BPS2026 – Computational analysis of sex-specific ventricular myocyte remodeling in an obese-diabetic mouse model of HFpEF

Heart failure with preserved ejection fraction (HFpEF) impairs quality of life and increases arrhythmia risk. Although HFpEF displays clear sex differences in presentation and outcomes, the underlying cellular mechanisms remain unclear. Here, we integrated experiments and computational modeling to investigate sex-dependent remodeling in ventricular myocytes from a preclinical HFpEF model (i.e., leptin receptor-deficient db/db mice with aldosterone infusion), which mimics key human features. We updated our control model of the murine ventricular myocyte by incorporating a mouse-specific myofilament model and by adjusting Ca 2+ cycling regulation to enable the analysis of fast pacing rates. Experiments on HFpEF myocytes showed that both sexes exhibited increased capacitance, downregulated principal K + currents, and upregulated late Na + current (greater in males). Male HFpEF cells showed reduced L-type Ca 2+ current (unchanged in females) and increased troponin I phosphorylation (slightly decreased in females). Using these data, we built sex-specific HFpEF parameterizations that reproduced proarrhythmic action potential (AP) prolongation in both sexes but not the observed Ca 2+ transient (CaT) properties (i.e., elevated diastolic Ca 2+ and slower decay in male HFpEF vs. control, and non-significant changes in females). We then performed multi-objective parameter optimizations that indicated that additional sex-specific changes in RyR, SERCA, and Na + /Ca 2+ exchange functions are required to reproduce both AP and CaT phenotypes. Model analysis suggested that altered troponin I phosphorylation may drive diastolic dysfunction in females, while exerting a compensatory effect in males. The male HFpEF model also showed increased susceptibility to delayed afterdepolarizations and alternans, consistent with in vitro observations. Future work with our sex-specific HFpEF myocyte models will enable quantitative attribution of remodeling components to contractile impairment and arrhythmogenesis at both single-cell and tissue levels, guiding sex-specific therapeutic strategies.