The Noble cardiac ventricular electrophysiology models in CellML

We present a review of the cardiac ventricular cell electrophysiology models developed by Prof. Denis Noble and colleagues as an example of how models may be published using a web-based CellML publication framework. The models reviewed have been marked-up in CellML and then used to compute all results presented here. The models are freely available from a website as are the specific numerical experiments discussed in this review and the tools used to perform the simulations.     

CellML: its future, present and past

Advances in biotechnology and experimental techniques have lead to the elucidation of vast amounts of biological data. Mathematical models provide a method of analysing this data; however, there are two issues that need to be addressed: (1) the need for standards for defining cell models so they can, for example, be exchanged across the World Wide Web, and also read into simulation software in a consistent format and (2) eliminating the errors which arise with the current method of model publication. CellML has evolved to meet these needs of the modelling community. CellML is a free, open-source, eXtensible markup language based standard for defining mathematical models of cellular function. In this paper we summarise the structure of CellML, its current applications (including biological pathway and electrophysiological models), and its future development—in particular, the development of toolsets and the integration of ontologies.     

The Cardiac Electrophysiology Web Lab

Computational modeling of cardiac cellular electrophysiology has a long history, and many models are now available for different species, cell types, and experimental preparations. This success brings with it a challenge: how do we assess and compare the underlying hypotheses and emergent behaviors so that we can choose a model as a suitable basis for a new study or to characterize how a particular model behaves in different scenarios? We have created an online resource for the characterization and comparison of electrophysiological cell models in a wide range of experimental scenarios. The details of the mathematical model (quantitative assumptions and hypotheses formulated as ordinary differential equations) are separated from the experimental protocol being simulated. Each model and protocol is then encoded in computer-readable formats. A simulation tool runs virtual experiments on models encoded in CellML, and a website (https://chaste.cs.ox.ac.uk/WebLab) provides a friendly interface, allowing users to store and compare results. The system currently contains a sample of 36 models and 23 protocols, including current-voltage curve generation, action potential properties under steady pacing at different rates, restitution properties, block of particular channels, and hypo-/hyperkalemia. This resource is publicly available, open source, and free, and we invite the community to use it and become involved in future developments. Investigators interested in comparing competing hypotheses using models can make a more informed decision, and those developing new models can upload them for easy evaluation under the existing protocols, and even add their own protocols.     

CellML2SBML: conversion of CellML into SBML

CellML and SBML are XML-based languages for storage and exchange of molecular biological and physiological reaction models. They use very similar subsets of MathML to specify the mathematical aspects of the models. CellML2SBML is implemented as a suite of XSLT stylesheets that, when applied consecutively, convert models expressed in CellML into SBML without significant loss of information. The converter is based on the most recent stable versions of the languages (CellML version 1.1; SBML Level 2 Version 1), and the XSLT used in the stylesheets adheres to the XSLT version 1.0 specification. Of all 306 models in the CellML repository in April 2005, CellML2SBML converted 91% automatically into SBML. Minor manual changes to the unit definitions in the originals raised the percentage of successful conversions to 96%. Availability: http://sbml.org/software/cellml2sbml/. Supplementary information: Instructions for use and further documentation available on http://sbml.org/software/cellml2sbml/     

The CellML Model Repository

SUMMARY: The CellML Model Repository provides free access to over 330 biological models. The vast majority of these models are derived from published, peer-reviewed papers. Model curation is an important and ongoing process to ensure the CellML model is able to accurately reproduce the published results. As the CellML community grows, and more people add their models to the repository, model annotation will become increasingly important to facilitate data searches and information retrieval. AVAILABILITY: The CellML Model Repository is publicly accessible at http://www.cellml.org/models.     

Bioinformatics, multiscale modeling and the IUPS Physiome Project

Multiscale modeling is required for linking physiological processes operating at the organ and tissue levels to signal transduction networks and other subcellular processes. Several XML markup languages, including CellML, have been developed to encode models and to facilitate the building of model repositories and general purpose software tools. Progress in this area is described and illustrated with reference to the heart Physiome Project which aims to understand cardiac arrhythmias in terms of structure-function relations from proteins up to cells, tissues and organs.     

OpenCMISS: A multi-physics & multi-scale computational infrastructure for the VPH/Physiome project

The VPH/Physiome Project is developing the model encoding standards CellML (cellml.org) and FieldML (fieldml.org) as well as web-accessible model repositories based on these standards (models.physiome.org). Freely available open source computational modelling software is also being developed to solve the partial differential equations described by the models and to visualise results. The OpenCMISS code (opencmiss.org), described here, has been developed by the authors over the last six years to replace the CMISS code that has supported a number of organ system Physiome projects.OpenCMISS is designed to encompass multiple sets of physical equations and to link subcellular and tissue-level biophysical processes into organ-level processes. In the Heart Physiome project, for example, the large deformation mechanics of the myocardial wall need to be coupled to both ventricular flow and embedded coronary flow, and the reaction-diffusion equations that govern the propagation of electrical waves through myocardial tissue need to be coupled with equations that describe the ion channel currents that flow through the cardiac cell membranes.In this paper we discuss the design principles and distributed memory architecture behind the OpenCMISS code. We also discuss the design of the interfaces that link the sets of physical equations across common boundaries (such as fluid-structure coupling), or between spatial fields over the same domain (such as coupled electromechanics), and the concepts behind CellML and FieldML that are embodied in the OpenCMISS data structures. We show how all of these provide a flexible infrastructure for combining models developed across the VPH/Physiome community.     

Organotypic heart slices for cell transplantation and physiological studies

Recent studies have significantly improved our ability to investigate cell transplantation and study the physiology of transplanted cells in cardiac tissue. Several previous studies have shown that fully-immersed heart slices can be used for electrophysiological investigations. Additionally, ischemic heart slices induced by glucose and oxygen deprivation offer a useful tool to investigate mechanical integration and to measure forces of contraction of engrafted cells, at least for short term analysis. A recent and novel model of heart slices, prepared from rat and human tissues, can be maintained in culture for up to two months. This new heart slice model can be used for long term in vitro cell transplantation studies and for pharmacological evaluation. This review will focus on describing these models and demonstrating the use of organotypic heart slices as a novel tool for drugs for studying electrophysiology and developing cellular therapeutic approaches to alleviate cardiac tissue damage.Key words: heart, organotypic, culture, stem cells, transplantation, electrophysiology, pharmacology     

Organotypic heart slices for cell transplantation and physiological studies

Recent studies have significantly improved our ability to investigate cell transplantation and study the physiology of transplanted cells in cardiac tissue. Several previous studies have shown that fully-immersed heart slices can be used for electrophysiological investigations. Additionally, ischemic heart slices induced by glucose and oxygen deprivation offer a useful tool to investigate mechanical integration and to measure forces of contraction of engrafted cells, at least for short term analysis. A recent and novel model of heart slices, prepared from rat and human tissues, can be maintained in culture for up to two months. This new heart slice model can be used for long term in vitro cell transplantation studies and for pharmacological evaluation. This review will focus on describing these models and demonstrating the use of organotypic heart slices as a novel tool for drug, for studying electrophysiology and for developing cellular therapeutic approaches to alleviate cardiac tissue damage.     

CESE

Cell electrophysiology simulation environment (CESE) is an integrated environment for performing simulations with a variety of electrophysiological models that have Hodgkin-Huxley and Markovian formulations of ionic currents. CESE is written in Java 2 and is readily portable to a number of operating systems. CESE allows execution of single-cell models and modification and clamping of model parameters, as well as data visualisation and analysis using a consistent interface. Model creation for CESE is facilitated by an object-oriented approach and use of an extensive modelling framework. The Web-based model repository is available. AVAILABILITY: CESE and the Web-based model repository are available at http://cese.sourceforge.net/.     

Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): standardised reporting for model reproducibility, interoperability, and data sharing

Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.     

Tissue-Specific Optical Mapping Models of Swine Atria Informed by Optical Coherence Tomography

Computational models and experimental optical mapping of cardiac electrophysiology serve as powerful tools to investigate the underlying mechanisms of arrhythmias. Modeling can also aid the interpretation of optical mapping signals, which may have different characteristics with respect to the underlying electrophysiological signals they represent. However, despite the prevalence of atrial arrhythmias such as atrial fibrillation, models of optical electrical mapping incorporating realistic structure of the atria are lacking. Therefore, we developed image-based models of atrial tissue using structural information extracted from optical coherence tomography (OCT), which can provide volumetric tissue characteristics in high resolution. OCT volumetric data of four swine atrial tissue samples were used to develop models incorporating tissue geometry, tissue-specific myofiber orientation, and ablation lesion regions. We demonstrated the use of these models through electrophysiology and photon scattering simulations. Changes in transmural electrical conduction were observed with the inclusion of OCT-derived, depth-resolved fiber orientation. Additionally, the amplitude of optical mapping signals were not found to correspond with lesion transmurality because of lesion geometry and electrical propagation occurring beyond excitation light penetration. This work established a framework for the development of tissue-specific models of atrial tissue derived from OCT imaging data, which can be useful in future investigations of electrophysiology and optical mapping signals with respect to realistic atrial tissue structure.     

基于心脏电生理模型的心律失常机制研究进展

揭示发病机制是心律失常诊断、治疗、药物研发和设备设计的关键.整合当前在心脏分子生物学、生物化学、生理学及解剖学方面的最新成果,构建从离子通道、心肌细胞、心肌纤维、心肌组织、心脏器官到躯体各个层次的多尺度多模态心脏电生理模型,用于系统研究微观局部变化发生、发展、转化为宏观心律失常表现的过程,将彻底改变传统从基因突变、蛋白质表达、细胞电生理、临床表现单独研究心律失常的方式,实现微观与宏观研究的统一,使心脏电生理模型成为系统研究心律失常发病机制的有力手段.本文综述了心脏电生理模型的构建方法和研究进展,讨论了多尺度心脏电生理模型在揭示心律失常机制研究中的作用和地位,给出了基于心脏电生理模型心律失常研究的挑战和重要发展方向.     

Cell–cell junction remodeling in the heart: Possible role in cardiac conduction system function and arrhythmias?

Anchoring cell-cell junctions (desmosomes, fascia adherens) play crucial roles in maintaining mechanical integrity of cardiac muscle cells and tissue. Genetic mutations and/or loss of critical components in these macromolecular structures are increasingly being associated with arrhythmogenic cardiomyopathies; however, their specific roles have been primarily attributed to effects within the working (ventricular) cardiac muscle. Growing evidence also points to a key role for anchoring cell-cell junction components in cardiac muscle cells of the cardiac conduction system. This is not only evidenced by the molecular and ultra-structural presence of anchoring cell junctions in specific compartments/structures of the cardiac conduction system (sinoatrial node, atrioventricular node, His-Purkinje system), but also because conduction system-related arrhythmias can be found in humans and mouse models of cardiomyopathies harboring defects and/or mutations in key anchoring cell-cell junction proteins. These studies emphasize the clinical need to understand the molecular and cellular role(s) for anchoring cell-cell junctions in cardiac conduction system function and arrhythmias. This review will focus on (i) experimental findings that underline an important role for anchoring cell-cell junctions in the cardiac conduction system, (ii) insights regarding involvement of these structures in age-related cardiac remodeling of the conduction system, (iii) summarizing available genetic mouse models that can target cardiac conduction system structures and (iv) implications of these findings on future therapies for arrhythmogenic heart diseases.