BPS2026 - Predicting long QT type 3 arrhythmia risk for variable extracellular ionic concentrations

Ventricular arrhythmias are a major cause of sudden cardiac death and can occur when repolarization reserve is reduced by electrolyte imbalances and natural variation in ion-channel expression. Long QT syndrome type 3 (LQT3), caused by a gain-of-function mutation in Nav1.5, is an established exemplar; however, clinical presentation of disease-associated symptoms can vary substantially. Here, we examined how electrolyte state and intrinsic variability in ionic current conductances collectively influence arrhythmia risk. We used the Tomek-O’Hara-Rudy (ToR-ORd) human ventricular myocyte model, with expression of the LQT3-associated ΔKPQ mutant or wild-type (WT) Na + channel to simulate 30,000 virtual cells. Subsequently, WT cells were assessed and filtered for physiological measures of action potential (AP) and calcium transient characteristics, resulting in 5,478 cells. Each cell was paced under nine extracellular Na + /K + combinations (hypo/normal/hyper) in the presence of the ΔKPQ mutant channel. APD90 (action potential duration to 90% repolarization) ≥ 500 ms or presence of an early afterdepolarization (EAD) defined “susceptible” myocytes. In general, cells with longer APD90 at baseline electrolyte conditions were more likely to susceptible following altered extracellular Na + or K + concentration. Susceptibility increased for reduced K + o and elevated Na + o . Interestingly, across all nine conditions, ∼50% of cells were never susceptible, ∼20% were susceptible in every condition, while ∼30% showed selective susceptibility (i.e., only susceptible to specific extracellular ionic conditions). Mechanistically, late-plateau reactivation of ICaL, supported by increased late INa and reduced IKr and IK1, triggered EADs. Conductance patterns separated cells by susceptibility: non-susceptible cells exhibited higher Ito, ICaL, IKr, and IKb, whereas susceptible cells had higher IK1. These results connect common electrolyte disturbances and a critical set of ionic currents to condition-dependent EADs and may explain the incomplete penetrance of ΔKPQ-mediated LQT3.