LIRYC L’Institut de RYthmologie et modélisation Cardiaque

Le Cœur électrique – rôle des sciences numériques et

opportunités de transfert

The University Hospital Institutes (IHU)

Objectives

Scientific quality and coherence - International attractiveness

Innovation and valorization –Attractiveness for the industry

From research to patient care - and teaching

Autofinancing

Bordeaux Electrical diseases of the heart

Paris • Neuroscience • Genetics • Nutrition

Study, diagnosis and treatment of cardiac electrical

dysfonctions

15 M€ 45 M€

Marseille Infectious diseases

Strasbourg Minimally

invasive surgery

IHU LIRYC

Research Themes ATRIAL FIBRILLATION

Europe: 5 millions

Major Cause of Stroke

VENTRICULAR ARRHYTHMIAS AND SUDDEN CARDIAC DEATH

Europe: 350 000 deaths/year

HEART FAILURE AND ELECTRICAL DYSSYNCHRONY

Europe: 9 millions

350 000 deaths/year

Cardiovascular Diseases : 1st cause of Adult Mortality in the world 29% of deaths vs 16.2% infections & 13% Cancers- WHO 2011

2nd cause in Europe (28% vs 30% for Cancers) 700 000 cardiac-specific deaths : half due to Heart failure and half due to Sudden death 110 000 deaths in France

-Prevention-Education -Drugs : Statins- BB- RAS block -AntiPlatelet –Thrombolysis -Coronary/Infarct Intervention

Last 10 years : emergence of therapies targeting cardiac electrical diseases

Proven Impact of Cardiovascular Research on Mortality Reduction 1980-2005

ARYTHMOGENESIS= The Heart is an electromechanical organ

100 000 pulses a day

Research Domains

Cardiac Electrophysiology

Structural Imaging Signal Processing

Computer Modelling and Simulation

Effects of diffusive inclusions on bidomain model

Carmen -

PhD Anđela Davidović / CARMEN

Segmentation + Inclusions

MRI images

Volume fraction

SIMULATION PARAMETERS:

Mesh on segmentation Cell ionic model (Mitchel Schaeffer) Fiber orientation COMPUTE: Inclusion geometry + Volume fraction

= modified electrical conductivities

Fiber orientation

Animal Models and Human hearts Persistent AF (sheep), Infarct (sheep), Ischemia-reperfusion (sheep), AV block (pig), congenital heart disease (pig), etc

Left Ventricle Right Ventricle

sham

rTOF

Explanted human hearts: «FIBRILLATION CARDIAQUE ET DYSSYNCHRONIE ELECTRIQUE DU CŒUR» (CADeNCE) – March 2015.

Atrial Fibrillation : Pulmonary Vein triggers and Atrial Substrate

Haissaguerre et al NEJM (1998)

Pulmonary Venous cells

12

Cell-Molecular target using Optical Mapping/EP ( Animals and Human Hearts) • Specific 2P stretch receptors ..Strong mediator for Auto Nerv System

Computational Pharmacology • Integrated model predicting effects to screen the most appropriate drugs – • Substrate ablation strategies in computer models

ONLY 2%

treated

Atrial Fibrillation – LIRYC objectives

Specific Drug therapy targeting venous cells

Create or optimise ablation tools

Imaging the atrial substrate : structure and function

Atrial Fibrillation

14

Ventricular Fibrillation : Purkinje triggers and Ventricular Substrate

Haissaguerre et al Circulation (2002)

Purkinje cells

Occurrence of Sudden death

At Home : 80%

Public places : 10%

Workplace : 1 - 2%

Stadium, pools, tennis,golfs: 1 - 2%

Commotio Cordis VF due to modest thoracic trauma without cardiac lesion

Precise ‘Timing’ ±10 ms

Pig Experiment

18

Mechanisms of Purkinje triggering Mechanisms of VF maintenance

Mapping Explanted Human Hearts

Computer model of vulnerability to Sudden Death

Molecular target for Purkinje firing Specific embryology AP, ionic features, oxygenation-

distinct peptides

New Therapies using Stimulation or Intervention

Sudden Cardiac Death – LIRYC objectives

Therapies : drugs or devices

Molecular Mechanism of Purkinje Firing

B Stuyvers et al

Non-invasive mapping for VF mapping

• 43 Patients (19 SHD / 24 noSHD) • 97 episodes of VF 20.8±12 s • LV vs RV and SHD vs noSHD

▪ Frequencies ▪ Number of Breakthrough ▪ Number of rotors ▪ Area covered by the rotor

Rotor Trajectories noSHD SHD

To be published

Relationship to the structure

submitted

22

Identify the patients at risk of death

Genetic predisposition (cohort ~ 500 resuscitated European patients ) Processing of Electrical Signal

Unique

Technologies

Characterisation by novel structural or functional imaging

Sudden Cardiac Death : a major scientific challenge

23

Identify the individual patients with dysynchrony

Mechanisms and Therapies

Investigate the link between electrical and mechanical dysfunction

Mapping - Models of electro-mechanical interaction

Resynchronisation at early stage of HF for prevention

New therapeutic device strategies LV site – multiple sites- leadless

Regeneration of Conduction system

Improve Imaging/ECG Prediction of individual CRT response Expand indications of resynchronisation narrow QRS complex- Right ventricular diseases-Congenital…

Heart Failure and Metabolism – LIRYC objectives

Dyssynchrony and resynchronization

6 mm x 42 mm

Professeurs Invités LIRYC Prof. Igor Efimov

Washington University at St Louis Juin – Juillet 2013

Cardiac ElectroTherapy and Defibrillation (Cardialen)

Optical mapping of human hearts Prof. Ed White University of Leeds Septembre – Octobre 2013 Electrophysiological remodeling in RV heart failure Cellular electrophysiology

Prof. Ruben Coronel Academic Medical Centre Amsterdam

50% LIRYC in 2014

Ventricular Fibrillation

Prof. Prash Sanders University of

Adelaide

2014

Clinical EP

Modifiez les styles du texte du masque

Deuxième niveau

Troisième niveau

Quatrième niveau

Cinquième niveau

Composition - INRIA CARMEN 3 "fonctionnaires permanents”

Y. Coudière, Prof. Univ. Bordeaux, team

leader

N. Zemzemi, junior research follow

J. Henry, Senior Research Scientist Inria, Emeritus.

2 almost permanent members:

M. Potse, senior researcher 1/2 time (50%

U. Lugano)

F. Caro, junior researcher, on secondment (renewable every 3 years)

Postdoc: Michal Kinia (2 yrs from 6/2015)

4 PhDs: A. Davidovic, G. Ravon, P.-E. Becue, C.

Douanla Lontsi

2 Engineer: E. Abbate, M. Fuentes

During last period:

Engineers: M. Juhoor (2 yrs, ended 11/2014), D. Amenga (13 months, ended 1/2015), C. Corrado (9 months, ended 2/2014)

Postdoc: J. Bouissier (16 months, ended Feb. 2015)

26

Edward Vigmond

Jason Bayer (JHU) - financed by Whitaker, started 3/2013

Ali Pashaei - financed by ANR MONU started 2/2014

Caroline Roney (ICL) - financed by LIRYC, started 5/2015

Modifiez les styles du texte du masque

Deuxième niveau

Troisième niveau

Quatrième niveau

Cinquième niveau

International Collaborators LIRYC- CARMEN

27

N Trayanova/P Boyle

G Plank

M Bishop

Nanthakumar

A Nygren E Behradfar

F Ng

E DiMartino

B Boukens

J Kaur

S Niederer

Y Bourgault

B Rodriguez

R Coronel J de Bakker

R

Aboulaich

Amel Ben

Abda

F. Alonso-

Atienza

Etats-Unis

Canada

Australie

Nouvelle-Zélande

Japon Chine

Inde

Tunisie Algérie Qatar

Fellows / Doctorants / Post-Doctorants

Médecins étrangers venus en observation

Brésil

Russie

Iran

Mongolie

Royaume-Uni

Espagne

Allemagne

Italie

Belgique

Suisse

Pays-Bas Irlande

Grèce

Slovénie

Norvège

Lettonie

Mexique

Finlande

Pologne

Kazakstan

Liban

LIRYC in numbers: Publications (2011-14)

Peer-reviewed: 301 IF>10: 37

10>IF>5: 34

IF<5: 240

Review papers: 18

Book chapters: 14

>300 abstracts at international meetings

26 JACC 6 Circulation 6 Eur Heart J 1 Circ Res 5 Int J Cardiol 2 Cardiovasc Res 21 Circ Arrhythmia 51 Heart Rhythm 1 Radiology 2 Plos ONE …

Largest annual international conference in cardiac electrophysiology worldwide.

Competitive selection of abstracts

Heart Rhythm Society Meeting 2013 (7-10 May 2013):

44 presentations by LIRYC members!

For comparison: P. Sanders (Adelaide): 33 S. Narayan (San Diego): 24

- A. Natale (Texas): 24 D. Packer (Mayo Clinic): 16

Heart Rhythm Society Meeting 2014 (7-10 May 2014):

53 contributions!

Heart Rhythm Society Meeting 2015 (12-15 May 2015):

52 contributions!

Industrial partnerships and innovation

31

INDUSTRIAL PARTNERSHIPS

IHU LIRYC

SORIN MED-

TRONIC

CARDIO-

INSIGHT

GUER-BET

CEVA

SIEMENS

IMAGE GUIDE

D THERA

PY

LEMER

PAX/ LICAR

DI

BIOSENSE

WEBSTER

BOSTON SC.

St JUDE

MEDICAL

BARD

Signed

Finalizing the details

Under negociation

Master Research Agreement

Collaboration Agreement

Chair

INDUSTRIAL TRANSFER

MAP Catheter (Finalizing the details) • Exclusive Licence • Lump sum payment 50 000 USD • Royalties-5% • Capped at 3M USD/year

LemerPax • Exclusive Licence • Royalties-3% on CathPax AF • Royalties-3% on CathPax CRM

PATENTS Devices for heart valve diseases

(Louis Labrousse – Lionel Leroux) • Filed on January 2014

• PCT on January 2015

• First prototype ready

• Cost: • Patent study: 2000 Euros

• Patent: 7900 Euros

• In-vivo experiment: 1000 Euros

• Prototyping: 3000 Euros

PATENTS

System for automated rhythm-based control of cardiac ablation close to the atrioventricular node (D. Hook, V. Meillet, R. Dubois) • Filed in May 2015

PATENTS Automatic Myocardial Fat Quantification

in ARVC (Hubert Cochet – Pierre Jaïs) • Filed May 2015 • IP Cost:

Method for noncontact stimulation and ablation (F. Marquet, B. Quesson, P. Bour, F. Vaillant, R. Dubois)

• 2 patents in 2014 • IP Cost : 11 000 Euros • Research cost: >250 kEuros

Method for noncontact stimulation and ablation (F. Marquet, B. Quesson, P. Bour, F. Vaillant, R. Dubois)

• 2 patents in 2014 IP Cost : 11 000 Euros Research cost: >250 kEuros

Bruno Quesson – DR CNRS Julie Magat, MRI research engineer Jérôme Naulin, MRI technician Valery Ozenne, Post-doc MRI Fabrice Marquet, Post-doc ultrasound José LR Garcia, Post-doc, vet Solenn Toupin, PhD student 2013-2016 – Siemens Pierre Bour, PhD student 2014-2017 – IGT Mathilde Merle, SW Engineer Florent Collot, SW Engineer Thibaud Troadec, M2 Arnaud Fouillet, M2

MUSIC PROJECT – MULTIMODAL IMAGING PLATFORM

MAXIME SERMESANT (INRIA SOPHIA)- PIERRE JAIS – HUBERT COCHET

A MAJOR PROJECT : ECG IMAGING

252 electrode vest ⇒ Potentials from the torso UT

CT-Scan/MRI

Propagation in the torso (Laplace Law)

⇒ Discretization (MFS*)

Mathematical Optimization ⇒ Epicardial potentials UH

-div(sTÑu) = 0 on W

T

u = UT on T

sTÑu .n = 0 on T

u = UH

on H

ì

í

ïï

î

ïï

T

H

WT

Malmivuo, 1995

UT= AU

H

* Y. Wang , Y. Rudy, Ann of biomed Eng, 2006.

Phase mapping

Gradient and Laplacian solution

Signal averaging

Extraction of heart motions

Heart Extraction

Langendorff Perfusion and Heart Placement

Simultaneous Tank and Optical Mapping

Post-Experiment MRI with heart in place

Perfused heart suspended in correct anatomical position

252 leads recording tank potentials

Dual-camera set up for optical mapping of

heart

TORSO TANK

SIGNAL PROCESSING -SIMULATION FOR VALIDATION Signal Processsing Remi Dubois

AF Mapping Jason Bayer, Ed Vigmond

Phase Mapping from non-invasive Data Mark Potse, Yves Coudière

Bidomain TNNP Ventricles Model

Transmembrane Potentials

‘Gold Standard’ Phase

Bi-domain equation

Phase

Surface ECG on 252 electrodes

Electrocardiographic mapping

Comparison

1930 Albert S. Hyman decided on the need to resuscitate persons by "artificial pacemaker" operated by a hand crank and spring motor which turned a magnet (DC current generator) to supply the electricity . The device received press coverage, though not acceptance by the medical community. The concept was also criticized as interfering with natural events.

WORKSHOP LIRYC – 24 OCT 2014

Château Pape Clément

118 participants (équipes LIRYC, conseil scientifique international, professeurs invités, collaboration nationale, partenaires académiques et industriels, CRA, AST, ANR et CGI)

Total ~8000m2 for animal & modelling research

A Unique Structure in Europe and abroad Synchrotron

A Ripart - Président

Governance

BOARD OF DIRECTORS

M Haissaguerre - Director

M Hocini - Vice Director

P Jais - Vice Director

O Bernus - Scientific Director

J Boussuge-Roze - Executive Director

R Dubois - Knowledge tranfert Manager

R Marthan - Teaching Director

H Normand - Administrative and Financial Manager

INTERNATIONAL SCIENTIFIC

COUNCIL M Janse - A Kleber

S Nattel – T Meinertz

F Gaita - M Ladzunski– A Carpentier

Meets once a year

Is consulted on main scientific orientations

Assesses the LIRYC scientific activities

Makes recommendations for LIRYC’s international development and recognition

Produces a report for the administration council

5800m² (500m² clos couvert)

500m2 free space for future extension

DIFFICULTES RENCONTREES

Partage PI et valorisation Décision Multipartenariale Médecins hors CEE

Therapeutic targets

Haissaguerre et al Circulation (2002)

Purkinje cells

Haissaguerre et al NEJM (1998)

Pulmonary Venous cells

LIRYC Administration

LEGAL STRUCTURE

• Private Foundation for research purposes since November 2014

• LIRYC Foundation under the umbrella of Bordeaux University Foundation

• 5 founding members

LIRYC - Restoring the rhythm of life 52

Julie Boussuge-Roze Executive Director

Sophie Vialle Communication Manager

March 2014

Loïc Durand IT Manager

Sophie Panteix Financial Assistant

Delphine Gé Administrative Assistant

Pippa McKelvie-Sebileau Grant officer

April 2015

Fanny Bourrée Quality Manager

Hervé Normand Administrative

and Financial Manager October 2014

Grégory Darriet IT Technician

July 2014

Administrative Team

HEALTH AND RESEARCH INFRASTRUCTURES

Haut-Lévêque Cardiologic Hospital

IHU LIRYC

Building construction

(~6000m² )

IV. PROJET IMMOBILIER

Novel structural or functional imaging

252 ELECTRODE

VEST

HEART-TORSO GEOMETRY (CT –MRI underway)

ECM* ALGORITHMS SOLVES “INVERSE PROBLEM”

PRE or PER-Procedural instantaneous maps

40 TÂCHES À ACCOMPLIR PAR L’ÉQUIPE DE PARTENAIRES

POUR L’ ÉCHÉANCE 2020…

ET L’EQUILIBRE FINANCIER…

SOUS LE REGARD VIGILANT DE LA CGI ET LE COMITÉ DE SURVEILLANCE JUPPÉ-ROCARD

WP1/ SCIENTIFIC

OBJECTIVES

SWP 1.A : ATRIAL FIBRILLATION

Task N°1 : Mechanism and modelling of pulmonary vein firing

Task N°2 : Development of arrhythmogenic atrial substrate

Task N°3 : Pathophysiological link between structure and function

Task N°4 : Markers for AF burden and thrombo-embolic risk

Task N°5 : Risk Predictors for the development of AF

Task N°6 : Risk of dementia associated with AF

Task N°7 : To quantify the complexity of AF

Task N°8 : Recognition of active sources by novel methods of signal acquisition and

processing

Task N°9 : Substrate ablation in computer models

Task N°10 : Specific drugs for pulmonary veins of atrial substrate

SWP 1.B : PURKINJE NETWORK

Task N°1 : Cellular Mechanisms of triggered activity in Purkinje fibers leading to VF

Task N°2 : Topologic properties of Purkinje system network

Task N°3 : Mechanism of Ventricular arrhythmias associated with diseased ventricular substrates

Task N°4 : Mechanism of VF in primary electrical disorders

Task N°5 : Predictors of Sudden Death

Task N°6 : Predictors of ventricular arrhythmias associated with abnormal ventricular substrates

Task N°7 : Predictors of VF in primary electrical disorders

Task N°8 : Multisite Ventricular Pacing to prevent VF recurrence

Task N°9 : Novel interventional therapies targeting ventricular arrhythmogenic substrate

Task N°10 : Novel medical therapies

WORK PACKAGES

SWP 1.C : ELECTRICAL DYSSYNCHRONY IN HEART FAILURE

Task N°1 : Assessment of Electrical Dyssynchrony in varied aetiologies of HF

Task N°2 : Characterization of terminal Purkinje-muscle junctions system in Electrical dyssynchrony

Task N°3 : Investigating the link between electrical and mechanical dysfunction of the heart

Task N°4 : Mechanisms of reverse remodelling by resynchronization

Task N°5 : Novel electrocardiographic and imaging predictors of the impact of CRT on HF outcome

Task N°6 : Impact of electrical/mechanical dyssynchrony on HF outcome

Task N°7 : Left ventricular endocardial pacing in HF

Task N°8 : Multisite left ventricular pacing in HF

Task N°9 : Leadless pacing in HF

Task N°10 : Resynchronization combined with vagal stimulation

Task N°11 : Electrical regenerative therapeutic strategies

Task N°12 : Resynchronization in patients with narrow QRS complex

Task N°13 : Resynchronization in patients with right ventricular dysfunction

Task N°14 : Resynchronization in prevention of heart failure

SWP 1.D : ENERGETICS OF HEART

Task N°1 : Heart-specific mitochondrial activation by calcium

Task N°2 : Shaping of calcium signalling by mitochondria in normal contraction and

fibrillation

Task N°3 : Development of non-traumatic NMR methods of heart energetics and

function

Task N°4 : Integrated analysis (system's biology) of drug effects

Task N°5 : Evaluation of the adaptation of heart energetics to aging and exercise

Task N°6 : System bioenergetics of heart pathology

Task N°7 : Novel diagnosis of heart dysfunction by system's biology

Task N°1 : Implementation of integrated/mapping systems to assist interventional/surgical procedures

Task N°2 : Development of a new electrocardiographic system for non-invasive mapping by optimized

signal processing

Task N°3 : Design and validation of dedicated catheters for multisite monophasic action potentials

recordings

Task N°4 : Design of Innovative imaging techniques/contrast agents of myocardial structure or function

Task N°5 : Development of a new computer based platform for clinical decision/knowledge diffusion

Task N°6 : Design and validation of new tools and catheters for ablation/surgery of atrial fibrillation

Task N°7 : Design of new drugs based on specific peptides associated with arrhythmogenicity of PV

cardiomyocytes or Purkinje arrhythmogenicity

Task N°8 : Design of simulator

Task N°9 : Endocardial and multisite ventricular pacing

Task N°10 : Leadless pacing system

Task N°11 : Computer-guided and robotic implantation

Task N°12 : Hemodynamic sensors and monitoring of heart failure patients with telemedicine

Task N°13 : CRT combined with vagal stimulation

WP2/ TECHNOLOGICAL

INNOVATIONS CARDIAC ATRIAL ARRHYTHMIAS

Task N°1 : Earlier diagnosis – Biomarkers

Task N°2 : Prediction improvement

Task N°3 : Therapies

SUDDEN DEATH AND VENTRICULAR ARRHYTHMIAS

Task N°4 : Identification of risk

Task N°5 : Management of heart diseases

Task N°6 : Therapies

ELECTRICAL DYSSYNCHRONY AND HEART FAILURE

Task N°7 : Earlier diagnosis

Task N°8 : Expand indications in broad population of HF patients

Task N°9 : Therapies

Task N°10 : Irradiation exposure

WP3/ PATIENT CARE

WP4/ TRAINING WP5/ MANAGEMENT

SWP 4.A : DEGREE PROGRAM

SWP 4.B: NON DEGREE PROGRAM

SWP 4.C : CONTINUOUS EDUCATION

SWP 4.D : PATIENTS AND POPULATION EDUCATION

PROGRAM

Task N°1 : Management of liaison with the partners

Task N°2 : Recruiting and managing staff

Task N°3 : Defining and financing research, training and transfer programs

Task N°4 : Creating, managing and supporting shared centres of services and platforms

Task N°5 : Providing offices and training space, reception areas and accommodations, managing and

maintaining

TECHNOLOGICAL PLATFORM