The Carmen team develops and uses models and numerical methods to simulate the electrophysiology of the heart from the molecular to the whole-organ scale, and its relation to measurable signals inside the heart and on the body surface. It aims at:
The numerical models used and developed by the team incorporate the gating dynamics of the ion channels in the cardiac cell membranes and the heterogeneities and coupling processes on the cellular scale into macroscopic reaction-diffusion models. At the same time we use reduced models to solve the inverse problems related to non-invasive electrical imaging of the heart.
The fields involved in our research are: ordinary and partial differential equations (PDE), inverse problems, numerical analysis, high-performance computing, image segmentation, and mesh construction.
A main goal of the team is to contribute to the work packages
defined in the IHU LIRYC (http://
We cooperate with physiologists and cardiologists on several projects. The team is building new models and powerful simulation tools that will help to understand the mechanisms behind cardiac arrhythmias and to establish personalized and optimized treatments. A particular challenge consists in making the simulations reliable and accessible to the medical community.
The contraction of the heart is coordinated by a complex electrical activation process which relies on about a million ion channels, pumps, and exchangers of various kinds in the membrane of each cardiac cell. Their interaction results in a periodic change in transmembrane potential called an action potential. Action potentials in the cardiac muscle propagate rapidly from cell to cell, synchronizing the contraction of the entire muscle to achieve an efficient pump function. The spatio-temporal pattern of this propagation is related both to the function of the cellular membrane and to the structural organization of the cells into tissues. Cardiac arrythmias originate from malfunctions in this process. The field of cardiac electrophysiology studies the multiscale organization of the cardiac activation process from the subcellular scale up to the scale of the body. It relates the molecular processes in the cell membranes to the propagation process and to measurable signals in the heart and to the electrocardiogram, an electrical signal on the torso surface.
Several improvements of current models of the propagation of the action potential are being developed in the Carmen team, based on previous work 35 and on the data available at IHU LIRYC:
These models are essential to improve our in-depth understanding of cardiac electrical dysfunction. To this aim, we use high-performance computing techniques in order to numerically explore the complexity of these models.
We use these model codes for applied studies in two important areas of cardiac electrophysiology: atrial fibrillation 39 and sudden-cardiac-death (SCD) syndromes 7, 642. This work is performed in collaboration with several physiologists and clinicians both at IHU Liryc and abroad.
The medical and clinical exploration of the cardiac electric signals is based on accurate reconstruction of the patterns of propagation of the action potential. The correct detection of these complex patterns by non-invasive electrical imaging techniques has to be developed. This problem involves solving inverse problems that cannot be addressed with the more compex models. We want both to develop simple and fast models of the propagation of cardiac action potentials and improve the solutions to the inverse problems found in cardiac electrical imaging techniques.
The cardiac inverse problem consists in finding the cardiac activation maps or, more generally, the whole cardiac electrical activity, from high-density body surface electrocardiograms. It is a new and a powerful diagnosis technique, which success would be considered as a breakthrough. Although widely studied recently, it remains a challenge for the scientific community. In many cases the quality of reconstructed electrical potential is not adequate. The methods used consist in solving the Laplace equation on the volume delimited by the body surface and the epicardial surface. Our aim is to:
Of course we will use our models as a basis to regularize these inverse problems. We will consider the following strategies:
Additionaly, we will need to develop numerical techniques dedicated to our simplified eikonal/level-set equations.
We want our numerical simulations to be efficient, accurate, and reliable with respect to the needs of the medical community. Based on previous work on solving the monodomain and bidomain equations 37, 36, 45, 28, we will focus on:
Existing simulation tools used in our team rely, among others, on mixtures of explicit and implicit integration methods for ODEs, hybrid MPI-OpenMP parallellization, algebraic multigrid preconditioning, and Krylov solvers. New developments include high-order explicit integration methods and task-based dynamic parallellism.
Numerical models of whole-heart physiology are based on the approximation of a perfect muscle using homogenisation methods. However, due to aging and cardiomyopathies, the cellular structure of the tissue changes. These modifications can give rise to life-threatening arrhythmias. For our research on this subject and with cardiologists of the IHU LIRYC Bordeaux, we aim to design and implement models that describe the strong heterogeneity of the tissue at the cellular level and to numerically explore the mechanisms of these diseases.
The literature on this type of model is still very limited 51. Existing models are two-dimensional 43 or limited to idealized geometries, and use a linear (purely resistive) behaviour of the gap-juction channels that connect the cells. We propose a three-dimensional approach using realistic cellular geometry (figure 1), nonlinear gap-junction behaviour, and a numerical approach that can scale to hundreds of cells while maintaining a sub-micrometer spatial resolution (10 to 100 times smaller than the size of a cardiomyocyte) 31, 30, 29. P-E. Bécue defended his PhD thesis on this topic in December 2018.
The University Hospital of Bordeaux (CHU de Bordeaux) is
equipped with a specialized cardiology hospital, the Hôpital
Cardiologique du Haut-Lévêque, where the group of Professor
Michel Haïssaguerre has established itself as a global leader in the
field of cardiac electrophysiology 41, 40, 33.
Their discoveries in the area of
atrial fibrillation and sudden cardiac death syndromes are widely
acclaimed, and the group is a national and international referral
center for treatment of cardiac arrhythmia. Thus
the group also sees large numbers of patients with rare cardiac
diseases.
In 2011 the group has won the competition for a 40 million euro
Investissements d'Avenir grant for the establishment of IHU
Liryc, an institute that combines clinical, experimental, and
numerical research in the area of cardiac arrhythmia
(http://
The Carmen team was founded to partner with IHU Liryc. We bring applied mathematics and scientific computing closer to experimental and clinical cardiac electrophysiology. In collaboration with experimental and clinical researchers at Liry we work to enhance fundamental knowledge of the normal and abnormal cardiac electrical activity and of the patterns of the electrocardiogram, and we develop new simulation tools for training, biological, and clinical applications.
Our modeling is carried out in coordination with the experimental teams from IHU Liryc. It help to write new concepts concerning the multiscale organisation of the cardiac action potentials that will serve our understanding in many electrical pathologies. For example, we model the structural heterogeneities at the cellular scale 32, and at an intermediate scale between the cellular and tissue scales.
At the atrial level, we apply our models to understand the mechanisms of complex arrythmias and the relation with the heterogeneities at the insertion of the pulmonary veins. We will model the heterogeneities specific to the atria, like fibrosis or fatty infiltration 4839. These heterogeneities ara thought to play a major role in the development of atrial fibrillation.
At the ventricular level, we focus on (1) modeling the complex coupling between the Purkinje network and the ventricles, which is supposed to play a major role in sudden cardiac death, and (2) modeling the heteogeneities related to the complex organization and disorganization of the myocytes and fibroblasts, which is important in the study of infarct scars for instance.
Treatment of cardiac arrhythmia is possible by pharmacological means, by implantation of pacemakers and defibrillators, and by curative ablation of diseased tissue by local heating or freezing. In particular the ablative therapies create challenges that can be addressed by numerical means. Cardiologists would like to know, preferably by noninvasive means, where an arrhythmia originates and by what mechanism it is sustained.
We address this issue in the first place using inverse models, which attempt to estimate the cardiac activity from a (high-density) electrocardiogram. A new project aims at performing this estimation on-site in the catheterization laboratory and presenting the results, together with the cardiac anatomy, on the screen that the cardiologist uses to monitor the catheter positions 44.
An important prerequisite for this kind of interventions and for inverse modeling is the creation of anatomical models from imaging data. The Carmen team contributes to better and more efficient segmentation and meshing through the IDAM project.
CEMPACK is a new collection of software that was previously
archived in different places. It includes the high-performance
simulation code Propag and a suite of software for the creation of
geometric models, preparing inputs for Propag, and analysing its
outputs. In 2017 the code was collected in an archive
on Inria's GitLab platform, and a public website was created
for documentation (http://
Applied modeling studies performed by the Carmen team in
collaboration with IHU Liryc and foreign partners
749, 39, 38, 34
rely on high-performance computations on
the national supercomputers Irene, Occigen, and Turing. The Propag-5
code is optimized for these systems. It is the
result of a decades-long development first at the Université
de Montréal in Canada, then at Maastricht University in the
Netherlands, and finally at the Institute of Computational
Science of the Università della Svizzera italiana in Lugano,
Switzerland. Since 2016 most of the development on Propag has been
done by M. Potse at the Carmen team 50.
The code scales excellently to large
core counts and, as it is controlled completely with command-line
flags and configuration files, it can be used by non-programmers. It
also features:
The code has been stable and reliable for several years. It can be considered the workhorse for our HPC work until CEPS takes over.
Convergence proof of the numerical scheme for the virtual element method for a nonlocal
FitzHugh–Nagumo model of cardiac electrophysiology (Mostafa Bendahmane in collaboration with Veronica Anaya and David Mora (university Bip-Bio, Concepcion, Chile),
Development of a new method on cartesian grids to solve the inverse problem of Electrical Impe-
dance Tomography in 2 dimensions (Ph.D thesis of Niami Nasr, co-supervised by J. Dardé, IMT Toulouse),
Model of cardiac mitochondria that can be coupled to cardiac electrophysiology models, para-
meter identification results. It is an interdisciplinairy work between Liryc teams (modelling and metabolism) and other laboratories (ISM Bordeaux and LASS Toulouse), Ph.D. thesis of Bachar Tarraf,
We have participated in a Grand Challenge call of TGCC, the computing center of the CEA, on the occasion of the installation of a new partition of the national supercomputer Irène Joliot-Curie. This competitive call for proposals has given us 20 million compute hours and a preferential access to this new cluster computer with more than 260 thousand compute cores, allowing us to test our simulation code on a scale 1000 times larger than our routine simulations. The test results were positive, showing that the code remains efficient at this scale and that we can essentially make our computations as large as the machine can store in its memory. This gives us confidence for our projects on future supercomputers at an even larger scale.
For 3 years, collaboration with University bio-Bio, Chile, PI: Mostafa Benhdamane for Bordeaux University/Liryc.
In Fall 2020, visits of Khouloud Kordoghli et Abir Amri (Ph.D. student).
Simulation of Cardiac Devices and Drugs for in-silico Testing and Certification in Accelerating the uptake of computer simulations for testing medicines and medical devices – TOPIC ID:SC1-DTH-06-2020, himself in Digital transformation in Health and Care (H2020-SC1-DTH-2018-2020), which is in WP Health, demographic change and wellbeing, 857 875 € for UB/Liryc. Main costs: PhD, engineers, experiments with animals, experiments with torso tank, PI: M. Sermesant from Inria, PI for Bordeaux University/Liryc: Yves Coudière.
5.8M€ (1.6 M€ for UBx) with 10 European partners, both academic and industrial. The project aims to build a software code that will be able to simulate the heart cell-by-cell on future “exascale” supercomputers. PI: Mark Potse for Bordeaux University/Liryc.
an interdisciplinary research and training project involving several countries, several scientific fields. The aim of the project is the individual-specific characterization of AF substrate in order to increase the treatment efficiency, 278k euros, for UBx (IHU-LIRYC), PI: Nejib Zemzemi for Bordeaux University/Liryc.
Granted by ANR in July 2018, it is a collaborative project with computer scientists from Labri that targets hexascale computing in cardiac electrophysiology, it serves as a sandbox to prepare the project EuroHPC Microcard. PI for Bordeaux University/Liryc: Yves Coudière.
The MITOCARD project (Electrophysiology of Cardiac Mitochondria), coordinated by S. Arbault (Université de Bordeaux, ISM), was granted by the ANR in July 2017. The objective of MITOCARD is to improve understanding of cardiac physiology by integrating the mitochondrial properties of cell signaling in the comprehensive view of cardiac energetics and rhythm pathologies. It was recently demonstrated that in the heart, in striking contrast with skeletal muscle, a parallel activation by calcium of mitochondria and myofibrils occurs during contraction, which indicates that mitochondria actively participate in Ca2+ signaling in the cardiomyocyte. We hypothesize that the mitochondrial permeability transition pore (mPTP), by rhythmically depolarizing inner mitochondrial membrane, plays a crucial role in mitochondrial Ca2+ regulation and, as a result, of cardiomyocyte Ca2+ homeostasis. Moreover, mitochondrial reactive oxygen species (ROS) may play a key role in the regulation of the mPTP by sensing mitochondrial energetics balance. Consequently, a deeper understanding of mitochondrial electrophysiology is mandatory to decipher their exact role in the heart's excitation-contraction coupling processes. However, this is currently prevented by the absence of adequate methodological tools (lack of sensitivity or selectivity, time resolution, averaged responses of numerous biological entities). The MITOCARD project will solve that issue by developing analytical tools and biophysical approaches to monitor kinetically and quantitatively the Ca2+ handling by isolated mitochondria in the cardiomyocyte.
MITOCARD is a multi-disciplinary project involving 4 partners of different scientific fields: the CARMEN team as well as:
The project will:
The model may serve both to assess biological assumptions on the role of mitochondria in Ca2+ signaling and to integrate pathological data and provide clues for their global understanding.
co-funding from Région Nouvelle Aquitaine-INRIA/Liryc to support the Ph.D. of Andony Arrieula on a real time algorithm to predict accurately the exit site of a ventricular extrasystole based on its 12-lead ECG, PI for Bordeaux University/Liryc: Mark Potse, collaboration with Pierre Jaïs.
Yves Coudière is vice-head of the Mathematics Department.
The 2 assistant professors and 1 professor of the team teach at several levels of the Bordeaux University programs in Mathematics and Neurosciences (respectively, 192, 192 and 96 h/year on average). The researchers also have a regular teaching activity, contributing to several courses in the Applied Mathematics at the Bachelor and Master levels (usually between 16 and 32 h/year).
The PhD student are used to teach between 32 and 64 h/year, usually courses of general mathematics in L1 or mathematics for biologists in L1 or L2.
Teaching responsibilities at the University of Bordeaux:
Courses (L for Bachelor level, M for Master level):