Basic usage of single cell tool bench - Limit cycle experiments

Author: Gernot Plank gernot.plank@medunigraz.at

To run the experiments of this tutorial change directories as follows:

Modeling EP at the cellular level

This tutorial introduces the basic steps of setting up EP simulations in an isolated myocytes. A more detailed account on modeling EP at the cellular scale is given in the manual. For all experiments shown in this tutorial we use the single cell EP tool bench. Before starting we recommend therefore to look up the basic command line options in the bench section of the manual. In this introductory tutorial we focus on simple pacing protocols for finding a stable limit cycle. We model an isolated myocyte which we stimulate using an electrode for intracellular current injection. The setup is shown in fig-single-cell-EP.

Setup for single cell EP experiments. The myocyted is activated with a suprathreshold stimulus current to initiate action potentials at a pacing cycle lenght of 500 ms.
Setup for single cell EP experiments. The myocyted is activated with a suprathreshold stimulus current to initiate action potentials at a pacing cycle lenght of 500 ms.

Experimental Parameters

The following parameters are exposed to steer the experiment:

Each experiment stores the state of myocyte and myofilament in the current directory in a file to be used as initial state vector in subsequent experiments.

Limit cycle experiments

Background on the computaiton of limit cycles is found in the limit cycle section of the manual. Briefly, models of cellular dynamics are virtually never used with the values given for the initial state vector. Rather, cells are based to a given limit cycle to approximate the experimental conditions one is interested in. The state of the cell can be frozen at any given instant in time and this state can be reused then in subsequent simulations as initial state vector. In the following experiments the procedures for finding an initial state vector for a given model and a given basic cycle length are elucidated. To run the experiments of this tutorial change directories as follows:

To see all the exposed parameters itemized above in experimental parameters section.

run

Experiment exp01 (short pacing protocol)

We start with pacing the TT2 human myocycte model at a pacing cycle length of 500 ms for a duration of 5 seconds (5000 msecs).

You will get an overview of current traces of the model.

Experiment exp02 (limit cycle pacing protocol)

In experiment exp01 we observed that the state variables of the model did not stabilize at a stable limit cycle. We increase therefore the duration of our pacing protocol to 20 seconds (20000 msecs).

At the end of the pacing protocol the initial state vector is saved in the file exp02_TT2_bcl_500_ms_dur_20000_ms.sv.

Ionic model parameter modification experiments

Model behavior can be modified by providing parameter modification string through --imp-par. Modifications strings are of the following form:

where param is the name of the paramter one wants to modify such as, for instance, the peak conductivity of the sodium channel, GNa. Not all parameters of ionic models are exposed for modification, but a list of those which are can be retrieved for each model using imp-info. As an example, let's assume we are interested in specializing a generic human ventricular myocyte based on the ten Tusscher-Panfilov model to match the cellular dynamics of myocytes as they are found in the halo around an infract, i.e.in the peri-infarct zone (PZ). In the PZ various current are downregulated. Patch-clamp studies of cells harvested from the peri-infract zone have reported a 62% reduction in peak sodium current, 69% reduction in L-type calcium current and a reduction of 70% and 80% in potassium currents \(I_{\mathrm {Kr}}\) and \(I_{\mathrm K}\), respectively. In the model these modifcations are implemented by altering the peak conductivities of the respective currents as follows:

In this experiment EP model parameters strings can be passed in using the --EP-par which expects parameter strings as input. The results of such modifications are illustrated in the following experiments.

Experiment exp03 (short pacing with modified myocyte)

In this experiment we modify the behavior of a TT2 myocyte to match experimental observations of myocytes harvested from peri-infarct zones in humans. Initially, we simulated one cycle only to observe the effect of parameter modifications relative to the baseline TT2 model. The referece traces are passed in and you can compared the experiment output.

Make sure that the parameter modification string is correctly interpreted by bench by inspecting the output log:

Experiment exp04 (limit cycle pacing with modified myocyte)

We repeat exp03 as a limit cycle experiment now by pacing for 20 seconds (20000 msecs). State variable and current traces stored in the baseline experiment exp02 are used as a reference.

Visual comparison of the traces reveals that Calcium-cycling in the peri-infarct myocyte shows alternans. The difference in initial state vectors between baseline and peri-infarct myocyte stored at the end of the pacing protocol can be inspected with the meld or any other diff program of your choice.

Comparing initial state vectors of baseline and peri-infarct TT2 human ventricular myocyte model after 20 seconds of pacing at a basic cycle length of 500 ms.
Comparing initial state vectors of baseline and peri-infarct TT2 human ventricular myocyte model after 20 seconds of pacing at a basic cycle length of 500 ms.

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