Papadatos G Alex, Wallerstein Polly M R, Head Catherine E G, Ratcliff Rosemary, Brady Peter A, Benndorf Klaus, Saumarez Richard C, Trezise Ann E O, Huang Christopher L-H, Vandenberg Jamie I, Colledge William H, Grace Andrew A
Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, United Kingdom.
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6210-5. doi: 10.1073/pnas.082121299. Epub 2002 Apr 23.
Voltage-gated sodium channels drive the initial depolarization phase of the cardiac action potential and therefore critically determine conduction of excitation through the heart. In patients, deletions or loss-of-function mutations of the cardiac sodium channel gene, SCN5A, have been associated with a wide range of arrhythmias including bradycardia (heart rate slowing), atrioventricular conduction delay, and ventricular fibrillation. The pathophysiological basis of these clinical conditions is unresolved. Here we show that disruption of the mouse cardiac sodium channel gene, Scn5a, causes intrauterine lethality in homozygotes with severe defects in ventricular morphogenesis whereas heterozygotes show normal survival. Whole-cell patch clamp analyses of isolated ventricular myocytes from adult Scn5a(+/-) mice demonstrate a approximately 50% reduction in sodium conductance. Scn5a(+/-) hearts have several defects including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. These findings reconcile reduced activity of the cardiac sodium channel leading to slowed conduction with several apparently diverse clinical phenotypes, providing a model for the detailed analysis of the pathophysiology of arrhythmias.
电压门控钠通道驱动心脏动作电位的初始去极化阶段，因此对兴奋在心脏中的传导起着关键决定作用。在患者中，心脏钠通道基因SCN5A的缺失或功能丧失突变与多种心律失常有关，包括心动过缓（心率减慢）、房室传导延迟和心室颤动。这些临床病症的病理生理基础尚未明确。在此我们表明，小鼠心脏钠通道基因Scn5a的破坏导致纯合子在子宫内死亡，伴有严重的心室形态发生缺陷，而异合子显示正常存活。对成年Scn5a(+/-)小鼠分离的心室肌细胞进行的全细胞膜片钳分析表明，钠电导降低了约50%。Scn5a(+/-)心脏存在多种缺陷，包括房室传导受损、心肌内传导延迟、心室不应期延长以及具有折返性兴奋特征的室性心动过速。这些发现使导致传导减慢的心脏钠通道活性降低与几种明显不同的临床表型相协调，为详细分析心律失常的病理生理学提供了一个模型。
