Munro Michelle L, van Hout Isabelle, Aitken-Buck Hamish M, Sugunesegran Ramanen, Bhagwat Krishna, Davis Philip J, Lamberts Regis R, Coffey Sean, Soeller Christian, Jones Peter P
Department of Physiology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
Department of Cardiothoracic Surgery, Dunedin Hospital, Dunedin, New Zealand.
Front Cell Dev Biol. 2021 Feb 25;9:633704. doi: 10.3389/fcell.2021.633704. eCollection 2021.
The release of Ca by ryanodine receptor (RyR2) channels is critical for cardiac function. However, abnormal RyR2 activity has been linked to the development of arrhythmias, including increased spontaneous Ca release in human atrial fibrillation (AF). Clustering properties of RyR2 have been suggested to alter the activity of the channel, with remodeling of RyR2 clusters identified in pre-clinical models of AF and heart failure. Whether such remodeling occurs in human cardiac disease remains unclear. This study aimed to investigate the nanoscale organization of RyR2 clusters in AF patients - the first known study to examine this potential remodeling in diseased human cardiomyocytes. Right atrial appendage from cardiac surgery patients with paroxysmal or persistent AF, or without AF (non-AF) were examined using super-resolution (dSTORM) imaging. Significant atrial dilation and cardiomyocyte hypertrophy was observed in persistent AF patients compared to non-AF, with these two parameters significantly correlated. Interestingly, the clustering properties of RyR2 were remarkably unaltered in the AF patients. No significant differences were identified in cluster size (mean ∼18 RyR2 channels), density or channel packing within clusters between patient groups. The spatial organization of clusters throughout the cardiomyocyte was also unchanged across the groups. RyR2 clustering properties did not significantly correlate with patient characteristics. In this first study to examine nanoscale RyR2 organization in human cardiac disease, these findings indicate that RyR2 cluster remodeling is not an underlying mechanism contributing to altered channel function and subsequent arrhythmogenesis in human AF.
雷诺丁受体（RyR2）通道释放钙离子对心脏功能至关重要。然而，RyR2活性异常与心律失常的发生有关，包括人类心房颤动（AF）中自发性钙释放增加。有研究表明，RyR2的聚集特性会改变通道活性，在AF和心力衰竭的临床前模型中已发现RyR2簇发生重塑。这种重塑是否发生在人类心脏疾病中仍不清楚。本研究旨在调查AF患者中RyR2簇的纳米级组织——这是首次在患病的人类心肌细胞中研究这种潜在重塑的已知研究。使用超分辨率（dSTORM）成像检查了阵发性或持续性AF患者或无AF（非AF）的心脏手术患者的右心耳。与非AF患者相比，持续性AF患者观察到明显的心房扩张和心肌细胞肥大，这两个参数显著相关。有趣的是，AF患者中RyR2的聚集特性明显未改变。患者组之间在簇大小（平均约18个RyR2通道）、密度或簇内通道堆积方面未发现显著差异。各组中心肌细胞内簇的空间组织也未改变。RyR2聚集特性与患者特征无显著相关性。在这项首次研究人类心脏疾病中纳米级RyR2组织的研究中，这些发现表明，RyR2簇重塑不是导致人类AF中通道功能改变和随后心律失常发生的潜在机制。
