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A Mathematical Model of the Mouse Atrial Myocyte With Inter-Atrial Electrophysiological Heterogeneity.

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 ?-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.

SUBMITTER: Zhang H

PROVIDER: S-EPMC7425199 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Mathematical Model of the Mouse Atrial Myocyte With Inter-Atrial Electrophysiological Heterogeneity.

Zhang Henggui H Zhang Shanzhuo S Wang Wei W Wang Kuanquan K Shen Weijian W

Frontiers in physiology 20200806

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 ...[more]

PMID: 32848887

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Project description:RationalePostoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown.ObjectiveTo identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery.Methods and resultsMulticellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca2+]i-recordings in atrial cardiomyocytes, along with protein-expression levels in tissue homogenates or cardiomyocytes, were assessed in 265 atrial samples from patients without or with POAF. No indices of electrical, profibrotic, or connexin remodeling were noted in POAF, but Ca2+-transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca2+-release events and L-type Ca2+-current alternans occurred more frequently. CaMKII (Ca2+/calmodulin-dependent protein kinase-II) protein-expression, CaMKII-dependent phosphorylation of the cardiac RyR2 (ryanodine-receptor channel type-2), and RyR2 single-channel open-probability were significantly increased in POAF. SR Ca2+-content was unchanged in POAF despite greater SR Ca2+-leak, with a trend towards increased SR Ca2+-ATPase activity. Patients with POAF also showed stronger expression of activated components of the NLRP3 (NACHT, LRR, and PYD domains-containing protein-3)-inflammasome system in atrial whole-tissue homogenates and cardiomyocytes. Acute application of interleukin-1β caused NLRP3-signaling activation and CaMKII-dependent RyR2/phospholamban hyperphosphorylation in an immortalized mouse atrial cardiomyocyte cell-line (HL-1-cardiomyocytes) and enhanced spontaneous SR Ca2+-release events in both POAF cardiomyocytes and HL-1-cardiomyocytes. Computational modeling showed that RyR2 dysfunction and increased SR Ca2+-uptake are sufficient to reproduce the Ca2+-handling phenotype and indicated an increased risk of proarrhythmic delayed afterdepolarizations in POAF subjects in response to interleukin-1β.ConclusionsPreexisting Ca2+-handling abnormalities and activation of NLRP3-inflammasome/CaMKII signaling are evident in atrial cardiomyocytes from patients who subsequently develop POAF. These molecular substrates sensitize cardiomyocytes to spontaneous Ca2+-releases and arrhythmogenic afterdepolarizations, particularly upon exposure to inflammatory mediators. Our data reveal a potential cellular and molecular substrate for this important clinical problem.

Dataset Information

A Mathematical Model of the Mouse Atrial Myocyte With Inter-Atrial Electrophysiological Heterogeneity.

Publications

A Mathematical Model of the Mouse Atrial Myocyte With Inter-Atrial Electrophysiological Heterogeneity.

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