Key result
In a computational model, selective inhibition of the late sodium current by GS-458967 modified all TRIaD-related parameters, suggesting a reduction in acquired Long-QT Syndrome arrhythmia risk.
Why the study?
Does selective inhibition of the cardiac late Na current by GS-458967 suppress proarrhythmic markers in a computational model of ventricular myocytes?
Does selective inhibition of the cardiac late Na current by GS-458967 suppress proarrhythmic markers in a computational model of ventricular myocytes?
In silico modeling demonstrates that selective inhibition of the late sodium current by GS-458967 may mitigate proarrhythmia risk for drugs with unintended hERG blocking effects.
Questions QT prolongation as reliable proarrhythmia surrogate; leaves open whether select agents merit further development.
Background The QT interval is a phase of the cardiac cycle that corresponds to action potential duration (APD) including cellular repolarization (T-wave). In both clinical and experimental settings, prolongation of the QT interval of the electrocardiogram (ECG) and related proarrhythmia have been so strongly associated that a prolonged QT interval is largely accepted as surrogate marker for proarrhythmia. Accordingly, drugs that prolong the QT interval are not considered for further preclinical development resulting in removal of many promising drugs from development. While reduction of drug interactions with hERG is an important goal, there are promising means to mitigate hERG block. Here, we examine one possibility and test the hypothesis that selective inhibition of the cardiac late Na current (I NaL ) by the novel compound GS-458967 can suppress proarrhythmic markers. Methods and results New experimental data has been used to calibrate I NaL in the Soltis-Saucerman computationally based model of the rabbit ventricular action potential to study effects of GS-458967 on I NaL during the rabbit ventricular AP. We have also carried out systematic in silico tests to determine if targeted block of I NaL would suppress proarrhythmia markers in ventricular myocytes described by TRIaD : T riangulation , R everse use dependence, beat-to-beat I nstability of action potential duration, and temporal and spatial action potential duration D ispersion . Conclusions Our computer modeling approach based on experimental data, yields results that suggest that selective inhibition of I NaL modifies all TRIaD related parameters arising from acquired Long-QT Syndrome, and thereby reduced arrhythmia risk. This study reveals the potential for adjunctive pharmacotherapy via targeted block of I NaL to mitigate proarrhythmia risk for drugs with significant but unintended off-target hERG blocking effects.
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Yang et al. (2016) studied Long-QT Syndrome and proarrhythmia. GS-458967 (selective inhibition of late Na current) was evaluated on TRIaD proarrhythmia markers (Triangulation, Reverse use dependence, beat-to-beat Instability, and Dispersion of action potential duration). In a computational model, selective inhibition of the late sodium current by GS-458967 modified all TRIaD-related parameters, suggesting a reduction in acquired Long-QT Syndrome arrhythmia risk.
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