Model Mathematics

Component: environment

Component: Membrane

i_tot=i_f+i_Kr+i_Ks+i_to+i_NaK+i_NaCa+i_Na+i_CaL+i_CaT+i_KACh ddtimeV_ode=-i_totC RTONF=R⁢TF V=V_clampifclamp_mode≥1V_odeotherwise

Component: Voltage_clamp

V_clamp=V_testiftime>t_holding∧time<t_holding+t_testV_holdingotherwise

Component: Rate_modulation_experiments

Component: Ionic_values

E_Na=RTONF⁢ln⁡NaoNai E_K=RTONF⁢ln⁡KoKi E_Ca=0.5⁢RTONF⁢ln⁡CaoCa_sub

Component: Nai_concentration

ddtimeNai_=-1⁢i_Na+i_fNa+i_siNa+3⁢i_NaK+3⁢i_NaCa1⁢V_i+V_sub⁢F Nai=7.5ifBAPTA_10_mM>0Nai_otherwise

Component: i_f

g_f_Na=0.03⁢1-0.66ifIva_3_uM≥10.03otherwise g_f_K=0.03⁢1-0.66ifIva_3_uM≥10.03otherwise ICs_on_Icontrol=10.6015510.60155+ⅇ-0.71⁢V25ifCs_5_mM≥11otherwise i_fNa=y2⁢KoKo+Km_f⁢g_f_Na⁢V-E_Na⁢ICs_on_Icontrol i_fK=y2⁢KoKo+Km_f⁢g_f_K⁢V-E_K⁢ICs_on_Icontrol i_f=i_fNa+i_fK

Component: i_f_y_gate

ACh_shift=-1-9.898⁢1e-6⁢ACh0.6181e-6⁢ACh0.618+0.00122423ifACh>00otherwise Iso_shift=7.5ifIso_1_uM>00otherwise ANS_shift_i_f_y_gate=Ki_f⁢cAMPni_fK_05i_fni_f+cAMPni_f-18.76ifANS>00otherwise tau_y=0.71665290.0708⁢ⅇ-V+5-ACh_shift-Iso_shift-ANS_shift_i_f_y_gate20.2791+10.6⁢ⅇV-ACh_shift-Iso_shift-ANS_shift_i_f_y_gate18 y_infinity=11+ⅇV+52.5-ACh_shift-Iso_shift-ANS_shift_i_f_y_gate9 ddtimey=y_infinity-ytau_y

Component: i_NaK

Iso_increase=1.2ifIso_1_uM>01otherwise ANS_cond_i_NaK=-0.2152+K_i_NaK⁢PKA10.0808K_05i_NaK10.0808+PKA10.0808ifANS>00otherwise i_NaK=Iso_increase⁢1+ANS_cond_i_NaK⁢i_NaK_max⁢1+Km_KpKo1.2-1⁢1+Km_NapNai1.3-1⁢1+ⅇ-V-E_Na+11020-1

Component: i_NaCa

i_NaCa=K_NaCa⁢x2⁢k21-x1⁢k12x1+x2+x3+x4 x1=k41⁢k34⁢k23+k21+k21⁢k32⁢k43+k41 x2=k32⁢k43⁢k14+k12+k41⁢k12⁢k34+k32 x3=k14⁢k43⁢k23+k21+k12⁢k23⁢k43+k41 x4=k23⁢k34⁢k14+k12+k14⁢k21⁢k34+k32 k43=NaiK3ni+Nai k12=Ca_subKci⁢ⅇ-Qci⁢VRTONFdi k14=NaiK1ni⁢NaiK2ni⁢1+NaiK3ni⁢ⅇQn⁢V2⁢RTONFdi k41=ⅇ-Qn⁢V2⁢RTONF di=1+Ca_subKci⁢1+ⅇ-Qci⁢VRTONF+NaiKcni+NaiK1ni⁢1+NaiK2ni⁢1+NaiK3ni k34=NaoK3no+Nao k21=CaoKco⁢ⅇQco⁢VRTONFdo k23=NaoK1no⁢NaoK2no⁢1+NaoK3no⁢ⅇ-Qn⁢V2⁢RTONFdo k32=ⅇQn⁢V2⁢RTONF do=1+CaoKco⁢1+ⅇQco⁢VRTONF+NaoK1no⁢1+NaoK2no⁢1+NaoK3no

Component: i_Na

E_mh=RTONF⁢ln⁡Nao+0.12⁢KoNai+0.12⁢Ki i_Na=g_Na⁢m3⁢h⁢V-E_mh

Component: i_Na_m_gate

E0_m=V+41 alpha_m=2000if|E0_m|<delta_m200⁢E0_m1-ⅇ-0.1⁢E0_motherwise beta_m=8000⁢ⅇ-0.056⁢V+66 ddtimem=alpha_m⁢1-m-beta_m⁢m

Component: i_Na_h_gate

alpha_h=20⁢ⅇ-0.125⁢V+75 beta_h=2000320⁢ⅇ-0.1⁢V+75+1 ddtimeh=alpha_h⁢1-h-beta_h⁢h

Component: i_CaL

Iso_increase=1.23ifIso_1_uM>01otherwise ANS_cond_i_CaL=-0.2152+K_i_CaL1⁢PKA10.0808K_05i_CaL110.0808+PKA10.0808ifANS>00otherwise i_siCa=2⁢P_CaL⁢1-ACh_block⁢Iso_increase⁢1+ANS_cond_i_CaL⁢V-0RTONF⁢1-ⅇ-1⁢V-0⁢2RTONF⁢Ca_sub-Cao⁢ⅇ-2⁢V-0RTONF⁢dL⁢fL⁢fCa i_siK=0.000365⁢P_CaL⁢1-ACh_block⁢Iso_increase⁢1+ANS_cond_i_CaL⁢V-0RTONF⁢1-ⅇ-1⁢V-0RTONF⁢Ki-Ko⁢ⅇ-1⁢V-0RTONF⁢dL⁢fL⁢fCa i_siNa=0.0000185⁢P_CaL⁢1-ACh_block⁢Iso_increase⁢1+ANS_cond_i_CaL⁢V-0RTONF⁢1-ⅇ-1⁢V-0RTONF⁢Nai-Nao⁢ⅇ-1⁢V-0RTONF⁢dL⁢fL⁢fCa ACh_block=0.31⁢1e-6⁢ACh1e-6⁢ACh+0.00009 i_CaL=i_siCa+i_siK+i_siNa

Component: i_CaL_dL_gate

Iso_shift=-8ifIso_1_uM>00otherwise ANS_shift_i_CaL_dL_gate=-K_ANS_shift_red_ICaL_dL_gate⁢K_i_CaL2⁢PKA9.281K_05i_CaL29.281+PKA9.281-18.76ifANS>00otherwise K_ANS_shift_red_ICaL_dL_gate=1-0.741-PKA⁢32.258ifPKA≦0.741∧PKA≥0.710ifPKA<0.711ifPKA>0.741 Iso_slope=0.69ifIso_1_uM>01otherwise ANS_slope_i_CaL=-1.199⁢PKA+1.8526ifANS>01otherwise dL_infinity=11+ⅇ-V+20.3-Iso_shift-ANS_shift_i_CaL_dL_gateIso_slope⁢ANS_slope_i_CaL⁢4.2 tau_dL=0.001alpha_dL+beta_dL alpha_dL=-0.02839⁢adVm+41.8-Iso_shift-ANS_shift_i_CaL_dL_gateⅇ-adVm+41.8-Iso_shift-ANS_shift_i_CaL_dL_gate2.5-1-0.0849⁢adVm+6.8-Iso_shift-ANS_shift_i_CaL_dL_gateⅇ-adVm+6.8-Iso_shift-ANS_shift_i_CaL_dL_gate4.8-1 adVm=-41.80001ifV=-41.80ifV=0-6.80001ifV=-6.8Votherwise beta_dL=0.01143⁢bdVm+1.8-Iso_shift-ANS_shift_i_CaL_dL_gateⅇbdVm+1.8-Iso_shift-ANS_shift_i_CaL_dL_gate2.5-1 bdVm=-1.80001ifV=-1.8Votherwise ddtimedL=dL_infinity-dLtau_dL

Component: i_CaL_fL_gate

fL_infinity=11+ⅇV+37.45.3 tau_fL=0.001⁢44.3+230⁢ⅇ-V+36102 ddtimefL=fL_infinity-fLtau_fL

Component: i_CaL_fCa_gate

fCa_infinity=Km_fCaKm_fCa+Ca_sub tau_fCa=0.001⁢fCa_infinityalpha_fCa ddtimefCa=fCa_infinity-fCatau_fCa

Component: i_CaT

i_CaT=2⁢P_CaT⁢VRTONF⁢1-ⅇ-1⁢V⁢2RTONF⁢Ca_sub-Cao⁢ⅇ-2⁢VRTONF⁢dT⁢fT

Component: i_CaT_dT_gate

dT_infinity=11+ⅇ-V+38.35.5 tau_dT=0.0011.068⁢ⅇV+38.330+1.068⁢ⅇ-V+38.330 ddtimedT=dT_infinity-dTtau_dT

Component: i_CaT_fT_gate

fT_infinity=11+ⅇV+58.73.8 tau_fT=116.67⁢ⅇ-V+7583.3+16.67⁢ⅇV+7515.38 ddtimefT=fT_infinity-fTtau_fT

Component: Ca_SR_release

koCa=koCa_max⁢RyR_min-RyR_max⁢PKAnRyRK_05RyRnRyR+PKAnRyR+1ifANS>010000otherwise j_SRCarel=ks⁢O⁢Ca_jsr-Ca_sub kCaSR=MaxSR-MaxSR-MinSR1+EC50_SRCa_jsrHSR koSRCa=koCakCaSR kiSRCa=kiCa⁢kCaSR ddtimeR=kim⁢RI-kiSRCa⁢Ca_sub⁢R-koSRCa⁢Ca_sub2⁢R-kom⁢O ddtimeO=koSRCa⁢Ca_sub2⁢R-kom⁢O-kiSRCa⁢Ca_sub⁢O-kim⁢I ddtimeI=kiSRCa⁢Ca_sub⁢O-kim⁢I-kom⁢I-koSRCa⁢Ca_sub2⁢RI ddtimeRI=kom⁢I-koSRCa⁢Ca_sub2⁢RI-kim⁢RI-kiSRCa⁢Ca_sub⁢R

Component: Ca_intracellular_fluxes

b_up=-0.25ifIso_1_uM>00.7⁢1e-6⁢ACh1e-6⁢ACh+0.00009ifACh>00otherwise P_up=P_up_basal⁢1-b_up j_Ca_dif=Ca_sub-Caitau_dif_Ca j_tr=Ca_nsr-Ca_jsrtau_tr F_PLBp=3.3931⁢PLBp4.06950.28054.0695+PLBp4.0695ifPLBp>0.231.698⁢PLBp13.58420.224013.5842+PLBp13.5842otherwise j_up=0.9⁢P_up⁢F_PLBp1+K_upCaiifANS>0P_up1+K_upCaiotherwise

Component: Ca_buffering

ddtimefTC=delta_fTC delta_fTC=kf_TC⁢Cai⁢1-fTC-kb_TC⁢fTC ddtimefTMC=delta_fTMC delta_fTMC=kf_TMC⁢Cai⁢1-fTMC+fTMM-kb_TMC⁢fTMC ddtimefTMM=delta_fTMM delta_fTMM=kf_TMM⁢Mgi⁢1-fTMC+fTMM-kb_TMM⁢fTMM ddtimefCMi=delta_fCMi delta_fCMi=kf_CM⁢Cai⁢1-fCMi-kb_CM⁢fCMi ddtimefCMs=delta_fCMs delta_fCMs=kf_CM⁢Ca_sub⁢1-fCMs-kb_CM⁢fCMs ddtimefCQ=delta_fCQ delta_fCQ=kf_CQ⁢Ca_jsr⁢1-fCQ-kb_CQ⁢fCQ

Component: Ca_dynamics

BAPTA=10ifBAPTA_10_mM>0∧time>T0otherwise ddtimeCai=1⁢j_Ca_dif⁢V_sub-j_up⁢V_nsrV_i-CM_tot⁢delta_fCMi+TC_tot⁢delta_fTC+TMC_tot⁢delta_fTMC-kfBAPTA⁢Cai⁢BAPTA-fBAPTA-kbBAPTA⁢fBAPTA ddtimefBAPTA=kfBAPTA⁢Cai⁢BAPTA-fBAPTA-kbBAPTA⁢fBAPTA ddtimeCa_sub=j_SRCarel⁢V_jsrV_sub-i_siCa+i_CaT-2⁢i_NaCa2⁢F⁢V_sub+j_Ca_dif+CM_tot⁢delta_fCMs-kfBAPTA⁢Ca_sub⁢BAPTA-fBAPTA_sub-kbBAPTA⁢fBAPTA_sub ddtimefBAPTA_sub=kfBAPTA⁢Ca_sub⁢BAPTA-fBAPTA_sub-kbBAPTA⁢fBAPTA_sub ddtimeCa_nsr=j_up-j_tr⁢V_jsrV_nsr ddtimeCa_jsr=j_tr-j_SRCarel+CQ_tot⁢delta_fCQ

Component: Cell_parameters

V_cell=0.000000001⁢π⁢R_cell2⁢L_cell V_sub=0.000000001⁢2⁢π⁢L_sub⁢R_cell-L_sub2⁢L_cell V_jsr=V_jsr_part⁢V_cell V_i=V_i_part⁢V_cell-V_sub V_nsr=V_nsr_part⁢V_cell

Component: i_to

i_to=g_to⁢V-E_K⁢q⁢r

Component: i_to_q_gate

q_infinity=11+ⅇV+4913 tau_q=0.001⁢0.6⁢65.170.57⁢ⅇ-0.08⁢V+44+0.065⁢ⅇ0.1⁢V+45.93+10.1 ddtimeq=q_infinity-qtau_q

Component: i_to_r_gate

r_infinity=11+ⅇ-V-19.315 tau_r=0.001⁢0.66⁢1.4⁢15.591.037⁢ⅇ0.09⁢V+30.61+0.369⁢ⅇ-0.12⁢V+23.84+2.98 ddtimer=r_infinity-rtau_r

Component: i_Kr

i_Kr=g_Kr⁢V-E_K⁢0.9⁢paF+0.1⁢paS⁢piy

Component: i_Kr_pa_gate

alfapaF=11+ⅇ-V+23.26.60.8465535437.2⁢ⅇV11.9+0.96⁢ⅇ-V18.5 betapaF=4⁢37.2⁢ⅇV15.9+0.96⁢ⅇ-V22.50.84655354-11+ⅇ-V+23.210.60.8465535437.2⁢ⅇV15.9+0.96⁢ⅇ-V22.5 pa_infinity=11+ⅇ-V+14.88.5 tau_paS=0.846553544.2⁢ⅇV17+0.15⁢ⅇ-V21.6 tau_paF=130⁢ⅇV10+ⅇ-V12 ddtimepaS=pa_infinity-paStau_paS ddtimepaF=pa_infinity-paFtau_paF

Component: i_Kr_pi_gate

tau_pi=1100⁢ⅇ-V54.645+656⁢ⅇV106.157 pi_infinity=11+ⅇV+28.617.1 ddtimepiy=pi_infinity-piytau_pi

Component: i_Ks

g_Ks=1.2⁢0.0016576ifIso_1_uM>00.0016576otherwise ANS_cond_i_Ks=-0.2152+K_i_Ks1⁢PKA10.0808K_05i_Ks110.0808+PKA10.0808ifANS>00otherwise E_Ks=RTONF⁢ln⁡Ko+0⁢NaoKi+0⁢Nai i_Ks=g_Ks⁢1+ANS_cond_i_Ks⁢V-E_Ks⁢n2

Component: i_Ks_n_gate

Iso_shift=-14ifIso_1_uM>00otherwise ANS_shift_i_Ks_n_gate=-K_i_Ks2⁢PKA9.281K_05i_Ks29.281+PKA9.281-18.76ifANS>00otherwise n_infinity=141+ⅇ-V-40-Iso_shift-ANS_shift_i_Ks_n_gate12141+ⅇ-V-40-Iso_shift-ANS_shift_i_Ks_n_gate12+1⁢ⅇ-V-Iso_shift-ANS_shift_i_Ks_n_gate45 tau_n=1alpha_n+beta_n alpha_n=281+ⅇ-V-40-Iso_shift-ANS_shift_i_Ks_n_gate3 beta_n=1⁢ⅇ-V-Iso_shift-ANS_shift_i_Ks_n_gate-shift-525 ddtimen=n_infinity-ntau_n

Component: i_KACh

i_KACh=K_g_ACh_max⁢g_KACh⁢V-E_K⁢aifANS>0∧ACh_cas>0g_KACh⁢V-E_K⁢1+ⅇV+2020⁢aifACh>00otherwise

Component: i_KACh_a_gate

alpha_a=K_alpha⁢0.001⁢12.32K_alpha_add+K_alpha_divACh_cas⁢1e-6ifANS>03.5988-0.0256411+0.00000121551e-6⁢ACh1.6951+0.025641otherwise beta_a=0.001⁢K_beta⁢ⅇ0.0133⁢V+40ifANS>010⁢ⅇ0.0133⁢V+40otherwise a_infinity=alpha_aalpha_a+beta_a tau_a=1alpha_a+beta_a ddtimea=a_infinity-atau_a

Component: cAMP

ddtimecAMP=diff_cAMP diff_cAMP=kiso-kach⁢ATPi+k1⁢ATPi-k2⁢cAMP-k3⁢cAMP60 kiso=K_iso+0.1181⁢Iso_casnisoK_05isoniso+Iso_casniso kach=K_ach⁢0.0146⁢ACh_casnachK_05achnach+ACh_casnach k1=K_k1⁢K_ACI+K_AC1+ⅇK_Ca-kb_CM⁢fCMikf_CM⁢1-fCMiK_ACCa k2=1.1⁢237.9851⁢cAMP⁢6005.10120.10776.101+cAMP⁢6006.101 k3=kPKA⁢cAMPnPKA-1kPKA_cAMPnPKA+cAMPnPKA

Component: PLBp

ddtimePLBp=diff_PLBp diff_PLBp=k4-k560 k4=kPLBp⁢PKAnPLBkPKA_PLBnPLB+PKAnPLB k5=kPP1⁢PP1⁢PLBpkPP1_PLB+PLBp

Component: PKA

PKA=-0.9483029⁢ⅇ-cAMP⁢600⁢0.06561479+0.97781646ifcAMP⁢600<25.87-0.45260509⁢ⅇ-cAMP⁢600⁢0.03395094+0.99221714otherwise

Component: ATPi

ATPi=ATPi_max⁢kATP⁢cAMP⁢100cAMPbnATPkATP05+cAMP⁢100cAMPbnATP-KATP_min100