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

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.