grandi-2010_modified.mmt

[[model]]
name: grandi-2010
author: Michael Clerx
desc: """
    Grandi 2010 model of the human ventricular myocyte.

    ---------------------------------------------------------------------------

    A novel computational model of the human ventricular action potential and
    Ca transient

    Geoffrey Nunns
    Bioengineering Institute, University of Auckland
    
    This CellML model is part of a CellML 1.1 model, this segment contains all
    the model equations describing cellular species. It is imported by smaller
    CellML models which describe different voltage protocols, and does not run
    as a standalone model. The units are consistent throughout.
    
    ABSTRACT: We have developed a detailed mathematical model for Ca handling
    and ionic currents in the human ventricular myocyte. Our aims were to: (1)
    simulate basic excitation-contraction coupling phenomena; (2) use realistic
    repolarizing K current densities; (3) reach steady-state. The model relies
    on the framework of the rabbit myocyte model previously developed by our
    group, with subsarcolemmal and junctional compartments where ion channels
    sense higher [Ca] vs. bulk cytosol. Ion channels and transporters have been
    modeled on the basis of the most recent experimental data from human
    ventricular myocytes. Rapidly and slowly inactivating components of I(to)
    have been formulated to differentiate between endocardial and epicardial
    myocytes. Transmural gradients of Ca handling proteins and Na pump were
    also simulated. The model has been validated against a wide set of
    experimental data including action potential duration (APD) adaptation and
    restitution, frequency-dependent increase in Ca transient peak and [Na](i).
    Interestingly, Na accumulation at fast heart rate is a major determinant of
    APD shortening, via outward shifts in Na pump and Na-Ca exchange currents.
    We investigated the effects of blocking K currents on APD and
    repolarization reserve: I(Ks) block does not affect the former and slightly
    reduces the latter; I(K1) blockade modestly increases APD and more strongly
    reduces repolarization reserve; I(Kr) blockers significantly prolong APD,
    an effect exacerbated as pacing frequency is decreased, in good agreement
    with experimental results in human myocytes. We conclude that this model
    provides a useful framework to explore excitation-contraction coupling
    mechanisms and repolarization abnormalities at the single myocyte level.
    
    The original paper reference is cited below:
    
    A novel computational model of the human ventricular action potential and
    Ca transient, Eleonora Grandi, Francesco S. Pasqualini, Donald M. Bers,
    2010, Journal of Molecular and Cellular Cardiology, volume 48, 112-121.
    """
# Initial values
membrane.V    = -8.17787190210759292e+01
ina.m         =  3.54679797550979010e-03
ina.h         =  6.37518080871252391e-01
ina.j         =  6.35359766463064912e-01
inal.h        =  6.37518080871252391e-01
ikr.x_kr      =  3.06611993147495980e-02
iks.x_ks      =  4.18445578799132075e-03
ito.x_to_s    =  4.29617909070972501e-04
ito.y_to_s    =  7.41622038444247456e-01
ito.x_to_f    =  4.29612359729970644e-04
ito.y_to_f    =  9.99996104517911877e-01
ical.d        =  2.77068022513104505e-06
ical.f        =  9.95322303939510267e-01
ical.f_Ca_Bj  =  2.15008830800119295e-02
ical.f_Ca_Bsl =  1.38888168414593397e-02
caflux.Ry_Rr  =  8.75077121070150121e-01
caflux.Ry_Ro  =  4.11199541044039948e-07
caflux.Ry_Ri  =  5.87363415790563762e-08
bufna.Na_Bj   =  3.58213444446927065e+00
bufna.Na_Bsl  =  7.81698668905209226e-01
bufca.Tn_CL   =  7.53838610928425114e-03
bufca.Tn_CHc  =  1.07853333366311643e-01
bufca.Tn_CHm  =  1.52016011086265855e-02
bufca.CaM     =  2.44045247704509897e-04
bufca.Myo_c   =  1.29620654465419246e-03
bufca.Myo_m   =  1.38196302221029049e-01
bufca.SRB     =  1.83224364395441854e-03
bufca2.SLL_j  =  6.41717782985620419e-03
bufca2.SLL_sl =  8.94195355945789049e-03
bufca2.SLH_j  =  6.70229305164633804e-02
bufca2.SLH_sl =  1.06210503478607152e-01
bufca3.Csqn_b =  1.04780102739851411e+00
bufca3.Ca_sr  =  4.38778100992401832e-01
sodium.Na_j   =  9.02772294161908739e+00
sodium.Na_sl  =  9.02976602719007815e+00
sodium.Na_i   =  9.03014355539893643e+00
potassium.K_i =  120.0
calcium.Ca_j  =  1.52139683151191081e-04
calcium.Ca_sl =  9.63365107530515948e-05
calcium.Ca_i  =  7.18777439568944510e-05

#
# Simulation engine inputs
#
[engine]
time = 0 in [ms] bind time
pace = 0 bind pace

#
# Cell type
#
[type]
epi = 1
    desc: 1 For epicardial cell, 0 for endocardial cell

#
# Membrane potential
#
# Supplement 1.17, page 10
#
[membrane]
dot(V) = -(i_ion + stimulus.i_stim)
    in [mV]
    label membrane_potential
i_ion = I_Na_tot + I_Cl_tot + I_Ca_tot + potassium.I_K_tot
    in [A/F]
    label cellular_current
I_Ca_tot = calcium.I_Ca_tot_junc + calcium.I_Ca_tot_sl
    in [A/F]
I_Cl_tot = iclca.iclca + iclb.IClb
    in [A/F]
I_Na_tot = sodium.I_Na_tot_junc + sodium.I_Na_tot_sl
    in [A/F]

#
# Stimulus current
#
[stimulus]
i_stim = engine.pace * stim_amplitude
stim_amplitude = -80

#
# Fast sodium current
#
# Supplement 1.1, page 2
#
[ina]
use membrane.V
GNa = 23 [mS/uF]
I_Na_junc = frac.Fjunc * GNa * m ^ 3 * h * j * (V - rev.ena_junc)
    in [A/F]
I_Na_sl = frac.Fsl * GNa * m ^ 3 * h * j * (V - rev.ena_sl)
    in [A/F]
dot(m) = (inf - m) / tau
    inf = 1 / (1 + exp(-(56.86 + V) / 9.03)) ^ 2
    tau = 0.1292 * exp(-((V + 45.79) / 15.54) ^ 2) + 0.06487 * exp(-((V - 4.823) / 51.12) ^ 2)
dot(h) = (hss - h) / tauh
    hss = 1 / (1 + exp((V + 71.55) / 7.43)) ^ 2
    ah = if(V >= -40 , 0, 0.057 * exp(-(V + 80) / 6.8))
    bh = if(V >= -40 , 0.77 / (0.13 * (1 + exp(-(V + 10.66) / 11.1))), 2.7 * exp(0.079 * V) + 310000 * exp(0.3485 * V))
    tauh = 1 / (ah + bh)
dot(j) = (jss - j) / tauj
    jss = 1 / (1 + exp((V + 71.55) / 7.43)) ^ 2
    aj = piecewise(V >= -40 , 0, (-25428 * exp(0.2444 * V) - 6.948e-6 * exp(-0.04391 * V)) * (V + 37.78) / (1 + exp(0.311 * (V + 79.23))))
    bj = piecewise(V >= -40 , 0.6 * exp(0.057 * V) / (1 + exp(-0.1 * (V + 32))), 0.02424 * exp(-0.01052 * V) / (1 + exp(-0.1378 * (V + 40.14))))
    tauj = 1 / (aj + bj)


# Late sodium current (Gomez 2014)
#
# Methods Gomez 2014
#
[inal]
use membrane.V
use ina.m
th = 233.0 [ms] : Time constant of inactivation

INaL_junc = frac.Fjunc*GNal*m^3*h*(V-rev.ena_junc)
INaL_sl = frac.Fsl*GNal*m^3*h*(V-rev.ena_sl)
dot(h) = (shp - h)/th
    desc: Inactivation gate for INaL channels
shp = 1/(1 + exp((V+91)/6.1))
    desc: The steady state in-activation gate

GNal = 0.015 [mS/uF]: The maximum conductance


#
# Background sodium current
#
# Supplement 1.2, page 3
#
[inab]
use membrane.V
GNaB = 0.000597 [mS/uF]
I_nabk_junc = frac.Fjunc * GNaB * (V - rev.ena_junc)
    in [A/F]
I_nabk_sl = frac.Fsl * GNaB * (V - rev.ena_sl)
    in [A/F]

#
# Na/K pump current
#
# Supplement 1.3, page 3
#
[inak]
use membrane.V
KmKo = 1.5 [mM]
KmNaip = 11 [mM]
IbarNaK = 1.8 [A/F]
I_nak = I_nak_junc + I_nak_sl
    in [A/F]
I_nak_junc = frac.Fjunc * IbarNaK * fnak * ion.Ko / (1 + (KmNaip / sodium.Na_j) ^ 4) / (ion.Ko + KmKo)
    in [A/F]
I_nak_sl = frac.Fsl * IbarNaK * fnak * ion.Ko / (1 + (KmNaip / sodium.Na_sl) ^ 4) / (ion.Ko + KmKo)
    in [A/F]
fnak = 1 / (1 + 0.1245 * exp(-0.1 * V * phys.FRT) + 0.0365 * sigma * exp(-V * phys.FRT))
    sigma = (exp(ion.Nao / 67.3) - 1) / 7

#
# Rapidly activating potassium current
#
# Supplement 1.4, page 3
#
[ikr]
use membrane.V
I_kr = gkr * x_kr * rkr * (V - rev.ek)
    in [A/F]
gkr = 0.035 * sqrt(ion.Ko / 5.4)
    in [mS/uF]
rkr = 1 / (1 + exp((V + 74) / 24))
dot(x_kr) = (xrss - x_kr) / tauxr
    xrss = 1 / (1 + exp(-(V + 10) / 5))
    tauxr = 550 / (1 + exp((-22 - V) / 9)) * 6 / (1 + exp((V - -11) / 9)) + 230 / (1 + exp((V - -40) / 20))

#
# Slowly activating potassium current
#
# Supplement 1.5, page 4
#
[iks]
use membrane.V
I_ks = I_ks_junc + I_ks_sl
    in [A/F]
I_ks_junc = frac.Fjunc * gks_junc * x_ks ^ 2 * (V - rev.eks)
    in [A/F]
I_ks_sl = frac.Fsl * gks_sl * x_ks ^ 2 * (V - rev.eks)
    in [A/F]
gks_junc = 0.0035 [mS/uF]
gks_sl = 0.0035 [mS/uF]
dot(x_ks) = (xsss - x_ks) / tauxs
    tauxs = 990.1 / (1 + exp(-(V + 2.436) / 14.12))
    xsss = 1 / (1 + exp(-(V + 3.8) / 14.25))

#
# Plateau potassium current
#
# Supplement 1.6, page 4
#
[ikp]
use membrane.V
gkp = 0.002 [mS/uF]
I_kp = I_kp_junc + I_kp_sl
    in [A/F]
I_kp_junc = frac.Fjunc * gkp * kp_kp * (V - rev.ek)
    in [A/F]
I_kp_sl = frac.Fsl * gkp * kp_kp * (V - rev.ek)
    in [A/F]
kp_kp = 1 / (1 + exp(7.488 - V / 5.98))

#
# Transient outward potassium current (fast and slow components)
#
# Supplement 1.7, page 4
#
[ito]
use membrane.V
ito = I_tos + I_tof
    in [A/F]
I_tof = GtoFast * x_to_f * y_to_f * (V - rev.ek)
    in [A/F]
I_tos = GtoSlow * x_to_s * y_to_s * (V - rev.ek)
    in [A/F]
GtoFast = if(type.epi == 1, 1 * 0.13 * 0.88, 0.13 * 0.3 * 0.036)
    in [mS/uF]
GtoSlow = if(type.epi == 1, 1 * 0.13 * 0.12, 0.13 * 0.3 * 0.964)
    in [mS/uF]
xtoss = 1 / (1 + exp(-(V - 19) / 13))
ytoss = 1 / (1 + exp((V + 19.5) / 5))
dot(x_to_f) = (xtoss - x_to_f) / tauxtof
    tauxtof = 8.5 * exp(-((V + 45) / 50) ^ 2) + 0.5
dot(x_to_s) = (xtoss - x_to_s) / tauxtos
    tauxtos = 9 / (1 + exp((V + 3) / 15)) + 0.5
dot(y_to_f) = (ytoss - y_to_f) / tauytof
    tauytof = 85 * exp(-(V + 40) ^ 2 / 220) + 7
dot(y_to_s) = (ytoss - y_to_s) / tauytos
    tauytos = 800 / (1 + exp((V + 60) / 10)) + 30

#
# Inward recitifer potassium current
#
# Supplement 1.8, page 5
#
[ik1]
use membrane.V
I_k1 = 1 * 0.35 * sqrt(ion.Ko / 5.4) * inf * (V - rev.ek)
    in [A/F]
inf = a / (a + b)
    a = 1.02 / (1 + exp(0.2385 * (V - rev.ek - 59.215)))
    b = (0.49124 * exp(0.08032 * (V + 5.476 - rev.ek)) + exp(0.06175 * (V - rev.ek - 594.31))) / (1 + exp(-0.5143 * (V - rev.ek + 4.753)))

#
# Calcium activated Chloride current
#
# Supplement 1.9, page 5
#
[iclca]
use membrane.V
KdClCa = 0.1 [mM]
GClCa = 0.5 * 0.109625
    in [mS/uF]
iclca = I_ClCa_junc + I_ClCa_sl
    in [A/F]
I_ClCa_junc = frac.Fjunc * GClCa / (1 + KdClCa / calcium.Ca_j) * (V - rev.ecl)
    in [A/F]
I_ClCa_sl = frac.Fsl * GClCa / (1 + KdClCa / calcium.Ca_sl) * (V - rev.ecl)
    in [A/F]

#
# Background Chloride current
#
# Supplement 1.10, page 5
#
[iclb]
GClB = 1 * 0.009
IClb = GClB * (membrane.V - rev.ecl)
    in [A/F]

#
# L-type calcium current
#
# Supplement 1.11, page 6
#
[ical]
use membrane.V
fcaCaMSL = 0
fcaCaj = 0
Q10CaL = 1.8
Q = Q10CaL ^ phys.Qpow * 0.45
pCa = 0.5 * 0.00054
    in [cm/s]
pK = 0.5 * 2.7e-7
    in [cm/s]
pNa = 0.5 * 1.5e-8
    in [cm/s]
I_Ca_junc = frac.Fjunc_CaL * ibarca_j * d * f * (1 - f_Ca_Bj + fcaCaj) * Q
    in [A/F]
    desc: Equation 75
I_CaNa_sl = frac.Fsl_CaL * ibarna_sl * d * f * (1 - f_Ca_Bsl + fcaCaMSL) * Q
    in [A/F]
    desc: Equation 76
I_CaK = ibark * d * f * (frac.Fjunc_CaL * (fcaCaj + (1 - f_Ca_Bj)) + frac.Fsl_CaL * (fcaCaMSL + (1 - f_Ca_Bsl))) * Q
    in [A/F]
I_CaNa_junc = frac.Fjunc_CaL * ibarna_j * d * f * (1 - f_Ca_Bj + fcaCaj) * Q
    in [A/F]
I_Ca_sl = frac.Fsl_CaL * ibarca_sl * d * f * (1 - f_Ca_Bsl + fcaCaMSL) * Q
    in [A/F]
dot(d) = (dss - d) / taud
    dss = 1 / (1 + exp(-(V + 5) / 6))
    taud = dss * (1 - exp(-(V + 5) / 6)) / (0.035 * (V + 5))
dot(f) = (fss - f) / tauf
    fss = 1 / (1 + exp((V + 35) / 9)) + 0.6 / (1 + exp((50 - V) / 20))
    tauf = 1 / (0.0197 * exp(-(0.0337 * (V + 14.5)) ^ 2) + 0.02)
dot(f_Ca_Bj) = 1.7 * calcium.Ca_j / 1 * (1 - f_Ca_Bj) - 0.0119 * f_Ca_Bj
dot(f_Ca_Bsl) = 1.7 * calcium.Ca_sl / 1 * (1 - f_Ca_Bsl) - 0.0119 * f_Ca_Bsl
ibarca_j = pCa * 4 * V * phys.F * phys.FRT * (0.341 * calcium.Ca_j * exp(2 * V * phys.FRT) - 0.341 * ion.Cao) / (exp(2 * V * phys.FRT) - 1)
    in [A/F]
ibarca_sl = pCa * 4 * V * phys.F * phys.FRT * (0.341 * calcium.Ca_sl * exp(2 * V * phys.FRT) - 0.341 * ion.Cao) / (exp(2 * V * phys.FRT) - 1)
    in [A/F]
ibark = pK * V * phys.F * phys.FRT * (0.75 * potassium.K_i * exp(V * phys.FRT) - 0.75 * ion.Ko) / (exp(V * phys.FRT) - 1)
    in [A/F]
ibarna_j = pNa * V * phys.F * phys.FRT * (0.75 * sodium.Na_j * exp(V * phys.FRT) - 0.75 * ion.Nao) / (exp(V * phys.FRT) - 1)
    in [A/F]
ibarna_sl = pNa * V * phys.F * phys.FRT * (0.75 * sodium.Na_sl * exp(V * phys.FRT) - 0.75 * ion.Nao) / (exp(V * phys.FRT) - 1)
    in [A/F]

#
# Sodium/Calcium exchanger current
#
# Supplement 1.12, page 7
#
[incx]
use membrane.V
IbarNCX = 4.5 [A/F]
Kdact = 0.00015 [mM]
KmCai = 0.00359 [mM]
KmCao = 1.3 [mM]
KmNai = 12.29 [mM]
KmNao = 87.5 [mM]
Q10NCX = 1.57
ksat = 0.32
nu = 0.27
I_ncx_junc = frac.Fjunc * IbarNCX * Q10NCX ^ phys.Qpow * Ka_junc * (s1_junc - s2_junc) / s3_junc / (1 + ksat * exp((nu - 1) * V * phys.FRT))
    in [A/F]
    Ka_junc = 1 / (1 + (Kdact / calcium.Ca_j) ^ 2)
    s1_junc = exp(nu * V * phys.FRT) * sodium.Na_j ^ 3 * ion.Cao
    s2_junc = exp((nu - 1) * V * phys.FRT) * ion.Nao ^ 3 * calcium.Ca_j
    s3_junc = KmCai * ion.Nao ^ 3 * (1 + (sodium.Na_j / KmNai) ^ 3) + KmNao ^ 3 * calcium.Ca_j * (1 + calcium.Ca_j / KmCai) + KmCao * sodium.Na_j ^ 3 + sodium.Na_j ^ 3 * ion.Cao + ion.Nao ^ 3 * calcium.Ca_j
I_ncx_sl = frac.Fsl * IbarNCX * Q10NCX ^ phys.Qpow * Ka_sl * (s1_sl - s2_sl) / s3_sl / (1 + ksat * exp((nu - 1) * V * phys.FRT))
    in [A/F]
    Ka_sl = 1 / (1 + (Kdact / calcium.Ca_sl) ^ 2)
    s1_sl = exp(nu * V * phys.FRT) * sodium.Na_sl ^ 3 * ion.Cao
    s2_sl = exp((nu - 1) * V * phys.FRT) * ion.Nao ^ 3 * calcium.Ca_sl
    s3_sl = KmCai * ion.Nao ^ 3 * (1 + (sodium.Na_sl / KmNai) ^ 3) + KmNao ^ 3 * calcium.Ca_sl * (1 + calcium.Ca_sl / KmCai) + KmCao * sodium.Na_sl ^ 3 + sodium.Na_sl ^ 3 * ion.Cao + ion.Nao ^ 3 * calcium.Ca_sl

#
# Sarcolemmal calcium pump current
#
# Supplement 1.13, page 8
#
[ipca]
use membrane.V
use calcium.Ca_j, calcium.Ca_sl
KmPCa = 0.0005 [mM]
Q10SLCaP = 2.35
IbarSLCaP = 0.0673 [A/F]
I_pca_junc = frac.Fjunc * Q10SLCaP ^ phys.Qpow * IbarSLCaP * Ca_j ^ 1.6 / (KmPCa ^ 1.6 + Ca_j ^ 1.6)
    in [A/F]
I_pca_sl = frac.Fsl * Q10SLCaP ^ phys.Qpow * IbarSLCaP * Ca_sl ^ 1.6 / (KmPCa ^ 1.6 + Ca_sl ^ 1.6)
    in [A/F]

#
# Background calcium current
#
# Supplement 1.14, page 8
#
[icabk]
use membrane.V
GCaB = 0.0005513 [mS/uF]
I_cabk_junc = frac.Fjunc * GCaB * (V - rev.eca_junc)
    in [A/F]
I_cabk_sl = frac.Fsl * GCaB * (V - rev.eca_sl)
    in [A/F]

#
# SR fluxes: calcium release, SR calciump pump, SR calcium leak
#
# Supplement 1.15, page 8
#
[caflux]
use calcium.Ca_i, calcium.Ca_j
Kmf = 0.000246 [mM]
Kmr = 1.7 [mM]
Q10SRCaP = 2.6
ec50SR = 0.45 [mM]
hillSRCaP = 1.787
kim = 0.005 [mS/uF]
kom = 0.06 [mS/uF]
kiCa = 0.5 [1/mM/ms]
koCa = 10 [1/mM^2/ms]
ks = 25 [mS/uF]
J_SRCarel = ks * Ry_Ro / 1 * (bufca3.Ca_sr - Ca_j)
    in [mM/ms]
J_SRleak = 5.348e-6 * (bufca3.Ca_sr - Ca_j)
    in [mM/ms]
J_serca = Q10SRCaP ^ phys.Qpow * env.Vmax_SRCaP * ((Ca_i / Kmf) ^ hillSRCaP - (bufca3.Ca_sr / Kmr) ^ hillSRCaP) / (1 + (Ca_i / Kmf) ^ hillSRCaP + (bufca3.Ca_sr / Kmr) ^ hillSRCaP)
    in [mM/ms]
MaxSR = 15
MinSR = 1
RI = 1 - Ry_Rr - Ry_Ro - Ry_Ri
    in [mM]
kCaSR = MaxSR - (MaxSR - MinSR) / (1 + (ec50SR / bufca3.Ca_sr) ^ 2.5)
kiSRCa = kiCa * kCaSR
koSRCa = koCa / kCaSR
dot(Ry_Ri) = kiSRCa * Ca_j * Ry_Ro - kim * Ry_Ri - (kom * Ry_Ri - koSRCa * Ca_j ^ 2 * RI)
    in [mM]
dot(Ry_Ro) = koSRCa * Ca_j ^ 2 * Ry_Rr - kom * Ry_Ro - (kiSRCa * Ca_j * Ry_Ro - kim * Ry_Ri)
    in [mM]
dot(Ry_Rr) = kim * RI - kiSRCa * Ca_j * Ry_Rr - (koSRCa * Ca_j ^ 2 * Ry_Rr - kom * Ry_Ro)
    in [mM]

#
# Sodium buffers
#
# Supplement 1.16.1, page 9
#
[bufna]
Bmax_Naj = 7.561 [mM]
Bmax_Nasl = 1.65 [mM]
koff_na = 0.001 [mS/uF]
kon_na = 0.0001 [1/mM/ms]
dot(Na_Bj) = dNa_Bj_dt
    in [mM]
dot(Na_Bsl) = dNa_Bsl_dt
    in [mM]
dNa_Bj_dt = kon_na * sodium.Na_j * (Bmax_Naj - Na_Bj) - koff_na * Na_Bj
    in [mM/ms]
dNa_Bsl_dt = kon_na * sodium.Na_sl * (Bmax_Nasl - Na_Bsl) - koff_na * Na_Bsl
    in [mM/ms]

#
# Cytosolic calcium buffers
#
# Supplement 1.16.2, page 9
#
[bufca]
Bmax_CaM = 0.024 [mM]
Bmax_SR = 19 * 0.0009
Bmax_TnChigh = 0.14 [mM]
Bmax_TnClow = 0.07 [mM]
Bmax_myosin = 0.14 [mM]
koff_cam = 0.238 [mS/uF]
koff_myoca = 0.00046 [mS/uF]
koff_myomg = 5.7e-5 [mS/uF]
koff_sr = 0.06 [mS/uF]
koff_tnchca = 3.2e-5 [mS/uF]
koff_tnchmg = 0.00333 [mS/uF]
koff_tncl = 0.0196 [mS/uF]
kon_cam = 34 [1/mM/ms]
kon_myoca = 13.8 [1/mM/ms]
kon_myomg = 0.0157 [1/mM/ms]
kon_sr = 100 [1/mM/ms]
kon_tnchca = 2.37 [1/mM/ms]
kon_tnchmg = 0.003 [1/mM/ms]
kon_tncl = 32.7 [1/mM/ms]
dot(CaM) = kon_cam * calcium.Ca_i * (Bmax_CaM - CaM) - koff_cam * CaM
    in [mM]
J_CaB_cytosol = kon_tncl * calcium.Ca_i * (Bmax_TnClow - Tn_CL) - koff_tncl * Tn_CL + kon_tnchca * calcium.Ca_i * (Bmax_TnChigh - Tn_CHc - Tn_CHm) - koff_tnchca * Tn_CHc + kon_tnchmg * ion.Mgi * (Bmax_TnChigh - Tn_CHc - Tn_CHm) - koff_tnchmg * Tn_CHm + kon_cam * calcium.Ca_i * (Bmax_CaM - CaM) - koff_cam * CaM + kon_myoca * calcium.Ca_i * (Bmax_myosin - Myo_c - Myo_m) - koff_myoca * Myo_c + kon_myomg * ion.Mgi * (Bmax_myosin - Myo_c - Myo_m) - koff_myomg * Myo_m + (kon_sr * calcium.Ca_i * (Bmax_SR - SRB) - koff_sr * SRB)
    in [mM/ms]
dot(Myo_c) = kon_myoca * calcium.Ca_i * (Bmax_myosin - Myo_c - Myo_m) - koff_myoca * Myo_c
    in [mM]
dot(Myo_m) = kon_myomg * ion.Mgi * (Bmax_myosin - Myo_c - Myo_m) - koff_myomg * Myo_m
    in [mM]
dot(SRB) = kon_sr * calcium.Ca_i * (Bmax_SR - SRB) - koff_sr * SRB
    in [mM]
dot(Tn_CHc) = kon_tnchca * calcium.Ca_i * (Bmax_TnChigh - Tn_CHc - Tn_CHm) - koff_tnchca * Tn_CHc
    in [mM]
dot(Tn_CHm) = kon_tnchmg * ion.Mgi * (Bmax_TnChigh - Tn_CHc - Tn_CHm) - koff_tnchmg * Tn_CHm
    in [mM]
dot(Tn_CL) = kon_tncl * calcium.Ca_i * (Bmax_TnClow - Tn_CL) - koff_tncl * Tn_CL
    in [mM]

#
# Junctional and SL calcium buffers
#
# Supplement 1.16.3, page 9
#
[bufca2]
koff_slh = 0.03 [mS/uF]
koff_sll = 1.3 [mS/uF]
kon_slh = 100 [1/mM/ms]
kon_sll = 100 [1/mM/ms]
Bmax_SLhighj = 0.00165 * env.Vmyo / env.Vjunc * 0.1
    in [mM]
Bmax_SLhighsl = 0.0134 * env.Vmyo / env.Vsl
    in [mM]
Bmax_SLlowj = 0.0046 * env.Vmyo / env.Vjunc * 0.1
    in [mM]
Bmax_SLlowsl = 0.0374 * env.Vmyo / env.Vsl
    in [mM]
J_CaB_junction = kon_sll * calcium.Ca_j * (Bmax_SLlowj - SLL_j) - koff_sll * SLL_j + (kon_slh * calcium.Ca_j * (Bmax_SLhighj - SLH_j) - koff_slh * SLH_j)
    in [mM/ms]
J_CaB_sl = kon_sll * calcium.Ca_sl * (Bmax_SLlowsl - SLL_sl) - koff_sll * SLL_sl + (kon_slh * calcium.Ca_sl * (Bmax_SLhighsl - SLH_sl) - koff_slh * SLH_sl)
    in [mM/ms]
dot(SLH_j) = kon_slh * calcium.Ca_j * (Bmax_SLhighj - SLH_j) - koff_slh * SLH_j
    in [mM]
dot(SLH_sl) = kon_slh * calcium.Ca_sl * (Bmax_SLhighsl - SLH_sl) - koff_slh * SLH_sl
    in [mM]
dot(SLL_j) = kon_sll * calcium.Ca_j * (Bmax_SLlowj - SLL_j) - koff_sll * SLL_j
    in [mM]
dot(SLL_sl) = kon_sll * calcium.Ca_sl * (Bmax_SLlowsl - SLL_sl) - koff_sll * SLL_sl
    in [mM]

#
# SR calcium buffer
#
# Supplement 1.16.4, page 9
#
[bufca3]
koff_csqn = 65 [mS/uF]
kon_csqn = 100 [1/mM/ms]
Bmax_Csqn = 0.14 * env.Vmyo / env.Vsr
    in [mM]
dot(Ca_sr) = caflux.J_serca - (caflux.J_SRleak * env.Vmyo / env.Vsr + caflux.J_SRCarel) - (kon_csqn * Ca_sr * (Bmax_Csqn - Csqn_b) - koff_csqn * Csqn_b)
    in [mM]
dot(Csqn_b) = kon_csqn * Ca_sr * (Bmax_Csqn - Csqn_b) - koff_csqn * Csqn_b
    in [mM]

#
# Sodium concentrations
#
# Supplement 1.16.5, page 10
#
[sodium]
I_Na_tot_junc = ina.I_Na_junc + inab.I_nabk_junc + 3 * incx.I_ncx_junc + 3 * inak.I_nak_junc + ical.I_CaNa_junc + inal.INaL_junc
    in [A/F]
I_Na_tot_sl = ina.I_Na_sl + inab.I_nabk_sl + 3 * incx.I_ncx_sl + 3 * inak.I_nak_sl + ical.I_CaNa_sl + inal.INaL_sl
    in [A/F]
dot(Na_i) = env.J_na_slmyo / env.Vmyo * (Na_sl - Na_i)
    in [mM]
dot(Na_j) = -I_Na_tot_junc * phys.Cmem / (env.Vjunc * phys.F) + env.J_na_juncsl / env.Vjunc * (Na_sl - Na_j) - bufna.dNa_Bj_dt
    in [mM]
dot(Na_sl) = -I_Na_tot_sl * phys.Cmem / (env.Vsl * phys.F) + env.J_na_juncsl / env.Vsl * (Na_j - Na_sl) + env.J_na_slmyo / env.Vsl * (Na_i - Na_sl) - bufna.dNa_Bsl_dt
    in [mM]

#
# Potassium concentrations
#
# Supplement 1.16.6, page 10
#
[potassium]
I_K_tot = ito.ito + ikr.I_kr + iks.I_ks + ik1.I_k1 - 2 * inak.I_nak + ical.I_CaK + ikp.I_kp
    in [A/F]
dot(K_i) = 0 [mM/ms]
    in [mM]

#
# Calcium concentrations
#
# Supplement 1.16.7, page 10
#
[calcium]
dot(Ca_i) = -caflux.J_serca * env.Vsr / env.Vmyo - bufca.J_CaB_cytosol + env.J_ca_slmyo / env.Vmyo * (Ca_sl - Ca_i)
    in [mM]
dot(Ca_j) = -I_Ca_tot_junc * phys.Cmem / (env.Vjunc * 2 * phys.F) + env.J_ca_juncsl / env.Vjunc * (Ca_sl - Ca_j) - bufca2.J_CaB_junction + caflux.J_SRCarel * env.Vsr / env.Vjunc + caflux.J_SRleak * env.Vmyo / env.Vjunc
    in [mM]
dot(Ca_sl) = -I_Ca_tot_sl * phys.Cmem / (env.Vsl * 2 * phys.F) + env.J_ca_juncsl / env.Vsl * (Ca_j - Ca_sl) + env.J_ca_slmyo / env.Vsl * (Ca_i - Ca_sl) - bufca2.J_CaB_sl
    in [mM]
I_Ca_tot_junc = ical.I_Ca_junc + icabk.I_cabk_junc + ipca.I_pca_junc - 2 * incx.I_ncx_junc
    in [A/F]
I_Ca_tot_sl = ical.I_Ca_sl + icabk.I_cabk_sl + ipca.I_pca_sl - 2 * incx.I_ncx_sl
    in [A/F]

#
# Nernst potentials
#
# Supplement 1.18, page 11
#
[rev]
use phys.RTF
eca_junc = 0.5 * RTF * log(ion.Cao / calcium.Ca_j)
    in [mV]
eca_sl = 0.5 * RTF * log(ion.Cao / calcium.Ca_sl)
    in [mV]
ecl = RTF * log(ion.Cli / ion.Clo)
    in [mV]
ek = RTF * log(ion.Ko / potassium.K_i)
    in [mV]
ena_junc = RTF * log(ion.Nao / sodium.Na_j)
    in [mV]
ena_sl = RTF * log(ion.Nao / sodium.Na_sl)
    in [mV]
eks = 1 / phys.FRT * log((ion.Ko + pNaK * ion.Nao) / (potassium.K_i + pNaK * sodium.Na_i))
    in [mV]
pNaK = 0.01833

#
# Physical constants/parameters
#
# Supplement 2.1, page 12
#
[phys]
Cmem = 1.381e-10 [F]
F = 96485 [C/mol]
R = 8314 [mJ/mol/K]
T = 310 [K]
RTF = R * T / F
FRT = F / (R * T)
Qpow = (phys.T - 310) / 10

#
# Environmental parameters
#
# Supplement 2.2, page 12
#
[env]
cellLength = 100 [um]
cellRadius = 10.25 [um]
Vcell =  3.14159265358979312 * cellRadius ^ 2 * cellLength * 1e-15
Vjunc = 0.0539 * 0.01 * Vcell
Vmax_SRCaP = 0.0053114 [mM/ms]
Vmyo = 0.65 * Vcell
Vsl = 0.02 * Vcell
Vsr = 0.035 * Vcell
J_ca_juncsl = 8.2413e-13
J_ca_slmyo = 3.2743e-12 
J_na_juncsl = 1.8313e-14
J_na_slmyo = 1.6386e-12

#
# Fractional currents
#
# Supplement 2.3, page 12
#
[frac]
Fjunc = 0.11
Fjunc_CaL = 0.9
Fsl = 1 - Fjunc
Fsl_CaL = 1 - Fjunc_CaL

#
# Fixed ion concentrations
#
# Supplement 2.4, page 12
#
[ion]
Cli = 15 [mM]
Mgi = 1 [mM]
Clo = 150 [mM]
Ko = 5.4 [mM]
Nao = 140 [mM]
Cao = 1.8 [mM]

[[protocol]]
# Level  Start    Length   Period   Multiplier
1.0      100.0    0.5      1000.0   0

[[script]]
import matplotlib.pyplot as pl
import myokit

# Get model and protocol, create simulation
m = get_model()
p = get_protocol()
s = myokit.Simulation(m, p)

# Run simulation
d = s.run(1000)
d = s.run(1000)

# Display the results
pl.figure()
pl.plot(d['engine.time'], d['membrane.V'])
pl.show()