Determinants of electrical propagation and propagation block in Arrhythmogenic Cardiomyopathy.
Determinants of electrical propagation and propagation block in Arrhythmogenic Cardiomyopathy.
复制标题
致心律失常性心肌病中电传播和传播阻滞的决定因素。
DOI：
10.1016/j.yjmcc.2023.11.003
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发表时间：
2024
影响因子：
5
通讯作者：
Kleber,AndreG
中科院分区：
文献类型：
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作者：
Jin,Qianru;Lee,KeelYong;Selimi,Zoja;Shimura,Daisuke;Wang,Ethan;Zimmerman,JohnF;Shaw,RobinM;Kucera,JanP;Parker,KevinKit;Saffitz,JeffreyE;Kleber,AndreG
致心律失常性心肌病（ACM）的早期即发生缝隙连接和离子通道重构，但其致病后果尚未阐明。在这里，我们确定了致瘤底物，包括传播减慢和传导阻滞，在ACM模型表达两种不同的桥粒基因变体。转导新生大鼠心室肌细胞表达桥粒蛋白质斑珠蛋白或斑嗜蛋白-2基因的变体。在工程细胞和各向异性组织中进行研究，以量化传导速度、单向传播形成、细胞-细胞电耦合和离子电流的变化。在两种ACM模型中，传导速度分别降低了71%和63%。SB 216763是糖原合成酶激酶-3 β的抑制剂，可将传导速度恢复至接近正常水平。与对照组相比，两种ACM模型均表现出更大的单向传导阻滞倾向，在更高的刺激频率下进一步增加。在两个ACM模型中，在细胞对中测量的细胞-细胞电导分别降低了86%和87%。计算机建模显示，模拟和实验确定的传导速度的变化之间的密切对应关系。模拟结果表明，细胞间电耦合减弱是导致传导缓慢的主要因素，而细胞间电耦合减弱、钠电流和内向整流钾电流减弱共同作用解释了单向阻滞的发生。两种不同的ACM变体的表达显著降低了细胞-细胞电耦合和传导速度，并大大增加了发生单向阻滞的可能性-这两个都是肿瘤发生的关键特征。本研究首次定量分析了ACM早期折返性心律失常的细胞电生理变化。
Gap junction and ion channel remodeling occur early in Arrhythmogenic Cardiomyopathy (ACM), but their pathogenic consequences have not been elucidated. Here, we identified the arrhythmogenic substrate, consisting of propagation slowing and conduction block, in ACM models expressing two different desmosomal gene variants. Neonatal rat ventricular myocytes were transduced to express variants in genes encoding desmosomal proteins plakoglobin or plakophilin-2. Studies were performed in engineered cells and anisotropic tissues to quantify changes in conduction velocity, formation of unidirectional propagation, cell–cell electrical coupling, and ion currents. Conduction velocity decreased by 71% and 63% in the two ACM models. SB216763, an inhibitor of glycogen synthase kinase-3 beta, restored conduction velocity to near normal levels. Compared to control, both ACM models showed greater propensity for unidirectional conduction block, which increased further at greater stimulation frequencies. Cell–cell electrical conductance measured in cell pairs was reduced by 86% and 87% in the two ACM models. Computer modeling showed close correspondence between simulated and experimentally determined changes in conduction velocity. The simulation identified that reduced cell–cell electrical coupling was the dominant factor leading to slow conduction, while the combination of reduced cell–cell electrical coupling, reduced sodium current and inward rectifier potassium current explained the development of unidirectional block. Expression of two different ACM variants markedly reduced cell–cell electrical coupling and conduction velocity, and greatly increased the likelihood of developing unidirectional block – both key features of arrhythmogenesis. This study provides the first quantitative analysis of cellular electrophysiological changes leading to the substrate of reentrant arrhythmias in early stage ACM.