The clinical response to mexiletine in LQT3 patients correlated with the voltage dependence of channel availability and shifts of steady-state inactivation of specific SCN5A mutations.
Observational (n=5)
Can the clinical response to mexiletine in LQT3 patients be predicted by the biophysical properties of their specific SCN5A mutations?
The clinical response to mexiletine in LQT3 patients is mutation-specific and correlates with the voltage dependence of channel availability, suggesting in vitro testing can predict therapeutic efficacy.
BACKGROUND: Mexiletine (Mex) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 (LQT3) caused by mutations in the cardiac sodium channel gene (SCN5A). The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations. We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations. METHODS AND RESULTS: We identified 4 SCN5A mutations in 5 symptomatic LQT3 patients with different responses to Mex (6 to 8 mg . kg(-1) . d(-1)). We classified the mutations as sensitive to Mex (P1332L, R1626P; >/=10% of QTc shortening and QTc S941N=WT>M1652R, suggesting that Mex-sensitive mutants present prolonged recovery from Mex block. CONCLUSIONS: We propose that voltage dependence of channel availability and shifts of V(1/2) of steady-state inactivation correlate with the clinical response observed in LQT3 patients. This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3.
Ruan et al. (Tue,) conducted a observational in Long-QT syndrome type 3 (LQT3) (n=5). Mexiletine was evaluated on Clinical response to mexiletine (QTc shortening and arrhythmias). The clinical response to mexiletine in LQT3 patients correlated with the voltage dependence of channel availability and shifts of steady-state inactivation of specific SCN5A mutations.