Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

Abstract

Transgenic mice overexpressing tumor necrosis factor-α (TNF-α mice) possess many of the features of human heart failure, such as dilated cardiomyopathy, impaired Ca2+ handling, arrhythmias, and decreased survival. Although TNF-α mice have been studied extensively with a number of experimental methods, the mechanisms of heart failure are not completely understood. We created a mathematical model that reproduced experimentally observed changes in the action potential (AP) and Ca2+ handling of isolated TNF-α mice ventricular myocytes. To study the contribution of the differences in ion currents, AP, Ca2+ handling, and intercellular coupling to the development of arrhythmias in TNF-α mice, we further created several multicellular model tissues with combinations of wild-type (WT)/reduced gap junction conductance, WT/prolonged AP, and WT/decreased Na+ current ( INa) amplitude. All model tissues were examined for susceptibility to Ca2+ alternans, AP propagation block, and reentry. Our modeling results demonstrated that, similar to experimental data in TNF-α mice, Ca2+ alternans in TNF-α tissues developed at longer basic cycle lengths. The greater susceptibility to Ca2+ alternans was attributed to the prolonged AP, resulting in larger inactivation of INa, and to the decreased SR Ca2+ uptake and corresponding smaller SR Ca2+ load. Simulations demonstrated that AP prolongation induces an increased susceptibility to AP propagation block. Programmed stimulation of the model tissues with a premature impulse showed that reduced gap junction conduction increased the vulnerable window for initiation reentry, supporting the idea that reduced intercellular coupling is the major factor for reentrant arrhythmias in TNF-α mice.

Effect of lysophosphatidic acid on the immune inflammatory response and the connexin 43 protein in myocardial infarction

“…Animals overexpressing TNF suffer from severe heart disease, including arrhythmia (26)(27)(28). This indicates that upregulation of TNF expression is closely associated with the dysfunction of cardiac myocytes (29,30). The results of the present study demonstrated that LPA is able to induce TNF-α release in cultured Jurkat T cells.…”

A Mathematical Model of the Mouse Ventricular Myocyte Contraction

“…This model is based on our previously published models for epicardial and endocardial cells [19], [20], [21], [22], which includes a comprehensive description of action potential, ionic currents, and Ca 2+ dynamics. For a description of myocyte contraction, we adopted Model 4 developed by Rice et al [15] by fitting experimental data on contraction for mice.…”

“…A mathematical model for mouse ventricular myocyte contraction is a natural extension of our previously published models for action potential and Ca 2+ dynamics in mouse ventricular myocytes [19], with model improvements from [20], [21], [22] (Fig. 1A), developed for room temperature (298°K, or +25°C).…”

“…Endocardial cells have more prolonged action potentials and larger intracellular [Ca 2+ ] i transients compared to epicardial cells [22]. We incorporated the Rice et al [15] contraction model 4 in our model of electrical activity and Ca 2+ handling [19], [20], [21], [22] (See Appendix S1) and adjusted model parameters to fit experimental data on myocyte contraction obtained for room temperatures.…”

“…We employed our previously published models for action potential and Ca 2+ dynamics in mouse ventricular myocytes [19], [20], [21], [22], which were also developed for room temperature (298°K, or +25°C), and incorporated a myocyte contraction model from Rice et al [15]. These models were successfully employed for simulations of proarrhythmic activities in mouse cardiac cells and tissues [21], [22].…”