Effects of isoproterenol#
using ModelingToolkit
using OrdinaryDiffEq, SteadyStateDiffEq, DiffEqCallbacks
using Plots
using CSV
using DataFrames
using Dates
using CaMKIIModel
using CaMKIIModel: second, μM
Plots.default(lw=1.5)
Setup model#
sys = build_neonatal_ecc_sys(simplify=true, reduce_iso=true, reduce_camk=true)
tend = 205second
prob = ODEProblem(sys, [], tend)
stimstart = 30second
stimend = 120second
alg = KenCarp47()
KenCarp47(; linsolve = nothing, nlsolve = OrdinaryDiffEqNonlinearSolve.NLNewton{Rational{Int64}, Rational{Int64}, Rational{Int64}, Nothing}(1//100, 10, 1//5, 1//5, false, true, nothing), precs = DEFAULT_PRECS, smooth_est = true, extrapolant = linear, controller = PI, autodiff = ADTypes.AutoForwardDiff(),)
Without isoproterenol#
@unpack Istim = sys
callback = build_stim_callbacks(Istim, stimend; period=1second, starttime=stimstart)
@time sol = solve(prob, alg; callback)
10.978953 seconds (19.61 M allocations: 945.449 MiB, 2.78% gc time, 93.37% compilation time)
retcode: Success
Interpolation: 3rd order Hermite
t: 4071-element Vector{Float64}:
0.0
0.019333123284849308
0.09098129546757994
0.20735582943983855
0.45611910276862533
1.0472562928406122
2.0342667657223696
3.451776641148454
6.733792423912806
12.450117081023194
⋮
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u: 4071-element Vector{Vector{Float64}}:
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⋮
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i = (sys.t / 1000, sys.vm)
plot(sol, idxs=i, tspan=(100second, 101second), title="Action potential", xlabel="Time (s)")
plot(sol, idxs=(sys.t / 1000, [sys.Cai_sub_SR, sys.Cai_sub_SL, sys.Cai_mean]), tspan=(100second, 101second), title="Calcium transient", xlabel="Time (s)", ylabel="Conc. (μM)", label=["Ca (SR)" "Ca (SL)" "Ca (avg)"])
plot(sol, idxs=(sys.t / 1000, sys.CaMKAct * 100), title="Active CaMKII", label=false, ylabel="Active fraction (%)", xlabel="Time (s)")
0.1uM isoproterenol#
prob2 = remake(prob, p=[sys.ISO => 0.1μM])
sol2 = solve(prob2, alg; callback)
retcode: Success
Interpolation: 3rd order Hermite
t: 4138-element Vector{Float64}:
0.0
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0.09097534627605569
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0.4561200538541287
1.0549952720719427
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3.5324261824253345
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⋮
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205000.0
u: 4138-element Vector{Vector{Float64}}:
[150952.75035000002, 13838.37602, -68.79268, 0.12113, 0.12113, 0.12113, 0.12113, 0.12113, 0.12113, 0.12113 … 0.26081, 0.00977, 0.00188, 0.09243, 0.22156, 0.966, 0.00702, 830.0, 830.0, 0.0026]
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⋮
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[151082.99594044487, 13700.121315675331, -70.30685771442971, 0.12486681627358946, 0.1248669929359439, 0.12486716490613299, 0.12486733212443828, 0.12486749452873408, 0.12486765205436451, 0.12486780463401277 … 0.0011372511426252887, 0.0015820251283859097, 0.0024488971146818706, 0.001537920336017425, 0.999742676664399, 0.9997408078707505, 0.006338953528064392, 923.4938704460691, 922.0500067523433, 0.006915552382399907]
[151127.81298684722, 13655.370303294154, -70.22192860927998, 0.1242938299946404, 0.12429400186166206, 0.12429416927680431, 0.12429433218423981, 0.12429449052589163, 0.12429464424131842, 0.12429479326759252 … 0.001152306521523222, 0.0015920469986002194, 0.0024644027648663166, 0.0015568059542885476, 0.9997382835800502, 0.9997360201470814, 0.006375667093786704, 923.657084738738, 922.2361636601547, 0.006804459843891177]
[151173.81665812104, 13609.434645286381, -70.13370024196757, 0.1237126276168541, 0.1237127945278469, 0.1237129572232062, 0.12371311565088065, 0.12371326975672094, 0.12371341948437255, 0.1237135647751622 … 0.001168074850819175, 0.0016025195294372657, 0.0024806130596337454, 0.001576666451342757, 0.9997332832916821, 0.9997309526604555, 0.006414030167677571, 923.8125540137345, 922.4148307355978, 0.006692241743160747]
[151223.466573965, 13559.858390115198, -70.03725613107402, 0.12309331860229751, 0.123093480019859, 0.12309363747355163, 0.1230937909153088, 0.12309394029512596, 0.12309408556096196, 0.12309422665863391 … 0.0011856577953648256, 0.0016140477936521628, 0.002498452995810272, 0.001598658839833547, 0.9997276295982898, 0.9997253010153646, 0.006456227895199014, 923.9665888621122, 922.5934983498439, 0.006573203267322105]
[151266.33084832662, 13517.057904806577, -69.95294083197554, 0.12256542139079514, 0.12256557800396242, 0.12256573086329174, 0.1225658799239867, 0.12256602513944476, 0.12256616646116517, 0.12256630383865115 … 0.0012012301821989948, 0.0016241926698933754, 0.0025141532138654244, 0.0016181313950834966, 0.9997225836604149, 0.999720262839051, 0.006493344733551902, 924.0880576543809, 922.7358937570431, 0.00647216934281195]
plot(sol2, idxs=(sys.t / 1000, sys.vm), tspan=(100second, 101second), title="Action potential", xlabel="Time (s)")
plot(sol2, idxs=(sys.t / 1000, [sys.Cai_sub_SR, sys.Cai_sub_SL, sys.Cai_mean]), tspan=(100second, 101second), title="Calcium transcient", xlabel="Time (s)", ylabel="Conc. (μM)", label=["Ca (SR)" "Ca (SL)" "Ca (avg)"])
plot(sol2, idxs=(sys.t / 1000, sys.CaMKAct * 100), title="Active CaMKII", label=false, ylabel="Active fraction (%)", xlabel="Time (s)")
Comparison#
i = (sys.t / 1000, sys.Cai_mean)
tspan = (100second, 101second)
plot(sol, idxs=i, title="Calcium transcient", lab="ISO (-)"; tspan)
plot!(sol2, idxs=i, lab="ISO (0.1uM)", xlabel="Time (s)", ylabel="Concentration (μM)"; tspan)
Compare the numbers
ca_ctl = sol(tspan[1]:1:tspan[2], idxs=sys.Cai_mean)
println(extrema(ca_ctl))
(0.2350505644679326, 0.5781214777887043)
ca_iso = sol2(tspan[1]:1:tspan[2], idxs=sys.Cai_mean)
println(extrema(ca_iso))
(0.19033626526941844, 0.7110939450930854)
savefig("iso-caT.pdf")
savefig("iso-caT.png")
"/home/github/actions-runner-2/_work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/iso-caT.png"
i = (sys.t / 1000, sys.CaMKAct * 100)
plot(sol, idxs=i, title="Active CaMKII", lab="ISO (-)")
plot!(sol2, idxs=i, lab="ISO (0.1uM)", ylabel="Active fraction (%)", xlabel="Time (s)")
savefig("iso-camkact.pdf")
savefig("iso-camkact.png")
"/home/github/actions-runner-2/_work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/iso-camkact.png"
i = (sys.t / 1000, sys.vm)
tspan = (100second, 101second)
plot(sol, idxs=i, title="Action potential", lab="ISO (-)"; tspan)
plot!(sol2, idxs=i, lab="ISO (0.1uM)", xlabel="Time (ms)", ylabel="Voltage (mV)"; tspan)
Experimental data#
chemicaldf = CSV.read(joinpath(@__DIR__, "data/CaMKAR-chemical.csv"), DataFrame)
ts = Dates.value.(chemicaldf[!, "Time"]) ./ 10^9
ctl = chemicaldf[!, "Ctrl Mean"]
ctl_error = chemicaldf[!, "Ctrl SD"] ./ sqrt.(chemicaldf[!, "Ctrl N"])
iso = chemicaldf[!, "isoproterenol 100nM Mean"]
iso_error = chemicaldf[!, "isoproterenol 100nM SD"] ./ sqrt.(chemicaldf[!, "isoproterenol 100nM N"])
plot(ts, ctl, yerr=ctl_error, lab="Control", color=:blue, markerstrokecolor=:blue)
plot!(ts, iso, yerr=iso_error, lab="ISO 100nM", color=:red, markerstrokecolor=:red)
plot!(xlabel="Time (sec.)", ylabel="CaMKII activity (A.U.)")
savefig("iso-exp.pdf")
"/home/github/actions-runner-2/_work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/iso-exp.pdf"
This notebook was generated using Literate.jl.