Laura Bonato

Matthieu Virot
email: matthieu.virot@cea.fr

Xavier Le Goff

Philippe Moisy

Sergey I Nikitenko

Sonochemical dissolution of nanoscale ThO2 and partial conversion into a Thorium Peroxo Sulfate

The influence of the sample morphology and experimental conditions towards the sonochemical dissolution of nanoscale ThO2 samples in sulfuric acid media is described. Significant sonochemical dissolution rates and yields are observed at 20 kHz under Ar/O2 atmosphere in dilute 0.5 M H2SO4 at room temperature, contrasting with the generallyreported high refractory behavior for ThO2. The dissolution of ThO2 combines the physical effects driven by acoustic cavitation phenomenon, the complexing affinity of Th(IV) in sulfuric medium and the sonochemical generation of H2O2. These sonochemical conditions further allow the observation of the partial conversion of ThO2 into a scarce Th(IV) peroxo sulfate with 1D morphology resulting from one or both following processes: dissolution/reprecipitation or formation of an intermediate Th(IV) surface complex.

Introduction

Natural thorium-232 is a weakly radioactive element much more abundant than uranium on earth's crust. Potentially, thorium can be a key to developing a new generation of nuclear fuel for power stations [START_REF] Ichimiya | A generation IV sodium-cooled fast reactor concept and its R&D program[END_REF][START_REF] Hoffelner | Materials for the Very High Temperature Reactor (VHTR): A versatile nuclear power station for combined cycle electricity and heat production[END_REF]. Th-based fuels indeed allow to decrease the production of minor actinides during the burn-up and represent an interesting alternative for the reduction of the proportion of long-lived isotopes (transmutation of minor actinides) [START_REF] Heisbourg | The kinetics of dissolution of Th1-xUxO2 solid solutions in nitric media[END_REF][START_REF] Claparede | Multiparametric dissolution of thorium-cerium dioxide solid solutions[END_REF]. Thorium oxide is nevertheless a highly refractory material towards dissolution. The dissolution of ThO2 in nitric acid solution is very low, particularly because no redox reaction is possible during the dissolution of this oxide [START_REF] Greiling | Properties of ThO2, UO2 and PuO2 as function of pretreatment and their dissolution in HNO3[END_REF]. The use of high-fired ThO2-based fuel thus constitutes a serious problem in the nuclear fuel cycle in particular for the reprocessing step [START_REF] Desigan | Dissolution of nuclear materials in aqueous acid solutions[END_REF]. Several studies have reported that the addition of small amounts of hydrofluoric acid as surface complexing agent in nitric aqueous solutions dramatically enhances the dissolution of thorium oxide [START_REF] Akabori | Dissolution of ThO2 based oxides in nitric acid solutions at elevated temperatures[END_REF][START_REF] Keshtkar | Activation energy determination and kinetic modeling of thorium oxide dissolution in nitric acid/ hydrofluoric acid system: Influence of fluoride ion on ThO2 dissolution[END_REF][START_REF] Takeuchi | Kinetics and mechanism of the dissolution of thorium oxide in hydrofluoric acid and nitric acid mixtures[END_REF][START_REF] Simonnet | Multiparametric study of thorium oxide dissolution in aqueous media[END_REF]. Simonnet et al. proposed recently a dissolution mechanism for ThO2 in HNO3-HF mixture which takes into account the important effect of HF and the related formation of ThF4 [START_REF] Simonnet | Thorium oxide dissolution in HNO3-HF mixture: kinetics and mechanism[END_REF]. Other processing methods have been reported by changing the dissolution medium with CF3SO3H [START_REF] Lyczko | Conversion of thorium(IV) oxide into thorium(IV) trifluoromethanesulfonate: Crystal structure of thorium(IV) trifluoromethanesulfonate dihydrate[END_REF] or H3PO4 [START_REF] Mirashi | Dissolution of sintered thorium dioxide in phosphoric acid using autoclave and microwave methods with detection by gamma spectrometry[END_REF] for instance, or by using alternative techniques such as pyrochemistry [START_REF] Sato | Sulfurization behavior of thorium dioxide with carbon disulfide[END_REF], autoclaves and microwaves [START_REF] Mirashi | Dissolution of sintered thorium dioxide in phosphoric acid using autoclave and microwave methods with detection by gamma spectrometry[END_REF][START_REF] Malav | Use of indigenous microwave system for dissolution and treatment of waste from nuclear materials[END_REF]. Nevertheless, these methods are difficult to be applied in the current reprocessing processes because of safety requirements and due to the high corrosion of the equipment with fluoride ions.

Nanosized thorium oxide may be suggested as a more reactive thorium-based fuel. Nanostructured materials can be defined as materials with a substructure of the order of a few nanometers (1-10 nm) [START_REF] Gleiter | Nanostructured materials: Basic concepts and microstructure[END_REF][START_REF] Fernández-García | Nanostructured oxides in chemistry: Characterization and properties[END_REF]. These materials are of growing interest due to their attractive physical and chemical properties potentially optimized through their size, 2 morphology and structure [START_REF] Teulon | On the operational aspects of measuring nanoparticle sizes[END_REF][START_REF] Stark | Industrial applications of nanoparticles[END_REF]. The nanoscale particles or crystallites composing these materials have a large surface-to-volume ratio and provide a greater amount of active sites in comparison to bulk materials thus increasing their reactivity. In parallel, ThO2 is largely studied because of its isomorphism with other tetravalent actinide oxides, its low solubility in aqueous solutions and its good resistance to irradiation [START_REF] Heisbourg | Kinetic and thermodynamic studies of the dissolution of thoria-urania solid solutions[END_REF][START_REF] Hubert | Influence of the precursor and the calcination temperature on the dissolution of thorium dioxide[END_REF][START_REF] Myllykylä | Solution composition and particle size effects on the dissolution and solubility of a ThO2 microstructural analogue for UO2 matrix of nuclear fuel[END_REF]. Particularly, Th(IV) crystallizes as oxide in the CaF2 fluorite crystal system (Fm-3m space group) similarly with UO2 and PuO2. Furthermore, nanoscale actinide oxides are currently stirring up the curiosity of scientists due to their potential contribution in environmental migration of actinides and the safety considerations related to interactions with groundwater during storage of spent nuclear fuel. Thorium, which only exists at the +IV oxidation state, therefore, offers the possibility of simulating the behavior of Pu-based oxide materials in less restrictive conditions without any contribution of redox processes (with however a difference in ionic radii for both elements: 1.05 Å against 0.96 Å for Th(IV) and Pu(IV), respectively, in 8-fold coordination [START_REF] Shannon | Revised effective ionic radii and systematic studies of interatomic distances in halides and chalcogenides[END_REF]). Sonochemistry appears as a suitable alternative for the dissolution of refractory materials and its efficiency towards dissolution has been reported with various refractory materials, including oxides such as ThO2, PuO2, CeO2, etc. [START_REF] Nikitenko | Potential applications of sonochemistry in spent nuclear fuel reprocessing: A short review[END_REF][START_REF] Juillet | Ultrasound effects on the dissolution of refractory oxides (CeO2 and PuO2) in nitric acid[END_REF][START_REF] Ph | Sonochemical dissolution of metallic plutonium in a mixture of nitric and formic acid[END_REF] The influence of sonication and HNO3 concentration has, for instance, been discussed during the dissolution of uranium carbide in nitric aqueous solutions [START_REF] Virot | Uranium carbide dissolution in nitric solution: Sonication vs. silent conditions[END_REF]. In addition to the well-known physical effects driven by the acoustic cavitation, which generally dramatically enhance solid materials reactivity (e.g., surface erosion, particle fragmentation, mass transfer, etc.), the sonochemical in-situ generation of active species (H2O2, HO°, HO2°, H2, Ti 3+ , etc.) has been reported to significantly improve the dissolution of PuO2 and CeO2 in aqueous nitric acid solutions [START_REF] Virot | Sonochemical redox reactions of Pu(III) and Pu(IV) in aqueous nitric solutions[END_REF][START_REF] Beaudoux | Ultrasound-assisted reductive dissolution of CeO2 and PuO2 in the presence of Ti particles[END_REF]. More recently, a study highlighted the accumulation of intrinsic Pu(IV) colloids during the 20 kHz sonolysis of PuO2 in pure water under Ar/(10%)CO atmosphere [START_REF] Dalodière | Insights into the sonochemical synthesis and properties of salt-free intrinsic plutonium colloids[END_REF]. Moreover, it has been reported that sonochemistry can also induce the phase conversion of a solid. The topotactic conversion of chloroapatite into hydroxyapatite was for instance achieved by sonication of the former in deionized water (25°C) at 35 kHz [START_REF] Bouyarmane | Nanoscale conversion of chlorapatite into hydroxyapatite using ultrasound irradiation[END_REF]. In another study, the transformation of anatase into rutile was observed during the synthesis of nanostructured TiO2 via ultrasound assisted sol-gel technique [START_REF] Prasad | Phase transformation of nanostructured titanium dioxide from anatase-to-rutile via combined ultrasound assisted sol-gel technique[END_REF]. This paper focuses on the sonochemical behavior of nanoscale ThO2 powders in pure water and dilute aqueous solutions of H2SO4. H2SO4 has been selected because of its stability under ultrasound irradiation in combination to previous reports that demonstrated its significant effect towards dissolution when compared to other conventional inorganic acids [START_REF] Hubert | Effect of inorganic ligands and hydrogen peroxide on ThO2 dissolution. Behaviour of Th0.87Pu0.13O2 during leaching test[END_REF]. The reactivity of these materials is compared in terms of sonochemical effect towards dissolution and morphology evolutions. Particularly, the significant dissolution of ThO2 and its partial conversion into a scarce Th peroxo sulfate is reported.

Experimental Section

Caution! 232 Th is an α-emitting radioisotope and standard precautions should be followed for handling this chemical element.

Syntheses

All the used reagents were of analytical grade and were supplied by Sigma-Aldrich. The various aqueous solutions were prepared using deionized water (18.2 mΩ.cm at 25°C). Nanostructured thorium oxide samples exhibiting platelet morphology (n-STR) were obtained by the conventional oxalic route [START_REF] Claparede | Multiparametric dissolution of thorium-cerium dioxide solid solutions[END_REF][START_REF] Beaudoux | Ultrasound-assisted reductive dissolution of CeO2 and PuO2 in the presence of Ti particles[END_REF][START_REF] Beaudoux | Vitamin C boosts ceria-based catalyst recycling[END_REF]. Briefly, a 0.1 M thorium solution was prepared at room temperature by dissolving 3.239 g of Th(NO3)4.5H2O in 50 mL of 1 M nitric acid solution before being slowly added to 53.89 mL of 0.5 M oxalic acid solution (previously prepared by dissolving 6.3 g of oxalic acid in 100 mL of 1 M nitric acid). One hour after mixing the solutions (using a magnetic stir bar), Th(IV) oxalate precipitate was separated from the supernatant by centrifugation (9000 rpm during 5 min), washed twice with water and dried at room temperature under vacuum. The reference material (ThO2 bulk) was obtained by firing Th(IV) oxalate precipitates (similar to nanostructured ThO2) in air at 1000 °C during 2 h. Thorium oxide nanopowders (n-PWD) were obtained in basic conditions in the presence of a polymer at room temperature [START_REF] Morosini | Sonochemical water splitting in the presence of powdered metal oxides[END_REF]. A 0.1 M thorium solution was prepared by dissolving 3.239 g of Th(NO3)4.5H2O with 0.033 g of polyethylene glycol (PEG, M= 3000 g.mol -1 , 2.5 wt.%) in 50 mL of water. A solution of NH4OH (30%) was slowly added to the thorium solution until the pH reached a value of 10 (about 3 mL). One hour after mixing the solutions (using a magnetic stir bar), Th(IV) hydroxide precipitate was separated from the supernatant by centrifugation (9000 rpm during 5 min), washed twice with water and dried at room temperature under vacuum. The different precursors (oxalate and ammonia routes) were then calcined under air at 485°C (during 2 h or 4 h) to obtain ThO2 exhibiting different refractory behavior according to their nanoscale morphology (nanostructured, n-STR vs. nanopowder, n-PWD) and particle size (crystallites) differences [START_REF] Bonato | Probing the local structure of nanoscaled actinide oxides: A comparison between PuO2 and ThO2 nanoparticles rules out PuO2+x hypothesis[END_REF].

Table 1 summarizes the SEM, HR-TEM and SBET characterizations performed on the ThO2 samples. The nanostructuration (n-STR) of the oxides prepared by thermal conversion of oxalate precursors at 485°C is evidenced by HR-TEM with the observation of sintered nanoparticles (or crystallites) forming squared platelets. These nanoparticles are found to be monodispersed, quasi-spherical and crystalline, and measure about 7.6 ± 2.1 nm in diameter. Thorium oxide nanopowder (n-PWD), synthesized at 485°C from basic conditions, is also composed of agglomerates of spherical, monodispersed and crystalline nanoparticles measuring about 7.7 ± 1.4 nm. These values contrast with the high sizes of the coherent domains already reported for ThO2 calcined at high temperature (fired at 1000°C and used as a reference material in this study) but agree with a previous report evidencing the small crystallite sizes for low fired oxide precursors [START_REF] Bonato | Probing the local structure of nanoscaled actinide oxides: A comparison between PuO2 and ThO2 nanoparticles rules out PuO2+x hypothesis[END_REF]. HR-TEM measurement of nanoparticle size are found to be consistent with values obtained from XRD (Table 1, Rietveld refinement) thus confirming our observations and extracted values.

Sonochemical experiments

Two kinds of sonochemical reactors were used in this study, depending on the applied frequency. The experiments at low frequency ultrasound (20 kHz) were performed in a thermostated batch reactor containing 50 mL of solution with controlled saturating gas. Ultrasound was supplied with a 1 cm 2 titanium alloy probe fitted on top of the reactor and connected to a 750 W generator (Sonics & materials, Vibracell VCX 750) [START_REF] Nikitenko | Comparative study of sonochemical reactors with different geometry using thermal and chemical probes[END_REF]. The experiments at high frequency ultrasound (345 kHz) were performed in a thermostated cylindrical reactor (250 mL of solution) mounted on top of a 25 cm 2 high-frequency transducer (ELAC Nautik) and connected to a 125 W multifrequency generator. For high frequency experiments, an additional mechanical stirring fixed at 100 rpm was ensured by a glass blade to homogenize the suspensions and avoid formation of standing waves. For all of the experiments, the solution was sparged with Ar/(20%)O2 about 20 min before sonication and during the whole ultrasonic treatment at a controlled rate of 100 mL.min -1 . Some of the experiments have been performed in the presence of Ar/(10%)CO gas mixture. Carbon monoxide is known to be an effective scavenger of OH radicals leading to the inhibiting of H2O2 formation [START_REF] Nikitenko | Sonochemical disproportionation of carbon monoxide in water: Evidence for treanor effect during multibubble cavitation[END_REF]. The temperature inside the reactor during the sonolysis was maintained at 20°C with a cryostat (Lauda Eco RE 1050) connected to the reactors. The temperature was measured by a thermocouple immersed into the solution. The acoustic power density, Pac (W.mL -1 ), transmitted to the solution, was measured using the conventional thermal probe method [START_REF] Nikitenko | Comparative study of sonochemical reactors with different geometry using thermal and chemical probes[END_REF] and reached 0.34 and 0.19 W.mL -1 at 20 and 345 kHz, respectively. All the experiments were performed with the same quantity of thorium oxide powders (3.5 g.L -1 ) that was suspended in different aqueous solutions (H2O, 0.05 M H2SO4, 0.5 M H2SO4). The sonolyses of the different solutions without any powder were considered as reference experiments.

Analyses and characterizations

UV-Vis absorption spectroscopy. The sonochemical formation of H2O2 was followed by UV-Vis absorption spectroscopy. During sonolysis, aliquots of solutions (1 mL) were collected with a syringe through a septum and filtered with 0.2 µm PTFE filters (without any volume adjustment). Then, a small volume of the as-collected solution was mixed (1:1) with a 0.02 M Ti(IV) solution (previously prepared in 0.5 M H2SO4 by dissolution of TiOSO4 salt) to form a yellow complex absorbing at 410 nm (ε= 722 cm -1 .M -1 ). A calibration curve was previously plotted with a commercial H2O2 solution previously titrated with a KMnO4 solution. Absorption spectra were recorded in a 1 cm quartz cell from 280 to 800 nm using a Thermo Evolution 220 spectrophotometer. The statistical error for H2O2 formation rate was estimated to be lower than 10%.

Inductively Coupled Plasma -Optical Emission Spectroscopy (ICP-OES).

The sonochemical dissolution of ThO2 was followed by ICP-OES analysis with a Spectro Arcos apparatus (Spectro Analytical Instruments GmbH) equipped for axial plasma observation. A small volume of the collected solution aliquots (described above) was diluted with 0.3 M HNO3 in the appropriate range of concentration prior to analysis. The concentration of thorium in solution was determined against an external calibration curve (0.1-15 mg.L -1 ) prepared with certified standard solutions of 1000 µg.mL -1 (SCP Science). The thorium content in solution was followed using several analytical wavelengths (401.913, 283.730, 274.716, 283.231 nm). The given value is a mean of three replicates. The statistical error for ThO2 dissolution rate was estimated to be lower than 10%. SBET measurements. The specific surface area of ThO2 samples (Table 1) was determined using nitrogen adsorption at 77 K after overnight degassing under vacuum at 573 K with a Micromeritics ASAP 2020 apparatus.

Powder X-Ray Diffraction (PXRD). PXRD diagrams were obtained with the use of a Bruker D8 Advance X-ray diffractometer equipped with a linear Lynx-eye detector (Cu Kα1,2 radiation, λ = 1.54184 Å). PXRD patterns were recorded between 5° and 120° (θ-2θ mode) at room temperature, with a step size of Δ(2θ) = 0.02° and a counting time of 1.8 s.step -1 . Powder X-Ray Diffraction (PXRD) confirmed the characteristic patterns of the fluorite structure (Fm-3m space group) typical for ThO2 for all of the studied samples in agreement with the literature and our previous report [START_REF] Bonato | Probing the local structure of nanoscaled actinide oxides: A comparison between PuO2 and ThO2 nanoparticles rules out PuO2+x hypothesis[END_REF]. LaB6 measurements were used to extract the instrumental functions. The collected data were refined by the Rietveld method when possible using the Fullprof_suite package [39].

Raman spectroscopy. Raman spectra were collected using a Horiba -Jobin Yvon Aramis apparatus equipped with an edge filter and a Nd:YAG laser (λ = 532 nm). The laser beam was focused onto the sample simply deposited on a glass lamella (1 µm 2 ) with the use of an Olympus BX41 microscope. The spectra were recorded between 100 and 1500 cm -1 . Before the analysis of the sample, the apparatus was calibrated with a silicon wafer, using the firstorder Si line at 520.7 cm -1 .

Scanning Electron Microscopy (SEM).

The starting oxides and the solid residues obtained after sonolysis were characterized with SEM using a FEI Quanta 200 electron microscope. The samples were directly deposited onto carbon tapes without additional preparation.

High-Resolution Transmission Electron Microscopy (HR-TEM)

. HR-TEM measurements were performed with a Jeol 2200 FS microscope (200 kV) equipped with a CCD GATAN USC camera. For HR-TEM analyses, sample aliquots were dispersed in absolute ethanol or pure water using an ultrasonic bath. One drop was then deposited onto a carbon-coated copper grid which was air-dried prior to analysis. For chemical analysis, the samples were characterized by Energy-Dispersive X-ray Spectroscopy (EDS) using a Silicon Drift Detector (SDD). Particle size measurements from HR-TEM analyses were determined by a statistical measurement using Image J software. The average value was given from at least 50 parallel measurements.

Results and Discussion

Effect of the different media on ThO2 dissolution

The sonication of nanoscale ThO2 powders (nanostructured ThO2, n-STR, from oxalic route and ThO2 nanopowder, n-PWD, from basic route) in aqueous solutions allows the observation of Th(IV) accumulation in solution as well as the formation of a solid residue at the end of the experiment (obtained by centrifugation and water washing of the sonicated mixture). Th(IV) accumulation kinetics are compared in Figure 1 for the different aqueous systems. A comparable behavior can be noticed for both sonicated ThO2 samples which are found highly resistant in pure water but significantly dissolve in sulfuric media. The dissolution rates and yields are furthermore found to significantly increase from 0.05 M H2SO4 to 0.5 M H2SO4 for ThO2 n-STR. Higher yields (38% dissolved in 0.5 M H2SO4 in 900 min) are nevertheless observed for ThO2 n-PWD which in addition exhibits practically zeroorder dissolution kinetics. The complexing affinity of sulfate-anion with Th(IV) cation has been reported to enhance the dissolution of ThO2 with the formation of surface complexes at the solid/liquid interface [START_REF] Hubert | Effect of inorganic ligands and hydrogen peroxide on ThO2 dissolution. Behaviour of Th0.87Pu0.13O2 during leaching test[END_REF]. The dissolution kinetics differences for both oxides can be related to their morphology and specific surface area. ThO2 n-STR is indeed composed of square platelets assembled from sintered particles whereas ThO2 n-PWD is composed of small grain aggregates which facilitate its dissolution (increased surface availability). The induction period observed for the nanostructured sample (ThO2 n-STR) at the beginning of its dissolution can be attributed to a first induction period related to platelets breaking and fragmentation which increase the available surface area and reactivity of the powder and improve the dissolution rate of the oxide.

Sonication effect on ThO2 dissolution

The effect of the ultrasonic wave and applied frequency on the dissolution rate of nanostructured ThO2 and ThO2 nanopowder in 0.05 M H2SO4 is illustrated on Figure 2. Whatever the oxide, mechanical agitation without ultrasound (silent conditions) does not lead to significant accumulation of Th after 480 minutes of treatment. Figure 2 also demonstrates the significant effect of low frequency ultrasound for the dissolution of these refractory ThO2 samples which usually requires the addition of fluoride ions in concentrated nitric acid medium [START_REF] Simonnet | Multiparametric study of thorium oxide dissolution in aqueous media[END_REF]. A lower dissolution rate is indeed observed when applying high frequency ultrasound (345 kHz) in comparison to low frequency experiment (20 kHz). Generally, chemical effects have been reported to be favored at high frequency whereas 20 kHz ultrasound generates stronger physical effects expressed by surface erosion, particle fragmentations, decrease of diffusion layers, etc. As described above (see part 3.1.), this effect is clearly observable when comparing the sonochemical initial dissolution rates of nanostructured ThO2 and ThO2 nanopowder on Figure 1. Whereas Th accumulation rates is found linear when considering ThO2 nanopowder, the ultrasound-assisted dissolution of nanostructured ThO2 indeed shows a time-increasing accumulation rate for Th (not linear) evidencing an induction period at the first stage of dissolution. Such observation also explains that for similar conditions, higher yields are observed with n-PWD samples in comparison to n-STR (Figure 2

Effect of the H2O2 formation on ThO2 dissolution

The sonication of these samples in aqueous solutions (pure H2O, 0.05 M H2SO4 and 0.5 M H2SO4) allowed to observe the accumulation of H2O2 which initial kinetics (W0(H2O2)), measured in the presence or absence of ThO2 powder, are represented in Figure 3. The kinetic values related to the initial H2O2 formation rates are gathered in Table S1, ESI. The higher formation rates observed at high frequency ultrasound (345 kHz) compared to low frequency at 0.05 M H2SO4 are attributed to the dissociation of O2 molecules in the cavitation bubble and the recombination of the generated radical products which increase H2O2 accumulation rates through various mechanisms [START_REF] Petrier | Unexpected frequency effects on the rate of oxidative processes induced by ultrasound[END_REF][START_REF] Beckett | Impact of ultrasonic frequency on aqueous sonoluminescence and sonochemistry[END_REF][START_REF] Dalodière | Effect of ultrasonic frequency on H2O2 sonochemical formation rate in aqueous nitric acid solutions in the presence of oxygen[END_REF][START_REF] Pflieger | Effect of operational conditions on sonoluminescence and kinetics of H2O2 formation during the sonolysis of water in the presence of Ar/O2 gas mixture[END_REF]. In the studied experimental domain, the initial H2O2 formation rate shows a decreasing trend in the presence of ThO2 powder whatever the medium or the applied acoustic frequency except for the experiment carried out in 0.5 M H2SO4. Several hypotheses may explain the general tendency for H2O2 kinetics observed in the presence of oxide, including: (i) the complexation or catalytic decomposition of H2O2 on the surface of the oxide [START_REF] Morosini | Sonochemical water splitting in the presence of powdered metal oxides[END_REF], (ii) the complexation reaction between H2O2 and dissolved Th(IV) [START_REF] Raman | Physico-chemical studies on thorium peroxosulphate[END_REF][START_REF] Bhattacharjee | New heteroligand peroxothorates(IV) of the type A2[Th(O2)F2(OH)2].nH2O (A = NH4, n = 3; A = Na or K, n = 1) and molecular peroxothorium(IV) complexes of the type [Th2(O2)3L(H2O)4].5H2O (L = C2O4 or SO4)[END_REF][START_REF] Bhattacharjee | Peroxothorium(IV) complexes containing hydroxo and phosphato coligands. Spectroscopic evidence for ɳ2 and σ:σ peroxide[END_REF], (iii) the redox or complexation reactions of H2O2 with Ti products resulting from the sonotrode erosion (only at 20 kHz), which is significantly depassivated in sonicated sulfuric media. Probably, the discrepancies noted in 0.5 M H2SO4 regarding H2O2 accumulation rates can be partly attributed to interactions with Ti products. Note that a previous work reported a similar decrease in H2O2 formation rate in the presence of oxide powder related to a catalytic H2O2 decomposition [START_REF] Morosini | Sonochemical water splitting in the presence of powdered metal oxides[END_REF]. Further work must be performed to explain the differences observed in the initial H2O2 formation in sulfuric acid media. The effects of the saturating atmosphere (Ar/20%O2, Ar/10%CO, Ar) and the addition of H2O2 on the sonochemical dissolution rate of ThO2 n-STR at 20 kHz are illustrated in Figure 4. In 0.5 M H2SO4, the ultrasound-assisted dissolution rate of ThO2 n-STR is much lower under Ar and Ar/CO than under Ar/O2. In the presence of O2, the formation rate of H2O2 is enhanced because of the scavenging of H radicals by O2 [START_REF] Dalodière | Effect of ultrasonic frequency on H2O2 sonochemical formation rate in aqueous nitric acid solutions in the presence of oxygen[END_REF][START_REF] Pflieger | Effect of operational conditions on sonoluminescence and kinetics of H2O2 formation during the sonolysis of water in the presence of Ar/O2 gas mixture[END_REF]. Conversely, the presence of CO, which reduces the dissolution rate, inhibits the accumulation of H2O2 similar to that observed in homogeneous aqueous solutions. In addition to the importance of the physical effects reported in part 3.2., these results confirm that the sonochemical generation of H2O2 significantly affect the dissolution of thorium oxide (Figure 1). This last assertion is confirmed with the observation of a significant increase of Th accumulation rate when adding hydrogen peroxide ([H2O2] = 0.01 M) in the reactor during the 20 kHz sonication of nanostructured ThO2 in 0.05 M H2SO4 (Figure 4.b.). It is interesting to note that these observations agree with previous investigations that demonstrated the significant effect of dilute hydrogen peroxide solutions for ThO2 dissolution in comparison to conventional inorganic acids (in silent conditions). [START_REF] Hubert | Effect of inorganic ligands and hydrogen peroxide on ThO2 dissolution. Behaviour of Th0.87Pu0.13O2 during leaching test[END_REF] Figure 4: (a.) Sonochemical dissolution curves observed for nanostructured ThO2 in 0.5 M H2SO4 at 20 kHz (20°C, 0.34 W.mL -1 ) for the different atmosphere used. (b.) Sonochemical (20 kHz, Ar/(20%)O2, 20°C, 0.34 W.mL -1 ) dissolution curves for nanostructured ThO2 suspended in 0.05 M H2SO4 without the addition of H2O2 and in the presence of 0.01 M H2O2 introduced in the reactor at t = 0 min.

Characterization of the residual solid phase

SEM images acquired on the dissolution residues (obtained by centrifugation and pure water washing of the suspension mixture during sonolysis) generated in water during the treatment of the nanostructured sample (ThO2 n-STR, oxalic route) confirm the progressive size reduction of the oxide platelets in agreement with the sonication time (Figure 5). This phenomenon is attributed to the physical effects driven by the collapsing acoustic bubbles (micro-jets, shock waves, particle collisions, etc.). The contrasting higher refractory behavior of reference ThO2 calcined at 1000°C has been confirmed by studying its sonochemical reactivity in 0.5 M H2SO4 (Figure S1,ESI). For a similar platelet morphology, the resulting dissolution rate is much lower than that observed for the nanoscale oxide calcined at 485 °C which agree with the generally-observed increased refractory behavior of high-fired oxides. This can be related to its lower specific surface area (Table 1) which results from the elimination of the porosity and crystal defects that occur when increasing the firing temperature or duration. Several studies already evidenced the relation between the specific surface area of the oxide and its dissolution in acidic solutions [START_REF] Hubert | Influence of the precursor and the calcination temperature on the dissolution of thorium dioxide[END_REF][START_REF] Claparede | Dissolution of Th1-xUxO2: Effects of chemical composition and microstructure[END_REF]. Furthermore, a nanoscale effect often linked to the improved number of surface active sites, lattice stress, strains, etc. can also be proposed for the oxides fired at 485°C. It is important to remind that ThO2 is known to be highly refractive towards dissolution, the here observed significant dissolution can be related to the nanoscale composition of the oxides made out of ca. 7 nm nanoparticles. Previous studies already demonstrated that nanomaterials may offer significantly improved reactivity or physico-chemical properties [START_REF] Fernández-García | Nanostructured oxides in chemistry: Characterization and properties[END_REF][START_REF] Stark | Industrial applications of nanoparticles[END_REF][START_REF] Dalodière | Insights into the sonochemical synthesis and properties of salt-free intrinsic plutonium colloids[END_REF][START_REF] Patzke | Oxide nanomaterials: Synthetic developments, mechanistic studies, and technological innovations[END_REF]. Despite these important effects, the absence of dissolution for ThO2 powders in pure H2O as reported in Figure 1 (see part 3.1.), and inhibiting effect of CO (see Figure 4.a. in part 3.3.) indicate that the dissolution mechanism of ThO2 does not result solely from the physical effects of ultrasound but also depends on other parameters such as the complexing nature of the medium. The effects of the acoustic cavitation on both nanoscale oxides sonicated in sulfuric acid medium are showed on the HR-TEM pictures obtained on the corresponding dissolution residues (Figure 6). Sonication of these oxides in dilute sulfuric acid solution leads to the strong platelets size reduction and fragmentation without significant modification of the crystallite size (see Table 1). Raman spectra of the starting ThO2 samples and corresponding sonolysis residues obtained in sulfuric medium are gathered in Figure 7 and Figure S2 (ESI). Both starting ThO2 samples spectra are also compared to the one of the reference material ThO2 calcined at 1000°C. An enlargement of the T2g band located at 465 cm -1 (FWHM) is observed with the decrease of the calcination temperature of ThO2 samples. This phenomenon is a fingerprint for nanocrystals and can be explained by the confinement of optical phonons in nanosized particles (crystallites) in agreement with the literature [START_REF] Tyrpekl | Low temperature decomposition of U(IV) and Th(IV) oxalates to nanograined oxide powders[END_REF][START_REF] Popa | A low-temperature synthesis method for AnO2 nanocrystals (An = Th, U, Np, and Pu) and associate solid solutions[END_REF][START_REF] Arora | Raman spectroscopy of optical phonon confinement in nanostructured materials[END_REF][START_REF] Kamali | High pressure Raman spectroscopic studies on nanocrystalline ThO2[END_REF][START_REF] Cappia | High-temperature and melting behaviour of nanocrystalline refractory compounds: an experimental approach applied to thorium dioxide[END_REF]. Further enlargement of the FWHM combined to a red shift of the T2g band is clearly observed for the sonicated nanoscale ThO2 sample residues. A similar observation has been made on nanostructured sample residues (ThO2 n-STR) after sonication in pure water (Figure S3, ESI) evidencing that the observed peak features are not related to the dissolution progress itself. The enlargement of the FWHM parameter is generally attributed to the shrinking particle size of oxide nanocrystals while the red shift is often correlated with the presence of defects, volume expansion, grain size distribution, etc. [START_REF] Tyrpekl | Low temperature decomposition of U(IV) and Th(IV) oxalates to nanograined oxide powders[END_REF] The evolution of these two parameters for the T2g band of the sonolysis residues cannot be explained by a particle size reduction since the size of the nanoparticles composing ThO2 powders are found similar before and after sonication (Table 1 and Figure 6). By contrast, the increased generation of strains, defects, and stress provided by the acoustic cavitation at the surface of the nanoparticles could significantly favor the interface reactivity involving a shift and enlargement of the T2g band. Such effects influence the atomic surface configuration and its potential hydration and hydrolysis can be viewed as an additional surface stress that may influence these two processes. Particularly, surface hydrolysis kinetics has been reported to exhibit significant geometry variation (in comparison to ThO2) and strongly depend on the concentration and nature of surface defects [START_REF] Anicˇić | Fewer defects in the surface slows the hydrolysis rate, decreases the ROS generation potential, and improves the non-ROS antimicrobial activity of MgO[END_REF][START_REF] Vasiliu | Reliable potential energy surfaces for the reactions of H2O with ThO2 , PaO2 + , UO2 2+ , and UO2 +[END_REF]. In addition, the catalytic activity of many metal centers is known to be partly determined by the strength and amount of Lewis and Brønsted acid-base sites standing at the surface of the catalysts. ThO2 exhibit catalytic properties (which are strengthened at the nanoscale) and ultrasonic treatment may increase the surface concentration of such moieties.

Partial conversion of ThO2 into a thorium peroxo sulfate

The sonolysis residues recovered after treatment of the nanoscale ThO2 powders in different aqueous solutions were characterized by PXRD analysis (Figure 8 and Figure S4, ESI). The PXRD diagrams for the starting ThO2 samples are gathered on Figure S5, ESI. The sonication residue diagrams for the nanoscale oxides display the characteristic patterns of the fluorite structure (Fm-3m space group) typical for ThO2 (ICSD 01-071-6407). Some diffraction peaks corresponding to Ti (ICSD 00-044-1294) and attributed to the sonotrode erosion during the prolonged 20 kHz ultrasonic treatment, can also be observed. The PXRD diagrams of the sonolysis residues obtained in sulfuric acid (0.05 M and 0.5 M) also show some additional diffraction peaks principally located at small angles that are not observed for the sonolysis residue obtained in pure water. These PXRD patterns correspond to a recently studied thorium peroxo sulfate, Th(O2)(SO4)(H2O)2, which crystallizes in the space group Pna21 of the orthorhombic system as evidenced by a combination of synchrotron PXRD and EXAFS approaches [START_REF] Bonato | Deciphering the crystal structure of a scarce 1D polymeric thorium peroxo sulfate[END_REF]. In this compound, peroxo ligands coordinate Th centers in a scarce µ3η 2 :η 2 :η 2 bridging mode forming infinite 1D chains decorated with sulfato ligands. The corresponding purple PXRD diagram presented in Figure 8 shows diffraction peaks matching with those observed at small angles for the sonolysis residues. This result indicates the partial conversion of both nanoscale ThO2 samples into a thorium peroxo sulfate during sonolysis. The low intensity of the diffraction peaks for this neoformed compound indicates its low proportion in the sample residue as well as its low crystallinity. This observation combined with the atomic form factor explains that the diffraction peaks at 2θ> 20° are poorly distinguishable. Furthermore, the crystallinity of the Th peroxo sulfate in silent conditions has been demonstrated to strongly depend upon the synthesis medium as evidenced in Figure S6 (ESI) which strengthens the observed low intensity of the diffraction peaks in the residue but also explains the better crystallinity noticed on XRD diagrams for this new compound in 0.05 M H2SO4 (in comparison to 0.5 M H2SO4). Although high-frequency ultrasound generally enhance the sonochemical generation of H2O2 as expressed in Figure 3 (see part 3.3.), the 345 kHz sonolysis of nanoscale ThO2 in 0.05 M H2SO4 does not lead to the formation of Th peroxo sulfate species (Figure S7,ESI). This can be explained by the low dissolution of ThO2 in these conditions (Figure 2, see part 3.2.) as a result of the absence of ThO2 fragmentation and dispersion for such frequency. As it can be seen from PXRD data (Figure S7, ESI), a similar assessment can be mentioned in silent conditions, whatever the considered oxide. Although evidenced by PXRD (Figure S4, ESI), the formation of thorium peroxo sulfate during the sonication of ThO2 nanopowder in 0.05 M sulfuric acid is not obvious with SEM observation. Sample residue indeed shows a padded morphology with ill-defined small grain aggregates (Figure S8, ESI). By contrast, SEM characterizations confirmed the formation of this new crystalline phase in the dissolution residue obtained after sonication of nanostructured ThO2 (n-STR) in 0.05 M H2SO4 (Figure 9). A clear fragmentation and size reduction of the oxide platelets combined to the growth of a new phase forming fibers in agreement with the recently reported Th peroxo sulfate morphology [START_REF] Bonato | Deciphering the crystal structure of a scarce 1D polymeric thorium peroxo sulfate[END_REF], can be noted after 900 min of ultrasound. TEM experiments coupled with EDX spectroscopy consolidated the observation of the partial sonochemical conversion of ThO2 into thorium peroxo sulfate. Figure 10 shows a TEM image where a fiber particle is observed close to small thorium oxide platelets. The EDX mapping confirmed the presence of thorium, oxygen and sulfur elements which support the formation of Th peroxo sulfate during the sonication of thorium oxide in sulfuric medium. The ThO2 squared platelets also show thorium, oxygen and sulfur; the latter most probably resulting from the adsorption of sulfate on the surface of thorium oxide during sonolysis.

ThO2 dissolution mechanism

The results described in the above discussion demonstrate that the significant dissolution of nanoscale ThO2 samples observed in our conditions results from the physical (particle fragmentation and generation of defects) and chemical (generation of H2O2) effects driven by the 20 kHz acoustic cavitation phenomenon combined to an appropriate medium (sulfuric media in this case). The various results that arose this conclusion are summarized in Table 2 to help in the proposition of a relevant dissolution mechanism for nanoscale ThO2 samples.

Usually, the dissolution of thorium oxide described in the literature involves a surface mechanism with ion adsorption on the surface sites of the oxide, chemical complexation reaction between the solid surface and the adsorbed species and finally, desorption of the thorium complex [START_REF] Simonnet | Thorium oxide dissolution in HNO3-HF mixture: kinetics and mechanism[END_REF][START_REF] Claparede | Dissolution of Th1-xUxO2: Effects of chemical composition and microstructure[END_REF]. The formation of thorium peroxo sulfate during the sonolysis of ThO2 in sulfuric acid solution can be interpreted by two different processes: (i) a solution decomposition or splitting of sulfuric species are unlikely in these conditions. Previous studies indeed demonstrated the possible degradation of sulfuric media at much higher concentrations (> 9 M) when non-dissociated H2SO4 molecules predominate in solution and are able to enter the cavitation bubble which is not the case in our study. [START_REF] Sharipov | Sonoluminescence of aqueous solutions of sulfuric acid and sulfur dioxide[END_REF][START_REF] Nikonov | The destruction of sulfuric acid induced by ultrasonic vibrations[END_REF][START_REF] Moshaii | Sonoluminescence radiation from different concentrations of sulfuric acid[END_REF] Speciation diagram provided in Figure S9 (ESI) confirms that in our conditions (pHth= 0.3 and 1.23 respectively in 0.5 and 0.05 M H2SO4), HSO4 -is the predominant specie.

Conclusion

This study confirms the enhanced reactivity of nanoscale thorium oxides under ultrasound irradiation. Although being highly refractive towards dissolution in silent conditions, the significant dissolution of ThO2 can be achieved under 20 kHz sonication in dilute aqueous solutions of H2SO4. Dissolution rates and yields are strongly dependent upon (i) the physical effects driven by the acoustic cavitation such as the particle fragmentation or surface activation (strain, stress, hydrolysis, hydration, etc.), (ii) the sonochemical activity through the in-situ generation of hydrogen peroxide, and (iii) the complexing affinity of the medium (sulfate) towards the oxide surface. The highest dissolution yields are observed with ThO2 nanopowder sonicated at 20 kHz under Ar/(20%)O2 atmosphere in 0.5 M H2SO4. Characterizations of the sonolysis residues with PXRD, SEM and HR-TEM revealed the partial conversion of ThO2 into a scarce Th peroxo sulfate complex, which can be explained by one or both of the following mechanisms: dissolution/reprecipitation process and/or formation of a surface activated complex. Further experiments are planned to clarify the dissolution mechanism and synthesize directly this compound under ultrasound with a thorium nitrate starting solution and with other counter-ions. In addition, the sonochemical reactivity of nanoscale PuO2 in sulfuric acid solution will be studied while assuming the potential formation of an analogous Pu(IV) peroxo compound.

Figure 1 :

 1 Figure 1: ThO2 dissolution curves observed under 20 kHz ultrasound (20°C, Ar/(20%)O2, 0.34 W.mL -1 ) in pure H2O, 0.05 M H2SO4 and 0.5 M H2SO4 for (a.) ThO2 n-STR and (b.) ThO2 n-PWD.

  .a. vs. 2.b.).

Figure 2 :

 2 Figure 2: Dissolution curves (Ar/(20%)O2, 20°C) observed for (a.) ThO2 n-STR and (b.) ThO2 n-PWD suspended in 0.05 M H2SO4 at 20 kHz (0.34 W.mL -1 ), 345 kHz (0.19 W.mL -1 ) and in silent conditions.

Figure 3 :

 3 Figure 3: Representation of the initial H2O2 formation rates observed in the different sonicated media (Ar/(20%)O2, 20°C) for ThO2 n-STR and ThO2 n-PWD calcined at 485°C at 20 kHz (0.34 W.mL -1 ) or 345 kHz (0.19 W.mL -1 ).

Figure 5 :

 5 Figure 5: SEM images acquired on the starting nanostructured ThO2 (485°C) and its corresponding sonolysis residue obtained in pure H2O for different sonolysis times (20 kHz, Ar/(20%)O2, 20°C, 0.34 W.mL -1 ).

Figure 6 :

 6 Figure 6: HR-TEM images of the starting nanostructured or nanopowdered ThO2 samples and their corresponding sonolysis residues observed in 0.05 M H2SO4 (20 kHz, Ar/(20%)O2, 20°C, 0.34 W.mL -1 ).

Figure 7 :

 7 Figure 7: Normalized Raman spectra observed on reference material ThO2 (1000°C), nanopowdered (n-PWD) ThO2 (485°C) and its sonolysis residue obtained in 0.5 M H2SO4 (20 kHz, Ar/(20%)O2, 20°C, 0.34 W.mL -1 ). *artefact attributed to dust on the mirror of the spectrometer.

Figure 8 :

 8 Figure 8: (a.) Normalized PXRD diagrams (background corrected) acquired on the sonolysis residues for nanostructured ThO2 (485°C) treated in different media (20 kHz, Ar/(20%)O2, 20°C, 0.34 W.mL -1 ), and compared with the one of a thorium peroxo sulfate synthesized without ultrasound (purple spectrum).[56] Ticks stand for ICSD files for ThO2 (ICSD 01-071-6407) and Ti (ICSD 00-044-1294). (b.) Magnification of the normalized PXRD diagram (background corrected) acquired on the sonolysis residue for nanostructured ThO2 treated in 0.05 M H2SO4 (20 kHz, Ar/(20%)O2, 20°C, 0.34 W.mL -1 ), and compared with the one of a thorium peroxo sulfate synthesized without ultrasound.

Figure 9 :

 9 Figure 9: SEM images of nanostructured ThO2 before (left) and after (right) sonication (20 kHz, Ar/(20%)O2, 0.05 M H2SO4, 20°C, 0.34 W.mL -1 ).

Figure 10 :

 10 Figure 10: TEM images coupled with EDX mapping of the sonolysis residue obtained after 20 kHz sonication of nanostructured ThO2 (485°C) in 0.05 M H2SO4 (Ar/(20%)O2, 20°C, 0.34 W.mL -1 ).

Figure 11 :

 11 Figure 11: Scheme of the ultrasound-assisted dissolution of ThO2.

Table 1 :

 1 ThO2 sample characteristics and related nanoparticle sizes composing them and the sonolysis residues in different media (20 kHz, Ar/(20%)O2, 20°C, 0.34 W.mL -1 ) both determined by HR-TEM and XRD measurements (Rietveld refinement, when possible).

		Nanostructured ThO2 (n-STR)	ThO2 nanopowder (n-PWD)	Reference material ThO2
	Synthesis route	oxalic route	basic route	oxalic route
	(conditions)	(485°C, 4 h)	(485°C, 2 h)	(1000°C, 2 h)
	SEM morphology	Squared platelets	Agglomerated NPs	Squared platelets
	SBET (m 2 .g -1 )	13.5 ± 0.1	82.4 ± 0.1*	4.7 ± 0.1
	Particle size (nm)	HR-TEM	XRD	HR-TEM	XRD	HR-TEM	XRD
		7.6 ± 2.1	6.4 ± 0.7	7.7 ± 1.4	5.7 ± 0.1	66.6 ± 27.1	63.6 ± 1.5

Particle size for the sonolysis residue (nm)

	Water 8.8 ± 2.2	9.1 ± 0.9	7.0 ± 1.7	7.5 ± 1.1	-
	0.05 M H2SO4 7.6 ± 1.5	-	6.2 ± 1.2	-	-
	0.5 M H2SO4 7.9 ± 1.2	-	-	-	-
	*value taken as an indicator from a previous report (ThO2 n-PWD prepared at 450°C)[35]

Acknowledgements

We acknowledge the financial support of RCHIM and PRATA research programs of CEA, the French Alternative Energies and Atomic Energy Commission. The authors are thankful to Adel Mesbah who performed the Rietveld refinements.

coordination mechanism then precipitation, (ii) a surface complexation mechanism, or (iii) a combination of both processes. [H2O2] = 0.01 M -11 X In the former case, a dissolution/reprecipitation process would involve the presence of Th(IV) in solution that could then be complexed with sulfate and generated H2O2 in agreement with the previous report described elsewhere [START_REF] Bonato | Deciphering the crystal structure of a scarce 1D polymeric thorium peroxo sulfate[END_REF]. In this case, the low precipitation kinetics already observed for this compound combined with the low amount of species available in solution (e.g., H2O2 consumption occurs through dissolution and catalytic decomposition at ThO2 surface, see part 3.3.) would explain the low conversion yields (kinetics and solubility product). The absence of Th peroxo sulfate at high ultrasonic frequency and at silent conditions (see part 3.5.) favors this mechanism, so as the observation of fibers having very different morphology if compared with initial ThO2 (Figure 9, see part 3.5.).

Alternatively, H2O2 and sulfate ligands can form surface complexes and facilitate the dissolution of ThO2 in the form of Th(IV) peroxo and/or sulfate complexes. According to Table 2, the sonochemical generation of H2O2 is mandatory for ThO2 dissolution. Most probably, H2O2 adsorption can occur by the replacement of H2O molecules at ThO2 surface as it was reported recently (Figure 11). [START_REF] Lousada | Mechanism of H2O2 decomposition on transition metal oxide surfaces[END_REF] The effect of H2SO4 concentration could be assigned to the protonation of ThO2 surface (initial steps described by the equations Eq. 1-2, the symbol ")))" stands for 20 kHz ultrasound irradiation) although the adsorption of sulfate cannot be excluded in agreement with the literature. [START_REF] Kitadai | A comprehensive predictive model for sulfate adsorption on oxide minerals[END_REF] The formation of a mixed surface complex could also be hypothesized. Nevertheless, the exact dissolution mechanism needs further investigations.

Surface hydrolysis and protonation

Note that mixtures of concentrated H2O2 and H2SO4 solutions are used reactants for the preparation of Caro's acid (peroxymonosulfuric acid). The formation of such strong oxidant acid remains however highly unlikely in our conditions due to the low amount of involved reactants and the high instability of peroxymonosulfuric acid. Furthermore, sonolytic


Florian Schrub

Emmanuel Oger

Auriane Bidaut

Camilla Hage

Marion Charton

Jean Claude Daubert

Chrtistophe Leclercq

Cecila Linde

Lars Lund

Erwan Donal
email: erwan.donal@chu-rennes.fr

Heart failure with preserved ejection fraction A clustering approach to a heterogenous syndrome

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

séparée en groupes sur la base de 55 variables, en étudiant la distribution des décès et des hospitalisations.

Résultats. -Trois clusters ont été identifiés sur 356 patients analysables (âge moyen = 76,1 ± 9,31 ans ; 43,5 % d'hommes) : cluster 1 (n = 128) avec des hommes, plus jeunes, en surpoids, à haut risque cardiovasculaire, en rythme sinusal, de fonction rénale altérée ; cluster 2 (n = 134) avec des femmes, une fonction ventriculaire gauche la plus préservée ; cluster 3 (n = 94) avec l'incidence la plus haute de régurgitation mitrale, de remodelage auriculaire et de troubles du rythme. Il n'y pas de différence significative, hormis une tendance à la mortalité précoce dans le groupe 3.

Conclusions. -L'analyse par « clustering » semble être efficace pour individualiser des sous-groupes de différentes physiopathologies. L'impact clinique de ces trois phénotypes reste à démontrer.

KEYWORDS

Background

Within the broad spectrum of "heart failure" (HF), heart failure with preserved ejection fraction (HFpEF) remains a diagnostic and therapeutic challenge. The prevalence is continuing to rise, with HFpEF representing 50% of HF cases [START_REF] Owan | Trends in prevalence and outcome of heart failure with preserved ejection fraction[END_REF][START_REF] Shah | Heart Failure With Preserved, Borderline, and Reduced Ejection Fraction: 5-Year Outcomes[END_REF] -mostly older women [START_REF] Dunlay | Epidemiology of heart failure with preserved ejection fraction[END_REF] with multiple co-morbidities such as hypertension, atrial fibrillation (AF), obesity and kidney disease [START_REF] Dunlay | Epidemiology of heart failure with preserved ejection fraction[END_REF].

Higher ejection fraction (EF) does not mean better prognosis. Shah et al. [START_REF] Shah | Heart Failure With Preserved, Borderline, and Reduced Ejection Fraction: 5-Year Outcomes[END_REF] found the same poor 5-year outcome in the three categories of HF (preserved EF, mid-range EF and altered EF), with a mortality rate of 75% and a rehospitalization rate of approximately 83%. Cause of death is the main difference between HF categories, with a twofold higher rate of non-cardiovascular death among patients with HFpEF, mostly linked to the fragility of this older and co-morbid population with more infection and cancer [START_REF] Vaduganathan | Mode of Death in Heart Failure With Preserved Ejection Fraction[END_REF].

First presented as "diastolic dysfunction" [START_REF] Paulus | How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology[END_REF], the latest guidelines define HFpEF as an association of "clinical signs and symptoms", "functional and morphological abnormalities" and "modification of biomarkers" [START_REF] Ponikowski | ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF]; this contrasts with heart failure with reduced ejection fraction (HFrEF), which is mainly defined by an EF < 40% [START_REF] Ponikowski | ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF].

Physiopathology is determined by a complex interaction between many factors, such as systolic dysfunction and deformation impairment, chronotropic incompetence and impaired contractility reserve, left atrial (LA) dysfunction and AF, arterial stiffening and abnormal ventricular-arterial coupling, autonomic imbalance and endothelial dysfunction [START_REF] Borlaug | The pathophysiology of heart failure with preserved ejection fraction[END_REF]. Synergy between systemic inflammation and coronary microvascular endothelial dysfunction appears to be the theory unifying the different cardiovascular and extracardiovascular factors, leading to dysfunctional myocardial signalling and multiorgan alterations [START_REF] Franssen | Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction[END_REF]. Instead of being a precise and well defined "disease", it seems rather to be a complex "syndrome" with various clinical presentations [START_REF] Senni | New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes[END_REF][START_REF] Shah | Matchmaking for the optimization of clinical trials of heart failure with preserved ejection fraction: no laughing matter[END_REF].

All previous clinical trials involving drugs have failed to have a significant impact on HFpEF [START_REF] Senni | New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes[END_REF]; one reason for this that has been highlighted by different authors in the literature is the vast heterogeneity of the population and the physiopathological mechanisms [START_REF] Shah | Matchmaking for the optimization of clinical trials of heart failure with preserved ejection fraction: no laughing matter[END_REF].

Instead of focusing on one target, a new statistical approach known as "clustering" or "phenomapping" has shown its relevance in cardiology in identifying subgroups with similar characteristics. In chronic HF, Ahmad et al. [START_REF] Ahmad | Clinical implications of chronic heart failure phenotypes defined by cluster analysis[END_REF] found four specific clusters with specific responses to exercise training and different prognoses. In Japan, three subtypes of acute HF were highlighted, corresponding to previous physiopathological concepts [START_REF] Horiuchi | Identifying novel phenotypes of acute heart failure using cluster analysis of clinical variables[END_REF]. In addition, two recent papers used the same statistical technique at rest [START_REF] Shah | Phenomapping for novel classification of heart failure with preserved ejection fraction[END_REF] and during exercise [START_REF] Przewlocka-Kosmala | Contribution of Cardiovascular Reserve to Prognostic Categories of Heart Failure With Preserved Ejection Fraction: A Classification Based on Machine Learning[END_REF] in HFpEF, with consistent findings.

Diagnosis of HF according to the guidelines has been previously validated [START_REF] Persson | Importance of structural heart disease and diastolic dysfunction in heart failure with preserved ejection fraction assessed according to the ESC guidelines -A substudy in the Ka (Karolinska) Ren (Rennes) study[END_REF], and many substudies have explored different dimensions and phenotypes [START_REF] Lund | Association between cardiovascular vs. non-cardiovascular co-morbidities and outcomes in heart failure with preserved ejection fraction[END_REF].

The aims of our study were: [START_REF] Owan | Trends in prevalence and outcome of heart failure with preserved ejection fraction[END_REF] to apply a clustering approach to the KaRen study cohort to identify specific subgroups; and (2) to study the physiopathological, clinical and prognostic meaning of the phenotypes.

Methods

KaRen was a prospective multicentre international observational study of patients with HFpEF. The design of the study has been published previously [START_REF] Donal | Rationale and design of the Karolinska-Rennes (KaRen) prospective study of dyssynchrony in heart failure with preserved ejection fraction[END_REF], and the primary echocardiographic characteristics have also been reported [START_REF] Donal | Value of exercise echocardiography in heart failure with preserved ejection fraction: a substudy from the KaRen study[END_REF]. The KaRen study included patients with HF symptoms admitted to the emergency ward. The following inclusion criteria were used: (1) acute presentation to the hospital with clinical signs and symptoms of HF, according to the Framingham criteria; (2) B-type natriuretic peptide > 100 pg/mL or N-terminal prohormone of B-type natriuretic peptide > 300 pg/mL; and (3) left ventricular EF > 45% by echocardiography within the first 72 hours. The measurements were performed according to previously established guidelines [START_REF] Ponikowski | ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF]. All three inclusion criteria were verified within 72 hours of presentation. Enrollment occurred during the initial visit, provided that any exclusion criteria had been ruled out. Information concerning clinical history, co-morbidities, clinical signs and symptoms, standard biology and treatments was collected prospectively during a scheduled hospital visit 4-8 weeks after initiating treatment for acute HF.

Echocardiographic methods and definitions

All patients were followed and reassessed during a visit scheduled 4-8 weeks after the acute visit, including an extensive echocardiographic assessment [START_REF] Cosyns | Education Committee of the European Association of Cardiovascular Imaging. Update of the echocardiography core syllabus of the European Association of Cardiovascular Imaging (EACVI)[END_REF]. Doppler echocardiography was performed using a ViVid 7 echo-platform (GE VingMed, Horten, Norway). The acquisitions were standardized to images of the left and right heart. Thereafter, all examinations were analysed at the core laboratory in Rennes. Each measurement was performed three times and averaged. The echocardiography reader was blinded to the clinical history of any patient [START_REF] Donal | Value of exercise echocardiography in heart failure with preserved ejection fraction: a substudy from the KaRen study[END_REF]. This KaRen substudy included all patients with analysable trasnthoracic echocardiography at the visit at 4-8 weeks, according to the European Association of Cardiovascular Imaging/American Society of Echocardiography recommendations [START_REF] Nagueh | Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF].

Analysis of left ventricular longitudinal deformation was conducted for each patient using the loops from the apical four-, three-and two-chamber views. According to the regional thickness of each segment, the region of interest was adapted to systematically include the endocardial and epicardial borders. The regional adaptation of the size of the region of interest was possible on the EchoPAC version we were using (EchoPAC B13; GE Healthcare, Horten, Norway). The same approach was used for the right ventricle, focusing on the free wall in the apical four-chamber view.

Follow-up

Patients were included between May 2007 and December 2011, and were followed prospectively from the initial hospitalization until November 2012. Vital status was assessed by clinical visit, telephone contact or, in Sweden, by the Swedish National Patient Register and Population Register. [START_REF] Nagueh | Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF]

Study endpoints

The primary outcome was all-cause mortality or first hospitalization for HF. Hospitalization for HF was defined as admission to the hospital for any length of time, including day care, with either HF treatment or HF as the primary reason for admission. The secondary outcome was time to all-cause mortality [START_REF] Nagueh | Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF]. Because this variable was measured from the visit at 4-8 weeks, the index date and start of follow-up were defined as the date of the visit at 4-8 weeks and data collection.

Statistical analysis

Before analysis, missing data were imputed using the SVDimpute function within the impute package in R. The percentage of missing values for features ranged from 0% to 28% (for LA volume index).

Before the cluster analysis was performed, the Gower dissimilarity measure was chosen to measure the closeness between each observation; it implies standardization, which is set to range for interval and ordinal variables. A hierarchical cluster analysis was conducted in PROC CLUSTER (SAS, version 9.4; SAS Institute, Cary, NC, USA) using two-stage density linkage, specifying five neighbours for k-nearest neighbour density estimation. All clustering was performed blinded to clinical outcome data.

Hierarchical cluster analysis is an attempt to classify data of previously unknown structure into discrete groups. Each observation begins in a cluster by itself. The two closest clusters are merged to form a new cluster that replaces the two old clusters. Merging of the two closest clusters is repeated until only one cluster is left. The various clustering methods differ in how the distance between two clusters is computed. The two-stage density linkage is a modification of density linkage that ensures that all points are assigned to modal clusters before the modal clusters are permitted to join. In the first stage, disjoint modal clusters are formed. Two clusters are joined only if at least one of the two clusters has fewer members than the number specified (in our analysis, five). At the end of the first stage, each point belongs to one modal cluster. In the second stage, the modal clusters are hierarchically joined by single linkage. The final number of clusters can exceed one when there are wide gaps between the clusters or when the smoothing parameter is small. Once clusters were defined, we compared differences in demographic, clinical and echocardiographic characteristics between clusters, using the χ 2 test (or Fisher's exact test, when appropriate) for categorical variables and analysis of variance (or the Kruskal-Wallis test, when appropriate) for continuous variables. Fifty-five variables were finally included in the analysis (see Table 1 for details).

For outcomes analyses, we used Kaplan-Meier survival estimates to determine the independent association between clusters and outcomes.

Results

The overall KaRen population has been described previously [START_REF] Donal | Baseline characteristics of patients with heart failure and preserved ejection fraction included in the Karolinska Rennes (KaRen) study[END_REF]. Cluster analysis included 356 patients with evaluable echocardiography, including 55 variables to identify three clusters. The mean age was 76.1 ± 9.31 years and 56.5% were female; a large majority of patients (79.4%) had hypertension and 45.4% had renal insufficiency. Sinus rhythm was present at enrollment in 56.3%. Subclinical left ventricular dysfunction was observed, with a mid-altered two-dimensional (2D) strain peak (-14.6 ± 3.96%) and moderate LA remodelling, with a mean LA volume index of 49.4 ± 18 mL/m². Distribution of chronic pulmonary obstructive disease, peak of tricuspid regurgitation and E/e' ratio were not significantly different between the clusters. Patient characteristics overall, and within the different clusters are shown in Table 2.

Cluster 1 (n = 128)

This cluster can be summed up as the "cardiovascular risk group" with the highest rates of hypertension (89.1%) and diabetes (60.2%), despite a relatively young age (73.8 ± 10.3 years), and the highest proportion of males (60.2%). Obesity was more prevalent (mean body mass index 31.2 ± 6.55 kg/m 2 ) and renal inufficiency was more frequent (60.2%) than in the other clusters, with a lower concentration of haemoglobin (118 ± 21 g/L). Fewer rhythm disorders occurred than in the other clusters, with 88.3% in sinus rhythm at enrolment. Concerning echocardiography variables, left ventricular remodelling was predominant (interventricular septal thickness 12.0 ± 2.53 mm), with moderate left ventricular deformation (mean 2D strain peak -14.0 ± 3.47%). Right ventricular function was preserved, with a mean tricuspid annulus plan systolic excursion of 18.8 ± 4.74 mm, and we observed the smallest LA dilatation (45.7 ± 2.4 mL/m 2 ) and the lowest rate of severe mitral regurgitation (2.3%) in this cluster.

Cluster 2 (n = 134)

This cluster had the highest proportion of females (68.7%) and the lowest rates of diabetes (11.9%) and hypertension (73.1%). A sinus rhythm electrocardiogram was less frequent (67.2%) than in cluster 1. Renal function was most preserved in this cluster (only 35.1% had renal insufficiency), and it was the only group with subnormal left ventricular systolic function, with a mean 2D strain peak of -17.3 ± 3.05% in association with a preserved left ventricular EF. The results were concordant with the mean population values for LA dilatation, mitral regurgitation severity and other echocardiographic variables.

Cluster 3 (n = 94)

This cluster had the oldest population (mean age 78.3 ± 6.92 years), with a majority of females (61.7%); the rates of diabetes (23.4%) and hypertension (75.5%) were lower than in cluster 1, but higher than in cluster 2. These patients had the highest rate of rhythm disorders, with only 12.8% in sinus rhythm. Mitral regurgitation was more frequent: five times the rate in cluster 1 for class III-IV (10.6% vs 2.3%) and twice the rate in cluster 1 for class II (22.3% vs 10.9%). Left ventricular systolic and diastolic dysfunction were altered (mean 2D strain peak -11.6 ± 2.87%), with severe LA enlargment (LA volume index 54.3 ± 15.7 mL/m²).

Cluster association and clinical outcomes

Fig. 1, Fig. 2 and Fig. 3 compare outcomes between the different clusters. There were no statistical differences between the three clusters for the primary endpoint.

We found a tendency towards a worse long-term outcome for patients in cluster 2. When death was the only criterion analysed, cluster 3 showed higher rates of short-and mid-term mortality (40% vs 22% and 23% in clusters 1 and 2, respectively, at 500 days of follow-up), but no difference in longterm survival (35% vs 66% and 63% in clusters 1 and 2, respectively, at 1000 days of follow-up).

Discussion

HFpEF: Heterogenous and complex remodelling with fibrosis and energetic impairement

From diastolic dysfunction to the impact of multiple co-morbidities, a new paradigm [START_REF] Paulus | A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation[END_REF] has emerged, presenting HFpEF as the final expression of a complex interaction between multiorgan dysfunction, neurohormonal activation and haemodynamic stress, linked by the same pathological disorder, systemic inflammation and endothelial dysfunction, resulting in myocardial stiffness and hypertrophy.

Clustering approach

New methods are needed to be more discriminating in future trials and to help to improve the specific diagnosis of patients. Clustering is a new statistical method belonging to the category of nonsupervised analysis, without predefined classes. The goal is to sort objects into different subgroups, "the clusters", and each cluster includes objects with similarities to each other, and dissimilarities to objects outside the subgroup. The hierarchical method is based on progressive step-by-step aggregation of patients, until one specific class is found.

Following the path opened by Shah et al. [START_REF] Shah | Phenomapping for novel classification of heart failure with preserved ejection fraction[END_REF] and Przewlocka-Kosmala et al. [START_REF] Przewlocka-Kosmala | Contribution of Cardiovascular Reserve to Prognostic Categories of Heart Failure With Preserved Ejection Fraction: A Classification Based on Machine Learning[END_REF], a cluster analysis technique was applied to the 356 patients with HFpEF from the KaRen cohort in order to individualize phenotypic groups with specific patterns of co-morbidites. Three clusters, summarized in Table 3, were discovered, based on multiple clinical and paraclinical variables, selected for their "physiological" meaning and the absence of high statistical redundance between each other.

Metabolic syndrome and young HFpEF

Cluster 1 included the youngest, mostly male patients from the population, with a high rate of cardiovascular co-morbidities. These findings resonate with previous literature. In the RELAX trial [START_REF] Lewis | Biological Phenotypes of Heart Failure With Preserved Ejection Fraction[END_REF], diabetes, hypertension, obesity and renal dysfunction were predominant in young men. In the study by Zacharias et al. [START_REF] Zacharias | Clinical epidemiology of heart failure with preserved ejection fraction (HFpEF) in comparatively young hospitalized patients[END_REF], younger patients hospitalized for acute HF were more likely to be male, obese and have a history of diabetes and chronic kidney disease than older patients with HFpEF. This specific phenotype may be related to a well-known clinical entity, the "metabolic syndrome" mediated by a pathological insulin cycle. In synergy with radical oxygen species, insulin resistance enhances diastolic dysfunction, leading to HF [START_REF] Fontes-Carvalho | Diastolic dysfunction in the diabetic continuum: association with insulin resistance, metabolic syndrome and type 2 diabetes[END_REF]. This hormonal disorder stands at the crossroads of many comorbidities, as both a cause and a consequence of them, thus increasing the development of HFpEF functional impairment, but also its risk factors. Renal dysfunction seems to be part of another "vicious cycle" with HFpEF and the other cardiovascular risk factors Cluster 1 patients may benefit from adapted therapies. Aerobic training and calorie restriction may help with recovery of insulin sensitivity, loss of weight and restoration of an efficient energy cycle. Kitzman et al. found an significant improvement in peak oxygen consumption (VO2) in patients with obesity and HFpEF [START_REF] Kitzman | Effect of Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial[END_REF]. From another perspective, sodium-glucose cotransporter inhibitors effectively reduced HF hospitalization and cardiovascular death in patients with non-insulin-dependent diabetes.

Interference with calcium homeostasis, improvement in mitochondrial function, decrease in inflammation and the production of reactive oxygen species and restoration of nitric oxide formation represent some of the mechanisms behind these effects, and each of them is involved in HFpEF development [START_REF] Uthman | Direct Cardiac Actions of Sodium Glucose Cotransporter 2 Inhibitors Target Pathogenic Mechanisms Underlying Heart Failure in Diabetic Patients[END_REF].

Mitral regurgitation: An atrial remodelling endpoint

Cluster 3 included the oldest patients, with the worst left ventricular systolic and diastolic dysfunction, the highest degree of LA remodelling and moderate-to-severe mitral regurgitation, and with fewer patients in sinus rhythm, because of the loss of atrioventricular coupling. A continuous process of inflammation, microvascular and diastolic dysfunction, increasing left ventricular filling pressure and LA stress means that the patient with HFpEF is more dependent on LA contraction than control subjects [START_REF] Borlaug | The pathophysiology of heart failure with preserved ejection fraction[END_REF]. Mediated by LA fibrosis, LA dilatation and altered LA reservoir function lead to high filling pressure and AF. HFpEF and AF are known to influence each other's development and persistence, and to worsen LA mechanics, thus leading to altered geometry and dynamic function of the mitral annulus and leaflets [START_REF] Pai | Effect of atrial fibrillation on the dynamics of mitral annular area[END_REF], causing functional mitral regurgitation. More than a risk factor, mitral regurgitation may represent the severity of an evolved HFpEF form. Kajimoto et al. [START_REF] Kajimoto | Investigators of the Acute Decompensated Heart Failure Syndromes Registry. Functional mitral regurgitation at discharge and outcomes in patients hospitalized for acute decompensated heart failure with a preserved or reduced ejection fraction[END_REF] found a prognostic association between mitral regurgitation, even at a mild grade, and outcomes for HFpEF, whereas this prognostic association is observed for moderate-to-severe mitral regurgitation in HFrEF. This sequence of LA remodelling-AF-functional mitral regurgitation in cluster 3 may explain the tendency towards short-and mid-term mortality, whereas there is no significant difference in long-term outcome; it can be linked to the older age of this subgroup, but also to a cumulative impact of LA size or dysfunction, AF and mitral regurgitation [START_REF] Kajimoto | Investigators of the Acute Decompensated Heart Failure Syndromes Registry. Functional mitral regurgitation at discharge and outcomes in patients hospitalized for acute decompensated heart failure with a preserved or reduced ejection fraction[END_REF]. A therapeutic strategy may need to take into account the abnormal mitral subvalvular and valvular system, with the objectives of reducing congestion and treating risk factors, or invasive treatment may be required, despite controversial data on the subject.

Cluster 2 seems to a be a "previous" stage of cluster 3, with younger patients, less diabetes and lower rates of mitral regurgitation and arrhythmia. Global preserved left ventricular function may be a marker of less inflammation and better systolic-diastolic dynamics, slowing evolution of LA dysfunction. This clinical phenotype can be similar to "exercise intolerance" previously presented by Shah [START_REF] Shah | Matchmaking for the optimization of clinical trials of heart failure with preserved ejection fraction: no laughing matter[END_REF], and may benefit from a sport practice programme. Sacubitril-valsartan may represent another effective therapy, by reducing left ventricular filling pressure and LA stress, restoring fluid balance and vasodilation function or improving ventricular-arterial coupling.

Clusters in the literature

Table 4 presents some of the main studies using clustering analysis in HF. No specific phenotype seems to perfectly fit every study, but some similarities can be noted. Cluster 3 in the studies by Shah et al. [START_REF] Shah | Phenomapping for novel classification of heart failure with preserved ejection fraction[END_REF] and Horiuchi et al. [START_REF] Horiuchi | Identifying novel phenotypes of acute heart failure using cluster analysis of clinical variables[END_REF] and our cluster 3 share the same high level of cardiac remodelling and AF in older patients. Obesity and diabetes coexist in each study, supporting the insulin resistance concept. The main difference concerns the youngest part of the population, with a predominance of men in our study, and of women in the phenomapping study. The relative homogeneity of the E/e' ratio, tricupsid regurgitation and right ventricular function in our analysis may be explained the absence of statistical prognostic value in the study.

Another explanation may be the harmonious management of patients in the KaRen study, without any specific intervention adapted to a particular phenotype. Indeed, in another trial, Ahmad et al. [START_REF] Ahmad | Clinical implications of chronic heart failure phenotypes defined by cluster analysis[END_REF] found a significant prognostic difference between four clusters extracted from a HFrEF cohort, when an exercise training programme was applied to the population. Testing a specific intervention in different phenotypes may highlight positive results in terms of morbimortality for some subgroups previously defined.

Study limitations

A complete and analysable echocardiographic recording was unfortunately only available for 356/539 patients (66%). No significant prognostic difference was found between clusters. At first glance, the conclusion appears to be only negative, with prognostic heterogeneity still to be proven. However, from another point of view, this statement reinforces our misunderstanding of this pathology and the lack of effective treatments.

Conclusions

HFpEF is a heteregenous syndrome, with complex entanglement between multiple co-morbidites and cellular and molecular remodelling, all sharing the same initial phenomenon -systemic inflammation.

The lack of effective therapy influences current and perhaps future trials, targeting the approach of "selected therapy" for "specific phenotype".

Cluster analysis applied to a well-known HFpEF cohort seems to be effective at individualizing new phenotypes with different characteristics, emphasizing a common physiopathology. Further studies are needed to prove the clinical relevance of these results, and their implications for the therapeutic strategy in patients.

Sources of funding

None. a Two-dimensional strain, mean peak.

  Abbreviations: 2D, two-dimensional; AF, atrial fibrillation; EF, ejection fraction; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LA, left atrial.

Figure 1 .

 1 Figure 1. Stacked bar chart of outcomes by clusters. CV: cardiovascular.

Figure 2 .

 2 Figure 2. Kaplan-Meier survival free of cardiovascular (CV) hospitalization or death.

Figure 3 .

 3 Figure 3. Kaplan-Meier survival curve.

Table 1

 1 Variables that served as features for the clustering analysis, including clinical variables, physical characteristics, laboratory data and

	echocardiographic variables.
	Domain	Variables
	Demographics	Age, sex
	Physical characteristics	Body mass index, sinus rhythm
	Medical history	Renal insufficiency, COPD, arterial hypertension, diabetes mellitus
	Laboratory	Haemoglobin
	Echocardiography
	Left heart structure	LV end-diastolic volume, LV end-systolic volume, LV end-diastolic diameter, LV end-systolic diameter, septal wall thickness,
		LV mass, LV fractional shortening, LA volume, LA diameter
	LV systolic function	LVEF
		LV pre-ejection time interval, LV ejection time duration
	LV diastolic function	Mitral inflow characteristics (E-wave deceleration time, end-diastolic mitral inflow A -wave, E/A ratio, IVRT, mitral inflow
		velocity time integral, mitral inflow duration/cycle length)
		Tissue Doppler characteristics (e′ velocities, LV septal e' velocity, E/e′ ratio)
		E-wave/LV end-diastolic peak
	Right heart structure RV diameter
	RV function	RV fractional area change, TAPSE, RV shortening

2D: two-dimensional; COPD: chronic obstructive pulmonary disease; DTI: Doppler tissue imaging; IVRT: isovolumic relaxation time; LV: left ventricular; LVEF: left ventricular ejection fraction; LVOT: left ventricular outflow tract; RV: right ventricular; TAPSE: tricuspid annular plane systolic excursion.

Table 2

 2 Patient characteristics across clusters.

	Characteristics	Missing values	Total	Cluster 1	Cluster 2	Cluster 3	P
			(n = 356)	(n = 128)	(n = 134)	(n = 94)
	Male sex	0	155 (43.5)	77 (60.2)	42 (31.3)	36 (38.3)	< 0.0001
	Age (years)	0	76.1 ± 9.31	73.8 ± 10.3	76.7 ± 9.36	78.3 ± 6.92	0.0010
	Body mass index (kg/m²)	17 (4.77)	28.5 ± 6.48	31.2 ± 6.55	28.6 ± 6.17	28.5 ± 5.81	0.0009
	Haemoglobin (g/L)	8 (2.25)	123 ± 20	118 ± 21	125 ± 17	126 ± 18	0.0048
	Renal insufficiency	6 (1.68)	159 (45.4)	77 (60.2)	47 (35.1)	35 (37.2)	< 0.0001
	Sinus rhythm at enrolment	33 (9.27)	182 (56.3)	113 (88.3)	90 (67.2)	12 (12.8)	< 0.0001
	COPD	0	45 (12.6)	14 (10.9)	19 (14.2)	12 (12.8)	0.73
	Hypertension	1 (0.28)	282 (79.4)	114 (89.1)	98 (73.1)	71 (75.5)	0.0033
	Diabetes mellitus	0	115 (32.3)	77 (60.2)	16 (11.9)	22 (23.4)	< 0.0001
	Mitral regurgitation	16 (4.49)					0.0002
	0		74 (21.8)	42 (32.8)	22 (16.4)	10 (10.6)
	1		186 (54.7)	69 (53.9)	80 (59.7)	53 (56.4)
	2		59 (17.3)	14 (10.9)	24 (17.9)	21 (22.3)
	3-4		21 (6.18)	3 (2.3)	8 (6.0)	10 (10.6)
	RV pre-ejection time interval (ms)	28 (7.86)	84.2 ± 24.1	80.1 ± 24.3	82.4 ± 22.5	92.3 ± 20.5	0.0003

Data are expressed as number (%) or mean ± standard deviation. COPD: chronic obstructive pulmonary disease; IVST: interventricular septal thickness; LA: left atrial; LV: left ventricular; RV: right ventricular; TAPSE: tricuspid annulus plan systolic excursion.

Table 3

 3 Main features of the clusters.

	Cluster 1	Young, male, history of hypertension, diabetes mellitus, impaired renal function,
		obesity, sinusal rhythm, anaemia
	Cluster 2	Female, preserved LV systolic function, less renal dysfunction, moderate atrial
		remodelling
	Cluster 3	Elderly, female, rhythm disorders, midly impaired LV systolic function (GLS), atrial
		remodelling, mitral regurgitation
	GLS : global longitudinal strain; LV: left ventricular.

Table 4

 4 Clustering in heart failure research. BNP: B-type natriuretic peptide; CKD: chronic kidney disease; HF: heart failure; HFmrEF: heart failure with mid-range ejection fraction; HFpEF: heart

	Study	Pathology	Cluster 1	Cluster 1	Cluster 1	Cluster 1	Prognosis
	Shah et al. [13]	Chronic HFpEF	Young, female, low BNP,	Obesity, diabetes mellitus,	Oldest, CKD, AF, high	-	Cluster 1 > 2 > 3
	(n = 397)		low cardiac	OSA, worst relaxation,	cardiac remodelling
			remodelling/dysfunction	high pulmonary pressure	(mass, LA dilatation, E/e'),
					worst RV function
	Horiuchi et al.	Acute HF	"Vascular": hypertension,	"Cardiac": male, CKD,	"HFpEF": oldest, anaemia,	-	Cluster 1 > 2 and 3
	[12] (n = 345)		diabetes mellitus, mildly	BNP, impaired diastolic	AF, HFpEF or HFmrEF
			impaired systolic function,	and systolic function
			high LV mass
	Ahmad et al.	Chronic HFrEF	Eldest, caucasian, ICM,	Young, obese, less ICM,	Caucasian, ICM, angina,	Caucasian, female,	Death, ++ cluster 1;
	[11] (n = 1619)		co-morbidites	low BNP, African,	hospitalization	non-ICM, low rates of	hospitalization, +++
				hospitalization		co-morbidities	clusters 1 & 3
	Schrub et al. (n	Chronic HFpEF	Young, male, obesity,	Female, preserved LV	Eldest, female, AF, midly	-	No statistical
	= 356)		hypertension, CKD,	function, moderate atrial	impaired systolic function,		difference
			anaemia, LV mass, low	remodelling	atrial remodelling, mitral
			atrial remodelling		regurgitation
	AF: atrial fibrillation;

failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; ICM: ischaemic heart disease; LA: left atrial; LV: left ventricular; OSA: obstructive sleep apnoea; RV: right ventricular.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.


Rémi Adelin

Eric Alata

Vincent Migliore

Vincent Nicomette

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