Contents

📒 Gauthier 2012

Toward an integrative computational model of the Guinea pig cardiac myocyte 1

Sciwheel

Introduction

https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g001.jpg

  • Local control model of CICR: graded release, high gain, stable APs are possible. Biophysically realistic.
kinetic and steady-state properties of the LCC model

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  • maximal peak of −32 ΌA/ÎŒF at +10 mV
the fraction of total SR Ca2+ released by an AP at varying SR loads.

https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g003.jpg

Ion channels and Ca2+ cycling

  • Based-on ECME model
  • delayed rectifier (IK) : Zeng, 1995 (IKs + IKr)
  • NCX: Weber, 2011
  • A mitochondrial Na+-H+ exchanger: Wei, 2011
  • ATP-dependent K+ current: Ferrero 1996
  • For Ca removal, the SR Ca2+-ATPase (SERCa) takes up 65.9% of the transported cytosolic Ca2+, NCX removes 28.9%, and the sarcolemmal (SL) Ca-pump removes 5.1% https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g004.jpg

Results

CICR during the action potential vs experiments

https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g005.jpg https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g006.jpg https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g007.jpg

Response of LCC and RyR

https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g008.jpg

  • Graded release is possible.

Ca transient

https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g009.jpg

  • Incorporation of the local control model of the CaRU into the myocyte model allows for the prediction of localized subspace Ca2+ levels
  • During 1 Hz pacing, the predicted average subspace Ca2+ level peaks near 2 ΌM, four times higher than the peak of the cytosolic transient. Subspace Ca2+ for dyads with open LCCs and RyRs reaches a maximum of 45 ΌM during the AP plateau.

APD restitution

  • Quick pacing => incomplete recovery from inactivation of ICa,L and INa => shorter APD

https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g010.jpg

Frequency-dependence of APD and ECC

https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g011.jpg

Mitochondrial energetics

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  • a higher ADP:ATP ratio results from the increased ATP consumption at rapid contraction rates
  • an abrupt decrease in NADH before restoration to a new steady-state at the higher pacing frequency (TCA cycle and mitochondrial ca dynamics is slower)

Uniporter block

https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g013.jpg

  • After 75% of mitochondrial Ca2+ uniporters are blocked in the model, the cytosolic Ca2+ transient peak increases 51%, similar to experiments
  • The significance of beat-to-beat buffering of cytosolic Ca2+ by the mitochondria
  • the Ca2+ buffering properties of the mitochondria affect the amplitude of the cytosolic Ca2+ transient. This in turn modulates the amplitude of the force transient

Discussion

  • biophysically based model of local control of SR Ca2+ release: gradedness of Ca2+ release, voltage-dependent ECC gain, without the need of expensive stochastic simulations
  • Without a mechanistic description of this mechanism, common pool models are unstable because the strong negative feedback on ICa,L via CDI resulting from regenerative RyR Ca2+ release into the common pool essentially switches LCC trigger flux off prematurely

Local control model predicts effects of AP shape on calcium-release

  • the Ca2+ transient peaks during the late phase of the AP; the force transient is also delayed, having a peak that occurs after the AP is repolarized https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g014.jpg
  • the relative timing of the Ca2+ transient cannot be reconstructed using a common pool model
  • This model result emphasizes the role of the plateau potential in the nature of SR release triggering
  • differences in AP morphology (Figure ​(Figure15A)15A) can result in very different trigger L-Type Ca2+ currents https://www.frontiersin.org/files/Articles/25359/fphys-03-00244-r2/image_m/fphys-03-00244-g015.jpg
  • The canine AP has a significant early repolarization notch and a significantly longer APD. Canine [Ca]i transient peak is approximately aligned with the AP notch, while the guinea pig [Ca]i transient peak occurs during the late plateau phase
  • Use of a local control model such as this one featuring AP shape-dependent release will have important implications regarding behavior of tissue level model electro-mechanics. e.g. transmural differences
  • Among rabbit, canine, and human, all of which express Ito, the AP notch is more prominent in recordings from epicardial than endocardial myocytes
  • The current model predicts that these differences in notch depth and initial plateau height may significantly influence the timing of Ca2+ release and force generation in these different species, emphasizing the importance of the inclusion of graded release in electromechanical models.
  • The all-or-none release produced by such common pool models fails to capture the sensitivity of the intracellular Ca2+ transient, and thus force transient, to changes in AP shape

Critique of the model

  • IKs model resulting in APD restitution time constant different from experiments
  • This model is unable to simultaneously achieve this frequency-dependent behavior and match the experimentally measured rate of AP restitution
  • this model is not able to reproduce the Ca2+ restitution and related short-term interval-force relationships
  • NSR and JSR are of the smae compartment in this model (experiment: diffusion time constant = 90ms)
  • the concentrations of ions in close proximity to the sarcolemma may vary from those of the bulk cytosol => subsarcolemmal compartment, esp in atrial CMC models.
  • An alternative approach to modeling graded release in deterministic myocyte models is to utilize more abstracted release descriptions e.g. ORd model: Jrel is a function on ICaL. But they cannot be used to predict the effects of events such as fundamental changes in RyR gating on ECC gain properties without additional assumptions

Reference


  1. Gauthier LD, Greenstein JL, Winslow RL. Toward an integrative computational model of the Guinea pig cardiac myocyte. Front. Physiol. 2012;3:244. doi:10.3389/fphys.2012.00244. PMC3389778↩︎