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Single-cell APD restitution

Author: Jason Bayer jason.bayer@ihu-liryc.fr

Introduction

APD restitution is an important property of cardiac tissue. As pacing frequency is increased, APD shortens to maintain a one to one stimulus to response. For this tutorial, the user will be shown how to construct APD restitution curves to describe the repolarization properties of cardiac cells in response to various pacing protocols. For details see the APD restitution section in the manual.

Problem setup

Single-cell models

This tutorial uses the cardiac cell models in CARP''s LIMPET library and the single-cell tool bench. The single-cell model is a user input. To see a list of all available models, please type the following command.

bench
  --list-imps

Restitution protocols

Single-cell models are paced with 2-ms-long stimuli at twice capture amplitude with all restitution protocols. Restitutions protocols are designed to reveal different features of AP restitution. The S1S2 protocol illustrated in fig-apd-restitutions-S1S2-protocol is used to gauge the propensity towards developing an arrhythmia. The dynamic protocol rather reflects restitution for slower transitions between BCLs. For an S1S2 pacing protocol, the user sets the basic cycle length (BCL) and number of beats, nbeats, for the S1 pacing. Following S1 pacing, a single S2 beat is applied at a range of coupling intervals (CI) chosen by the user. The basics of the S1S2 protocol are illustrated in fig-apd-restitutions-S1S2-protocol.

When using a dynamic pacing protocol, the S1 cycle length is decremented sequentially and continuously after a user chosen number of beats, nbeats until the minimum CI of CI0 is reached. The protocol is graphically illustrated in `fig-apd_restitutions-dynamic-protocol.

Action potential duration

Activation potential duration is computed as the time it takes to reach 90% repolarization (\(APD_{90}\)) from the maximum action potential upstroke potential.

Usage

The following optional arguments are available (default values are indicated):

./run.py
  --help 

    --Protocol          Default:
  S1S2

                        Restitution protocol, either S1S2 or Dynamic

    --prebeats          Default:
  20

                        Number of pre-pacing beats for S1 pacing at BCL

    --inital            Initial
  state vector representing limit cycle for chosen BCL

    --nbeats            Default:
  10

                        Number of beats for S1 pacing at BCL

    --CI0               Default:
  50 ms

                        Shortest S2 coupling interval

    --CI1               Default:
  BCL

                        S1 cycle length and longest S2 coupling interval

    --CIinc             Default:
  25 ms

                        Decrement for time interval from CI1 to CI0

    --imp               Default:
  GTT2_fast

                        Single-cell model to use

    --params            Default:
  ' '

                        Parameters of single-cell model to modify

The run.py script formats these user inputs into the following file for an S1S2 pacing protocol using bench,

1             #
  protocol selection 1=S1S2 0=dynamic

  prebeats      #
  number of prepacing beats before starting protocol

  BCL           #
  basic cycle length

  CI1           #
  S2 prematurity start

  CI0           #
  S2 prematurity end

  nbeats        #
  number of beats preceding premature one

  CIinc         #
  decrement in S2 prematurity in ms

and the following for a dynamic pacing protocol,

0             #
  protocol selection 1=S1S2 0=dynamic

  prebeats      #
  number of prepacing beats before starting protocol

  BCL           #
  initial basic cycle length

  CI0           #
  final basic cycle length

  nbeats        #
  number of beats per basic cycle length

  CIinc         #
  decrement of bcl in ms

The script run.py then feeds these user input scripts to the function --restitute in bench. The results for DI and APD are output into the ASCII file restout_APD_restitution.dat in the corresponding output directory for the given input parameters. The format of this file is described in the CARP manual under section the describing the function --restitute in bench (3.1.2). The details of the file format are shown below.

Col
  1 #Beat         : Beat number of an AP

  Col
  2 Prematurity   : P (premature beat) or * (no prematurity)

  Col
  3 Steady State  : O (not in steady state), 1 (in steady
  state)

  Col
  4 APD           : Action potential duration

  Col
  5 DI(n)         : Diastolic interval of current beat

  Col
  6 DI(n-1)       : Diastolic interval of previous beat

  Col
  7 Triangulation : APD90-APD30

  Col
  8 Vm_min        : Minimum potential of current beat

  Col
  9 Vm_max        : Maximum potential of current beat

If run.py is ran with the --visualize option, the APD restitution curve (APD Col 4 vs. DI Col 6) in the output file will be plotted using pythons plotting functions.

Note, if the user input for CI0 is too small, you may need to trim the restout_APD_restitution.dat files after a loss of capture occurs. The visualization feature does not remove these values permanently from the output file.

Tasks

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

cd
  ${TUTORIALS}/01_EP_single_cell/02B_APD_restitution

1. Compare the restitution curves for two or more different ionic models. Examples are shown below.

./run.py
  --imp GTT2_fast --visualize

  

  ./run.py
  --imp COURTEMANCHE --visualize

  

  ./run.py
  --imp SHANNON --visualize

2. Using Table 2 from [Tusscher2006], generate a APD restitution curve for the parameter settings -params ''G_Kr=0.172,G_Ks=0.441,G_pCa=0.8666,G_pK=0.00219,G_tf=2'' and compute the maximum slope of the restitution curve. It should be well above 1.0 and look similar to Figure 5 in the Tusscher2006 paper.

./run.py
  --imp GTT2_fast --params G_Kr=0.172,G_Ks=0.441,G_pCa=0.8666,G_pK=0.00219,G_tf=2
  --visualize

3. Do the same as above in 2, but for the parameter settings -params ''G_Kr=0.134,G_Ks=0.270,G_pCa=0.0619,G_pK=0.0730,G_tf=0.6''. The maximum slope of the restitution curve should be well below 1.0, which promotes alternans and arrhythmogenesis.

./run.py
  --imp GTT2_fast --params G_Kr=0.134,G_Ks=0.270,G_pCa=0.0619,G_pK=0.0730,G_tf=0.6
  --visualize

Notes:

1. It could be useful in the future for Gernot to modify the --restitute option to determine CI0 internally rather than having the user determine it.
2. An adaptive decrement for S2 would be useful to better define the slope of the APD restitution curve. For example, it is small when APD does not change much to the next decrement, and is increased when APD does change above a certain threshold.
3. It would also maybe be useful to print out the Vm for each S1S2 coupling interval to better visualize the restitution behavior. The run.py currently uses the option --res-trace to output restout.txt, but the Vm in the file format is not well described in the carpmanual or bench documentation.
4. Lastly, you may need to adjust CI0 and CI1 to the bounds at which the chosen single-cell model was constrained to. The best thing to do is find an APD restitution protocol in the published manuscript for the model, then try to reproduce it.

References

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01_basic_bench 03A_voltage_clamp