Sex-aware virtual populations demonstrated that female cohorts have a higher simulated risk of proarrhythmic events across long QT syndrome subtypes and 109 multichannel drug block profiles.
Does a sex-aware tissue-scale virtual population model quantify sex differences in inherited and acquired proarrhythmic susceptibility?
Sex-aware tissue-scale virtual populations can quantify proarrhythmic risk beyond mean ΔQTc and provide mechanistic drivers for sex differences in arrhythmia susceptibility.
BACKGROUND AND AIMS: Women are at higher risk of serious ventricular arrhythmias, including torsades de pointes (TdP), when repolarization reserve is reduced, but sex-stratified mechanisms and quantitative risk assessment remain challenging. We aimed to develop scalable, tissue-scale, sex-aware ventricular virtual populations to quantify and explain sex differences in inherited and acquired proarrhythmic susceptibility. METHODS: We constructed male and female virtual cohorts using a one-dimensional (1D) ventricular cable model with pseudo-electrocardiogram (pseudo-ECG), integrating sex-specific ionic conductance backgrounds and acute sex-hormone modulation. Virtual populations were filtered under multi-condition stress tests and calibrated to clinical corrected QT interval (QTc) distributions. We generated long QT syndrome types 1-3 (LQT1-3) cohorts, simulated sympathetic stress, and performed virtual drug trials for 109 compounds using multichannel block profiles at 1× effective free therapeutic plasma concentration (EFTPC). Proarrhythmic risk was defined by tissue-scale instability events (premature ventricular complexes, T-wave alternans, or repolarization failure). Drivers were analyzed using regression and channel-sensitivity analysis, and clinical 24h concentration-electrocardiogram (ECG) data after dosing were used for external validation. RESULTS: The female cohorts exhibited higher simulated event risk across long QT syndrome subtypes and across multichannel drug block profiles, including drugs with <10 ms mean QTc prolongation. Female-to-male risk ratios tracked clinical risk categories. Simulated QTc time-courses and concentration-QTc trends agreed with 24h clinical ECG data for key reference drugs. CONCLUSIONS: Sex-aware tissue-scale virtual populations enable in silico trials that quantify proarrhythmic risk beyond mean ΔQTc, provide mechanistic drivers, and support sex-informed cardiac safety evaluation and monitoring strategies.
Sui et al. (Thu,) conducted a other in Proarrhythmic susceptibility and long QT syndrome. Virtual drug trials (109 compounds) vs. Male virtual cohorts was evaluated on Tissue-scale instability events (premature ventricular complexes, T-wave alternans, or repolarization failure). Sex-aware virtual populations demonstrated that female cohorts have a higher simulated risk of proarrhythmic events across long QT syndrome subtypes and 109 multichannel drug block profiles.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: