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.
Show 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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