Source: Wang LJ, Sobie EA. Mathematical model of the neonatal mouse ventricular action potential. Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2565-75.
Abstract
Therapies for heart disease are based largely on our understanding of the adult myocardium. The dramatic differences in action potential (AP) shape between neonatal and adult cardiac myocytes, however, indicate that a different set of molecular interactions in neonatal myocytes necessitates different treatment for newborns. Computational modeling is useful for synthesizing data to determine how interactions between components lead to systems-level behavior, but this technique has not been used extensively to study neonatal heart cell function. We created a mathematical model of the neonatal (day 1) mouse myocyte by modifying, on the basis of experimental data, the densities and/or formulations of ion transport mechanisms in an adult cell model. The new model reproduces the characteristic AP shape of neonatal cells, with a brief plateau phase and longer duration than the adult (action potential duration at 80% repolarization = 60.1 vs. 12.6 ms). The simulation results are consistent with experimental data, including 1) decreased density and altered inactivation of transient outward K+ currents, 2) increased delayed rectifier K+ currents, 3) Ca2+ entry through T-type as well as L-type Ca2+ channels, 4) increased Ca2+ influx through Na+/Ca2+ exchange, and 5) Ca2+ transients resulting from transmembrane Ca2+ entry rather than release from the sarcoplasmic reticulum (SR). Simulations performed with the model generated novel predictions, including increased SR Ca2+ leak and elevated intracellular Na+ concentration in neonatal compared with adult myocytes. This new model can therefore be used for testing hypotheses and obtaining a better quantitative understanding of differences between neonatal and adult physiology.
PMID: 18408122 | PMCID: PMC3032983 | EndNote Citation
Description: This paper describes a novel mathematical model of electrical signaling and calcium handling in ventricular cells from the neonatal (day 1) mouse. Neonatal mouse and rat hearts are commonly used in experimental studies, but the lack of a mathematical description of action potentials and calcium transients in these cells previously made quantitative interpretation difficult. We created the first mathematical model of the neonatal mouse myocyte by modifying, based on experimental data, the densities and/or formulations of ion transport mechanisms in an adult cell model. The new model reproduces the characteristic AP shape of neonatal cells, with a brief plateau phase and longer duration than the adult (APD80=60.8 vs. 12.6 ms). As shown in the Figure, the model correctly reproduces the responses of adult and neonatal cells to drugs that block specific potassium channels in the cell membrane.
Equations and parameters describing the model: Supplementary materials on Am J Physiol Heart Circ Physiol website
MatLab Code: The two files, "Wang_ode.m" and "dydt_wang.m" must be in the same directory to run the model. wang_ode.m is the master script that defines the model parameters and electrical stimulation protocol. This program then uses Matlab's ODE solvers and calls the other program to integrate the differential equations. When the simulation is complete, wang_ode.m plots the action potential and various ionic currents.