Role of natural inter-individual variability in the different penetrance of congenital long QT syndromes (LQTS) types 1 and 2: an in silico approach.

Congenital Long QT Syndrome types 1 and 2 (LQT1 and LQT2) are caused bymutations in the KCNQ1 and KCNH2 genes, responsible for the IKs and IKr currents, respectively. However, the penetrance of these mutations is highly variable, since some carriers remain asymptomatic, while others exhibit severe clinical manifestations. To elucidate how physiological variability in other cardiac ionic currents may influence the arrhythmic phenotype, human ventricular action potentials were simulated in silico using the O'Hara-Rudy dynamic model implemented in the Virtual Assay software. Conductances of nine key ionic currents were randomly modified within physiologically plausible ranges and the resulting population of models was validated under stress conditions. LQT1 and LQT2 cohorts were generated by reducing IKs by 80% and IKr by 60%, respectively. These cohorts were stratified into four risk categories based on action potential duration (APD) under different conditions and the occurrence of arrhythmic events. LQT1 models demonstrated impaired adaptation to adrenergic stimulation, whereas LQT2 models showed marked APD prolongation at rest. Risk stratification revealed a higher incidence of arrhythmic events in LQT2 (7.6%) compared to LQT1 (0.55%). Regression analyses identified IKr and IK1 as protective currents, while INaL and ICaL were major contributors to APD prolongation in both types. Simulated blockade of L-type Ca²⁺ channels effectively shortened APD and reduced the proportion of high-risk models. The natural variability in ionic current profiles contributes to the phenotypic expression of LQTS and support the potential use of calcium channel blockers as therapeutic alternatives in patients unresponsive to β-blockers.