A Mathematical Model of Action Potential Heterogeneity in Adult Rat Left Ventricular Myocytes

Model Status

This cell model was developed by Liren Li and represents the MOUSE VENTRICULAR MYOCYTE VARIANT. It reads both in PCenv and COR and is able to produce action potentials under multiple stimuli.

Model Structure

The transgenic mouse has become an important new tool in the study of human diseases and the design of new therapies. With increasing genetic manipulations applied to the mice, it is important to characterise and understand the electrical and biophysical properties of the ionic currents expressed in the mouse heart. A computational model of the mouse action potentials, based on experimental measurements and findings, has been developed to help explore the complexities of the cardiac electrophysiology.

The mouse ventricular myocyte model is a modification from the Pandit rat LV epicardial cell model. The rat LV epicardial model was first modified to match experimental recordings from rat RV cells. The RV model was then used as the control model for the development of the mouse model. To summarise, from the original rat LV epicardial model, the following modifications have been made:

I_Na : The conductance of the sodium channel was increased by 33% compared with that for the rat LV epicardium (control model), to match experimental findings of higher expression of this channel in RV myocytes. And this higher conductance value was carried onto the mouse model.

I_CaL : The conductance of I_CaL was increased by 10%, so that the influx of Ca²⁺ ions via I_CaL (Q_CaL), and the APD₉₀ value during a simulated RV action potential were comparable to corresponding experimental measurements in rat RV myocytes. And this was carried onto the mouse model.

I_t : The formulation for It in the rat LV epicardial model had three gating variables. They are one activation variable (r) and two inactivation variables, i.e. fat (s) and slow (s_slow) inactivation variables. But the formulation for It in the mouse model only contains one activation variable (r) and one inactivation variable (s).

I_ss : In the rat LV epicardial cells, the steady-state outward K+ current (I_ss) is characterized as a rapidly activating, very slowly inactivating current. The model contains both an activation variable (r_ss) and an inactivation variable (s_ss). However, in the mouse model, the inactivation variable has been removed, and the channel is only gated by rss.

I_kslow : This additional current arises in the mouse model as a result of experimental findings that the outward current of adult mouse ventricular myocytes have an incomplete inactivation phase characterized by a sum of a pedestal and two exponentials with a fast time constant similar to that of classic I_to and a slow time constant. It is believed that this additional current in mouse is a main factor contributing to the faster rate of repolarization seen in mouse compared to rats.

The complete original paper references are cited below:

A Mathematical Model of Action Potential Heterogeneity in Adult Rat Left Ventricular Myocytes, , Sandeep V. Pandit, Robert B. Clark, Wayne R. Giles and Semahat S. Demir, 2001, Biophysical Journal , 81, 3029-3051. (Original rat LV cell models Full text and PDF versions of the article are available for Journal Members on the Biophysical Journal website.) PubMed ID: 11720973

A Mathematical Model of the Electrophysiological Alterations in Rat Ventricular Myocytes in Type-I Diabetes, , Sandeep V. Pandit, Wayne R. Giles and Semahat S. Demir, 2003 Biophysical Journal , 84, 832 - 841. (Rat RV model Full text and PDF versions of the article are available for Journal Members on the Biophysical Journal website.) PubMed ID: 12547767

Electrical Activity in Murine Ventricular Myocytes: Simulation Studies. Chapter 5: Ionic Basis of Cardiac Repolarization in Mouse: Quantitative Insights. Sandeep V. Pandit, Ph.D. Thesis, University of Memphis, 2003. (A summary of the model formulation can be found in Appendix C: Model Formulation of the Adult Mouse Ventricular Myocytes, ).

An Integrative Model of Mouse Cardiac Electrophysiology from Cell to Torso, , Joseph V. Tranquillo, James Hlavacek, Craig S. Henriquez, 2005 Europace , 7,S56-S70. (This paper uses the Pandit mouse cellular model to simulate mouse cardiac electrophysiology on both cellular and torso levels Full text and PDF versions of the article are available for Journal Members on the Europace website.)PubMed Id: 16102504

The raw CellML description of the Pandit et al 2001 model of action potential heterogeneity in adult rat left ventricular myocytes can be downloaded in various formats as described in .

A fluid compartment model of the rat epicardial/endocardial ventricular cell.