Caffeine Effects

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
using DiffEqCallbacks
using Plots
using CaMKIIModel
using CaMKIIModel: second, metre, Farad
Plots.default(lw=1.5)

sys = build_neonatal_ecc_sys(simplify=true, reduce_iso=true, reduce_camk=true)
tend = 500.0second
prob = ODEProblem(sys, [], tend)
stimstart = 100.0second
stimend = 300.0second
alg = TRBDF2()
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"#115#117"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#116#118"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}, SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#115#117"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#116#118"{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"#115#117"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#116#118"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}(DiffEqCallbacks.var"#115#117"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}(100000.0:1000.0:300000.0), CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}(-80.0, 1, Istim), DiffEqCallbacks.var"#116#118"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}}(SciMLBase.INITIALIZE_DEFAULT, true, 100000.0:1000.0:300000.0, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}(-80.0, 1, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing), SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#115#117"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#116#118"{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"#115#117"{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"#116#118"{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"#115#117"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#116#118"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}, SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#115#117"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#116#118"{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"#115#117"{Vector{Float64}}, typeof(Main.var"##230".add_coffee_affect!), DiffEqCallbacks.var"#116#118"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, Vector{Float64}, typeof(Main.var"##230".add_coffee_affect!)}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}}}((), (SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#115#117"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#116#118"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}(DiffEqCallbacks.var"#115#117"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}(100000.0:1000.0:300000.0), CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}(-80.0, 1, Istim), DiffEqCallbacks.var"#116#118"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}}(SciMLBase.INITIALIZE_DEFAULT, true, 100000.0:1000.0:300000.0, CaMKIIModel.var"#13#15"{Float64, Int64, Symbolics.Num}(-80.0, 1, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing), SciMLBase.DiscreteCallback{DiffEqCallbacks.var"#115#117"{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}}, CaMKIIModel.var"#14#16"{Float64, Int64, Symbolics.Num}, DiffEqCallbacks.var"#116#118"{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"#115#117"{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"#116#118"{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"#115#117"{Vector{Float64}}, typeof(Main.var"##230".add_coffee_affect!), DiffEqCallbacks.var"#116#118"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, Vector{Float64}, typeof(Main.var"##230".add_coffee_affect!)}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing}(DiffEqCallbacks.var"#115#117"{Vector{Float64}}([200000.0]), Main.var"##230".add_coffee_affect!, DiffEqCallbacks.var"#116#118"{typeof(SciMLBase.INITIALIZE_DEFAULT), Bool, Vector{Float64}, typeof(Main.var"##230".add_coffee_affect!)}(SciMLBase.INITIALIZE_DEFAULT, true, [200000.0], Main.var"##230".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)

 10.049190 seconds (21.47 M allocations: 1.005 GiB, 4.10% gc time, 74.06% compilation time)
  4.783404 seconds (3.98 M allocations: 245.006 MiB, 1.44% gc time, 42.99% compilation time)

retcode: Success
Interpolation: 3rd order Hermite
t: 22255-element Vector{Float64}:
      0.0
      0.00037376965588217846
      0.004111466214703963
      0.03981907054375368
      0.06090491262855715
      0.1655435225566852
      0.2409336011179059
      0.5227875405036884
      1.0858597487365014
      2.388889121726196
      ⋮
 486612.6617039646
 488740.25414558785
 490410.81760149135
 492522.9781453525
 494113.7000322476
 496241.0658518241
 497855.4062649577
 499776.4840116451
 500000.0
u: 22255-element Vector{Vector{Float64}}:
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 [0.0025999722040421203, 829.9999902796054, 829.9999993331091, 0.007020004989170199, 0.9660000353355825, 0.22156007721482085, 0.09242995488968388, 0.0018799969383422777, 0.009769997724445615, 0.2608099143344817  …  0.12113, 0.12113, 0.12113, 0.12113, 0.12113000000000289, 0.12113000000167641, 0.12113000088893845, -68.79276368828553, 13838.376014261732, 150952.7503511151]
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 ⋮
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 [0.10546411454131159, 52.08825892944785, 53.329998054434434, 0.006945469597429997, 0.9996536599760798, 0.9996553961331668, 0.0018651922266818334, 0.002706002809387078, 0.0017481743518270062, 0.001400392445667644  …  0.12903861482880713, 0.1290386292124471, 0.12903864090298628, 0.12903864995681527, 0.12903865642810103, 0.1290386603688958, 0.12903866182923984, -68.9626635601953, 12907.894306232236, 151969.89020297062]

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)")
_images/7b912de1277829a6fa48c00cdc1e785939b85a115f28100aa6f534ed9010b65c.png 
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)")
_images/0a57e3c8baea2aa2af17916f8049e16fe7e14161eb13930d0787bfea8447153c.png 
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)")
_images/775a8b814fd27553b9e0e2c174c817ce081d70c3ce4a4b2901f403e1974c14d9.png 
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))
_images/f1a430deb66006e53a5f34a4eb4d4819548785b33924e5bb3fab0e87573d44d4.png 
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)")
_images/fa9f56410f6cebe81ea96780d018af5127576ea1e0d557526f9313580c595044.png 
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)")
_images/61d093aa57f549ff46508c93eea8ffeb9be63804e81684e27a59dbf94a386e0a.png 
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)")
_images/860d980d4dd4ecd002fc74603114e03140ed689eede3aa2c01b6987a4fceb9a7.png

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)

prob = ODEProblem(sys, [], tend)
prob_caf = ODEProblem(sys, [sys.RyRsensitivity => 10], tend)
prob_nif_caf = ODEProblem(sys, [sys.RyRsensitivity => 10, sys.GCaL => 6.3e-6 * (metre^3 / second / Farad)], tend)
@time sol = solve(prob, alg; callback)
@time sol_caf = solve(prob_caf, alg; callback)
@time sol_nif_caf = solve(prob_nif_caf, alg; callback)

  2.583087 seconds (181.24 k allocations: 45.042 MiB)
  2.792333 seconds (180.24 k allocations: 44.797 MiB, 1.78% gc time)
  1.963091 seconds (131.62 k allocations: 32.928 MiB)

retcode: Success
Interpolation: 3rd order Hermite
t: 16155-element Vector{Float64}:
      0.0
      0.00036475171141220293
      0.0040122688255342315
      0.04002730220813219
      0.06107844755187036
      0.1668983916346115
      0.24249368910866453
      0.5251299051276579
      0.9022279165786617
      1.4954385373044485
      ⋮
 436720.0038013915
 445297.82828101015
 451990.2195297975
 461048.46857879194
 468119.9009713256
 477565.21371905616
 484800.21770803235
 494503.53485934966
 500000.0
u: 16155-element Vector{Vector{Float64}}:
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 ⋮
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i = (sys.t/1000, sys.vm)
tspan = (198second, 205second)
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)")
_images/ee4b2fc7c30e4b28f26c087f558f6c7b5215b66942f20e0dcde7b3ff29fe654f.png 
i = (sys.t/1000, sys.Cai_sub_SR * 1000)
tspan=(198second, 205second)
plot(sol, idxs=i, title="Calcium transient", lab="Ctl";tspan)
plot!(sol_caf, idxs=i, lab="Caf", ylabel="Subspace calcium (nM)";tspan)
plot!(sol_nif_caf, idxs=i, lab="Caf + Nif", ylabel="Subspace calcium (nM)", xlabel="Time (s)";tspan)
_images/c5b1f9b904c42ee8be592d3e3fa36477558b5967fd35cc3ec42e2539044b09f9.png 
i = (sys.t/1000, sys.CaJSR)
tspan=(198second, 205second)
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)
_images/ee2617534eadfa0c4e84461e39f95e2c52b57ba77040d78ccd04a812a72f8f13.png 
i = (sys.t/1000, sys.CaMKAct*100)
plot(sol, idxs=i, title="CaMKII", lab="Ctl")
plot!(sol_caf, idxs=i, lab="Caf")
plot!(sol_nif_caf, idxs=i, lab="Caf + Nif", ylabel="Active fraction (%)", xlabel="Time (s)")
_images/a96c121a6ed9223e2d0560e8be8352a5478c523fcdce9586dc37c6a37254ba6a.png

This notebook was generated using Literate.jl.