Effects of isoproterenol

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

[ 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

Setup model

sys = build_neonatal_ecc_sys(simplify=true, reduce_iso=true, reduce_camk=true)
tend = 205second
prob = ODEProblem(sys, [], tend)
stimstart = 30second
stimend = 120second
alg = KenCarp47()

KenCarp47(; linsolve = nothing, nlsolve = NLNewton{Rational{Int64}, Rational{Int64}, Rational{Int64}, Nothing}(1//100, 10, 1//5, 1//5, false, true, nothing), precs = DEFAULT_PRECS, smooth_est = true, extrapolant = linear, controller = PI, autodiff = ADTypes.AutoForwardDiff(),)

Without isoproterenol

@unpack Istim = sys
callback = build_stim_callbacks(Istim, stimend; period=1second, starttime=stimstart)
@time sol = solve(prob, alg; callback)

  9.928643 seconds (23.26 M allocations: 1.224 GiB, 1.86% gc time, 92.11% compilation time)

retcode: Success
Interpolation: 3rd order Hermite
t: 4019-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
      ⋮
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 153105.87173409184
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 168819.53333337096
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 189877.09234962234
 197904.13271346927
 205000.0
u: 4019-element Vector{Vector{Float64}}:
 [150952.75035000002, 13838.37602, -68.79268, 0.12113, 0.12113, 0.12113, 0.12113, 0.12113, 0.12113, 0.12113  …  0.26081, 0.00977, 0.00188, 0.09243, 0.22156, 0.966, 0.00702, 830.0, 830.0, 0.0026]
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 ⋮
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i = (sys.t / 1000, sys.vm)
plot(sol, idxs=i, tspan=(100second, 101second), title="Action potential", xlabel="Time (s)")

plot(sol, idxs=(sys.t / 1000, [sys.Cai_sub_SR, sys.Cai_sub_SL, sys.Cai_mean]), tspan=(100second, 101second), title="Calcium transient", xlabel="Time (s)", ylabel="Conc. (μM)", label=["Ca (SR)" "Ca (SL)" "Ca (avg)"])

plot(sol, idxs=(sys.t / 1000, sys.CaMKAct * 100), title="Active CaMKII", label=false, ylabel="Active fraction (%)", xlabel="Time (s)")

0.1uM isoproterenol

prob2 = remake(prob, p=[sys.ISO => 0.1μM])
sol2 = solve(prob2, alg; callback)

retcode: Success
Interpolation: 3rd order Hermite
t: 4135-element Vector{Float64}:
      0.0
      0.0193322110715843
      0.09097534627605619
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     12.881140201769878
     22.49832960597836
     35.58379357534269
     53.3125926398934
      ⋮
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 156343.54776739283
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 187606.5812407107
 193771.36169472226
 202258.5546944703
 205000.0
u: 4135-element Vector{Vector{Float64}}:
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 [150952.75679928518, 13838.346581408403, -69.27157622080777, 0.12134675555621605, 0.12130680044052823, 0.12127196546348167, 0.12124217405786951, 0.12121718646328612, 0.12119663497761277, 0.12118006281992981  …  0.26045565430474177, 0.009762833375314839, 0.0018222096890642776, 0.09218048699222062, 0.22198703092009986, 0.9661946906443825, 0.0068472036120339344, 830.1479502978362, 829.9585434198331, 0.002461099964775718]
 [150952.76194966168, 13838.326681500257, -69.58534388478576, 0.12141446087873134, 0.12137666702212285, 0.12134186045923342, 0.12131020885887848, 0.12128178469153819, 0.12125657408666768, 0.12123448815456438  …  0.26032881924894974, 0.009763716676849107, 0.0017811002406865244, 0.09200417115231563, 0.22228882452599166, 0.9663315006590419, 0.00669900373399294, 830.2409658671871, 829.9422438990155, 0.0023827586833013678]
 [150952.77573103318, 13838.282994292276, -70.2425024040955, 0.12148370617698095, 0.12145532836849135, 0.12142753330789131, 0.12140056903109958, 0.12137464276885107, 0.1213499207966514, 0.1213265289708668  …  0.2603166532077402, 0.009783000857592001, 0.0016985405358012696, 0.0915927469726206, 0.22299376432344578, 0.9666490840575152, 0.006398335505979063, 830.4298664467993, 829.9364424528658, 0.002249831541002491]
 [150952.80458617522, 13838.215505646505, -71.1550700755306, 0.12146599978828701, 0.12145339981894875, 0.12143960641561419, 0.12142480441004629, 0.12140916126316044, 0.12139282572293218, 0.12137592664517353  …  0.2607890677215021, 0.009862701804147046, 0.0015916044910949678, 0.09088324181611294, 0.22421393887512647, 0.9671939916127574, 0.006003854581032515, 830.6928613527689, 829.9982399691283, 0.002123918294455039]
 [150952.8616536535, 13838.122495950769, -72.15638575409744, 0.12127303565518076, 0.12127792055105953, 0.12128047669019508, 0.12128078692755696, 0.12127892787139628, 0.12127496903108642, 0.12126897201355086  …  0.2616039691254254, 0.010066850253124765, 0.0014852940400847771, 0.08974136902301866, 0.226195072013618, 0.9680692720167795, 0.00559992791149385, 831.0299370796422, 830.1961996740982, 0.002043756904619385]
 [150952.95232341983, 13838.015849102601, -72.89797298395173, 0.12089050922981197, 0.12090768017344662, 0.12092217882228606, 0.12093401401019802, 0.12094319319109635, 0.1209497220291765, 0.12095360399633776  …  0.2613818205988868, 0.010374411026605777, 0.0014166683582658396, 0.08820843503293029, 0.2288934815034348, 0.9692421333840218, 0.005318857432641635, 831.4206406215297, 830.5349745441919, 0.002010130362014417]
 [150953.0873486748, 13837.888088474529, -73.32024943624373, 0.12034382762427788, 0.12036686895969642, 0.12038740073385053, 0.12040539217713231, 0.12042081224252121, 0.12043362943174785, 0.12044381161406674  …  0.2586415589272934, 0.010683610282549095, 0.0013873205295735292, 0.08617167905558495, 0.23254736845547558, 0.9707843714308044, 0.005165285805355317, 831.914732271086, 831.0219466889984, 0.0019919550000229574]
 ⋮
 [150868.57792969127, 13914.227496567912, -70.69976703403357, 0.12769889905152434, 0.12769909800408807, 0.12769929107785602, 0.12769947819362037, 0.1276996592689618, 0.12769983421808598, 0.12770000295164952  …  0.001070140092671572, 0.0015364913036187526, 0.0023784147304040993, 0.0014534320992531508, 0.9981720814215561, 0.9997618570640584, 0.006171823682557662, 922.5513238516847, 920.9930115384866, 0.007471313819928355]
 [150895.9077211093, 13886.937163146473, -70.65094777282852, 0.1273293351701255, 0.12732953118381007, 0.12732972146481406, 0.12732990593620486, 0.12733008451791905, 0.12733025712660265, 0.1273304236754417  …  0.0010782737552193316, 0.0015420746091594413, 0.002387061139046297, 0.0014636698668379535, 0.999161004952174, 0.999759337633275, 0.006192348798200278, 922.6867813814238, 921.1435024765897, 0.007398170855575605]
 [150923.70785119603, 13859.177270979826, -70.60087635275637, 0.12695610782314581, 0.12695630068111305, 0.12695648797756454, 0.12695666963849725, 0.12695684558691622, 0.12695701574268187, 0.12695718002234765  …  0.0010866572346522484, 0.001547822959384787, 0.0023959620805009737, 0.0014742529136752835, 0.999539923312339, 0.9997567249196991, 0.0062134709261020896, 922.8198829769782, 921.2917515028904, 0.0073245197719056234]
 [150956.6187147592, 13826.314189776862, -70.54110277547377, 0.12651778225698412, 0.12651797196376646, 0.12651815629295968, 0.12651833517362307, 0.12651850853195237, 0.1265186762911339, 0.1265188383711891  …  0.0010967794809075475, 0.0015547183343237651, 0.0024066315107807144, 0.0014869831924248325, 0.9996909553239575, 0.9997535701805159, 0.006238780040877805, 922.971075373069, 921.4606991590817, 0.007238228951575744]
 [150993.3250348188, 13789.661340753633, -70.47384314763443, 0.12603297147267323, 0.12603315749211752, 0.12603333833678584, 0.1260335139390861, 0.1260336842286991, 0.12603384913243948, 0.12603400857410785  …  0.0011082167393088522, 0.0015625100254287247, 0.002418693176625084, 0.0015014376432098348, 0.9997360968472492, 0.9997499718312494, 0.006267381163349558, 923.1323809169393, 921.6415965711435, 0.007143086075388378]
 [151030.95198954563, 13752.08938708879, -70.40424484723755, 0.1255404661522541, 0.12554064827705233, 0.12554082542915063, 0.12554099754425377, 0.1255411645554723, 0.12554132639318946, 0.12554148298492185  …  0.0011202341467272728, 0.0015706131858370133, 0.0024312364688979424, 0.001516539547629021, 0.999744768640635, 0.9997461919294898, 0.006297113591478004, 923.2897084836691, 921.8187771390185, 0.00704675786760096]
 [151074.03077395892, 13709.07379239066, -70.3237244461183, 0.12498223734955859, 0.1249824149500789, 0.12498258781596323, 0.12498275588682323, 0.12498291909983734, 0.12498307738962662, 0.12498323068812273  …  0.0011343095994690384, 0.0015800472776391747, 0.0024458303181922594, 0.0015341954465510688, 0.9997434153103265, 0.9997417491177489, 0.006331688104796494, 923.4597999739248, 922.0113036830816, 0.006937996984118315]
 [151115.85948465823, 13667.306651234054, -70.24467520578284, 0.12444604318154842, 0.12444621639949686, 0.12444638510377543, 0.12444654923757184, 0.12444670874178305, 0.12444686355489831, 0.124447013612875  …  0.0011482354065336258, 0.0015893578618842773, 0.0024602408443038922, 0.0015517256493502826, 0.9997395313805453, 0.9997373118314591, 0.006365813483196116, 923.6146819742337, 922.1876724309261, 0.006833930884968582]
 [151163.40866070002, 13619.827718569324, -70.15375730957557, 0.12384349404642822, 0.12384366205109126, 0.12384382579012292, 0.12384398521068285, 0.12384414025779981, 0.12384429087426266, 0.12384443700050499  …  0.0011644922679930215, 0.0016001339858296311, 0.0024769187511507066, 0.0015721281378393182, 0.9997344347951828, 0.9997321134613302, 0.006405289011420214, 923.7784770864921, 922.3755365431966, 0.006717471837774962]
 [151200.82606813576, 13582.46575828045, -70.0813955648416, 0.12337470083653851, 0.12337486479310114, 0.12337502467231169, 0.12337518042431692, 0.12337533199725298, 0.12337547933714323, 0.1233756223877889  …  0.001177599345285002, 0.001608762385461543, 0.002490272527087365, 0.0015885561820287806, 0.9997302316254224, 0.9997279021130013, 0.006436881287716186, 923.8981206351701, 922.5138490527056, 0.006627221043422825]
 [151250.65169011973, 13532.71417217486, -69.98390525508839, 0.12275782332068579, 0.12275798179961825, 0.12275813644931892, 0.12275828722382258, 0.12275843407530986, 0.12275857695401286, 0.12275871580811433  …  0.0011954951124043243, 0.0016204577080472665, 0.002508372823612225, 0.0016109545458471704, 0.9997244452962354, 0.9997221251109589, 0.006479679154486839, 924.0449298643186, 922.6851457937693, 0.006508950781421128]
 [151266.33920149156, 13517.050030534614, -69.95293244206611, 0.1225653274313242, 0.1225654840868531, 0.1225656369887973, 0.12256578609240996, 0.12256593135113784, 0.1225660727165292, 0.12256621013813575  …  0.0012012351502659548, 0.0016241917933535663, 0.0025141525378536873, 0.00161813616769132, 0.9997225815274668, 0.999720262204486, 0.006493340266769187, 924.088116506726, 922.735955904178, 0.006472154406684705]

plot(sol2, idxs=(sys.t / 1000, sys.vm), tspan=(100second, 101second), title="Action potential", xlabel="Time (s)")

plot(sol2, idxs=(sys.t / 1000, [sys.Cai_sub_SR, sys.Cai_sub_SL, sys.Cai_mean]), tspan=(100second, 101second), title="Calcium transcient", xlabel="Time (s)", ylabel="Conc. (μM)", label=["Ca (SR)" "Ca (SL)" "Ca (avg)"])

plot(sol2, idxs=(sys.t / 1000, sys.CaMKAct * 100), title="Active CaMKII", label=false, ylabel="Active fraction (%)", xlabel="Time (s)")

Comparison

i = (sys.t / 1000, sys.Cai_mean)
tspan = (100second, 101second)
plot(sol, idxs=i, title="Calcium transcient", lab="ISO (-)"; tspan)
plot!(sol2, idxs=i, lab="ISO (0.1uM)", xlabel="Time (s)", ylabel="Concentration (μM)"; tspan)

savefig("iso-caT.pdf")

"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/docs/iso-caT.pdf"

Maximal and minimal calcium concentrations in calcium transients.

ca_ctl = sol(tspan[1]:1:tspan[2], idxs=sys.Cai_mean)
println(extrema(ca_ctl))

(0.23504352227636677, 0.5781129853775007)

ca_iso = sol2(tspan[1]:1:tspan[2], idxs=sys.Cai_mean)
println(extrema(ca_iso))

(0.1903362696321693, 0.7110939356326587)

i = (sys.t / 1000, sys.CaMKAct * 100)
plot(sol, idxs=i, title="Active CaMKII", lab="ISO (-)")
plot!(sol2, idxs=i, lab="ISO (0.1uM)", ylabel="Active fraction (%)", xlabel="Time (s)")

savefig("iso-camkact.pdf")

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

i = (sys.t / 1000, sys.vm)
tspan = (100second, 101second)
plot(sol, idxs=i, title="Action potential", lab="ISO (-)"; tspan)
plot!(sol2, idxs=i, lab="ISO (0.1uM)", xlabel="Time (ms)", ylabel="Voltage (mV)"; tspan)

Experimental data

chemicaldf = CSV.read(joinpath(@__DIR__, "data/CaMKAR-chemical.csv"), DataFrame)
ts = Dates.value.(chemicaldf[!, "Time"]) ./ 10^9
ctl = chemicaldf[!, "Ctrl Mean"]
ctl_error = chemicaldf[!, "Ctrl SD"] ./ sqrt.(chemicaldf[!, "Ctrl N"])

42-element Vector{Float64}:
 0.02305850621757014
 0.023225557529411765
 0.023536003837902393
 0.022995786588235295
 0.023056161133316953
 0.02236794743822152
 0.02448575734900888
 0.02631837493460871
 0.029628792824062226
 0.0306227531696316
 0.03440544933688571
 0.03638835689675227
 0.03637182395488222
 ⋮
 0.028657939696241287
 0.02769675888235294
 0.027350470452150753
 0.02665056333747046
 0.02525893438851731
 0.024749347823716496
 0.024158682609370527
 0.023572491294117648
 0.0240760416039372
 0.023230166
 0.023759599761907887
 0.02369791084482974

iso = chemicaldf[!, "isoproterenol 100nM Mean"]
iso_error = chemicaldf[!, "isoproterenol 100nM SD"] ./ sqrt.(chemicaldf[!, "isoproterenol 100nM N"])

42-element Vector{Float64}:
 0.01906411500114547
 0.019397124616823788
 0.019533446274478245
 0.019307032321568045
 0.0188119595
 0.019208707594448062
 0.020659484720981783
 0.022823236115241556
 0.02568418993766601
 0.02954342161034184
 0.03238614946756098
 0.033998006747069244
 0.033618037698890234
 ⋮
 0.023909718528548993
 0.023521321658818695
 0.022584741326751114
 0.022059148111952916
 0.020698453917127702
 0.020674867906488113
 0.019922601239830914
 0.019312468873824668
 0.019367967435545023
 0.018689615199686285
 0.01921783399052236
 0.01872515441384824

plot(ts, ctl, yerr=ctl_error, lab="Control", color=:blue, markerstrokecolor=:blue)
plot!(ts, iso, yerr=iso_error, lab="ISO 100nM", color=:red, markerstrokecolor=:red)
plot!(xlabel="Time (sec.)", ylabel="CaMKII activity (A.U.)")

savefig("iso-exp.pdf")

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