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

Article

关键词: LONG-QT SYNDROME;    CARDIAC SODIUM-CHANNELS;    ST-SEGMENT ELEVATION;    NA+ CHANNEL;    BRUGADA-SYNDROME;    ANTIARRHYTHMIC DRUGS;    VENTRICULAR MYOCYTES;    MOLECULAR MECHANISM;    LIDOCAINE BLOCK;    INACTIVATION;   

DOI  :  10.1161/hc3501.093797

来源: SCIE

【 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.

【 授权许可】

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