Franck Touret
email: franck.touret@univ-amu.fr

Xavier De Lamballerie
email: xavier.de-lamballerie@univ-amu.fr

Of Chloroquine and COVID-19

Keywords: SARS-CoV-2, COVID-19, 2019-nCoV, Chloroquine, antiviral

Recent publications have brought attention to the possible benefit of chloroquine, a broadly used antimalarial drug, in the treatment of patients infected by the novel emerged coronavirus (SARS-CoV-2). The scientific community should consider this information in light of previous experiments with chloroquine in the field of antiviral research.

Recent publications have brought attention to the possible benefit of chloroquine, a broadly used antimalarial drug, in the treatment of patients infected by the novel emerged coronavirus (SARS-CoV-2) [START_REF] Colson | Chloroquine for the 2019 novel coronavirus SARS-CoV-2[END_REF][START_REF] Gao | Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies[END_REF]. The scientific community should consider this information in light of previous experiments with chloroquine in the field of antiviral research.

The sulfate and phosphate salts of chloroquine have both been commercialised as antimalarial drugs. Hydroxychloroquine has also been used as an antimalarial, but in addition is now broadly used in autoimmune diseases such as lupus and rheumatoid arthritis. Of note, chloroquine and hydroxychloroquine are considered to be safe and side-effects are generally mild and transitory. However, the margin between the therapeutic and toxic dose is narrow and chloroquine poisoning has been associated with cardiovascular disorders that can be lifethreatening [START_REF] Frisk-Holmberg | Chloroquine intoxication [letter[END_REF]. Chloroquine and hydroxychloroquine use should therefore be subject to strict rules, and self-treatment is not recommended.

The in vitro antiviral activity of chloroquine has been identified since the late 1960's [START_REF] Inglot | Comparison of the antiviral activity in vitro of some non-steroidal antiinflammatory drugs[END_REF][START_REF] Miller | Antihistaminics, local anesthetics, and other amines as antiviral agents[END_REF][START_REF] Shimizu | Effect of chloroquine on the growth of animal viruses[END_REF] and the growth of many different viruses can be inhibited in cell culture by both chloroquine and hydroxychloroquine, including the SARS coronavirus [START_REF] Keyaerts | In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine[END_REF]. Some evidence for activity in mice has been found for a variety of viruses, including human coronavirus OC43 [START_REF] Keyaerts | Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice[END_REF], enterovirus EV-A71 [START_REF] Tan | An evaluation of Chloroquine as a broadacting antiviral against Hand, Foot and Mouth Disease[END_REF], Zika virus [START_REF] Li | Chloroquine, a FDA-approved Drug, Prevents Zika Virus Infection and its Associated Congenital Microcephaly in Mice[END_REF] and influenza A H5N1 [START_REF] Yan | Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model[END_REF]. However, chloroquine did not prevent influenza infection in a randomized, double-blind, placebo-controlled clinical trial [START_REF] Paton | Chloroquine for influenza prevention: a randomised, doubleblind, placebo controlled trial[END_REF], and had no effect on dengue-infecteds patient in a randomized controlled trial in Vietnam [START_REF] Tricou | A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults[END_REF]. Chloroquine was also active ex vivo but not in vivo in the case of ebolavirus in mice [START_REF] Dowall | Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model[END_REF][START_REF] Falzarano | Lack of protection against ebola virus from chloroquine in mice and hamsters[END_REF], Nipah [START_REF] Pallister | Chloroquine Administration Does Not Prevent Nipah Virus Infection and Disease in Ferrets[END_REF] and influenza virus [START_REF] Vigerust | Chloroquine is effective against influenza A virus in vitro but not in vivo[END_REF] in ferrets.

The case of chikungunya virus (CHIKV) is of specific interest: chloroquine showed promising antiviral activity in vitro [START_REF] Coombs | Effects of chloroquine and cytochalasin B on the infection of cells by Sindbis virus and vesicular stomatitis virus[END_REF][START_REF] Delogu | Chikungunya disease and chloroquine treatment[END_REF], but was shown to enhance alphavirus replication in various animal models [START_REF] Maheshwari | Chloroquine enhances replication of Semliki Forest virus and encephalomyocarditis virus in mice[END_REF][START_REF] Roques | Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection[END_REF][START_REF] Seth | Acceleration of viral replication and upregulation of cytokine levels by antimalarials: implications in malaria-endemic areas[END_REF], most probably because of the immune modulation and anti-inflammatory properties of chloroquine in vivo [START_REF] Connolly | Alteration of interleukin-1 activity and the acute phase response in adjuvant arthritic rats treated with disease modifying antirheumatic drugs[END_REF][START_REF] Katz | Re-evaluation of antimalarials in treating rheumatic diseases: re-appreciation and insights into new mechanisms of action[END_REF][START_REF] Savarino | Effects of chloroquine on viral infections: an old drug against today's diseases[END_REF]. In a nonhuman primate model of CHIKV infection, chloroquine treatment was shown to exacerbate acute fever and delay the cellular immune response, leading to an incomplete viral clearance [START_REF] Roques | Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection[END_REF]. A clinical trial conducted during the chikungunya outbreak in 2006 in Réunion Island showed that oral chloroquine treatment did not improve the course of the acute disease [START_REF] De Lamballerie | On chikungunya acute infection and chloroquine treatment[END_REF] and that chronic arthralgia on day 300 post-illness was more frequent in treated patients than in the control group [START_REF] Roques | Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection[END_REF]. Altogether, the assessment of previous trials indicates that, to date, no acute virus infection has been successfully treated by chloroquine in humans.

Chloroquine has also been tested in chronic viral diseases. Its use in the treatment of HIV-infected patients has been considered inconclusive [START_REF] Chauhan | The enigma of the clandestine association between chloroquine and HIV-1 infection[END_REF] and the drug has not been included in the panel recommended for HIV treatment. The only modest effect of chloroquine in the therapy of human virus infection was found for chronic hepatitis C: an increase of the early virological response to pegylated interferon plus ribavirin [START_REF] Helal | Hydroxychloroquine augments early virological response to pegylated interferon plus ribavirin in genotype-4 chronic hepatitis C patients[END_REF] and, in a small sample size pilot trial in non-responder HCV patients, a transient viral load reduction [START_REF] Peymani | New use of an old drug: chloroquine reduces viral and ALT levels in HCV non-responders (a randomized, triple-blind, placebo-controlled pilot trial)[END_REF] were observed. This was not enough to include chloroquine in the standardised therapeutic protocols for hepatitis C patients.

Recently, Wang and colleagues [START_REF] Wang | Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro[END_REF] evaluated in vitro five FDAapproved drugs and two broad spectrum antivirals against a clinical isolate of SARS-CoV-2.

One of their conclusions was that "chloroquine (is) highly effective in the control of 2019-nCoV infection in vitro" and that its "safety track record suggests that it should be assessed in human patients suffering from the novel coronavirus disease". At least 16 different trials for SARS-CoV-2 already registered in the Chinese Clinical Trial Registry (ChiCTR2000029939, ChiCTR2000029935, ChiCTR2000029899, ChiCTR2000029898, ChiCTR2000029868, ChiCTR2000029837, ChiCTR2000029826, ChiCTR2000029803, ChiCTR2000029762, ChiCTR2000029761, ChiCTR2000029760, ChiCTR2000029741, ChiCTR2000029740, ChiCTR2000029609, ChiCTR2000029559, ChiCTR2000029542) propose to use chloroquine or hydroxychloroquine in the treatment of COVID-19 ("Chinese Clinical Trial Register" (ChiCTR)). In a recent publication [START_REF] Gao | Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies[END_REF], Gao and colleagues indicate that, "according to the news briefing", "results from more than 100 patients have demonstrated that chloroquine phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus negative conversion, and shortening the disease course". This would represent the first successful use of chloroquine in humans for the treatment of an acute viral disease, and is undoubtedly excellent news, since this drug is cheap and widely available. However, it should be considered carefully before drawing definitive conclusions, since no data has been provided yet to support this announcement. Results were produced in ten different hospitals and possibly from a number of different clinical protocols among those listed above, which include various designs for control groups (none, different antivirals, placebo, etc.) and various outcome primary indicators. The final interpretation is therefore technically demanding, and in the absence of published data, it is difficult to reach any firm conclusion. It will be of the utmost importance to know if the observed efficacy is associated specifically with chloroquine phosphate, or if this includes other salts (e.g., sulfate) of chloroquine, and hydroxychloroquine. It is also necessary to determine if the benefit of chloroquine therapy depends on the age class, the clinical presentation or the stage of the disease.

In conclusion, the option of using chloroquine in the treatment of SARS-CoV-2 should be examined with attention in light of the recent promising announcements, but also of the potential detrimental effect of the drug observed in previous attempts to treat acute viral diseases. We urge Chinese scientists to report the interim trial results currently running in China as soon as they are available. This should be preferentially done in a peer-reviewed publication with detailed information to allow the international scientific community to analyse the results, to confirm in prospective trials the efficacy of the proposed treatment and to guide future clinical practice.


María-José Valero-Pedraza

Damien Alligier

Eddy Petit

Didier Cot

Dominique Granier

Karim Adil

Pascal G Yot

Umit B Demirci
email: umit.demirci@umontpellier.fr

Diammonium tetraborate dihydrate as hydrolytic by-product of ammonia borane in aqueous alkaline conditions

Keywords: Ammonia borane, Borate, Hydrogen storage, Hydrolysis, Polyborate, Tetraborate

Introduction

Ammonia borane NH3BH3 (AB) is a prominent boron-based material in the field of chemical hydrogen storage. Though known since the middle of the last century [START_REF] Li | Ammonia borane, past as prolog[END_REF], the interest in it, for the mentioned application, started in the mid-2010s, especially as a result of two pioneering works.

On the one hand, Gutowska et al. [START_REF] Gutowska | Nanoscaffold mediates hydrogen release and the reactivity of ammonia borane[END_REF] demonstrated that the dehydrogenation properties of AB under heating are substantially improved when a nanoscaffold (e.g. mesoporous silica) is used to destabilize it. On the other hand, Chandra and Xu [START_REF] Chandra | A high-performance hydrogen generation system: Transition metalcatalyzed dissociation and hydrolysis of ammonia-borane[END_REF] showed that rapid dehydrogenation of AB is feasible, at ambient conditions, by dissociation and catalytic hydrolysis. Since then, dehydrogenation of AB by thermolysis or hydrolysis has been widely investigated, each of these approaches having their own advantages and drawbacks [START_REF] Smythe | Ammonia borane as a hydrogen carrier: Dehydrogenation and regeneration[END_REF][START_REF] Demirci | Ammonia borane, a material with exceptional properties for chemical hydrogen storage[END_REF][START_REF] Demirci | About the technological readiness of the H2 generation by hydrolysis of B(-N)-H compounds[END_REF].

Before AB, another boron-based material, namely sodium borohydride NaBH4, showed interesting dehydrogenation properties by hydrolysis [START_REF] Kojima | Hydrogen generation using sodium borohydride solution and metal catalyst coated on metal oxide[END_REF]. AB was suggested to be a good alternative mainly because NaBH4 is not stable in aqueous solution [START_REF] Bartkus | A semi-global reaction rate model based on experimental data for the self-hydrolysis kinetics of aqueous sodium borohydride[END_REF]. For example, Chandra and Xu [START_REF] Chandra | Dissociation and hydrolysis of ammonia-borane with solid acids and carbon dioxide: An efficient hydrogen generation system[END_REF] reported that a slightly concentrated (0.1 M) solution of AB (pH of 9.1) kept under argon atmosphere is fairly stable and, above all, much more stable than a NaBH4 solution. Hence, hydrolysis of AB requires a catalyst to generate H2 with fast kinetics [START_REF] Chandra | A high-performance hydrogen generation system: Transition metalcatalyzed dissociation and hydrolysis of ammonia-borane[END_REF], which has given rise to great efforts in developing a lot of active catalysts [START_REF] Jiang | Catalytic hydrolysis of ammonia borane for chemical hydrogen storage[END_REF][START_REF] Muir | Progress in sodium borohydride as a hydrogen storage material: Development of hydrolysis catalysts and reaction systems[END_REF][START_REF] Akbayrak | Ammonia borane as hydrogen storage materials[END_REF][START_REF] Alpaydın | A review on the catalysts used for hydrogen production from ammonia borane[END_REF]. In contrast, other aspects related to the hydrolysis reaction (e.g. effective storage capacity maximization, H2 purity, reaction intermediates analysis, by-products identification) have been far less explored [START_REF] Demirci | Ammonia borane, a material with exceptional properties for chemical hydrogen storage[END_REF][START_REF] Demirci | About the technological readiness of the H2 generation by hydrolysis of B(-N)-H compounds[END_REF].

The basic argument against hydrolysis of NaBH4 is that sodium tetrahydroxyborate NaB(OH)4, the reaction by-product, is awkwardly transformed (i.e. reduced) back into NaBH4 [START_REF] Andersson | Large-scale storage of hydrogen[END_REF]. Simply put, the B-O bond in the anion B(OH)4 -is, roughly, as stable as the C-O bond in CO2 [START_REF] Kildahl | Bond energy data summarized[END_REF], both compounds facing thus comparable conversion challenges. This also applies to AB in hydrolysis, and yet, little is known about its by-products.

Chandra and Xu [START_REF] Chandra | A high-performance hydrogen generation system: Transition metalcatalyzed dissociation and hydrolysis of ammonia-borane[END_REF][START_REF] Chandra | Dissociation and hydrolysis of ammonia-borane with solid acids and carbon dioxide: An efficient hydrogen generation system[END_REF] reported, without further discussion, the formation of boric acid B(OH)3 and of the metaborate anion BO2 -, as well as the formation of other borates that coexist in solution via pH-dependent equilibria:

NH3BH3 (aq) + 2H2O (l) → NH4 + (aq) + BO2 -(aq) + 3H2 (g) (1)
NH3BH3 (aq) + 3H2O (l) → NH3 (aq) + B(OH)3 (aq) + 3H2 (g)

Mohajeri et al. [START_REF] Mohajeri | Hydrolytic cleavage of ammonia-borane complex for hydrogen production[END_REF] corroborated and, added that the by-product in solid state was crystallized B(OH)3. Using in situ 11 B NMR, Liu et al. [START_REF] Liu | Hydrogen generated from hydrolysis of ammonia borane using cobalt and ruthenium based catalysts[END_REF] concluded that the formation of aqueous B(OH)3 (Eq. 2) took place, whereas Rachiero et al. [START_REF] Rachiero | Bimetallic RuCo and RuCu catalysts supported on γ-Al2O3. A comparative study of their activity in hydrolysis of ammonia-borane[END_REF][START_REF] Rachiero | Facile synthesis by polyol method of a ruthenium catalyst supported on γ-Al2O3 for hydrolytic dehydrogenation of ammonia borane[END_REF], stressed on the formation of aqueous B(OH)4 -:

NH3BH3 (aq) + 4H2O (l) → NH4 + (aq) + B(OH)4 -(aq) + 3H2 (g) (3)
Both species, i.e. B(OH)3 and B(OH)4 -, are likely to form and their formation is mainly pHdependent (pKa of B(OH)3/B(OH)4 -equal to 9.1). Rachiero et al. [START_REF] Rachiero | Bimetallic RuCo and RuCu catalysts supported on γ-Al2O3. A comparative study of their activity in hydrolysis of ammonia-borane[END_REF][START_REF] Rachiero | Facile synthesis by polyol method of a ruthenium catalyst supported on γ-Al2O3 for hydrolytic dehydrogenation of ammonia borane[END_REF] and Hannauer et al. [START_REF] Hannauer | Enhanced hydrogen release by catalyzed hydrolysis of sodium borohydride-ammonia borane mixtures: a solutionstate 11 B NMR study[END_REF] suggested reactions between the B(OH)3 and B(OH)4 -entities, resulting in equilibria with polyborate species like B3O3(OH)4 -. The following path was notably suggested:

2B(OH)3 (aq) + B(OH)4 -(aq) ↔ B3O3(OH)4 -(aq) + 3H2O (l) (4)
For the solid recovered after water extraction, they identified, by pattern matching, ammonium tetraborate tetrahydrate (NH4)2B4O7⋅4H2O. Ramachandran and Gagare [START_REF] Ramachandran | Preparation of ammonia borane in high yield and purity, methanolysis, and regeneration[END_REF] studied a concentrated AB solution (10.8 M). A crystallized borate salt was recovered and, by X-ray crystallography, its structure was determined, at 50% probability, as ammonium tetraborate hydrate (NH4)2B4O5(OH)4⋅1.4H2O. Moussa et al. [START_REF] Moussa | Borates in hydrolysis of ammonia borane[END_REF] prepared a set of borates by extraction of water at different temperatures (-50, 0, 80, 120, 200 and 300°C). A series of ammonium pentaborates (e.g. NH4B5O6(OH)4⋅2H2O and NH4B5O6(OH)4) were suggested together with B(OH)3, HBO2 and B2O3 (depending on the temperature). Chou et al. [START_REF] Chou | Hydrogen production from hydrolysis of ammonia borane with limited water supply[END_REF] focused on incomplete hydrolysis of AB, which was performed by using a limited amount of water (less than the stoichiometry in Eq. 3). Mixtures of B(OH)3 and metaboric acid HBO2 were found to be the dominant products in such conditions.

It is important to have a sound understanding of the borates forming by hydrolysis of AB. Borates form, but their nature depends on a number of experimental factors (AB concentration, solution pH, water amount, atmosphere, water extraction and drying processes). On another note, AB is not so stable in aqueous alkaline solution. For example, a careful analysis of the 11 B NMR data reported by Chandra and Xu [START_REF] Chandra | A high-performance hydrogen generation system: Transition metalcatalyzed dissociation and hydrolysis of ammonia-borane[END_REF][START_REF] Chandra | Dissociation and hydrolysis of ammonia-borane with solid acids and carbon dioxide: An efficient hydrogen generation system[END_REF] shows at least one additional signal at a positive chemical shifts, which was due to a borate species. Hence, we initiated a new study aiming at recovering and analyzing crystallized borates forming by spontaneous hydrolysis of AB (10 M). We isolated crystals of diammonium tetraborate dihydrate (NH4)2B4O5(OH)4⋅2H2O (263.39 g mol -1 ). This compound is a less-hydrated ammonium analog of borax Na2B4O5(OH)4⋅8H2O (disodium tetraborate octahydrate). Our results are described hereafter and discussed to bring elements of response to the questions concerning storage of AB in aqueous solution.

Experimental

Ammonia borane NH3BH3 (borane-ammonia complex; CAS number 13774-81-7; 97% from Merck) was stored in an argon-filled glove box (MBraun M200B; O2 and H2O < 0.1 ppm).

Sodium hydroxide NaOH (CAS number 1310-73-2; from Alfa Aesar) was also used as received.

With respect to deionized ultra-pure water (Milli-Q grade, resistivity > 18 MΩ cm), it was systematically bubbled with argon just after extraction from our purification system, and it was used to prepare an alkaline solution (pH adjusted at 8) under argon flux. All of the solutions were in fact kept under argon atmosphere to avoid dissolution of carbon dioxide CO2 from air and subsequent formation of carbonic acid H2CO3:

H2O (l) + CO2 (g) ↔ H2CO3 (aq) (5a)
H2CO3 (aq) + H2O (l) ↔ H3O + (aq) + HCO3 -(aq) (5b)

The NH3BH3 solution (10 M) was prepared as follows. In the glove box, 308 mg of NH3BH3 was weighted and transferred in a vial which was sealed with a septum. Under argon, 1 mL of the aqueous alkaline solution was injected through the septum. After complete dissolution of NH3BH3, the sealed vial, under an argon atmosphere, was put in a heat chamber initially at 35 °C (dark conditions). The temperature of the chamber was decreased by 1 °C every week. Degassing (to evacuate the generated H2) was performed when the septum got curved, which was done by briefly puncturing the septum. Crystals were visible when the temperature dropped below 25 °C.

They were extracted from the solution and transferred in a clean vial (in the glove box). They were put under vacuum overnight and finally stored under argon atmosphere.

The crystals were visualized using a digital microscope Microloop. The data collection was performed at -173 °C and at ambient temperature. The asobtained unit cell and space group showed that the structures were identical. We therefore decided to report the data collected at -173 °C. The single crystal X-ray diffraction allowed collecting a total of 1496 frames. The total exposure time was 8.31 h. The frames were integrated with the Bruker SAINT Software package using a narrow-frame algorithm. The integration of the data using a monoclinic unit cell yielded a total of 4196 reflections to a maximum θ angle of 55.06° (resolution of 0.94 Å). The final cell constants (as reported hereafter, in sub-section 3.4) are based upon the refinement of the XYZ-centroids of 3948 reflections above 20 σ(I) with 12.38° < 2θ < 110.1°. The data were corrected for absorption effects using the Multi-Scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.797. The space group was determined using XPREP implemented in APEX3. The structure was solved using SHELXS-97 (direct methods) and refined using SHELXL-2014 (full-matrix least-squares on F 2 ) contained in WinGX. The crystal data, refinement conditions and crystal structure are reported hereafter, in sub-section 3.4.

Results

Preliminary observation

Crystallization (and precipitation) of pure AB generally results in needle-like forms [START_REF] Bowden | The thermal decomposition of ammonia borane: A potential hydrogen storage material[END_REF]. In our conditions, bulky and shaped crystals were recovered. An example is shown in Figure 1. The crystal looks very similar to crystals of ammonium pentaborate (NH4)2O⋅5B2O3⋅8H2O [START_REF] Balakrishnan | Growth, structural, optical, thermal and mechanical properties of ammonium pentaborate single crystal[END_REF]. From this observation, evolution of AB into a borate, by hydrolysis, was assumed to take place.

Hereafter, the as-formed solid will be called borate crystal.

Analysis by spectroscopy

The formation of a borate was first verified by 11 B NMR spectroscopy. Fragments of the borate crystal were solubilized in two different solvents, namely water and methanol (Figure 2). With the former solvent, a singlet peaking at +16.2 ppm is noticed; it is typical of a borate [START_REF] Salentine | High-field 11 B NMR of alkali borates. Aqueous polyborate equilibria[END_REF]. With methanol as solvent, there are two overlapping singlets peaking at +18.8 and +17 ppm. It is likely that some -OH groups of the borate were substituted by -OCH3 groups. The FTIR fingerprint of the borate crystal (Figure 3) is comparable to that of di-, tetra-and penta-borates [START_REF] Jun | FT-IR and Raman spectroscopic study of hydrated borates[END_REF].

Thermal and calorimetric analysis

The thermal behavior of the borate crystal was studied by TG analysis and DSC (Figure 6). The similar energy (67 kJ mol -1 ) was reported for (NH4)2O⋅5B2O3⋅5H2O; this polyborate liberated 2 equiv H2O in a process peaking at 311 °C [START_REF] Balakrishnan | Growth, structural, optical, thermal and mechanical properties of ammonium pentaborate single crystal[END_REF].

Our TG and DSC curves were compared to curves obtained with a compound reported to be ammonium tetraborate tetrahydrate (263.2 g mol -1 ) [START_REF] Demir | Production of granular boron oxide by calcination of ammonium tetraborate tetrahydrate[END_REF]. Unfortunately, there is no detail about its preparation or origins. From the information that can be found on the internet (especially from suppliers of chemicals), this compound would be (NH4)2B4O7⋅4H2O (Figure 7). The comparison shows similarities (Table 1): above 75 °C the TG results are similar; the endothermic signals peak at similar temperatures; there is the co-release of H2O and NH3 over the range 75-400 °C.

The comparison also shows one key difference: with (NH4)2B4O7⋅4H2O, there is a preliminary weight loss, below 75 °C, due to the release of 1 equiv H2O (release of crystal water), which is associated to an endothermic signal peaking at 59 °C. In terms of weight loss measured at 400

°C, the values are roughly comparable: the loss is 43% for the present borate and it is 40.2% for (NH4)2B4O7⋅4H2O (if the dehydration process occurring below 75 °C is not taken into account).

From these observations, it is reasonable to conclude that the borate reported herein and the (NH4)2B4O7⋅4H2O reported elsewhere looks similar, even though our borate has structure water only.

20-400

Weight loss by TG analysis 43 47.1

Structural analysis

A portion of the borate crystal was analyzed by single crystal X-ray diffraction. The crystal data and the refinement conditions are shown in Table 2. In good agreement with the results reported above, the borate crystal was identified to be an ammonium polyborate salt of formulae (NH4)2B4O5(OH)4⋅2H2O (diammonium tetraborate dihydrate; 263.39 g mol -1 ). The crystal system is monoclinic, and the space group is P21. The cell constants were found to be such as: a = Diammonium tetraborate dihydrate is structured around the anion B4O5(OH)4 2-(Figure 9), as is the case for borax [START_REF] Gainsford | Redetermination of the borax structure from laboratory X-ray data at 145 K[END_REF]. They both crystallize in monoclinic system, but they have different space groups (P21 and C2/c respectively). Diammonium tetraborate dihydrate is comparable to the compound reported by Ramachandran and Gagare [START_REF] Ramachandran | Preparation of ammonia borane in high yield and purity, methanolysis, and regeneration[END_REF]. They suggested the formulae (NH4)2B4O5(OH)4⋅1.4H2O, which was crystallographically determined at 50% probability. Our

Discussion

In our conditions, the concentrated solution of AB (10 M) evolved towards formation and precipitation of diammonium tetraborate dihydrate (NH4)2B4O5(OH)4⋅2H2O. For diluted solutions of AB, the main products are generally B(OH)3 and B(OH)4 -. Depending on the experimental conditions, especially the pH, these two species were suggested to coexist [START_REF] Chandra | A high-performance hydrogen generation system: Transition metalcatalyzed dissociation and hydrolysis of ammonia-borane[END_REF][START_REF] Chandra | Dissociation and hydrolysis of ammonia-borane with solid acids and carbon dioxide: An efficient hydrogen generation system[END_REF][START_REF] Mohajeri | Hydrolytic cleavage of ammonia-borane complex for hydrogen production[END_REF] or preferentially form (the one at the expense of the other) [START_REF] Liu | Hydrogen generated from hydrolysis of ammonia borane using cobalt and ruthenium based catalysts[END_REF][START_REF] Rachiero | Bimetallic RuCo and RuCu catalysts supported on γ-Al2O3. A comparative study of their activity in hydrolysis of ammonia-borane[END_REF][START_REF] Rachiero | Facile synthesis by polyol method of a ruthenium catalyst supported on γ-Al2O3 for hydrolytic dehydrogenation of ammonia borane[END_REF]. Nevertheless, some form of consensus exists on the fact that, after the hydrolysis reaction, B(OH)3 and B(OH)4 - interact, polyborates form, and equilibria between all of these species take place [START_REF] Chandra | A high-performance hydrogen generation system: Transition metalcatalyzed dissociation and hydrolysis of ammonia-borane[END_REF][START_REF] Chandra | Dissociation and hydrolysis of ammonia-borane with solid acids and carbon dioxide: An efficient hydrogen generation system[END_REF][START_REF] Mohajeri | Hydrolytic cleavage of ammonia-borane complex for hydrogen production[END_REF][START_REF] Liu | Hydrogen generated from hydrolysis of ammonia borane using cobalt and ruthenium based catalysts[END_REF][START_REF] Rachiero | Bimetallic RuCo and RuCu catalysts supported on γ-Al2O3. A comparative study of their activity in hydrolysis of ammonia-borane[END_REF][START_REF] Rachiero | Facile synthesis by polyol method of a ruthenium catalyst supported on γ-Al2O3 for hydrolytic dehydrogenation of ammonia borane[END_REF][START_REF] Moussa | Borates in hydrolysis of ammonia borane[END_REF].

In fact, this is a well-documented property of B(OH)3 and B(OH)4 -. For instance, Spessard [START_REF] Spessard | Investigations of borane equilibria in neutral salt solutions[END_REF] and Mesmer et al. [START_REF] Mesmer | Acidity measurements at elevated temperatures. VI. Boric acid equilibria[END_REF] in the 1970s, and more recently Zhou et al. [START_REF] Zhou | Polyborates in aqueous borate solution at 298.15 K[END_REF], investigated such equilibria in different conditions (pH, in the presence of neutral salt, at elevated temperature). It It is of interest to discuss the two "free" NH3 molecules shown in Eq. 6d. They can pass in the gas phase, being then liberated together with H2 generated by hydrolysis, as reported elsewhere [START_REF] Liu | Hydrogen generated from hydrolysis of ammonia borane using cobalt and ruthenium based catalysts[END_REF][START_REF] Ramachandran | Preparation of ammonia borane in high yield and purity, methanolysis, and regeneration[END_REF][START_REF] Brockman | A study of catalytic hydrolysis of concentrated ammonia borane solutions[END_REF]. This causes problems. The first one is related to the pollution of the H2 stream [START_REF] Uribe | Effect of ammonia as potential fuel impurity on proton exchange membrane fuel cell performance[END_REF].

Purification is then required which is detrimental to the cost of the technology. The second problem can be discussed in terms of "green chemistry" [START_REF] Anastas | Green chemistry: principles and practice[END_REF]. Loss of the aforementioned NH3 molecules runs counter to the "green chemistry" principles like the following ones: "prevent waste", "maximize atom economy", "design chemicals and products to degrade after use".

As briefly mentioned in the introduction, sodium borohydride in hydrolytic conditions has been criticized because of its instability in water at any pH [START_REF] Bartkus | A semi-global reaction rate model based on experimental data for the self-hydrolysis kinetics of aqueous sodium borohydride[END_REF]. AB was then presented as a stable alternative and it has been widely investigated. However, AB also evolves, spontaneously, in aqueous alkaline solution (i.e. in the absence of a catalyst). In our conditions, the AB concentration is high (10 M), which is realistic from the point of the view of a possible technological application. In such conditions, crystals of (NH4)2B4O5(OH)4⋅2H2O precipitate after some days. In other words, AB in hydrolytic conditions should encounter the same problems as sodium borohydride [START_REF] Lapena-Rey | A fuel cell powered unmanned aerial vehicle for low altitude surveillance missions[END_REF], namely, difficult long-term storage of concentrated AB solutions because of evolution by hydrolysis, safety issues because of uncontrolled generation of H2, and plugging of storage system pipes due to precipitation of borate crystals.

Little efforts have been focused on the identification of the condition-dependent borate products and, in conjunction with this, on the development of AB-dedicated recycling and regeneration approaches [START_REF] Demirci | Ammonia borane, a material with exceptional properties for chemical hydrogen storage[END_REF][START_REF] Demirci | About the technological readiness of the H2 generation by hydrolysis of B(-N)-H compounds[END_REF]. Here, we have shown the precipitation of (NH4)2B4O5(OH)4⋅2H2O. It is an analog of borax Na2B4O5(OH)4⋅2H2O. Borax is the boron source in the process leading to the production of NaBH4 via the so-called Brown-Schlesinger process: i.e. acidic attack (H2SO4) of Na2B4O5(OH)4⋅2H2O to form B(OH)3; reaction of B(OH)3 with methanol resulting in B(OCH3)3; and, reduction of B(OCH3)3 by NaH to get NaBH4 [START_REF] Liu | The concept about the regeneration of spent borohydrides and used catalysts from green electricity[END_REF]. The present (NH4)2B4O5(OH)4⋅2H2O could be directly used to be transformed into NaBH4 by slightly adapting the aforementioned process. Otherwise, the NMR results presented above have shown transformation of (NH4)2B4O5(OH)4⋅2H2O by reaction with methanol. One may assume that B(OCH3)3 formed.

Further works are required to clear up this point; for instance, such B(OCH3)3 might be the key compound of a modified version of the aforementioned Brown-Schlesinger process.

Conclusion

In the present work, we considered an aqueous alkaline solution of concentrated AB (10 M).

Spontaneous hydrolysis of AB took place, resulting in generation of H2 and, formation and precipitation of borate crystals. Aqueous AB is thus not stable, in our conditions, and long-term storage of such a fuel appears to be difficult. The borate crystals were isolated to be analyzed by various techniques, and the collected data indicated the formation of diammonium tetraborate dihydrate (NH4)2B4O5(OH)4⋅2H2O (263.39 g mol -1 ), an ammonium analog of borax Na2B4O5(OH)4⋅8H2O. The crystal structure was solved and was found to be as follows: In hydrolytic conditions, AB can be compared to NaBH4. The present work has shown that both encounter the same problems, namely difficult long-term storage of their aqueous alkaline solutions, safety issues due to uncontrolled H2 generation, and precipitation of borates. In fact, AB in hydrolytic conditions encounters another problem. More than one borate seems to form, depending on the hydrolysis conditions. This is an issue from the recycling point of view. Further works are required to clear up this point, mainly because the industrial future of AB, if any, will be entirely dependent on its regeneration from its various borate by-products.

Figure 1 .

 1 Figure 1. Digital microscope observation of one of our millimeter-scale borate crystals recovered after hydrolysis of AB in alkaline conditions: magnification ×100; angle of rotation 0°; scale bar 100 µm.

Figure 2 .

 2 Figure 2. 11 B NMR spectra of the borate crystal in water and in methanol.

Figure 3 .

 3 Figure 3. FTIR spectrum of the borate crystal (* for O-H bonds involved in hydrogen bonding).

  Stretching and deformation modes for B-O, O-H (including O-H involved in hydrogen bonding), B-O-H, and N-H bonds can be seen. They confirm the transformation of AB into a borate species.Similar observations can be made for the Raman spectrum (Figure4). Otherwise, there is an intense band at 583 cm -1 due to B-O bonds. Interestingly, it matches the band due to B-O bonds found in the anion B4O5(OH)4 2-[START_REF] Applegarth | Raman spectroscopic and ab initio investigation of aqueous boric acid, borate, and polyborate speciation from 25 to 80°C[END_REF][START_REF] Peng | Investigations on Mg-borate kinetics and mechanisms during evaporation, dilution and crystallization by Raman spectroscopy[END_REF], and specifically in borax Na2B4O5(OH)4⋅8H2O[START_REF] Kipcak | Characterisation and determination of the neutron transmission properties of sodium-calcium and sodium borates from different regions in Turkey[END_REF].

Figure 4 .

 4 Figure 4. Raman spectrum of the borate crystal.

Figure 5 .

 5 Figure 5. XPS spectra of the borate crystal: i.e. survey scan, and focuses on B (1s), N (1s) and O (1s).

  released gases were analyzed by MS (Figure 6) and the following m/z values were collected (in order of the signals intensity): 17, 18, 16 and 15. The intensity of the signal m/z = 18 is comparable to that of the signal m/z = 17. For pure H2O, the relative intensity between these two signals should have been 5:1. In our conditions, the relative intensity is close to 1. Our results thus indicate that H2O (with m/z = 18, 17 and 16) formed by dehydration and NH3 (with m/z = 17, 16 and 15) formed by deammoniation. Similar observations are reported elsewhere, for the thermal decomposition of (NH4)2O⋅5B2O3⋅8H2O [25].

Figure 7 .

 7 Figure 7. (a) B4O7 2-anion of (NH4)2B4O7⋅4H2O in ref. [32]. (b) B4O5(OH)4 2-anion of (NH4)2B4O5(OH)4⋅2H2O of the present work and of the borax mineral Na2B4O5(OH)4⋅10H2O.

7 .

 7 15996(6) Å, b = 10.6344(9) Å, c = 7.2331(6) Å, β = 98.593(3)°, V = 544.55(5) Å 3 . The crystal structure is shown in Figure 8.

(

  NH4)2B4O5(OH)4⋅2H2O and the (NH4)2B4O5(OH)4⋅1.4H2O are isostructural (monoclinic, s.g. P21). The cell constants of (NH4)2B4O5(OH)4⋅1.4H2O were calculated as being as follows: a = 7.1997(8) Å, b = 10.6039(6) Å, c = 7.2604(8) Å, β = 98.537(6)°, V = 548.153 Å 3 .

Figure 8 .

 8 Figure 8. Crystal structure of the borate crystal (NH4)2B4O5(OH)4⋅2H2O along the a, b and c crystallographic axes. The pink, green, red and blue spheres correspond to the H, B, O and N atoms respectively.

Figure 9 .

 9 Figure 9. The B4O5(OH)4 2-anion of the diammonium tetraborate dihydrate, consistently with the molecular structure shown in Figure 7b. The NH4 + cations and the two H2O molecules are also shown.

  monoclinic, space group P21, Z = 2, a = 7.15996(6) Å, b = 10.6344(9) Å, c = 7.2331(6) Å, β = 98.704(3) °, V = 544.5(5) Å 3 . Diammonium tetraborate dihydrate is a new borate. It was not known as a possible borate forming by hydrolysis of AB. Henceforth, it contributes to expanding the list of the possible borate by-products coming from AB.

  Bruker AVANCE-300; probe head BBO10, 96.29 MHz, D2O in a capillary tube) was used to analyze the solutions obtained by dissolution of the crystals in deionized water and methanol (CAS number 67-56-1; ≥99.9% from Merck).

(Keyence VHX-6000) and, analyzed by different techniques: Fourier transform infrared (FTIR) spectroscopy (FTIR; IS50 Thermo Fisher Scientific); Raman spectroscopy (Horiba Jobin Yvon LabRAM 1B; laser Ar/Kr 100 mW 647.1 nm); X-ray photoelectron spectroscopy (XPS; ESCALAB 250 from Thermo Electron; monochromatic source Al Kα ray 1486.6 eV; analyzed surface of 400 µm diameter; binding energies (BE) of all core levels referred to the C-C of C1s carbon at 284.8 eV); thermogravimetric (TG) analysis (Netzsch STA 449 F1 Jupiter) coupled to mass spectrometry (MS; Netzsch QMS 403D Aëolos Quadro) for gas analysis; and, differential scanning calorimetry (DSC; DSC; Q600, TA Instruments). 11 B nuclear magnetic resonance (NMR) spectroscopy (Part of the as-obtained single crystal was analyzed by X-ray diffraction. X-ray single-crystal structural data were collected on a Bruker D8 VENTURE equipped with a PHOTON II CPAD detector and a microfocus X-ray source with Cu-Kα radiation (λ = 1.54184 Å) operating at 50 kV and 1 mA. A suitable crystal was chosen and mounted on a 150 µm aperture Dual-Thickness

Table 1 .

 1 Comparison of the present borate crystal to (NH4)2B4O7⋅4H2O in reference[START_REF] Demir | Production of granular boron oxide by calcination of ammonium tetraborate tetrahydrate[END_REF], in terms of TG analysis, DSC and MS results.

	Temperature range		The borate crystal	(NH4)2B4O7⋅4H2O
	(°C)		present work	in ref. [32]
		Weight loss (%) by TG analysis	0	6.9
	20-75	DSC peak temperature (°C)		59
		Evolving gases by MS		H2O
		Weight loss (%) by TG analysis	33.2	28.2
	75-250	DSC peak temperature (°C)	109	110
		Evolving gases by MS	H2O and NH3	H2O and NH3
		Weight loss (%) by TG analysis	9.8	12
	251-400	DSC peak temperature (°C)	347	335
		Evolving gases by MS	H2O and NH3	H2O and NH3

Table 2 .

 2 Space group, unit cell parameters, goodness of fit (GoF), R values, and structural parameters for the refined structure of the borate crystal identified to be (NH4)2B4O5(OH)4⋅2H2O.

	Empirical formula		(NH4)2B4O5(OH)4⋅2H2O B4H16N2O11
	Formula weight (g mol -1 )		263.39
	Temperature (°C)		-173
	Wavelength (Å)		1.54178
	Crystal system, space group		Monoclinic, P21
		a (Å)	7.15996(6)
	Unit cell dimensions	b (Å) c (Å)	10.6344(9) 7.2331(6)
		β (°)	98.593(3)
	Cell volume (Å 3 )		544.55(8)
	Z		2
	Calculated density (g cm -3 )		1.606
	Absorption coefficient (mm -1 )		1.42
	F(000)		276
	Crystal size (mm)		0.02 × 0.03 × 0.03
	θ range for data collection (°)		6.2-68.3
	Limiting indices
	Completeness to θ = 68.3°		99.7%
	Refinement method		Full-matrix least-squares on F 2
	Data / restraints / parameters		1989 / 14 /191
	Goodness-of-fit on F 2		1.14
	Final R indices [I > 2σ(I)]		0.036 and 0.039
	R indices (all data)		0105 and 0.114
	Largest diff. peak and hole (e Å -3 )		0.50 and -0.56

-8 ≤ h ≤ 8, -12 ≤ k ≤ 12, -8 ≤ l ≤ 8

Acknowledgments

UBD thanks the Agence Nationale pour la Recherche (ANR) for: (i) the LabEx CheMISyst project called A3 funded within the program "Investissement d'Avenir" with the reference ANR-10-LABX-05-01; (ii) the project called MobiDiC funded within the program "AAP Générique PRC" with the reference ANR-16-CE05-0009.

The thermal decomposition of the borate crystal is stepwise, showing two main weight losses.

From 75 to 250 °C, the borate crystal overcomes a significant loss of H2O and NH3 (33.2% in weight); the process is featured by an endothermic signal (153 kJ mol -1 ) peaking at 109 °C. A roughly comparable energy (187 kJ mol -1 ) was reported for dehydration (3 H2O out of 8) of (NH4)2O⋅5B2O3⋅8H2O, the process peaking at higher temperature (175 °C) [START_REF] Balakrishnan | Growth, structural, optical, thermal and mechanical properties of ammonium pentaborate single crystal[END_REF]. Above 250 °C and up to 400 °C, the borate crystal continues to decompose. The weight loss is less important (9.8%). This event is featured by an endothermic signal (69 kJ mol -1 ) peaking at 347 °C. A


Ali Houeijeh

François Godart

Zakaria Jalal

Caroline Ovaert

François Heitz

Pierre Mauran

Alban-Elouen Baruteau

Lisa Guirguis

Khaled Hadeed

Jean-Benoit Baudelet

Fermeture

Xavier Iriart

Philippe Aldebert

Philippe Acar

Alain Fraisse

Ender Odemis

Clément Karsenty

Jean Benoit Thambo

Sébastien Hascoët

Transcatheter closure of a perimembranous ventricular septal defect with Nit-Occlud Lê VSD Coil: A French multicentre study

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

Nit-Occlud Lê VSD.

Méthodes. -Toutes les procédures de fermeture de CIVpm réalisées en France entre janvier 2015 et décembre 2018 dans les vingt centres spécialisés de prise en charge des cardiopathies congénitales complexes (réseau maladies rare M3C) ont été incluses rétrospectivement et analysées.

Résultats. -46 procédures ont été réalisées dans cinq centres. Les indications de fermeture étaient la surcharge diastolique du ventricule gauche (76%), une dyspnée à l'effort (17.4), un antécédent d'endocardite (4.3) et une hypertension artérielle pulmonaire modérée (2.2%). L'âge médian (interquartile) était de 13.9 (5.7-31.8) ans. Un anévrysme du septum interventriculaire a été observé dans 91.3% des cas . La taille médiane (interquartile) des CIV était de 8 (7-10) mm sur le versant ventriculaire gauche et 5 [START_REF] Butera | Transcatheter closure of perimembranous ventricular septal defects: early and long-term results[END_REF][START_REF] Carminati | Transcatheter closure of congenital ventricular septal defects: results of the European Registry[END_REF][START_REF] Predescu | Complete heart block associated with device closure of perimembranous ventricular septal defects[END_REF] mm sur le versant ventriculaire droit. Le taux de réussite d'implantation de la prothèse était de 87.0 % (IC 95 %, 73.7-95.1 %). Des complications sévères ont été observées chez six patients (13.0 %, IC 95 %, 4.9-26.3 %). L'hémolyse persistante était la complication sévère la plus fréquente (8.7 %, IC 95 % 2.4-20.8 %). Une lésion de la valve aortique a nécessité une valvuloplastie aortique chirurgicale. La survenue de complications est liée à la présence de l'hémolyse (P = 0.001) d'un shunt résiduel (P = 0.007) et la présence de CIV avec anévrysme multi-perforée (P = 0.005). Un shunt résiduel a été documenté dans 40 % des cas juste après l'intervention et 15 % durant le suivi (durée médiane de suivi de 27 mois). Aucun cas de migration de prothèse ni de bloc atrioventriculaire de haut grade n'a été rapporté Conclusion. -La fermeture percutanée de CIVpm avec le coil Nit-Occlud Lê VSD est réalisable chez les grands enfants et les adultes. La présence d'un shunt résiduel important provoquant une hémolyse parfois sévère est une complication redoutable et ne doit pas être tolérée. La place de cette prothèse dans l'algorithme de prise en charge des CIVpm reste controversée. être toléré.

KEYWORDS

Background

Percutaneous perimembranous ventricular septal defect (pmVSD) closure is technically challenging [START_REF] Lock | Transcatheter closure of ventricular septal defects[END_REF]. Others shunt closure techniques, particularly of atrial septal defects and ductus arteriosus, have improved over the last two decades, with the transcatheter method being the preferred option [START_REF] Jalal | Long-Term Outcomes After Percutaneous Closure of Ostium Secundum Atrial Septal Defect in the Young: A Nationwide Cohort Study[END_REF][START_REF] Baruteau | Transcatheter closure of patent ductus arteriosus: past, present and future[END_REF].

However, catheter closure of pmVSD remains controversial. The risk of immediate or delayed complete atrioventricular block (AVB) observed with previous devices has limited the development of this technique [START_REF] Butera | Transcatheter closure of perimembranous ventricular septal defects: early and long-term results[END_REF][START_REF] Carminati | Transcatheter closure of congenital ventricular septal defects: results of the European Registry[END_REF][START_REF] Predescu | Complete heart block associated with device closure of perimembranous ventricular septal defects[END_REF][START_REF] Thanopoulos | Transcatheter closure of perimembranous ventricular septal defects in infants and children using the Amplatzer perimembranous ventricular septal defect occluder[END_REF]. With its low rate of complications, surgical closure is still the preferred approach in France when pmVSD closure is indicated [START_REF] Barrey | Surgical closure of interventricular communications before 2 years of age. Long-term clinical and electrocardiographic course[END_REF]. Previously, most pmVSD in patients without heart failure or pulmonary hypertension (type I and type IIa) were not closed to avoid surgery. In recent years, some studies have shown that adults with these defects have a higher risk of endocarditis, left ventricular diastolic dysfunction, supraventricular arrhythmia and pulmonary hypertension [START_REF] Soufflet | Behavior of unrepaired perimembranous ventricular septal defect in young adults[END_REF][START_REF] Videbaek | Long-Term Nationwide Follow-Up Study of Simple Congenital Heart Disease Diagnosed in Otherwise Healthy Children[END_REF][START_REF] Karonis | Clinical course and potential complications of small ventricular septal defects in adulthood: Late development of left ventricular dysfunction justifies lifelong care[END_REF][START_REF] Goldberg | Long-term Follow-up of "Simple" Lesions -Atrial Septal Defect, Ventricular Septal Defect, and Coarctation of the Aorta[END_REF]. In the same timeframe, other devices have appeared as alternatives to the historic Amplatzer device to close pmVSD, e.g. Amplatzer Duct Occluder 1, Amplatzer Duct Occluder II, Amplatzer Vascular Plug II (Abbott, Chicago, USA), Nit-Occlud Lê VSD Coil (PFM, Koln, Germany) and Cera duct occluder (Lifetech, Shenzen, China) [START_REF] Haas | Interventional VSD-Closure with the Nit-Occlud® Le VSD-Coil in 110 Patients: Early and Midterm Results of the EUREVECO-Registry[END_REF][START_REF] Nguyen | Nit-Occlud Le VSD coil versus Duct Occluders for percutaneous perimembranous ventricular septal defect closure[END_REF][START_REF] Odemis | Transcatheter closure of perimembranous ventricular septal defects using Nit-Occlud® Le VSD coil: early and mid-term results[END_REF][START_REF] Chungsomprasong | The results of transcatheter closure of VSD using Amplatzer® device and Nit Occlud® Le coil[END_REF][START_REF] Ebeid | Percutaneous Closure of Perimembranous Ventricular Septal Defects Using the Second-Generation Amplatzer Vascular Occluders[END_REF][START_REF] Qin | Transcatheter closure of perimembranous ventricular septal defect using a modified double-disk occluder[END_REF][START_REF] Chen | Transcatheter Closure of Intracristal Ventricular Septal Defect With Mild Aortic Cusp Prolapse Using Zero Eccentricity Ventricular Septal Defect Occluder[END_REF].

Currently, surgery remains the preferred technique for pmVSD closure in small children < 1 year old who present with heart failure, and results are excellent. A percutaneous technique may be an alternative in older patients. The Nit-Occlud Lê VSD Coil may be an interesting device for pmVSD closure as it has several advantages: low profile, retrievable device and small introducing sheath. Some reports, including a multicentre European study, have suggested that it is effective and safe for pmVSD closure, without causing complete AVB [START_REF] Haas | Interventional VSD-Closure with the Nit-Occlud® Le VSD-Coil in 110 Patients: Early and Midterm Results of the EUREVECO-Registry[END_REF][START_REF] Nguyen | Nit-Occlud Le VSD coil versus Duct Occluders for percutaneous perimembranous ventricular septal defect closure[END_REF][START_REF] Odemis | Transcatheter closure of perimembranous ventricular septal defects using Nit-Occlud® Le VSD coil: early and mid-term results[END_REF][START_REF] Chungsomprasong | The results of transcatheter closure of VSD using Amplatzer® device and Nit Occlud® Le coil[END_REF]. However, some cases of haemolysis were reported with this coil [START_REF] Odemis | Transcatheter closure of perimembranous ventricular septal defects using Nit-Occlud® Le VSD coil: early and mid-term results[END_REF][START_REF] Chungsomprasong | The results of transcatheter closure of VSD using Amplatzer® device and Nit Occlud® Le coil[END_REF]. Indications and effectiveness of pmVSD closure with the Nit-Occlud Lê VSD Coil remain controversial among the French paediatric cardiology community. We aimed to study the results and outcomes of consecutive cases performed in France to evaluate its feasibility and safety.

Methods

We designed an observational, multicentre, nationwide cohort study. We retrospectively included all cases of percutaneous closure of pmVSD with or without aneurismal tissue using the Nit-Occlud Lê VSD Coil performed in France over the first 3 years of device availability (January 2015 to December 2018) among 20 catheterization laboratories of paediatric and adult congenital cardiology centres.

Selection of patients for pmVSD closure was according to each centre's protocol. We ensured inclusion of all cases by cross-checking with data from the manufacturer.

Written informed consent was obtained from patients or their legal guardians. Demographic data, clinical information and non-cardiac comorbidities were collected.

All patients were examined in a paediatric and congenital cardiology tertiary centre (M3C network for complex congenital heart diseases). Using echocardiography, left ventricle size was measured in a parasternal long-axis view and an apical four-chamber view. Left ventricular end diastolic diameter (LVEDD) Z-score was calculated using the Detroit Formula [START_REF] Pettersen | Regression equations for calculation of z scores of cardiac structures in a large cohort of healthy infants, children, and adolescents: an echocardiographic study[END_REF]. Left ventricle overload was considered significant when the LVEDD Z-score was ≥ 2. Pulmonary pressures were estimated by pulmonary regurgitation, ventricular septal shape and Doppler gradient through the ventricular septal defect (VSD), and then directly during catheterization. The indication for closure was determined by local practitioners.

Percutaneous pmVSD closure with the Nit-Occlud Lê VSD coil was undertaken using a standard method, as has been previously reported [START_REF] Odemis | Transcatheter closure of perimembranous ventricular septal defects using Nit-Occlud® Le VSD coil: early and mid-term results[END_REF][START_REF] Chungsomprasong | The results of transcatheter closure of VSD using Amplatzer® device and Nit Occlud® Le coil[END_REF]. To assess the appropriate device size, leftand right-sided opening of the VSD, aneurysm length and distance to the aortic rim were measured in two-and three-dimensional transthoracic echography and transoesophageal echography (TOE) views, with the largest measurement being recorded. All procedures were performed under general anaesthesia and two-or three-dimensional TOE guidance. Some cases were guided by fusion between echocardiography and fluoroscopy (Echonavigator software®, Phillips) [START_REF] Hadeed | Usefulness of echocardiographic-fluoroscopic fusion imaging in children with congenital heart disease[END_REF]. All procedures were performed by experienced operators and/or with the support of highly trained operators for pmVSD closure. Short 5F and 6F sheaths were introduced in the femoral artery and femoral vein, respectively.

Intravenous heparin (50-100 IU/kg according to the institutional protocol) was given. An angiogram was performed in the left lateral view to measure the VSD. The defect was crossed retrogradely from the arterial route using a multipurpose catheter or a cut pigtail and an exchange guidewire, which was snared in the right side (pulmonary artery or superior vena cava) to create an arteriovenous loop. The device left-side size was selected as at least twice the minimal diameter of the VSD (on the right ventricular side) as measured by echocardiography and angiogram, and equal to or 1-2 mm greater than the diameter of the VSD at the left ventricular opening. The device right-side diameter should be greater than the minimal size. The delivery sheath was introduced from the venous route into the ascending aorta and a Nit-Occlud Lê VSD Coil was usually implanted into the aneurysm under TOE and angiographic control (Fig. 1). In patients without aneurismal tissue, the left side of the coil was implanted in the left side of the ventricular septum and the right side was positioned in the right ventricle. Post-procedure evaluation and follow-up were performed according to local institutional protocols. Generally, clinical, electrocardiographic and echocardiographic assessments were performed within 24 hours, at 1, 6 and 12 months, and yearly thereafter. Complications were classified as minor (category 1 or 2) or severe (category 3 or more) [START_REF] Bergersen | Catheterization for Congenital Heart Disease Adjustment for Risk Method (CHARM)[END_REF]. Medium-term clinical success was defined as successful pmVSD closure without residual shunt, severe complication or device-related aortic or tricuspid valve lesion. Aneurysmal tissue was identified in 42 patients (91.3%). Median (IQR) VSD size was 8 [START_REF] Thanopoulos | Transcatheter closure of perimembranous ventricular septal defects in infants and children using the Amplatzer perimembranous ventricular septal defect occluder[END_REF][START_REF] Barrey | Surgical closure of interventricular communications before 2 years of age. Long-term clinical and electrocardiographic course[END_REF][START_REF] Soufflet | Behavior of unrepaired perimembranous ventricular septal defect in young adults[END_REF][START_REF] Videbaek | Long-Term Nationwide Follow-Up Study of Simple Congenital Heart Disease Diagnosed in Otherwise Healthy Children[END_REF] mm on the left side and 5 (7-10) mm on the right side. The median (IQR) distance to the aortic annulus was 5 (4-6) mm. Multiple-exit pmVSD was described in four cases (8.7%). The median (IQR) LVEDD Z-score was 2.6 (2.0-3.3).

Statistical analysis

In 45 patients (97.8%), one coil was implanted. In eight of these cases, closure was attempted using more than one device (three devices in four patients, two devices in four patients). In two cases, two devices were implanted to close multifenestrated pmVSD.

In one patient, the coil got stuck in the aortic valve before positioning, inducing aortic valve regurgitation, and was retrieved. In five patients, the coil was positioned, but not released, and was removed due to aortic valve regurgitation (n = 1), severe tricuspid regurgitation related to the device (n = 1), significant residual shunt (n = 2) or instability of the device (n = 1).

Overall successful coil implantation was achieved in 40 patients (87.0%, 95% confidence interval [CI] 73.7-95.1%). Procedural characteristics and device sizes are detailed in Table 2.

Residual shunt on angiogram or day 0 echocardiography was identified in 16 patients (40.0% of patients with implanted devices).

Periprocedural complications occurred in 16 cases (34.8%, 95% CI 21.4-50.3%), of which six (13.0%, 95% CI 4.9-26.3%) were severe (mainly severe haemolysis [8.7%, 95% CI 2.4-20.8%]). The most common complication was mechanical haemolysis (n = 8); residual shunt was present in all of these cases. Haemolysis was transient and self-limiting in four patients. In the other four patients, it required blood transfusion and an additional invasive procedure (residual shunt closure with an Amplatzer duct Occluder II in one patient (Fig. 2) and removal of the device and surgical VSD closure in three patients). In one of the surgical VSD closure cases, the device was trapped in the tricuspid valve, which required additional tricuspid valvuloplasty (Fig. 3). The second most common complication was aortic valve regurgitation (n = 5: two minor cases, which disappeared during followup; two resolved by immediate device retrieval; one needing surgical management due to aortic valve perforation when the device passed through the valve). The other complications were minor groin haematoma (n = 2), tricuspid valve regurgitation (n = 1; resolved by device retrieval), grade 1 AVB (n = 1) and haemodynamic instability with sinus bradycardia (n = 1; resolved rapidly under anaesthesiologist support and pmVSD closure was then completed).

The occurrence of severe complications was significantly related to the presence of haemolysis (P = 0.001), residual shunt (P = 0.007), multiple-exit VSD (P = 0.005) and higher LVEDD Z-score (P = 0.03). Age, weight, VSD size and absence of aneurysm were not significantly associated with severe complications (Table 1), nor was centre intervention volume. There was a non-significant trend towards a lower rate of severe complications in the last 23 patients compared to the first 23 (n = 4 [17.4%] and n = 2 [8.7%], P = 0.7). Rate of severe complications by centre varied from 0% to 25% (Fig. 4).

After a median follow-up of 27 months(range 2-50 months), median LVEDD Z-score was 1.3 (IQR 0.9, 2.0). A tiny residual shunt was observed in six patients (15.0% of patients with implanted coil; 37.5% of patients with immediate post procedure residual shunt). No delayed severe complications were reported (in particular, no endocarditis, haemolysis, aortic valve lesions, tricuspid valve lesions, AVB or embolization). The medium-term clinical success (pmVSD closure without residual shunt or complications) rate was 65.2%.

Discussion

We report the initial French experience with pmVSD closure using Nit-Occlud Lê VSD Coils during the first 4 years after its introduction in France. The main observations of this study are: (1) the number of procedures was low; 2) there was a high feasibility of transcatheter closure of pmVSD using this device and 3) there was a high rate of complications. The number of procedures remains limited, at only 46 patients over 4 years in France. Despite a retrospective study design, we are certain that no procedure was missed, having cross-checked with data from the manufacturer. Several reasons may have led to the low rate. Firstly, in France, symptomatic infants with pmVSD and significant left ventricle overload are often referred for surgery within the first year of life. Asymptomatic patients with restrictive pmVSD with or without mild left ventricle overload are not referred for closure as their long-term outcome is excellent [START_REF] Kleinman | Spontaneous regression of left ventricular dilation in children with restrictive ventricular septal defects[END_REF]. Thus, there are a very limited number of patients that are candidates for this percutaneous technique. It may mainly be considered in adults and children aged over 1 year with pmVSD and a history of endocarditis and/or significant LV overload. The second explanation for the low number of procedures may be related to practitioner's caution. Among more than 20 congenital cardiac catheterization centres in France, only five started a program of pmVSD closure with the Nit-Occlud Lê VSD Coil. The coil was considered to be an interesting alternative, given its profile, the lack of material on the rim of the VSD and the absence of AVB reported in the first studies [START_REF] Haas | Interventional VSD-Closure with the Nit-Occlud® Le VSD-Coil in 110 Patients: Early and Midterm Results of the EUREVECO-Registry[END_REF][START_REF] Nguyen | Nit-Occlud Le VSD coil versus Duct Occluders for percutaneous perimembranous ventricular septal defect closure[END_REF][START_REF] Odemis | Transcatheter closure of perimembranous ventricular septal defects using Nit-Occlud® Le VSD coil: early and mid-term results[END_REF][START_REF] Chungsomprasong | The results of transcatheter closure of VSD using Amplatzer® device and Nit Occlud® Le coil[END_REF]. Good feasibility and outcomes were observed in a European multicentre study [START_REF] Haas | Interventional VSD-Closure with the Nit-Occlud® Le VSD-Coil in 110 Patients: Early and Midterm Results of the EUREVECO-Registry[END_REF]. However, in the low-risk population of patients that are candidates for percutaneous pmVSD closure, any severe complication is unacceptable.

Previous experiences with Amplatzer pmVSD occluder devices with early, as well as delayed, complete AVB, had cooled the enthusiasm of specialists [START_REF] Butera | Transcatheter closure of perimembranous ventricular septal defects: early and long-term results[END_REF][START_REF] Carminati | Transcatheter closure of congenital ventricular septal defects: results of the European Registry[END_REF]. Several practitioners were already concerned by the risk of residual shunting after coil positioning and haemolysis, which was described in some cases [START_REF] Odemis | Transcatheter closure of perimembranous ventricular septal defects using Nit-Occlud® Le VSD coil: early and mid-term results[END_REF]. To maximise the rate of success and decrease the potential learning curve impact in the current study, all procedures were performed by very experienced specialists of paediatric catheterization, assisted by the technical support of international specialists experienced with coil handling.

In our study, the feasibility of the procedure was confirmed. Positioning of the coil was achieved in > 95% of patients, as has been previously reported [START_REF] Haas | Interventional VSD-Closure with the Nit-Occlud® Le VSD-Coil in 110 Patients: Early and Midterm Results of the EUREVECO-Registry[END_REF][START_REF] Nguyen | Nit-Occlud Le VSD coil versus Duct Occluders for percutaneous perimembranous ventricular septal defect closure[END_REF][START_REF] Odemis | Transcatheter closure of perimembranous ventricular septal defects using Nit-Occlud® Le VSD coil: early and mid-term results[END_REF][START_REF] Chungsomprasong | The results of transcatheter closure of VSD using Amplatzer® device and Nit Occlud® Le coil[END_REF]. In one case, a coil got stuck in the aortic valve. After discussing the case with experienced colleagues, it seems that the coil could have been freed from the aortic valve by pushing the device rather than by withdrawing it. The latter manoeuvre leads to a severe aortic valve lesion that requires surgery. However, the rate of coil deployment and release was lower than expected given that, in some cases, the coil was retrieved due to residual shunting or associated lesions of the tricuspid or aortic valves. The handling of this device is more difficult than for other coils in other indications or for self-expandable nitinol devices.

Manipulating the coil, the guide catheter and the sheath at the same time in the tricky area within the aortic, tricuspid and mitral valves, and the conduction tissues is challenging. The coil is partially released before positioning with limited control of its position and rotation. The training of echocardiographers is also a key issue to extensively describe the shape and geometry of the VSD in order to select suitable candidates and help to select appropriate devices.

The efficacy of the device was confirmed after mid-term follow-up by normalization of left ventricle size, as has been reported by others [START_REF] Nguyen | Nit-Occlud Le VSD coil versus Duct Occluders for percutaneous perimembranous ventricular septal defect closure[END_REF].

The complication rate was higher in this study compared to previous ones [START_REF] Haas | Interventional VSD-Closure with the Nit-Occlud® Le VSD-Coil in 110 Patients: Early and Midterm Results of the EUREVECO-Registry[END_REF][START_REF] Nguyen | Nit-Occlud Le VSD coil versus Duct Occluders for percutaneous perimembranous ventricular septal defect closure[END_REF][START_REF] Odemis | Transcatheter closure of perimembranous ventricular septal defects using Nit-Occlud® Le VSD coil: early and mid-term results[END_REF][START_REF] Chungsomprasong | The results of transcatheter closure of VSD using Amplatzer® device and Nit Occlud® Le coil[END_REF]. The main complication was mechanical haemolysis. Haemolytic anaemia related to intracardiac prosthetic material is a well-known condition. Gu et al. documented haemolysis in 9% of patients after implantation of Amplatzer pmVSD devices [START_REF] Gu | Transcatheter closure of postoperative residual perimembranous ventricular septal defects[END_REF], whereas the incidence was 2% with the ADO1 device [START_REF] Nguyen | Nit-Occlud Le VSD coil versus Duct Occluders for percutaneous perimembranous ventricular septal defect closure[END_REF]. In the two aforementioned series, haemolysis was transient and resolved by medical therapy alone. Mechanical haemolysis is also observed in patients with paravalvular leak, and can even occur after percutaneous closure [START_REF] Hascoet | Multimodality imaging guidance for percutaneous paravalvular leak closure: Insights from the multi-centre FFPP register[END_REF]. Mechanical haemolysis seems to be more frequent after Nit-Occlud Lê VSD positioning due to a tendency of more residual shunt. Odemis et al. documented haemolysis in 3/18 patients with the Nit-Occlud Lê VSD coil and surgical removal of the device was necessary in one of them [START_REF] Odemis | Transcatheter closure of perimembranous ventricular septal defects using Nit-Occlud® Le VSD coil: early and mid-term results[END_REF]. In our study, haemolysis was observed in half of the patients with residual shunt while no case of haemolysis was reported after complete shunt closure. Shunt suppression is mandatory to avoid or cure persistent haemolysis. Haemolysis was significantly related to the presence of residual shunt and multiple-exit VSD. Details about the type of residual shunt (paraversus intra-prosthetic leaks) were not available in all patients. The fact that haemolysis was associated with multiple-exit VSD and resolved by additional device implantation suggests that residual para-prosthetic leak is the main mechanism. Several strategies could be attempted before surgery to abolish persistent haemolysis: implanting another coil, implanting another device (e.g. ADO II), as reported in our study and by others [START_REF] Odemis | Transcatheter closure of perimembranous ventricular septal defects using Nit-Occlud® Le VSD coil: early and mid-term results[END_REF][START_REF] Bulut | Treatment of severe hemolysis following Nit-Occlud Le VSD coil implantation with Amplatzer Duct Occluder II[END_REF]. During the procedure, in case of residual shunt, it may be recommended to implant another device or withdraw the device before release to avoid the high risk of foreseeable persistent haemolysis, as was done in three cases in this study in the centre with the lowest rate of severe complications. The absence of a self-expandable characteristic leading to a 'stent' effect into the defect could explain the tendency of higher rate of residual shunt with this device, mainly shortly after the procedure. The rate of residual shunt decreased during follow-up, probably by the coagulating effect of the polyester fibres included in the device [START_REF] Haas | Interventional VSD-Closure with the Nit-Occlud® Le VSD-Coil in 110 Patients: Early and Midterm Results of the EUREVECO-Registry[END_REF][START_REF] Nguyen | Nit-Occlud Le VSD coil versus Duct Occluders for percutaneous perimembranous ventricular septal defect closure[END_REF][START_REF] Odemis | Transcatheter closure of perimembranous ventricular septal defects using Nit-Occlud® Le VSD coil: early and mid-term results[END_REF]. However, nearly half of the patients with residual shunt after the procedure still had a tiny residual shunt at the end of follow-up.

The second main issue in this study was the rate of aortic and tricuspid valve lesions, which were transient, resolved by device withdrawal or definitive (needing surgical valvuloplasty in a few cases). A learning curve impact may have affected this result and attention should be focused on the valves by echocardiographers during the procedure. The multiple steps required to implant the coil may have contributed to this complication. Firstly, an arteriovenous loop is necessary. A 'butter wire' effect on the valves may be prevented by the 'kissing technique'. Secondly, the sheath has to be advanced from the right ventricular side through the pmVSD into the aorta. Thirdly, the coil is partially released in the aorta and then has to be very gently moved back through the aortic valve. Finally, when the coil is positioned and deployed, it can trap tricuspid chordae.

In our study, it is noteworthy to mention the absence of complete AVB, although there was one case of transient grade 1 AVB. Complete AVB is rare with this device and can be resolved by surgical removal [START_REF] Nguyen | Nit-Occlud Le VSD coil versus Duct Occluders for percutaneous perimembranous ventricular septal defect closure[END_REF]. However, long-term outcomes should be reported to confirm this finding. Similarly, no cases of endocarditis or embolization were reported.

Finally, the trend towards a lower rate of complications at the end of the study suggests a learning curve bias despite the presence of an experienced operator and proctor for all interventions.

Meticulous patient selection should be done, with exclusion of multiple-exit pmVSD. Further, during procedure, residual shunting should not be tolerated. To date, only two French centres continue to perform pmVSD closure with Nit-Occlud Lê VSD. Some other centres have moved to pmVSD occlusion using alternative devices.

Limitations

The number of procedures was low. We cannot exclude that a learning curve effect and lack of experience affected our results, despite the precautions taken by specialists. Indeed, results tended to be better in the second part of the study, particularly with strategies to prevent residual shunt and attention focused on the valves. The follow-up period is also relatively short, so we cannot confirm the absence of late complications, especially complete AVB. A more prolonged follow-up will be mandatory, in particular to know the effect of residual shunt on the occurrence of endocarditis.

Perspectives: This study demonstrates the complexity of the management of pmVSD with significant left-to-right shunt in older children and adults. Both surgical and percutaneous techniques have risks. New devices for this indication are under investigation and will need to be carefully assessed. The optimal therapeutic strategy in this selected population remains to be determined in the modern arena. Therefore, the French heart association started the FRANCISCO study (Observatoire français des Communications Interventriculaires périmembraneuses Congénitales avec hyper débit pulmonaire, NCT03363932) to investigate the long-term outcome of these patients according to therapeutic strategy and assess anatomic predictors of complications.

Conclusions

pmVSD closure is feasible with the Nit-Occlud Lê VSD Coil in older children and adults. Residual shunting leading to haemolysis is a dreaded complication. The place of pmVSD closure with the Nit-Occlud Lê VSD in the therapeutic strategy remains controversial and is limited to selected patients.

Residual shunting after coil implantation should not be tolerated.

  Abbreviations: AVB, atrioventricular block; CI, confidence interval; IQR, interquartile range; LV, left ventricle; LVEDD, left ventricular end diastolic diameter; pmVSD, perimembraneous ventricular septal defect; RV, right ventricle; TOE, transoesophageal echography; VSD, ventricular septal defect.

  Statistical analyses were carried out using SPSS version 23 (IBM, New York, USA) and Stata software version 11.2 (StataCorp, College Station, Texas, USA). Non-normally distributed quantitative variables are shown as medians (interquartile ranges [IQRs]). Clinical and procedural data were compared between patients with and without severe complications using the Mann-Whitney test and the exact Fischer test. Alpha risk was set at 5%. Results pmVSD percutaneous closure was attempted in 46 patients in five centres (CHRU Lille [n = 17]; CHU Bordeaux [n = 14]; CHU Toulouse [n = 8]; CHU Marseille [n = 5]; CHU Reims [n = 2]). Patient and VSD characteristics are detailed in Table 1. The median (IQR) age was 13.9 (5.7-31.8) years, although patients aged 0.7-60.4 years were included. Closure indications were left ventricular overload in 35 patients (76.1%), exertional dyspnoea in eight patients (17.4%), infective endocarditis history in two patients (4.3%), and mild pulmonary hypertension with significant left-to-right shunt in one patient (2.2%; mean pulmonary artery pressure 31 mmHg; left-to-right output ratio 3.4; LVEDD 27 mm; Z-score +4.7).

Figure 1 .

 1 Figure 1. Step-by-step closure of pmVSD using the Nit-Occlud Lê VSD. A. VSD assessment by left anterior oblique projection angiogram. B. A guidewire was introduced retrogradely through the VSD towards the pulmonary artery and was snared by a lasso introduced from the venous side. C. A 7F sheath was advanced from the venous access to the ascending aorta through the VSD. D. The first loop of the coil was deployed in the ascending aorta. E. The second loop of the coil was deployed, and then the coil pulled back into the VSD aneurysm under TOE and angiographic control. F. Deployment of the third loop into the right ventricle before device release. pmVsd: perimembranous ventricular septal defect; VSD: ventricular septal defect; TOE: transoesophageal echography.

Figure 2 .

 2 Figure 2. Residual shunt closure using an arterial duct occluder type II device. The device was placed in the VSD residual shunt from the arterial route. VSD: ventricular septal defect.

Figure 3 .

 3 Figure 3. Nit-Occlud Lê VSD trapped in the tricuspid valve. This patient had moderate tricuspid regurgitation and a residual shunt. During surgical intervention, it became clear that the device had become embedded in the septal leaflet of the tricuspid valve. The patient had surgical VSD closure with tricuspid valvuloplasty with a good result. VSD: ventricular septal defect.

Figure 4 .

 4 Figure 4. Rates of severe complications at the different centres.

Table 1 .

 1 Patient and VSD characteristics. Data are expressed as median (interquartile range) or number (%). LV: left ventricle; LVEDD: left ventricular end diastolic diameter; RV: right ventricle; VSD: ventricular septal defect.

		All patients	No/mild	Severe	P
		(n = 46)	complications	complications
			(n = 40)	(n = 6)
	Age (years)	13.9 (5.7-31.8)	13.6 (5.7-32.3)	17.8 (5.7-27.3)	0.87
	Weight (kg)	36.7 (18-60)	36.7 (18-58.5)	38.5 (15-60)	0.98
	Height (cm)	142 (116-170)	141 (118-168.5)	166.5 (109-178)	0.43
	Female sex	18 (39.1)	15 (37.5)	3 (50.0)	0.68
	VSD LV side size (mm)	8 (7-10)	8 (8-11)	8 (7-9)	0.56
	VSD RV side size (mm)	5 (4-6)	5 (4-6)	4.4 (4-6)	0.62
	Aortic rim (mm)	5 (4-6)	5 (4-6)	4.5 (3-6)	0.42
	LVEDD (mm)	47 (36-55)	47 (36-55)	49 (33-58)	0.87
	LVEDD Z-score	2.6 (2.0-3.3)	2.3 (1.7-3.3)	3.6 (3.0-4.9)	0.03
	Aneurysm	42 (91.3)	36 (90.0)	6 (100)	1.00
	Multiples exits	4 (8.7)	1 (2.5)	3 (50.0)	0.005
	Pulmonary hypertension	1 (2.2)	1 (2.5)	0	1.00
	Endocarditis history	2 (4.3)	2 (5.0)	0	1.00
	Residual shunt	16/40 (40.0)	11 (27.5)	5 (83.3)	0.007
	Haemolysis	8	3	5	0.001

Table 2

 2 Procedural characteristics and device sizes.

	All patients
	(n = 46)

Data are expressed as median (range) or number (%).TOE: transoesophageal echocardiography.

Acknowledgements

This work was supported by the French Government as part of the 'Investments of the future' program managed by the National Research Agency (ANR) (Grant reference ANR-10-IAHU-04).

Disclosure of interest

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