Abstract 2249: Overlap Between LQT3 and Brugada Syndrome: Clinical Features in a Common Mutation and Underlying Biophysical Mechanisms
Introduction: Features of the Brugada syndrome (BrS) have been sporadically reported in type-3 long QT syndrome (LQT3). However, it is not clear whether such phenotypic overlap is determined by the biophysical properties of the mutant channel, or by other factors such as co-inherited genetic variations, gender, or ethnicity. To address this question, we report here the clinical features and biophysical properties of a single SCN5A mutation, E1784K, identified in multiple families of diverse ethnicities.
Methods and Results: Among 37 LQT3 families (Asian 20, Caucasian 17) enrolled in 6 referral centers, 11 (30%) were carriers of E1784K, with a total of 33 mutation carriers (15 men, 18 women, 26±20 years; mean±SD). Two probands were the victims of sudden cardiac death. The LQT3 phenotype was highly penetrant: 30/33 (90.9%) mutation carriers had abnormally long QT intervals (carriers: QTc= 484±32 ms, n=33; non-carriers: QTc= 402±31 ms, n=21; p<0.001; mean±SD). In addition, 13/33 carriers (39%) showed sinus node dysfunction, and a diagnosis of BrS was established in 7/33. Four of five carriers exhibited coved-type ST elevation after class IC drug challenge. E1784K channels heterologously expressed in tsA201 cells in the presence of β1 subunit showed late Na current characteristic of LQT3. In addition, E1784K displayed properties seen with other mutations sporadically reported to generate a mixed clinical phenotype (1795insD, ΔKPQ, ΔK1500): a large (−15.0 mV) negative shift in the voltage-dependence of inactivation (V1/2: wild type= −86.8±1.1 mV, n=25; E1784K= −101.8±1.3 mV, n=17; p<0.001, mean±SE), and a marked (7.5-fold) increase in flecainide affinity for rested channels (IC50: wild type= 150.3 μM, E1784K= 20.4 μM). These properties are not reported with T1304M, an LQT3 mutation that has not been associated with BrS.
Conclusions: E1784K is a highly prevalent SCN5A mutation in different ethnicities, producing LQT3 as well as BrS and sinus node dysfunction. In vitro studies suggest that a negative shift of steady-state inactivation and enhanced channel inhibition at rest by class IC drugs identify LQT3 mutations that can generate such a mixed phenotype. Class IC drugs should be avoided in patients with LQT3 mutations displaying these behaviors.