📒 Gauthier 2012
Toward an integrative computational model of the Guinea pig cardiac myocyte 1
- Local control model of CICR: graded release, high gain, stable APs are possible. Biophysically realistic.
kinetic and steady-state properties of the LCC model
- maximal peak of −32 μA/μF at +10 mV
the fraction of total SR Ca2+ released by an AP at varying SR loads.
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%
CICR during the action potential vs experiments
Response of LCC and RyR
- Graded release is possible.
- 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 μM, four times higher than the peak of the cytosolic transient. Subspace Ca2+ for dyads with open LCCs and RyRs reaches a maximum of 45 μM during the AP plateau.
- Quick pacing => incomplete recovery from inactivation of ICa,L and INa => shorter APD
Frequency-dependence of APD and ECC
- 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)
- 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
- 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
- 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
- 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