INa and IKv4.3 heterogeneity in canine LV myocytes (Flaim et al 2006)

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Accession:83491
"The roles of sustained components of INa and IKv43 in shaping the action potentials (AP) of myocytes isolated from the canine left ventricle (LV) have not been studied in detail. Here we investigate the hypothesis that these two currents can contribute substantially to heterogeneity of early repolarization and arrhythmic risk.... The resulting simulations illustrate ways in which KChIP2- and Ca2+- dependent control of IKv43 can result in a sustained outward current that can neutralize INaL in a rate- and myocyte subtype-dependent manner. Both these currents appear to play significant roles in modulating AP duration and rate dependence in midmyocardial myocytes. ... By design, these models allow upward integration into organ models or may be used as a basis for further investigations into cellular heterogeneities." See paper for more and details.
Reference:
1 . Flaim SN, Giles WR, McCulloch AD (2006) Contributions of sustained INa and IKv43 to transmural heterogeneity of early repolarization and arrhythmogenesis in canine left ventricular myocytes. Am J Physiol Heart Circ Physiol 291:H2617-29 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Neuron or other electrically excitable cell; Electrogenic pump;
Brain Region(s)/Organism:
Cell Type(s): Heart cell; Cardiac ventricular cell;
Channel(s): I Na,t; I A; I K; Late Na; Na/Ca exchanger; I_Na,Ca; I_SERCA; Na/K pump;
Gap Junctions:
Receptor(s):
Gene(s): Kv4.3 KCND3;
Transmitter(s):
Simulation Environment: MATLAB;
Model Concept(s): Ion Channel Kinetics; Action Potentials; Heart disease; Sodium pump; Markov-type model;
Implementer(s): Flaim, Sarah [flaim at comlab.ox.ac.uk];
Search NeuronDB for information about:  I Na,t; I A; I K; Late Na; Na/Ca exchanger; I_Na,Ca; I_SERCA; Na/K pump;
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flaim_ajp
NewerICs
readme.txt
fcn_fgm.m
Script_FGM.m
                            
Readme for the model associated with the paper:

Flaim, Sarah N., Wayne R. Giles, and Andrew D. McCulloch.
Contributions of sustained INa and IKv43 to transmural
heterogeneity of early repolarization and arrhythmogenesis in canine
left ventricular myocytes. Am J Physiol Heart Circ Physiol
291: H2617-H2629, 2006. First published July 7, 2006;
doi:10.1152/ajpheart.00350.2006

Abstract:

The roles of sustained components of INa and IKv43 in shaping the
action potentials (AP) of myocytes isolated from the canine left
ventricle (LV) have not been studied in detail. Here we investigate
the hypothesis that these two currents can contribute substantially to
heterogeneity of early repolarization and arrhythmic
risk. Quantitative data from voltage clamp and expression profiling
experiments were used to complete meaningful modifications to an
existing "local control" model of canine midmyocardial myocyte
excitation-contraction coupling for epicardial and endocardial
cells. We include 1) heterogeneous IKv43, IKs, and ISERCA density; 2)
modulation of IKv43 by Kv channel interacting protein type 2 (KChIP2)
channel subunits; 3) a possible Ca2+ dependent open-state inactivation
of IKv43; and 4) a sustained component of the inward Na+ current,
INaL. The resulting simulations illustrate ways in which KChIP2- and
Ca2+- dependent control of IKv43 can result in a sustained outward
current that can neutralize INaL in a rate- and myocyte
subtype-dependent manner. Both these currents appear to play
significant roles in modulating AP duration and rate dependence in
midmyocardial myocytes. Furthermore, an increased ratio of IKv43 to
INaL is capable of protecting epicardial myocytes from the early
afterdepolarizations resulting from the SCN5A-I1768V mutation-induced
increase in INaL. Experimentally observed transmural differences in
Ca2+ handling, including greater sarcoplasmic reticulum Ca2+ content
and faster Ca2+ transient decay rates on the epicardium, were
recapitulated in our simulations. By design, these models allow upward
integration into organ models or may be used as a basis for further
investigations into cellular heterogeneities.

Usage:
1) Extract the archive into the work folder (e.g. c:\matlab7\work)
2) Add the dir to the path, for example
	addpath(path,'c:\matlab7\work\flaim\ajp')
3) Run the script
	Script_FGM
The program will run for about a minute and then produce a graph
of a train of action potentials.

These scripts were supplied by Dr Sarah Flaim.

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