Sex-specific virtual population for the prediction and assessment of arrhythmia risk

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ID: 315402
2026
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Abstract
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.
Reference Key
openalex_W7162855198 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Fengze Sui, Dasen Yan, Xiangbin Meng, Chengxiang Duan, Yu Zhang, Wen Gao, Zhen Song
Journal EP Europace
Year 2026
DOI
10.1093/europace/euag133
URL
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