A Novel Computational Model of the Human Ventricular Action Potential and Ca transient

Abstract

We have developed a detailed mathematical model for Ca handling and ionic currents in the human ventricular myocyte. Our objective was to implement a model that: 1) accurately reflects Ca-dependent Ca release; 2) uses repolarizing K currents with realistic amplitude; 3) comes to steady state; 4) simulates basic excitation-contraction coupling phenomena; and 5) runs on a normal desktop computer. The model relies on the framework of the rabbit myocyte model developed by Shannon et al. in our laboratory, and includes a subsarcolemmal compartment (in addition to the other two commonly formulated cytosolic compartments, junctional and bulk) where the ion channels sense ion concentrations that differ from the bulk. Ion channels and transporters have been modeled on the basis of the most recent experimental data obtained in our group and from the literature. In particular, novel formulations of the rapidly and slowly inactivating components of Ito have been implemented and utilized to differentiate between endocardial and epicardial myocytes. The model has been validated against a wide set of experimental data including action potential adaptation and restitution properties, frequency dependent inotropy and intracellular sodium staircase. It also correctly predicts the effect of pharmacological intervention on K currents (e.g. chromanol 293 B and dofetilide administration) on ventricular repolarization. We conclude that this model is more robust than previously existing models and provides a useful framework to explore excitation-contraction coupling mechanisms and repolarization abnormalities at the single cell level. To overcome the substantial limitations to experimental studies involving human cardiac tissue, due to its low computational cost this model is suitable to be integrated into multi-scale models of tissue and/or heart.