["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend Schematic illustrating the in silico study pipeline. A total of 50,000 virtual myocytes were generated, which were then filtered to 7093 myocytes that fit experimentally constrained biomarkers for physiological electrical and calcium behaviour under wild‐type conditions. This population was then simulated with a long QT syndrome type 3 (LQT3) mutation and combinations of extracellular ionic concentration perturbations. Analysis detailed the characteristics of myocytes ‘susceptible’ and ‘non‐susceptible’ to pro‐arrhythmic behaviour.\n\n\n\n\n\n\n\n\n\nAbstract\nVentricular 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 the voltage‐gated sodium channel, 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 simulated a population of human ventricular myocytes, with the expression of the LQT3‐associated ΔKPQ mutant. Each cell was paced under nine extracellular Na+/K+ combinations (hypo/normal/hyper) in presence of the ΔKPQ mutant channel. Action potential duration (APD) > 500 ms or the presence of an early afterdepolarization (EAD) defined ‘susceptible’ myocytes. In general cells with longer APD at baseline electrolyte conditions were more likely to be susceptible following altered extracellular Na+ or K+ concentrations. Susceptibility increased for reduced [K+]o and elevated [Na+]o. Interestingly across all nine conditions ∼$ \\sim $50% of cells were never susceptible, ∼$ \\sim $30% were susceptible in every condition, whereas ∼$ \\sim $20% showed selective susceptibility (i.e. only susceptible to specific extracellular ionic conditions). Ionic current conductance profiles separated cells by susceptibility: non‐susceptible cells exhibited higher Ito, ICaL, IKr and IKb, whereas susceptible cells had higher IK1. Collectively these results connect common electrolyte disturbances and a critical set of ionic currents to condition‐dependent EADs and severe APD prolongation, and provide plausible mechanistic insight into the variable expression and incomplete penetrance of ΔKPQ‐mediated LQT3.\n\n\n\n\n\n\n\n\n\nKey points\n\nVentricular arrhythmias can arise in the setting of long QT syndrome type 3 (LQT3)‐associated mutations and are altered by electrolyte imbalance and natural ion‐channel variability.\nA population of human ventricular myocytes with LQT3 was simulated under nine conditions with altered extracellular sodium and potassium concentrations.\nCells with longer baseline action potential duration (APD) were susceptible to early afterdepolarizations (EADs) and severe APD prolongation under hypokalaemia or hypernatraemia.\nApproximately 50% of cells were never susceptible, 30% were always susceptible and 20% were conditionally susceptible across the tested extracellular ionic conditions.\nIonic current conductance profiles were associated with enhanced arrhythmia susceptibility.\n\n\n"]