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)
[ Info: Precompiling GRIJuliaExt [84369c5d-ffb2-5a92-8288-3470980d96d0] 



SYSTEM: caught exception of type :MethodError while trying to print a failed Task notice; giving up

[ Info: Precompiling IJuliaExt [2f4121a4-3b3a-5ce6-9c5e-1f2673ce168a] 



SYSTEM: caught exception of type :MethodError while trying to print a failed Task notice; giving up

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
add_coffee_affect! (generic function with 1 method)
@unpack Istim = sys
callback = build_stim_callbacks(Istim, stimend; period=1second, starttime=stimstart)
# Add caffeine at t = 200 econd
callback_caf = CallbackSet(build_stim_callbacks(Istim, stimend; period=1second, starttime=stimstart), PresetTimeCallback(200.0second, add_coffee_affect!))
CallbackSet{Tuple{}, Tuple{DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#20#21"{Float64, Float64, Num}}, CaMKIIModel.var"#20#21"{Float64, Float64, Num}, DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#20#21"{Float64, Float64, Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}, DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#22#23"{Float64, Float64, Num}}, CaMKIIModel.var"#22#23"{Float64, Float64, Num}, DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#22#23"{Float64, Float64, Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}, DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{Vector{Float64}, typeof(SciMLBase.INITIALIZE_DEFAULT), typeof(add_coffee_affect!)}, typeof(add_coffee_affect!), DiffEqCallbacks.PresetTimeFunction{Vector{Float64}, typeof(SciMLBase.INITIALIZE_DEFAULT), typeof(add_coffee_affect!)}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}}}((), (DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#20#21"{Float64, Float64, Num}}, CaMKIIModel.var"#20#21"{Float64, Float64, Num}, DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#20#21"{Float64, Float64, Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}(DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#20#21"{Float64, Float64, Num}}(100000:1000:300000, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#20#21"{Float64, Float64, Num}(-80.0, 0.5, Istim)), CaMKIIModel.var"#20#21"{Float64, Float64, Num}(-80.0, 0.5, Istim), DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#20#21"{Float64, Float64, Num}}(100000:1000:300000, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#20#21"{Float64, Float64, Num}(-80.0, 0.5, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing, ()), DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#22#23"{Float64, Float64, Num}}, CaMKIIModel.var"#22#23"{Float64, Float64, Num}, DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#22#23"{Float64, Float64, Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}(DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#22#23"{Float64, Float64, Num}}(100000.5:1000.0:300000.5, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#22#23"{Float64, Float64, Num}(0.0, 0.5, Istim)), CaMKIIModel.var"#22#23"{Float64, Float64, Num}(0.0, 0.5, Istim), DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#22#23"{Float64, Float64, Num}}(100000.5:1000.0:300000.5, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#22#23"{Float64, Float64, Num}(0.0, 0.5, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing, ()), DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{Vector{Float64}, typeof(SciMLBase.INITIALIZE_DEFAULT), typeof(add_coffee_affect!)}, typeof(add_coffee_affect!), DiffEqCallbacks.PresetTimeFunction{Vector{Float64}, typeof(SciMLBase.INITIALIZE_DEFAULT), typeof(add_coffee_affect!)}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}(DiffEqCallbacks.PresetTimeFunction{Vector{Float64}, typeof(SciMLBase.INITIALIZE_DEFAULT), typeof(add_coffee_affect!)}([200000.0], true, SciMLBase.INITIALIZE_DEFAULT, Main.add_coffee_affect!), Main.add_coffee_affect!, DiffEqCallbacks.PresetTimeFunction{Vector{Float64}, typeof(SciMLBase.INITIALIZE_DEFAULT), typeof(add_coffee_affect!)}([200000.0], true, SciMLBase.INITIALIZE_DEFAULT, Main.add_coffee_affect!), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing, ())))

Single-dose caffeine

@time sol = solve(prob, alg; callback)
@time sol_caf = solve(prob, alg; callback=callback_caf)
 10.566174 seconds (23.33 M allocations: 1.454 GiB, 1.55% gc time, 83.60% compilation time)
  4.372727 seconds (8.12 M allocations: 864.756 MiB, 2.53% gc time, 60.84% compilation time)
retcode: Success
Interpolation: 3rd order Hermite
t: 8773-element Vector{Float64}:
      0.0
      0.019333123284849377
      0.09098129546758026
      0.20735582943983927
      0.4561191027686269
      1.047256292840616
      2.0342667657223767
      3.4517766411484665
      6.733792423912831
     12.45011708102324
     21.597356188110254
     34.569649574420886
     51.60556465685166
      ⋮
 373132.402876846
 381293.49993619946
 390502.30635751394
 400587.1730516022
 410672.0397456905
 421716.44761840976
 434008.49190990673
 450151.06267123023
 462974.23931692366
 480604.5572769363
 498234.87523694895
 500000.0
u: 8773-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]
 [150952.75062244057, 13838.374513299192, -68.81607005265552, 0.12115248970210647, 0.12113624253259858, 0.12113143375871602, 0.12113027926811751, 0.12113004704056851, 0.12113000693481112, 0.12113000089551408  …  0.26078941009382306, 0.009769459049732313, 0.0018789042446514422, 0.09241901973901424, 0.2215787945110049, 0.9660085993318799, 0.00702008986027517, 829.9998348635061, 829.9976422525165, 0.002593310524681686]
 [150952.7509740238, 13838.372555328333, -68.84681913285226, 0.12118951551963696, 0.12115723910142134, 0.12114109135582982, 0.12113403405679991, 0.12113131833063846, 0.12113038966346883, 0.12113010483012127  …  0.2607638707001999, 0.009768805322556195, 0.0018766436937193197, 0.09240497563401104, 0.22160283236040595, 0.9660195931792828, 0.007017234889558555, 829.9996133960318, 829.9946506157202, 0.0025849478335103772]
 [150952.7517373371, 13838.368384399068, -68.91207316777846, 0.12125418995384042, 0.12120713813483534, 0.12117519662647318, 0.12115494411090462, 0.12114295934422188, 0.12113633873395535, 0.12113292110288301  …  0.2607122383588733, 0.00976754294689657, 0.001869919626294057, 0.0923749578279845, 0.2216542075240971, 0.9660430731013478, 0.007003014305234393, 829.9990964774663, 829.9883445519497, 0.0025677078010499796]
 [150952.75361533565, 13838.358559292059, -69.06429960994139, 0.12136450208851986, 0.12130632552358439, 0.12125925929399749, 0.12122229800810431, 0.12119414515426226, 0.12117335985880448, 0.1211584926966588  …  0.26060507831375035, 0.009765228548607825, 0.0018505337694469416, 0.09230364339951613, 0.22177624785138977, 0.9660987611411453, 0.006946470397388756, 829.9976227528975, 829.9738229154025, 0.0025298083713907]
 [150952.75694915713, 13838.34240329337, -69.31024285744344, 0.1214919651325425, 0.12142927821043346, 0.1213742637991964, 0.12132672249013038, 0.12128628091507475, 0.12125242557826563, 0.12122454121844704  …  0.26047114911179464, 0.009763403076884485, 0.0018178174419014655, 0.09218462776986637, 0.2219798989175973, 0.9661914345949096, 0.006833754172875444, 829.9944193668179, 829.9509077855928, 0.002474807978215895]
 [150952.76215620188, 13838.319723120678, -69.64637448767434, 0.12162015426876964, 0.12155743299711909, 0.12149988983034504, 0.12144759471003595, 0.12140052118634267, 0.12135855488207911, 0.12132150441596078  …  0.2603648729749554, 0.009765046552800477, 0.0017738156907532213, 0.09201383579531924, 0.22227216398019892, 0.9663239343003682, 0.0066755120626567415, 829.9883533251192, 829.9205247545176, 0.0024106893964811306]
 [150952.77598869594, 13838.2694938995, -70.35063788657429, 0.12180447948880603, 0.12174768443532381, 0.12169340184085989, 0.12164180995533579, 0.12159304920072045, 0.12154722283384199, 0.12150439833798565  …  0.26041507667541997, 0.009786689200123853, 0.00168558990949223, 0.09161908329520764, 0.22294828828976576, 0.9666286957812559, 0.006355039713677853, 829.9689941817725, 829.8589858006806, 0.002310655727734336]
 [150952.80529264064, 13838.18882346682, -71.35304509818073, 0.1219637836440816, 0.12191937753328323, 0.1218757903829034, 0.12183318573340736, 0.12179171693004404, 0.12175152667167365, 0.12171274673876364  …  0.26104417804603025, 0.009873892913308327, 0.0015688568862426027, 0.09093422465365385, 0.22412560303273427, 0.9671554512230358, 0.005926150085676066, 829.923524981244, 829.7704141396295, 0.002228995040224513]
 [150952.86299380922, 13838.073886537528, -72.4735918016508, 0.12206907365211363, 0.12204000912238945, 0.1220110851640203, 0.12198240835565052, 0.12195408498965715, 0.12192622071360422, 0.12189892020522224  …  0.26219196277470147, 0.010096953727758097, 0.0014509791455665651, 0.08984663594439561, 0.22601226798739724, 0.967993228113323, 0.005481992553581978, 829.835522704537, 829.6517809213686, 0.002196550994865595]
 [150952.95992241168, 13837.930366929982, -73.3680187246281, 0.12214002318717763, 0.12212362030065525, 0.12210735547152661, 0.12209128572970773, 0.12207547016063591, 0.1220599697635786, 0.12204484731342843  …  0.26245103149935634, 0.010460774283167064, 0.0013687018299841105, 0.08832396891068775, 0.228694606159479, 0.9691706237716892, 0.0051520931233999395, 829.6998293673863, 829.5000486863437, 0.0022048519780075433]
 [150953.10134272132, 13837.760056594308, -73.87449731227231, 0.12223586969586354, 0.12222699265995365, 0.12221851425171158, 0.12221046390801742, 0.12220287294990832, 0.12219577456109872, 0.12218920376366489  …  0.26014121758021924, 0.010837804894547892, 0.0013321803801861305, 0.08636165834435419, 0.23222051356391082, 0.9706806820175085, 0.004974280036814663, 829.5173289776985, 829.3085691237902, 0.0022267170411342492]
 ⋮
 [151483.3022972105, 13395.446478800399, -70.05062843752334, 0.13416291822941365, 0.13416293037520513, 0.13416293754126526, 0.13416293962988252, 0.13416293653940078, 0.13416292816401845, 0.13416291439357447  …  0.0011835542732606327, 0.0016124613578997818, 0.002495970952762429, 0.0015958834122774006, 0.9997280438513091, 0.9997260556527803, 0.006450360889894667, 50.48311888086189, 49.14638787560664, 0.12027220258767524]
 [151524.99878464048, 13353.761196407359, -69.97137351990422, 0.133647015797937, 0.13364702609324602, 0.13364703161140243, 0.13364703225839952, 0.13364702793643507, 0.1336470185437182, 0.13364700397426324  …  0.0011981642961178018, 0.0016219864291699016, 0.0025107116146599433, 0.0016141536142595374, 0.9997233086008899, 0.999721335049639, 0.00648521258746095, 50.75179646395453, 49.42475573149471, 0.11873037907442716]
 [151570.23972939063, 13308.53173139085, -69.88444951746847, 0.13309410771584032, 0.13309411605076468, 0.13309411982753044, 0.13309411895614778, 0.1330941133429931, 0.13309410289062365, 0.13309408749758064  …  0.0012143901095032462, 0.001632497130848363, 0.002526977608956792, 0.0016344271697890692, 0.9997180159198088, 0.9997160639962657, 0.006523651891510296, 51.04382314073815, 49.727138484429815, 0.11709040412832021]
 [151617.6676592487, 13261.115089921832, -69.79226031208901, 0.1325222509745926, 0.13252225738575027, 0.13252225946706916, 0.1325222571327741, 0.13252225029362644, 0.1325222388567477, 0.13252222272543157  …  0.0012318407145399332, 0.0016437171132340357, 0.0025443412202716138, 0.0016562010175567839, 0.999712289565461, 0.9997103653553531, 0.00656466248745671, 51.350329001024605, 50.044323004799274, 0.115407907233062]
 [151662.98368801433, 13215.809140524345, -69.70313014241552, 0.13198341629455648, 0.13198342106338237, 0.13198342172031022, 0.13198341818362508, 0.131983410368313, 0.1319833981858924, 0.1319833815442357  …  0.0012489507778964324, 0.0016546371159752405, 0.0025612404919185556, 0.0016775215870001295, 0.9997066419289161, 0.9997047470874393, 0.006604554777213319, 51.643412591601084, 50.347438135877425, 0.11383532954450551]
 [151710.30673930817, 13168.495907932493, -69.60892118803808, 0.13142872799590954, 0.1314287313223141, 0.13142873076453182, 0.13142872624513433, 0.13142871768356684, 0.13142870499598855, 0.1314286880951032  …  0.001267289894171816, 0.0016662599533203907, 0.002579227556422485, 0.0017003472952818626, 0.9997005540036995, 0.9996986884554673, 0.006646996318156452, 51.94957514605457, 50.66389625800978, 0.1122294374515424]
 [151760.2768320601, 13118.535431464285, -69.5081814029278, 0.13085191887946276, 0.130851920740174, 0.1308519189553221, 0.130851913451993, 0.13085190415432818, 0.13085189098337457, 0.13085187385692496  …  0.0012872048952438473, 0.0016787760463155051, 0.002598596191368288, 0.0017250944283408766, 0.9996939010960414, 0.9996920724410305, 0.006692668893964975, 52.27265495674743, 50.99764934817281, 0.11057349973713322]
 [151821.82285620715, 13057.000208053652, -69.38225539818865, 0.13015436298139466, 0.13015436331034388, 0.1301543602854011, 0.1301543538392183, 0.13015434390172795, 0.13015433040000418, 0.13015431325811516  …  0.0013125371907681568, 0.0016945515225815888, 0.002623008775847405, 0.0017565205192994384, 0.9996853754371718, 0.9996835988371647, 0.006750196341662394, 52.669984323265304, 51.407840682047784, 0.10859009372114425]
 [151867.62161195502, 13011.208765438236, -69.28718604073126, 0.129644636814347, 0.12964463619644956, 0.12964463243996532, 0.12964462548169214, 0.12964461525587573, 0.12964460169407915, 0.1296445847250447  …  0.0013319950194807383, 0.0017065584238387316, 0.002641589270677801, 0.0017806175373668359, 0.9996787803273957, 0.9996770470658016, 0.006793952882277252, 52.96497273704035, 51.712196201042566, 0.10715401804989967]
 [151926.42556655762, 12952.413327034952, -69.16335640675119, 0.12900206903827027, 0.12900206742140347, 0.1290020629391372, 0.12900205553356603, 0.12900204514444594, 0.1290020317090752, 0.12900201516216758  …  0.0013577735754901903, 0.001722325323410439, 0.0026659882439735477, 0.001812489345798519, 0.9996699802073966, 0.9996683088789485, 0.006851380782062976, 53.342515523529606, 52.101509287684145, 0.10535972793783961]
 [151980.74692857257, 12898.099009846683, -69.04716026244081, 0.12842057830989534, 0.12842057596093734, 0.1284205709955261, 0.12842056336061755, 0.1284205530010255, 0.12842053985931212, 0.1284205238756721  …  0.0013824159994341742, 0.0017372497768260962, 0.0026890832862942935, 0.0018429012121774467, 0.9996615026901544, 0.9996598950775745, 0.00690569860319312, 53.68968063181806, 52.459289332119724, 0.10375143088643606]
 [151985.95219894202, 12892.894377572118, -69.03593427867983, 0.12836545533469, 0.12836545289178009, 0.1283654478538549, 0.12836544016835133, 0.12836542978058196, 0.12836541663362658, 0.1283654006682173  …  0.0013848250878191657, 0.0017386985654080562, 0.0026913251579741165, 0.001845871912028587, 0.9996606720946383, 0.9996590681190823, 0.006910970123733874, 53.7228354417192, 52.49344894514705, 0.10359972019584344]
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)")

Caffeine and electrophysiology

  • 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)
CallbackSet{Tuple{}, Tuple{DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#20#21"{Float64, Float64, Num}}, CaMKIIModel.var"#20#21"{Float64, Float64, Num}, DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#20#21"{Float64, Float64, Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}, DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#22#23"{Float64, Float64, Num}}, CaMKIIModel.var"#22#23"{Float64, Float64, Num}, DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#22#23"{Float64, Float64, Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}}}((), (DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#20#21"{Float64, Float64, Num}}, CaMKIIModel.var"#20#21"{Float64, Float64, Num}, DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#20#21"{Float64, Float64, Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}(DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#20#21"{Float64, Float64, Num}}(30000:1000:120000, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#20#21"{Float64, Float64, Num}(-80.0, 0.5, Istim)), CaMKIIModel.var"#20#21"{Float64, Float64, Num}(-80.0, 0.5, Istim), DiffEqCallbacks.PresetTimeFunction{StepRange{Int64, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#20#21"{Float64, Float64, Num}}(30000:1000:120000, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#20#21"{Float64, Float64, Num}(-80.0, 0.5, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing, ()), DiscreteCallback{DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#22#23"{Float64, Float64, Num}}, CaMKIIModel.var"#22#23"{Float64, Float64, Num}, DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#22#23"{Float64, Float64, Num}}, typeof(SciMLBase.FINALIZE_DEFAULT), Nothing, Tuple{}}(DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#22#23"{Float64, Float64, Num}}(30000.5:1000.0:120000.5, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#22#23"{Float64, Float64, Num}(0.0, 0.5, Istim)), CaMKIIModel.var"#22#23"{Float64, Float64, Num}(0.0, 0.5, Istim), DiffEqCallbacks.PresetTimeFunction{StepRangeLen{Float64, Base.TwicePrecision{Float64}, Base.TwicePrecision{Float64}, Int64}, typeof(SciMLBase.INITIALIZE_DEFAULT), CaMKIIModel.var"#22#23"{Float64, Float64, Num}}(30000.5:1000.0:120000.5, true, SciMLBase.INITIALIZE_DEFAULT, CaMKIIModel.var"#22#23"{Float64, Float64, Num}(0.0, 0.5, Istim)), SciMLBase.FINALIZE_DEFAULT, Bool[1, 1], nothing, ())))
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)
ODEProblem with uType Vector{Float64} and tType Int64. In-place: true
Initialization status: FULLY_DETERMINED
Non-trivial mass matrix: false
timespan: (0, 205000)
u0: 75-element Vector{Float64}:
 150952.75035000002
  13838.37602
    -68.79268
      0.12113
      0.12113
      0.12113
      0.12113
      0.12113
      0.12113
      0.12113
      0.12113
      0.12113
      0.12113
      ⋮
      0.07192
      0.07831
      0.26081
      0.00977
      0.00188
      0.09243
      0.22156
      0.966
      0.00702
    830.0
    830.0
      0.0026
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)
  0.769877 seconds (63.30 k allocations: 208.387 MiB, 5.68% gc time)
  0.869024 seconds (286.20 k allocations: 224.836 MiB, 3.79% gc time, 14.43% compilation time)
  0.448330 seconds (46.90 k allocations: 122.731 MiB, 3.25% gc time)
retcode: Success
Interpolation: 3rd order Hermite
t: 2780-element Vector{Float64}:
      0.0
      0.1842530093836164
      0.9882003294241174
      4.0712734063454485
     11.468877042666529
     25.163064632955443
     49.586038028951926
     83.36346955211738
    137.50303891933373
    206.18214075191028
    314.516892030102
    476.2542840631606
    728.7916831352557
      ⋮
 133969.815265158
 136663.63134103097
 140055.4258559289
 144181.8999375682
 149370.41327000043
 154558.92660243265
 161070.99389492723
 169013.16056859927
 178032.10045064535
 187357.12845898993
 196682.1564673345
 205000.0
u: 2780-element Vector{Vector{Float64}}:
 [152640.04602394556, 12238.844347207129, -67.47370318939181, 0.12238742933122324, 0.12238742928703969, 0.12238742923269894, 0.1223874291679882, 0.12238742909268607, 0.12238742900656217, 0.12238742890937654  …  0.0017638899722423758, 0.001952362450087965, 0.003021926989795491, 0.002307204591585509, 0.9995225437942479, 0.999522529858612, 0.007684751290720895, 57.619305316284475, 56.49698307150776, 0.08793706442329717]
 [152640.04602675923, 12238.844344472389, -67.47608385405596, 0.12238150246352823, 0.12238487899828919, 0.12238646228031345, 0.12238710396683712, 0.12238733097534742, 0.12238740218353872, 0.12238742223223555  …  0.0017638903432949167, 0.0019523622796301684, 0.003021791443131714, 0.002307204498140665, 0.9995225437995142, 0.9995225299226123, 0.007684556194472399, 57.61930533073416, 56.49698308631932, 0.08793706437212857]
 [152640.0460412888, 12238.844335628484, -67.4863419588738, 0.1223615384582426, 0.12236820385901406, 0.12237352433837904, 0.12237764766092506, 0.12238074283456951, 0.12238299054015957, 0.12238456892777363  …  0.0017639002894421544, 0.001952344562701918, 0.003019913817156804, 0.002307201868610228, 0.9995225439620977, 0.9995225317016053, 0.007681109442438214, 57.619305393782035, 56.49698315094613, 0.0879370641488662]
 [152640.04613117408, 12238.844369009661, -67.52375733772861, 0.12231878096368617, 0.12232726067935705, 0.12233499971402545, 0.12234201738668696, 0.12234833829539732, 0.12235399250991266, 0.12235901490648916  …  0.0017640459438024142, 0.001951923697210742, 0.003011514625036301, 0.0023071595625756254, 0.9995225466102455, 0.999522560183886, 0.007661875426907316, 57.619305635604306, 56.4969833987625, 0.0879370633001058]
 [152640.04655034712, 12238.84489100134, -67.60266725864268, 0.1222491074415269, 0.1222590594164575, 0.12226851979829308, 0.12227749456196159, 0.12228599082846867, 0.12229401691843596, 0.1223015823424691  …  0.0017648365861398052, 0.0019490721282138946, 0.0029938018661324487, 0.0023068702445830512, 0.9995225647721525, 0.9995227533412281, 0.007620380270868266, 57.619304101796516, 56.49698422891565, 0.08793612653190575]
 [152640.04795075575, 12238.847244104358, -67.7148791835132, 0.12214343863327022, 0.12215492461892645, 0.12216604256656051, 0.12217679480255758, 0.12218718403807635, 0.1221972133656129, 0.1222068862540012  …  0.0017667245465694675, 0.001939974898076939, 0.002968746195410057, 0.0023057740579724637, 0.9995226337805907, 0.999523474332407, 0.007561731153973638, 57.6192067202659, 56.497012425406844, 0.0879012449672452]
 [152640.05182398023, 12238.85439858778, -67.83680356837378, 0.12197763253750511, 0.121990404262627, 0.12200289319934955, 0.1220150987719831, 0.12202702049826185, 0.12203865798116212, 0.1220500109007837  …  0.001768804431439548, 0.0019217398393596324, 0.002941688101330225, 0.002302645361648815, 0.9995228323121723, 0.9995254812830298, 0.007498489491083083, 57.618450458683725, 56.497428326669294, 0.08768483274019537]
 [152640.05872927356, 12238.867184311712, -67.9145349932821, 0.12176796424585437, 0.12178112375242402, 0.12179404269592281, 0.12180671884972011, 0.12181914995295658, 0.12183133370425427, 0.12184326775510433  …  0.0017684333983344995, 0.0019036036640327674, 0.0029245250738852047, 0.002297124747454202, 0.9995231890396084, 0.9995288950919317, 0.007458460520247774, 57.616899372972775, 56.499171522987425, 0.08722104990388099]
 [152640.07121698445, 12238.888862142012, -67.95943296168402, 0.12145262459741218, 0.12146536388339307, 0.12147788147770658, 0.12149017449090486, 0.12150223994927498, 0.12151407478954794, 0.12152567585327985  …  0.001764199196622062, 0.001890588364224957, 0.002914671403603113, 0.002287499913165783, 0.9995238338263256, 0.9995345163031448, 0.007435512847136509, 57.61582107315886, 56.50479722352017, 0.08638377123655408]
 [152640.0878821591, 12238.91431161045, -67.98524694945176, 0.12107343199180916, 0.12108532476451642, 0.12109700275291573, 0.12110846294866884, 0.12111970224890595, 0.12113071745100744, 0.12114150524707776  …  0.001757303378289173, 0.0018848891864662522, 0.0029090700526981646, 0.0022753872135243816, 0.9995246924404243, 0.99954103152635, 0.00742243650902569, 57.61889479280782, 56.5165398633969, 0.08533600528765778]
 [152640.11510339673, 12238.947942442048, -68.01798121474687, 0.12051259610176444, 0.12052318419873367, 0.1205335648051565, 0.12054373487376638, 0.12055369125886642, 0.12056343071111011, 0.1205729498719478  …  0.0017462102083818669, 0.0018798999555184428, 0.0029020240414503514, 0.002257215590593954, 0.9995260901633272, 0.9995497463766083, 0.007405943937517387, 57.63405534731, 56.54451836497793, 0.08379501342528518]
 [152640.15744861547, 12238.984184157529, -68.06194185192987, 0.1197532870468516, 0.11976210553209785, 0.11977072748541648, 0.11977914983340998, 0.11978736940132956, 0.11979538290771939, 0.11980318695872394  …  0.0017300362635786085, 0.0018735183930777715, 0.002892593989227183, 0.002232238355518714, 0.9995282516862253, 0.999559974457344, 0.007383846816288654, 57.67750306359394, 56.60506388514048, 0.08174186371649152]
 [152640.22666070657, 12239.011689718429, -68.11944543398864, 0.11873781620740094, 0.11874424978900334, 0.11875050414720081, 0.11875657622804185, 0.11876246287430275, 0.11876816082003816, 0.11877366668479465  …  0.0017060629772566373, 0.0018650998655105767, 0.0028803166474621997, 0.002198070372410079, 0.999531748148637, 0.99957140388287, 0.007355048495990009, 57.78595480968577, 56.73589198087783, 0.07905613334429526]
 ⋮
 [152693.9094169941, 12184.884195061568, -68.0848417552605, 0.11555315567184533, 0.11555278111851595, 0.11555240401255659, 0.1155520242417691, 0.11555164168925715, 0.11555125623318797, 0.11555086774653917  …  0.0016040796500118894, 0.0018658472109752064, 0.0028880919114209016, 0.0021144988161448356, 0.9899331868619383, 0.9995815880061717, 0.007372310292433761, 62.494098387619246, 61.49167769309984, 0.0718558075488777]
 [152693.7349270515, 12185.028902344351, -68.08141851296837, 0.11564821742464812, 0.11564809196379079, 0.11564796564842346, 0.11564783844113273, 0.1156477103029277, 0.1156475811931598, 0.11564745106943795  …  0.0016058295200898863, 0.0018663542044110083, 0.002888820998639085, 0.002116108122445755, 0.9948710599904012, 0.9995810994199659, 0.007374029933257946, 62.602562833858, 61.59748372055049, 0.07211415766667986]
 [152693.51862785345, 12185.233993768281, -68.08081580638301, 0.11568389557390969, 0.1156838628941552, 0.11568383011251834, 0.11568379722190708, 0.11568376421492645, 0.11568373108386358, 0.11568369782067292  …  0.0016063389415162657, 0.0018664501309950709, 0.002888946406310852, 0.0021164799507669097, 0.9976711191114656, 0.9995807934004626, 0.007374296867021998, 62.64335278282527, 61.63726420692503, 0.07221198791220931]
 [152693.26001180694, 12185.48959099249, -68.08121163577833, 0.1156954443400513, 0.11569543825540965, 0.11569543218291896, 0.11569542612208146, 0.11569542007234727, 0.11569541403311275, 0.11569540800371819  …  0.001606291931051056, 0.001866398102651513, 0.002888865096970763, 0.0021164059913932384, 0.9989428859588773, 0.999580689265147, 0.007374124200127033, 62.65301516833919, 61.646623035724645, 0.07224338392822158]
 [152692.94148220762, 12185.807508555421, -68.08187526627945, 0.11570107513707062, 0.11570107605716645, 0.1157010770247509, 0.1157010780414748, 0.11570107910900512, 0.11570108022902607, 0.11570108140323979  …  0.0016062295439797291, 0.0018663052786664313, 0.002888712549611433, 0.002116221839583373, 0.9994207726430377, 0.9995812295762702, 0.007373656704163249, 62.652458675696856, 61.645939316201584, 0.07225709490663301]
 [152692.63002585256, 12186.118979693392, -68.08262780538278, 0.11570351709935411, 0.11570351667281244, 0.11570351631835661, 0.11570351603724614, 0.11570351583080105, 0.11570351570040462, 0.11570351564750629  …  0.0016059679351072206, 0.001866200914687765, 0.002888561122081898, 0.0021159810717152985, 0.9995408991472481, 0.9995811845158319, 0.007373406325148475, 62.65099191716847, 61.64443345089232, 0.07226260561216306]
 [152692.2488699209, 12186.500186041383, -68.08345919087942, 0.11570774868745277, 0.11570774925176999, 0.11570774987615821, 0.11570775056191906, 0.11570775131040643, 0.1157077521230291, 0.11570775300125352  …  0.0016056889143966266, 0.001866085919964952, 0.0028883840071190605, 0.002115725677701799, 0.9995739059972749, 0.9995813278251715, 0.007373028548984384, 62.64765994394472, 61.641028299376416, 0.07227200665284517]
 [152691.79744968357, 12186.951730803436, -68.08448651690412, 0.11571206600727083, 0.11571206612738491, 0.11571206630850304, 0.1157120665518736, 0.11571206685879545, 0.1157120672306206, 0.11571206766875704  …  0.0016054969563990644, 0.0018659450217724633, 0.0028881631937818925, 0.0021154234133918108, 0.9995804418148716, 0.9995814667714464, 0.007372462098276309, 62.64397091329136, 61.637266756729396, 0.07228161028593971]
 [152691.30458436458, 12187.444715802152, -68.0855859291069, 0.11571709813433517, 0.11571709855422545, 0.11571709903148317, 0.11571709956725161, 0.11571710016272127, 0.11571710081913254, 0.11571710153777814  …  0.0016052240705574288, 0.001865793093181328, 0.0028879343959607967, 0.002115099374294442, 0.9995813883988347, 0.9995822273840506, 0.00737214460101173, 62.63973269635586, 61.63294136957926, 0.07229330523873762]
 [152690.81450019413, 12187.934862119164, -68.08666137749051, 0.11572237181242624, 0.11572237300519034, 0.11572237425005179, 0.1157223755481652, 0.115722376900734, 0.11572237830901266, 0.1157223797743094  …  0.001604996637039195, 0.0018656451079984047, 0.0028876976129570153, 0.0021147745454111275, 0.999581642306344, 0.9995818264594976, 0.0073714159608775365, 62.635758052625675, 61.628877623064476, 0.07230423327507342]
 [152690.34446290907, 12188.40505801524, -68.08774071150177, 0.11572672704469153, 0.11572672750297519, 0.11572672801173878, 0.11572672857210893, 0.1157267291852564, 0.11572672985239814, 0.11572673057480008  …  0.0016046841235744075, 0.0018654943066299724, 0.002887466244914795, 0.002114440465045214, 0.9995816010171785, 0.9995816922358677, 0.007370842669770941, 62.63175302797355, 61.6248010418821, 0.07231367700297381]
 [152689.941462889, 12188.808146934349, -68.088640103516, 0.11573074721780516, 0.11573074752004323, 0.11573074787247822, 0.11573074827619276, 0.11573074873231155, 0.11573074924200386, 0.11573074980648565  …  0.001604456481001354, 0.0018653697052767896, 0.0028872740098933813, 0.002114166076709945, 0.9995816977395495, 0.9995816885158855, 0.007370435174449336, 62.6284128429165, 61.62139324907382, 0.07232248450078153]
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")
"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/docs/caf-ap.pdf"
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")
"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/docs/caf-cat.pdf"
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)

CaMKII activities

Simulations

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

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/docs/caf-exp.pdf"
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