Caffeine Effects

Caffeine increase RyR opening sensitivity to luminal and subspace calcium In this model, we decrease the mid saturation sub-SR calcium concentration for the opening rate

using ModelingToolkit
using OrdinaryDiffEq, SteadyStateDiffEq, DiffEqCallbacks
using Plots
using CSV
using DataFrames
using Dates
using CaMKIIModel
using CaMKIIModel: second
Plots.default(lw=1.5)

sys = build_neonatal_ecc_sys(simplify=true, reduce_iso=true, reduce_camk=true)
tend = 500second
prob = ODEProblem(sys, [], tend)
stimstart = 100second
stimend = 300second
alg = KenCarp47()
function add_coffee_affect!(integrator)
    integrator.ps[sys.RyRsensitivity] = 10
end

@unpack Istim = sys
callback = build_stim_callbacks(Istim, stimend; period=1second, starttime=stimstart)

SciMLBase.CallbackSet{Tuple{}, Tuple{SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#111#113"{StepRange{Int64, Int64}}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRange{Int64, Int64}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}, SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#111#113"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}}}((), (SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#111#113"{StepRange{Int64, Int64}}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRange{Int64, Int64}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}(DiffEqCallbacks.var"#111#113"{StepRange{Int64, Int64}}(100000:1000:300000), CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}(-80.0, 1, Istim), DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRange{Int64, Int64}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}}(SciMLBase.INITIALIZE_DEFAULT, true, 100000:1000:300000, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}(-80.0, 1, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing), SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#111#113"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}(DiffEqCallbacks.var"#111#113"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}(100000.5:1000.0:300000.5), CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}(0.0, 1, Istim), DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}}(SciMLBase.INITIALIZE_DEFAULT, true, 100000.5:1000.0:300000.5, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}(0.0, 1, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing)))

Add caffeine at t = 200 econd

callback_caf = CallbackSet(build_stim_callbacks(Istim, stimend; period=1second, starttime=stimstart), PresetTimeCallback(200.0second, add_coffee_affect!))

SciMLBase.CallbackSet{Tuple{}, Tuple{SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#111#113"{StepRange{Int64, Int64}}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRange{Int64, Int64}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}, SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#111#113"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}, SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#111#113"{Vector{Float64}}, typeof(Main.var"##237".add_coffee_affect!), DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, Vector{Float64}, typeof(Main.var"##237".add_coffee_affect!)}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}}}((), (SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#111#113"{StepRange{Int64, Int64}}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRange{Int64, Int64}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}(DiffEqCallbacks.var"#111#113"{StepRange{Int64, Int64}}(100000:1000:300000), CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}(-80.0, 1, Istim), DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRange{Int64, Int64}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}}(SciMLBase.INITIALIZE_DEFAULT, true, 100000:1000:300000, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}(-80.0, 1, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing), SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#111#113"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}(DiffEqCallbacks.var"#111#113"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}(100000.5:1000.0:300000.5), CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}(0.0, 1, Istim), DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}}(SciMLBase.INITIALIZE_DEFAULT, true, 100000.5:1000.0:300000.5, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}(0.0, 1, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing), SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#111#113"{Vector{Float64}}, typeof(Main.var"##237".add_coffee_affect!), DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, Vector{Float64}, typeof(Main.var"##237".add_coffee_affect!)}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}(DiffEqCallbacks.var"#111#113"{Vector{Float64}}([200000.0]), Main.var"##237".add_coffee_affect!, DiffEqCallbacks.var"#112#114"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, Vector{Float64}, typeof(Main.var"##237".add_coffee_affect!)}(SciMLBase.INITIALIZE_DEFAULT, true, [200000.0], Main.var"##237".add_coffee_affect!), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing)))

@time sol = solve(prob, alg; callback)
@time sol_caf = solve(prob, alg; callback=callback_caf)

  2.577012 seconds (134.33 k allocations: 455.922 MiB, 18.85% gc time)
  4.511306 seconds (4.33 M allocations: 704.886 MiB, 2.43% gc time, 51.18% compilation time)

retcode: Success
Interpolation: 3rd order Hermite
t: 8895-element Vector{Float64}:
      0.0
      0.019333123284849308
      0.09098129546757994
      0.20735582943983855
      0.45611910276862533
      1.0472562928406122
      2.0342667657223696
      3.451776641148454
      6.733792423912806
     12.450117081023194
      ⋮
 404642.83277566
 414876.9573868354
 425667.5596113841
 437210.4237575505
 449697.91725670267
 462185.41075585486
 477837.27038342203
 495715.4103120649
 500000.0
u: 8895-element Vector{Vector{Float64}}:
 [0.0026, 830.0, 830.0, 0.00702, 0.966, 0.22156, 0.09243, 0.00188, 0.00977, 0.26081  …  0.12113, 0.12113, 0.12113, 0.12113, 0.12113, 0.12113, 0.12113, -68.79268, 13838.37602, 150952.75035000002]
 [0.0025985659590295374, 829.9994975880693, 829.9999654017583, 0.007020208561323646, 0.9660018276402699, 0.2215639938807744, 0.09242766669618695, 0.001879826176081169, 0.009769882842069916, 0.2608055799112056  …  0.12113000000000405, 0.12113000000038378, 0.12113000001389383, 0.12113000037367234, 0.12113000811850358, 0.1211301421535992, 0.1211319185255175, -68.79732946186226, 13838.375711519551, 150952.7504077194]
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 [0.00256770780104998, 829.9883445519497, 829.9990964774663, 0.0070030143052343926, 0.9660430731013478, 0.2216542075240971, 0.0923749578279845, 0.0018699196262940568, 0.00976754294689657, 0.2607122383588733  …  0.12113292110288301, 0.12113633873395535, 0.12114295934422187, 0.12115494411090462, 0.12117519662647316, 0.12120713813483534, 0.12125418995384041, -68.91207316777846, 13838.368384399068, 150952.7517373371]
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 [0.0023106557277343394, 829.8589858006806, 829.9689941817725, 0.006355039713677859, 0.9666286957812559, 0.22294828828976576, 0.09161908329520764, 0.0016855899094922325, 0.009786689200123853, 0.26041507667541997  …  0.12150439833798571, 0.12154722283384205, 0.12159304920072048, 0.1216418099553358, 0.12169340184085986, 0.12174768443532376, 0.12180447948880598, -70.35063788657428, 13838.2694938995, 150952.77598869594]
 [0.002228995040224517, 829.7704141396295, 829.923524981244, 0.005926150085676071, 0.9671554512230358, 0.22412560303273427, 0.09093422465365385, 0.0015688568862426045, 0.009873892913308327, 0.26104417804603025  …  0.12171274673876392, 0.1217515266716739, 0.12179171693004434, 0.12183318573340766, 0.12187579038290373, 0.1219193775332836, 0.121963783644082, -71.35304509818071, 13838.18882346682, 150952.80529264064]
 ⋮
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 [0.10397555004145233, 52.40885175170439, 53.64072566637212, 0.006897952772589172, 0.9996611034768826, 0.9996627216040298, 0.0018385490653550706, 0.0026857883113884807, 0.0017351204907156686, 0.0013788849913950116  …  0.12850186934324995, 0.12850188550685013, 0.12850189878773277, 0.1285019092465232, 0.1285019169414519, 0.12850192192847246, 0.12850192426137202, -69.06367777763383, 12905.767961358117, 151973.07403430092]
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i = (sys.t / 1000, sys.vm)
plot(sol, idxs=i, title="Action potential", lab="Ctl", tspan=(198second, 205second))
plot!(sol_caf, idxs=i, lab="Caf", tspan=(198second, 205second), ylabel="Voltage (mV)", xlabel="Time (s)")

i = (sys.t / 1000, sys.Cai_sub_SR * 1000)
plot(sol, idxs=i, title="Calcium transient (During caffeine addition)", lab="Ctl", tspan=(198second, 205second))
plot!(sol_caf, idxs=i, tspan=(198second, 205second), lab="Caf", ylabel="Subspace calcium (nM)", xlabel="Time (s)")

i = (sys.t / 1000, sys.PO1RyR)
plot(sol, idxs=i, title="RyR open (During caffeine addition)", lab="Ctl", tspan=(198second, 205second))
plot!(sol_caf, idxs=i, tspan=(198second, 205second), lab="Caf", ylabel="Open probability", ylims=(0, 1), xlabel="Time (s)")

i = (sys.t / 1000, sys.Cai_sub_SR * 1000)
plot(sol, idxs=i, title="Calcium transient (After caffeine addition)", lab="Ctl", ylabel="Subspace calcium (nM)", tspan=(198second, 205second))
plot!(sol_caf, idxs=i, lab="Caf", xlabel="Time (s)", tspan=(198second, 205second))

i = (sys.t / 1000, sys.CaJSR)
plot(sol, idxs=i, title="SR Calcium (During caffeine addition)", lab="Ctl", ylabel="SR calcium (μM)", tspan=(198second, 205second))
plot!(sol_caf, idxs=i, tspan=(198second, 205second), lab="Caf", ylims=(0, 850), xlabel="Time (s)")

i = (sys.t / 1000, sys.Jrel)
plot(sol, idxs=sys.Jrel, title="Ca flux", lab="Ctl  (Jrel)", tspan=(198second, 205second))
plot!(sol_caf, idxs=sys.Jrel, lab="Caf (Jrel)", tspan=(198second, 205second), ylabel="μM/ms", xlabel="Time (s)")

i = (sys.t / 1000, sys.CaMKAct * 100)
plot(sol, idxs=i, title="Active CaMKII", lab="Ctl")
plot!(sol_caf, idxs=i, lab="Caf", ylabel="CaMKII activity (%)", xlabel="Time (s)")

Simulation vs experimental data

Add caffeine in the beginning of the simulation Add caffeine and nifedipine in the beginning of the simulation (nifedipine blocks 90% of L-type calcium channel)

sys = build_neonatal_ecc_sys(simplify=true, reduce_iso=true, reduce_camk=true)
tend = 205second
stimstart = 30second
stimend = 120second
alg = KenCarp47()
@unpack Istim = sys
callback = build_stim_callbacks(Istim, stimend; period=1second, starttime=stimstart)

prob = ODEProblem(sys, [], tend)
prob_caf = ODEProblem(sys, [sys.RyRsensitivity => 10], tend)
gCaL = prob.ps[sys.GCaL]
prob_nif_caf = ODEProblem(sys, [sys.RyRsensitivity => 10, sys.GCaL => 0.1 * gCaL], tend)

ssalg = DynamicSS(alg)
sprob_caf = SteadyStateProblem(prob_caf)
sssol = solve(sprob_caf, ssalg; abstol=1e-10, reltol=1e-10)

@time sol = solve(prob, alg; callback)
@time sol_caf = solve(remake(prob_caf, u0=sssol.u), alg; callback)
@time sol_nif_caf = solve(remake(prob_nif_caf, u0=sssol.u), alg; callback)

  1.028423 seconds (65.98 k allocations: 212.864 MiB, 6.57% gc time)
  1.681251 seconds (1.06 M allocations: 267.697 MiB, 3.17% gc time, 37.84% compilation time)
  0.693741 seconds (88.91 k allocations: 147.626 MiB, 2.55% gc time)

retcode: Success
Interpolation: 3rd order Hermite
t: 2868-element Vector{Float64}:
      0.0
      0.1842516287447695
      0.9881966448057977
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      ⋮
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 149346.25860848115
 154988.35512024
 161140.21728263333
 169117.5486088547
 177094.87993507608
 185072.21126129746
 197681.0658829473
 205000.0
u: 2868-element Vector{Vector{Float64}}:
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i = (sys.t / 1000, sys.vm)
tspan = (100second, 102second)
plot(sol, idxs=i, title="Action potential", lab="Ctl"; tspan)
plot!(sol_caf, idxs=i, lab="Caf"; tspan)
plot!(sol_nif_caf, idxs=i, lab="Caf + Nif", tspan=tspan, ylabel="Voltage (mV)", xlabel="Time (s)")

savefig("caf-ap.pdf")
savefig("caf-ap.png")

"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/caf-ap.png"

i = (sys.t / 1000, sys.Cai_sub_SR * 1000)
tspan = (100second, 102second)
plot(sol, idxs=i, title="Calcium transient", lab="Ctl"; tspan)
plot!(sol_caf, idxs=i, lab="Caf"; tspan)
plot!(sol_nif_caf, idxs=i, lab="Caf + Nif", ylabel="Subspace calcium (nM)", xlabel="Time (s)"; tspan)

savefig("caf-cat.pdf")
savefig("caf-cat.png")

"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/caf-cat.png"

i = (sys.t / 1000, sys.CaJSR)
tspan = (100second, 102second)
plot(sol, idxs=i, title="SR Calcium", lab="Ctl", ylabel="SR calcium (μM)"; tspan)
plot!(sol_caf, idxs=i, lab="Caf"; tspan)
plot!(sol_nif_caf, idxs=i, lab="Caf + Nif", ylims=(0, 850), xlabel="Time (s)"; tspan)

i = (sys.t / 1000, sys.CaMKAct * 100)
plot(sol, idxs=i, title="Simulation", lab="Ctl")
plot!(sol_caf, idxs=i, lab="Caf")
plot!(sol_nif_caf, idxs=i, lab="Caf + Nif", ylabel="CaMKII active fraction (%)", xlabel="Time (s)")

savefig("caf-camkact.pdf")
savefig("caf-camkact.png")

"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/caf-camkact.png"

experiments

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"])

caf = chemicaldf[!, "caffeine 20mM Mean"]
caf_error = chemicaldf[!, "caffeine 20mM SD"] ./ sqrt.(chemicaldf[!, "caffeine 20mM N"])

plot(ts, ctl, yerr=ctl_error, lab="Control", color=:blue, markerstrokecolor=:blue)
plot!(ts, caf, yerr=caf_error, lab="Caffeine 20mM", color=:red, markerstrokecolor=:red)
plot!(xlabel="Time (s)", ylabel="CaMKII activity (A.U.)", title= "Experiment")

savefig("caf-exp.pdf")

"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/caf-exp.pdf"

---

This notebook was generated using Literate.jl.