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)
12.771041 seconds (18.02 M allocations: 870.290 MiB, 2.11% gc time, 94.58% compilation time)
retcode: Success
Interpolation: 3rd order Hermite
t: 4019-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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169613.39023539683
176344.17440754455
183686.4801103698
191261.3478353637
199430.11091792677
205000.0
u: 4019-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]
[150952.7504077194, 13838.375711519551, -68.79732946186226, 0.1211319185255175, 0.1211301421535992, 0.12113000811850358, 0.12113000037367234, 0.12113000001389383, 0.12113000000038378, 0.12113000000000405 … 0.2608055799112056, 0.009769882842069916, 0.001879826176081169, 0.09242766669618695, 0.2215639938807744, 0.9660018276402699, 0.007020208561323646, 829.9999654017583, 829.9994975880693, 0.0025985659590295374]
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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
0.019332211071584192
0.09097534627605569
0.20734339686524408
0.4561200538541287
1.0549952720719427
2.0687580593126613
3.5324261824253345
6.954473747659736
12.881140201769806
⋮
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197588.12178364221
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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[151082.99594044525, 13700.121315674525, -70.30685771442826, 0.12486681627358771, 0.12486699293594235, 0.1248671649061315, 0.12486733212443689, 0.12486749452873275, 0.12486765205436326, 0.12486780463401143 … 0.0011372511426383002, 0.001582025128386009, 0.002448897114682002, 0.0015379203360177576, 0.9997426766643972, 0.9997408078707501, 0.006338953528064957, 923.4938704460986, 922.050006752374, 0.006915552382403408]
[151127.81298684754, 13655.370303293366, -70.22192860927966, 0.12429382999461625, 0.12429400186163785, 0.12429416927678007, 0.12429433218421551, 0.1242944905258673, 0.12429464424129406, 0.12429479326756815 … 0.001152306521536151, 0.0015920469986004698, 0.0024644027648662984, 0.001556805954288391, 0.9997382835800489, 0.9997360201470813, 0.006375667093786818, 923.6570847388133, 922.2361636602303, 0.006804459843892744]
[151173.81665812136, 13609.434645285612, -70.13370024196674, 0.12371262761683535, 0.1237127945278281, 0.12371295722318736, 0.12371311565086184, 0.12371326975670212, 0.12371341948435374, 0.12371356477514343 … 0.0011680748508234727, 0.0016025195294372806, 0.002480613059633831, 0.001576666451342601, 0.999733283291682, 0.9997309526604555, 0.006414030167677887, 923.8125540137186, 922.4148307355821, 0.00669224174316096]
[151223.4665739653, 13559.858390114443, -70.03725613107062, 0.12309331860231157, 0.12309348001987308, 0.12309363747356575, 0.12309379091532292, 0.12309394029514012, 0.12309408556097615, 0.12309422665864812 … 0.0011856577953655483, 0.0016140477936525694, 0.0024984529958109215, 0.0015986588398342685, 0.9997276295982896, 0.9997253010153645, 0.006456227895200551, 923.9665888621072, 922.5934983498383, 0.006573203267324507]
[151266.33084832682, 13517.057904805864, -69.95294083197592, 0.12256542139076239, 0.12256557800392963, 0.1225657308632589, 0.12256587992395379, 0.12256602513941178, 0.12256616646113216, 0.1225663038386181 … 0.001201230182199704, 0.0016241926698933845, 0.002514153213865367, 0.001618131395084189, 0.9997225836604148, 0.9997202628390508, 0.00649334473355177, 924.0880576543755, 922.7358937570392, 0.006472169342803762]
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))
(0.23504331833749922, 0.5781129229554962)
ca_iso = sol2(tspan[1]:1:tspan[2], idxs=sys.Cai_mean)
println(extrema(ca_iso))
(0.1903362652693955, 0.7110939450930367)
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.