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bioRxiv · 10.1101/2025.03.24.645031

T-World: A highly general computational model of a human ventricular myocyte

Tomek, J.·Zhou, X.·Martinez-Navarro, H.·Holmes, M.·Bury, T.·Arantes Berg, L.·Tomkova, M.·Jo, E.·Nagy, N.·Bertrand, A.·Bueno-Orovio, A.·Colman, M. A.·Rodriguez, B.·Bers, D. M.·Heijman, J.
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Abstract

Cardiovascular disease is the leading cause of death, demanding new tools to improve mechanistic understanding and overcome limitations of stem cell and animal-based research. We introduce T-World, a highly general virtual model of human ventricular cardiomyocyte suitable for multiscale studies. T-World shows comprehensive agreement with human physiology, from electrical activation to contraction, and is the first to replicate all key cellular mechanisms driving life-threatening arrhythmias. Extensively validated on unseen data, it demonstrates strong predictivity across applications and scales. Using T-World we revealed a likely sex-specific arrhythmia risk in females related to restitution properties, identified arrhythmia drivers in type 2 diabetes, and describe unexpected pro-arrhythmic role of NaV1.8 in heart failure. T-World demonstrates strong performance in predicting drug-induced arrhythmia risk and opens new opportunities for predicting and explaining drug efficacy, demonstrated by unpicking effects of mexiletine in Long QT syndrome 2. T-World is available as open-source code and an online app.

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Tomek, J., Zhou, X., Martinez-Navarro, H., Holmes, M., Bury, T., Arantes Berg, L., Tomkova, M., Jo, E., Nagy, N., Bertrand, A., Bueno-Orovio, A., Colman, M. A., Rodriguez, B., Bers, D. M., Heijman, J.. 2025-03-25. T-World: A highly general computational model of a human ventricular myocyte. https://doi.org/10.1101/2025.03.24.645031

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