A mathematical model of the murine ventricular myocyte: a data-driven biophysically based approach applied to mice overexpressing the canine NCX isoform

Mathematical modeling of Ca2+dynamics in the heart has the potential to provide an integrated understanding of Ca2+-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 Ca2+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 Ca2+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 Ca2+dynamics, action potential shape, dependence of action potential duration on cycle length, and electrical restitution. Using this framework, the implications of cardiac Na+/Ca2+exchanger (NCX) overexpression in transgenic mice were investigated. These simulations showed that heterozygous overexpression of the canine cardiac NCX increases intracellular Ca2+concentration transient magnitude and sarcoplasmic reticulum Ca2+loading, in agreement with experimental observations, whereas acute overexpression of the murine cardiac NCX results in a significant loss of Ca2+from the cell and, hence, depressed sarcoplasmic reticulum Ca2+load and intracellular Ca2+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.