Mechanisms of spontaneous Ca2+ release‐mediated arrhythmia in a novel 3D human atrial myocyte model: I. Transverse‐axial tubule variation
Authors: Zhang Xianwei , Ni Haibo , Morotti Stefano , Smith Charlotte E. R. , Sato Daisuke , Louch William E. , Edwards Andrew G. , Grandi Eleonora 
Published: September 2022

Intracellular calcium (Ca2+) cycling is tightly regulated in the healthy heart ensuring effective contraction. This is achieved by transverse (t)‐tubule membrane invaginations that facilitate close coupling of key Ca2+‐handling proteins such as the L‐type Ca2+ channel and Na+‐Ca2+ exchanger (NCX) on the cell surface with ryanodine receptors (RyRs) on the intracellular Ca2+ store. Although less abundant and regular than in the ventricle, t‐tubules also exist in atrial myocytes as a network of transverse invaginations with axial extensions known as the transverse‐axial tubule system (TATS). In heart failure and atrial fibrillation, there is TATS remodelling that is associated with aberrant Ca2+‐handling and Ca2+‐induced arrhythmic activity; however, the mechanism underlying this is not fully understood. 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 extensively parameterized and validated our model against experimental data to build a robust tool examining TATS regulation of subcellular Ca2+ release. We found that varying TATS density and thus the localization of key Ca2+‐handling proteins has profound effects on Ca2+ handling. Following TATS loss, there is reduced NCX that results in increased cleft Ca2+ concentration through decreased Ca2+ extrusion. This elevated Ca2+ increases RyR open probability causing spontaneous Ca2+ releases and the promotion of arrhythmogenic waves (especially in the cell interior) leading to voltage instabilities through delayed afterdepolarizations. In summary, the present study demonstrates a mechanistic link between TATS remodelling and Ca2+‐driven proarrhythmic behaviour that probably reflects the arrhythmogenic state observed in disease.

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Key points

Transverse‐axial tubule systems (TATS) modulate Ca2+ handling and excitation–contraction coupling in atrial myocytes, with TATS remodelling in heart failure and atrial fibrillation being associated with altered Ca2+ cycling and subsequent arrhythmogenesis.

To investigate the poorly understood mechanisms linking TATS variation and spontaneous Ca2+ release, we built, parameterized and validated a 3D human atrial myocyte model coupling electrophysiology and spatially‐detailed subcellular Ca2+ handling governed by the TATS.

Simulated TATS loss causes diastolic Ca2+ and voltage instabilities through reduced Na+‐Ca2+ exchanger‐mediated Ca2+ removal, cleft Ca2+ accumulation and increased ryanodine receptor open probability, resulting in spontaneous Ca2+ release and promotion of arrhythmogenic waves and delayed afterdepolarizations.

At fast electrical rates typical of atrial tachycardia/fibrillation, spontaneous Ca2+ releases are larger and more frequent in the cell interior than at the periphery.

Our work provides mechanistic insight into how atrial TATS remodelling can lead to Ca2+‐driven instabilities that may ultimately contribute to the arrhythmogenic state in disease.