Contents

πŸ“’ Ohara 2011

Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation1

Sciwheel.

Model introduction

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g005

  • ORd (O’Hara-Rudy dynamic) model with new EP measurements for the L-type Ca2 +current, K+currents, and Na+/Ca2 +exchange current from undiseased human ventricle.
  • Ca2+/calmodulin dependent protein kinase II (CaMKII) effects on ionic currents and Ca cycling
  • Early afterdepolarizations (EADs) and alternans were reproduc
  • All HH-type gating, no Markov-type ODEs for parameter constraint, efficiency and numerical stability
  • No sigularities and condition statements
  • Transmural Heterogeneity (endo, epi, M cells)

L-type Ca2+ Current (ICaL)

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g001

Transient Outward K+ Current (Ito)

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g002

Na+/Ca2+ Exchange Current (INaCa)

  • Kang and Hilgemann 2 model
  • Slip allowed (stoichiometry > 3.0)
  • 20% of the exchanger in the subspace

Inward Rectifier K+ Current (IK1)

Voltage dependent, but not pacing rate dependent

Rapid Delayed Rectifier K+ Current (IKr)

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g003 Participation in AP shortening during steady state pacing at fast rate. (APD90 was a function of IKr conductance) Voltage dependent, but not pacing rate dependent.

Slow Delayed Rectifier K+ Current (IKs)

Ca2 + dependence of IKs was incorporated

Fast Na+ Current and late Na+ current

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g004

  • nonfailing human ventricular data from Sakakibara et al
  • Fast and late Na currents have long been understood to represent different gating modes.

Na+/K+ ATPase Current (INaK)

Smith and Crampin model. https://user-images.githubusercontent.com/40054455/86705650-aebcab80-c048-11ea-8612-33f0e40cf71c.png https://user-images.githubusercontent.com/40054455/86705667-b2e8c900-c048-11ea-94c2-b060c9c66b5b.png

Human AP Characteristics and APD

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g006
human endocardial AP traces from experiments (small tissue preparations) and model simulations

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g007
Undiseased human endocardial AP response to pacing protocols from experiments (small tissue preparations) and model simulations

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g008
Pacing protocols with block of various currents

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g009
Rate dependence of currents at steady state

Transmural Heterogeneity

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g010
Transmural heterogeneity and validation of transmural cell type models

Early Afterdepolarization (EAD)

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g011

Na+ and Ca2+ Rate Dependence

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g012

Ca2+ Cycling and CaMK

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g013

Alternans

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g014

  • APD alternans appeared at CLs <300 ms (rates >200 bpm)

Currents Participating in Steady State APD Rate Dependence and APD Restitution

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g015
I–V curves during steady state rate dependent pacing at various CLs (A) and S1S2 restitution at various DIs (panel B)

Ionic Basis for APD Rate Dependence and Restitution

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g016
Major causes of steady state APD rate dependence and S1S2 APD restitution

Comparison with Other Human Ventricular AP Models

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g017
IKr deactivation is important for APD restitution at very short DIs

https://journals.plos.org/ploscompbiol/article/figure/image?download&size=large&id=info:doi/10.1371/journal.pcbi.1002061.g018
Comparison with other human ventricular AP models

Discussion

This model reproduces

  • CDI versus VDI inactivation of ICaL
  • Reformulated, detailed and accurate kinetics (using weighted time constants) for Ito,INaCa,IK1,IKr,IKs, fast INa, and late INa
  • AP repolarization rate from 30% to 90% repolarization
  • APD at all physiological pacing rates with/without block of major currents
  • APD restitution with/without block of delayed rectifier currents
  • transmural heterogeneity causing upright pseudo ECG T-wave
  • early afterdepolarizations (EADs)
  • effects of CaMK
  • AP and Ca2+ transient alternans

Limitations

  • Direct measurement of INaK
  • Sarkar and Sobie developed a method for quantitative analysis of parameter constraint and relationships between parameters and target outputs in AP model

  1. O’Hara T, VirΓ‘g L, VarrΓ³ A, Rudy Y. Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation. PLoS Comput. Biol. 2011;7(5):e1002061. doi:10.1371/journal.pcbi.1002061. ↩︎

  2. Kang TM, Hilgemann DW. Multiple transport modes of the cardiac Na+/Ca2+ exchanger. Nature 2004;427(6974):544-548. doi:10.1038/nature02271. Nature ↩︎