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


RESULTS
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.


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.
Viswanathan
P C
PC
Department of Anesthesiology, Vanderbilt University, Nashville, Tennessee, USA.
Bezzina
C R
CR
George
A L
AL
Roden
D M
DM
Wilde
A A
AA
Balser
J R
JR
D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology*; D002460:Cell Line; D004562:Electrocardiography / Q000187:drug effects; D005424:Flecainide / Q000494:pharmacology*; D049452:Green Fluorescent Proteins; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D013577:Syndrome; D014162:Transfection
D000889:Anti-Arrhythmia Agents; D008164:Luminescent Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011993:Recombinant Fusion Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels; D049452:Green Fluorescent Proteins; D005424:Flecainide