Sex-specific amplification of I Kr -blocker–induced action potential prolongation by reduced female I Ks repolarization reserve: a computational study using the O’Hara-Rudy human ventricular model
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Background
Women experience drug-induced Torsades de Pointes (TdP) at approximately twice the rate of men across more than 50 QT-prolonging drug classes, yet the quantitative ionic basis of this sex disparity remains incompletely characterised. The slow delayed rectifier current ( I Ks ) is reduced by ∼45% in female compared with male human ventricular cardiomyocytes, reducing the repolarization reserve available to compensate pharmacological I Kr block.
Methods
We implemented the O’Hara-Rudy (ORd) 2011 undiseased human ventricular epicardial action potential model in Python and parameterised sex variants using the most robustly established human ionic difference: G Ks reduced by 45% in females [Kurokawa et al., 2016]. We simulated graded I Kr blockade (0–95% in steps of 5%) at three physiologically relevant pacing rates (2 Hz, 1 Hz, 0.5 Hz) after 60 beats of warm-up to approach electrophysiological steady state. Action potential duration at 90% repolarization (APD 90 ), triangulation (APD 90 −APD 30 ), and repolarization failure (defined as APD 90 > 500 ms, a conservative cellular risk marker informed by clinical QTc safety thresholds, or failure to repolarize within the cycle length) were quantified. All simulations used SciPy’s Radau solver (rtol = 10 − , atol = 10 −8 ) with a Numba-JIT–compiled right-hand side for computational efficiency.
Results
At baseline (0% block), the female model exhibited longer APD 90 than the male at all pacing rates (+2.8 ms at 2 Hz; +4.6 ms at 1 Hz; +4.6 ms at 0.5 Hz). Under progressive I Kr blockade, the absolute sex difference in APD 90 amplified non-linearly: at 85% block and 1 Hz pacing the female APD 90 exceeded the male by 60.4 ms (versus 4.6 ms at baseline; 13-fold amplification). At slow pacing (0.5 Hz), the sex gap was most pronounced: at 85% block, female APD 90 was 1127 ms versus 939 ms for the male (+188 ms; 20% more prolonged). The critical APD threshold (>500 ms) was reached by female cells at 5 percentage points lower I Kr block than male cells at 1 Hz pacing (55% vs. 60% block), both reported at the first simulated 5%-grid block level exceeding the criterion. Repolarization failure occurred 5 percentage points earlier in females at 1 Hz (90% vs. 95% block). Action potential triangulation was consistently greater in the female model at all block levels and pacing rates.
Conclusion
A 45% reduction in I Ks conductance is sufficient in this model to produce measurably greater APD 90 prolongation under I Kr blockade across all tested pacing rates. The non-linear amplification of the sex gap is consistent with the hypothesis that reduced I Ks repolarization reserve contributes to greater female susceptibility to drug-induced QT prolongation, and supports testing sex-specific parameterizations in CiPA-style in silico cardiac safety workflows.
