EAD Mechanisms in Hypertrophic Mouse Ventricular Myocytes: Insights from a Compartmentalized Mathematical Model.

Abstract

Transverse aortic constriction (TAC) is one of the experimental mouse models that are designed to investigate cardiac hypertrophy and heart failure. Most of the studies with this model are devoted to the stage of developed heart failure. However, several studies of the early stages (hypertrophy after 1 week of TAC) of this disease found significant changes in the β-adrenergic system, electrical activity, and Ca²⁺ dynamics in mouse ventricular myocytes. To provide a quantitative description of cardiac hypertrophy, we developed a new compartmentalized mathematical model of hypertrophic mouse ventricular myocytes for the early stage after the TAC procedure. The model described the changes in cell geometry, action potentials, [Ca²⁺]_i transients, and β₁- and β₂-adrenergic signaling systems. We also showed that the hypertrophic myocytes demonstrated early afterdepolarizations (EADs) upon stimulation with isoproterenol at relatively long stimulation periods. Simulation of the hypertrophic myocyte activities revealed that the synergistic effects of the late Na⁺ current, the L-type Ca²⁺ current, and the T-type Ca²⁺ current were responsible for the initiation of EADs. The mechanisms of EAD and its suppression were investigated and sensitivity analysis was performed. Simulation results obtained with the hypertrophic cell model were compared to those from the normal ventricular myocytes. The developed mathematical model can be used for the explanation of the existing experimental data, for the development of the models for other hypertrophic phenotypes, and to make experimentally testable predictions of a hypertrophic myocyte's behavior.