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, 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.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}}, CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}, DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}, SciMLBase.DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}}, CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}, DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}}}((), (SciMLBase.DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}}, CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}, DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}(DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}}(100000:1000:300000, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}(-80.0, 0.5, Istim)), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}(-80.0, 0.5, Istim), DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}}(100000:1000:300000, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}(-80.0, 0.5, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing, ()), SciMLBase.DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}}, CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}, DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}(DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}}(100000.5:1000.0:300000.5, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}(0.0, 0.5, Istim)), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}(0.0, 0.5, Istim), DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}}(100000.5:1000.0:300000.5, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}(0.0, 0.5, 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.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}}, CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}, DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}, SciMLBase.DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}}, CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}, DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}, SciMLBase.DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{Vector{Float64}, typeof(SciMLBase.INITIALIZE_DEFAULT), typeof(Main.var"##239".add_coffee_affect!)}, typeof(Main.var"##239".add_coffee_affect!), DiffEqCallbacks.PresetTimeFunction{Vector{Float64}, typeof(SciMLBase.INITIALIZE_DEFAULT), typeof(Main.var"##239".add_coffee_affect!)}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}}}((), (SciMLBase.DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}}, CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}, DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}(DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}}(100000:1000:300000, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}(-80.0, 0.5, Istim)), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}(-80.0, 0.5, Istim), DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}}(100000:1000:300000, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#15#17"{Float64, Float64, Symbolics.Num}(-80.0, 0.5, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing, ()), SciMLBase.DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}}, CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}, DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}(DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}}(100000.5:1000.0:300000.5, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}(0.0, 0.5, Istim)), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}(0.0, 0.5, Istim), DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}}(100000.5:1000.0:300000.5, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#16#18"{Float64, Float64, Symbolics.Num}(0.0, 0.5, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing, ()), SciMLBase.DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{Vector{Float64}, typeof(SciMLBase.INITIALIZE_DEFAULT), typeof(Main.var"##239".add_coffee_affect!)}, typeof(Main.var"##239".add_coffee_affect!), DiffEqCallbacks.PresetTimeFunction{Vector{Float64}, typeof(SciMLBase.INITIALIZE_DEFAULT), typeof(Main.var"##239".add_coffee_affect!)}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}(DiffEqCallbacks.PresetTimeFunction{Vector{Float64}, typeof(SciMLBase.INITIALIZE_DEFAULT), typeof(Main.var"##239".add_coffee_affect!)}([200000.0], true, SciMLBase.INITIALIZE_DEFAULT, Main.var"##239".add_coffee_affect!), Main.var"##239".add_coffee_affect!, DiffEqCallbacks.PresetTimeFunction{Vector{Float64}, typeof(SciMLBase.INITIALIZE_DEFAULT), typeof(Main.var"##239".add_coffee_affect!)}([200000.0], true, SciMLBase.INITIALIZE_DEFAULT, Main.var"##239".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)

  2.312183 seconds (126.91 k allocations: 444.296 MiB, 24.33% gc time)
  4.356511 seconds (4.63 M allocations: 706.510 MiB, 2.45% gc time, 58.51% compilation time)

retcode: Success
Interpolation: 3rd order Hermite
t: 8769-element Vector{Float64}:
      0.0
      0.019333123284849308
      0.09098129546757994
      0.20735582943983855
      0.45611910276862533
      1.0472562928406122
      2.0342667657223696
      3.451776641148454
      6.733792423912806
     12.450117081023194
      ⋮
 410733.5618623793
 421223.7787354648
 432671.0133968798
 444118.24805829476
 455565.48271970975
 467012.71738112473
 481612.9643611904
 498981.03509962815
 500000.0
u: 8769-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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 [150952.77598869594, 13838.2694938995, -70.35063788657428, 0.12180447948880577, 0.12174768443532356, 0.12169340184085964, 0.12164180995533558, 0.12159304920072024, 0.12154722283384184, 0.12150439833798556  …  0.26041507667541997, 0.009786689200123853, 0.0016855899094922325, 0.09161908329520764, 0.22294828828976576, 0.9666286957812559, 0.006355039713677859, 829.9689941817725, 829.8589858006806, 0.002310655727734339]
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 ⋮
 [151663.27769689527, 13215.513707614977, -69.70252844061322, 0.13198002872297873, 0.13198003369659003, 0.13198003457964635, 0.13198003129088554, 0.13198002374575196, 0.13198001185622854, 0.1319799955306582  …  0.0012491193046074232, 0.0016547150295928403, 0.002561357740604503, 0.001677661580946772, 0.9997066082809954, 0.9997047077869452, 0.0066048345850841595, 51.645918718831965, 50.35000355683728, 0.11382553618453263]
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 [151985.96840840144, 12892.875789939704, -69.03589628114874, 0.12836519568650662, 0.12836519309208538, 0.12836518790620302, 0.12836518007626493, 0.12836516954755378, 0.1283651562631209, 0.12836514016367134  …  0.0013848269259465861, 0.0017387034665093972, 0.0026913330030161114, 0.0018458754694475248, 0.9996606715344514, 0.9996590674128528, 0.006910989250147859, 53.722974591760796, 52.493592824507274, 0.10359900307031657]

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/7e61099ebdd5249ddc737a71d987f5b9bbceca0a9d5e171f02ddd07512bb0465.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/3b825882869a7692b8fb7cdfa5896eec70567c60dcbc379b7a543e6fb6475ed0.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/1a12f1d7e986674dfa4f77b5578ec925084c3c310367f83d2ab2a530e3578683.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/de92e6e52d345f9f51f6de89c43b57af0c5b23077b5978ed8e958d0fe460bb5b.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/451bd9dbbac3fd5f119406f8faa5ebe0e0c9ac00373e13af71761183c666008a.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/37f80f16c59594a3283244c36e7b385d45ca12bcfd331f9fd85161f146c78bfe.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/ff39e84925ddc5269e46449f57aeddd4413d844e9dfa026fd936f66b3f4b11b6.png

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)

  1.057926 seconds (61.80 k allocations: 208.078 MiB, 5.19% gc time)
  0.927409 seconds (243.79 k allocations: 223.002 MiB, 4.60% gc time, 9.56% compilation time)
  0.466060 seconds (45.93 k allocations: 122.814 MiB, 2.24% gc time)

retcode: Success
Interpolation: 3rd order Hermite
t: 2779-element Vector{Float64}:
      0.0
      0.18425164710745895
      0.9881968891786936
      4.071270110657321
     11.468897716484786
     25.163136004062377
     49.58622336610172
     83.36383106142347
    137.50361695337466
    206.18316321697307
      ⋮
 144494.24258331547
 149073.96837679698
 154337.92267623727
 162353.84439230544
 168891.15388059878
 175428.46336889212
 184109.21706764342
 195066.38406434815
 205000.0
u: 2779-element Vector{Vector{Float64}}:
 [152640.00597251163, 12238.884398036022, -67.47380947158396, 0.1223877320296651, 0.12238773198494962, 0.12238773192995428, 0.12238773186446368, 0.12238773178825384, 0.1223877317010915, 0.1223877316027339  …  0.001763860922444772, 0.0019523470685825558, 0.0030219031924643824, 0.002307169668687784, 0.9995225549031342, 0.9995225408000866, 0.007684695828104704, 57.61909255769596, 56.4967649846878, 0.08793781783891962]
 [152640.00597535807, 12238.884395268526, -67.47619008701882, 0.12238180528243248, 0.12238518175664855, 0.12238676500423265, 0.1223874066735665, 0.12238763367430464, 0.12238770487895019, 0.12238772492566194  …  0.0017638612935034312, 0.0019523468981434465, 0.0030217676497593087, 0.0023071695752755277, 0.999522554908391, 0.9995225408640744, 0.007684500736796288, 57.61909257231998, 56.49676499967806, 0.087937817787133]
 [152640.00599003056, 12238.884386281603, -67.48644802814846, 0.12236184154871016, 0.12236850685668701, 0.12237382725967631, 0.12237795052075698, 0.12238104564611738, 0.12238329331472309, 0.12238487167470105  …  0.0017638712393607664, 0.0019523291817324336, 0.0030198900671645663, 0.0023071669459609197, 0.9995225550709278, 0.999522542642948, 0.007681054053569664, 57.61909263612881, 56.496765065084915, 0.08793781756117303]
 [152640.00608046405, 12238.884419113803, -67.52386288832177, 0.12231908456557655, 0.12232756416817914, 0.12233530309954924, 0.122342320678403, 0.12234864150245076, 0.12235429564104178, 0.12235931796996367  …  0.0017640168890572158, 0.0019519083256054573, 0.0030114910560057246, 0.002307124641653274, 0.999522557718822, 0.9995225711239405, 0.007661820429718684, 57.61909288086994, 56.49676531589329, 0.08793781670206566]
 [152640.0065009527, 12238.884939787456, -67.60277182354385, 0.12224941172750843, 0.12225936357158378, 0.12226882382974452, 0.1222777984767955, 0.12228629463359973, 0.12229432062061814, 0.12230188594827711  …  0.0017648075074343122, 0.0019490568077314128, 0.002993778654533245, 0.0023068353319773585, 0.9995225758797562, 0.9995227642741393, 0.007620326085780995, 57.619091354058796, 56.4967661532288, 0.08793687990202351]
 [152640.00790379502, 12238.887290445178, -67.71498197616297, 0.1221437439913276, 0.12215522982265414, 0.12216634762181161, 0.12217709971510807, 0.12218748881361839, 0.12219751800974833, 0.12220719077223507  …  0.0017666954027570647, 0.0019399597487554732, 0.0029687235698457395, 0.0023057391745070956, 0.999522644885227, 0.9995234852395498, 0.007561678306079314, 57.618993985290516, 56.496794363132196, 0.0879019981296342]
 [152640.01178135257, 12238.894440545622, -67.8369037625009, 0.12197793956345102, 0.12199071110568502, 0.12200319986437422, 0.12201540526379749, 0.12202732682165468, 0.12203896414088505, 0.1220503169015488  …  0.0017687751860565176, 0.001921725091881603, 0.002941666253734278, 0.002302610561634407, 0.9995228434088902, 0.9995254921178498, 0.007498438426106791, 57.61823774750182, 56.497210288906714, 0.08768558548954591]
 [152640.0186926198, 12238.907220159273, -67.91463286943976, 0.12176827338873729, 0.12178143269172914, 0.1217943514357399, 0.12180702739414903, 0.1218194583061066, 0.12183164187024356, 0.12184357573805953  …  0.001768404101456165, 0.00190358943617685, 0.0029245038627222237, 0.002297090103416995, 0.9995232001220485, 0.9995289057981203, 0.007458410918804918, 57.61668670322952, 56.49895351747599, 0.08722180308188877]
 [152640.03118985487, 12238.9288880942, -67.95952916540769, 0.12145293734861017, 0.12146567642450293, 0.12147819381228052, 0.12149048662253202, 0.12150255188158227, 0.12151438652620096, 0.12152598739798387  …  0.0017641699748748648, 0.0018905746403119783, 0.002914650630393208, 0.002287465573411036, 0.999523844881324, 0.9995345267780834, 0.007435464253737163, 57.61560848422022, 56.504579248621894, 0.08638452827432895]
 [152640.0478671261, 12238.954325043864, -67.9853424525158, 0.12107374819244374, 0.12108564075964685, 0.12109731854593242, 0.12110877854300539, 0.12112001764804026, 0.1211310326584631, 0.12114182026642548  …  0.001757274329162802, 0.0018848756874208943, 0.002909049471800105, 0.0022753532416452437, 0.9995247034605004, 0.99954104173997, 0.00742238835682836, 57.618682302715484, 56.516321927087745, 0.08533676591419492]
 ⋮
 [152693.14474336142, 12185.604804871873, -68.08143639658921, 0.11569707281755083, 0.11569706774933985, 0.11569706271000565, 0.1156970576995915, 0.11569705271812282, 0.11569704776560655, 0.11569704284203007  …  0.0016062716976563785, 0.0018663671879082667, 0.0028888155050396844, 0.0021163435852003896, 0.9989949025845385, 0.9995812285446606, 0.007374006907542238, 62.65205075886283, 61.64562569373483, 0.07224666605613841]
 [152692.86517570625, 12185.88387594838, -68.08207539960685, 0.11570114777851746, 0.1157011468584984, 0.11570114598291263, 0.1157011451523014, 0.11570114436722986, 0.11570114362828818, 0.11570114293609263  …  0.0016060550012975906, 0.0018662774527137102, 0.002888681052916776, 0.0021161457120668493, 0.9994077155006482, 0.9995809629439585, 0.007373685901257681, 62.65212711436838, 61.64561482906139, 0.0722573004900554]
 [152692.55055695746, 12186.198443240732, -68.08277763820563, 0.11570471562786147, 0.1157047160099676, 0.1157047164393298, 0.11570471691678129, 0.11570471744319846, 0.11570471801950295, 0.11570471864666354  …  0.0016059195794429087, 0.0018661810013553303, 0.0028885292153207087, 0.00211594029525763, 0.9995385156315031, 0.9995812572371781, 0.007373345300829444, 62.64987053634589, 61.64329341161036, 0.07226519068857497]
 [152692.0856466981, 12186.663461353055, -68.08382437101369, 0.11570958979635589, 0.11570959121576677, 0.11570959271442913, 0.11570959429395351, 0.1157095959560252, 0.11570959770240766, 0.11570959953494658  …  0.001605600767440278, 0.001866034577419952, 0.00288831043415991, 0.002115619789610662, 0.9995759971442738, 0.9995814285136717, 0.00737278877255268, 62.64517082211088, 61.63850209122965, 0.07227652664696282]
 [152691.71832525483, 12187.030637775086, -68.08460113176247, 0.11571386714772544, 0.1157138695896729, 0.11571387206298121, 0.11571387456876153, 0.11571387710814934, 0.1157138796823058, 0.11571388229241919  …  0.00160555311491179, 0.001865931782433003, 0.0028881383987116632, 0.0021154094764972934, 0.9995806885708898, 0.9995818462849286, 0.007372454568432376, 62.64272580499838, 61.63598875980231, 0.07228562651672522]
 [152691.36139451567, 12187.38768924761, -68.08546483520222, 0.11571640541697842, 0.11571640549074959, 0.1157164056301319, 0.11571640583643596, 0.11571640611103765, 0.11571640645538137, 0.11571640687098346  …  0.0016052808623838498, 0.0018658102232456523, 0.002887954275901275, 0.0021151326382049104, 0.9995814140053456, 0.9995815758046795, 0.007371946236008166, 62.64058584187258, 61.63380776747852, 0.07229100844746461]
 [152690.90287891554, 12187.846345096434, -68.0864818159656, 0.11572117656651983, 0.11572117702559244, 0.11572117753783788, 0.11572117810442396, 0.11572117872656576, 0.11572117940552788, 0.11572118014262728  …  0.0016049956073137218, 0.001865668323590997, 0.0028877359847134946, 0.0021148196326325696, 0.999581496062965, 0.9995815441863072, 0.0073714998854752, 62.636430631475335, 61.62957246743992, 0.0723014926432383]
 [152690.34839362281, 12188.400963240252, -68.08773034014246, 0.11572668897659169, 0.11572668937886764, 0.1157266898317868, 0.11572669033638855, 0.11572669089375745, 0.11572669150502547, 0.11572669217137439  …  0.0016046539059529532, 0.0018654946468077502, 0.002887468536225632, 0.002114438482349215, 0.9995814812848297, 0.9995814221077177, 0.007370876877745636, 62.63178293080287, 61.62483203457065, 0.07231353248143643]
 [152689.86902099647, 12188.88044505848, -68.08880748891822, 0.11573142893343108, 0.11573142919724051, 0.11573142950808783, 0.11573142986696619, 0.1157314302749095, 0.11573143073299469, 0.11573143124234382  …  0.0016044190074023645, 0.0018653466897897142, 0.0028872383706026066, 0.0021141179646444828, 0.9995816832588605, 0.9995818132300542, 0.007370316093016996, 62.627760721406155, 61.62073030697992, 0.0723239638316063]

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)")
_images/25cc6b9d699e0cb85ad4e46a72e52794f24e4ee0625c3cdeb2607819b64dde4f.png 
savefig("caf-ap.pdf")
savefig("caf-ap.png")

"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/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/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)
_images/02c4470bfb5de012508930af84102976b3f536a653af191607e08ee9c35c9ce6.png 
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)")
_images/373e3f711835337ff4aac32a8bbdcc71c9fd0f054d102763cb60563f259a8ada.png 
savefig("caf-camkact.pdf")
savefig("caf-camkact.png")

"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/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")
_images/c1d50585135f3fae158c7d5d9bc48b7ddad93745fb72f8b005b27093602d1c5b.png 
savefig("caf-exp.pdf")

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

This notebook was generated using Literate.jl.

Contents