T-World Virtual Human Cardiomyocyte. I. Development, Validation, and Cell Arrhythmogenesis

BACKGROUND: Cardiovascular disease is the leading global cause of morbidity and mortality. New technologies are needed to improve mechanistic understanding and inform therapeutic strategies. Human-centric cardiac simulations show great promise; however, existing cellular models can reproduce only a few arrhythmia-driving behaviors and show important discrepancies with experimental data. We aimed to develop a new model overcoming this lack of generality, which markedly limits the predictivity and translational utility of virtual cardiomyocytes. METHODS: We developed T-World, a novel virtual human cardiomyocyte, using data-driven differential equations to describe sex-specific excitation-contraction coupling, mechanical contraction, β-adrenergic signaling, and its effects on cellular targets. The model contains several key innovations, including a new approach to coupling L-type calcium channels and ryanodine receptors, with updated calcium-dependent-inactivation of the former and novel calcium-induced refractoriness and complete reparameterization of the latter. We also redeveloped the sodium-potassium pump and made major improvements to the sodium-calcium exchanger formulation. RESULTS: ATPase) inhibition, and AP prolongation. Combined with the model's ability to simulate physiological sex-specific differences in electrophysiology, this revealed increased proclivity of female cardiomyocytes to early afterdepolarizations and steep restitution of AP duration. CONCLUSIONS: T-World is a highly general and predictive open-source computer model of a human ventricular cardiomyocyte, suitable for multiscale research studies investigating determinants of arrhythmogenesis.