Mathematical model of the zebrafish ventricular cardiomyocyte action potential and calcium transient.

In recent decades, the use of zebrafish to study cardiac electrophysiology has expanded significantly, based on striking similarities between zebrafish and human action potentials, as well as the underlying ion channels involved. Here, we developed a detailed mathematical model of the zebrafish ventricular cardiomyocyte action potential. The model is based on a previously developed human cardiomyocyte framework, with a simple calcium dynamics component that allows realistic modelling of calcium transients and excitation-contraction coupling in zebrafish. It was reparameterized using published patch clamp data and newly generated L-type calcium current recordings from single cells to adjust the biophysical properties of the principal ionic currents. The principal ionic current conductances in the model were then calibrated and validated using new experimental data, including microelectrode measurements of membrane potential and optical measurements of intracellular calcium in isolated hearts during steady-state and restitution pacing protocols. The model was used to explore components underlying the zebrafish action potential and calcium transient, highlighting that: (1) the T-type calcium current contributes to the action potential upstroke; (2) the L-type calcium current strongly affects the plateau and is a greater contributor to the intracellular calcium transient than sarcoplasmic reticulum calcium release; and (3) both rapid and slow delayed rectifier potassium currents make significant contributions to action potential repolarization. Overall, the novel zebrafish-specific computational model presented here provides a valuable tool for studying cardiac electrophysiology in zebrafish and may be adapted in future work for use in large-scale models to study whole heart electrical activity. KEY POINTS: We have developed the first zebrafish-specific computational ventricular action potential model, based on new and existing patch clamp data from single cells, with model calibration and validation performed using newly generated voltage and calcium measurements in the whole heart. The model reinforces experimental findings, highlighting key roles of T- and L-type calcium currents in sustaining action potential depolarization and the intracellular calcium transient. Despite conflicting evidence regarding the existence of the slow delayed rectifier potassium current in zebrafish, the model suggested its important role in repolarization. While single-cell and tissue model simulations produced similar results, depolarization-related parameters (i.e. action potential upstroke speed and amplitude) varied, highlighting the importance of tissue-based simulations for accurate comparison with tissue-derived data. The model accurately predicted action potential prolongation with individual current block, aligning with experimental data. The effects of multi-channel block were greater than in human, emphasizing the need for caution when translating zebrafish pharmacology.