The efficacy of Ranolazine on E1784K is altered by temperature and calcium

E1784K is the most common mixed syndrome SCN5a mutation underpinning both Brugada syndrome type 1 (BrS1) and Long-QT syndrome type 3 (LQT3). The charge reversal mutant enhances the late sodium current (I_Na) passed by the cardiac voltage-gated sodium channel (Na_V1.5), delaying cardiac repolarization. Exercise-induced triggers, like elevated temperature and cytosolic calcium, exacerbate E1784K late I_Na. In this study, we tested the effects of Ranolazine, the late I_Na blocker, on voltage-dependent and kinetic properties of E1784K at elevated temperature and cytosolic calcium. We used whole-cell patch clamp to measure I_Na from wild type and E1784K channels expressed in HEK293 cells. At elevated temperature, Ranolazine attenuated gain-of-function in E1784K by decreasing late I_Na, hyperpolarizing steady-state fast inactivation, and increasing use-dependent inactivation. Both elevated temperature and cytosolic calcium hampered the capacity of Ranolazine to suppress E1784K late I_Na. In-silico action potential (AP) simulations were done using a modified O'Hara Rudy (ORd) cardiac model. Simulations showed that Ranolazine failed to shorten AP duration, an effect augmented at febrile temperatures. The drug-channel interaction is clearly affected by external triggers, as reported previously with ischemia. Determining drug efficacy under various physiological states in SCN5a cohorts is crucial for accurate management of arrhythmias.