Implementations of the several ionic models are included in LIMPET. Different validation methods were employed to ensure that the LIMPET implementations reproduce the behavior intended by the authors of the models. Three different scenarios are considered for validation:
  1. In cases where the source code is provided by the authors of the model, this source code is modified to ouput all state variables, currents and other quantities of importance at a reasonably high temporal granularity (typically 20 - 100 µs). These high resolution traces are used as a reference. LIMPET models are validated against these traces for one basic cycle length (BCL) first, and, in a subsequent step, for at least 1 minute of activity at a particular BCL. If published by the authors, other characteristic curves produced by the model like, for instance, restitution curves need to be validated as well. If there are no differences the implementation is incorporated in LIMPET. This is the most reliable way of validating a model. Even in cases where subtle deviations are observed the original code can be checked as well to track down the source of the deviations. Even problems in the original implementations can be found and fixed this way.
  2. If the source code is not available, but an executable, output traces produced by the executable are used for validation. This is the case, for instance, with the Puglisi- Bers model implemented in the LabHeart simulator.
  3. If neither source code nor executable are available traces in the original publications are used. This is a suboptimal way of validating a model. Using published traces more subtle problems cannot be detected.
The following models are implemented in LIMPET:

RNC: ***Canine atrial kinetic model based on:
  • Ramirez RJ, Nattel S, Courtemanche M. Mathematical analysis of canine atrial action potentials: rate, regional factors, and electrical remodeling. Am J Physiol Heart Circ Physiol. 2000 Oct;279(4):H1767-85. PMID: 11009464 [PubMed]

COU: * Human atrial kinetic model
  • Courtemanche M, Ramirez RJ, Nattel S. Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. Am J Physiol. 1998 Jul;275(1 Pt 2):H301-21. PMID: 9688927 [PubMed]

NYG: ***
  • Nygren A, Fiset C, Firek L, Clark JW, Lindblad DS, Clark RB, Giles WR. Mathematical model of an adult human atrial cell: the role of K+ currents in repolarization. Circ Res. 1998 Jan 9-23;82(1):63-81. PMID: 9440706 [PubMed]

PUG: ** Rabbit ventricular kinetics, validated against http://LabHeart simulator
  • Puglisi JL, Bers DM. LabHEART: an interactive computer model of rabbit ventricular myocyte ion channels and Ca transport. Am J Physiol Cell Physiol. 2001 Dec;281(6):C2049-60. PMID: 11698264 [PubMed]

EMCE: *** Guinea pig ventricular model. Thanks to Sonia Cortassa, Brian ORourke, Lufang, Joseph Greenstein and RaiWinslow for providing their implementation.
  • Cortassa S, Aon MA, O’Rourke B, Jacques R, Tseng HJ, Marban E, Winslow RL. A computational model integrating electrophysiology, contraction, and mitochondrial bioenergetics in the ventricular myocyte. Biophys J. 2006 Aug 15;91(4):1564-89. Epub 2006 May 5. PMID: 16679365 [PubMed]

LRDII: *** Guinea pig ventricular model. The implementation used for validation is provided by the original authors
  • Luo C.H., Rudy Y. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res 74:1071-96, 1994 [PubMed]
  • Luo C.H. Rudy, Y. A dynamic model of the cardiac ventricular action potential. II. Afterdepolarizations, triggered activity, and potentiation. Circ Res 74:1097-113, 1994 [PubMed]
  • Zeng J., Laurita K.R., Rosenbaum D.S., Rudy Y. Two components of the delayed rectifier K+ current in ventricular myocytes of the guinea pig type. Theoretical formulation and their role in repolarization. Circ Res 77:140-52, 1995 [PubMed]
  • Viswanathan P.C., Shaw R.M., Rudy Y. Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study. Circulation 99:2466-74, 1999 [PubMed]
  • Faber G.M., Rudy Y. Action potential and contractility changes in [Na(+)](i) overloaded cardiac myocytes: a simulation study. Biophys J 78:2392-404, 2000 [PubMed]

UCLA_RAB: *** Rabbit ventricular kinetic model. We are very grateful to Yohannes Shiferaw and Daisuke Sato for their invaluable help.
  • Mahajan A, Shiferaw Y, Sato D, Baher A, Olcese R, Xie LH, Yang MJ, Chen PS, Restrepo JG, Karma A, Grafinkel A, Qu Z, Weiss J. A RABBIT VENTRICULAR ACTION POTENTIAL MODEL REPLICATING CARDIAC DYNAMICS AT RAPID HEART RATES. Biophys J. 2007 May 4; [Epub ahead of print] PMID: 17483187 [PubMed]
Kurata: *
  • Kurata Y, Hisatome I, Imanishi S, Shibamoto T. Dynamical description of sinoatrial node pacemaking: improved mathematical model for primary pacemaker cell. Am J Physiol Heart Circ Physiol. 2002 Nov;283(5):H2074-101. PMID: 12384487 [PubMed]
TTRed: *** Human ventricular kinetic model with a reduced number of state variables. The validation code is provided by Kirsten ten Tusscher
  • ten Tusscher KH, Panfilov AV. Cell model for efficient simulation of wave propagation in human ventricular tissue under normal and pathological conditions. Phys Med Biol. 2006 Dec 7;51(23):6141-56. Epub 2006 Nov 8. PMID: 17110776 [PubMed]
TT: *** Earlier version of the human ventricular kinetic, The validation code is provided
by Kirsten ten Tusscher
  • ten Tusscher KH, Noble D, Noble PJ, PanfilovAV.Amodel for human ventricular tissue. Am J Physiol Heart Circ Physiol. 2004 Apr;286(4):H1573-89. Epub 2003 Dec 4. PMID: 14656705 [PubMed]
TT2: *** Second version of the human ventricular kinetic, The validation code is provided
by Kirsten ten Tusscher
  • ten Tusscher KH, Panfilov AV. Alternans and spiral breakup in a human ventricular tissue model. Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1088-100. Epub 2006 Mar 24. PMID: 16565318 [PubMed]

The following plugins which can be enabled to modify a particular ionic model are implemented:

  • DeBruin KA, Krassowska W. Electroporation and shock-induced transmembrane potential in a cardiac fiber during defibrillation strength shocks. Ann Biomed Eng. 1998 Jul- Aug;26(4):584-96. PMID: 9662151 [PubMed]
  • DeBruin KA, Krassowska W. Modeling electroporation in a single cell. I. Effects Of field strength and rest potential. Biophys J. 1999 Sep;77(3):1213-24. PMID: 10465736 [PubMed]
  • Ashihara T, Trayanova NA. Asymmetry in membrane responses to electric shocks: insights from bidomain simulations. Biophys J. 2004 Oct;87(4):2271-82. PMID: 15454429 [PubMed]
  • Cheng DK, Tung L, Sobie EA. Nonuniform responses of transmembrane potential during electric field stimulation of single cardiac cells. Am J Physiol. 1999 Jul;277(1 Pt 2):H351-62. PMID: 10409215 [PubMed]
  • Hunter PJ, McCulloch AD, ter Keurs HE. Modelling the mechanical properties of cardiac muscle. Prog Biophys Mol Biol. 1998;69(2-3):289-331. Review. PMID: 9785944 [PubMed]
  • Niederer SA, Hunter PJ, Smith NP. A quantitative analysis of cardiac myocyte relaxation: a simulation study. Biophys J. 2006 Mar 1;90(5):1697-722. Epub 2005 Dec 9. PMID: 16339881 [PubMed]
  • Kneller J, Zou R, Vigmond EJ, Wang Z, Leon LJ, Nattel S. Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties. Circ Res. 2002 May 17;90(9):E73-87. PMID: 12016272 [PubMed]
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