Gating-dependent mechanisms for flecainide action in SCN5A-linked arrhythmia syndromes

被引:52
作者
Viswanathan, PC
Bezzina, CR
George, AL
Roden, DM
Wilde, AAM
Balser, JR
机构
[1] Vanderbilt Univ, Sch Med, Dept Anesthesiol, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA
[4] Univ Amsterdam, Mol & Cellular Cardiol Grp, Amsterdam, Netherlands
关键词
flecainide; long-QT syndrome; ion channels; pharmacology;
D O I
10.1161/hc3501.093797
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-Mutations in the cardiac sodium (Na) channel gene (SCN5A) give rise to the congenital long-QT syndrome (LQT3) and the Brugada syndrome. Na channel blockade by antiarrhythmic drugs improves the QT interval prolongation in LQT3 but worsens the Brugada syndrome ST-segment elevation. Although Na channel blockade has been proposed as a treatment for LQT3, flecainide also evokes "Brugada-like" ST-segment elevation in LQT3 patients. Here, we examine how Na channel inactivation gating defects in LQT3 and Brugada syndrome elicit proarrhythmic sensitivity to flecainide. Methods and Results-We measured whole-cell Na current (I-Na) from tsA-201 cells transfected with Delta KPQ, a LQT3 mutation, and 1795insD, a mutation that provokes both the LQT3 and Brugada syndromes. The 1795insD and Delta KPQ channels both exhibited modified inactivation gating (from the closed state), thus potentiating tonic I-Na block. Flecainide (1 mu mol/L) tonic block was only 16.8+/-3.0% for wild type but was 58.0+/-6.0% for 1795insD (P<0.01) and 39.4+/-8.0% (P<0.05) for Delta KPQ. In addition, the 1795insD mutation delayed recovery from inactivation by enhancing intermediate inactivation, with a 4-fold delay in recovery from use-dependent flecainide block. Conclusions-We have linked 2 inactivation gating defects ("closed-state" fast inactivation and intermediate inactivation) to flecainide sensitivity in patients carrying LQT3 and Brugada syndrome mutations. These results provide a mechanistic rationale for predicting proarrhythmic sensitivity to flecainide based on the identification of specific SCN5A inactivation gating defects.
引用
收藏
页码:1200 / 1205
页数:6
相关论文
共 29 条
[1]   Brugada syndrome - Clinical data and suggested pathophysiological mechanism [J].
Alings, M ;
Wilde, A .
CIRCULATION, 1999, 99 (05) :666-673
[2]   Lidocaine block of LQT-3 mutant human Na+ channels [J].
An, RH ;
Bangalore, R ;
Rosero, SZ ;
Kass, RS .
CIRCULATION RESEARCH, 1996, 79 (01) :103-108
[3]   INTERACTIONS OF FLECAINIDE WITH GUINEA-PIG CARDIAC SODIUM-CHANNELS - IMPORTANCE OF ACTIVATION UNBLOCKING TO THE VOLTAGE DEPENDENCE OF RECOVERY [J].
ANNO, T ;
HONDEGHEM, LM .
CIRCULATION RESEARCH, 1990, 66 (03) :789-803
[4]   The cardiac sodium channel: Gating function and molecular pharmacology [J].
Balser, JR .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2001, 33 (04) :599-613
[5]   LIDOCAINE BLOCK OF CARDIAC SODIUM-CHANNELS [J].
BEAN, BP ;
COHEN, CJ ;
TSIEN, RW .
JOURNAL OF GENERAL PHYSIOLOGY, 1983, 81 (05) :613-642
[6]   MOLECULAR MECHANISM FOR AN INHERITED CARDIAC-ARRHYTHMIA [J].
BENNETT, PB ;
YAZAWA, K ;
MAKITA, N ;
GEORGE, AL .
NATURE, 1995, 376 (6542) :683-685
[7]  
Bezzina C, 1999, CIRC RES, V85, P1206
[8]   Genetic basis and molecular mechanism for idiopathic: ventricular fibrillation [J].
Chen, QY ;
Kirsch, GE ;
Zhang, DM ;
Brugada, R ;
Brugada, J ;
Brugada, P ;
Potenza, D ;
Moya, A ;
Borggrefe, M ;
Breithardt, G ;
Ortiz-Lopez, R ;
Wang, Z ;
Antzelevitch, C ;
O'Brien, RE ;
Schulze-Bahr, E ;
Keating, MT ;
Towbin, JA ;
Wang, Q .
NATURE, 1998, 392 (6673) :293-296
[9]   Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent [J].
Dumaine, R ;
Towbin, JA ;
Brugada, P ;
Vatta, M ;
Nesterenko, DV ;
Nesterenko, VV ;
Brugada, J ;
Brugada, R ;
Antzelevitch, C .
CIRCULATION RESEARCH, 1999, 85 (09) :803-809
[10]   Multiple mechanisms of Na+ channel-linked long-QT syndrome [J].
Dumaine, R ;
Wang, Q ;
Keating, MT ;
Hartmann, HA ;
Schwartz, PJ ;
Brown, AM ;
Kirsch, GE .
CIRCULATION RESEARCH, 1996, 78 (05) :916-924