Institute of Cardiovascular Sciences, University of Birmingham, Edgbaston, Wolfson Drive, Birmingham B15 2TT, UK.
Department of Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
Europace. 2023 Mar 30;25(3):1152-1161. doi: 10.1093/europace/euac218.
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF in patients.
We designed a new murine model carrying the Scn5a-M1875T mutation enabling us to study the effects of the Nav1.5 mutation in detail in vivo and in vitro using patch clamp and microelectrode recording of atrial cardiomyocytes, optical mapping, electrocardiogram, echocardiography, gravimetry, histology, and biochemistry. Atrial cardiomyocytes from newly generated adult Scn5a-M1875T+/- mice showed a selective increase in the early (peak) cardiac sodium current, larger action potential amplitude, and a faster peak upstroke velocity. Conduction slowing caused by the sodium channel blocker flecainide was less pronounced in Scn5a-M1875T+/- compared to wildtype atria. Overt hypertrophy or heart failure in Scn5a-M1875T+/- mice could be excluded.
The Scn5a-M1875T point mutation causes gain-of-function of the cardiac sodium channel. Our results suggest increased atrial peak sodium current as a potential trigger for increased atrial excitability.
心房颤动（AF）是最常见的心律失常。编码离子通道的基因中的致病变体与家族性 AF 有关。SCN5A 基因编码心脏钠离子通道 Nav1.5 的α亚基，其点突变 M1875T 与增加的心房兴奋性和家族性 AF 有关在患者中。
我们设计了一种携带 Scn5a-M1875T 突变的新型小鼠模型，使我们能够使用膜片钳和心房肌细胞的微电极记录、光学映射、心电图、超声心动图、称重、组织学和生物化学等方法在体内和体外详细研究 Nav1.5 突变的影响。新产生的成年 Scn5a-M1875T+/- 小鼠的心房肌细胞表现出早期（峰值）心脏钠离子电流的选择性增加、更大的动作电位幅度和更快的峰值上升速度。与野生型心房相比，钠通道阻滞剂 flecainide 引起的传导减慢在 Scn5a-M1875T+/- 中不那么明显。可以排除 Scn5a-M1875T+/- 小鼠明显的肥大或心力衰竭。
Scn5a-M1875T 点突变导致心脏钠离子通道功能获得。我们的结果表明增加的心房峰值钠离子电流可能是增加心房兴奋性的潜在触发因素。
