Mechanisms of spontaneous Ca²⁺ release‐mediated arrhythmia in a novel 3D human atrial myocyte model: II. Ca²⁺‐handling protein variation

Abstract

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

“…Similar to the baseline model, TATS loss continues to reduce the rate threshold of SCRs ( i ) and DADs ( ii ) in the hyperphosphorylated RyR simulation; however, this occurs at a lower TAT density. This is induced by lower SR load with leakier RyRs, which is in accordance with the conclusions in the companion paper (Zhang et al 2022). E , SCR occurrence in surface ( i ), inner coupled ( ii ), and inner uncoupled ( iii ) CRUs with respect to increasing tubular density from detubulated to densely tubulated cells.…”

“…The effect of altering the expression and distribution of key Ca 2+ handling proteins (i.e. NCX, RyR, and CSQ) on SCR and arrhythmogenic outcomes is the focus of a companion paper (Zhang et al., 2022).…”

“…This Ca 2+ elevation drives cleft Ca 2+ ‐dependent increases in RyR open probability ( P O ) and subsequent SCRs that demonstrate how atrial TATS remodelling can lead to Ca 2+ ‐driven proarrhythmic behaviour. In a companion paper (Zhang et al., 2022), we used this robustly validated framework to study the independent effects of varying key Ca 2+ handling protein expression and distribution on SCRs and DADs.…”

Electrical Remodelling in Cardiac Disease

“…Therefore, de-tubulation of cardiomyocytes associated with cardiac disease is linked to electrical remodelling with arrhythmogenic potential [19]. Disruption of the transverse-axial system as observed for instance in heart failure or atrial fibrillation is associated with dysfunction of Ca 2+ handling proteins that may lead to Ca 2+ -driven proarrhythmic effects [20].…”

Determinants and therapeutic potential of calcium handling abnormalities in atrial fibrillation: what can we learn from computer models?

“…In this issue of The Journal of Physiology , two back‐to‐back papers (Zhang, Ni et al., 2022; Zhang, Smith et al., 2022) provide a novel state‐of‐the‐art three‐dimensional human atrial cardiomyocyte model that can reproduce a wide range of Ca 2+ ‐handling features at the (sub)cellular scale. The model underscores the importance of subcellular structural remodelling of atrial cardiomyocytes for the development of proarrhythmic Ca 2+ ‐handling abnormalities, something that is challenging to study experimentally.…”