Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD
Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD
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DOI：
10.1161/circulationaha.106.653949
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发表时间：
2006-12-12
期刊：
影响因子：
37.8
通讯作者：
Bezzina, Connie R.
中科院分区：
文献类型：
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作者：
Remme, Carol Ann;Verkerk, Arie O.;Bezzina, Connie R.
背景-携带心脏钠通道（SCN 5A）突变1795 insD的患者表现出夜间猝死和多种心律失常综合征的体征，包括心动过缓、传导延迟、QT间期延长和右心前区ST段抬高。我们研究了小鼠等效突变1798 insD的转基因模型的电生理特征。方法和结果-在24小时连续遥测和体表心电图记录中，Scn 5a（1798 insD/+）杂合子小鼠的心率显著降低，（暂停>= 500 ms），并且与野生型小鼠相比PQ间期、QRS持续时间和QTc间期增加。钠通道阻滞剂氟卡尼在大多数Scn 5a（1798 insD/+）小鼠中诱导了显著的窦性心动过缓和/或窦性停搏，但在野生型小鼠中没有。在离体Langendorff灌注心脏上使用多电极网格进行心外膜标测，显示Scn 5a（1798 insD/+）心脏右心室的优先传导减慢。在全细胞膜片钳分析中，从Scn 5a（1798 insD/+）心脏分离的心室肌细胞显示动作电位延长，峰值钠电流密度降低39%，动作电位上行程速度也类似地降低。Scn 5a（1798 insD/+）心肌细胞钠电流衰减的时间过程较慢，但在激活和稳态失活、缓慢失活或失活恢复的电压依赖性方面无显著差异。此外，Scn 5a（1798 insD/+）心肌细胞表现出更大的河豚毒素敏感的持续内向电流相比，野生型myocyte.Conclusions小鼠携带相当于SCN 5A-1795 insD突变显示心动过缓，右心室传导减慢，QT间期延长，类似于人类表型。这些结果表明，单个SCN 5A突变的存在确实足以引起心脏钠通道疾病的重叠综合征。
Background - Patients carrying the cardiac sodium channel (SCN5A) mutation 1795insD show sudden nocturnal death and signs of multiple arrhythmia syndromes including bradycardia, conduction delay, QT prolongation, and right precordial ST-elevation. We investigated the electrophysiological characteristics of a transgenic model of the murine equivalent mutation 1798insD.Methods and Results - On 24-hour continuous telemetry and surface ECG recordings, Scn5a(1798insD/+) heterozygous mice showed significantly lower heart rates, more bradycardic episodes ( pauses >= 500 ms), and increased PQ interval, QRS duration, and QTc interval compared with wild-type mice. The sodium channel blocker flecainide induced marked sinus bradycardia and/or sinus arrest in the majority of Scn5a(1798insD/+) mice, but not in wild-type mice. Epicardial mapping using a multielectrode grid on excised, Langendorff-perfused hearts showed preferential conduction slowing in the right ventricle of Scn5a(1798insD/+) hearts. On whole-cell patch-clamp analysis, ventricular myocytes isolated from Scn5a(1798insD/+) hearts displayed action potential prolongation, a 39% reduction in peak sodium current density and a similar reduction in action potential upstroke velocity. Scn5a(1798insD/+) myocytes displayed a slower time course of sodium current decay without significant differences in voltage-dependence of activation and steady-state inactivation, slow inactivation, or recovery from inactivation. Furthermore, Scn5a(1798insD/+) myocytes showed a larger tetrodotoxin-sensitive persistent inward current compared with wild-type myocytes.Conclusions - Mice carrying the murine equivalent of the SCN5A-1795insD mutation display bradycardia, right ventricular conduction slowing, and QT prolongation, similar to the human phenotype. These results demonstrate that the presence of a single SCN5A mutation is indeed sufficient to cause an overlap syndrome of cardiac sodium channel disease.