T-World Virtual Human Cardiomyocyte. II. Organ-Scale Simulations and Applications

Area of Science:

• Cardiovascular Physiology
• Computational Biology
• Pharmacology

Background:

• Current human cardiomyocyte models lack the generality for predictive translation across scales.
• The T-World model reproduces major cellular arrhythmia mechanisms and aligns with experimental data.
• Demonstrating T-World's utility for organ-level and translational research is crucial.

Purpose of the Study:

• To demonstrate the utility of the T-World model for organ-level and translational cardiac research.
• To validate T-World's predictive capabilities in simulating arrhythmogenesis and whole-heart physiology.
• To assess T-World's application in drug safety, efficacy, and disease modeling.

Main Methods:

• Embedding T-World into anatomically realistic biventricular models for organ-scale simulations.
• Assessing drug safety using populations of single-cell models exposed to 60 compounds.
• Conducting mechanistic drug-efficacy studies and disease modeling for type 2 diabetes and Na_V1.8 expression.

Main Results:

• T-World accurately reproduced human ECG morphology and ventricular mechanics, simulating ventricular fibrillation under ischemia.
• The model achieved 87% accuracy and 100% specificity in torsadogenic risk assessment, identifying drug inaccuracies.
• Simulations elucidated mexiletine's antiarrhythmic benefits, linked type 2 diabetes to early afterdepolarizations, and identified Na_V1.8 as a trigger for arrhythmias.

Conclusions:

• T-World offers a unified, human-specific, open-source platform for multiscale cardiac research.
• Its predictive performance bridges cellular mechanisms to organ-level dynamics and translational outcomes.
• T-World is a powerful tool for cardiac digital twins, therapeutic discovery, and advancing regulatory science.