- Author:
- Hanne <Hanne@hanne-nielsens-macbook.local>
- Date:
- 2009-12-09 10:55:39+13:00
- Desc:
- added iamges in ai and svg ofrmat, removed non pub med references
- Permanent Source URI:
- https://models.cellml.org/workspace/iribe_kohl_noble_2006/rawfile/faa417bf6a55df07fd2265776a9dc76dd40ea94d/iribe_kohl_noble_2006.cellml
<?xml version="1.0"?>
<!--
This CellML file was generated on 27/11/2007 at 13:26:38 using:
COR (0.9.31.821)
Copyright 2002-2007 Dr Alan Garny
http://COR.physiol.ox.ac.uk/ - COR@physiol.ox.ac.uk
CellML 1.0 was used to generate this cellular model
http://www.CellML.org/
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<section id="sec_status">
<title>Model Status</title>
<para>
This model was created by Penny Noble of Oxford University. This file is known to run COR and OpenCell to reproduce the published results. The units have been checked and they are consistent.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
ABSTRACT: We hypothesize that slow inactivation of Ca2+/calmodulin-dependent kinase II (CaMKII) and its modulatory effect on sarcoplasmic reticulum (SR) Ca2+ handling are important for various interval-force (I-F) relations, in particular for the beat interval dependency in transient alternans during the decay of post-extrasystolic potentiation. We have developed a mathematical model of a single cardiomyocyte to integrate various I-F relations, including alternans, by incorporating a conceptual CaMKII kinetics model into the SR Ca2+ handling model. Our model integrates I-F relations, such as the beat interval-dependent twitch force duration, restitution and potentiation, positive staircase phenomenon and alternans. We found that CaMKII affects more or less all I-F relations, and it is a key factor for integration of the various I-F relations in our model. Alternans arises, in the model, out of a steep relation between SR Ca2+ load and release, owing to SR load-dependent changes in the releasability of Ca2+ via the ryanodine receptor. Beat interval-dependent CaMKII activity, owing to its kinetic properties and amplifying effect on SR Ca2+ load dependency of Ca2+ release, replicated the beat interval dependency of alternans, as observed experimentally. Additionally, our model enabled reproduction of the effects of various interventions on alternans, such as the slowing or accelerating of Ca2+ release and/or uptake. We conclude that a slow time-dependent factor, represented in the model by CaMKII, is important for the integration of I-F relations, including alternans, and that our model offers a useful tool for further analysis of the roles of integrative Ca2+ handling in myocardial I-F relations.
</para>
<para>The original paper reference is cited below:</para>
<para>Modulatory effect of calmodulin-dependent kinase II (CaMKII) on sarcoplasmic reticulum Ca2+ handling and interval-force relations: a modelling study, Gentaro Iribe, Peter Kohl and Denis Noble, 2006,
<emphasis>Philosophical Transactions of the Royal Society A</emphasis>, 364, (1842), 1107-1133. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16608699&query_hl=1&itool=pubmed_docsum">PubMed ID: 16608699</ulink>
</para>
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<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">50</cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>beta_x</ci>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_second">1.3</cn>
<apply>
<exp/>
<apply>
<times/>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_millivolt">0.06</cn>
</apply>
<apply>
<plus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">20</cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<exp/>
<apply>
<times/>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_millivolt">0.04</cn>
</apply>
<apply>
<plus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">20</cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>x</ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>alpha_x</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<ci>x</ci>
</apply>
</apply>
<apply>
<times/>
<ci>beta_x</ci>
<ci>x</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="time_independent_potassium_current">
<variable name="i_K1" public_interface="out" units="nanoA"/>
<variable initial_value="10" name="K_mk1" units="millimolar"/>
<variable initial_value="1" name="g_K1" units="microS"/>
<variable name="K_o" public_interface="in" units="millimolar"/>
<variable name="V" public_interface="in" units="millivolt"/>
<variable name="E_K" public_interface="in" units="millivolt"/>
<variable name="R" public_interface="in" units="millijoule_per_mole_kelvin"/>
<variable name="F" public_interface="in" units="coulomb_per_mole"/>
<variable name="T" public_interface="in" units="kelvin"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>i_K1</ci>
<apply>
<divide/>
<apply>
<times/>
<apply>
<divide/>
<apply>
<times/>
<ci>g_K1</ci>
<ci>K_o</ci>
</apply>
<apply>
<plus/>
<ci>K_o</ci>
<ci>K_mk1</ci>
</apply>
</apply>
<apply>
<minus/>
<ci>V</ci>
<ci>E_K</ci>
</apply>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<ci>F</ci>
<apply>
<minus/>
<apply>
<minus/>
<ci>V</ci>
<ci>E_K</ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">10</cn>
</apply>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="transient_outward_current">
<variable name="i_to" public_interface="out" units="nanoA"/>
<variable initial_value="0.005" name="g_to" units="microS"/>
<variable name="E_K" public_interface="in" units="millivolt"/>
<variable name="V" private_interface="out" public_interface="in" units="millivolt"/>
<variable name="s" private_interface="in" units="dimensionless"/>
<variable name="r" private_interface="in" units="dimensionless"/>
<variable name="time" private_interface="out" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>i_to</ci>
<apply>
<times/>
<ci>g_to</ci>
<ci>s</ci>
<ci>r</ci>
<apply>
<minus/>
<ci>V</ci>
<ci>E_K</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="transient_outward_current_s_gate">
<variable initial_value="0.95854" name="s" public_interface="out" units="dimensionless"/>
<variable name="alpha_s" units="per_second"/>
<variable name="beta_s" units="per_second"/>
<variable name="V" public_interface="in" units="millivolt"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>alpha_s</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_second">0.033</cn>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<minus/>
<ci>V</ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">17</cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>beta_s</ci>
<apply>
<divide/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_second">33</cn>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<exp/>
<apply>
<times/>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_millivolt">0.125</cn>
</apply>
<apply>
<plus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">10</cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>s</ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>alpha_s</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<ci>s</ci>
</apply>
</apply>
<apply>
<times/>
<ci>beta_s</ci>
<ci>s</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="transient_outward_current_r_gate">
<variable initial_value="1.5185e-8" name="r" public_interface="out" units="dimensionless"/>
<variable name="V" public_interface="in" units="millivolt"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>r</ci>
</apply>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_second">333</cn>
<apply>
<minus/>
<apply>
<divide/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<minus/>
<apply>
<plus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">4</cn>
</apply>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">5</cn>
</apply>
</apply>
</apply>
</apply>
<ci>r</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="L_type_Ca_channel">
<variable cmeta:id="L_type_Ca_channel_i_Ca_L" name="i_Ca_L" public_interface="out" units="nanoA"/>
<variable name="i_Ca_L_Na" public_interface="out" units="nanoA"/>
<variable name="i_Ca_L_K" public_interface="out" units="nanoA"/>
<variable name="i_Ca_L_Ca" public_interface="out" units="nanoA"/>
<variable initial_value="0.25" name="P_Ca_L_Ca" units="nanoA_per_millimolar"/>
<variable name="R" public_interface="in" units="millijoule_per_mole_kelvin"/>
<variable name="F" public_interface="in" units="coulomb_per_mole"/>
<variable name="T" public_interface="in" units="kelvin"/>
<variable name="V" private_interface="out" public_interface="in" units="millivolt"/>
<variable name="Ca_o" public_interface="in" units="millimolar"/>
<variable name="Ca_i" private_interface="out" public_interface="in" units="millimolar"/>
<variable name="K_o" public_interface="in" units="millimolar"/>
<variable name="K_i" public_interface="in" units="millimolar"/>
<variable name="Na_o" public_interface="in" units="millimolar"/>
<variable name="Na_i" public_interface="in" units="millimolar"/>
<variable name="d" private_interface="in" units="dimensionless"/>
<variable name="f" private_interface="in" units="dimensionless"/>
<variable name="time" private_interface="out" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>i_Ca_L_Ca</ci>
<apply>
<times/>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">4</cn>
<ci>d</ci>
<ci>f</ci>
<ci>P_Ca_L_Ca</ci>
<apply>
<minus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">50</cn>
</apply>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
</apply>
<apply>
<minus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">50</cn>
</apply>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>Ca_i</ci>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">100</cn>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<times/>
<ci>Ca_o</ci>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
</apply>
<apply>
<minus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">50</cn>
</apply>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>i_Ca_L_K</ci>
<apply>
<times/>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.002</cn>
<ci>d</ci>
<ci>f</ci>
<ci>P_Ca_L_Ca</ci>
<apply>
<minus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">50</cn>
</apply>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<minus/>
<apply>
<minus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">50</cn>
</apply>
</apply>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>K_i</ci>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">50</cn>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<times/>
<ci>K_o</ci>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<minus/>
<apply>
<minus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">50</cn>
</apply>
</apply>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>i_Ca_L_Na</ci>
<apply>
<times/>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.01</cn>
<ci>d</ci>
<ci>f</ci>
<ci>P_Ca_L_Ca</ci>
<apply>
<minus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">50</cn>
</apply>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<minus/>
<apply>
<minus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">50</cn>
</apply>
</apply>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>Na_i</ci>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">50</cn>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<times/>
<ci>Na_o</ci>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<minus/>
<apply>
<minus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">50</cn>
</apply>
</apply>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>i_Ca_L</ci>
<apply>
<plus/>
<ci>i_Ca_L_Ca</ci>
<ci>i_Ca_L_K</ci>
<ci>i_Ca_L_Na</ci>
</apply>
</apply>
</math>
</component>
<component name="L_type_Ca_channel_d_gate">
<variable initial_value="1.7908e-8" name="d" public_interface="out" units="dimensionless"/>
<variable name="alpha_d" units="per_second"/>
<variable name="beta_d" units="per_second"/>
<variable name="V" public_interface="in" units="millivolt"/>
<variable name="time" public_interface="in" units="second"/>
<variable name="E0_d" units="millivolt"/>
<variable initial_value="3" name="speed_d" units="dimensionless"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>E0_d</ci>
<apply>
<minus/>
<apply>
<plus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">24</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">5</cn>
</apply>
</apply>
<apply>
<eq/>
<ci>alpha_d</ci>
<piecewise>
<piece>
<apply>
<times/>
<ci>speed_d</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_second">120</cn>
</apply>
<apply>
<lt/>
<apply>
<abs/>
<ci>E0_d</ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">0.00001</cn>
</apply>
</piece>
<otherwise>
<apply>
<divide/>
<apply>
<times/>
<ci>speed_d</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_millivolt_second">30</cn>
<ci>E0_d</ci>
</apply>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<minus/>
<ci>E0_d</ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">4</cn>
</apply>
</apply>
</apply>
</apply>
</otherwise>
</piecewise>
</apply>
<apply>
<eq/>
<ci>beta_d</ci>
<piecewise>
<piece>
<apply>
<times/>
<ci>speed_d</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_second">120</cn>
</apply>
<apply>
<lt/>
<apply>
<abs/>
<ci>E0_d</ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">0.00001</cn>
</apply>
</piece>
<otherwise>
<apply>
<divide/>
<apply>
<times/>
<ci>speed_d</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_millivolt_second">12</cn>
</apply>
<ci>E0_d</ci>
</apply>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<exp/>
<apply>
<divide/>
<ci>E0_d</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">10</cn>
</apply>
</apply>
</apply>
</apply>
</otherwise>
</piecewise>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>d</ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>alpha_d</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<ci>d</ci>
</apply>
</apply>
<apply>
<times/>
<ci>beta_d</ci>
<ci>d</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="L_type_Ca_channel_f_gate">
<variable initial_value="1" name="f" public_interface="out" units="dimensionless"/>
<variable name="alpha_f" units="per_second"/>
<variable name="beta_f" units="per_second"/>
<variable name="V" public_interface="in" units="millivolt"/>
<variable initial_value="0.5" name="speed_f" units="dimensionless"/>
<variable name="E0_f" units="millivolt"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>E0_f</ci>
<apply>
<plus/>
<ci>V</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">34</cn>
</apply>
</apply>
<apply>
<eq/>
<ci>alpha_f</ci>
<piecewise>
<piece>
<apply>
<times/>
<ci>speed_f</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_second">25</cn>
</apply>
<apply>
<lt/>
<apply>
<abs/>
<ci>E0_f</ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">0.00001</cn>
</apply>
</piece>
<otherwise>
<apply>
<divide/>
<apply>
<times/>
<ci>speed_f</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_millivolt_second">6.25</cn>
<ci>E0_f</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
</apply>
<apply>
<exp/>
<apply>
<divide/>
<ci>E0_f</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">4</cn>
</apply>
</apply>
</apply>
</apply>
</otherwise>
</piecewise>
</apply>
<apply>
<eq/>
<ci>beta_f</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>speed_f</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_second">50</cn>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<minus/>
<ci>E0_f</ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millivolt">4</cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>f</ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>alpha_f</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<ci>f</ci>
</apply>
</apply>
<apply>
<times/>
<ci>beta_f</ci>
<ci>f</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="sodium_calcium_exchanger">
<variable name="i_NaCa" public_interface="out" units="nanoA"/>
<variable initial_value="0.0005" name="i_NaCa_max" units="nanoA_per_millimolar4"/>
<variable initial_value="0.5" name="gamma" units="dimensionless"/>
<variable name="Na_i" public_interface="in" units="millimolar"/>
<variable name="Na_o" public_interface="in" units="millimolar"/>
<variable name="Ca_i" public_interface="in" units="millimolar"/>
<variable name="Ca_o" public_interface="in" units="millimolar"/>
<variable name="R" public_interface="in" units="millijoule_per_mole_kelvin"/>
<variable name="F" public_interface="in" units="coulomb_per_mole"/>
<variable name="T" public_interface="in" units="kelvin"/>
<variable name="V" public_interface="in" units="millivolt"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>i_NaCa</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>i_NaCa_max</ci>
<apply>
<minus/>
<apply>
<times/>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<ci>gamma</ci>
<ci>V</ci>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
<apply>
<power/>
<ci>Na_i</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3</cn>
</apply>
<ci>Ca_o</ci>
</apply>
<apply>
<times/>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<minus/>
<ci>gamma</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
</apply>
<ci>V</ci>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
<apply>
<power/>
<ci>Na_o</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3</cn>
</apply>
<ci>Ca_i</ci>
</apply>
</apply>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<divide/>
<ci>Ca_i</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millimolar">0.0069</cn>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="sodium_potassium_pump">
<variable name="i_NaK" public_interface="out" units="nanoA"/>
<variable initial_value="1.36" name="i_NaK_max" units="nanoA"/>
<variable initial_value="1" name="K_mK" units="millimolar"/>
<variable initial_value="21.7" name="K_mNa" units="millimolar"/>
<variable name="K_o" public_interface="in" units="millimolar"/>
<variable name="Na_i" public_interface="in" units="millimolar"/>
<variable name="R" public_interface="in" units="millijoule_per_mole_kelvin"/>
<variable name="F" public_interface="in" units="coulomb_per_mole"/>
<variable name="T" public_interface="in" units="kelvin"/>
<variable name="V" private_interface="out" public_interface="in" units="millivolt"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>i_NaK</ci>
<apply>
<divide/>
<apply>
<times/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<divide/>
<apply>
<times/>
<ci>i_NaK_max</ci>
<ci>K_o</ci>
</apply>
<apply>
<plus/>
<ci>K_mK</ci>
<ci>K_o</ci>
</apply>
</apply>
<ci>Na_i</ci>
</apply>
<apply>
<plus/>
<ci>K_mNa</ci>
<ci>Na_i</ci>
</apply>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.1245</cn>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.1</cn>
</apply>
<ci>V</ci>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.0353</cn>
<apply>
<exp/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<minus/>
<ci>V</ci>
</apply>
<ci>F</ci>
</apply>
<apply>
<times/>
<ci>R</ci>
<ci>T</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="calcium_background_current">
<variable name="i_b_Ca" public_interface="out" units="nanoA"/>
<variable initial_value="0.00025" name="g_b_Ca" units="microS"/>
<variable name="E_Ca" public_interface="in" units="millivolt"/>
<variable name="V" public_interface="in" units="millivolt"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>i_b_Ca</ci>
<apply>
<times/>
<ci>g_b_Ca</ci>
<apply>
<minus/>
<ci>V</ci>
<ci>E_Ca</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="potassium_background_current">
<variable name="i_b_K" public_interface="out" units="nanoA"/>
<variable initial_value="0.0006" name="g_b_K" units="microS"/>
<variable name="E_K" public_interface="in" units="millivolt"/>
<variable name="V" public_interface="in" units="millivolt"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>i_b_K</ci>
<apply>
<times/>
<ci>g_b_K</ci>
<apply>
<minus/>
<ci>V</ci>
<ci>E_K</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="sodium_background_current">
<variable name="i_b_Na" public_interface="out" units="nanoA"/>
<variable initial_value="0.0006" name="g_b_Na" units="microS"/>
<variable name="E_Na" public_interface="in" units="millivolt"/>
<variable name="V" public_interface="in" units="millivolt"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>i_b_Na</ci>
<apply>
<times/>
<ci>g_b_Na</ci>
<apply>
<minus/>
<ci>V</ci>
<ci>E_Na</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="CaMKII_factor">
<variable initial_value="1.028" name="F_CaMK" public_interface="out" units="dimensionless"/>
<variable name="Inf_CaMK" units="dimensionless"/>
<variable initial_value="0.8" name="Tau_CaMK" units="second"/>
<variable name="Cmdn_Ca" public_interface="in" units="millimolar"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>Inf_CaMK</ci>
<apply>
<divide/>
<ci>Cmdn_Ca</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millimolar">0.00005</cn>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>F_CaMK</ci>
</apply>
<apply>
<divide/>
<apply>
<minus/>
<ci>Inf_CaMK</ci>
<ci>F_CaMK</ci>
</apply>
<ci>Tau_CaMK</ci>
</apply>
</apply>
</math>
</component>
<component name="RyR">
<variable name="j_rel" public_interface="out" units="millimolar_per_second"/>
<variable name="K_rel" units="per_second"/>
<variable name="F_rel" units="dimensionless"/>
<variable name="Ca_i" public_interface="in" units="millimolar"/>
<variable name="Ca_SR" public_interface="in" units="millimolar"/>
<variable name="i_Ca_L" public_interface="in" units="nanoA"/>
<variable name="F_CaMK" public_interface="in" units="dimensionless"/>
<variable initial_value="500" name="K_rel_max" units="per_second"/>
<variable initial_value="0.25089" name="F_SRCa_RyR" units="millimolar"/>
<variable initial_value="0.05" name="Tau_SRCa_RyR" units="second"/>
<variable name="N_CaMK" units="dimensionless"/>
<variable initial_value="1" name="gain_k1" units="dimensionless"/>
<variable initial_value="1" name="gain_k2" units="dimensionless"/>
<variable initial_value="1" name="gain_k3" units="dimensionless"/>
<variable initial_value="1" name="gain_k4" units="dimensionless"/>
<variable name="k_1" units="per_second"/>
<variable name="k_2" units="per_second"/>
<variable name="k_3" units="per_second"/>
<variable name="k_4" units="per_second"/>
<variable initial_value="0.5268" name="F_1" units="dimensionless"/>
<variable initial_value="8.7508e-6" name="F_2" units="dimensionless"/>
<variable name="F_3" units="dimensionless"/>
<variable name="time" public_interface="in" units="second"/>
<variable initial_value="0" name="K_leak_rate" units="per_second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>N_CaMK</ci>
<apply>
<power/>
<apply>
<divide/>
<ci>F_CaMK</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.7</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
</apply>
</apply>
<apply>
<eq/>
<ci>k_1</ci>
<apply>
<times/>
<ci>gain_k1</ci>
<apply>
<minus/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_millimolar2_per_second">30625000</cn>
<apply>
<power/>
<ci>Ca_i</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
</apply>
</apply>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_nanocoulomb">245</cn>
<ci>i_Ca_L</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>k_2</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>gain_k2</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_second">450</cn>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<divide/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millimolar">0.36</cn>
<ci>Ca_SR</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>k_3</ci>
<apply>
<times/>
<ci>gain_k3</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_second">1.885</cn>
<apply>
<power/>
<apply>
<divide/>
<ci>F_SRCa_RyR</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millimolar">0.22</cn>
</apply>
<ci>N_CaMK</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>k_4</ci>
<apply>
<times/>
<ci>gain_k4</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_second">1.8</cn>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>F_1</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<times/>
<ci>k_3</ci>
<ci>F_3</ci>
</apply>
<apply>
<times/>
<ci>k_4</ci>
<ci>F_1</ci>
</apply>
</apply>
<apply>
<times/>
<ci>k_1</ci>
<ci>F_1</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>F_2</ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>k_1</ci>
<ci>F_1</ci>
</apply>
<apply>
<times/>
<ci>k_2</ci>
<ci>F_2</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>F_3</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<plus/>
<ci>F_1</ci>
<ci>F_2</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>F_rel</ci>
<apply>
<power/>
<apply>
<divide/>
<ci>F_2</ci>
<apply>
<plus/>
<ci>F_2</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.25</cn>
</apply>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>F_SRCa_RyR</ci>
</apply>
<apply>
<divide/>
<apply>
<minus/>
<ci>Ca_SR</ci>
<ci>F_SRCa_RyR</ci>
</apply>
<ci>Tau_SRCa_RyR</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>K_rel</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>K_rel_max</ci>
<ci>F_SRCa_RyR</ci>
</apply>
<apply>
<plus/>
<ci>F_SRCa_RyR</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millimolar">0.2</cn>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>j_rel</ci>
<apply>
<times/>
<apply>
<plus/>
<apply>
<times/>
<ci>K_rel</ci>
<ci>F_rel</ci>
</apply>
<ci>K_leak_rate</ci>
</apply>
<apply>
<minus/>
<ci>Ca_SR</ci>
<ci>Ca_i</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="SERCA">
<variable name="j_up" public_interface="out" units="millimolar_per_second"/>
<variable name="F_CaMK" public_interface="in" units="dimensionless"/>
<variable initial_value="0.292" name="V_max_f" units="millimolar_per_second"/>
<variable initial_value="0.391" name="V_max_r" units="millimolar_per_second"/>
<variable name="f_b" units="dimensionless"/>
<variable name="r_b" units="dimensionless"/>
<variable name="Ca_i" public_interface="in" units="millimolar"/>
<variable name="Ca_SR" public_interface="in" units="millimolar"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>f_b</ci>
<apply>
<power/>
<apply>
<divide/>
<ci>Ca_i</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millimolar">0.00024</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
</apply>
</apply>
<apply>
<eq/>
<ci>r_b</ci>
<apply>
<power/>
<apply>
<divide/>
<ci>Ca_SR</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millimolar">1.64</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
</apply>
</apply>
<apply>
<eq/>
<ci>j_up</ci>
<apply>
<divide/>
<apply>
<minus/>
<apply>
<times/>
<ci>F_CaMK</ci>
<ci>V_max_f</ci>
<ci>f_b</ci>
</apply>
<apply>
<times/>
<ci>V_max_r</ci>
<ci>r_b</ci>
</apply>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<ci>f_b</ci>
<ci>r_b</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="calmodulin">
<variable initial_value="3.9636e-6" name="Cmdn_Ca" public_interface="out" units="millimolar"/>
<variable name="Ca_i" public_interface="in" units="millimolar"/>
<variable initial_value="0.02" name="Cmdn_tot" units="millimolar"/>
<variable initial_value="10000" name="alpha_cmdn" units="per_millimolar_per_second"/>
<variable initial_value="500" name="beta_cmdn" units="per_second"/>
<variable name="time" public_interface="in" units="second"/>
<variable name="dCmdn_Ca_dtime" public_interface="out" units="millimolar_per_second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>dCmdn_Ca_dtime</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>alpha_cmdn</ci>
<apply>
<minus/>
<ci>Cmdn_tot</ci>
<ci>Cmdn_Ca</ci>
</apply>
<ci>Ca_i</ci>
</apply>
<apply>
<times/>
<ci>beta_cmdn</ci>
<ci>Cmdn_Ca</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Cmdn_Ca</ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>alpha_cmdn</ci>
<apply>
<minus/>
<ci>Cmdn_tot</ci>
<ci>Cmdn_Ca</ci>
</apply>
<ci>Ca_i</ci>
</apply>
<apply>
<times/>
<ci>beta_cmdn</ci>
<ci>Cmdn_Ca</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="troponin">
<variable initial_value="2.7661e-4" name="Trpn_Ca" public_interface="out" units="millimolar"/>
<variable name="Ca_i" public_interface="in" units="millimolar"/>
<variable initial_value="0.07" name="Trpn_tot" public_interface="out" units="millimolar"/>
<variable initial_value="80000" name="alpha_trpn" public_interface="out" units="per_millimolar_per_second"/>
<variable initial_value="200" name="beta_trpn" public_interface="out" units="per_second"/>
<variable name="Force_norm" public_interface="in" units="dimensionless"/>
<variable name="time" public_interface="in" units="second"/>
<variable name="dTrpn_Ca_dtime" public_interface="out" units="millimolar_per_second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>dTrpn_Ca_dtime</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>alpha_trpn</ci>
<apply>
<minus/>
<ci>Trpn_tot</ci>
<ci>Trpn_Ca</ci>
</apply>
<ci>Ca_i</ci>
</apply>
<apply>
<times/>
<apply>
<divide/>
<apply>
<times/>
<ci>beta_trpn</ci>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<ci>Force_norm</ci>
</apply>
</apply>
</apply>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3</cn>
</apply>
<ci>Trpn_Ca</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Trpn_Ca</ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>alpha_trpn</ci>
<apply>
<minus/>
<ci>Trpn_tot</ci>
<ci>Trpn_Ca</ci>
</apply>
<ci>Ca_i</ci>
</apply>
<apply>
<times/>
<apply>
<divide/>
<apply>
<times/>
<ci>beta_trpn</ci>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<ci>Force_norm</ci>
</apply>
</apply>
</apply>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3</cn>
</apply>
<ci>Trpn_Ca</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="intracellular_calcium_concentration">
<variable initial_value="9.91e-6" name="Ca_i" public_interface="out" units="millimolar"/>
<variable name="i_Ca_L_Ca" public_interface="in" units="nanoA"/>
<variable name="i_b_Ca" public_interface="in" units="nanoA"/>
<variable name="i_NaCa" public_interface="in" units="nanoA"/>
<variable name="Cmdn_Ca" public_interface="in" units="millimolar"/>
<variable name="Trpn_Ca" public_interface="in" units="millimolar"/>
<variable name="j_rel" public_interface="in" units="millimolar_per_second"/>
<variable name="j_up" public_interface="in" units="millimolar_per_second"/>
<variable name="v_SR" public_interface="in" units="microlitre"/>
<variable name="v_i" public_interface="in" units="microlitre"/>
<variable name="F" public_interface="in" units="coulomb_per_mole"/>
<variable name="time" public_interface="in" units="second"/>
<variable name="dCmdn_Ca_dtime" public_interface="in" units="millimolar_per_second"/>
<variable name="dTrpn_Ca_dtime" public_interface="in" units="millimolar_per_second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Ca_i</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<plus/>
<ci>i_Ca_L_Ca</ci>
<ci>i_b_Ca</ci>
</apply>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<ci>i_NaCa</ci>
</apply>
</apply>
</apply>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<ci>v_i</ci>
<ci>F</ci>
</apply>
</apply>
<ci>j_up</ci>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>j_rel</ci>
<ci>v_SR</ci>
</apply>
<ci>v_i</ci>
</apply>
</apply>
<ci>dCmdn_Ca_dtime</ci>
</apply>
<ci>dTrpn_Ca_dtime</ci>
</apply>
</apply>
</math>
</component>
<component name="SR_calcium_concentration">
<variable initial_value="0.24886" name="Ca_SR" public_interface="out" units="millimolar"/>
<variable name="j_rel" public_interface="in" units="millimolar_per_second"/>
<variable name="j_up" public_interface="in" units="millimolar_per_second"/>
<variable name="v_SR" public_interface="in" units="microlitre"/>
<variable name="v_i" public_interface="in" units="microlitre"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Ca_SR</ci>
</apply>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<times/>
<ci>j_up</ci>
<ci>v_i</ci>
</apply>
<ci>v_SR</ci>
</apply>
<ci>j_rel</ci>
</apply>
</apply>
</math>
</component>
<component name="intracellular_sodium_concentration">
<variable initial_value="5.8041" name="Na_i" public_interface="out" units="millimolar"/>
<variable name="i_Na" public_interface="in" units="nanoA"/>
<variable name="i_b_Na" public_interface="in" units="nanoA"/>
<variable name="i_Ca_L_Na" public_interface="in" units="nanoA"/>
<variable name="i_NaCa" public_interface="in" units="nanoA"/>
<variable name="i_NaK" public_interface="in" units="nanoA"/>
<variable name="v_i" public_interface="in" units="microlitre"/>
<variable name="F" public_interface="in" units="coulomb_per_mole"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Na_i</ci>
</apply>
<apply>
<divide/>
<apply>
<minus/>
<apply>
<plus/>
<ci>i_Na</ci>
<ci>i_b_Na</ci>
<ci>i_Ca_L_Na</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3</cn>
<ci>i_NaCa</ci>
</apply>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3</cn>
<ci>i_NaK</ci>
</apply>
</apply>
</apply>
<apply>
<times/>
<ci>v_i</ci>
<ci>F</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="intracellular_potassium_concentration">
<variable initial_value="138.22" name="K_i" public_interface="out" units="millimolar"/>
<variable name="i_K1" public_interface="in" units="nanoA"/>
<variable name="i_K" public_interface="in" units="nanoA"/>
<variable name="i_to" public_interface="in" units="nanoA"/>
<variable name="i_b_K" public_interface="in" units="nanoA"/>
<variable name="i_Ca_L_K" public_interface="in" units="nanoA"/>
<variable name="i_NaK" public_interface="in" units="nanoA"/>
<variable name="v_i" public_interface="in" units="microlitre"/>
<variable name="F" public_interface="in" units="coulomb_per_mole"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>K_i</ci>
</apply>
<apply>
<divide/>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<plus/>
<ci>i_K1</ci>
<ci>i_K</ci>
<ci>i_to</ci>
<ci>i_b_K</ci>
<ci>i_Ca_L_K</ci>
</apply>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<ci>i_NaK</ci>
</apply>
</apply>
</apply>
<apply>
<times/>
<ci>v_i</ci>
<ci>F</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="Force">
<variable cmeta:id="Force_Force" name="Force" units="N_per_mm2"/>
<variable initial_value="0.1" name="zeta" units="N_per_mm2"/>
<variable name="Force_max" units="dimensionless"/>
<variable name="phi_SL" units="dimensionless"/>
<variable name="P_1_max" units="dimensionless"/>
<variable name="P_2_max" units="dimensionless"/>
<variable name="P_3_max" units="dimensionless"/>
<variable name="sigma_paths" units="dimensionless"/>
<variable initial_value="0.99917" name="N_0" units="dimensionless"/>
<variable initial_value="9.8593e-5" name="P_0" units="dimensionless"/>
<variable initial_value="1.3331e-4" name="P_1" units="dimensionless"/>
<variable initial_value="2.3505e-4" name="P_2" units="dimensionless"/>
<variable initial_value="1.5349e-4" name="P_3" units="dimensionless"/>
<variable name="N_1" units="dimensionless"/>
<variable name="alpha_tm" units="per_second"/>
<variable initial_value="40" name="beta_tm" units="per_second"/>
<variable name="K_tm" units="dimensionless"/>
<variable name="N_tm" units="dimensionless"/>
<variable initial_value="2.15" name="SL" units="micrometre"/>
<variable name="SL_norm" units="dimensionless"/>
<variable name="f_01" units="per_second"/>
<variable name="f_12" units="per_second"/>
<variable name="f_23" units="per_second"/>
<variable name="g_01" units="per_second"/>
<variable name="g_12" units="per_second"/>
<variable name="g_23" units="per_second"/>
<variable initial_value="10" name="f_XB" units="per_second"/>
<variable initial_value="30" name="g_XB" units="per_second"/>
<variable name="Trpn_Ca" public_interface="in" units="millimolar"/>
<variable name="Trpn_tot" public_interface="in" units="millimolar"/>
<variable name="alpha_trpn" public_interface="in" units="per_millimolar_per_second"/>
<variable name="beta_trpn" public_interface="in" units="per_second"/>
<variable name="Force_norm" public_interface="out" units="dimensionless"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>f_01</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3</cn>
<ci>f_XB</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>f_12</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">10</cn>
<ci>f_XB</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>f_23</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">7</cn>
<ci>f_XB</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>g_01</ci>
<apply>
<times/>
<ci>g_XB</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<ci>SL_norm</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>g_12</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<ci>g_XB</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<ci>SL_norm</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>g_23</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3</cn>
<ci>g_XB</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<ci>SL_norm</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>SL_norm</ci>
<apply>
<divide/>
<apply>
<minus/>
<ci>SL</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="micrometre">1.7</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="micrometre">0.7</cn>
</apply>
</apply>
<apply>
<eq/>
<ci>N_tm</ci>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3.5</cn>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2.5</cn>
<ci>SL_norm</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>K_tm</ci>
<apply>
<divide/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<divide/>
<apply>
<divide/>
<ci>beta_trpn</ci>
<ci>alpha_trpn</ci>
</apply>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millimolar">0.0017</cn>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="millimolar">0.0009</cn>
<ci>SL_norm</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>alpha_tm</ci>
<apply>
<times/>
<ci>beta_tm</ci>
<apply>
<power/>
<apply>
<divide/>
<ci>Trpn_Ca</ci>
<apply>
<times/>
<ci>Trpn_tot</ci>
<ci>K_tm</ci>
</apply>
</apply>
<ci>N_tm</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>N_0</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<times/>
<ci>beta_tm</ci>
<ci>P_0</ci>
</apply>
<apply>
<times/>
<ci>alpha_tm</ci>
<ci>N_0</ci>
</apply>
</apply>
<apply>
<times/>
<ci>g_01</ci>
<ci>N_1</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>P_0</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<apply>
<minus/>
<apply>
<plus/>
<ci>beta_tm</ci>
<ci>f_01</ci>
</apply>
</apply>
<ci>P_0</ci>
</apply>
<apply>
<times/>
<ci>alpha_tm</ci>
<ci>N_0</ci>
</apply>
<apply>
<times/>
<ci>g_01</ci>
<ci>P_1</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>P_1</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<apply>
<minus/>
<apply>
<plus/>
<ci>beta_tm</ci>
<ci>f_12</ci>
<ci>g_01</ci>
</apply>
</apply>
<ci>P_1</ci>
</apply>
<apply>
<times/>
<ci>alpha_tm</ci>
<ci>N_1</ci>
</apply>
<apply>
<times/>
<ci>f_01</ci>
<ci>P_0</ci>
</apply>
<apply>
<times/>
<ci>g_12</ci>
<ci>P_2</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>P_2</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<apply>
<minus/>
<apply>
<plus/>
<ci>f_23</ci>
<ci>g_12</ci>
</apply>
</apply>
<ci>P_2</ci>
</apply>
<apply>
<times/>
<ci>f_12</ci>
<ci>P_1</ci>
</apply>
<apply>
<times/>
<ci>g_23</ci>
<ci>P_3</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>P_3</ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<apply>
<minus/>
<ci>g_23</ci>
</apply>
<ci>P_3</ci>
</apply>
<apply>
<times/>
<ci>f_23</ci>
<ci>P_2</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>N_1</ci>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<plus/>
<ci>N_0</ci>
<ci>P_0</ci>
<ci>P_1</ci>
<ci>P_2</ci>
<ci>P_3</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>sigma_paths</ci>
<apply>
<plus/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>g_XB</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">2</cn>
<ci>g_XB</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">3</cn>
<ci>g_XB</ci>
</apply>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>f_01</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">2</cn>
<ci>g_XB</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">3</cn>
<ci>g_XB</ci>
</apply>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>f_01</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>f_12</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">3</cn>
<ci>g_XB</ci>
</apply>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>f_01</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>f_12</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>f_23</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>P_1_max</ci>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>f_01</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">2</cn>
<ci>g_XB</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">3</cn>
<ci>g_XB</ci>
</apply>
<ci>sigma_paths</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>P_2_max</ci>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>f_01</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>f_12</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">3</cn>
<ci>g_XB</ci>
</apply>
<ci>sigma_paths</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>P_3_max</ci>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>f_01</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>f_12</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">1</cn>
<ci>f_23</ci>
</apply>
<ci>sigma_paths</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>Force_max</ci>
<apply>
<plus/>
<ci>P_1_max</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<ci>P_2_max</ci>
</apply>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3</cn>
<ci>P_3_max</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>phi_SL</ci>
<piecewise>
<piece>
<apply>
<divide/>
<apply>
<minus/>
<ci>SL</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="micrometre">0.6</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="micrometre">1.4</cn>
</apply>
<apply>
<and/>
<apply>
<geq/>
<ci>SL</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="micrometre">1.7</cn>
</apply>
<apply>
<leq/>
<ci>SL</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="micrometre">2</cn>
</apply>
</apply>
</piece>
<piece>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<and/>
<apply>
<gt/>
<ci>SL</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="micrometre">2</cn>
</apply>
<apply>
<leq/>
<ci>SL</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="micrometre">2.2</cn>
</apply>
</apply>
</piece>
<piece>
<apply>
<divide/>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="micrometre">3.6</cn>
<ci>SL</ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="micrometre">1.4</cn>
</apply>
<apply>
<and/>
<apply>
<gt/>
<ci>SL</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="micrometre">2.2</cn>
</apply>
<apply>
<leq/>
<ci>SL</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="micrometre">2.3</cn>
</apply>
</apply>
</piece>
</piecewise>
</apply>
<apply>
<eq/>
<ci>Force_norm</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>phi_SL</ci>
<apply>
<plus/>
<ci>P_1</ci>
<ci>N_1</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2</cn>
<ci>P_2</ci>
</apply>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3</cn>
<ci>P_3</ci>
</apply>
</apply>
</apply>
<ci>Force_max</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>Force</ci>
<apply>
<times/>
<ci>zeta</ci>
<ci>Force_norm</ci>
</apply>
</apply>
</math>
</component>
<group>
<relationship_ref relationship="containment"/>
<component_ref component="Force">
<component_ref component="troponin"/>
</component_ref>
<component_ref component="CaMKII_factor">
<component_ref component="membrane_potential"/>
<component_ref component="RyR"/>
<component_ref component="SERCA"/>
</component_ref>
<component_ref component="intracellular_calcium_concentration">
<component_ref component="SR_calcium_concentration"/>
<component_ref component="intracellular_sodium_concentration"/>
<component_ref component="intracellular_potassium_concentration"/>
<component_ref component="calmodulin"/>
</component_ref>
<component_ref component="L_type_Ca_channel">
<component_ref component="L_type_Ca_channel_d_gate"/>
<component_ref component="L_type_Ca_channel_f_gate"/>
</component_ref>
<component_ref component="fast_sodium_current">
<component_ref component="fast_sodium_current_m_gate"/>
<component_ref component="fast_sodium_current_h_gate"/>
</component_ref>
<component_ref component="time_dependent_rectifier_potassium_current">
<component_ref component="time_dependent_rectifier_potassium_current_x_gate"/>
</component_ref>
<component_ref component="transient_outward_current">
<component_ref component="transient_outward_current_s_gate"/>
<component_ref component="transient_outward_current_r_gate"/>
</component_ref>
<component_ref component="sodium_background_current">
<component_ref component="calcium_background_current"/>
<component_ref component="potassium_background_current"/>
</component_ref>
</group>
<group>
<relationship_ref relationship="encapsulation"/>
<component_ref component="fast_sodium_current">
<component_ref component="fast_sodium_current_m_gate"/>
<component_ref component="fast_sodium_current_h_gate"/>
</component_ref>
<component_ref component="time_dependent_rectifier_potassium_current">
<component_ref component="time_dependent_rectifier_potassium_current_x_gate"/>
</component_ref>
<component_ref component="transient_outward_current">
<component_ref component="transient_outward_current_s_gate"/>
<component_ref component="transient_outward_current_r_gate"/>
</component_ref>
<component_ref component="L_type_Ca_channel">
<component_ref component="L_type_Ca_channel_d_gate"/>
<component_ref component="L_type_Ca_channel_f_gate"/>
</component_ref>
</group>
<connection>
<map_components component_1="environment" component_2="membrane_potential"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="fast_sodium_current"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="time_dependent_rectifier_potassium_current"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="transient_outward_current"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="L_type_Ca_channel"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="CaMKII_factor"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="RyR"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="calmodulin"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="troponin"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="intracellular_calcium_concentration"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="SR_calcium_concentration"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="intracellular_sodium_concentration"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="intracellular_potassium_concentration"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="Force"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="cell_parameters" component_2="membrane_potential"/>
<map_variables variable_1="Cm" variable_2="Cm"/>
</connection>
<connection>
<map_components component_1="cell_parameters" component_2="reversal_potentials"/>
<map_variables variable_1="R" variable_2="R"/>
<map_variables variable_1="T" variable_2="T"/>
<map_variables variable_1="F" variable_2="F"/>
<map_variables variable_1="Na_o" variable_2="Na_o"/>
<map_variables variable_1="K_o" variable_2="K_o"/>
<map_variables variable_1="Ca_o" variable_2="Ca_o"/>
</connection>
<connection>
<map_components component_1="cell_parameters" component_2="time_dependent_rectifier_potassium_current"/>
<map_variables variable_1="R" variable_2="R"/>
<map_variables variable_1="T" variable_2="T"/>
<map_variables variable_1="F" variable_2="F"/>
<map_variables variable_1="K_o" variable_2="K_o"/>
</connection>
<connection>
<map_components component_1="cell_parameters" component_2="time_independent_potassium_current"/>
<map_variables variable_1="R" variable_2="R"/>
<map_variables variable_1="T" variable_2="T"/>
<map_variables variable_1="F" variable_2="F"/>
<map_variables variable_1="K_o" variable_2="K_o"/>
</connection>
<connection>
<map_components component_1="cell_parameters" component_2="L_type_Ca_channel"/>
<map_variables variable_1="R" variable_2="R"/>
<map_variables variable_1="T" variable_2="T"/>
<map_variables variable_1="F" variable_2="F"/>
<map_variables variable_1="Na_o" variable_2="Na_o"/>
<map_variables variable_1="K_o" variable_2="K_o"/>
<map_variables variable_1="Ca_o" variable_2="Ca_o"/>
</connection>
<connection>
<map_components component_1="cell_parameters" component_2="sodium_calcium_exchanger"/>
<map_variables variable_1="R" variable_2="R"/>
<map_variables variable_1="T" variable_2="T"/>
<map_variables variable_1="F" variable_2="F"/>
<map_variables variable_1="Na_o" variable_2="Na_o"/>
<map_variables variable_1="Ca_o" variable_2="Ca_o"/>
</connection>
<connection>
<map_components component_1="cell_parameters" component_2="sodium_potassium_pump"/>
<map_variables variable_1="R" variable_2="R"/>
<map_variables variable_1="T" variable_2="T"/>
<map_variables variable_1="F" variable_2="F"/>
<map_variables variable_1="K_o" variable_2="K_o"/>
</connection>
<connection>
<map_components component_1="cell_parameters" component_2="intracellular_calcium_concentration"/>
<map_variables variable_1="F" variable_2="F"/>
<map_variables variable_1="v_SR" variable_2="v_SR"/>
<map_variables variable_1="v_i" variable_2="v_i"/>
</connection>
<connection>
<map_components component_1="cell_parameters" component_2="SR_calcium_concentration"/>
<map_variables variable_1="v_SR" variable_2="v_SR"/>
<map_variables variable_1="v_i" variable_2="v_i"/>
</connection>
<connection>
<map_components component_1="cell_parameters" component_2="intracellular_sodium_concentration"/>
<map_variables variable_1="F" variable_2="F"/>
<map_variables variable_1="v_i" variable_2="v_i"/>
</connection>
<connection>
<map_components component_1="cell_parameters" component_2="intracellular_potassium_concentration"/>
<map_variables variable_1="F" variable_2="F"/>
<map_variables variable_1="v_i" variable_2="v_i"/>
</connection>
<connection>
<map_components component_1="membrane_potential" component_2="fast_sodium_current"/>
<map_variables variable_1="V" variable_2="V"/>
<map_variables variable_1="i_Na" variable_2="i_Na"/>
</connection>
<connection>
<map_components component_1="membrane_potential" component_2="time_dependent_rectifier_potassium_current"/>
<map_variables variable_1="V" variable_2="V"/>
<map_variables variable_1="i_K" variable_2="i_K"/>
</connection>
<connection>
<map_components component_1="membrane_potential" component_2="time_independent_potassium_current"/>
<map_variables variable_1="V" variable_2="V"/>
<map_variables variable_1="i_K1" variable_2="i_K1"/>
</connection>
<connection>
<map_components component_1="membrane_potential" component_2="transient_outward_current"/>
<map_variables variable_1="V" variable_2="V"/>
<map_variables variable_1="i_to" variable_2="i_to"/>
</connection>
<connection>
<map_components component_1="membrane_potential" component_2="L_type_Ca_channel"/>
<map_variables variable_1="V" variable_2="V"/>
<map_variables variable_1="i_Ca_L" variable_2="i_Ca_L"/>
</connection>
<connection>
<map_components component_1="membrane_potential" component_2="sodium_calcium_exchanger"/>
<map_variables variable_1="V" variable_2="V"/>
<map_variables variable_1="i_NaCa" variable_2="i_NaCa"/>
</connection>
<connection>
<map_components component_1="membrane_potential" component_2="sodium_potassium_pump"/>
<map_variables variable_1="V" variable_2="V"/>
<map_variables variable_1="i_NaK" variable_2="i_NaK"/>
</connection>
<connection>
<map_components component_1="membrane_potential" component_2="calcium_background_current"/>
<map_variables variable_1="V" variable_2="V"/>
<map_variables variable_1="i_b_Ca" variable_2="i_b_Ca"/>
</connection>
<connection>
<map_components component_1="membrane_potential" component_2="potassium_background_current"/>
<map_variables variable_1="V" variable_2="V"/>
<map_variables variable_1="i_b_K" variable_2="i_b_K"/>
</connection>
<connection>
<map_components component_1="membrane_potential" component_2="sodium_background_current"/>
<map_variables variable_1="V" variable_2="V"/>
<map_variables variable_1="i_b_Na" variable_2="i_b_Na"/>
</connection>
<connection>
<map_components component_1="reversal_potentials" component_2="fast_sodium_current"/>
<map_variables variable_1="E_mh" variable_2="E_mh"/>
</connection>
<connection>
<map_components component_1="reversal_potentials" component_2="time_independent_potassium_current"/>
<map_variables variable_1="E_K" variable_2="E_K"/>
</connection>
<connection>
<map_components component_1="reversal_potentials" component_2="transient_outward_current"/>
<map_variables variable_1="E_K" variable_2="E_K"/>
</connection>
<connection>
<map_components component_1="reversal_potentials" component_2="calcium_background_current"/>
<map_variables variable_1="E_Ca" variable_2="E_Ca"/>
</connection>
<connection>
<map_components component_1="reversal_potentials" component_2="potassium_background_current"/>
<map_variables variable_1="E_K" variable_2="E_K"/>
</connection>
<connection>
<map_components component_1="reversal_potentials" component_2="sodium_background_current"/>
<map_variables variable_1="E_Na" variable_2="E_Na"/>
</connection>
<connection>
<map_components component_1="reversal_potentials" component_2="intracellular_potassium_concentration"/>
<map_variables variable_1="K_i" variable_2="K_i"/>
</connection>
<connection>
<map_components component_1="reversal_potentials" component_2="intracellular_sodium_concentration"/>
<map_variables variable_1="Na_i" variable_2="Na_i"/>
</connection>
<connection>
<map_components component_1="reversal_potentials" component_2="intracellular_calcium_concentration"/>
<map_variables variable_1="Ca_i" variable_2="Ca_i"/>
</connection>
<connection>
<map_components component_1="fast_sodium_current" component_2="intracellular_sodium_concentration"/>
<map_variables variable_1="i_Na" variable_2="i_Na"/>
</connection>
<connection>
<map_components component_1="fast_sodium_current" component_2="fast_sodium_current_m_gate"/>
<map_variables variable_1="m" variable_2="m"/>
<map_variables variable_1="time" variable_2="time"/>
<map_variables variable_1="V" variable_2="V"/>
</connection>
<connection>
<map_components component_1="fast_sodium_current" component_2="fast_sodium_current_h_gate"/>
<map_variables variable_1="h" variable_2="h"/>
<map_variables variable_1="time" variable_2="time"/>
<map_variables variable_1="V" variable_2="V"/>
</connection>
<connection>
<map_components component_1="time_dependent_rectifier_potassium_current" component_2="intracellular_potassium_concentration"/>
<map_variables variable_1="i_K" variable_2="i_K"/>
<map_variables variable_1="K_i" variable_2="K_i"/>
</connection>
<connection>
<map_components component_1="time_dependent_rectifier_potassium_current" component_2="time_dependent_rectifier_potassium_current_x_gate"/>
<map_variables variable_1="x" variable_2="x"/>
<map_variables variable_1="time" variable_2="time"/>
<map_variables variable_1="V" variable_2="V"/>
</connection>
<connection>
<map_components component_1="time_independent_potassium_current" component_2="intracellular_potassium_concentration"/>
<map_variables variable_1="i_K1" variable_2="i_K1"/>
</connection>
<connection>
<map_components component_1="transient_outward_current" component_2="intracellular_potassium_concentration"/>
<map_variables variable_1="i_to" variable_2="i_to"/>
</connection>
<connection>
<map_components component_1="transient_outward_current" component_2="transient_outward_current_s_gate"/>
<map_variables variable_1="s" variable_2="s"/>
<map_variables variable_1="time" variable_2="time"/>
<map_variables variable_1="V" variable_2="V"/>
</connection>
<connection>
<map_components component_1="transient_outward_current" component_2="transient_outward_current_r_gate"/>
<map_variables variable_1="r" variable_2="r"/>
<map_variables variable_1="time" variable_2="time"/>
<map_variables variable_1="V" variable_2="V"/>
</connection>
<connection>
<map_components component_1="L_type_Ca_channel" component_2="intracellular_calcium_concentration"/>
<map_variables variable_1="Ca_i" variable_2="Ca_i"/>
<map_variables variable_1="i_Ca_L_Ca" variable_2="i_Ca_L_Ca"/>
</connection>
<connection>
<map_components component_1="L_type_Ca_channel" component_2="intracellular_potassium_concentration"/>
<map_variables variable_1="K_i" variable_2="K_i"/>
<map_variables variable_1="i_Ca_L_K" variable_2="i_Ca_L_K"/>
</connection>
<connection>
<map_components component_1="L_type_Ca_channel" component_2="intracellular_sodium_concentration"/>
<map_variables variable_1="Na_i" variable_2="Na_i"/>
<map_variables variable_1="i_Ca_L_Na" variable_2="i_Ca_L_Na"/>
</connection>
<connection>
<map_components component_1="L_type_Ca_channel" component_2="RyR"/>
<map_variables variable_1="i_Ca_L" variable_2="i_Ca_L"/>
</connection>
<connection>
<map_components component_1="L_type_Ca_channel" component_2="L_type_Ca_channel_d_gate"/>
<map_variables variable_1="d" variable_2="d"/>
<map_variables variable_1="time" variable_2="time"/>
<map_variables variable_1="V" variable_2="V"/>
</connection>
<connection>
<map_components component_1="L_type_Ca_channel" component_2="L_type_Ca_channel_f_gate"/>
<map_variables variable_1="f" variable_2="f"/>
<map_variables variable_1="time" variable_2="time"/>
<map_variables variable_1="V" variable_2="V"/>
</connection>
<connection>
<map_components component_1="sodium_calcium_exchanger" component_2="intracellular_sodium_concentration"/>
<map_variables variable_1="Na_i" variable_2="Na_i"/>
<map_variables variable_1="i_NaCa" variable_2="i_NaCa"/>
</connection>
<connection>
<map_components component_1="sodium_calcium_exchanger" component_2="intracellular_calcium_concentration"/>
<map_variables variable_1="Ca_i" variable_2="Ca_i"/>
<map_variables variable_1="i_NaCa" variable_2="i_NaCa"/>
</connection>
<connection>
<map_components component_1="sodium_potassium_pump" component_2="intracellular_sodium_concentration"/>
<map_variables variable_1="Na_i" variable_2="Na_i"/>
<map_variables variable_1="i_NaK" variable_2="i_NaK"/>
</connection>
<connection>
<map_components component_1="sodium_potassium_pump" component_2="intracellular_potassium_concentration"/>
<map_variables variable_1="i_NaK" variable_2="i_NaK"/>
</connection>
<connection>
<map_components component_1="calcium_background_current" component_2="intracellular_calcium_concentration"/>
<map_variables variable_1="i_b_Ca" variable_2="i_b_Ca"/>
</connection>
<connection>
<map_components component_1="potassium_background_current" component_2="intracellular_potassium_concentration"/>
<map_variables variable_1="i_b_K" variable_2="i_b_K"/>
</connection>
<connection>
<map_components component_1="sodium_background_current" component_2="intracellular_sodium_concentration"/>
<map_variables variable_1="i_b_Na" variable_2="i_b_Na"/>
</connection>
<connection>
<map_components component_1="CaMKII_factor" component_2="calmodulin"/>
<map_variables variable_1="Cmdn_Ca" variable_2="Cmdn_Ca"/>
</connection>
<connection>
<map_components component_1="CaMKII_factor" component_2="RyR"/>
<map_variables variable_1="F_CaMK" variable_2="F_CaMK"/>
</connection>
<connection>
<map_components component_1="CaMKII_factor" component_2="SERCA"/>
<map_variables variable_1="F_CaMK" variable_2="F_CaMK"/>
</connection>
<connection>
<map_components component_1="RyR" component_2="intracellular_calcium_concentration"/>
<map_variables variable_1="Ca_i" variable_2="Ca_i"/>
<map_variables variable_1="j_rel" variable_2="j_rel"/>
</connection>
<connection>
<map_components component_1="RyR" component_2="SR_calcium_concentration"/>
<map_variables variable_1="Ca_SR" variable_2="Ca_SR"/>
<map_variables variable_1="j_rel" variable_2="j_rel"/>
</connection>
<connection>
<map_components component_1="SERCA" component_2="intracellular_calcium_concentration"/>
<map_variables variable_1="Ca_i" variable_2="Ca_i"/>
<map_variables variable_1="j_up" variable_2="j_up"/>
</connection>
<connection>
<map_components component_1="SERCA" component_2="SR_calcium_concentration"/>
<map_variables variable_1="Ca_SR" variable_2="Ca_SR"/>
<map_variables variable_1="j_up" variable_2="j_up"/>
</connection>
<connection>
<map_components component_1="calmodulin" component_2="intracellular_calcium_concentration"/>
<map_variables variable_1="Ca_i" variable_2="Ca_i"/>
<map_variables variable_1="Cmdn_Ca" variable_2="Cmdn_Ca"/>
<map_variables variable_1="dCmdn_Ca_dtime" variable_2="dCmdn_Ca_dtime"/>
</connection>
<connection>
<map_components component_1="troponin" component_2="intracellular_calcium_concentration"/>
<map_variables variable_1="Ca_i" variable_2="Ca_i"/>
<map_variables variable_1="Trpn_Ca" variable_2="Trpn_Ca"/>
<map_variables variable_1="dTrpn_Ca_dtime" variable_2="dTrpn_Ca_dtime"/>
</connection>
<connection>
<map_components component_1="troponin" component_2="Force"/>
<map_variables variable_1="Trpn_Ca" variable_2="Trpn_Ca"/>
<map_variables variable_1="Trpn_tot" variable_2="Trpn_tot"/>
<map_variables variable_1="alpha_trpn" variable_2="alpha_trpn"/>
<map_variables variable_1="beta_trpn" variable_2="beta_trpn"/>
<map_variables variable_1="Force_norm" variable_2="Force_norm"/>
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<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"><rdf:Description rdf:nodeID="n1"><maximumStepSize xmlns="http://www.cellml.org/metadata/simulation/1.0#" xml:lang="en">0.1</maximumStepSize><pointDensity xmlns="http://www.cellml.org/metadata/simulation/1.0#nonstandard-" xml:lang="en">1000</pointDensity><endingValue xmlns="http://www.cellml.org/metadata/simulation/1.0#" xml:lang="en">1</endingValue></rdf:Description><rdf:Description rdf:about="rdf:#04f8d57c-80dd-4af3-9af0-d2ca845b9aaa"><ORG xmlns="http://www.w3.org/2001/vcard-rdf/3.0#"><rdf:Description rdf:about="rdf:#826ed13e-3a92-49aa-a5be-6cef1d7bb8d6"/></ORG><N xmlns="http://www.w3.org/2001/vcard-rdf/3.0#"><rdf:Description rdf:about="rdf:#90981391-436d-418e-8852-b859fd0ff88f"/></N><EMAIL xmlns="http://www.w3.org/2001/vcard-rdf/3.0#"><rdf:Description rdf:about="rdf:#168f95b1-c557-4910-86ea-13b1d022084e"/></EMAIL></rdf:Description><rdf:Description rdf:about="rdf:#5b6136a0-50ec-442f-9953-de1bc5a21b05"><title xmlns="http://purl.org/dc/elements/1.1/" xml:lang="en">Philos Transact A Math Phys Eng Sci</title></rdf:Description><rdf:Description rdf:about="rdf:#71d66a3a-219d-4543-aa4a-b38f63d3f3e0"><cmeta:modifier><rdf:Description rdf:about="rdf:#a90f9cc9-eb2f-4842-9959-e80930fcba04"/></cmeta:modifier><rdf:value xml:lang="en">Curation of units and fixed a couple of errors.</rdf:value><modified xmlns="http://purl.org/dc/terms/"><rdf:Description rdf:about="rdf:#122b7ea1-1a96-4d42-b2e3-ad95d0ca91fb"/></modified></rdf:Description><rdf:Description rdf:about="rdf:#7730ac84-575e-4aa6-88d6-6a2ba642875b"><Given xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Peter</Given><Family xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Kohl</Family></rdf:Description><rdf:Description rdf:about="rdf:#122b7ea1-1a96-4d42-b2e3-ad95d0ca91fb"><W3CDTF xmlns="http://purl.org/dc/terms/" xml:lang="en">2008-05-08T04:13:19+12:00</W3CDTF></rdf:Description><rdf:Description rdf:about="rdf:#168f95b1-c557-4910-86ea-13b1d022084e"><rdf:type><rdf:Description rdf:about="http://imc.org/vCard/3.0#internet"/></rdf:type><rdf:value xml:lang="en">penny.noble@dpag.ox.ac.uk</rdf:value></rdf:Description><rdf:Description rdf:nodeID="n2"><boundIntervals xmlns="http://www.cellml.org/metadata/simulation/1.0#"><rdf:Description rdf:nodeID="n3"/></boundIntervals></rdf:Description><rdf:Description rdf:about="rdf:#826ed13e-3a92-49aa-a5be-6cef1d7bb8d6"><Orgunit xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en"></Orgunit><Orgname xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">University of Oxford</Orgname></rdf:Description><rdf:Description rdf:about="rdf:#e4675846-84f5-4f18-85f1-58aacc0ddaf6"><Given xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Denis</Given><Family xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Noble</Family></rdf:Description><rdf:Description rdf:nodeID="n3"><rdf:first><rdf:Description rdf:nodeID="n1"/></rdf:first><rdf:rest><rdf:Description rdf:about="http://www.w3.org/1999/02/22-rdf-syntax-ns#nil"/></rdf:rest></rdf:Description><rdf:Description rdf:about="rdf:#7d6d355d-e937-4463-9470-65ed8e2b346c"><rdf:type><rdf:Description rdf:about="http://www.cellml.org/bqs/1.0#Person"/></rdf:type><N xmlns="http://www.w3.org/2001/vcard-rdf/3.0#"><rdf:Description rdf:about="rdf:#e4675846-84f5-4f18-85f1-58aacc0ddaf6"/></N></rdf:Description><rdf:Description rdf:about="rdf:#642d0f5b-a4f8-4baa-ad5f-65bffc370e3a"><FN xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Penny Noble</FN></rdf:Description><rdf:Description rdf:about="rdf:#a90f9cc9-eb2f-4842-9959-e80930fcba04"><N xmlns="http://www.w3.org/2001/vcard-rdf/3.0#"><rdf:Description rdf:about="rdf:#d1b29776-8a7a-40db-9f84-af7208ea8496"/></N></rdf:Description><rdf:Description rdf:about="#iribe_kohl_noble_2006"><cmeta:comment><rdf:Description rdf:about="rdf:#9b12eab5-0f1b-4cad-9f5d-3615bb1a4f8c"/></cmeta:comment><reference xmlns="http://www.cellml.org/bqs/1.0#"><rdf:Description rdf:about="rdf:#190a1649-9332-418f-b3b3-0914e6fa941a"/></reference><reference xmlns="http://www.cellml.org/bqs/1.0#"><rdf:Description rdf:nodeID="n4"/></reference><simulation xmlns="http://www.cellml.org/metadata/simulation/1.0#"><rdf:Description rdf:nodeID="n2"/></simulation></rdf:Description><rdf:Description rdf:about="rdf:#7f5fbf85-77fb-49aa-8827-d6ca69ce7f1b"><W3CDTF xmlns="http://purl.org/dc/terms/" xml:lang="en">2008-05-08T00:00:00+00:00</W3CDTF></rdf:Description><rdf:Description rdf:about="rdf:#eeb779cc-ab04-4a63-aa51-f04ae493c585"><rdf:type><rdf:Description rdf:about="http://www.w3.org/1999/02/22-rdf-syntax-ns#Seq"/></rdf:type><rdf:_1><rdf:Description rdf:about="rdf:#4f389751-d839-4496-982b-3a284cadd91f"/></rdf:_1><rdf:_2><rdf:Description rdf:about="rdf:#e13cad3d-b6a3-4507-8c89-3fc44eae9c9e"/></rdf:_2><rdf:_3><rdf:Description rdf:about="rdf:#7d6d355d-e937-4463-9470-65ed8e2b346c"/></rdf:_3></rdf:Description><rdf:Description rdf:about="rdf:#90981391-436d-418e-8852-b859fd0ff88f"><Given xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Penny</Given><Family xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Noble</Family><Other xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en"></Other></rdf:Description><rdf:Description rdf:about="rdf:#190a1649-9332-418f-b3b3-0914e6fa941a"><Pubmed_id xmlns="http://www.cellml.org/bqs/1.0#" xml:lang="en">16608699</Pubmed_id><JournalArticle xmlns="http://www.cellml.org/bqs/1.0#"><rdf:Description rdf:about="rdf:#8946cd21-9768-4b1c-957e-0fb961441ea5"/></JournalArticle></rdf:Description><rdf:Description rdf:about="rdf:#9b12eab5-0f1b-4cad-9f5d-3615bb1a4f8c"><rdf:value xml:lang="en"></rdf:value><creator xmlns="http://purl.org/dc/elements/1.1/"><rdf:Description rdf:about="rdf:#dc560eef-7743-40d9-b33a-4d2bcf92be67"/></creator></rdf:Description><rdf:Description rdf:about="rdf:#cc267f5a-4a46-44ae-bbbc-b74d38f47558"><rdf:value xml:lang="en">We hypothesize that slow inactivation of Ca2+/calmodulin-dependent kinase II (CaMKII) and its modulatory effect on sarcoplasmic reticulum (SR) Ca2+ handling are important for various interval-force (I-F) relations, in particular for the beat interval dependency in transient alternans during the decay of post-extrasystolic potentiation. We have developed a mathematical model of a single cardiomyocyte to integrate various I-F relations, including alternans, by incorporating a conceptual CaMKII kinetics model into the SR Ca2+ handling model. Our model integrates I-F relations, such as the beat interval-dependent twitch force duration, restitution and potentiation, positive staircase phenomenon and alternans. We found that CaMKII affects more or less all I-F relations, and it is a key factor for integration of the various I-F relations in our model. Alternans arises, in the model, out of a steep relation between SR Ca2+ load and release, owing to SR load-dependent changes in the releasability of Ca2+ via the ryanodine receptor. Beat interval-dependent CaMKII activity, owing to its kinetic properties and amplifying effect on SR Ca2+ load dependency of Ca2+ release, replicated the beat interval dependency of alternans, as observed experimentally. Additionally, our model enabled reproduction of the effects of various interventions on alternans, such as the slowing or accelerating of Ca2+ release and/or uptake. We conclude that a slow time-dependent factor, represented in the model by CaMKII, is important for the integration of I-F relations, including alternans, and that our model offers a useful tool for further analysis of the roles of integrative Ca2+ handling in myocardial I-F relations.</rdf:value><creator xmlns="http://purl.org/dc/elements/1.1/"><rdf:Description rdf:about="rdf:#642d0f5b-a4f8-4baa-ad5f-65bffc370e3a"/></creator></rdf:Description><rdf:Description rdf:about="rdf:#e13cad3d-b6a3-4507-8c89-3fc44eae9c9e"><rdf:type><rdf:Description rdf:about="http://www.cellml.org/bqs/1.0#Person"/></rdf:type><N xmlns="http://www.w3.org/2001/vcard-rdf/3.0#"><rdf:Description rdf:about="rdf:#7730ac84-575e-4aa6-88d6-6a2ba642875b"/></N></rdf:Description><rdf:Description rdf:about="rdf:#4f389751-d839-4496-982b-3a284cadd91f"><rdf:type><rdf:Description rdf:about="http://www.cellml.org/bqs/1.0#Person"/></rdf:type><N xmlns="http://www.w3.org/2001/vcard-rdf/3.0#"><rdf:Description rdf:about="rdf:#25c5ba58-66cf-419d-83bd-0e55b3900923"/></N></rdf:Description><rdf:Description rdf:about="rdf:#8946cd21-9768-4b1c-957e-0fb961441ea5"><volume xmlns="http://www.cellml.org/bqs/1.0#" xml:lang="en">364</volume><issued xmlns="http://purl.org/dc/terms/"><rdf:Description rdf:about="rdf:#90e5579c-142f-48f7-bdac-36b41b2ab739"/></issued><creator xmlns="http://purl.org/dc/elements/1.1/"><rdf:Description rdf:about="rdf:#eeb779cc-ab04-4a63-aa51-f04ae493c585"/></creator><title xmlns="http://purl.org/dc/elements/1.1/" xml:lang="en">Modulatory effect of calmodulin-dependent kinase II (CaMKII) on sarcoplasmic reticulum Ca2+ handling and interval-force relations: a modelling study.</title><first_page xmlns="http://www.cellml.org/bqs/1.0#" xml:lang="en">1107</first_page><last_page xmlns="http://www.cellml.org/bqs/1.0#" xml:lang="en">1133</last_page><Journal xmlns="http://www.cellml.org/bqs/1.0#"><rdf:Description rdf:about="rdf:#5b6136a0-50ec-442f-9953-de1bc5a21b05"/></Journal></rdf:Description><rdf:Description rdf:about=""><cmeta:comment><rdf:Description rdf:about="rdf:#cc267f5a-4a46-44ae-bbbc-b74d38f47558"/></cmeta:comment><created xmlns="http://purl.org/dc/terms/"><rdf:Description rdf:about="rdf:#7f5fbf85-77fb-49aa-8827-d6ca69ce7f1b"/></created><cmeta:modification><rdf:Description rdf:about="rdf:#71d66a3a-219d-4543-aa4a-b38f63d3f3e0"/></cmeta:modification><publisher xmlns="http://purl.org/dc/elements/1.1/" xml:lang="en"></publisher><creator xmlns="http://purl.org/dc/elements/1.1/"><rdf:Description rdf:about="rdf:#04f8d57c-80dd-4af3-9af0-d2ca845b9aaa"/></creator></rdf:Description><rdf:Description rdf:about="rdf:#25c5ba58-66cf-419d-83bd-0e55b3900923"><Given xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Gentaro</Given><Family xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Iribe</Family></rdf:Description><rdf:Description rdf:about="rdf:#90e5579c-142f-48f7-bdac-36b41b2ab739"><W3CDTF xmlns="http://purl.org/dc/terms/" xml:lang="en">2006-05-00 00:00</W3CDTF></rdf:Description><rdf:Description rdf:about="rdf:#dc560eef-7743-40d9-b33a-4d2bcf92be67"><FN xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en"></FN></rdf:Description><rdf:Description rdf:nodeID="n5"><subject_type xmlns="http://www.cellml.org/bqs/1.0#" xml:lang="en">keyword</subject_type><rdf:value><rdf:Description rdf:nodeID="n6"/></rdf:value></rdf:Description><rdf:Description rdf:about="rdf:#d1b29776-8a7a-40db-9f84-af7208ea8496"><Given xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Penny</Given><Family xmlns="http://www.w3.org/2001/vcard-rdf/3.0#" xml:lang="en">Noble</Family></rdf:Description><rdf:Description rdf:nodeID="n6"><rdf:type><rdf:Description rdf:about="http://www.w3.org/1999/02/22-rdf-syntax-ns#Bag"/></rdf:type><rdf:_1 xml:lang="en">calcium dynamics</rdf:_1><rdf:_2 xml:lang="en">camkii</rdf:_2><rdf:_3 xml:lang="en">electrophysiology</rdf:_3><rdf:_4 xml:lang="en">excitation-contraction coupling</rdf:_4></rdf:Description><rdf:Description rdf:nodeID="n4"><subject xmlns="http://purl.org/dc/elements/1.1/"><rdf:Description rdf:nodeID="n5"/></subject></rdf:Description></rdf:RDF></model>
