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 ΔKPQ, a LQT3 mutation, and 1795insD, a mutation that provokes both the LQT3 and Brugada syndromes. The 1795insD and ΔKPQ channels both exhibited modified inactivation gating (from the closed state), thus potentiating tonic I_Na block. Flecainide (1 μmol/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 ΔKPQ. 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.