ORCID Angeliki Darma
email: angeliki.darma@helios-gesundheit.de

MD Arash Arya

; Pd

MD Nikolaos Dagres

MD Michael Kühl

MD Gerhard Hindricks

MD Sandra Eifert

MD Diyar Saeed

MD Michael Borger

MD;PhD Raphaël P Martins

MD;PhD Christophe Leclercq

MD Vincent Galand

Validation of the VT-LVAD Score for Prediction of Late VAs in LVAD Recipients

Keywords: LVAD, late ventricular arrhythmia, ICD, mortality, risk stratification angiotensin-converting enzyme, AF: atrial fibrillation, CABG: coronary artery bypass grafting, CI: confidence interval, ECMO: extracorporeal membrane oxygenation, HR: hazard ratio, ICD: implantable cardioverter-defibrillator, LVAD: left ventricular assist device, RVAD: right ventricular assist device, VA: ventricular arrhythmia, VF: ventricular fibrillation, VT: ventricular tachycardia

Objectives

This study sought to validate the performance of the VT-LVAD risk model in predicting late ventricular arrhythmias (VAs) in patients after left-ventricular assist device (LVAD) implantation.

Background

The need for ICD-implantation in LVAD-recipients is not well studied. A better selection of the patients with high risk for late VAs could lead to a more targeted ICDimplantation or replacement.

Methods

The study evaluated the performance of the VT-LVAD prognostic score [VAs prior LVAD, no ACE-inhibitor in medication, heart failure duration >12 months, early VAs post LVAD implantation, atrial fibrillation prior LVAD, idiopathic dilated cardiomyopathy] for the endpoint of the occurrence of late VAs in 357 LVAD-patients in Heart Centre of Leipzig.

Results

From the initial 460 patients, 357 (age 58 ± 10 years; left ventricular ejection fraction: 20 ± 6%; HeartWare: 50%; HeartMate III: 42%) were assigned to four risk groups according to their VT-LVAD-score varying from low risk to very high risk. After 25 months, late VAs occurred in 130 patients. The VT-LVAD score was an independent predictor of late VAs (multivariate analysis; p= <0.001; goodness-of-tip p=.347, OR 4.8). While there was no statistically significant difference between the low and intermediate risk group, risk stratification for patients with high risk and very high risk performed more accurately (pairwise comparison p=.005 and p<0.001, respectively).

.

Introduction

The advances in heart failure treatment over the last decades have prolonged the survival of patients with end-stage heart disease. Because of the ongoing lack of available organs, there is an increasing demand of mechanical circulatory support devices (LVAD) as bridge to heart transplantation (HTX) or destination therapy for these critically ill patients. {2} With the technical advantages of continuous flow LVADs, an 80% 1-year survival has been achieved, approaching that of heart transplantation (86%). {2-3} With the wide use of LVADs new questions arise in clinical practice. While the use of ICDs has been proved to reduce mortality in heart failure patients, especially in ischemic cardiomyopathy {4-5}, the benefit of ICDs in LVAD recipients remains controversial. The high rate of ICD-related adverse events, such as inappropriate therapies or infections, combined with the fact that many ventricular arrhythmias (VAs) remain because of the haemodynamic support asymptomatic in LVAD patients, makes a better selection of the right candidates urgent. {6-10} Furthermore, as ICD-implantation after LVAD implantation has been described as an independent predictor of LVAD infection {11}, these procedures should be limited to the patients who would most benefit. With this study we aim to evaluate the VT-LVAD for its predictive accuracy in identifying high risk LVAD recipients for late VAs.

Methods

Study design

We collected the data of consecutive patients who underwent implantation of LVADs at the Heart Centre of Leipzig in the period between January 2011 and March 2020.

All patients gave written informed consent for the operation, as is in accordance with the institutional guidelines. The type of LVAD device as well as the decision regarding ICD implantation was left on the attending physicians' discretion. All

Ventricular Arrhythmias

The definition of VAs was in accordance with the study of Galand et al {1}, as was their classification on VAs before LVAD implantation; early VAs post-LVAD implantation (occurring within 30 days after the surgery); and late VAs post-LVAD (VAs occurring after 30 days). Only episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF) lasting > 30 seconds in the monitor-zone or terminated by appropriate ICD therapy were analyzed. We did not distinguish between ventricular fibrillation and polymorphic ventricular tachycardia for analysis.

Follow-Up

All patients were followed up for occurrence of VAs, clinical status, echocardiographic parameters and LVAD control by clinic visits at 4-month intervals.

The ICD detection thresholds were analyzed both in patients with and without post-LVAD VAs. The ICD programming was not standardized and reprogramming was performed during follow up when needed.

Death was classified as cardiovascular death, when resulting from acute heart failure, sudden cardiac death, death due to stroke or death due to cardiovascular hemorrhage. The ICDs were not routinely interrogated post-mortem. The last date of the follow up was June 30, 2020; or the date of heart transplantation; or the date of death; whichever occurred first.

Statistical analysis

Continuous variables were reported as mean ± standard deviation and categorical variables as frequencies. Continuous variables were compared using the Student's ttest while categorical variables were compared using the χ 2 test. Univariate and multivariate cox regression analyses were performed in order to determine the predictive factors. Variables with a P-value of ≤0.2 in the univariate analysis or important clinical or procedural parameters were then included in the multivariate regression analysis for the determination of hazard ratio (HR) and its 95% confidence interval (CI). A P-value of ≤0.05 was considered to be statistically significant.

Mortality rates were calculated and graphically depicted with the Kaplan-Meier curves. The Chi-square Goodness of fit test for independence was used to assess the predictive value of the score. All analyses were performed using SPSS v24.0 (SPSS Inc., Chicago, IL, USA).

Results

Study population

From the initial 460 LVAD recipients, three had a congenital heart disease, seventysix died during initial hospitalization, fifteen underwent heart transplantation within the first three months, nine had missing data and were excluded, thereby leaving 357 patients in the final analysis. The clinical characteristics of these patients are listed in Table 1. Eighty-eight percent of the patients in our cohort were men, 47% had an ischemic cardiomyopathy and the median heart failure duration was 36 months .

Accepted Article

(range 1-204). Sixty percent of the population had atrial fibrillation (AF) and 39%

were under antiarrhythmic therapy. Seventy-five percent of the patients underwent ICD implantation before the LVAD placement; among them 36% acquired a CRTdevice. The majority of the patients received a HeartWare device (50%) and the most common indication in our cohort was destination therapy with 40%. The median follow-up was 25 months. When compared to the study of Galand et al {1}, less patients had ICM (47% vs 63%), more had AF (60% vs 46%), much less patients received a HeartMate II device (8% vs 73%) and were candidates for HTX (30% vs 64%). 3), as well as a high VT-LVAD-score with ≥ 5 points (p < 0.001, HR 3.1; CI 2.0 -4.9) to be strong independent predictors of late VAs. (Table 3)

Prevalence and predictors of VAs

The VT-LVAD score accurately predicted late VAs in patients with high or very high risk were (AUC = 0.7; goodness-of-tip p = 0.347, OR 4.8). In pairwise comparison analysis of VT-LVAD score groups, we found low risk and intermediate risk group not having a statistically significant difference in predicting late VAs (p = 0.627; Figure 2).

Therefore, we combined low and intermediate risk group in one low risk group, so that significant differences among all three groups were present (Group 1-2: p < 0.001; Group 1-3: p < 0.001; Group 2-3: p= 0.005 in pairwise comparison, respectively, Figure 3).

Outcomes

During the follow-up period 66 patients (19%) received heart transplantation, 14 patients (4%) recovered and underwent an occlusion or removal of their LVAD device and 131 patients (37%) died. The majority of the deaths (49%) occurred because of cardiovascular events, with right heart failure being the most common cause (24%), followed by stroke or bleeding (12%). Sepsis with 15% was the most common noncardiovascular cause of death (Table 4). The occurrence of late VAs was associated with more cardiovascular death, not only due to electrical storm but also due to right heart failure. (Table 4) Regardless, the occurrence of late VAs was not an independent mortality predictor in this analysis (log rank: p = 0.176, Figure 4a-b). On the same note, the presence of a high LVAD-VT score also did not predict worse survival in our cohort (log rank, p = 0.121). On the contrary, the presence of an ICD prior LVAD was associated with worse outcome in the multivariate mortality analysis in our cohort (log rank: p= 0.009, Figure 4a-b). Lastly, 19% of the LVAD recipients in our cohort suffered ICD-related complications, mostly due to inappropriate therapies, electrode dysfunctions and infections.

Discussion

This is the first study to our knowledge to validate the VT-LVAD score for occurrence of late VAs in an independent cohort. According to the VT-LVAD-score, 11% of the patients were low risk (n=39; vs 9% in the study of Galand et al), 34% were intermediate risk (n=122; vs 43%), 30% were high risk (n=107; vs 24%) and 25%

were very high risk (n=89; vs 18%). (Table 2, Figure 1)

In our study, we found the score to be accurate in predicting late VAs in high and very-high risk group, whereas we saw no statistically significant difference between the low and intermediate risk population. Moreover, in addition to VT-LVAD score, use of antiarrhythmic drugs (p < 0.001, HR 2.3; CI 1.6 -3.4) and presence of diabetes mellitus (p = 0.016, HR 1.6; CI 1.1 -2.3) were found to be independent predictors of late VAs in our cohort. Late arrhythmias were associated with more cardiovascular death, mainly following right heart failure, but were not an independent mortality predictor (log rank: p = 0.176, Figure 4a). The presence of implanted ICD before the LVAD placement was associated with a worse outcome in our study (log rank: p= 0.009, Figure 4b). This could be explained through a longer heart failure duration or history of VAs, which could have worsened the patients' prognosis.

Late VAs appears to be a common problem in LVAD-recipients (19-59% {1, 9, 12})

and have been associated with worse survival, especially for patients with continuous flow VAD devices {6-7}. These arrhythmias are mainly reentry tachycardias caused by fibrosis, either pre-existing or caused from the apical wedge around the inflow cannula {8}. The ongoing reverse remodelling, the mechanical trauma caused by the LVAD, as well as the physiological adaption to the device can increase the electrical vulnerability, not only at the first postoperative period but also as a late phenomenon {13}. While sudden cardiac death or syncope is not as common as with the first generation VAD devices {6}, recurrent VAs can have severe consequences, such as progressive right ventricular and renal failure, low output condition with consecutive suction and increased thrombogenicity {14, 15, 16, 17}. As a result, recurrent VAs tend to increase unscheduled hospitalisations and morbidity in these patients. {18}

Previous studies regarding ICD implantation in LVAD patients as a primary prevention have been inconclusive and clear recommendations are lacking {8}. On one hand, ICDs come with a risk as high as 6.1% complications per year needing hospitalisation or operation {18}. On the other hand, in a recent meta-analysis of six observational studies {10}, ICD implantation was associated with a significant reduction in mortality in LVAD patients, but not for the patients with continuous flow LVADs. This highlights the need for a risk stratification strategy and a patient-tailored approach to address this increasing problem. In our study, the VT-LVAD score was predictive of late VAs for the high and very high-risk population. Furthermore, given that 41% of the patients in our cohort received a HeartMate III device, which was not included in the study of Galand, the VT-LVAD score can also be applied to patients with state-of-the-art devices. Although the predictive value of the score was more moderate when compared to the study of Galand et al, the score appears to be a useful tool for risk stratification in LVAD recipients and can be helpful in guiding the implantation or replacement of ICDs.

Limitations

There were several limitations in our study. Our study is a retrospective, observational, single centre analysis. 25% of the patients did not have an implanted ICD and asymptomatic VAs may have been missed. Nevertheless, recurrent or sustained VAs tend to become clinically apparent through right heart decompensation or syncope and would have been eventually recognised. Moreover, the ICD-programming was adjusted to each patient's needs, which could have influenced the detection of asymptomatic VAs. Nevertheless, this only underlies the fact that not all VAs are clinically relevant for this population. Lastly, a post-mortem ICD interrogation did not take place routinely and cardiac deaths due to VAs may have been underestimated.

Conclusions

The VT-LVAD score predicted accurately the occurrence of VAs in high risk population in an independent cohort and could be used as a guide for ICD implantation in LVAD recipients. Late VAs did not influence the survival in our cohort.

patients ≥ 18

 18 Abbott Park, IL), centrifugal HeartWare (Medtronic, Columbia Heights, Minnesota) or

  As far as VAs prior to LVAD are concerned, 153 (43%) patients had experienced previous ventricular arrhythmias and 77 patients (22%) experienced VAs in the first 30 days of the postoperative period. Overall, the occurrence rate of VAs on LVAD support was 36% (n=153) and the median time from LVAD placement to the first VA episode was 16 months (range 1-94). The VAs were terminated through antitachycardic pacing (ATPs) in 8% of the cohort and these patients remained asymptomatic, whereas shock or both therapies occurred in 28%. The main symptom described was the shock itself, while a minority of patients described syncope, palpitations or dyspnoea. Forty-nine patients (14%) without any history of VAs reached the endpoint of late VAs, whereas 81 patients with history of VAs (53%) continue to experience VAs postoperatively. Eight patients died after complications to electrical storm and two were listed as high-urgency because of the incessant arrhythmias and received a heart transplant. Compared to the arrhythmia free patients, the patients with late VAs were older, had more comorbidities, more early VAs, longer heart failure duration, and were more likely to have an ICD and antiarrhythmic medication at baseline (

Figure 1 .

 1 Figure 1. Bar chart of the classification of the LVAD recipients and the distribution of late VAs in the four risk groups (blue bar: patients without late VAs, green bar: patients with late VAs).

Figure 2 .

 2 Figure 2. Kaplan Meier analysis of the four risk groups (blue line: low risk group, green line: intermediate risk, yellow line: high risk, red line: very high risk, n = number at risk).

Figure 3 .

 3 Figure 3. Kaplan Meier curves after combining low risk and intermediate risk group in one low risk group (low risk: blue line, high risk: green line, very high risk: yellow line, n = number at risk).

Figure

  Figure 4a-b. Influence of late VAs (a) (blue line: control group, green line: patients with late VAs) and pre-existing ICD (b) (blue line: patients without ICDs, green line: ICD-recipients) on survival.

Table

  ). Forty-four patients had history of catheter ablation of VAs, among them nine patients that underwent ablation after

	LVAD placement.
	The multivariate analysis identified early VAs (p < 0.001, HR 2.5; CI 1.7 -3.4), use of
	antiarrhythmic drugs (p < 0.001, HR 2.3; CI 1.6 -3.4), presence of diabetes mellitus
	(p = 0.016, HR 1.6; CI 1.1 -2.

Table 3 . Multivariable analysis for prediction of late VAs.

 3

	Variable	Univariable	Multivariable HR	Multivariable
		analysis	(95% CI)	analysis
		p-Value		p-Value
	Gender	0.024		0.902
	Age	0.003		0.118
	Art. hypertension	0.074		0.657
	Diabetes mellitus	0.009	1.6 (1.1 -2.3)	0.016
	Atrial fibrillation	<0.001		0.685
	Cardiomyopathy	0.187		0.855
	Heart failure duration	0.036		0.587
	VAs-history	<0.001		0.219
	LV-EDV before LVAD	0.077		0.935
	GFR	0.060		0.646
	HeartMate II	0.074		0.592
	HeartWare	0.001		0.212
	HeartMate III	<0.001		0.104
	Bridge to	0.003		0.063
	decision/recovery
	Destination therapy	<0.001		0.132
	Early VAs	<0.001	2.5 (1.7 -3.4)	<0.001
	Antiarrhythmics	<0.001	2.3 (1.6 -3.4)	<0.001
	Amiodarone	<0.001		0.541
	High VT-LVAD score (≥ 5)	<0.001	3.1 (2.0 -4.9)	<0.001

Table 4 . Outcomes after LVAD placement.

 4

	Variable	Total	Control Group Late VA Group P-Value
	Heart transplantation	66	42 (19%)	24 (19%)	0.992
	Total death	131	63 (28%)	68 (52%)	< 0.001
	-Cardiovascular	64	29 (13%)	35 (27%)	0.001
	-Non-cardiovascular	3	1 (0.4%)	2 (2%)	0.274
	-Sepsis	20	9 (4%)	11 (9%)	0.075
	-Unknown cause	42	24 (11%)	18 (14%)	0.356
	Cardiovascular death
	-LVAD thrombosis	6	4 (2%)	2 (2%)	0.874
	-RH-failure	32	14 (6%)	18 (14%)	0.015
	-Electrical storm	8	0 (0%)	8 (6%)	<0.001
	-LVAD dysfunction	2	0 (0%)	2 (2%)	0.061
	-Stroke/bleeding	16	10 (4%)	6 (4%)	0.926

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflict of interest

Dr. Leclercq has served as a speaker for Biotronic, BSI, Medtronic, Abbott, and LivaNova. Dr. Martins has received honoraria from Medtronic, Abbott, and LivaNova.

All other authors have reported they have no relationships relevant to the contents of this paper to disclosure. Funding: None.

Accepted Article


Charles Paleo
email: charles.paleo@univ-lyon1.fr

Véronique Dupuis

Fabrice Wilhelm

Andrei Rogalev

Olivier Proux

Olivier Boisron

Isabelle Kieffer

Thierry Epicier

Matthieu Bugnet

Damien Le Roy

Interplay between local structure and magnetic properties of graded exchange-coupled Co@FePt nanocomposite films

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.

Hard-magnetic nanocomposites are attractive materials for integration in various microsystems and for building next generation permanent magnets. However, exploiting their full potential requires to control their microstructure at the nanometre scale. Studying these materials in model systems synthesised by nanofabrication routes gives interesting insights about the interplay between the microstructure and the magnetic performances. Here, by using a combination of mass-selected low energy cluster beam deposition and electron-beam evaporation, we have prepared nanocomposite films where Co nanoinclusions are integrated in a hard magnetic FePt matrix. Local atomic structures and element selective magnetic properties of such nanocomposites have been thoroughly investigated using polarisation dependent hard X-ray absorption spectroscopies. These results demonstrate that magnetically soft inclusions are stabilised at room temperature, emphasising the role of the interdiffusion in the preparation of nanocomposites.

I. INTRODUCTION

Hard magnetic materials with high magnetisation are attracting a lot of attention for various applications, from spintronics [START_REF] Nguyen | co/pd]-nife exchange springs with tunable magnetization tilt angle[END_REF] to magnetic recording media [START_REF] Mitin | Exchange coupled l10 fecupt/fe heterostructures: Magnetic properties and reversal behavior at elevated temperatures[END_REF][START_REF] Ma | Exchange coupled composite fept/tbco/[co/ni]n films with an tbco interlayer[END_REF] or in bulk permanent magnet for energy conversion technologies [START_REF] Coey | Perspective and prospects for rare earth permanent magnets[END_REF]. The figure of merit of a permanent magnet is the energy product (BH) max ≤ 1 4 µ 0 M 2 s . The limit is attained for an ideal microstructure and an uniaxial texture, which is nearly achieved in NdFeB sintered and oriented magnets. With an outstanding combination of a relatively large magnetisation µ 0 M s of 1.61 T and a large magnetocrystalline anisotropy leading term K 1 of 4.3 MJ.m -3 , they lead the performances of permanent magnets for about 30 years, approaching the (BH) max theoretical limit of 516 kJ.m -3 for these non-nanostructured elements [START_REF] Coey | Perspective and prospects for rare earth permanent magnets[END_REF]. Designing a hard magnetic material with magnetisation µ 0 M s higher than 1.61 T is a necessary -although not sufficient-condition to surpass the performances of nowadays best rare earth (RE) magnets. Fe-Co alloys could be among the most attractive candidates for permanent magnets, with µ 0 M s ≥ 1.81 T for pure Co and up to µ 0 M s = 2.45 T for Fe 65 Co 35 . In the latter case, it could push the limit of reachable (BH) max up to nearly 1.2 MJ.m -3 , if a square magnetisation loop with a coercive field in excess of 1.2 T could be achieved (µ 0 H c ≥ µ0Ms

2 ). However, this relies on our ability to significantly increase the relatively low magnetocrystalline anisotropy (K 1 ≤ 20 kJ.m -3 ) [START_REF] Coey | Magnetism and Magnetic Materials[END_REF], so far predicted but not fully achieved experimentally [START_REF] Burkert | Giant magnetic anisotropy in tetragonal feco alloys[END_REF], even if promising results have recently been reported [START_REF] Li | Novel bimorphological anisotropic bulk nanocomposite materials with high energy products[END_REF].

In addition to these challenges, the risks associated with the sourcing and the fluctuating cost of RE metals due to geostrategic availability, and the pollution during extraction of the raw elements and recycling of the used materials are driving the need to reduce the dependency to the REs in high performance permanent magnets [START_REF] Lucas | Rare earths: science, technology, production and use[END_REF][START_REF] Mcguiness | Replacement and original magnet engineering options (romeos): A european seventh framework project to develop advanced permanent magnets without, or with reduced use of, critical raw materials[END_REF][START_REF] Rial | Severe tuning of permanent magnet properties in gas-atomized mnal powder by controlled nanostructuring and phase transformation[END_REF].

An elegant approach to design a magnet with high value of energy product was proposed by Kneller and Harwig, that consists in fabrication of a nanocomposite (NC) materials combining a hard magnetic phase exchange coupled to a strongly magnetic soft phase [START_REF] Kneller | The exchange-spring magnet: a new material principle for permanent magnets[END_REF]. The beneficial effect of this approach was initially demonstrated in 1989 by Coehoorn on Nd 2 Fe 14 B-Fe 3 B ribbons [START_REF] Coehoorn | Meltspun permanent magnet materials containing fe3b as the main phase[END_REF]. This finding stimulated further investigations, including theoretical and modelling studies to optimise the NC structure [START_REF] Kneller | The exchange-spring magnet: a new material principle for permanent magnets[END_REF][START_REF] Skomski | Giant energy product in nanostructured two-phase magnets[END_REF]. In order to develop new magnets with unprecedented performances, the volume fraction of the hard magnetic phase should be limited to the minimum needed to fulfil the coercive field criterion [START_REF] Skomski | Giant energy product in nanostructured two-phase magnets[END_REF] µ 0 M s /2 in an ideal uniaxial anistropic case, further extended to realistic cases by Skomski et al. [START_REF] Skomski | Predicting the future of permanent-magnet materials[END_REF]. Under the assumptions of zero magnetic anisotropy in the softer phase and sharp interface between soft and hard magnetic phases, the maximum size of the soft phase regions is twice the size of the domain wall width of the hard phase. Therefore, to exploit the full potential of nanocomposite magnets, one needs to control their microstructure at the nanometre scale, including the size of the soft inclusions, their concentration and the roughness of the interface between the hard and soft phases. In this context, nanocomposite films made from nanofabrication routes are foreseen to bring interesting insights in view of guiding the synthesis of bulk systems [START_REF] Skomski | Predicting the future of permanent-magnet materials[END_REF][START_REF] Rui | High-energy product exchangespring fept/fe cluster nanocomposite permanent magnets[END_REF][START_REF] Yue | Fabrication of bulk nanostructured permanent magnets with high energy density: challenges and approaches[END_REF].

In this work, we investigate the principle of thin-film nanocomposite magnets of Co nanometre-sized grains embedded in a hard FePt matrix (named Co@FePt). The fine microstructure analysis requires techniques allowing the chemical distinction of Fe and Co at the nanometric scale. The chemically ordered L1 0 -FePt phase presents a magnetocrystalline anisotropy K 1 of 6.6 MJ.m -3 and a magnetisation of µ 0 M s = 1.43 T (a maximum (BH) max of 407 kJ.m -3 ), slightly inferior to the one of NdFeB [START_REF] Coey | Magnetism and Magnetic Materials[END_REF]. Besides, the use of expensive elements like Pt for bulk magnets is excluded. However, when it comes to microtechnologies where the fabrication costs generally dominate over the raw material costs, FePt films can be of great interest. Indeed, they offer higher resistance against corrosion, as compared to RE-based films, which makes them more compatible with standard microfabrication processes. NC films of Co 50 @(FePt) 50 would potentially exhibit 28% higher (BH) max than the L1 0 -FePt alone.

II. METHODS

A. Sample Preparation

These Co@FePt transition metal-based nanocomposite are made from Co soft clusters embedded in a L1 0 -FePt matrix: the clusters are pre-formed in the gas phase using a laser vaporisation source working in a Low Energy Cluster Beam Deposition (LECBD) system [START_REF] Dupuis | Intrinsic magnetic properties of bimetallic nanoparticles elaborated by cluster beam deposition[END_REF]. Deposited in a soft landing regime, the clusters are not fragmented or distorted at the impact on the substrate. Moreover, a quadrupolar electrostatic mass-deviator allows to tighten the size dispersion and to obtain a Gaussian distribution centred at a desired mean value ranging from 2 to 10 nm [START_REF] Alayan | Application of a static quadrupole deviator to the deposition of size-selected cluster ions from a laser vaporization source[END_REF].

The ultra-high vacuum chamber (base pressure in the range of 10 -10 mbar) is equipped with an electron-beam evaporator with three targets (Fe, Pt and Co) that serve to grow films (for matrix, references and nanofilms samples) by successive atomic depositions.

To prepare the nanocomposites samples, a first layer of Co clusters is deposited on a Si substrate, then a 1.15 nm film of Fe, then a 1.40 nm third film of Pt from electrongun evaporation. These three steps are repeated six times in total (see Supporting Information [19] Fig. S1a). CoFePt nanofilms (NF) samples are prepared entirely by electron gun evaporation, with the same atomic Co content as NC samples (Fig. S1b). Finally, a L1 0 -FePt NF without Co was prepared as a reference (L1 0 -FePt ref.

).

The total thickness of the samples is between 15.3 nm (for L1 0 -FePt ref.) and 21.3 nm (for 30% Co samples in atomic proportion).

The formation of the magnetically hard L1 0 phase is thermally activated upon high vacuum annealing at 700 • C for 20 min [START_REF] Zeng | Orientation-controlled nonepitaxial l10 copt and fept films[END_REF][START_REF] Liu | Aligned and exchange-coupled l10 (fe,co)pt-based magnetic films[END_REF][START_REF] Hong | Microstructure of fept/pt magneticthin films with high perpendicular coercivity[END_REF] (Fig. S1c). The chemical order-ing has been observed for annealing temperatures higher than 650 • C with the appearance of the (001) line owing to stacking of pure element planes. The (001)/(110) peak intensity ratio is greater than the one expected for an isotropic polycrystalline system; indicating a partial c-axis texture. However, the co-existence of strong ( 111) and ( 001) peaks indicate a relatively large angular dispersion in the preferential orientation. Note that similar observations were reported previously in films prepared from alternative deposition of Fe and Pt thin layers [START_REF] Zeng | Orientation-controlled nonepitaxial l10 copt and fept films[END_REF] where the authors assigned the preferential c-axis texture to the growth process.

B. TEM Analysis

Bright field transmission electron microscopy (TEM) imaging of the mass-selected Co clusters protected by a carbon film was performed in a Jeol 2100 HT, operated at 200 kV. The TEM-energy-dispersive X-ray (TEM-EDX) experiments were performed in a FEI Titan ETEM G2 60-300, operated at 300 kV. For this purpose, a FePt/Co clusters/FePt specimen was deposited by LECBD directly on the Si 3 N 4 membrane of a DENSsolutions Wildfire MEMS chip, maintained at room temperature in the present study.

C. XMCD, XLD and XANES analyses

Polarisation dependent X-ray absorption, X-ray linear dichroism (XLD) and X-ray magnetic circular dichroism (XMCD) experiments have been performed at the ID12 beamline [START_REF] Rogalev | Magnetic circular dichroism in the hard x-ray range[END_REF] of the European Synchrotron Radiation Facility (ESRF). The X-ray source for these measurements was the first harmonic of APPLE-II type helical undulator (HU-38) in a pure helical mode. The X-ray beam was monochromatised with a fixed-exit double-crystal monochromator equipped with a pair of Si(111) crystals. The X-ray absorption spectra were recorded using the total fluorescence yield detection mode. The Xray fluorescence signal from the samples were collected in the back-scattering geometry, using Si photodiodes. The XLD signal is obtained as a difference between two absorption spectra measured with X-ray polarisation vector being either parallel or nearly perpendicular (80 degrees) to the sample surface. To minimise any eventual experimental artefacts, we kept the sample orientation constant and polarisation of X-rays using a 0.9 mm thick diamond quarter wave plate. X-ray quarter wave plate allowed us to transform the incoming circular polarised beam into two orthogonal linearly polarised beams at each energy point of the scan. The absorption was recorded from the same part of the sample for both polarisations. The local magnetic properties of the Fe and Co sites were studied using XMCD method at the Fe and Co K-edge. Measurements were performed at 295 K and under an applied magnetic field of 4 T provided by a supercon-ducting solenoid. The angle between the sample surface and the applied field is 10 degrees. The XMCD spectra were obtained as the difference between two consecutive X-ray absorption near edge structure (XANES) spectra recorded with opposite photon helicities of the incoming photons. Measurements were performed for both directions of applied magnetic field parallel and anti-parallel to the incoming X-ray wave vector in order to ensure the absence of experimental artefacts. The element-selective magnetisation curves were recorded by monitoring the intensity of XMCD signal as a function of an applied magnetic field.

D. EXAFS Fitting

The software suite Demeter [START_REF] Ravel | Athena, artemis, hephaestus: data analysis for x-ray absorption spectroscopy using ifeffit[END_REF], which includes Athena (data normalisation) and Artemis (simulation), was used. This software allows the fitting of the extended X-ray absorption fine structure (EXAFS) formula signal, allowing for each atomic shell j around the target atom i the determination of N j the coordination number of the atom i, S 2 i the reduction factor from multi-electronic effects, F j the backscattering amplitude, σ 2 j the Debye-Waller factor, k = 2eme 2 (E -E 0 ) the photoelectron wave vector, λ the mean free path of the photoelectron, r j the interatomic distance and φ ij the phase shift.

After the extraction of the EXAFS signal χ(k) from the absorption signal, its FT (χ(R)) has been restricted to fit the neighbouring of the absorbing atom. The fitting is done by modelling the expected spectrum with FEFF6 [START_REF] Rehr | Theoretical approaches to xray absorption fine structure[END_REF][START_REF] Rehr | Ab initio theory and calculations of x-ray spectra[END_REF], choosing the main paths of the photoelectron, then fitting with more paths as the fitting window is increased to higher radial distances. The S 2 i parameter, which accounts for the relaxation of the other electrons of the absorbing atom [START_REF] Teo | EXAFS: Basic Principles and Data Analysis[END_REF], is kept fixed in the fits to a value obtained using pure reference foils of each element: 0.73 for Fe, 0.70 for Co, and 0.84 for Pt. The fitted parameters are: the energy edge E 0 , allowed to slightly vary according to the sample, the radial distances R ef f , to account for distortion of the tested crystal structure R along the a and c-axis (while maintaining the cell volume for cubic structures), and the Debye-Waller σ.

The L1 0 -FePt ref. sample provided a calibration mean to the procedure which led to the best fit with the L1 0 structure for this film.

III. RESULTS

The mean size of mass-selected Co clusters is around 7.9 nm in diameter as-deposited, as obtained from TEM observation (Fig. 1a andb). To verify the cluster diameter in the FePt matrix, a single Co cluster layer embedded between two FePt on a Si 3 N 4 substrate has been prepared to perform EDX images, provided in Fig. 1c, where the clusters observed in the metallic matrix have a size compatible with the diameter found by TEM imaging. Both measurements give consistent cluster diameter pre-annealing, even when embedded in metallic matrix. The distribution of Fe and Pt is not perfectly homogeneous but reveals "cloudslike" formations, similar to thin films deposition, which most likely disappear when the thickness increases [START_REF] Figueroa | Structural and magnetic properties of granular co-pt multilayers with perpendicular magnetic anisotropy[END_REF].

A. Magnetic properties

The magnetic properties of Co@FePt nanocomposites were studied by superconducting quantum interference device (SQUID) magnetometry and XMCD experiments performed at room temperature. Fig. 2 presents the magnetisation curves of NC and NF containing 30% Co, and a reference L1 0 -FePt film (L1 0 -FePt ref). On the one hand, both NC and NF samples have higher saturation magnetisation than the L1 0 -FePt ref., which can be attributed to the higher magnetisation of Co as compared to FePt. On the other hand, the NC sample exhibits a higher coercivity than the NF, which is magnetically soft as expected for cubic L1 2 phase. The remanence magnetisation, measured in plane, is relatively high in all cases (superior to 80%), and indicates only partial out-of-plane c-texture. Despite the higher magnetisation value of the NC, the estimated energy product (BH) max is lower compared to the one in L1 0 -FePt ref. because of lower coercive field (Table I). In the ideal case of a sharp interface between the hard FePt and the soft Co phases, element specific studies permit to separately probe both components. The dependence of the XMCD signal as a function of the applied magnetic field (Fig. 3) shows that Fe and Co exhibit the same behaviour and switch at the same field value for every concentration (in the studied range 0 -30% Co), indicating a strong coupling. A slight difference is observed in the coercive field values extracted from XMCD (Fig. 3) and SQUID (Fig. 2) measurements, on the same samples. This is attributed to the difference in the probed regions, larger in the case of SQUID measurements. Isolated face-centred cubic (fcc) Co clusters with a diameter of 7.9 nm are expected to be superparamagnetic at room temperature and, therefore, magnetically soft [START_REF] Jamet | Magnetic anisotropy of a single cobalt nanocluster[END_REF]. Here, there is no kink at low field on the magnetisation curve, showing that the whole film behaves like a single magnetic phase and there is no indication of the presence of a secondary magnetic phase. However, it does not give access to the degree of interdiffusion at the cluster-matrix interface, which may lead to different intermixing states (as illustrated in Fig. S2). Such an interdiffusion is expected to result in a modulation of the composition with an intermediate diffused layer between a Co core and a FePt matrix that could be denoted as (Co@Co x Fe y Pt z @FePt). The ultimate stage of interdiffusion would be a homogeneous alloyed film, which is rather unlikely as the magnetic properties of NC differ significantly from the reference homogeneous NF. Apart from the latter hypothesis of a homogeneous configuration, definitely ruled out by SQUID magnetometry measurements, it would be very difficult to discern between non cluster-matrix interdiffusion and Co@Co x Fe y Pt z @FePt by TEM imaging. X-ray absorption spectroscopy (XAS) studies have thus been performed to clarify the local structural properties of the samples.

B. Structural properties

XANES and XMCD signals at the Co K-edge are presented in Fig. 4, for a 20% Co NC sample and references Co hexagonal close-packed (hcp) and L1 0 -CoPt. The 20% Co NC XANES signal is very different from a Co hcp signal, which shows an important dip on A and a B 2 peak at higher energy [START_REF] Park | Characterization of superparamagnetic core-shell nanoparticles and monitoring their anisotropic phase transition to ferromagnetic solid solution nanoalloys[END_REF], whereas the NC sample and references have a symmetric B 1 and B 2 feature close to one another, characteristic of face-centred tetragonal (as in L1 0 -FePt and L1 0 -CoPt) alloyed phases [START_REF] Park | Characterization of superparamagnetic core-shell nanoparticles and monitoring their anisotropic phase transition to ferromagnetic solid solution nanoalloys[END_REF][START_REF] Souza-Neto | Depth dependent local structures in copt thin films[END_REF]. This splitting suggests some alloying of Co with Fe and Pt from the matrix in the NC sample, as expected for the L1 0 -CoPt reference. Nevertheless, the B 1 -B 2 splitting is also present in Co hcp [START_REF] Kozinkin | Mechanisms of formation of near-edge fine structure of k x-ray absorption spectra of metallic cu, ni, co (hcp and fcc phases), and cr[END_REF][START_REF] Mazalski | Xas and xmcd studies of magnetic properties modifications of pt/co/au and pt/co/pt trilayers induced by ga+ ions irradiation[END_REF], and EXAFS measurements were performed to better understand the structure of the NC sample, and will be detailed later. The XMCD signal of the NC is close to the L1 0 -CoPt signal, demonstrating that Co is not in pure metallic state, neither hcp nor fcc. XLD measurements at the Fe K-edge for 20% Co NC, NF and the L1 0 -FePt reference (Fig. S3) reveal significant XLD signal which proves a -at least partialtexturation of the sample, favoured by the alternative stacking of the layers [START_REF] Zeng | Orientation-controlled nonepitaxial l10 copt and fept films[END_REF]. The XANES peaks B 1 and B 2 appears asymmetric only for NF sample (B 2 feature higher than B 1 ), which is consistent with an enrichment in Co for NF samples, as observed in other studies [START_REF] Hlil | X-ray absorption edges in platinum-based alloys. 2. influence of ordering and of the nature of the second metal[END_REF] and the XANES of the hcp Co. The shoulder A, mainly due to Co and Fe 4p orbitals [START_REF] Souza-Neto | Depth dependent local structures in copt thin films[END_REF] is larger for the NF, as expected for a more complete mixing in the NF as compared to in the NC.

To study the local structure of the samples, XAS measurement have been performed to obtain the specific EX-AFS signature at the Fe and Co K-edges and Pt L 3 -edge (see SI methods for details [START_REF] Ravel | Athena, artemis, hephaestus: data analysis for x-ray absorption spectroscopy using ifeffit[END_REF][START_REF] Teo | EXAFS: Basic Principles and Data Analysis[END_REF]). Fig. 5 presents the modulus and real part of the Fourier transform (FT) of the EXAFS signal for 30% Co NC and NF, giving an additional qualitative indication of different local environments in both systems. The comparison to the L1 0 -FePt ref. (Fig. S4), shows that the NC is much closer to this phase at the Fe K-edge. This is an argument in favour of a stronger Co-matrix diffusion in the NF than in the NC, which could also explain the low coercivity obtained on this NF sample. As Co and Fe show similar binary phase diagram with Pt [START_REF] Smithells | Smithells metals reference book[END_REF], the more atomic interdiffusion occurs, the more the stable phase shifts towards the higher Co+Fe content values, leading to a magnetically soft L1 2 -X 3 Pt (with X = Co, F e) when Co content is high enough (as in 30% Co samples). Two different kinds of simulation have been realised to analyse the spectra: a first fit is performed on a wide radial distance (typically between 1.5 and 5.5 Å) at each edge, with different possible crystal alloy phases, by setting the nature and number of neighbouring atoms N j . The best fits from this method for each edge is provided on Table II (detailed EXAFS results are provided in the SI Tables).

For the 30% NC sample, the EXAFS simulations at the Fe K-edge and Pt L 3 -edge lead to L1 0 -FePt structure. On the contrary, for the NF sample, the optimised structure is a mixed X 3 Pt structure at the Fe K-edge and Pt L 3edge, confirming the strong Co-matrix intermixing in this sample. Distinguishing Fe from Co neighbouring atoms based on EXAFS measurements is a difficult task (as ∆Z = 1). Nevertheless, the fact that the Co 3 Pt phase fits only at Co K-edge in the NC samples (Fig. 6) while L1 0 -FePt phase fits at Fe K and Pt L 3 -edge suggests the persistence of Co-rich regions.

To quantify atomic interdiffusion between cluster and matrix in the NC, another fit is performed at the Co Kedge on NC samples, by choosing small radial distances (between 1.5 and 3.0 Å) to limit to the first neighbours of the Co atoms. The fit is realised with Co (accounting for both Co or Fe atoms) and Pt atoms, initially at positions found from the previous Co 3 Pt fit. The coordination numbers N j are then set free (but restraining to N Co,F e + N P t = 12) and have been obtained by the fit at different angles. The number of Co-Co bonds is found to be in average centred on N Co-Co = 4.2 (Fig. S5).

In addition, a diffusion of the cluster is simulated from an initial truncated-octahedron Co cluster (stable shape of fcc clusters [START_REF] Van Hardeveld | The statistics of surface atoms and surface sites on metal crystals[END_REF]) of 11 atoms/ridge (which size corresponds to the size observed by TEM) inserted in a FePt matrix. A simple iterative diffusion algorithm is then applied to every atom by giving a 50% probability of swapping its place with a neighbouring atom. The mean number of Co-Co bonds is then calculated and compared to the number obtained by EXAFS fitting. These steps are repeated until the coordination number of the model is equal or lower than the one obtained from the EX-AFS. It results that this 4.2 coordination number can occur when matrix atoms reach the centre of the cluster (Fig. S6), but the Co concentration remains above 75% in a 1.8 nm radius at least. For NC, the important criterion is the core size of the soft inclusion. According to the Co-Pt (or Fe-Pt) phase diagrams, the edge of the L1 0 phase is at least 35% content in Co (or Fe) [START_REF] Smithells | Smithells metals reference book[END_REF]. Therefore, with Co-content clusters embedded in hard L1 0 matrix, the soft inclusion of X 3 Pt remains around 7.4 nm diameter after annealing (Fig. S7).

IV. CONCLUSION

Magnetic measurements of the composition dependence of the coercive field as well as the EXAFS fitting and simulation treatment prove that, after annealing at 700 • C for 20 min, NC still present high Co content inclusions well coupled to the matrix, contrary to the NF where the interdiffusion is complete. To explain such result, one can first mention that clusters have a well-defined shape as prepared and are particularly stable [START_REF] Ferrando | Structure and properties of nanoalloys[END_REF]. Secondly, for the same amount of Co in a sample, the thickness of the Co layer in NF (1.0 nm for 30% Co) is smaller than the radius of a cluster as prepared, favouring the total Co-atomic diffusion in matrix during annealing. This lower diffusion in NC allows the matrix to stay in the L1 0 stability domain, keeping the magnetic hardness of the sample. Moreover, the cluster diffusion simulation does not take into account the different miscibility as well as the different sizes of Fe, Co, or Pt atoms, which can lead to different diffusion coefficients [START_REF] Smithells | Smithells metals reference book[END_REF]. As such, heavy Pt atoms of the matrix are less likely to diffuse into the Co cluster. The crystal distortions of the fcc Co-rich regions in the face-centred tetragonal (fct) L1 0 matrix have also been neglected in the simulation, but are revealed by the EXAFS fitting.

One of the key factor to improve the (BH) max is a better control of the cluster-matrix interdiffusion: with thinner layers of Fe and Pt and a larger number of repetition, the annealing to form the L1 0 phase can be achieved at lower temperature and faster. Moreover the maximum of coercivity for non-epitaxial thin films is not reached for Fe 50 Pt 50 , but rather for Fe 53 Pt 47 [START_REF] Hong | Microstructure of fept/pt magneticthin films with high perpendicular coercivity[END_REF][START_REF] Watanabe | Perpendicular magnetization of epitaxial fept(001) thin films with high squareness and high coercive force[END_REF]. Although pure Co clusters provide the opportunity to visualise soft and hard phases individually, they are not in favour of a high (BH) max , as the highest moment per atom is reached for Fe 65 Co 35 [START_REF] Coey | Magnetism and Magnetic Materials[END_REF]. Finally, the texturation of the hard magnetic matrix could be improved using a MgO crystal substrate. These Co@FePt samples are a proof of concept of NC permanent magnets, stabilising the moments of the soft clusters at room temperature.

FIG. 1 .

 1 FIG. 1. (a) Bright field TEM image of the mass-selected Co clusters protected by a C film. (b) Size histogram deduced from TEM observations along with the Gaussian fit.(c) EDX images of a FePt/Co clusters/FePt sample on a Si3N4 substrate, along with the annular dark-field scanning transmission electron microscopy (STEM-ADF) image. Both measurements give consistent cluster diameter pre-annealing, even when embedded in metallic matrix. The distribution of Fe and Pt is not perfectly homogeneous but reveals "cloudslike" formations, similar to thin films deposition, which most likely disappear when the thickness increases[START_REF] Figueroa | Structural and magnetic properties of granular co-pt multilayers with perpendicular magnetic anisotropy[END_REF].

FIG. 2 .

 2 FIG.2. Hysteresis loops at 300 K for two samples with the same Co content and the FePt matrix without Co. The NC sample has higher saturation magnetisation than the bare L10-FePt ref. which is brought by the Co, but keeps a sizeable coercivity whereas the NF are magnetically soft. The inset shows the dependence of the coercive field µ0Hc with the Co content for NF and NC (the dashed lines are a guide for the eye).

FIG. 3 .

 3 FIG.3. Hysteresis loops at 290 K of a 20% Co NC sample at Fe and Co K-edges. Both elements show the same coercivity. Note that the deviation of Fe and Co magnetic moment curves between 0.5 and 1 T is attributed to lower density of Co clusters at the edge of the probed area in grazing incidence.

FIG. 4 .

 4 FIG.[START_REF] Coey | Perspective and prospects for rare earth permanent magnets[END_REF]. XANES and XMCD signal at the Co K-edge of a 20% Co NC, a Co hcp metallic foil (from private communication with A. Rogalev and F. Wilhelm) and a L10-CoPt reference (from Maziewski et al.[START_REF] Maziewski | Tailoring of magnetism in pt/co/pt ultrathin films by ion irradiation[END_REF]).

FIG. 5 .

 5 FIG. 5. Comparison of the magnitude (a) and real part of the (b) of the EXAFS signal for 30% Co NC and 30% Co NF at each edge.

FIG. 6 .

 6 FIG.6. Weighted EXAFS oscillations, magnitude of the filtered signal, and real part of the FT of the 30% Co NC sample at the Co K-edge, along with the Co3Pt fit.

TABLE I .

 I Coercive field and energy product for a NC, a NF, the L10-FePt ref., and a Nd2Fe14B random bonded magnet from Coey[START_REF] Coey | Perspective and prospects for rare earth permanent magnets[END_REF].

		µ0Hc (T) Ms (MA.m -1 ) (BH)max (kJ.m -3 )
	30% Co NC	0.18	1.0	63
	30% Co NF	0.01	1.0	< 1
	L10-FePt ref.	1.4	0.8	119
	Nd2Fe14B	∼ 0.8	1.3	63

TABLE II .

 II Structure giving the best fits for a window between 1.5 and 5.5 Å (X = Co, F e).

	Best fit at	NC	NF
	Co K-edge	X3Pt	X3Pt
	Fe K-edge	L10-FePt	X3Pt
	Pt L3-edge	L10-FePt	X3Pt

ACKNOWLEDGMENTS

The authors thank Florent Tournus (iLM laboratory) for his help on the cluster modelling, Nicholas Blanchard (iLM laboratory) for TEM imaging, and José Penuelas (STMS/INL) for the XRD measurements. The TEM-EDX experiments were performed at the Consortium Lyon St-Etienne de Microscopie. XMCD, XLD, XANES and EXAFS measurements were made at ESRF, on beamline ID12 and French CRG BM30B FAME for the latter. This work is supported by the ANR through the collaborative project SHAMAN (ANR-16-CE09-0019), and the doctoral school ED PHAST 52. The authors are also grateful to the ILMTECH platform for clusters synthesis at PLYRA and SQUID measurements at the Centre de Magnétométrie de Lyon.