Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a

被引:312
作者
Papadatos, GA
Wallerstein, PMR
Head, CEG
Ratcliff, R
Brady, PA
Benndorf, K
Saumarez, RC
Trezise, AEO
Huang, CLH
Vandenberg, JI
Colledge, WH
Grace, AA
机构
[1] Univ Cambridge, Dept Biochem, Sect Cardiovasc Biol, Cambridge CB2 1QW, England
[2] Univ Cambridge, Dept Physiol, Cambridge CB2 3EG, England
[3] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England
[4] Univ Jena, Inst Physiol, Abt Herz Kreislauf Physiol, D-07740 Jena, Germany
[5] Univ Queensland, Dept Anat & Dev Biol, St Lucia, Qld 4072, Australia
关键词
D O I
10.1073/pnas.082121299
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 approximate to50% 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.
引用
收藏
页码:6210 / 6215
页数:6
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