Updated Faber and Rudy 2000 model with a corrected description of T-type calcium current

Computational modeling of inhibition of voltage-gated Ca channels: identification of different effects on uterine and cardiac action potentials.

Model Status

In this version of the Faber and Rudy 2000 model of a mammalian ventricular cardiomyocyte, the ICaT is reformulated to describe the biophysical characteristics that are more commonly ascribed to this current. The CellML equations are validated using OpenCell and all units are consistent. The model can be run in both OpenCell (version 0.8) and OpenCOR (version 0.4) environments.

Model Structure

The original formulation of ICaT did not describe the current correctly so we replaced it with a new formulation. All the other model components, and the abstract below, remain the same as the original Faber and Rudy 2000 model.

ABSTRACT: Sodium overload of cardiac cells can accompany various pathologies and induce fatal cardiac arrhythmias. We investigate effects of elevated intracellular sodium on the cardiac action potential (AP) and on intracellular calcium using the Luo-Rudy model of a mammalian ventricular myocyte. The results are: 1) During rapid pacing, AP duration (APD) shortens in two phases, a rapid phase without Na(+) accumulation and a slower phase that depends on [Na(+)](i). 2) The rapid APD shortening is due to incomplete deactivation (accumulation) of I(Ks). 3) The slow phase is due to increased repolarizing currents I(NaK) and reverse-mode I(NaCa), secondary to elevated [Na(+)](i). 4) Na(+)-overload slows the rate of AP depolarization, allowing time for greater I(Ca(L)) activation; it also enhances reverse-mode I(NaCa). The resulting increased Ca(2+) influx triggers a greater [Ca(2+)](i) transient. 5) Reverse-mode I(NaCa) alone can trigger Ca(2+) release in a voltage and [Na(+)](i)-dependent manner. 6) During I(NaK) block, Na(+) and Ca(2+) accumulate and APD shortens due to enhanced reverse-mode I(NaCa); contribution of I(K(Na)) to APD shortening is negligible. By slowing AP depolarization (hence velocity) and shortening APD, Na(+)-overload acts to enhance inducibility of reentrant arrhythmias. Shortened APD with elevated [Ca(2+)](i) (secondary to Na(+)-overload) also predisposes the myocardium to arrhythmogenic delayed afterdepolarizations.

The references for the papers containing this information are cited below:

Computational modeling of inhibition of voltage-gated Ca channels: identification of different effects on uterine and cardiac action potentials. Wing-Chiu Tong, Iffath Ghouri and Michael J. Taggart, 2014, Frontiers in Physiology, 5, 399. PubMed ID: 25360118

Action potential and contractility changes in [Na(+)](i) overloaded cardiac myocytes: a simulation study, Gregory M. Faber and Yoram Rudy, 2000, Biophysical Journal, 78, 2392-2404. PubMed ID: 10777735

Comparison of the original Faber & Ruddy (2000) (panel A, left hand side) and the new Tong et. al. (2014) (panel A, right hand side) ICaT formulations: simulations of (A) current tracings at different voltage steps and (B) the corresponding I-V plot.

A schematic diagram of the Faber and Rudy 2000 cardiac myocyte model.