Computer model of action potential of mouse ventricular myocytes

Abstract

We have developed a mathematical model of the mouse ventricular myocyte action potential (AP) from voltage-clamp data of the underlying currents and Ca2+ transients. Wherever possible, we used Markov models to represent the molecular structure and function of ion channels. The model includes detailed intracellular Ca2+ dynamics, with simulations of localized events such as sarcoplasmic Ca2+ release into a small intracellular volume bounded by the sarcolemma and sarcoplasmic reticulum. Transporter-mediated Ca2+ fluxes from the bulk cytosol are closely matched to the experimentally reported values and predict stimulation rate-dependent changes in Ca2+ transients. Our model reproduces the properties of cardiac myocytes from two different regions of the heart: the apex and the septum. The septum has a relatively prolonged AP, which reflects a relatively small contribution from the rapid transient outward K+ current in the septum. The attribution of putative molecular bases for several of the component currents enables our mouse model to be used to simulate the behavior of genetically modified transgenic mice.

Transient outward potassium current and Ca2+ homeostasis in the heart: beyond the action potential

“…Both experimental data and mathematical models have shown that I to magnitude and composition (i.e., the relative contributions of I to,f and I to,s to total I to ) may markedly affect AP duration and shape (7)(8)(9)(10)(11)(12)(13). Expression of I to,f and I to,s channel proteins is highly regulated, and may vary with species, developmental stage, and region of the heart (6,11).…”

Effects of the Transient Outward Potassium Current on Action Potential Upstroke Velocities Tested Using the Dynamic Clamp Technique

“…The Ito,f equations of Bondarenko et al [6] are based on experimental data obtained at room temperature and the Bondarenko et al AP model "is nominally adjusted for room temperature of 25°C" [6]. Fig.…”

“…Unfortunately, these divalent ions induce a positive shift in voltage dependence of Ito1. Accordingly, Bondarenko et al [6] have taken into account an ≈10 mV shift in their Ito,f equations. However, the shift in voltage dependence of Ito,f is not exactly known.…”

Cardiac cell modelling: Observations from the heart of the cardiac physiome project

“…Cardiac electrophysiology models often do not include tension development, but given that peak tension is reached during the decay phase of the calcium transient and that calcium buffering will have the greatest effect during peak calcium, the static unbinding rate of calcium could be approximated as ~100s -1 . This is not easily compatible with the routinely used values of 19.6s -1 (Bondarenko et al 2004, Mahajan et al 2008, Shannon et al 2000, 40s -1 (Iyer et al 2004, Pandit et al 2001) and 200s -1 (Noble et al 1998). …”

“…Right: Microelectrode recordings of canine Purkinje cells at a cycle length of 400 ms at a temperature of 37°C (black) and at a cycle length of 900 ms at a temperature of 25°C (red). At the lower temperature, action potentials prolong so dramatically that pacing at 400 ms no longer obtains a 1:1 response; in addition, pronounced alternans occurs at the relatively long cycle length of 900 ms. (Bondarenko et al 2004), canine (Hund and Rudy 2004) and guinea pig (Livshitz and Rudy 2007) cell cardiac cell models simulated under different conditions. All models solved to limit cycle in Cellular Open Resource (Garny et al 2003).…”