-AF strategies targeting structural remodeling.

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