Mutation Specific Drug Response and Cardiac Risk in Long QT Type 3

Abstract

Long QT type 3 (LQT3) is caused by mutations that cause an increase in the cardiac sodium current during late phases of the cardiac action potential. For a number of LQT3 mutants this is caused by a failure to inactivate fully, and a consequent increase in late sodium current. For several mutations, shifts in voltage dependence of activation and inactivation cause increased sodium channel contribution to more depolarized voltages, an effect referred as increase in window current. The goal of this study was to perform a study in a large number of LQT3 associated mutations and compare the biophysical effect of the mutation to cardiac risk in LQT3 patients and response to treatment. We measured the function of eight common mutations associated with LQT3 with different mechanism underlying channel dysfunction. We compared the functional effects of the channel with the clinical course of these patients and observed that for the two mutations tested with increased sustained current but without increase in current availability (window current), D1784K and D1790G, the patients had significant lower risk of cardiac events, suggesting an increase in current availability may be associated with increased risk for these patients. In addition, we measured mutation specific effects of ranolazine for these mutants. For all mutants tested, ranolazine preferentially blocked late sodium currents. Ranolazine shifts steady-state availability of the inactivation was dependent on the specific mutant tested. Our results suggest that ranolazine may have a mutation dependent effect. Mutations dysfunction may affect drug binding and drug actions in the channel and may alter treatment effectiveness in patients.