Mechanistic links between Na+ channel (SCN5A) mutations and impaired cardiac pacemaking in sick sinus syndrome.
Mechanistic links between Na+ channel (SCN5A) mutations and impaired cardiac pacemaking in sick sinus syndrome.
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DOI：
10.1161/circresaha.110.219949
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发表时间：
2010-07-09
影响因子：
20.1
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Butters TD;Aslanidi OV;Inada S;Boyett MR;Hancox JC;Lei M;Zhang H
家族性病态窦房结综合征 (SSS) 与 SCN5A 基因功能丧失突变有关，导致内向 Na+ 电流 INa 减少。然而，INa 在心脏起搏中的功能作用存在争议，并且 SSS 中突变与窦房结功能障碍 (SND) 之间的机制联系尚不清楚。确定 SCN5A 突变损害心脏起搏的机制。兔窦房结 (SAN) 细胞的动作电位 (AP) 模型经过修改，纳入了实验报告的由两组 SCN5A 基因突变（分别影响 INa 的激活和失活）诱导的 INa 变化。细胞模型被纳入完整 SAN 中庭的详细解剖学二维模型中。研究了单细胞和组织水平上突变和迷走神经活动对心脏起搏的影响。对完整 SAN 心房制剂的激活模式进行多电极细胞外电位记录，以测试模型的预测。在单细胞水平上，突变减慢了外周细胞的起搏速率，但控制心律的中枢 SAN 细胞却没有减慢。然而，在组织模拟中，突变不仅减慢了起搏速度，而且还损害了 SAN 心房的 AP 传导，导致可能的 SAN 出口阻塞或窦性停搏，这是 SSS 的主要特征。模拟的迷走神经活动放大了突变的心动过缓效应。两组 SCN5A 突变在损害 SAN 驱动周围心房的能力方面表现出细微的差异，这主要是因为它们对心房兴奋性和传导安全性的影响不同。河豚毒素和卡巴胆碱的实验数据证实了模拟结果。我们的研究证实了 SCN5A 基因突变与 SSS 之间的因果关系，并阐明了突变损害 SAN 驱动能力的机制。
Familial sick sinus syndrome (SSS) has been linked to loss-of-function mutations of the SCN5A gene, which result in decreased inward Na+ current, INa. However, the functional role of INa in cardiac pacemaking is controversial, and mechanistic links between the mutations and sinus node dysfunction (SND) in SSS are unclear. To determine mechanisms by which the SCN5A mutations impair cardiac pacemaking. Action potential (AP) models for rabbit sinoatrial node (SAN) cells were modified to incorporate experimentally reported INa changes induced by two groups of SCN5A gene mutations (affecting the activation and inactivation of INa, respectively). The cell models were incorporated into an anatomically detailed 2D model of the intact SAN-atrium. Effects of the mutations and vagal nerve activity on cardiac pacemaking at the single cell and tissue levels were studied. Multi-electrode extracellular potential recordings of activation pattern from intact SAN-atrium preparations were performed to test predictions of the models. At the single cell level, the mutations slowed down pacemaking rates in peripheral, but not in central SAN cells that control the heart rhythm. However, in tissue simulations, the mutations not only slowed down pacemaking, but also compromised AP conduction across the SAN-atrium, leading to a possible SAN exit block or sinus arrest, the major features of SSS. Simulated vagal nerve activity amplified the bradycardiac effects of the mutations. Two groups of SCN5A mutations showed subtle differences in impairing the ability of the SAN to drive the surrounding atrium – primarily, due to their differential effects on atrial excitability and conduction safety. Experimental data with tetrodotoxin and carbachol confirmed the simulation outcomes. Our study substantiates the causative link between SCN5A gene mutations and SSS, and illustrates mechanisms by which the mutations impair the driving ability of the SAN.