Abstract
Biophysically detailed mathematical models of cardiac electrophysiology provide an alternative to experimental approaches for investigating possible ionic mechanisms underlying the genesis of electrical action potentials and their propagation through the heart. The aim of this study was to develop a biophysically detailed mathematical model of the action potentials of mouse atrial myocytes, a popular experimental model for elucidating molecular and cellular mechanisms of arrhythmogenesis. Based on experimental data from isolated mouse atrial cardiomyocytes, a set of mathematical equations for describing the biophysical properties of membrane ion channel currents, intracellular Ca2+ handling, and Ca2+-calmodulin activated protein kinase II and β-adrenergic signaling pathways were developed. Wherever possible, membrane ion channel currents were modeled using Markov chain formalisms, allowing detailed representation of channel kinetics. The model also considered heterogeneous electrophysiological properties between the left and the right atrial cardiomyocytes. The developed model was validated by its ability to reproduce the characteristics of action potentials and Ca2+ transients, matching quantitatively to experimental data. Using the model, the functional roles of four K+ channel currents in atrial action potential were evaluated by channel block simulations, results of which were quantitatively in agreement with existent experimental data. To conclude, this newly developed model of mouse atrial cardiomyocytes provides a powerful tool for investigating possible ion channel mechanisms of atrial electrical activity at the cellular level and can be further used to investigate mechanisms underlying atrial arrhythmogenesis.
Highlights
Murine hearts are commonly used as animal models in cardiac research for investigating possible molecular and cellular bases of cardiac arrhythmias (Martin et al, 2012; Huang, 2016)
Examples include the first mathematical model of mouse sinoatrial node by Mangoni et al (2006), which was further updated by incorporating biophysical properties of membrane ionic currents and intracellular Ca2+ handling mechanisms by Kharche et al (2011), the first mouse ventricular cell models developed by Bondarenko et al (2004), which were updated by incorporating newer experimental data by Li et al (2010)
The main goal of this study is to develop a mathematical model of mouse atrial myocytes to simulate mouse atrial action potentials (APs) and intracellular Ca2+ handling mechanisms
Summary
Murine hearts are commonly used as animal models in cardiac research for investigating possible molecular and cellular bases of cardiac arrhythmias (Martin et al, 2012; Huang, 2016). Mathematical Model of Murine Atrial Cells these experimental data obtained at different scales into an integrated mathematical model for systematically elucidating better functional roles of ion channels in atrial electrical excitations and arrhythmogenesis. Mouse ventricular cell models with β-adrenergic signaling regulation and with calmodulin (CaM) mediating Ca2+-dependent regulation were developed by Yang and Saucerman (2012) and Morotti et al (2014), respectively. These models provide useful tools for underpinning insights into the regulation of Ca2+ handling in physiological and pathological conditions
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