Exploring the mechanisms of sex-specific proarrhythmia in long QT syndrome through computational modeling

Females exhibit longer QT intervals and a higher risk of long QT syndrome (LQTS) associated arrhythmogenesis compared with males. Although several studies suggest these sex disparities result from the effect of sex hormones on cardiac ion channels, the underlying mechanisms remain incompletely understood. This research investigates the arrhythmogenic effects, sex-specific risk, and mechanisms associated with LQTS linked to either to loss-of-function of the rapidly activating delayed rectifier K⁺ current (I_Kr), or gain-of-function of the L-type Ca²⁺ current (I_CaL). We primarily used the Tomek-Rodriguez (ToR-ORd) model of human ventricular cardiomyocytes and incorporated sex-specific parameterizations based on previous studies. The O'Hara-Rudy and Grandi-Bers models were used to demonstrate model-independence of the findings. We used a populations-of-models approach to assess early afterdepolarization (EAD) susceptibility in control and LQTS male and female groups. All female models had consistently longer action potentials and were more prone to EADs than male models. In the ToR-ORd model, I_Kr loss-of-function led to EADs in 65.8% of females versus 22.8% of males. I_CaL gain-of-function led to EADs in 66.2% of females but only 3.6% of males. Using logistic regression analysis, we identified key ionic predictors of EAD susceptibility, with maximal conductance of the L-type Ca²⁺ current (G_CaL) and maximal transport rate of the Na⁺/Ca²⁺ exchanger (G_NCX) consistently emerging as positively and maximal conductance of the rapidly activating delayed rectifier K⁺ current (G_Kr) as negatively associated to EADs across both sexes and LQTS types. Notably, higher G_NCX but lower G_Kr in female versus male cardiomyocytes could explain heightened female EAD risk. Our studies explore the ionic traits that favor (or confer resilience against) EADs with potential implications for personalized treatments. NEW & NOTEWORTHY We explored sex disparities in long QT syndrome (LQTS) using sex-specific human ventricular cardiomyocyte models. We showed that females exhibit greater susceptibility to early afterdepolarizations (EADs) than males, and identified key ionic predictors of EAD risk, including increases in the voltage-gated L-type Ca²⁺ current and electrogenic Na⁺/Ca²⁺ exchanger, and downregulation of the rapidly activating delayed rectifier K⁺ current. These findings offer new insights into sex-specific mechanisms underlying arrhythmogenesis in LQTS, with potential implications for personalized treatments.