title: A mathematical model of the murine ventricular myocyte: a data-driven biophysically based approach applied to mice overexpressing the canine NCX isoform.
abstract: Mathematical modeling of Ca(2+) dynamics in the heart has the potential to provide an integrated understanding of Ca(2+)-handling mechanisms. However, many previous published models used heterogeneous experimental data sources from a variety of animals and temperatures to characterize model parameters and motivate model equations. This methodology limits the direct comparison of these models with any particular experimental data set. To directly address this issue, in this study, we present a biophysically based model of Ca(2+) dynamics directly fitted to experimental data collected in left ventricular myocytes isolated from the C57BL/6 mouse, the most commonly used genetic background for genetically modified mice in studies of heart diseases. This Ca(2+) dynamics model was then integrated into an existing mouse cardiac electrophysiology model, which was reparameterized using experimental data recorded at consistent and physiological temperatures. The model was validated against the experimentally observed frequency response of Ca(2+) dynamics, action potential shape, dependence of action potential duration on cycle length, and electrical restitution. Using this framework, the implications of cardiac Na(+)/Ca(2+) exchanger (NCX) overexpression in transgenic mice were investigated. These simulations showed that heterozygous overexpression of the canine cardiac NCX increases intracellular Ca(2+) concentration transient magnitude and sarcoplasmic reticulum Ca(2+) loading, in agreement with experimental observations, whereas acute overexpression of the murine cardiac NCX results in a significant loss of Ca(2+) from the cell and, hence, depressed sarcoplasmic reticulum Ca(2+) load and intracellular Ca(2+) concentration transient magnitude. From this analysis, we conclude that these differences are primarily due to the presence of allosteric regulation in the canine cardiac NCX, which has not been observed experimentally in the wild-type mouse heart.
authors.affiliation: Computing Laboratory, University of Oxford and John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: S A
authors.initials: SA
authors.lastname: Niederer
authors.forename: W
authors.initials: W
authors.lastname: Idigo
authors.forename: Y H
authors.initials: YH
authors.lastname: Zhang
authors.forename: P
authors.initials: P
authors.lastname: Swietach
authors.forename: B
authors.initials: B
authors.lastname: Casadei
authors.forename: N P
authors.initials: NP
authors.lastname: Smith
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D055592:Biophysical Phenomena / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D004285:Dogs; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D019831:Sodium-Calcium Exchanger; D002118:Calcium