Viswanathan P C, Bezzina C R, George A L, Roden D M, Wilde A A, Balser J R
Department of Anesthesiology, Vanderbilt University, Nashville, Tennessee, USA.
Circulation. 2001 Sep 4;104(10):1200-5. doi: 10.1161/hc3501.093797.
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.
We measured whole-cell Na current (I(Na)) from tsA-201 cells transfected with DeltaKPQ, a LQT3 mutation, and 1795insD, a mutation that provokes both the LQT3 and Brugada syndromes. The 1795insD and DeltaKPQ channels both exhibited modified inactivation gating (from the closed state), thus potentiating tonic I(Na) block. Flecainide (1 micromol/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 DeltaKPQ. 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.
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.
心脏钠（Na）通道基因（SCN5A）突变可导致先天性长QT综合征（LQT3）和Brugada综合征。抗心律失常药物对钠通道的阻滞可改善LQT3患者的QT间期延长，但会加重Brugada综合征的ST段抬高。尽管已提出钠通道阻滞作为LQT3的一种治疗方法，但氟卡尼也会在LQT3患者中诱发“Brugada样”ST段抬高。在此，我们研究LQT3和Brugada综合征中的钠通道失活门控缺陷如何引发对氟卡尼的促心律失常敏感性。
我们测量了转染了LQT3突变DeltaKPQ和引发LQT3及Brugada综合征的1795insD突变的tsA-201细胞的全细胞钠电流（I(Na)）。1795insD和DeltaKPQ通道均表现出改变的失活门控（从关闭状态开始），从而增强了持续性I(Na)阻滞。氟卡尼（1微摩尔/升）对野生型的持续性阻滞仅为16.8±3.0%，但对1795insD为58.0±6.0%（P<0.01），对DeltaKPQ为39.4±8.0%（P<0.05）。此外，1795insD突变通过增强中间失活延迟了失活恢复，使用依赖性氟卡尼阻滞的恢复延迟了4倍。
我们已将两种失活门控缺陷（“关闭状态”快速失活和中间失活）与携带LQT3和Brugada综合征突变患者对氟卡尼的敏感性联系起来。这些结果为基于特定SCN5A失活门控缺陷的识别来预测对氟卡尼促心律失常敏感性提供了机制依据。
