Mechanisms of spontaneous Ca2+ release-mediated arrhythmia in a novel 3D human atrial myocyte model: I. Transverse-axial tubule variation

Abstract

AbstractIntracellular 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 (LCC) and Na+-Ca2+ exchanger (NCX) on the cell surface with ryanodine receptors (RyRs) on the intracellular Ca2+ store. Though 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 remodeling 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 promotion of arrhythmogenic waves (especially in the cell interior) that leads to voltage instabilities through delayed afterdepolarizations. In summary, this study demonstrates a mechanistic link between TATS remodeling and Ca2+-driven proarrhythmic behavior that likely reflects the arrhythmogenic state observed in disease.Key PointsTransverse-axial tubule systems (TATS) modulate Ca2+ handling and excitation-contraction coupling in atrial myocytes, with TATS remodeling in heart failure and atrial fibrillation 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 NCX-mediated Ca2+ removal, cleft Ca2+ accumulation and increased RyR 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 remodeling can lead to Ca2+- driven instabilities that may ultimately contribute to the arrhythmogenic state in disease.