Jérôme Claverie

Siham Kamali-Bernard

J M M Cordeiro

Fabrice Bernard

João Manuel

Marques Cordeiro

Assessment of mechanical, thermal properties and crystal shapes of monoclinic tricalcium silicate from atomistic simulations

Keywords: Tricalcium silicate, Mechanical properties, Thermal properties, Cleavage energy, Crystal shape, Molecular dynamics

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

The research in cementitious materials is experiencing new challenges mainly due to the need to preserve the environment and save energy. To reduce CO 2 emissions and energy cost of production, alternative binders are under study [START_REF] Biernacki | Cements in the 21st century: Challenges, perspectives, and opportunities[END_REF]. However, ordinary Portland cement (OPC) should continue to be employed for a long time and understanding of its principal constituents is primordial for its improvement. Another way to reduce the environmental impact of Portland cement is to enhance its reactivity which will involve less content of cement in concrete for the same strength. Since alite is the principal phase of Portland clinker that most contributes to strength development of Portland cement and particularly at early ages, a deep understanding of its properties is crucial to Email address: siham.kamali-bernard@insa-rennes.fr (Siham Kamali- Bernard) improve its quality and reactivity. Alite is a tricalcium silicate (C 3 S) with minor oxides usually called impurities. It presents a large grade of polymorphism depending on different factors, among them: the nature and the amount of impurities, the temperature of preheating or burning [START_REF] Staněk | The influence of the alite polymorphism on the strength of the Portland cement[END_REF]. Seven structures were reported in industrial alite: three triclinic (T 1 , T 2 and T 3 ) , three monoclinic (M 1 , M 2 and M 3 ), and a rhombohedral form R. These polymorphs appear via successive and reversible phase transitions [START_REF] Taylor | Cement Chemistry[END_REF]:

T 1 620 • C ← ---→ T 2 920 • C ← ---→ T 3 980 • C ← ---→ M 1 990 • C ← ---→ M 2 1060 • C ← ----→ M 3 1070 • C ← ----→ R (1)
It is well known that impurities in alite stabilize high temperature polymorphs at low temperatures [START_REF] Taylor | Cement Chemistry[END_REF][START_REF] Maki | Redistribution of impurity during recrystallization of alite in portland cement clinker[END_REF]. The two main C 3 S polymorphs present in industrial clinker are M 1 and M 3 . According to Maki and Goto [START_REF] Maki | Factors influencing the phase constitution of alite in portland cement clinker[END_REF], MgO in clinker promotes the stable growth of alite in favor of the occurrence of M 3 . In contrary, decreased MgO/SO 3 ratio lead to M 1 stabilization [START_REF] Staněk | The influence of the alite polymorphism on the strength of the Portland cement[END_REF][START_REF] Maki | Factors influencing the phase constitution of alite in portland cement clinker[END_REF]. It was also reported that preheating of the raw meal may result in the disappearance of the M3 polymorph [START_REF] Staněk | The influence of the alite polymorphism on the strength of the Portland cement[END_REF]. This modifications in the structure of C 3 S can have a significant impact on strength as reported in few experimental results in the literature [START_REF] Staněk | The influence of the alite polymorphism on the strength of the Portland cement[END_REF][START_REF] Zhou | Research on the formation of M1type alite doped with MgO and SO 3 -A route to improve the quality of cement clinker with a high content of MgO[END_REF]. The transformation of M 3 to M 1 polymorph may result in a 10% increase in the compressive strength [START_REF] Staněk | The influence of the alite polymorphism on the strength of the Portland cement[END_REF]. The origin of this observed variation in strength could be explained by a greater amount of non-bonding electrons in oxygens of M 1 C 3 S, leading to a higher reactivity when compared to the M 3 polymorph. The impact of structure at the nanoscale on the properties like strength is a complex topic and investigation at the atomic level via molecular modelling and simulation should be helpful to improve our understanding of Portland cement.

Over recent years, the properties of cementitious materials were addressed using atomistic models, with particular attention on the main hydration product of OPC: calcium silicate hydrates (C-S-H) [START_REF] Qomi | Anomalous composition-dependent dynamics of nanoconfined water in the interlayer of disordered calcium-silicates[END_REF][START_REF] Bauchy | Order and disorder in calcium-silicatehydrate[END_REF]. In comparison, only few studies at the atomic scale focused on OPC clinker phases [START_REF] Mishra | cemff : A force field database for cementitious materials including validations, applications and opportunities[END_REF]. Computation of thermal and mechanical properties at the molecular scale can provides important information on the behaviour of OPC clinker and hydrated product. From the computation of surface energies, crystal shapes can be theoretically constructed for different polymorphs and help to understand morphological changes [START_REF] Azevedo | Surface and electronic properties of rutile TiO2 thin films coated with PbO2[END_REF]. The knowledge of preferential cleavage planes and crystal shapes of C 3 S polymorphs is fundamental to understand their growth during the clinkering process [START_REF] Maki | Phase identification of alite in portland cement clinker[END_REF].

It could also explain C 3 S dissolution mechanisms [START_REF] Nicoleau | Analytical Model for the Alite (C3S) Dissolution Topography[END_REF] or cleavage modes during clinker grinding [START_REF] Mishra | Force Field for Tricalcium Silicate and Insight into Nanoscale Properties: Cleavage, Initial Hydration, and Adsorption of Organic Molecules[END_REF][START_REF] Mishra | En route to multi-model scheme for clinker comminution with chemical grinding aids[END_REF]. Determination of such properties by experimental methods are most of the time limited, especially in the case of surface energies [START_REF] Tran | Surface energies of elemental crystals[END_REF]. In all cases, a proper synthesis procedure of pure C 3 S is necessary, and the determination of the amount of each polymorph in a sample is neither trivial nor accurate [START_REF] Pustovgar | Influence of aluminates on the hydration kinetics of tricalcium silicate[END_REF].

In this work, the mechanical, thermal and surface properties of M 1 and M 3 C 3 S (the main forms of alite encountered in industrial OPC [START_REF] Noirfontaine | Tricalcium silicate Ca3SiO5 superstructure analysis: a route towards the structure of the M1 polymorph[END_REF]) were characterized by molecular dynamics (MD) simulations. The present article is divided into four sections: crystal structures and force fields, mechanical properties, thermal properties, and cleavage energies and equilibrium shapes. The last three sections include a description of the method employed and a presentation and discussion of results. To finish, a general conclusion resumes the different findings.

M 1 C 3 S M 3 C 3 S

Crystal structures and force fields

The atomistic systems investigated were built from the pure M 1 [START_REF] Noirfontaine | Tricalcium silicate Ca3SiO5 superstructure analysis: a route towards the structure of the M1 polymorph[END_REF] and M 3 [START_REF] Mumme | Crystal structure of tricalcium silicate from a Portland cement clinker and its application to quantitative XRD analysis[END_REF] crystal structures depicted in Fig. 1. While the latter has already been used [START_REF] Mishra | Force Field for Tricalcium Silicate and Insight into Nanoscale Properties: Cleavage, Initial Hydration, and Adsorption of Organic Molecules[END_REF][START_REF] Manzano | Insight on Tricalcium Silicate Hydration and Dissolution Mechanism from Molecular Simulations[END_REF][START_REF] Manzano | Impact of Chemical Impurities on the Crystalline Cement Clinker Phases Determined by Atomistic Simulations[END_REF], this is the first time that a M 1 C 3 S model has been employed in a MD investigation, despite of its predominance in alite of Portland clinker with high SO 3 content [START_REF] Maki | Factors influencing the phase constitution of alite in portland cement clinker[END_REF]. Regarding atomic structural organization along the (010) direction, and b parameters, the two cells are very close. However, the two models are shifted by 1/4 in cell units in the (010) direction, meaning that the (010) Ca-rich plane of the M 1 model corresponds to the (040) plane of the M 3 model. The atomic organization along (001) axis in the M 1 model is close to M 3 model in the (100), and the c and a parameters in M 1 and M 3 respectively are almost equal. Conversely, the a parameter of the M 1 unit cell is approximately 3 times larger than the c parameter for M 3 , and the major structural difference is expected in the (100) direction for M 1 and (001) direction for M 3 .

Understanding the mechanical properties of C 3 S is important for various reasons; among them: 1) the total hydration of a cement paste is never achieved, so clinker components are, to some extent, involved in the final microstructure of hydrated cement [START_REF] Ash | Estimations of degree of hydration of portland cement pastes[END_REF][START_REF] Vandamme | Nanogranular packing of C-S-H at substochiometric condi-tions[END_REF], and mainly at early ages; and 2) to optimize the grinding of clinker during cement manufacturing. The investigation of elastic properties of cementitious materials are most of the time related to hydrated products and very few data can be found in the literature concerning elastic properties of clinker components. Synthetic alite can be made by solid state sintering of decarbonated calcium oxide and fine silica, with possible addition of impurities (alumina, magnesium, sulfates), depending on the polymorph to be reached [START_REF] Nicoleau | The di-and tricalcium silicate dissolutions[END_REF]. The elastic properties are typically determined by nanoindentation experiments and at the macroscale by resonance frequency measurements [START_REF] Velez | Determination by nanoindentation of elastic modulus and hardness of pure constituents of Portland cement clinker[END_REF][START_REF] Brunarski | Recommendations for the use of resonance methods for testing concrete[END_REF]. Nanoindentation experiments are most of the time performed on hydrated mortar or cement paste [22, 26-3 28], and more rarely on pure and doped clinker phases [START_REF] Velez | Determination by nanoindentation of elastic modulus and hardness of pure constituents of Portland cement clinker[END_REF]. Unhydrated clinker phases are known to exhibit stiffnesses by 3-5 times larger and hardnesses by one order of magnitude larger than hydrated phases [START_REF] Vandamme | Nanogranular packing of C-S-H at substochiometric condi-tions[END_REF][START_REF] Velez | Determination by nanoindentation of elastic modulus and hardness of pure constituents of Portland cement clinker[END_REF][START_REF] Manzano | Elastic properties of the main species present in Portland cement pastes[END_REF].

Two force fields (FF) introduced in the cemff database [START_REF] Mishra | cemff : A force field database for cementitious materials including validations, applications and opportunities[END_REF] were employed to describe atomic interactions in C 3 S: INTERFACE FF (IFF) [START_REF] Mishra | Force Field for Tricalcium Silicate and Insight into Nanoscale Properties: Cleavage, Initial Hydration, and Adsorption of Organic Molecules[END_REF][START_REF] Heinz | Thermodynamically Consistent Force Fields for the Assembly of Inorganic, Organic, and Biological Nanostructures: The INTERFACE Force Field[END_REF] and ClayFF [START_REF] Cygan | Molecular models of hydroxide, oxyhydroxide, and clay phases and the development of a general force field[END_REF]. The PCFF implementation of IFF, used inhere, includes quadratic bonded terms for covalent bonds in silicates, an electrostatic term and a 9-6 Lennard-Jones (LJ) potential for short-range interactions:

E IF F = ij 4 n=2 K r,ij (r ij -r 0,ij ) n + ijk 4 n=2 K θ,ij (θ ij -θ 0,ij ) n + 1 4πε 0 ε r ij q i q j r ij + ij ε 0,ij 2 σ ij r ij 9 -3 σ ij r ij 6 (2)
ClayFF is a general force field initially developed to describe interfaces between clays and water [START_REF] Cygan | Molecular models of hydroxide, oxyhydroxide, and clay phases and the development of a general force field[END_REF], and in particular adsorption of ions for, inter alia, environmental application. It uses a flexible single point charge (SPC) water model and its potential energy includes a 12-6 Lennard-Jones potential:

E ClayF F = K r,ij (r ij -r 0,ij ) 2 + K θ,ij (θ ij -θ 0,ij ) 2 + 1 4πε 0 ε r ij q i q j r ij + ij ε 0,ij σ ij r ij 12 - σ ij r ij 6 (3)
For dehydrated species, its interaction potential is the sum of a 12-6 LJ potential and electrostatic interactions. ClayFF does not account explicitly for covalent bonding in silicates, and larger charges are used for silicon atoms (2.1e) when compared to IFF (1.0e).

The ionic nature of these bonds is thus overestimated in ClayFF, and impacts substantially computed surface tension [START_REF] Mishra | Force Field for Tricalcium Silicate and Insight into Nanoscale Properties: Cleavage, Initial Hydration, and Adsorption of Organic Molecules[END_REF]. We also expect an influence of this assumption on the elastic behaviour [START_REF] Heinz | Thermodynamically Consistent Force Fields for the Assembly of Inorganic, Organic, and Biological Nanostructures: The INTERFACE Force Field[END_REF]. Results in better agreement with experimental measurements are expected with IFF, for which parameters were optimized especially for C 3 S [START_REF] Mishra | Force Field for Tricalcium Silicate and Insight into Nanoscale Properties: Cleavage, Initial Hydration, and Adsorption of Organic Molecules[END_REF]. Every simulation in the present paper were performed with the LAMMPS simulation code [START_REF] Plimpton | Fast Parallel Algorithms for Short-Range Molecular Dynamics[END_REF]. A 12 Å cutoff, and an Ewald summation with precision of 10 -5 were adopted for short-range and long-range interaction, respectively.

Mechanical properties

Methods

Elastic properties of solids are generally computed by applying a strain or a stress in the desired directions and by determining the strain-stress or strain-energy relations.

Two type of methods are used and discussed in this work: static optimization methods and time integration methods.

1. Static optimization methods are typically applied at 0 K, or where anharmonical vibrations can be neglected, although lattice vibration frequency can be included through quasi-harmonic approximation techniques [START_REF] Qomi | Methodology for Estimation of Nanoscale Hardness via Atomistic Simulations[END_REF]. In this case, a small strain ∆ε j is applied positively and negatively in each direction j:

C + ij = - σ i (∆ε j ) -σ i (0) ∆ε j C - ij = σ i (-∆ε j ) -σ i (0) ∆ε j (4)
The stiffness constants can be obtained by averaging C + ij and C - ij and the symmetric constants:

C ij = C + ij + C - ij + C + ji + C - ji 4 (5)
This method performs quick calculation, minimizing the energy of the system before and after application of a small strain ∆ε. However, it does not provide the stressstrain behavior nor give a prediction of the failure point. This computational scheme can be extended by applying a strain on multiple steps followed by an energy minimization after each step. The stiffness constants are therefore obtained by linear regression on the desired strain range.

For a system of particles with a volume V , the stress components can be computed as the sum of the kinetic and virial terms over the N particles:

σ ij = N k m k v ki v kj V + N k r ki f kj V ( 6
)
where i and j are the directions x, y and z. m k , r ki , v ki are the mass, position and velocity respectively, and f kj is the force applied on the particle k. In the case of a molecular mechanics (MM) optimization, the kinetic term is zero.

2. Time integration methods use equilibrium MD (EMD) or non-equilibrium (NEMD) simulations to compute the deformation of the simulation box while controlling the stress or vice versa. In EMD, the equilibrium is reached before each production run, which provides time-averaged values of the computed properties. In NEMD, the strain, or the stress, is changed continuously during the run. This is convenient because only a single run is needed. However, the strain/stress rate may influence the result. The simulation can be either strain or stress controlled. In the first case, a strain rate is applied on the desired direction and with a fixed stress (usually 0 GPa) on the other directions. In the second case, a stress rate is applied in one direction while keeping the others at 0 GPa. The simulation box is thus allowed to relax in the other directions.

The elastic properties of M 1 and M 3 C 3 S were first computed from the static MM calculation method on unit cells. The enthalpy of the cell was minimized at 0 GPa, allowing free movement of atoms and cell parameters. Then a deformation was applied in the desired direction and the energy of the system was minimized, allowing the atoms to move while fixing the cell parameters. The process was repeated negatively and positively in each direction, to calculate the 21 components of the stiffness matrix according to the Eq. ( 5). The unit cells experienced maximal deformations of ±0.2, with increments of 1 × 10 -4 , but the values C ± ij were obtained by linear fitting on values from zero to ±0.02

deformation. Homogeneous values of bulk and shear moduli for large crystals randomly dispersed were obtained by calculating Reuss and Voigt bounds. The Voigt-Reuss-Hill (or VRH) estimation for monoclinic crystals is obtained as the arithmetic average of Voigt and Reuss bounds on bulk and shear modulus [START_REF] Wu | Crystal structures and elastic properties of superhard IrN 2 and IrN 3 from first principles[END_REF][START_REF] Fu | Assessment of the elastic properties of amorphous calcium silicates hydrates (I) and (II) structures by molecular dynamics simulation[END_REF][START_REF] Bernard | Multiscale modelling approach to determine the specific heat of cementitious materials[END_REF].

In order to determine elastic properties at finite temperature supercells of 1296 atoms (1 × 4 × 2 and 2 × 4 × 3, with dimensions 27.87 Å × 28.24 Å × 24.52 Å and 24.47 Å × 28.29 Å × 27.89 Å, for M 1 and M 3 C 3 S respectively) were created from the unit cells presented in Fig. 1. For each polymorph, three replicas were created by using different seeds for the initial velocities of atoms. Equilibration runs were performed during 500 ps at 300 K in the NpT ensemble at hydrostatic pressure σ varying between 0 and 15 GPa, followed by a production run of 1 ns. Nose-Hoover thermostat and barostat [START_REF] Nosé | A unified formulation of the constant temperature molecular dynamics methods[END_REF][START_REF] Hoover | Canonical dynamics: Equilibrium phase-space distributions[END_REF] were employed with the Verlet algorithm [START_REF] Verlet | Computer "Experiments" on Classical Fluids. I. Thermodynamical Properties of Lennard-Jones Molecules[END_REF] to integrate Newton's equations of motion.

Long-range interaction were computed with an Ewald summation with precision of 10 -5

and a cutoff of 10 Å was applied for van der Waals interactions.

The bulk modulus K was calculated from EMD simulations in the NpT ensemble with incremental equilibrium pressure. In NEMD simulations, the supercells underwent 1 ns runs of compression and tension at a strain rate of 1 × 10 8 s -1 up to 20 %, while maintaining the pressure to 0 GPa in the other directions. The stress components were computed from Eq. ( 6). No noticeable influence was reported for rates of one order of magnitude above and bellow 1 × 10 8 s -1 . This is predictable because the resulting dislocation velocity is ∼0.28 m s -1 for the largest dimension. This dislocation velocity is large when compared to macroscale tests, but is negligible compared to the velocity of acoustic waves in C 3 S. Based on the values of bulk modulus K, Poisson's ratio ν and density ρ from previous acoustic measurements, compressive and shear waves are calculated as 7200 and 3700 m s -1 respectively [START_REF] Boumiz | Modelling the development of the elastic moduli as a function of the hydration degree of cement pastes and mortars[END_REF]. This ensures that atoms will respond instantaneously to the deformation of the simulation box [START_REF] Elder | Nanovoid formation and mechanics: a comparison of poly(dicyclopentadiene) and epoxy networks from molecular dynamics simulations[END_REF][START_REF] Teich-Mcgoldrick | Molecular Dynamics Simulations of Structural and Mechanical Properties of Muscovite: Pressure and Temperature Effects[END_REF]. Elastic parameters were calculated by the direct relations, where i = j are the x, y and z coordinates:

E ii = σ ii ε ii G ij = σ ij ε ij (7) ν ij = - ε ii ε jj

Results and discussion

The stiffness constants, homogenized stiffness constants and elastic moduli of M 1 and EMD calculations where performed with the IFF at 0, 1, 2. As an important feature of the C 3 S, the change in coordination between calcium cations Ca and oxygen in silicates (Os) as a function of the hydrostatic pressure was analyzed by radial distribution function (RDF) (see Fig. 3). The increasing hydrostatic pressure seems to influence the C 3 S structure at short range (∼4 Å). The second coordination shell is flattened and shifted to the left by the effect of the pressure. The same behavior is observed for both polymorphs.

M 3 C 3 S,
The stress-strain curves for NEMD and static MM simulations are plotted in Fig. 4.

The general behavior of the M 1 and M 3 polymorphs seems similar. However, the compressive strength seems to be larger for the M 1 polymorph in the x direction, and for the M 3 polymorph in the z direction. The structural correspondence of the (001) direction for the M 1 unit cell with the (100) direction for the M 3 unit cell explains this result.As already noticed for the elastic behaviour (see Fig. 2), a more isotropic yield behaviour is observed for M 1 when compared to M 3 . The difference in compressive strength along the x and z directions is greater for M 3 C 3 S (∼ 15 and 30 GPa) than for M 1 C 3 S (∼ 21 and 16 GPa). The elastic moduli obtained from these NEMD simulation are presented in MM simulations results in a stiffer elastic behaviour than for MD simulations, due to the larger structural relaxation induced by the thermal motion. Nonetheless, the values obtained by these two methods are in good agreement. The static calculation method provides a good representation of elastic properties and is very fast, but does not allow to assess the yield stress properly, in particular in compression, since no relaxation is permitted in the transversal directions. This restriction causes hardening for negative strains. The yield stress could be assessed by enthalpy minimization, but such calculation is not trivial and the calculation can easily stuck in a local minima because the objective function is changing while the simulation box dimensions change.

M 1 M 3 M 3 a [

Thermal properties

During its lifetime, concrete undergoes temperature changes. The thermal expansion and contraction of concrete as temperature increases and decreases, is influenced by the aggregate type, the cement type, and the water/cement ratio. Although the aggregate type has the larger influence on the expansion and contraction of concrete, the thermal properties of hydrated and dry cement is of great interest. Thermal cracking of concrete generally occurs during the first days after casting. During the exothermic hydration of cement, the temperature rises, and drops faster on the surface than in the bulk. The surface tends to contract with the cooling and stress arises because the bulk remains hot, resulting in cracks. Naturally, this phenomenon occurs more likely in larger volumes.

The assessment of vibrational spectra and specific heat of cement phase is a first step toward a microstructural modelling and further understanding of heat propagation in the cement paste.

Methods

In the canonical ensemble, one can derive the fluctuation relationship between specific heat and internal energy E:

C V = 1 kT 2 (∆E) 2 ( 8
)
where k is the Boltzmann constant. By using fluctuation methods, the specific heat can be computed at any temperature with a single, long enough run. However, these methods rely strongly on the temperature relaxation parameter used to thermostat the system (and in the case of the NpT ensemble, on the pressure relaxation parameter) [START_REF] Hickman | Temperature fluctuations in canonical systems: Insights from molecular dynamics simulations[END_REF]. Moreover values obtained by fluctuation method depends on the time interval used for block averages [START_REF] Hickman | Temperature fluctuations in canonical systems: Insights from molecular dynamics simulations[END_REF], often leads to large uncertainties and to bad agreements with experimental results [START_REF] Wang | Molecular Dynamics Simulation of Poly(ethylene terephthalate) Oligomers[END_REF]. For this reason, non-fluctuation, or direct method, is preferred. It consists on running several simulations at finite temperature and calculating the time average energies for each one. The specific heat is calculated by definition, as the slope of the internal energy with respect to the temperature, at the desired temperature. The chosen temperature increment must be large enough to compute accurately the variation of energy between each simulation, but small enough, for the fitting to be representative. The specific heat capacity can also be computed from the velocity autocorrelation function (VACF) of atoms. Considering a solid made by quantum harmonic oscillator, the phonon density of states g(ω) is proportional to the Fourier transform of the velocity autocorrelation function of the atoms:

g(ω) = 1 3N kT +∞ -∞ N i=1 v i (t) • v i (0) e iωt dt ( 9
)
where k is the Boltzmann constant, N is the number of atoms and T is the temperature of the system. The occupational states of phonons follows a Bose-Einstein distribution f BE and at energy largely below the Debye temperature, the internal energy of the system can be reduced to the vibrational energy E v [START_REF] Qomi | Physical Origins of Thermal Properties of Cement Paste[END_REF][START_REF] Atkins | Physical Chemistry[END_REF]:

E v = +∞ 0 hω g(ω)f BE (ω) + 1 2 dω ( 10
)
The specific heat c v in 3N k units is calculated as the partial derivative of internal energy with respect to temperature:

c v = +∞ 0
u 2 e u (1 -e u ) 2 g(ω)dω +∞ 0 g(ω)dω [START_REF] Maki | Phase identification of alite in portland cement clinker[END_REF] where u = hω/kT . One has to note that the phonon spectrum computed this way is semi-classical and is different from the quantum phonon spectrum [START_REF] Winkler | Thermodynamic properties of MgSiO3 perovskite derived from large scale molecular dynamics simulations[END_REF]. Although the Eq. ( 9) includes quantum effects, the density of states is obtained by classical MD. We consider that this method is applicable at standard temperature and that anharmonic interactions are negligible.

Most of the time, experimental measurement of specific heat capacities is performed at constant pressure. From thermodynamics, the specific heat capacities at constant volume and pressure c v and c p , are related by the equation:

c p -c v = T α 2 ρβ ( 12
)
where ρ is the density, α = (1/V )( ∂V /∂T ) p is the thermal expansion coefficient, and β = -(1/V )( ∂V /∂P ) T is the compressibility, inverse of the bulk modulus K.

Specific heat and thermal expansion coefficient were computed on three replicas of C 3 S supercells. The simulations were performed in the NpT ensemble with the same MD parameters as previously. The systems were relaxed during 0.5 ns, and the data were collected for 1 ns. Within the direct method, the specific heat c p was computed by linear fitting of the enthalpy with respect to the temperature at five points around the temperature of interest (e.g., 280, 290, 300, 310 and 320 K to compute the specific heat at 300 K). The same method was employed to calculate the expansion coefficient, fitting the volume variation with respect to the temperature. To avoid the external influence of thermostating or barostating, the relaxed systems were equilibrated for 500 ps in the NVE ensemble, before running simulation of 100 ps, dumping the trajectory at each time step to be able to observe high vibrational frequencies. For the calculation using the ClayFF, a geometric mixing rule for LJ parameters was used in place of the original arithmetic mixing. Indeed, this mixing rule provides more accurate value of density obtained during NpT simulations. The VACF were computed on ten correlation windows of 10 ps on three replica for each polymorph. The phonon density of states (DOS) obtained from simulations in the NVE ensemble are presented in Fig. 5.The phonon DOS obtained for M 1 and M 3 are almost identical, so as the resulting specific heat. Thus the structural difference between both polymorph does not influence their thermal properties. However, the force field does affect the results. The main difference between the phonon DOS obtained with IFF and ClayFF relies principally in their description of bonds in silicate. In the case of IFF, where Si-O bonds are described by harmonic oscillators in addition to the short and long range description, the partial DOS (PDOS) of Os and Si atoms form a sharp peak near 935 cm -1 , in agreement with infrared spectroscopy measurements [START_REF] Hughes | Determining cement composition by Fourier transform infrared spectroscopy[END_REF], while the in-plane bending vibration of Os-Si-Os angle is measured as a band bellow 500 cm -1 [START_REF] Hughes | Determining cement composition by Fourier transform infrared spectroscopy[END_REF]. This bending contribution happens at larger frequencies in our results (near 550 cm -1 ). Wave numbers ω bellow 500 cm -1 are associated to stretching between calcium and oxygen atoms [START_REF] Qomi | Physical Origins of Thermal Properties of Cement Paste[END_REF][START_REF] Yu | Structure of Calcium Silicate Hydrate (C-S-H): Near-, Mid-, and Far-Infrared Spectroscopy[END_REF], in agreement with the PDOS obtained with both IFF and ClayFF. For ClayFF, the purely non-bonded description of Si-Os bonds allows for more degrees of freedom of atoms. The PDOS obtained for Si and Os atoms are thus more sparse. Generally, for the IFF, a shift of the DOS is observed towards higher vibrational frequencies. No 200, 300 and 400 K and extrapolated linearly, because this quantity vary proportionally with temperature (see Eq. ( 12)). The thermal expansion coefficient α, the compressibility β, and the density ρ, computed from simulations in the NpT ensemble are presented in Table 3.

Results and discussion

Temperature (K) α (K -1 ) β (Pa -1 ) ρ (g cm -3 ) c p -c v (J g -1 K) M 1 200 4.6(18)
The specific heat c p obtained for M 1 and M 3 C 3 S are plotted with respect to the temperature in Fig. 6. The values obtained at 300 K by the direct method are 0.86 ± 0.10 and (0.87 ± 0.04) J g -1 K -1 for M 1 and M 3 C 3 S respectively, which is much larger than experimental measurements. As for the phonon DOS, no significant variation of c p was found between M 1 and M 3 . The VACF method with ClayFF results in c p = (0.751 ± 0.013) J g -1 K -1 , which is very close to experimental values of 0.756 J g -1 K -1 [START_REF] Matschei | Thermodynamic properties of Portland cement hydrates in the system CaO-Al 2 O 3 -SiO 2 -CaSO 4 -CaCO 3 -H 2 O[END_REF] and 0.753 J g -1 K -1 [START_REF] Todd | Low-temperature Heat Capacities and Entropies at 298.16°K of Crystalline Calcium Orthosilicate, Zinc Orthosilicate and Tricalcium Silicate[END_REF]. The IFF provided a value slightly lower than experimental measurements: (0.723 ± 0.013) J g -1 K -1 . [START_REF] Matschei | Thermodynamic properties of Portland cement hydrates in the system CaO-Al 2 O 3 -SiO 2 -CaSO 4 -CaCO 3 -H 2 O[END_REF] Exp. [START_REF] Todd | Low-temperature Heat Capacities and Entropies at 298.16°K of Crystalline Calcium Orthosilicate, Zinc Orthosilicate and Tricalcium Silicate[END_REF] Figure 6: Specific heat of M1 and M3 C3S obtained by the direct and VACF method, plotted as function of the temperature. The transparent areas represent the error. Previously computed value from VACF calculation, as well as fitting of experimental measurements [START_REF] Matschei | Thermodynamic properties of Portland cement hydrates in the system CaO-Al 2 O 3 -SiO 2 -CaSO 4 -CaCO 3 -H 2 O[END_REF] and direct measurements [START_REF] Todd | Low-temperature Heat Capacities and Entropies at 298.16°K of Crystalline Calcium Orthosilicate, Zinc Orthosilicate and Tricalcium Silicate[END_REF] are plotted in addition to the results.

c p (J g -1 K -1 ) 3Nk = 0.983 J g -1 K -1 Direct -M1 C3S Direct -M3 C3S VACF -IFF VACF -ClayFF Sim. Qomi -CSH FF (2015) Exp.

Cleavage energies and equilibrium shapes

In the current section, the cleavage energies of M 1 and M 3 C 3 S were calculated from energy difference of cleaved and unified slabs. From these energies, the crystal shapes of both polymorphs were constructed using the Wulff construction method [START_REF] Wulff | Zur Frage der Geschwindigkeit des Wachstums und der Auflösung der Krystallflagen[END_REF].

Methods

The calculation of cleavage energies for multiple planes of the two monoclinic C 3 S models under study involved creation of cleaved and unified systems. For non-symmetric planes, reorganization of surface ions was performed to minimize superficial dipole moments. For each plane, five unified and cleaved systems were constructed with random distribution of surface species. A 10 nm vacuum was employed in cleaved systems. Series of steep temperature gradients were applied on ions within the uppermost and lowermost atomic layer of slabs in unified and cleaved systems. This method was previously employed and allows to relax the surfaces to the configuration of lower energy [START_REF] Mishra | Force Field for Tricalcium Silicate and Insight into Nanoscale Properties: Cleavage, Initial Hydration, and Adsorption of Organic Molecules[END_REF][START_REF] Fu | Cleavage Energy of Alkylammonium-Modified Montmorillonite and Relation to Exfoliation in Nanocomposites: Influence of Cation Density, Head Group Structure, and Chain Length[END_REF]. The systems with lower energies were selected to performed the calculation over 300 ps runs, after 200 ps equilibration runs. For more details on the method, we refer the reader to ref.

M 1 C 3 S
[58]

Results and discussion

The cleavage energy was computed classically from Eq. ( 13) and results are given in Table 4.

E cleav = E cleaved -E unif ied 2A (13)
The computed values are in the range of 1.14 to 1.55 J m -2 (1.32 J m -2 in average) for M 3 C 3 S, and 1.04 to 1.76 J m -2 (1.35 J m -2 in average) for M 1 C 3 S, in good agreement with previous atomistic simulation studies [START_REF] Manzano | Insight on Tricalcium Silicate Hydration and Dissolution Mechanism from Molecular Simulations[END_REF][START_REF] Durgun | The Characterization, Stability, and Reactivity of Synthetic Calcium Silicate Surfaces from First Principles[END_REF]. In general, the average values are very close between the two models. The energies obtained for particular planes vary as a function of the structure of each polymorph, and are particularly influenced by The Wulff construction can give theoretical insights on the shape of a crystal at equilibrium [START_REF] Wulff | Zur Frage der Geschwindigkeit des Wachstums und der Auflösung der Krystallflagen[END_REF]. It is based on the assumption that a crystal growth in a such way that the Gibbs free energy of its surface is minimized [START_REF] Gibbs | The collected works of J. Willard Gibbs[END_REF]. This results in a proportional relationship between the surface energy of a facet and its distance from the crystal center.

M 1 C 3 S M 3 C 3 S
From the lowest energy obtained in each direction, the equilibrium shapes of M 1 and M 3 C 3 S in Fig. 7 were created with the construction algorithm implemented in the pymatgen library [START_REF] Tran | Surface energies of elemental crystals[END_REF][START_REF] Ong | Python Materials Genomics (pymatgen): A robust, open-source python library for materials analysis[END_REF]. In the M 1 polymorph, the crystal grows only along three planes, while in the M 3 , seven planes are available. Maki related that the equilibrium form of alite is usually made up of three special forms: one pedion and two rhombohedra [START_REF] Maki | Relationship of processing parameters to clinker properties; influence of minor components[END_REF].

The author proposed a morphology similar to the M 1 obtained by Wulff construction, though more flat and with only one rhombohedra form. Maki explains that the crystal form of alite changes during recrystallization from platelet to massive granules with well developed pyramidal faces (10 11) and (1 102) [START_REF] Maki | Effect of recrystallization on the characters of alite in Portland cement clinker[END_REF]. The ratio between the width and the length of the platelet is function of the environment during the growth. One should note that the obtained equilibrium shapes are not fully definitive, since they were determined on a relatively finite number of planes. More calculations would probably refine these shapes, and produce a more accurate prediction.

Conclusion

This research aimed to provide knowledge at the atomic scale on the influence of alite polymorphism on its mechanical and thermal properties as well as on its equilibrium shape. The two main polymorphs of C 3 S in industrial OPC, M 1 and M 3 , were inves-tigated. This knowledge may contribute to the understanding of the influence of alite polymorphism on the variation in strength of Portland cement. This work also provide input data that are necessary in microscale modelling of Portland cement hydration and the development of its mechanical and thermal behavior [START_REF] Kamali-Bernard | Effect of tensile cracking on diffusivity of mortar: 3d numerical modelling[END_REF][START_REF] Bernard | Performance simulation and quantitative analysis of cement-based materials subjected to leaching[END_REF]. Cleavage energy values may improve our understanding of alite reactivity and dissolution kinetic, and crystal shapes could help for identification of polymorphs by SEM. In addition, this study explored and discussed different calculation methods and compared the performance of two force fields widely used to described cementitious systems.

The elastic constants were calculated by static and dynamical methods. The moduli found by Voigt-Reuss-Hill homogenization of the stiffness constants obtained in static calculation with IFF were found in good agreement with experimental measurements. However, the results obtained with ClayFF overestimated and underestimated experimental results, respectively. An isotropic distribution of elastic moduli in space was observed for the M 1 polymorph, whereas an anisotropic distribution was found for M 3 . The assessment of stress-strain curves for both polymorphs also indicates a more anisotropic behaviour for M 3 C 3 S regarding the yield compressive stress. Bulk modulus was obtained by EMD, and elastic, shear modulus, as well as Poisson's ratio were calculated by NEMD. The results are in good agreement with static calculations and experimental measurements.

Specific heat capacities were calculated by the direct method and from VACF. The direct method provides results greater than experimental measurements, and with much larger error than the VACF method. On the other hand, the VACF allowed to analyse the phonon density of states and provide results much more accurate. The results obtained with ClayFF are very close to previous experimental measurements, and results from IFF are slightly smaller. The DOS obtained from VACF are in good agreement with infrared spectroscopy measurements, and the differences between IFF and ClayFF arise mainly from the bond description in silicates.

Cleavage energy calculations were performed on both M 1 and M 3 C 3 S polymorphs, using a temperature gradient method to relax superficial ions to configurations of lower energy. These calculations allowed the construction of equilibrium shapes which are significantly different. The M 1 crystal possess three facets against seven for the M 3 polymorph. The energies obtained for both polymorphs are in the same range. Despite different morphologies, low index crystal planes with the lowest energies are the (100) and (001) for both polymorphs. The cleavage energies were calculated for a relatively limited number of planes, and further calculation could lead to even more accurate shapes.

Figure 1 :

 1 Figure 1: Unit cells of M1 C3S (cell parameters: a = 27.874 Å, b = 7.059 Å, c = 12.257 Å, β = 116.03°) [17] and M3 C3S (cell parameters: a = 12.235 Å, b = 7.073 Å, c = 9.298 Å, β = 116.31°) [18]. Color code: calcium cations in green, oxygen anions and silicate oxygen in red and silicon atoms in blue

for M 1

 1 and close to recent results from DFT calculations on the T 1 C 3 S [44]. Very similar results were obtained by Manzano et al. [29], employing the Buckingham FF and a M 3 C 3 S model proposed by de la Torre et al. [45]. The lowest elastic modulus is obtained in the x and z direction for the M 1 and M 3 polymorph respectively. This result is predictable because of the correspondence of the c parameter of the M 1 unit cell with the a parameter of the M 3 unit cell. Spacial distributions of Young's modulus were plotted with the ELATE open-source Python package[START_REF] Gaillac | ELATE: an open-source online application for analysis and visualization of elastic tensors[END_REF] and reveal a much more anisotropic elasticity for M 3 than for M 1 C 3 S (see Fig.2).

Figure 2 :

 2 Figure 2: Spacial distribution of Young's modulus for the M1 C3S, and M3 C3S computed with IFF using the static MM method.

5 and 5

 5 GPa. The bulk moduli obtained by linear fitting of the hydrostatic pressure with respect to the volume variation are (101 ± 2) GPa and (103 ± 2) GPa for M 1 and M 3 C 3 S polymorphs, respectively. A larger difference with static MM calculation is observed for M 1 . This could rely on the fact that the M 1 model, which is not averaged, experienced a structural relaxation during the MD run.

Figure 3 :Figure 4 :

 34 Figure 3: Radial distribution function of Ca-Os pairs as a function of the hydrostatic pressure for M3 C3S, with IFF. The RDF obtained for the M1 polymorph is very similar.

Figure 5 :

 5 Figure 5: Total phonon density of states (top), and partial density of states with VACF in insets (bottom) of M1 and M3 C3S obtained with IFF and ClayFF.

Figure 7 :

 7 Figure 7: Equilibrium shapes of M1 and M3 C3S

Table 1 :

 1 computed by static MM method, as well as experimental results from literature, are reported in Table1. ClayFF tends to underestimate by a factor of approximately 2 the stiffness constants and thus the elastic moduli. This very probably results from the Stiffness constants and elastic moduli of M3 C3S obtained by static MM, in GPa.

	non-bonded nature of atomic interactions in ClayFF, where the covalent nature of O-Si
	bonds in silicates is underestimated, thus decreasing their stiffness. Previous calculations
	on the same M 3 unit cell, via second derivative of the binding energy with the GULP
	code, lead to very similar results [43]. The homogenized elastic moduli computed with
	IFF agree relatively with experiments. The values obtained for M 3 C 3 S are smaller than

a Acoustic measurements. b Resonance frequency. c Nanoindentation.

Table 2 .

 2 They are in good agreement with values from previous stress controlled NEMD

Table 2 :

 2 Elastic moduli obtained from NEMD simulations with IFF.

a Results from previous stress controlled NEMD.

Table 3 :

 3 Thermal properties of M1 and M3 C3S.

Table 4 :

 4 Cleavage energies of M1 and M3 C3S. Only the lowest energy plane is given in the (100) direction for M1. Results for M3 C3S are from our previous study[START_REF] Claverie | Water s behaviour on Ca-rich tricalcium silicate surfaces for various degrees of hydration: A molecular dynamics investigation[END_REF].

Acknowledgments

The authors acknowledge Brazilian science agencies CAPES (PDSE process n°88881.188619/2018-01) and CNPq for financial support.


Patrick R Benusiglio
email: patrick.benusiglio@cantab.net

Clément Korenbaum

Roseline Vibert

Joël Ezenfis

Sophie Geoffron

Charlotte Paul

Sandrine Richard

Veronique Byrde

Manon Lejeune

Erell Guillerm

Utility of a mainstreamed genetic testing pathway in breast and ovarian cancer patients during the COVID-19 pandemic

Keywords: breast cancer, COVID-19, genetic counseling, genetic testing, hereditary breast and ovarian cancer syndrome, ovarian cancer

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

On 16 th March 2020, as the exponential increase in COVID-19 cases was threatening to overwhelm the French health care system, the country went into lockdown. People were not allowed outdoors but for very specific reasons, and working from home became normal for most individuals. Non-urgent medical care, including clinical cancer genetics, was suspended or drastically reduced in order to minimize patients' and medical professionals' exposure to the virus.

Mainstreamed genetic testing (MGT) obviates the need for a cancer genetics consultation for most eligible cancer patients, since trained oncologists (O) and gynecologists (G) provide genetic counseling, prescribe germline testing and deliver results (1). Only complex cases and pathogenic variant (PV) carriers are referred to the cancer genetics team. It was only proposed recently as an alternative to traditional cancer genetics clinics-based pathways (2). Following reports from the United Kingdom of favorable outcomes in ovarian cancer (OC) patients (2), we implemented MGT in breast and ovarian cancer (BC/OC) patients for the first time in France at one teaching and two regional hospitals in the Paris region. We report herein our results and show how it guaranteed continuity of care during the COVID-19 lockdown and de-confinement phase 1.

Methods

An MGT pathway for BC/OC patients was established in January 2018 between the Assistance Publique -Hôpitaux de Paris (AP-HP) .Sorbonne Université Cancer Genetics team and the Oncology and Gynecology departments at Tenon University Hospital (Paris), Centre Hospitalier Sud Francilien regional hospital, and Groupe Hospitalier de l'Est Francilien regional hospital. Its aims were to improve access to testing in patients from the Ile-de-France region living far from Paris-based genetics clinics, and to bypass increasing consultation waiting times. Approval was obtained from the Institut Universitaire de Cancérologie -Sorbonne Université scientific committee.

O+G participated on a voluntary basis, as traditional referral pathways remained available. They received a 20-minute custom-made e-learning audio slideshow summarizing the principles of BC/OC genetic susceptibility, patient selection, informed consent, germline testing, carrier management, and cascade testing in relatives of positive cases (figure 1). First-line referral of complex cases to cancer genetics, e.g. those suggestive of the rare Li-Fraumeni syndrome, was strongly encouraged. If a cancer susceptibility PV had already been identified in the family, patients were excluded. BC/OC patients were evaluated using an excel version of the latest Manchester Scoring System, with minor modifications (supplementary table 1) (3). A 12-point threshold was recommended for testing, which corresponds to a 6-10% PV detection rate in the BRCA1-BRCA2 major BC/OC susceptibility genes in a British population (3,4). O/G provided basic genetic counseling and prescribed testing at or shortly after cancer diagnosis. Patients were given an one-page document summarizing the information given during a traditional cancer genetics consultation. On February 4 th , 2020, an educational video created with the Geneticancer patient association was made available online to patients (https://www.youtube.com/watch?v=5YzBOw8jxeI&t). Blood was drawn immediately afterwards.

O/G could contact the cancer genetics team at any stage of the process.

Although the MGT program was developed for BC/OC patients, testing prescription was tolerated in patients with other cancers when the context was suggestive of BRCA1-2/PALB2/RAD51C-Dassociated susceptibility.

A single academic laboratory centralized testing, using a next generation sequencing panel including the BRCA1, BRCA2, PALB2, RAD51C and RAD51D genes. Results were delivered to the patient by O/G, or at the O/Gs' request, by the cancer geneticist. All PV carriers had to be referred to the cancer genetics clinic. Multidisciplinary team discussion of cases for whom no PV was identified was encouraged. Variants of unknown significance were discussed on a case by case basis.

Results are reported for the 2 nd January 2018 to 1 st June 2020 period. That includes the eight-week COVID-19 lockdown (16 th March -11 th May 2020) and the following three weeks (de-confinement phase 1) when travelling restrictions were still present, hospital activity had not returned to normal, and most patients were reluctant to attend non-essential consultations. As of 25 th August 2020, results were available for 231/234 patients. Of those, 195 had their results delivered by the O/G and 24 by the cancer genetics team. Eight patients are yet to attend their medical appointment and four died shortly after genetic testing. Median turnaround time for testing was 70 days, similar to the turnaround time in the traditional pathway (68 days).

Results

A

Twenty-eight patients (12.1%) carried a PV in BRCA1, BRCA2, PALB2, RAD51C or RAD51D (table 1). All but three carriers who had their results delivered by the O/G were referred to the cancer genetics clinic. Two are yet to accept and one died.

Of the 27 patients tested during the COVID-19 period, three carried a PV, two in BRCA1 and one in RAD51C. The two BRCA1 PV carriers were female patients aged 40 (patient 1) and 54 (patient 2) with triple-negative ductal breast cancer, bilateral and unilateral respectively. Both were undergoing neoadjuvant chemotherapy at the time of writing. Given the genetic results, patient 1 will now have bilateral mastectomy instead of the initially-planned double lumpectomy. Risk-reducing salpingooophorectomy will be scheduled afterwards. As for patient 2, lumpectomy will be performed, but in association with reduction mammoplasty and risk-reducing salpingo-oophorectomy. Double mastectomy will follow in the subsequent months. Regarding the RAD51C PV carrier, debulking surgery has just been performed after three cycles of chemotherapy.

Discussion

Monahan et al. recently predicted that the suspension of screening colonoscopies in Lynch syndrome patients during the COVID-19 pandemic, and their only slow resumption afterwards, would result in an excess of advanced-stage colorectal cancer diagnoses (5). In the English population as a whole, substantial increases in the number of avoidable cancer deaths in England are predicted as a result of diagnostic delays (6). As for genetic susceptibility to BC/OC, we expect that the unavailability of genetic testing will lead to suboptimal cancer treatment and risk management in patients carrying PV, and as a result in avoidable deaths in the long term. France, but slightly higher than rates reported in British patients (3,4). This warrants further exploration.

Finally, all but two eligible PV carriers have attended the recommended cancer genetics consultation.

Flaum et al. also reported that a small minority (2/39) of PV carriers identified via MGT pathways in Northwestern England declined their cancer genetics appointment (4). Nevertheless, long-term risk management and the importance of cascade testing in relatives have been addressed by an expert team in the vast majority of cases from our series, and we are hopeful that in the end the two remaining patients will understand the importance of a referral to our cancer genetics clinic.

Gligorov: Roche-Genentech, Novartis, Onxeo, Dachii Sankyo, MSD, Isai, Genomic Health, Ipsen, Macrogenics, Pfizer, Mylan, Lilly, Immunomedics, Sandoz. Honoraria or symposium/travel funding.

Figure 1 .

 1 Figure 1. Mainstreamed genetic testing pathway for breast and ovarian cancer patients. MDT:

COVID-19 period 11 Mar 2020 -1 Jun 2020

  total of 234 patients had MGT (table1), 223 women and 11 men. Of those, 27 had testing during the COVID-19 period. Mean age at cancer diagnosis was 52 (range 22-90). Among women, 166 had BC, 52 OC, two BC and OC, one pancreatic cancer and one endometrial cancer with a BC family history. Diagnosis was missing for one patient. All men had BC.

		Tested (N)	Results	PV identified	PV detection
			available (N) a	(N)	rate
	Overall
	2 Jan 2018 -1 Jun 2020
	All cases	234	231	28	12.1%
	Female breast cancer	166	165	19	11.5%
	Ovarian cancer	52	50	5	10%
	Breast and ovarian cancer	2	2	0	0%
	Male breast cancer	11	11	3	27.3%
	Other	3	3	1	33.3%
	All cases	27	25	3	12%
	Breast cancer b	18	17	2	11.8%
	Ovarian cancer	7	6	1	16.7%
	Breast and ovarian cancer	1	1	0	0%
	Other	1	1	0	0%

Table 1 .

 1 Patients who had mainstreamed genetic testing since program inception, and specifically during the

	COVID-19 lockdown and de-confinement phase 1. Next generation sequencing of the BRCA1, BRCA2, PALB2,
	RAD51C, and RAD51D genes was performed. PV: pathogenic variant. a as of 25 August 2020.

b

Female only, no male patients with breast cancer had genetic testing during the COVID-19 period.

  Genetic testing in cancer patients was until very recently exclusively provided by clinical cancer genetics services. With MGT, testing is integrated into oncology care. It was first introduced in the United Kingdom in OC patients in the mid-2010s(2,[START_REF] Rahman | Mainstreamed genetic testing for women with ovarian cancer: first-year experience[END_REF]. MGT seemed the only way to guarantee testing in all women with high-grade OC, as recommended by national guidelines following the development of PARP-inhibitors. MGT was subsequently expanded to BC, and proved to be highly acceptable to both patients and O/G (8).The French AP-HP .Sorbonne Université MGT program was launched in January 2018. On 16 th March 2020, the first lockdown day, 207 patients had already been included. Our paper shows how MGT guaranteed continuity of care during the COVID-19 pandemic, as BC/OC patients were still prescribed genetic testing while genetics clinics had discontinued their activity. Among the 27 patients tested between 16 th March and 1 st June 2020, three carried a PV in a cancer susceptibility gene. The clinical impact was immediate for two BRCA1-positive BC cases, since double mastectomy and risk-reducing salpingo-oophorectomy will now be performed using two-step strategies. With the looming threat of re-confinement due to the rising number of new COVID-19 cases in France and in neighboring countries, functioning MGT pathways such as ours are more needed than ever.More generally, we have shown for the first time that MGT could be successfully implemented in France, a country with a more conservative attitude to genetic testing compared to the UK or US. It allowed for the rapid testing of 234 patients at their point of care. O/G were comfortable using a computerized version of the Manchester Scoring System for patient selection. The 12.1% PV detection rate at the 12-point threshold was comparable to rates observed in more traditional settings in

Acknowledgments

We are grateful to Laetita Mendes and Elisabeth Boissin from the Geneticancer patient association, and to Anais Fouet. They conceived and created with our collaboration the genetic susceptibility to breast and ovarian cancer information video (https://www.youtube.com/watch?v=5YzBOw8jxeI&t).

Author contributions

Study concept and design: Benusiglio, Ezenfis, Byrde, Chabbert-Buffet, Gligorov, Coulet.

Acquisition, analysis, or interpretation of data: all authors

Drafting of the manuscript: Benusiglio Critical revision of the manuscript for important intellectual content: all authors

Conflicts of Interest

Benusiglio: Astra Zeneca (honoraria), Roche (honoraria), Geneticancer (patient association, scientific committee member).

Chabbert-Buffet: Geneticancer (patient association, scientific committee director).


Pascal Lim

Emmanuel Teiger

Damien Fard
email: damien.fard@aphp.fr

Raphaëlle Huguet

Athanasios Koutsoukis

Camille Deguillard

Anne-Sophie Tuffreau

Jean-François Deux

Myocardite et maladie à COVID-19 : où en est-on ?

Keywords: myocardite, coronavirus, Covid-19, SARS-CoV-2, atteinte cardiaque myocarditis, coronavirus, Covid-19, SARS-CoV-2, cardiac injury

Introduction

La maladie à Covid-19 est liée à un virus émergent à ARN, appelé SARS-CoV-2, et appartenant à la famille des Coronaviridae, virus respiratoires ubiquitaires parmi les humains et les mammifères. Le diagnostic positif est obtenu par une RT-PCR (RetroTranscriptase Polymerase Chain Reaction) sur un prélèvement respiratoire (écouvillonnage naso-pharyngé ou liquide d'aspiration bronchique). Il apparaît que la maladie est caractérisée par une première phrase virale peu symptomatique, marquée par la pénétration du coronavirus dans les cellules de l'hôte via le récepteur ACE-2 (récepteur de l'enzyme de conversion de l'angiotensine II), présent au niveau du poumon, des reins et du coeur. Les principaux symptômes sont pseudo-grippaux, à savoir la fièvre, la toux, les céphalées et les myalgies [START_REF] Guan | Clinical Characteristics of Coronavirus Disease 2019 in China[END_REF]. Cette première phase est suivie, chez certains patients (majoritairement comorbides ou âgés), d'une phase inflammatoire liée à un orage cytokinique et marquée par une dégradation clinique rapide vers une défaillance essentiellement respiratoire [START_REF] Huang | Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China[END_REF]. Au total, 81% des patients présenteront des symptômes modérés, 14% présenteront des symptômes sévères nécessitant une hospitalisation et 5% présentent une forme critique nécessitant une prise en charge en réanimation [START_REF] Wu | Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention[END_REF]. La mortalité est difficile à estimer, et se situe aux alentours de 2 à 3% environ. Des études récentes suggèrent une transmissibilité supérieure à celle du virus de la grippe, ce qui en fait un réel problème de santé publique [START_REF] Zhang | Estimation of the reproductive number of novel coronavirus (COVID-19) and the probable outbreak size on the Diamond Princess cruise ship: A data-driven analysis[END_REF]. Des manifestations extra-respiratoires ont également été décrites et dans environ 20% des cas, la maladie à Covid-19 peut être responsable d'atteintes cardiaques [START_REF] Bavishi | Acute myocardial injury in patients hospitalized with COVID-19 infection: A review[END_REF][START_REF] Wang | Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China[END_REF][START_REF] Deng | Suspected myocardial injury in patients with COVID-19: Evidence from front-line clinical observation in Wuhan, China[END_REF] qui doivent être bien connues des cliniciens. Ces atteintes cardiaques, définies par l'élévation d'un marqueur de nécrose cardiomyocytaire (troponine et/ou CPK), prennent essentiellement la forme d'évènements thrombotiques veineux ou artériels mais peuvent également se manifester par une myocardite aiguë dont le 1 er cas suspecté a été rapporté en avril 2020 [START_REF] Zeng | How to balance acute myocardial infarction and COVID-19: the protocols from Sichuan Provincial People's Hospital[END_REF]. Ces atteintes cardiaques sont associées à une surmortalité [START_REF] Guo | Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)[END_REF][START_REF] Shi | Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China[END_REF]. L'objectif de cette mise au point est d'aider à la compréhension des myocardites aiguës dans le cadre d'une infection à Covid-19. Après un rappel sur le diagnostic de myocardite, nous examinerons les données de la littérature qui suggèrent l'existence de myocardites à Covid-19 et en particulier en termes de caractéristiques cliniques et de modalités diagnostiques et thérapeutiques de cette entité particulière.

Généralités sur la myocardite

Définition et épidémiologie : La myocardite est une maladie inflammatoire du myocarde dont la définition repose sur les critères histologiques de Dallas. Le diagnostic nécessite la mise en évidence d'un infiltrat inflammatoire myocardique à prédominance lymphocytaire défini par la présence de > 14 leucocytes/mm 3 dont plus de 4 monocytes > mm 3 et 7 lymphocytes T CD3+/mm 3 , associé à une nécrose myocytaire d'origine non ischémique [START_REF] Caforio | Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases[END_REF].

Dans les pays européens, la principale étiologie des myocardites aiguës est virale. Les hypothèses physiopathologiques sont variables et comprennent à la fois la lyse cellulaire liée à une toxicité virale directe, et des phénomènes inflammatoires liés à l'activation de la réponse immunitaire innée (production de cytokines pro-inflammatoires) puis cellulaire spécifique. Dans certaines situations, cette activation peut être excessive et conduit alors à une destruction importante des cardiomyocytes, responsables de dysfonction ventriculaire gauche pouvant évoluer vers un état de choc cardiogénique dans les formes les plus sévères (myocardite fulminante). Dans tous les cas, cette nécrose cardiomyocytaire est responsable de l'élévation de la troponine qui est un élément clé de la suspicion diagnostique.

Présentation clinique : Le phénotype clinique de la myocardite est très polymorphe, ce qui rend son diagnostic positif difficile. Le tableau clinique aigu peut aller de la douleur thoracique atypique à la défaillance hémodynamique foudroyante de la myocardite fulminante. La myocardite peut également être découverte au stade de cardiopathie dilatée. Dans la grande majorité des cas, la présentation clinique mime un syndrome coronarien aigu (douleur thoracique, modifications électriques) pouvant être associés à des signes d'insuffisance cardiaque. Une fois la coronaropathie éliminée (par une coronarographie ou un coroscanner selon le terrain et les facteurs de risque cardio-vasculaires), le diagnostic est suspecté devant la symptomatologie clinique associée à une élévation de la troponine et éventuellement des marqueurs inflammatoires.

Diagnostic positif : L'échocardiographie est un examen clé de la prise en charge, permettant de rechercher des signes de gravité (dysfonction ventriculaire gauche, bas débit cardiaque) et de rechercher un épanchement péricardique associé. Cependant, il n'existe pas de signe échographique spécifique de myocardite.

Le gold standard reste donc à ce jour la biopsie endomyocardique. Une biopsie du ventricule droit et/ou du ventricule gauche est réalisée permettant ainsi l'analyse de multiples fragments. La biopsie des deux ventricules permet d'augmenter le rendement diagnostique et limite ainsi le risque de faux négatif en cas de lésion discontinues. Cependant, il s'agit d'un examen invasif pouvant se compliquer de tamponnade liée à une perforation des cavités cardiaques. Ainsi, il est proposé de réserver la biopsie endomyocardique aux situations suivantes, conformément aux recommandations :

-Suspicion de myocardite aiguë avec dysfonction ventriculaire gauche (FEVG<50%) -Myocardite fulminante en état de choc cardiogénique, si le patient est stabilisé et transportable -Choc cardiogénique sur une cardiopathie à coronaires saines à priori idiopathique, si le patient est stabilisé et transportable Depuis quelques années, l'IRM cardiaque est ainsi devenue une alternative fiable et robuste avec l'utilisation des critères de Lake Louise [START_REF] Friedrich | Cardiovascular magnetic resonance in myocarditis: A JACC White Paper[END_REF]. Plus récemment, les séquences paramétriques dites de mapping (T1 et T2) ont été proposées pour augmenter la pertinence diagnostique des critères précédemment décrits [START_REF] Ferreira | Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation: Expert Recommendations[END_REF]. Le diagnostic de myocardite aiguë est donc posé devant la présence d'un critère T1 (allongement du T1 myocardique, du volume extracellulaire ou présence d'un rehaussement tardif pathologique) et d'un critère T2 (allongement global ou segmentaire du T2 myocardique ou hypersignal myocardique en T2).

Traitement : Il n'y a pas de traitement spécifique de la myocardite lymphocytaire. Lorsqu'il existe une dysfonction ventriculaire gauche, le traitement recommandé reste celui de l'insuffisance cardiaque associé à la contre-indication sportive en raison du risque rythmique à l'effort. Les études évaluant les immunosuppresseurs et les corticoïdes ont donné des résultats contrastés et leur intérêt est toujours débattu. En l'état actuel des connaissances, ces traitements sont réservés aux myocardites compliquées de dysfonction ventriculaire gauche résistantes au traitement médical de l'insuffisance cardiaque, aux formes fulminantes ou en cas d'étiologie spécifique [START_REF] Caforio | Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases[END_REF][START_REF] Mason | A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators[END_REF][START_REF] Wei | Glucocorticoid and immunoglobulin to treat viral fulminant myocarditis[END_REF]. Les myocardites fulminantes peuvent bénéficier d'assistance circulatoire en cas de défaillance hémodynamique aiguë, et ce d'autant qu'elles sont associées à un bon pronostic et à une récupération fonctionnelle fréquente.

Premiers indices de l'existence d'une atteinte cardiaque de la maladie à Covid-19

La prévalence exacte de la myocardite aiguë associée à une maladie à Covid-19 reste inconnue car il existe une grande variété d'atteintes cardiaques potentielles du SARS-CoV-2 [START_REF] Fried | The Variety of Cardiovascular Presentations of COVID-19[END_REF]. Les premières données suggérant l'existence de myocardite aiguë reposent sur la mise en évidence d'une atteinte cardiaque appelée « cardiac injury ». Selon les séries et la définition utilisée pour l'atteinte cardiaque (élévation de la troponine et/ou des peptides natriurétiques), celle-ci représente entre 19.7 et 27.8% des 603 patients des 2 principales cohortes chinoises de Wuhan. Ainsi, une élévation de la troponine est objectivée chez 10 à 12 % des patients avec une nette prédominance chez les patients graves de réanimation [START_REF] Huang | Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China[END_REF], avec une association similaire pour le NT-pro-BNP [START_REF] Chen | SARS-CoV-2: a potential novel etiology of fulminant myocarditis[END_REF]. Cette élévation de la troponine est associée à une mortalité significativement plus élevée (51.2 à 59.6% vs 4.5 à 8.9%) [START_REF] Guo | Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)[END_REF][START_REF] Shi | Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China[END_REF]. Cependant, la signification exacte de l'élévation de ces biomarqueurs reste controversée. Elle peut être liée à l'hypoxie, à l'état septique ou au syndrome inflammatoire de réponse systémique [START_REF] Imazio | COVID-19 pandemic and troponin: indirect myocardial injury, myocardial inflammation or myocarditis?[END_REF].

Elle peut également être le témoin d'évènements thrombo-emboliques veineux [START_REF] Chen | Findings of Acute Pulmonary Embolism in COVID-19 Patients[END_REF][START_REF] Klok | Incidence of thrombotic complications in critically ill ICU patients with COVID-19[END_REF][START_REF] Xie | COVID-19 Complicated by Acute Pulmonary Embolism[END_REF] ou artériels [START_REF] Bangalore | ST-Segment Elevation in Patients with Covid-19 -A Case Series[END_REF][START_REF] Akhmerov | COVID-19 and the Heart[END_REF], en rapport avec un état hypercoagulable [START_REF] Tang | Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia[END_REF]. Elle peut enfin être en lien avec d'authentiques atteintes cardiaques virales et/ou inflammatoires prenant la forme de myocardites aiguës [START_REF] Peretto | Acute myocardial injury, MINOCA, or myocarditis? Improving characterization of coronavirus-associated myocardial involvement[END_REF].

Quelle est la forme clinique des myocardites à Covid-19 ?

La présentation clinique des patients atteints ou suspects de myocardite aiguë est aspécifique. Elle comprend des symptômes classiques de Covid-19 (fièvre, asthénie, myalgies, toux, céphalées) associés à des symptômes évocateurs de myocardite aiguë (douleur thoracique, dyspnée, asthénie). Quatre-vingt dix pourcent des patients avaient une élévation de la troponine, et 75% présentaient des modifications électriques (troubles du rythme [18%], décalage du segment ST [59%], modification de la polarité des ondes T [13.6%]) [START_REF] Ho | Coronavirus-induced myocarditis: A metasummary of cases[END_REF]. Devant l'association d'une douleur thoracique et/ou d'une défaillance hémodynamique associée à une élévation de troponine, il est important de se rappeler que le principal diagnostic différentiel reste le syndrome coronarien aigu, et ce d'autant plus que l'état hypercoagulable lié à l'infection à SARS-CoV-2 est propice aux thromboses coronaires. La première étape est donc d'éliminer une lésion coronaire aiguë [START_REF] Siripanthong | Recognizing COVID-19-related myocarditis: The possible pathophysiology and proposed guideline for diagnosis and management[END_REF].

L'échographie cardiaque, chez ces patients, a montré une dysfonction VG avec une FEVG moyenne mesuré à 38.5%. Un épanchement péricardique a été objectivé chez 37% des patients.

Parmi les 51 patients rapportés par Ho et al [START_REF] Ho | Coronavirus-induced myocarditis: A metasummary of cases[END_REF], il est intéressant de noter que seuls 12 ont eu un diagnostic confirmé soit par l'IRM (n=10), soit par la biopsie myocardique (n=2) [START_REF] Inciardi | Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19)[END_REF][START_REF] Kim | COVID-19-related myocarditis in a 21-year-old female patient n[END_REF][START_REF] Luetkens | Diffuse Myocardial Inflammation in COVID-19 Associated Myocarditis Detected by Multiparametric Cardiac Magnetic Resonance Imaging[END_REF][START_REF] Doyen | Myocarditis in a patient with COVID-19: a cause of raised troponin and ECG changes[END_REF][START_REF] Paul | Myocarditis revealing COVID-19 infection in a young patient[END_REF][START_REF] Beşler | Acute myocarditis associated with COVID-19 infection[END_REF][START_REF] Coyle | A Recovered Case of COVID-19 Myocarditis and ARDS Treated With Corticosteroids, Tocilizumab, and Experimental AT-001[END_REF]. Les patterns d'imagerie remnographique objectivés comprenaient de l'oedème myocardique (n=8) et un réhaussement tardif sur l'imagerie de rétention (n=10), pouvant varier d'une prise de contraste subépicardique à transmurale. Un exemple est proposé figures 1 et 2. La topographie prédominante des lésions de réhaussement tardif était inféro-latérale. Seuls deux patients ont bénéficié d'un diagnostic histologique. L'un présentait un infiltrat lymphocytaire T diffus [START_REF] Sala | Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection[END_REF]. L'autre présentait, sur une analyse histologique post-mortem (mort subite), un infiltrat inflammatoire composé de lymphocytes, macrophages et éosinophiles avec de multiples localisations de nécrose myocytaire [START_REF] Craver | Fatal Eosinophilic Myocarditis in a Healthy 17-Year-Old Male with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2c)[END_REF]. Aucun cas clinique rapporté dans la littérature n'a cependant mis en évidence le génome viral dans les tissus myocardiques, ce qui pose la question de l'imputabilité directe du virus.

Quelles sont les hypothèses physiopathologiques de la myocardite à Covid-19 ?

De la même façon que les autres coronavirus, le SARS-CoV-2 utilise le récepteur de l'enzyme de conversion de l'angiotensine II (ACE-2) pour l'entrée cellulaire. Ce récepteur est surexprimé dans les cellules alvéolaires pulmonaires mais également dans les cardiomyocytes ce qui peut faciliter des lésions cellulaires par toxicité directe du virus, comme cela a été montré avec le MERS [START_REF] Kuba | A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury[END_REF][START_REF] Alhogbani | Acute myocarditis associated with novel Middle east respiratory syndrome coronavirus[END_REF]. Des modèles animaux du SARS et du MERS ont confirmé l'existence d'un tropisme cardiaque des coronavirus [START_REF] Agrawal | Generation of a transgenic mouse model of Middle East respiratory syndrome coronavirus infection and disease[END_REF][START_REF] Schaecher | An immunosuppressed Syrian golden hamster model for SARS-CoV infection[END_REF]. L'hypothèse d'une toxicité directe par effet cytopathogène est donc plausible, et ce d'autant que cet effet a été mis en évidence chez un patient ayant présenté un choc cardiogénique sévère dans un contexte d'infection à SARS-CoV-2 [START_REF] Tavazzi | Myocardial localization of coronavirus in COVID-19 cardiogenic shock[END_REF]. Là encore, le génome viral n'a pas été mis en évidence et seules des particules virales de morphologie évocatrices d'un coronavirus ont été objectivées en microscopie électronique dans des cellules interstitielles. Par ailleurs, les cardiomyocytes présentaient des caractéristiques aspécifiques (lyse myofibrillaire, vacuoles lipidiques), sans que des particules virales soient observées dans les cellules ou l'endothélium.

Après la phase de pénétration cellulaire du virus, les mécanismes de l'immunité innée entrent en jeu.

Les premières données biologiques issues des patients pris en charge dans l'épicentre de Wuhan ont montré une franche surproduction des protéines de l'inflammation (interleukines, interféron, TNFalpha et VEGF) comparativement à des adultes sains. Ces concentrations étaient encore plus élevées chez les patients graves de réanimation comparé aux autres patients [START_REF] Huang | Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China[END_REF]. La production de ces protéines pro-inflammatoires par les lymphocytes T est la conséquence de la présentation des antigènes viraux aux lymphocytes T naïfs de l'hôte par les cellules dendritiques pulmonaires [START_REF] Zhu | Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response[END_REF]. La suractivation de l'immunité innée est à l'origine de ce qui est appelé « l'orage cytokinique » essentiellement liée à l'interleukine-6 [START_REF] Lee | Current concepts in the diagnosis and management of cytokine release syndrome[END_REF] qui exerce une toxicité directe sur les myocytes, comme cela a déjà été montré être en rapport avec la dégradation de la fonction cardiaque en réanimation (cardiomyopathie septique) [START_REF] Sato | A review of sepsis-induced cardiomyopathy[END_REF]. Les mécanismes sous-jacents sont nombreux et probablement imbriqués : toxicité du NO et des radicaux libres, dysfonction microcirculatoire et endothéliale [START_REF] Varga | Endothelial cell infection and endotheliitis in COVID-19[END_REF], inadéquation besoins/flux coronaires en situation d'élévation des besoins métaboliques. De nombreuses études ont montré que l'élévation importante des protéines de l'inflammation était associé à un plus mauvais pronostic et à un plus grand nombre de défaillances multiviscérales, ce qui conforte l'hypothèse inflammatoire [START_REF] Ruan | Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China[END_REF].

Myocardite à Covid-19 : comment s'assurer du diagnostic ?

Bien que l'existence de la myocardite aiguë à Covid-19 soit supportée par l'existence de lésions histologiques et remnographiques typiques de myocardite, l'imputabilité directe du virus reste difficile à établir [START_REF] Zhou | Does SARS-CoV-2 cause viral myocarditis in COVID-19 patients?[END_REF]. Le remdesivir permet une diminution de la durée des symptômes sans bénéfice sur la mortalité [START_REF] Beigel | Remdesivir for the Treatment of Covid-19 -Preliminary Report[END_REF]. Une méta-analyse récente a démontré que l'hydroxycholoroquine n'apportait pas de bénéfice clinique net [START_REF] Fiolet | Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis[END_REF]. Les données sont donc insuffisantes pour recommander l'utilisation d'antiviraux ou d'hydroxychloroquine dans ce cadre.

Enfin, les traitements par plasma de patients convalescents restent actuellement à l'état de recherche et ne peuvent être recommandés de manière spécifique.

Conclusion

Légendes des figures

Figure 1 :

 1 Figure 1 : A : Séquence de relaxométrie T1 (dites de mapping) acquise en coupe petit axe. B et C : séquence de relaxométrie T2 acquise en petit axe à 2 niveaux de coupe à la partie moyenne du VG. D : séquence de rehaussement tardif acquise 15 minutes après injection en coupe 4 cavités. La séquence de T1 mapping objective une discrète élévation du T1 myocardique moyen (1070 ms) pour une normale à 1,5 T inférieure à 1000 ms. La séquence de T2 mapping détecte une élévation globale et franche du T2 myocardique qui est mesurée à 68 (B) et 72 ms en moyenne (couleur verte, flèches) pour une normale inférieure à 55 ms (couleur bleue). Noter une discrète hétérogénéité du T2 myocardique avec des zones anormales (vertes, flèches) et d'autres normales (bleues, tête de flèche). D : L'imagerie de rehaussement tardif ne retrouve pas d'anomalie particulière au niveau myocardique.

Figure 2 :

 2 Figure 2 : Même patiente que sur la Figure 1. L'imagerie paramétrique T2 montre une normalisation du T2 myocardique (mesuré à 50 et 54 ms respectivement sur les coupes petit axe en B et C) à distance de l'épisode aigu. Noter la coloration bleue du myocarde comparativement à la Figure 1 signant la disparition de l'oedème. L'imagerie T1 montre également une normalisation du T1 myocardique (mesuré à 950 ms). D : L'imagerie de rehaussement tardif ne montre pas d'anomalie.

  Nous venons de voir que deux mécanismes entrent en jeu dans le développement des « cardiac injury » dans un contexte d'infection à Covid-19. Il est impossible de faire la part des choses entre l'effet cytopathogène direct et conséquence de l'orage cytokinique. L'existence de myocardites à Covid-19 reste donc assez empirique, et basée sur les éléments précédemment publiés dans le cadre des infections à MERS et SARS au début des années 2000. Le diagnostic reste complexe chez ces patients souvent graves et surtout contagieux, et donc non transportables pour une IRM ou une biopsie myocardique. L'absence, à ce jour, de la mise en évidence du génome viral dans les biopsies myocardiques (et à fortiori, sa réplication), doit conduire à une grande prudence diagnostique. Plutôt que de parler de myocardite « à » Covid-19, il convient de parler tout au plus d'une myocardite « associée » à l'infection à Covid-19. Le diagnostic étant généralement suspecté devant une élévation de troponine, il semble raisonnable de s'en tenir d'abord à une évaluation échographique et d'éliminer en premier lieu un syndrome coronarien aigu. Si l'IRM cardiaque est réalisable, celle-ci doit être réalisée pour documenter le diagnostic. Il n'y a actuellement pas de raison de recommander une biopsie myocardique systématique chez ces patients, en l'absence de traitement spécifique disponible. Les indications habituelles de la biopsie doivent donc s'appliquer, et les investigations diagnostiques invasives se discutent au cas par cas.Dans le cas général, les recommandations de l'ESC sont de proposer en 1 ère intention un traitement symptomatique de l'insuffisance cardiaque par IEC et bêta-bloquants. De nombreuses controverses ont émergé concernant l'imputabilité potentielle des IEC dans l'aggravation des patients compte-tenu du récepteur ACE-2 utilisé par le SARS-CoV-2. Cependant, il a été récemment montré que ces traitements n'influaient pas sur le pronostic[START_REF] Fosbøl | Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality[END_REF]. Il n'y a donc pas de contre-indication spécifique à ces traitements.L'essai RECOVERY a montré un bénéfice de la dexamethasone chez les patients présentant une atteinte respiratoire sévère[START_REF]Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report[END_REF]. Les données sont insuffisantes pour appliquer ce traitement aux myocardites associées à la maladie à Covid-19, et il n'est donc pas recommandé de les utiliser en routine. Il semble raisonnable de s'en tenir aux indications habituelles des corticoïdes et des immunosuppresseurs dans la myocardite aiguë, à savoir les myocardites lymphocytaires avec persistance d'une dysfonction VG à 3 mois d'un traitement symptomatique.

	Traitement de la myocardite associée à l'infection à Covid-19

  Il existe un rationnel physiopathologique indéniable suggérant l'existence d'authentiques myocardites à Covid-19 même s'il existe des myocardites purement inflammatoires liées à l'orage cytokinique. Le diagnostic suit les mêmes principes que les myocardites non liées au Covid-19, à la différence près que l'accès aux outils du diagnostic reste plus difficile en raison d'une part de la gravité des malades et d'autre part du risque de contagion induit par le transport de ces patients. Il paraît important de ne réserver le terme « myocardite » aux seuls cas où il existe une preuve histologique ou des patterns IRM typiques. Le registre français MYOCOVID piloté par le CHU de Toulouse apportera certainement des informations précieuses dans la compréhension et la prise en charge de cette entité particulière. En attendant des études spécifiques, les principes du traitement restent pour l'instant calqués sur ceux d'une myocardite aiguë classique.