Abstract 15739: Effects of Ranolazine on Long QT3 Syndrome are Mutation Dependent
AIM: Long QT syndrome type 3 (LQT3) is attributable to mutations in SCN5A (Nav1.5) causing an increase in late sodium channel current (INa,L) and leading to delayed ventricular repolarization and Torsade de pointes (TdP). Ranolazine is an anti-anginal agent with potent actions to inhibit INa,L, and thus to suppress TdP in experimental models. This study is designed to determine the degree to which ranolazine inhibits INa,L associated with specific LQT3 mutations.
METHODS: We performed genetic analyses of LQTS patients and characterized the functional consequences of the SCN5A mutations. Wild-type (WT) and mutant channels, together with SCN1B, were transiently co-expressed in TSA201 cells and INa,L was recorded using patch-clamp techniques.
RESULTS: We examined the effect of ranolazine in 1 novel and 5 previously described LQT3 mutations (Table 1). The novel mutation involved a G-to-T transversion at nucleotide 5024, predicting a substitution of glycine (G) for valine (V) at residue 1675 (designated G1675V), which was absent in 125 ethnically-matched controls. G1675 is highly conserved among species. Ranolazine (10 µM) reduced INa,L by 45.09%, 57.85%, 56.72%, 61.43% and 55.65% in R18W, P1021S, R1623L, D1790G and V1951L, respectively. The blocking effect of 10 μM ranolazine was significantly less (16.34%) in the case of G1675V, a mutation involving the P-loop, previously shown to be a critical site for binding of local anesthetic molecules. In the case of D1790G mutation, we determined the effect of ranolazine over a wide range of concentrations demonstrating an IC50 of 6.73 μM for block of INa,L and IC50 of 70.72 μM for inhibition of peak INa,.
CONCLUSION: Our data suggest that ranolazine may be more effective at inhibiting INa,L in cases of LQT3 caused by SCN5A mutations that do not interfere with ranolazine's binding to the sodium channel. Additional studies are warranted to establish the range of genetic defects for which ranolazine may prove to be an effective therapy.
- © 2011 by American Heart Association, Inc.