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)
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 = OrdinaryDiffEqNonlinearSolve.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)
11.312235 seconds (19.62 M allocations: 946.074 MiB, 2.49% gc time, 93.04% compilation time)
retcode: Success
Interpolation: 3rd order Hermite
t: 4071-element Vector{Float64}:
0.0
0.019333123284849308
0.09098129546757994
0.20735582943983855
0.45611910276862533
1.0472562928406122
2.0342667657223696
3.451776641148454
6.733792423912806
12.450117081023194
⋮
153525.25012366346
158165.8598019807
163776.6411118618
169611.6642461836
176342.19489586214
183684.1140466068
191258.90946281631
199427.37350661293
205000.0
u: 4071-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, 0.0025849478335103777]
[150952.7517373371, 13838.368384399068, -68.91207316777846, 0.12125418995384041, 0.12120713813483534, 0.12117519662647316, 0.12115494411090462, 0.12114295934422187, 0.12113633873395535, 0.12113292110288301 … 0.2607122383588733, 0.00976754294689657, 0.0018699196262940568, 0.0923749578279845, 0.2216542075240971, 0.9660430731013478, 0.0070030143052343926, 829.9990964774663, 829.9883445519497, 0.00256770780104998]
[150952.75361533565, 13838.358559292059, -69.06429960994137, 0.12136450208851983, 0.1213063255235844, 0.12125925929399752, 0.12122229800810434, 0.12119414515426227, 0.1211733598588045, 0.12115849269665879 … 0.26060507831375035, 0.009765228548607825, 0.001850533769446942, 0.09230364339951613, 0.22177624785138977, 0.9660987611411453, 0.006946470397388757, 829.9976227528975, 829.9738229154025, 0.0025298083713907005]
[150952.75694915713, 13838.34240329337, -69.31024285744343, 0.1214919651325424, 0.12142927821043338, 0.12137426379919636, 0.12132672249013034, 0.12128628091507473, 0.12125242557826561, 0.12122454121844703 … 0.26047114911179464, 0.009763403076884485, 0.0018178174419014683, 0.09218462776986637, 0.2219798989175973, 0.9661914345949096, 0.0068337541728754475, 829.9944193668179, 829.9509077855928, 0.0024748079782158957]
[150952.76215620188, 13838.319723120678, -69.64637448767432, 0.12162015426876954, 0.12155743299711902, 0.12149988983034497, 0.1214475947100359, 0.12140052118634262, 0.12135855488207907, 0.12132150441596071 … 0.2603648729749554, 0.009765046552800477, 0.001773815690753224, 0.09201383579531924, 0.22227216398019892, 0.9663239343003682, 0.006675512062656749, 829.9883533251192, 829.9205247545176, 0.0024106893964811324]
[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]
[150952.80529264064, 13838.18882346682, -71.35304509818071, 0.12196378364408175, 0.12191937753328333, 0.12187579038290348, 0.1218331857334074, 0.12179171693004406, 0.12175152667167365, 0.12171274673876366 … 0.26104417804603025, 0.009873892913308327, 0.0015688568862426045, 0.09093422465365385, 0.22412560303273427, 0.9671554512230358, 0.005926150085676071, 829.923524981244, 829.7704141396295, 0.002228995040224517]
⋮
[151185.30233112013, 13607.749833006814, -70.4308244091814, 0.1369457851908891, 0.13694582943940015, 0.13694586953266724, 0.13694590539945092, 0.13694593696561688, 0.13694596415398844, 0.13694598688419007 … 0.0011157701814148247, 0.0015675234985922694, 0.0024264390093091297, 0.0015108660008012335, 0.9996108819600831, 0.9997476285219717, 0.006285742961033833, 784.9343641366892, 784.5705928361887, 0.0020427822499610067]
[151213.6576494461, 13579.42650863124, -70.37723151711728, 0.13663485729758507, 0.13663504734795034, 0.13663523554792348, 0.13663542189927316, 0.13663560640383327, 0.13663578906350513, 0.1366359698802619 … 0.0011251534126208364, 0.001573785829356949, 0.0024361230542041612, 0.0015226265701693443, 0.9997062624414006, 0.9997446880935222, 0.006308692511329212, 784.9757120846451, 784.6163365838676, 0.00202597500787535]
[151247.1533714861, 13545.998515545485, -70.31510224724539, 0.13623255413656493, 0.13623282219769817, 0.13623308974090412, 0.13623335680901974, 0.13623362344661186, 0.13623388970006559, 0.136234155617678 … 0.0011360309269206044, 0.001581071452399359, 0.0024473974939947405, 0.0015363302060716459, 0.9997341725464177, 0.999741241148309, 0.006335401714922374, 784.716034978723, 784.3627792024342, 0.001996646756049573]
[151281.09701808463, 13512.139339623396, -70.25249211840439, 0.13580882644152562, 0.13580912484065802, 0.13580942334341917, 0.13580972201059593, 0.13581002090543107, 0.13581032009375013, 0.13581061964409374 … 0.0011471355458900435, 0.0015884495451688387, 0.002458811488758601, 0.0015502379269448979, 0.9997378359259561, 0.9997377231755966, 0.006362431269317277, 784.2869668994574, 783.9403317537905, 0.001962324919877862]
[151319.15383306387, 13474.18574761771, -70.18213292915233, 0.13532825872817536, 0.13532856655164824, 0.13532887481281694, 0.13532918358088902, 0.13532949292787053, 0.13532980292870875, 0.13533011366144387 … 0.001159679080864857, 0.0015967773659847466, 0.002471700867703817, 0.001566002491975293, 0.9997354225164649, 0.9997337138514423, 0.0063929429404904715, 783.7134909839972, 783.3744083454467, 0.0019219897448596562]
[151359.36895294566, 13434.084114116054, -70.1072898181639, 0.13482108457133518, 0.13482139084450803, 0.13482169773054928, 0.13482200530182656, 0.13482231363363376, 0.13482262280433888, 0.13482293289554292 … 0.0011732157522990206, 0.0016056845198666068, 0.0024854848266383112, 0.0015829377999891094, 0.999731350326438, 0.9997293823003752, 0.006425558662513274, 783.0557065812874, 782.724566948103, 0.0018789903164308625]
[151399.48570823882, 13394.082755688229, -70.03198079055801, 0.1343188426676469, 0.13431914303210035, 0.13431944411464505, 0.13431974598856425, 0.13432004873010414, 0.13432035241862517, 0.13432065713676222 … 0.0011869691560639811, 0.00161469734802366, 0.0024994316026318666, 0.0016001571586327901, 0.9997269430821425, 0.9997249530520704, 0.006458544300803697, 782.3704791996294, 782.0471494870949, 0.0018365180658422315]
[151441.23701638906, 13352.452891572499, -69.9528521557419, 0.1338012723847627, 0.1338015647820892, 0.1338018579767593, 0.13380215204206808, 0.1338024470542738, 0.13380274309274917, 0.13380304024014197 … 0.0012015959628564176, 0.001624220043277371, 0.00251416884800811, 0.0016184463726739821, 0.9997221973027169, 0.9997202209587296, 0.006493384188984897, 781.6361029305928, 781.3207468474991, 0.0017930492874457912]
[151468.85017708497, 13324.92061087143, -69.90007814148856, 0.13346209988381597, 0.1334623865596649, 0.13346267407533832, 0.13346296250387318, 0.13346325192125835, 0.13346354240658564, 0.1334638340422095 … 0.0012114432486751738, 0.0016306023325555676, 0.0025240455006063944, 0.0016307574425665674, 0.9997189832869459, 0.9997170198596287, 0.006516724021089417, 781.1406117188286, 780.8304378388485, 0.0017647619023671139]
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: 4138-element Vector{Float64}:
0.0
0.019332211071584192
0.09097534627605569
0.20734339686524408
0.4561200538541287
1.0549952720719427
2.0687580593126613
3.5324261824253345
6.954473747659736
12.881140201769806
⋮
152270.482708526
157174.07587050938
162194.01343084572
168138.29627423352
174916.26987407374
181898.84288967986
189304.81131705493
197588.12178364221
205000.0
u: 4138-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]
[150952.75040560117, 13838.37575462767, -68.79688468304944, 0.1211309809540452, 0.12113006189494423, 0.12113000299821446, 0.1211300001166239, 0.12113000000364073, 0.12113000000008267, 0.12113000000000056 … 0.2608055790255411, 0.009769882789165586, 0.0018798283012559313, 0.0924276668078433, 0.221563993694571, 0.9660018275573545, 0.007020212947405008, 830.0014907812235, 829.9994983969723, 0.002598561776347308]
[150952.75061240065, 13838.374716348011, -68.81397720473576, 0.12114238287990785, 0.12113303174274752, 0.12113060640007198, 0.12113010200803158, 0.12113001474369577, 0.12113000185234848, 0.12113000020174947 … 0.26078938725640693, 0.009769457815727975, 0.0018789474208576141, 0.0924190204915213, 0.22157879333123556, 0.9660085988422271, 0.007020182507782679, 830.0069923279007, 829.9976597572193, 0.0025932333906583892]
[150952.75095089723, 13838.373018773336, -68.84205163448622, 0.12116438512395096, 0.12114443083154028, 0.1211353044921302, 0.12113171992467786, 0.12113049616083325, 0.12113012844945044, 0.12113003007199945 … 0.26076374828883014, 0.009768798977675412, 0.0018768406238241547, 0.09240497731310347, 0.22160283004278358, 0.9660195923730465, 0.007017680221388922, 830.0158577065781, 829.9947407323419, 0.002584621446261353]
[150952.7516853767, 13838.369406865842, -68.90160259182096, 0.12120393253792845, 0.1211735958345763, 0.12115399268330548, 0.12114231020892302, 0.12113588865795849, 0.12113262872712134, 0.12113109689132587 … 0.26071163727178975, 0.009767513260722714, 0.0018706615190431774, 0.09237495857236798, 0.22165420888269807, 0.9660430748851897, 0.007004853088813848, 830.0345419613458, 829.9887756080547, 0.0025665030871097365]
[150952.7535137264, 13838.360815589964, -69.0421184107563, 0.12127164038451914, 0.12123369231137104, 0.12120363670655872, 0.12118067468437907, 0.12116376521507281, 0.12115176909538257, 0.12114357362996761 … 0.26060065813180305, 0.009765055027054551, 0.0018527422088444533, 0.09230271445722965, 0.22177785078777174, 0.9660994972023292, 0.006952675605532075, 830.07814410011, 829.9758982053276, 0.002524878616001687]
[150952.75679928518, 13838.346581408403, -69.27157622080777, 0.12134675555621606, 0.12130680044052823, 0.12127196546348169, 0.12124217405786958, 0.12121718646328616, 0.12119663497761278, 0.12118006281992985 … 0.26045565430474177, 0.009762833375314839, 0.0018222096890642778, 0.09218048699222062, 0.22198703092009986, 0.9661946906443825, 0.0068472036120339344, 830.1479502978362, 829.9585434198331, 0.0024610999647757185]
[150952.76194966168, 13838.326681500257, -69.58534388478576, 0.12141446087873138, 0.12137666702212292, 0.12134186045923348, 0.12131020885887851, 0.1212817846915382, 0.12125657408666768, 0.12123448815456439 … 0.26032881924894974, 0.009763716676849107, 0.0017811002406865242, 0.09200417115231563, 0.22228882452599166, 0.9663315006590419, 0.006699003733992941, 830.2409658671871, 829.9422438990155, 0.002382758683301368]
[150952.77573103318, 13838.282994292276, -70.2425024040955, 0.12148370617698102, 0.12145532836849142, 0.12142753330789133, 0.1214005690310996, 0.1213746427688511, 0.12134992079665144, 0.12132652897086685 … 0.2603166532077402, 0.009783000857592001, 0.0016985405358012685, 0.09159274697262061, 0.22299376432344578, 0.9666490840575152, 0.006398335505979061, 830.4298664467993, 829.9364424528658, 0.00224983154100249]
[150952.80458617522, 13838.215505646505, -71.1550700755306, 0.12146599978828716, 0.1214533998189489, 0.12143960641561435, 0.12142480441004645, 0.1214091612631606, 0.12139282572293232, 0.12137592664517365 … 0.2607890677215021, 0.009862701804147046, 0.0015916044910949702, 0.09088324181611296, 0.22421393887512645, 0.9671939916127574, 0.0060038545810325245, 830.6928613527689, 829.9982399691283, 0.0021239182944550396]
⋮
[150927.44243964445, 13855.447607216065, -70.59411328186074, 0.12690624823441543, 0.12690644090797035, 0.1269066280353914, 0.12690680954292674, 0.12690698535384923, 0.1269071553883046, 0.12690731956315018 … 0.0010878271778324276, 0.0015486035494281644, 0.0023971671168706568, 0.0014756873624978488, 0.9995674489205065, 0.9997563697872099, 0.006216329537707399, 922.8372442674146, 921.3111350425919, 0.007314687500376852]
[150962.49883419095, 13820.442136579664, -70.5303674902552, 0.12643983697100486, 0.1264400261156667, 0.12644020991350105, 0.12644038829407445, 0.12644056118411226, 0.12644072850735377, 0.12644089018439816 … 0.0010985560900862263, 0.0015559585586874998, 0.0024085528978147644, 0.0014892812418434397, 0.9997032071128503, 0.9997529999609059, 0.00624333639730132, 922.9973924319162, 921.4901697335731, 0.0072229081855892845]
[150997.58514478029, 13785.406967561099, -70.46599490737586, 0.1259769588321469, 0.12597714433992277, 0.12597732469367884, 0.12597749982615816, 0.12597766966739224, 0.12597783414456273, 0.12597799318185446 … 0.0011095708614137995, 0.0015634241833136654, 0.0024201048896057534, 0.0015031331537498892, 0.9997381113366628, 0.9997495493507632, 0.0062707272540484, 923.1505571859383, 921.6620339612563, 0.007132108627796466]
[151038.1081545161, 13744.943213098719, -70.39092616933908, 0.1254473180297082, 0.12544749940724415, 0.12544767585454605, 0.12544784730803854, 0.1254480137015833, 0.12544817496634805, 0.12544833103066796 … 0.0011225355991201177, 0.0015721723973323345, 0.0024336452230380038, 0.0015194458293539784, 0.9997449540510898, 0.9997454633663886, 0.006302819980313453, 923.3186796524564, 921.8514954088417, 0.0070285830828955235]
[151082.99594044487, 13700.121315675331, -70.30685771442971, 0.12486681627358946, 0.1248669929359439, 0.12486716490613299, 0.12486733212443828, 0.12486749452873408, 0.12486765205436451, 0.12486780463401277 … 0.0011372511426252887, 0.0015820251283859097, 0.0024488971146818706, 0.001537920336017425, 0.999742676664399, 0.9997408078707505, 0.006338953528064392, 923.4938704460691, 922.0500067523433, 0.006915552382399907]
[151127.81298684722, 13655.370303294154, -70.22192860927998, 0.1242938299946404, 0.12429400186166206, 0.12429416927680431, 0.12429433218423981, 0.12429449052589163, 0.12429464424131842, 0.12429479326759252 … 0.001152306521523222, 0.0015920469986002194, 0.0024644027648663166, 0.0015568059542885476, 0.9997382835800502, 0.9997360201470814, 0.006375667093786704, 923.657084738738, 922.2361636601547, 0.006804459843891177]
[151173.81665812104, 13609.434645286381, -70.13370024196757, 0.1237126276168541, 0.1237127945278469, 0.1237129572232062, 0.12371311565088065, 0.12371326975672094, 0.12371341948437255, 0.1237135647751622 … 0.001168074850819175, 0.0016025195294372657, 0.0024806130596337454, 0.001576666451342757, 0.9997332832916821, 0.9997309526604555, 0.006414030167677571, 923.8125540137345, 922.4148307355978, 0.006692241743160747]
[151223.466573965, 13559.858390115198, -70.03725613107402, 0.12309331860229751, 0.123093480019859, 0.12309363747355163, 0.1230937909153088, 0.12309394029512596, 0.12309408556096196, 0.12309422665863391 … 0.0011856577953648256, 0.0016140477936521628, 0.002498452995810272, 0.001598658839833547, 0.9997276295982898, 0.9997253010153646, 0.006456227895199014, 923.9665888621122, 922.5934983498439, 0.006573203267322105]
[151266.33084832662, 13517.057904806577, -69.95294083197554, 0.12256542139079514, 0.12256557800396242, 0.12256573086329174, 0.1225658799239867, 0.12256602513944476, 0.12256616646116517, 0.12256630383865115 … 0.0012012301821989948, 0.0016241926698933754, 0.0025141532138654244, 0.0016181313950834966, 0.9997225836604149, 0.999720262839051, 0.006493344733551902, 924.0880576543809, 922.7358937570431, 0.00647216934281195]
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)
Compare the numbers
ca_ctl = sol(tspan[1]:1:tspan[2], idxs=sys.Cai_mean)
println(extrema(ca_ctl))
(0.2350505644679326, 0.5781214777887043)
ca_iso = sol2(tspan[1]:1:tspan[2], idxs=sys.Cai_mean)
println(extrema(ca_iso))
(0.19033626526941844, 0.7110939450930854)
savefig("iso-caT.pdf")
savefig("iso-caT.png")
"/home/github/actions-runner-2/_work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/iso-caT.png"
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")
savefig("iso-camkact.png")
"/home/github/actions-runner-2/_work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/iso-camkact.png"
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"])
iso = chemicaldf[!, "isoproterenol 100nM Mean"]
iso_error = chemicaldf[!, "isoproterenol 100nM SD"] ./ sqrt.(chemicaldf[!, "isoproterenol 100nM N"])
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/github/actions-runner-2/_work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/iso-exp.pdf"
This notebook was generated using Literate.jl.