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

Background-Mutations in the cardiac sodium (Na) channel gene (SCN5A) give r ise to the congenital long-QT syndrome (LQT3) and the Brugada syndrome. Na channel blockade by antiarrhythmic drugs improves the QT interval prolongat ion 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 synd rome elicit proarrhythmic sensitivity to flecainide. Methods and Results-We measured whole-cell Na current (I-Na) from tsA-201 c ells transfected with Delta KPQ, a LQT3 mutation, and 1795insD, a mutation that provokes both the LQT3 and Brugada syndromes. The 1795insD and Delta K PQ channels both exhibited modified inactivation gating (from the closed st ate), thus potentiating tonic I-Na block. Flecainide (1 mu mol/L) tonic blo ck 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 muta tion delayed recovery from inactivation by enhancing intermediate inactivat ion, with a 4-fold delay in recovery from use-dependent flecainide block. Conclusions-We have linked 2 inactivation gating defects ("closed-state" fa st inactivation and intermediate inactivation) to flecainide sensitivity in patients carrying LQT3 and Brugada syndrome mutations. These results provi de a mechanistic rationale for predicting proarrhythmic sensitivity to flec ainide based on the identification of specific SCN5A inactivation gating de fects.