Circ Res. 2026 Apr 8. doi: 10.1161/CIRCRESAHA.125.328123. Online ahead of print.
ABSTRACT
BACKGROUND: Mechanistic cardiac simulations are increasingly used in research, pharmaceutical development, and regulatory science, yet most existing human cardiomyocyte models lack the generality required for predictive translation across scales. Our recently developed T-World model overcomes this barrier by reproducing all major cellular arrhythmia mechanisms and showing comprehensive agreement with experimental and clinical data. Here, we aimed to demonstrate the utility of T-World for organ-level and translational research, from ionic mechanisms of arrhythmogenesis to emergent whole-heart physiology.
METHODS: T-World was embedded into anatomically realistic models of biventricular electrophysiology and electromechanics derived from clinical imaging for organ-scale simulations. Drug safety was assessed using populations-of-single-cell models exposed to 60 compounds with updated CredibleMeds annotations. Mechanistic drug-efficacy studies on mexiletine were conducted using long QT syndrome type 2 model variants. Disease applications included arrhythmia mechanisms in human type 2 diabetes and the proarrhythmic potential of NaV1.8, a neuronal sodium channel ectopically expressed in cardiac disease.
RESULTS: T-World reproduced human-like ECG morphology and ventricular mechanics (ejection fraction, 61%) and generated ventricular fibrillation under physiologically relevant ischemic conditions without parameter tuning. In the drug safety assessment of torsadogenic risk, T-World achieved 87% accuracy and 100% specificity, and exposed incomplete pharmacological descriptions based on in vitro measurements for lidocaine and cilostazol. Mexiletine simulations revealed that both INaL and ICaL inhibition underlie its antiarrhythmic benefit in long QT syndrome type 2. Cellular simulations of type 2 diabetes remodeling explained heightened vulnerability to early afterdepolarizations and increased risk of alternans associated with diastolic dysfunction, mechanistically linked to SERCA (sarco/endoplasmic reticulum Ca2+ ATPase) reduction. Finally, even minor expression of NaV1.8 can directly trigger early afterdepolarizations through uniquely right-shifted activation and inactivation properties.
CONCLUSIONS: T-World provides a unified, human-specific open-source platform bridging cellular mechanisms with organ-level dynamics and translational outcomes. Its predictive performance across arrhythmia, contraction, drug safety/mechanisms, and disease physiology makes it a powerful tool for multiscale cardiac research, therapeutic discovery, and next-generation cardiac digital twins.
PMID:41948815 | DOI:10.1161/CIRCRESAHA.125.328123