A compartmentalized mathematical model of the β1- and β2-adrenergic signaling systems in ventricular myocytes from mouse in heart failure

Mouse models of heart failure are extensively used to research human cardiovascular diseases. In particular, one of the most common is the mouse model of heart failure resulting from transverse aortic constriction (TAC). Despite this, there are no comprehensive compartmentalized mathematical models...

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Bibliographic Details
Published in:American Journal of Physiology: Cell Physiology 2023-02, Vol.324 (2), p.C263-C291
Main Authors: Asfaw, Tesfaye Negash, Bondarenko, Vladimir E
Format: Article
Language:English
Subjects:
Action potential
Animal models
Aorta
Calcium (intracellular)
Calcium (reticular)
Calcium signalling
Cardiac muscle
Cardiovascular diseases
Congestive heart failure
Heart failure
Mathematical models
Myocytes
Sarcoplasmic reticulum
Sensitivity analysis
Ventricle
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Summary:Mouse models of heart failure are extensively used to research human cardiovascular diseases. In particular, one of the most common is the mouse model of heart failure resulting from transverse aortic constriction (TAC). Despite this, there are no comprehensive compartmentalized mathematical models that describe the complex behavior of the action potential, [Ca2+]i transients, and their regulation by β1- and β2-adrenergic signaling systems in failing mouse myocytes. In this paper, we develop a novel compartmentalized mathematical model of failing mouse ventricular myocytes after TAC procedure. The model describes well the cell geometry, action potentials, [Ca2+]i transients, and β1- and β2-adrenergic signaling in the failing cells. Simulation results obtained with the failing cell model are compared with those from the normal ventricular myocytes. Exploration of the model reveals the sarcoplasmic reticulum Ca2+ load mechanisms in failing ventricular myocytes. We also show a larger susceptibility of the failing myocytes to early and delayed afterdepolarizations and to a proarrhythmic behavior of Ca2+ dynamics upon stimulation with isoproterenol. The mechanisms of the proarrhythmic behavior suppression are investigated and sensitivity analysis is performed. The developed model can explain the existing experimental data on failing mouse ventricular myocytes and make experimentally testable predictions of a failing myocyte's behavior.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00366.2022