Hadi Hachem

Olivier Jeannin

Marc Fourmigué

Dominique Lorcy

Influence of bulky groups in single-component conductors based on neutral radical gold bis(dithiolene) complexes

Keywords: Au complexes, dithiolene ligand, redox behavior, spectroelectrochemistry, conducting materials

A novel single component conductor derived from neutral radical gold bis(dithiolene) complexes is prepared based on the original reactivity of tBuN-substituted 1,3-thiazoline-2thione heterocycle to give a tBuS-substituted thiazole ring. The corresponding 2-(tertbutylthio)-1,3-thiazole-4,5-dithiolate ligand (tBuS-tzdt) forms the d 8 anionic complex [Au(tBuS-tzdt)2] -, easily oxidized through electrocrystallization into the neutral radical [Au(tBuS-tzdt)2] • . The effect of increasingly bulky R groups (R = Et, HO(CH2)2, tBu), in the series of such radical complexes [Au(RS-tzdt)2] • , is investigated, with a focus on their solid state organization, either into face-to-face dimers or into non-dimerized, uniform stacks.

Introduction

Over the last two decades, metal bis(dithiolene) complexes have demonstrated their great potential as precursors of Single-Component Molecular Conductors [1][2][3][4]. Within this family, two types of neutral complexes can be distinguished, (i) closed-shell complexes such as the neutral Ni bis(dithiolene) complexes abbreviated as [Ni(dt)2] 0 , [5][6][7][8] and (ii) open-shell complexes based on gold bis(dithiolene) complexes in their radical neutral form, [Au(dt)2] • . [9][10][11][12][13][14][15] In the gold series, we demonstrated that, when using a N-alkyl-1,3-thiazoline-2-thione-4,5dithiolate ligand, the corresponding complexes [Au(R-thiazdt)2] • (R = Et, [16][17] EtOH, [18] iPr, [19] Pr, [20]) exhibit high conductivities, becoming metallic under pressure while metallic at ambient pressure for the smallest substituent (R = Me) [21].

Interestingly, the presence of relatively bulky substituents on the thiazoline ring in [Au(R-thiazdt)2] • complexes still allowed the neutral radical complexes to form uniform stacks in the solid state, with overlap patterns favorable for strong intermolecular overlap interactions and associated high conductivities [18][19][20]. In the course of our work on such gold bis(dithiolene) complexes, we also investigated another dithiolene ligand having a 2-alkylthio-1,3-thiazole backbone, to provide the corresponding neutral radical gold complexes [Au(RStzdt)2] • . They can be considered as the S-isomers of the [Au(R-thiazdt)2]• complexes, but with now an aromatic thiazole ring [22][23][24]. With this idea in mind, we explored first the R = Me and R = Et substituents but both gold complexes, namely [Au(MeS-tzdt)2] • and [Au(EtS-tzdt)2] • , form in the solid state strongly dimerized stacks with associated pairing of the radical species into diamagnetic dimers and the associated low conductivity. On the other hand, the introduction of a bulkier hydroxyethyl substituent allowed the organization of [Au(HO(CH2)2Stzdt)2] • into uniform stacks thanks to hydrogen bonding (HB) inter-stack interactions [23], between the OH group as HB donor and the nitrogen atom of the thiazole ring as HB acceptor.

In the following, we want to investigate another stronger structural change in this tzdt series, which relies on the use of an even bulkier substituent such as a tert-butyl group in the corresponding [Au(tBuS-tzdt)2] -1,• complexes. We report here on the preparation of the anionic and neutral gold complexes, and describe and analyze their electronic and structural properties.

Results and discussion

The synthesis of the anionic complex [Au(tBuS-tzdt)2] -1 was performed according to the chemical route described in Scheme 1, starting from the N-tBu-1,3-thiazoline-2-thione proligand 1. We used a chemical transformation of N-tert-butyl-1,3-thiazoline-2-thione heterocycles into 2-alkylthio-1,3-thiazole derivatives that we recently evidenced [22]. The synthesis of 2-(tert-butylthio)-1,3-thiazole-4,5-dithiolene proligand 2 involves therefore the reaction of 1 in CH2Cl2 in the presence of an excess of I2. It is worth mentioning that when the reaction was performed in DMSO as previously described, we obtained instead the 2iodothiazole proligand [24]. Using dichloromethane rather than DMSO, no trace of the 2iodothiazole proligand was detected. Deprotection of the proligand 2 in the presence of sodium methanolate, followed by the addition of KAuCl4 and PPh4Br leads to the formation of the monoanionic gold complex as tetraphenylphosphonium salt, [Ph4P][Au(tBuS-tzdt)2].

Recrystallization from CH3CN afforded crystals amenable to X-ray diffraction (vide infra). The monoanionic complex was oxidized electrochemically via electrocrystallization, in order to generate the corresponding neutral radical complex [Au(tBuS-tzdt)2] • . Crystals of good quality of the neutral species were collected at the anode and also structurally characterized (vide infra).

Scheme 1 Synthetic route toward neutral gold bisdithiolene complex [Au(tBuS-tzdt)2] •

The redox properties of the anionic complex [PPh4][Au(tBuS-thiazdt)2] were studied by cyclic voltammetry (CV) and the redox potentials are collected in Table 1 together with those of reference complexes with other 2-alkylthio substituents. The CV exhibits two well reversible oxidation waves corresponding to the successive oxidation of the monoanionic complex to the neutral radical species and then to the monocationic state. The shape of this voltammogram stands out from all other CV obtained so far for gold complexes with a thiazole backbone.

Indeed, for all the other gold complexes with the RS-tzdt (R = Me, Et [22], (CH2)2OH [23]) or R'-tzdt (R' = I, H) [24] ligands, only one pseudo reversible system was observed upon oxidation, with a sharp cathodic peak of higher intensity than the anodic peak, a consequence of electrodeposition upon oxidation, followed on the reverse scan by a sharp desorption reduction peak. The fully reversible CV observed here for [PPh4][Au(tBuS-tzdt)2)] is due to a higher solubility of the neutral species generated upon oxidation, explaining the lack of adsorption phenomena (Fig. 1). As previously noted, the gold complex isomer with a N substituted ligand, tBu-thiazdt [25], exhibits also upon anodic scan two reversible oxidation waves assigned similarly to the oxidation of the monoanionic complex into the neutral radical one and then to the monocationic complex. The main difference between these two CVs, and not the least, concerns the potential difference between these two redox processes. The presence of the aromatic thiazole backbone in [PPh4][Au(tBuS-tzdt)2)] induces a larger potential difference (E = 460 mV) between the two redox processes, demonstrating the larger stability window of the radical species for the S-substituted ones, and a larger Coulombic repulsion U.

This could be assigned to the structure of the dithiolene ligand backbone, which is aromatic in the case of tzdt ligand and non-aromatic for thiazdt one. Indeed, the oxidation of the gold bis(dithiolene) complexes essentially affects the AuS2C2 metallacycles, inducing some bond length modifications, with a shortening of the C-S bonds and a lengthening of the C=C bond.

Both would induce for the tzdt ligand a loss of aromaticity. On the cathodic scan, as for all gold complexes of this family regardless of the substitution pattern of the ligand, an irreversible reduction process is observed for [PPh4][Au(tBuS-tzdt)2)], which corresponds to a metalcentered reduction of the monoanion to the dianionic species Epc (-1/-2) .

Table 1 Redox potentials in V vs SCE of gold bis(dithiolene) complexes.

Epc (-1/-2)
Epa/Epc (-1 /0) Epa/Epc (0/+1) Ref.

[

Spectroelectrochemical investigations

The higher solubility of [Au(tBuS-tzdt)2] • prompted us to realize a spectroelectrochemical investigation in order to determine the UV-Vis-NIR spectral signature of the different oxidation states of the gold complex. In its monoanionic state, the d 8 gold complex exhibits absorption bands limited to the UV-Vis region. Once the complex is oxidized to the neutral radical species, a broad band appears at 1614 nm, with a clear isosbestic point at 354 nm (Fig. 2). Further oxidation towards the monocation leads to the decrease of the 1614 nm absorption band, and the increase of a new absorption band centered at 1038 nm. Spectra of this cationic, high oxidation state are rare for gold bis(dithiolene) complexes, and have only been reported before by Wieghardt et al. for complexes with (tert-butylphenyl)2C2S2 dithiolate ligands [26]. This evolution of the spectrum from the monoanionic to the monocationic state for gold complexes, parallels that oberved from the dianionic to the neutral state for the Ni, Pd, and Pt complexes.

Furthermore, the absorption bands of the neutral gold complex are considerably red shifted when compared to the Ni complexes with the same ligands, as already mentionned with the gold and palladium bis(dithiolene) complexes of (tert-butylphenyl)2C2S2 dithiolate ligand [26].

Molecular structures

Both the monoanionic and the neutral crystalline complexes were investigated by single crystal X-ray diffraction. The molecular structures of the complex in both oxidation states are reported in Fig. 3. The monoanionic complex, [PPh4][Au(tBuS-tzdt)2] crystallizes in the triclinic system, space group 𝑃1 ̅ , with a Ph4P + cation and a gold complex located in general position in the unit cell. As shown in Fig. 3a, the complex is affected by disorder on both sides. In one side, the tBu group exhibits a rotational disorder. On the other side, the disorder model indicates unambiguously the presence of a cis-trans mixture, with 29% trans isomer (based on S5B, S6B) and 71% cis isomer (based on S5A, S6A).

The neutral radical complex, [Au(tBuS-tzdt)2] crystallizes in the triclinic system, space group 𝑃1 ̅ , with the gold atom now located on an inversion center (Fig. 3b), with only the trans 2), demonstrating that the aromatic thiazole ring is also affected by the oxidation. In the solid state, the radical complexes are not associated into dimers but form uniform stacks along the a axis, interacting sideways within ab layers (Fig. 4). Short S•••S contacts are evidenced between neighboring stacks, with the shortest contact at 3.505 Å involving sulfur atoms of the metallacycles. Within the stacks, a pronounced longitudinal slip is observed between the neighboring complexes with a plane-to-plane distance of 3.69 Å (Fig. 5). Compared with the hydroxyethyl substituted complex, the tBu groups here induce a slightly larger plane-to-plane distance, without hindering a uniform stacking of the complexes, an advantage for electronic delocalization but also a disadvantage for strong intra-stack interactions necessary for high conductivity. The complex exhibits three types of overlap interactions (I, II, and III) with neighboring molecules within a slab (Fig. 6). The calculated βHOMO-HOMO interaction energies (determined on the molecule with an in-plane orientation of This assumption is confirmed by the calculated band structure for this complex (Fig. 7).

It shows indeed a larger band dispersion along the stacks (  X) than in the perpendicular direction. The dispersion itself is rather weak (< 0.5 eV), in accordance with the larger planeto-plane distance and longitudinal slip mentioned above. Altogether, the structural and electronic properties of this compound suggest a Mott insulating state, i.e. a formally half-filled band system where the band dispersion (W) is too weak to compete with the Hubbard repulsion term U. Under such circumstances, the compound is expected to behave as a semiconductor. Resistivity measurements confirmed this hypothesis, with a semiconducting behavior observed upon cooling down to 230 K (Fig. 8). The room temperature conductivity was found to be 2.4 × 10 -5 S.cm -1 with an activation energy of 0.23 eV.

Conclusions

In this work, we have reported here a new RS-substituted thiazole-based gold complex bearing a bulky tert-butyl group [Au(tBu-tzdt)], and explored its electronic and structural properties in the monoanionic and neutral radical state. The solution properties showed an improved stability of the higher oxidation states relative to other complexes of the same family, evidenced by a fully reversible cyclic voltammetry and the observation of the absorption spectra of the monocationic species. Moreover, the bulky tBu group succeeded in preventing dimerization of the neutral species previously seen with the Me and Et analogues, and afforded uniform stacks that are favorable for conducting behavior. However, the weak intra-and interstack interactions, along with the disorder of the tBu group resulted in electronic localization and an insulating behavior of the complex. Further studies with different groups are underway to enhance the conducting properties within these series of gold bis(dithiolene) complexes.

Experimental

Reagent and apparatus

Chemicals and materials from commercial sources were used without further purification. All the reactions were performed under an argon atmosphere.

Fig. 1

 1 Fig. 1 Cyclic voltammogram of [PPh4][Au(tBuS-tzdt)2)], in CH2Cl2 with NBu4PF6 as a supporting electrolyte, at 100 mV.s -1

Fig. 2

 2 Fig. 2 UV-Vis-NIR absorption spectra of the electrochemical oxidation of [PPh4][Au(tBuStzdt)2], (a) monitoring from 0.3V to 0.8 V (in insert the absorption between 300 and 400 nm with the isosbestic point showing at 354 nm), (b) monitoring from 1 V to 1.5 V.

  isomer. The tBu moiety is disordered on two positions with almost 50:50 distribution, one where the S-CMe3 bond is in the molecular plane with a 51% occupancy, and the other with the S-CMe3 bond out of the molecular plane, rotated by 42°. Upon oxidation, a planarization of the metallacycles is observed with smaller dihedral angles along the S•••S hinge, from 3.66° in the monoanion to 1.98° in the neutral complex. Comparison of the bond distances between the monoanionic and neutral states (Table2) shows a behavior similar to that observed in other gold bis(dithiolene) complexes, which is to say upon oxidation, the C-S bonds of the metallacycle (b, b') shorten and the C=C bonds (c) lengthen. Those changes in the bond lengths indicate the evolution of the 1,2-dithiolate ligand upon oxidation toward a more 1,2dithioketone structure. Note also some modifications occurring on the thiazole ring: besides the lengthening of the C=C bond, the most significant ones are the lengthening of the C=N (g) bond and the shortening of the C-S (e) one (Table

Fig. 3

 3 Fig. 3 Molecular views of (a) the anionic [Au(tBuS-tzdt)2] -and, (b) the neutral radical [Au(tBuS-tzdt)2] • species. The disordered fragments are highlighted with black and light grey bonds (See text).

Fig. 4

 4 Fig. 4 Projection view along a of the unit cell of [Au(tBuS-tzdt)2] • with the shortest S•••S contacts indicated (dashed line, red : 3.505 Å and blue : 3.67 Å). Only the in-plane orientation of the tBu group is shown.

Fig. 5

 5 Fig. 5 Overlap pattern between neighboring molecules in the neutral radical complex [Au(tBuStzdt)2] • . Only the in-plane orientation of the tBu group is shown.

theFig. 6

 6 Fig. 6 Side view of the conducting slabs of [Au(tBuS-tzdt)2] • with the intermolecular interactions, the tBu groups have been omitted for clarity.

Fig. 7

 7 Fig. 7 Calculated band structure for [Au(tBuS-tzdt)2] • . The HOMO-based band is represented in blue and the HOMO-1 one in red, the dashed red line represents the Fermi level, assuming a metallic filling of the levels. Γ = (0, 0, 0), X = (1/2, 0, 0), M = (1/2, 1/2, 0), Y = (0,1/2, 0) of the Brillouin zone of the monoclinic lattice.

Fig. 8

 8 Fig. 8 Temperature dependence of the resistivity of [Au(tBu-S-tzdt)2] • .

Table 2

 2 Comparison of bond distances (Å) of the monoanionic and neutral complex

		a	a'	b	b'	c
	[Au(tBuS-tzdt)2] -1	2.362(8)	2.286(6)	1.752(17) 1.797(17) 1.32(2)
	[Au(tBuS-tzdt)2] •	2.3174(13) 2.3082(15) 1.704(5)	1.729(5)	1.370(7)
		d	e	f	g	h
	[Au(tBuS-tzdt)2] -1	1.742(14)	1.810(15)	1.752(13) 1.224(19) 1.42(2)
	[Au(tBuS-tzdt)2] •	1.729(5)	1.749(6)	1.740(5)	1.285(7)	1.417(7)

  Melting points were measured on a Kofler hot-stage apparatus and are uncorrected. Mass spectra were recorded by the Centre Régional de Mesures Physiques de l'Ouest, Rennes. Methanol, acetonitrile and dichloromethane were dried using Inert pure solvent column device. CVs were carried out on a 10 -3 M solution of complex in CH2Cl2 with NBu4PF6 0.1 M. Potentials were measured versus Saturated Calomel Electrode (SCE). The spectroelectrochemical setup was performed in CH2Cl2 with Bu4NPF6 0.2 M using a Pt grid as the working electrode, a Pt wire as the counter electrode and SCE reference electrode. A Shimatzu 3600 spectrophotometer was employed to record the UV-vis-NIR spectra. The proligands 1 was prepared as previously reported.

	Synthesis of 5-(tbutylthio)-1,3-Dithiolo[4,5-d]thiazol-2-one 2.
	Under inert atmosphere, to a solution of 1 (100 mg, 0.38 mmol) in 5 mL of CH2Cl2, iodine
	crystals (0.38 g, 1.52 mmol) was added. The reaction mixture was set to stirred at 45 o C for 4
	hours. The reaction was then quenched with a saturated solution of sodium thiosulfate (100 ml),
	the product was extracted with CH2Cl2 and the organic phase was washed with water and then
	dried over MgSO4. The solvent was evaporated under vacuum and the crude oil was purified
	by flash chromatography (eluent: DCM/Petroleum ether; 80:20) giving the compound as a
	white powder. Yield= 0.036 g, 36%; Rf = 0.73, (SiO2, CH2Cl2); mp = 88 °C; 1 H NMR (300
	MHz, CDCl3) δ (ppm): 1.48 (s, 9H, CH3); 13 C NMR (75 MHz, CDCl3) δ (ppm): 190.2 (C=O),
	162.5 (C=N), 143.6 (C=C), 120.5 (C=C), 51.2 (C-CH3), 19.9 (CH3); HRMS (ASAP) calcd for
	C8H10NOS4 + : 263.9639, Found : 263.9640; Anal. calcd for C8H9NOS4: C, 36.48; H, 3.44; N,
	5.32; S, 48.69. Found: C, 36.49; H, 3.29; N, 5.32; S, 48.83.
	Synthesis of [PPh4][Au(tBuS-tzdt)2]
	Under inert atmosphere, a solution of MeONa (Na: 40 mg, 1.47 mmol) in MeOH (20 mL) was
	added to the dithiole-2-one 2 (150 mg, 0.57 mmol). After complete dissolution, the solution
	was stirred for 30 min at room temperature. Then a solution of KAuCl4 (110 mg, 0.29 mmol)
	in MeOH (5 mL) was added followed 6 hours later by the addition of Ph4PBr (125 mg, 0.30
	mmol). After stirring for 15 h, the formed precipitate was filtered and recrystallized from
	acetonitrile to afford the monoanionic complex [PPh4][Au(tBuS-tzdt)2] as pink crystalline
	plates. Yield 51% (150 mg). mp = 144°C; 1 H NMR (CD2Cl2, 300 MHz) δ 7.86 -7.51 (m, 20H,
	PPh4), 1.35 (s, 18H, CH3); 13 C NMR (CD2Cl2, 75 MHz) δ 161.9 (C=N), 151.9 (C=C), 135.6
	(CAr), 134.4 (CAr), 130.7 (CAr), 118.1 (C=C), 116.8 (CAr), 49.36 (S-C(CH3)3), 30.9 (S-C(CH3)3);
	Anal. calcd. for C38H38AuN2PS8: C, 45.32; H, 3.80; N, 2.78; S, 25.47. Found: C, 44.99; H, 3.94;

N, 2.72; S, 25.40.

Electrosynthesis of [Au(tBuS-tzdt)2] •

Table 3 -

 3 Crystallographic data. CCDC 2238989 and 2238990 contain X-ray crystallographic files in CIF format for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.

	Compound	[PPh4][Au(tBuS-tzdt)2]	[Au(tBuS-tzdt)2] •
	CCDC	2238989	2238990
	Formula	C38H38AuN2PS8	C7H5Au0.5NS4
	FW (g•mol -1 )	1007.12	333.87
	Crystal system	triclinic	triclinic
	Space group	𝑃1 ̅	𝑃1 ̅
	a (Å)	11.3191(7)	4.8984(12)
	b (Å)	13.5579(9)	6.4182(16)
	c (Å)	14.9691(10)	16.954(3)
	α	86.600(2)	89.825(6)
	β	68.498(2)	86.037(6)
	γ	84.332(2)	87.433(7)
	V (Å 3 )	2126.2(2)	531.2(2)
	T (K)	296(2)	296(2)
	Z	2	2
	Dcalc (g•cm -3 )	1.859	1.724
	μ(mm -1 )	3.919	2.087
	Total refls.	50278	11527
	Abs. Corr .	multi-scan	multi-scan
	Uniq. refls. (Rint)	9780(0.0747)	2427(0.0426)
	Unique refls. (I > 2σ(I))	6659	2327
	R1, wR2	0.0711, 0.1545	0.0304, 0.0735
	R1, wR2 (all data)	0.1304, 0.1913	0.0340, 0.0771
	GoF	1.156	1.048
	Supplementary data

Acknowledgments

This work was supported by the Université de Rennes 1 (Ph. D. grant for H Hachem)

Under inert conditions in a U shaped electrocrystallization cell equipped with Pt electrodes, a supporting electrolyte Me4NBF4 (200 mg), and the monoanionic complex (10 mg) were dissolved in a 12 ml of CH3CN at room temperature. A constant current intensity was adjusted to 0.5 (µA) between the electrodes, and the reaction was left during seven days.

Crystals of the neutral complex were collected at the anode.

Band structure calculations

The tight-binding band structure calculations and βHOMO/LUMO interaction energies were based upon the effective one-electron Hamiltonian of the extended Hückel method [27], as implemented in the Caesar 2.0 chain of programs [START_REF] Ren | Crystal and Electronic Structure Analysis Using CAESAR[END_REF]. The off-diagonal matrix elements of the Hamiltonian were calculated according to the modified Wolfsberg-Helmholz formula [START_REF] Ammeter | [END_REF]. All valence electrons were explicitly considered in the calculations and the basis set consisted of double-ζ Slater-type orbitals for the metal and chalcogen atoms, and single-ζ Slater-type orbitals for the rest of the atoms.

X-ray diffraction

Suitable crystals of [PPh4][Au(tBuS-tzdt)2]and [Au(tBuS-tzdt)2] • for X-ray diffraction single crystal experiment were selected and mounted with a cryoloop on the goniometer head of a APEXII Bruker AXS diffractometer, using Mo-Kα radiation (λ = 0.71073 Å, multilayer monochromator). The structures were solved by dual-space algorithm using the SHELXT program [30], and the refined with full-matrix least-square methods based on F 2 (SHELXL) [31]. All non-hydrogen atoms were refined with anisotropic atomic displacement parameters. H atoms were finally included in their calculated positions. Crystallographic data on X-ray data collection and structure refinements are given in Table 3.

Contributions

Hadi Hachem realized the experiments and prepared all the figures, Olivier Jeannin performed the X-ray investigations, Dominique Lorcy conceived and designed the complexes, wrote de main manuscript text together with Marc Fourmigué. All the authors reviewed the manuscript.

Corresponding author

Correspondence to Dominique Lorcy: Dominique.lorcy@univ-rennes1.fr

Compliance with ethical standards

Competing interest

The authors declare no competing interests

Conflict of interest

The authors declare that they have no conflict of interest to this work


Theo Pezel

MD Magalie Viallon

PhD ; Pierre Croisille

PhD Laurent Sebbag

MD Thomas Bochaton

MD Jerome Garot

Joao A C Lima

PhD; Nathan Mewton
email: nathan.mewton@chu-lyon.fr

MD, PhD Joao Ac Lima

Nathan Pr

Mewton

Imaging Interstitial Fibrosis, Left Ventricular Remodeling, and Function in Stage A and B Heart Failure

Keywords: Interstitial Fibrosis, Left Ventricular Remodeling, Heart Failure, T1 mapping, Cardiovascular risk factors BMI: body mass index CMR: cardiac magnetic resonance ECV: extracellular volume EDV: end-diastolic volume ESV -locker inversion recovery

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

PATHOPHYSIOLOGY OF INTERSTITIAL FIBROSIS

Interstitial fibrosis and left ventricular (LV) adverse remodeling have been associated with different comorbidities including diabetes and hypertension. They are ultimately associated with congestive heart failure (HF) and arrhythmic events [START_REF] Shah | Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction: A Multiorgan Roadmap[END_REF]. LV remodeling and interstitial fibrosis also occur with ageing and in that setting may not necessarily translate into heart disease. The complex combination of ageing with modifiable risk factors such as hypertension, diabetes mellitus, obesity, smoking and lack of physical exercise may initiate systemic inflammation together with significant increase in myocardial mechanical stress.

Studies performed in HF with preserved ejection fraction (HFpEF) patients show a clear proinflammatory profile [START_REF] Cheng | Biomarkers of heart failure with normal ejection fraction: a systematic review[END_REF][START_REF] Sanders-Van Wijk | Circulating biomarkers of distinct pathophysiological pathways in heart failure with preserved vs. reduced left ventricular ejection fraction[END_REF]. In addition to these pathways, the involvement of extracardiac processes such as renal insufficiency and arterial vessel stiffening, together with renin angiotensin system hyperactivation, further increase chronic myocardial stress and interstitial collagen deposition [START_REF] Fernandes-Silva | Adiposity, body composition and ventricular-arterial stiffness in the elderly: the Atherosclerosis Risk in Communities Study[END_REF][START_REF] Maaten | Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation[END_REF][START_REF] Gori | Association between renal function and cardiovascular structure and function in heart failure with preserved ejection fraction[END_REF][START_REF] Petrie | Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms[END_REF][START_REF] Jia | Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity[END_REF].

Recently, obstructive and non-obstructive coronary artery disease have also been identified as potential aetiologies for interstitial fibrosis and LV remodeling. They share similar contributing factors (coronary microvascular dysfunction, increased conduit vessel stiffness, subclinical atherosclerosis, platelet dysfunction and abnormal adrenergic nerve function) to those that lead to the HFpEF syndrome [START_REF] Merz | Ischemia and No Obstructive Coronary Artery Disease (INOCA): Developing Evidence-Based Therapies and Research Agenda for the Next Decade[END_REF]. All these mechanisms may trigger acute clinical and sub-clinical events including arrhythmias (atrial fibrillation, sinus dysfunction) and ischemic events (myocardial infarction). These events cause abrupt increases in myocardial stress and result in myocardial cell death by necrosis which induces myocardial replacement fibrosis (scar). This in turn, further increases LV mechanical stress and adverse remodeling creating a vicious cycle that fuels the progression from stage A to B, C and D HF. The principal cellular pathways and mediators underlying such vicious cycle are summarized in In this review, we will focus only on heart failure etiologies related to the principal cardiovascular risk factors (hyperlipidemia, diabetes, hypertension, smoking, aging, obesity). Our review will not cover all other HF etiologies related to a structural/functional anomaly within the cardiomyocytes (primary dilated cardiomyopathy) or any other toxic, infiltrative or infectious cause (myocarditis, amyloid, chemotherapy…). In these settings, the pathophysiology is distinct from that of exposure to traditional cardiovascular risk factors.

The American College of Cardiology/American Heart Association (ACC/AHA) have proposed a heart failure classification system in four stages with increasing severity [START_REF] Hunt | ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure)[END_REF][START_REF] Yancy | ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[END_REF] Typically, myocardial tissue is approximately composed of 75% myocardial intracellular tissue, which consists of myocardial cells, other cells, and blood cells, while 25% constitutes the ECV with the space between all cells including plasma in the vasculature. Myocardial interstitial space accounts for approximately 90% of the ECV and is composed of fibrillary proteins (collagen I & III, elastin), non-fibrillary proteins (aminoglycans, fibronectin, laminin), bioactive proteins (transforming growth factor beta, matrix metalloproteinases) and cells (fibroblasts, resident monocytes) [START_REF] Schelbert | Why Clinicians Should Care About the Cardiac Interstitium[END_REF]. Interstitial fibrosis induced by the increase in TGF-beta secretion, results in the increase of collagen synthesis by activated resident fibroblasts. These fibroblasts are activated by the monocyte/macrophage myocardial infiltration [START_REF] Westermann | Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction[END_REF] in response to a wide array of stimuli leading to myocardial inflammation.

Each step of the collagen metabolism is altered in this pathological process, with increased collagen synthesis, anarchic collagen deposition and dysfunctional collagen degradation.

However, conversely to replacement fibrosis, interstitial fibrosis appears to be reversible and improved by pharmacological agents such as spironolactone and the combination of sacubitril with the angiotensin receptor blocker (ARB) valsartan [START_REF] Díez | Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients[END_REF][START_REF] Pfeffer | Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial[END_REF][START_REF] Zile | Plasma Biomarkers Reflecting Profibrotic Processes in Heart Failure With a Preserved Ejection Fraction: Data From the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Study[END_REF]. The interaction among all of these different pathophysiology tracks induce modifications in myocardial tissue composition as well as LV volumes, mass and shape. These early stage alterations can be reversibly modified by risk factor control.

Three pathophysiological phenotypes can be described in this setting and are depicted in the Central Illustration and Figure 2, depending on the principal risk factors.

The first phenotype corresponds to healthy ageing heart. In the normal process of ageing, systolic function is preserved as the LV cavities shrinks at a relatively fast pace. The LV end systolic and end diastolic volume decrease proportionally. LV mass also decreases with age, but at a much slower pace, which results in concentric remodeling and increased LV mass to volume ratio. At the tissue level, low rate diffuse cell death due to senescence and apoptosis occurs, associated with slightly increased interstitial fibrosis, which results in a relative extracellular volume increase.

The second phenotype corresponds to stage A HF [START_REF] Yancy | ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[END_REF]. The heart is exposed to various risk factors that influence LV tissue composition as well as LV structure. The factors that have the greatest impact are obesity, diabetes and hypertension. The interaction among these factors is complex. They are also potentially combined with ageing, smoking, lack of exercise and chronic ischemia due to microvascular disease alone, or in combination with epicardial coronary artery atherosclerosis. It is therefore difficult to specifically isolate the individual effect of each factor on LV architecture and myocardial tissue structure.

Conversely, in stage A HF, LV volumes may be moderately enlarged, and accompanied by significant increase in LV mass with concentric remodeling. At the tissue level, cardiomyocytes are significantly hypertrophied, and there may also be a significant increase in interstitial fibrosis first surrounding blood vessels and then more diffuse, in association with a reduction in capillary density. At this stage however, global LV systolic function may still be preserved, thanks to the hypertrophic process, augmented by greater LV torque [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF].

The third phenotype is stage B HF [START_REF] Yancy | ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[END_REF][START_REF] Goldberg | Stage B heart failure: management of asymptomatic left ventricular systolic dysfunction[END_REF]. The pathophysiological processes activated in stage A continue and the microstructural and macrostructural LV remodeling become more severe.

At this stage, two phenotypes can be individualized: the preserved ejection fraction phenotype and the reduced ejection phenotype:

-In the HFpEF phenotype, the interstitial fibrosis becomes irreversible and diffuse and causes the stiffening of the left ventricle along with the intracellular modifications that occur at the same time in hypertrophied cardiomyocytes (loss of titin phosphorylation), further increasing the concentric remodeling.

-In the reduced ejection phenotype, cardiomyocyte death is significantly more prominent (infarction, micro-infarcts during acute events) associated with abnormal cellular function (apoptosis, metabolic abnormalities, calcium handling derangement...). Therefore, a macroscopic scar tissue appears which causes a shift towards eccentric remodeling.

In the pathophysiology of stage A and B HF, monitoring of LV shape and functional status (LV remodeling and functional assessment) as well as tissue composition could be of significant therapeutic interest. Developing non-invasive robust and reproducible imaging techniques to define specific myocardial "imaging biomarkers" would potentially allow for: 1) definition of image endpoints in interventional randomized trials for stage A and B HF patients; 2) routine monitoring of patients at risk under effective therapy; 3) stratification of patients to facilitate decision making for therapeutic management. For these purposes, cardiac magnetic resonance (CMR) may appear to be a well-suited imaging technique. CMR is the gold standard for LV anatomy and functional assessment [START_REF] Hoffmann | Assessment of systolic left ventricular function: a multi-centre comparison of cineventriculography, cardiac magnetic resonance imaging, unenhanced and contrast-enhanced echocardiography[END_REF]. Late gadolinium enhancement (LGE) CMR imaging is also a major clinical feature to characterize macroscopic replacement fibrosis [START_REF] Kuruvilla | Late Gadolinium Enhancement on Cardiac Magnetic Resonance Predicts Adverse Cardiovascular Outcomes in Nonischemic Cardiomyopathy: A Systematic Review and Meta-Analysis[END_REF]. Finally, in the last ten years, the assessment of interstitial fibrosis has become accessible with T1 mapping sequences [START_REF] Mewton | Assessment of myocardial fibrosis with cardiovascular magnetic resonance[END_REF].

CMR IMAGING TECHNIQUES FOR INTERSTITIAL FIBROSIS

All technical and practical elements to achieve a quality native T1 mapping and ECV have been summarized by Robinson et al. in a recent review [START_REF] Robinson | Myocardial T1 and ECV Measurement[END_REF]. Up-front, it is important to remember that T1 mapping and ECV assessment are not specific of fibrosis and can also be significantly modified in case of edema (myocarditis/ acute infarction), and myocardial infiltration (amyloid). These specific clinical settings should be ruled out before further analysis of T1 mapping for fibrosis quantification. Also, a high-quality acquisition is mandatory in order to obtain a clinically relevant imaging study. We propose a brief summary of the main issues affecting T1 mapping accuracy as well as solutions to improve imaging acquisition, post-processing and analysis in Table 1.

Normal native T1 mapping time of the healthy myocardium is 976 ± 7 ms at 1.5-T and 1,159 ± 16 ms at 3.0-T [START_REF] Gottbrecht | Native T1 and Extracellular Volume Measurements by Cardiac MRI in Healthy Adults: A Meta-Analysis[END_REF]. Nevertheless, the normal range of T1 values differs between different T1 sequences, field strengths and different heart rates [START_REF] Taylor | T1 Mapping: Basic Techniques and Clinical Applications[END_REF].

INTERSTITIAL FIBROSIS AND REMODELING IN STAGE A HF

In the literature, many reports present T1 mapping results in different populations, with different sample sizes, various CMR acquisitions and post-processing protocols. In this study, we review the literature on interstitial fibrosis assessment by CMR, with particular details on data published as part of the Multi-Ethnic Study of Atherosclerosis (MESA) CMR literature.

The MESA study is a prospective study designed to evaluate mechanisms that underlie development and progression of subclinical cardiovascular disease among asymptomatic individuals in the general population. Details of the MESA study design have been previously described [START_REF] Bild | Multi-Ethnic Study of Atherosclerosis: objectives and design[END_REF]. In this multi-ethnic cohort followed-up through more than 15 years, serial CMR assessments were performed with extensive CMR phenotyping in various risk factor settings. There are therefore extensive data, assessing the pathophysiology of stage A and B HF with CMR assessment in this cohort. In MESA, data were acquired and postprocessed according to a standardized protocol. The following paragraphs review the results from those studies. Stage A HF is defined by patients at risk for HF who have not yet developed irreversible structural heart changes [START_REF] Hunt | ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure)[END_REF].

EFFECTS OF HEALTHY AGING ON LV INTERSTITIAL FIBROSIS, LV REMODELING AND LV FUNCTION

Table 2 summarizes the data obtained from the literature about the effects of healthy aging on all parameters of LV interstitial fibrosis, remodeling and function.

In the MESA cohort, LV remodeling during healthy aging is well described. First, LV mass significantly increased with age in men, and remained stable in women [START_REF] Eng | Adverse Left Ventricular Remodeling and Age Assessed with Cardiac MR Imaging: The Multi-Ethnic Study of Atherosclerosis[END_REF][START_REF] Ebong | Age at menopause and incident heart failure: the Multi-Ethnic Study of Atherosclerosis[END_REF][START_REF] Yoneyama | Natural History of Myocardial Function in an Adult Human Population: Serial Longitudinal Observations From MESA[END_REF][START_REF] Natori | Cardiovascular function in multi-ethnic study of atherosclerosis: normal values by age, sex, and ethnicity[END_REF]. At the same time, a significant decrease in LV EDV [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF][START_REF] Eng | Adverse Left Ventricular Remodeling and Age Assessed with Cardiac MR Imaging: The Multi-Ethnic Study of Atherosclerosis[END_REF][START_REF] Ebong | Age at menopause and incident heart failure: the Multi-Ethnic Study of Atherosclerosis[END_REF][START_REF] Yoneyama | Cardiovascular magnetic resonance in an adult human population: serial observations from the multi-ethnic study of atherosclerosis[END_REF][START_REF] Liu | Healthy aging of the left ventricle in relationship to cardiovascular risk factors: The Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF] and in LV stroke volume occurs [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF][START_REF] Liu | Healthy aging of the left ventricle in relationship to cardiovascular risk factors: The Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF]. This leads to an increased LV mass/volume ratio [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF][START_REF] Eng | Adverse Left Ventricular Remodeling and Age Assessed with Cardiac MR Imaging: The Multi-Ethnic Study of Atherosclerosis[END_REF][START_REF] Ebong | Age at menopause and incident heart failure: the Multi-Ethnic Study of Atherosclerosis[END_REF][START_REF] Yoneyama | Natural History of Myocardial Function in an Adult Human Population: Serial Longitudinal Observations From MESA[END_REF][START_REF] Yoneyama | Cardiovascular magnetic resonance in an adult human population: serial observations from the multi-ethnic study of atherosclerosis[END_REF]. This causes a LV concentric remodeling with an increase of LV mass/volume ratio of 0.03 g/mL every decade [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF].

Healthy aging is associated with a significant relative increase in LV tissue composition including interstitial fibrosis as measured by native T1 mapping (mean 988 ± 39 ms with 15 ms of increase/decade) and ECV (mean 28.7 ± 2.7 % with 2.2 % of increase/decade) [START_REF] Venkatesh | Association of longitudinal changes in left ventricular structure and function with myocardial fibrosis: the Multi-Ethnic Study of Atherosclerosis study[END_REF][START_REF] Liu | Evaluation of age-related interstitial myocardial fibrosis with cardiac magnetic resonance contrast-enhanced T1 mapping: MESA (Multi-Ethnic Study of Atherosclerosis)[END_REF] without any scar [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF][START_REF] Eng | Adverse Left Ventricular Remodeling and Age Assessed with Cardiac MR Imaging: The Multi-Ethnic Study of Atherosclerosis[END_REF][START_REF] Ebong | Age at menopause and incident heart failure: the Multi-Ethnic Study of Atherosclerosis[END_REF][START_REF] Yoneyama | Natural History of Myocardial Function in an Adult Human Population: Serial Longitudinal Observations From MESA[END_REF][START_REF] Natori | Cardiovascular function in multi-ethnic study of atherosclerosis: normal values by age, sex, and ethnicity[END_REF][START_REF] Yoneyama | Cardiovascular magnetic resonance in an adult human population: serial observations from the multi-ethnic study of atherosclerosis[END_REF][START_REF] Liu | Healthy aging of the left ventricle in relationship to cardiovascular risk factors: The Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF][START_REF] Venkatesh | Association of longitudinal changes in left ventricular structure and function with myocardial fibrosis: the Multi-Ethnic Study of Atherosclerosis study[END_REF][START_REF] Liu | Evaluation of age-related interstitial myocardial fibrosis with cardiac magnetic resonance contrast-enhanced T1 mapping: MESA (Multi-Ethnic Study of Atherosclerosis)[END_REF][START_REF] Cheng | Age-related left ventricular remodeling and associated risk for cardiovascular outcomes: the Multi-Ethnic Study of Atherosclerosis[END_REF]. Donekal et al. showed that a greater ECV (i.e. lower postcontrast T1 value) is associated with reduced body surface area indexed LV EDV and LV mass. In addition, greater ECV is associated with reduced circumferential shortening, lower early diastolic strain rate, and a preserved left ventricular ejection fraction (LVEF) in women.

In men, greater ECV is associated with LV systolic function abnormalities as reduced circumferential shortening, reduced LV torsion, and reduced LVEF [START_REF] Donekal | Interstitial fibrosis, left ventricular remodeling, and myocardial mechanical behavior in a population-based multiethnic cohort: the Multi-Ethnic Study of Atherosclerosis (MESA) study[END_REF].

In terms of LV systolic function, healthy aging subjects have a preserved LVEF associated with a reduction of LV strain [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF][START_REF] Eng | Adverse Left Ventricular Remodeling and Age Assessed with Cardiac MR Imaging: The Multi-Ethnic Study of Atherosclerosis[END_REF][START_REF] Ebong | Age at menopause and incident heart failure: the Multi-Ethnic Study of Atherosclerosis[END_REF][START_REF] Yoneyama | Natural History of Myocardial Function in an Adult Human Population: Serial Longitudinal Observations From MESA[END_REF][START_REF] Natori | Cardiovascular function in multi-ethnic study of atherosclerosis: normal values by age, sex, and ethnicity[END_REF][START_REF] Yoneyama | Cardiovascular magnetic resonance in an adult human population: serial observations from the multi-ethnic study of atherosclerosis[END_REF][START_REF] Liu | Healthy aging of the left ventricle in relationship to cardiovascular risk factors: The Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF][START_REF] Venkatesh | Association of longitudinal changes in left ventricular structure and function with myocardial fibrosis: the Multi-Ethnic Study of Atherosclerosis study[END_REF][START_REF] Liu | Evaluation of age-related interstitial myocardial fibrosis with cardiac magnetic resonance contrast-enhanced T1 mapping: MESA (Multi-Ethnic Study of Atherosclerosis)[END_REF][START_REF] Cheng | Age-related left ventricular remodeling and associated risk for cardiovascular outcomes: the Multi-Ethnic Study of Atherosclerosis[END_REF]. A lower circumferential shortening with a decrease of 0.14 points every decade was reported, as well as an increased torsion with progressive concentric remodeling [START_REF] Yoneyama | Natural History of Myocardial Function in an Adult Human Population: Serial Longitudinal Observations From MESA[END_REF].

EFFECTS OF CARDIOVASCULAR RISK FACTORS ON LV REMODELING AND

FIBROSIS

Each cardiovascular risk factor has detrimental effects on LV function, remodeling and interstitial fibrosis. Table 2 reports the effects of diabetes, hypertension, obesity, smoking and dyslipidemia on LV interstitial fibrosis, remodeling and function.

In MESA, there was no significant effect of any cardiovascular risk factors on LVEF.

However, as shown in Table 2, many studies showed significant changes in contractility measured by strain with MR myocardial tagging and cine-CMR.

Effect of diabetes mellitus

Patients with type 2 diabetes had an increased LV mass, a decreased LV EDV and LV stroke volume with a concentric LV remodeling and an increased LV mass/volume ratio.

Most data concerning the impact of diabetes on LV remodeling refers to type 2 diabetes patients. In this patient population, it is challenging to discriminate the impact of diabetes alone from hypertension and obesity. These conditions are often combined in the same patient. In MESA, type 2 diabetic patients had an increased LV mass [START_REF] Liu | Healthy aging of the left ventricle in relationship to cardiovascular risk factors: The Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF][START_REF] Yoneyama | Diabetes mellitus and insulin resistance associate with left ventricular shape and torsion by cardiovascular magnetic resonance imaging in asymptomatic individuals from the multi-ethnic study of atherosclerosis[END_REF] (except patients from the Asian ethnic group [START_REF] Bertoni | Diabetic cardiomyopathy and subclinical cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF]). In addition, diabetic patients presented a decreased LV EDV and a decreased LV stroke volume [START_REF] Bertoni | Diabetic cardiomyopathy and subclinical cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF]. Diabetes is associated with concentric LV remodeling independently of body mass index (BMI), with an increase in LV mass/volume ratio [START_REF] Yoneyama | Diabetes mellitus and insulin resistance associate with left ventricular shape and torsion by cardiovascular magnetic resonance imaging in asymptomatic individuals from the multi-ethnic study of atherosclerosis[END_REF][START_REF] Shah | Insulin resistance, subclinical left ventricular remodeling, and the obesity paradox: MESA (Multi-Ethnic Study of Atherosclerosis)[END_REF]. Turkbey et al. reported the same trends of LV remodeling abnormalities in patients with type 1 diabetes as described in patients with type 2 diabetes [START_REF] Turkbey | Myocardial structure, function, and scar in patients with type 1 diabetes mellitus[END_REF].

In terms of tissue composition including interstitial fibrosis, patients with type 1(40) or type 2(41) diabetes had a significant increase in native T1 native value (+54ms) and ECV (+0.8%) (using MOLLI sequence) compared to non-diabetic patients.

Diabetes mellitus was associated with reduced longitudinal and circumferential LV shortening together with reduced LV torsion as compared to healthy participants [START_REF] Yoneyama | Diabetes mellitus and insulin resistance associate with left ventricular shape and torsion by cardiovascular magnetic resonance imaging in asymptomatic individuals from the multi-ethnic study of atherosclerosis[END_REF].

Effect of hypertension

Overall, hypertensive patients had an increased LV mass, a decreased LV EDV with a concentric LV remodeling and an increase in LV mass/volume ratio.

Studies on hypertensive patients without history of previous cardiovascular events showed an increase in LV mass [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF][START_REF] Yoneyama | Natural History of Myocardial Function in an Adult Human Population: Serial Longitudinal Observations From MESA[END_REF]. In addition, LV mass was directly related to systolic and diastolic blood pressure (BP)(42) with a 9.6 g increase of LV mass for every 21 mmHg increase of systolic BP [START_REF] Heckbert | Traditional cardiovascular risk factors in relation to left ventricular mass, volume, and systolic function by cardiac magnetic resonance imaging: the Multiethnic Study of Atherosclerosis[END_REF]. Hypertension lead to a concentric remodeling with an increased LV mass/volume ratio. This was associated with a significant decrease in LV volumes [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF][START_REF] Yoneyama | Natural History of Myocardial Function in an Adult Human Population: Serial Longitudinal Observations From MESA[END_REF] and an increase in left atrium volume indexed to the body surface as a marker of LV enddiastolic filling pressure increase. Finally, an effective anti-hypertensive therapy was associated with significant LV mass reduction [START_REF] Yoneyama | Natural History of Myocardial Function in an Adult Human Population: Serial Longitudinal Observations From MESA[END_REF].

In terms of tissue composition including interstitial fibrosis, patients with hypertension had an increase in native T1 native value (+16 ms) and ECV (+2.3%) compared to healthy nonhypertensive controls (using MOLLI sequence) [START_REF] Venkatesh | Association of longitudinal changes in left ventricular structure and function with myocardial fibrosis: the Multi-Ethnic Study of Atherosclerosis study[END_REF][START_REF] Liu | Evaluation of age-related interstitial myocardial fibrosis with cardiac magnetic resonance contrast-enhanced T1 mapping: MESA (Multi-Ethnic Study of Atherosclerosis)[END_REF].

Hypertensive patients had a significant reduction in circumferential shortening [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF][START_REF] Yoneyama | Natural History of Myocardial Function in an Adult Human Population: Serial Longitudinal Observations From MESA[END_REF][START_REF] Rosen | Hypertension and smoking are associated with reduced regional left ventricular function in asymptomatic: individuals the Multi-Ethnic Study of Atherosclerosis[END_REF]. Also, in hypertensive patients LV torsion was increased [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF][START_REF] Yoneyama | Natural History of Myocardial Function in an Adult Human Population: Serial Longitudinal Observations From MESA[END_REF]. One hypothesis to explain the increased torsion is the compensatory mechanism to maintain an adequate stroke volume to balance the progressive reduction in LV volumes and myocardial shortening associated with hypertension [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF]. Conversely, in patients with efficient antihypertensive therapy there was a significant improvement in circumferential shortening and LV torsion was not significantly different from non-hypertensive participants [START_REF] Yoneyama | Age, sex, and hypertension-related remodeling influences left ventricular torsion assessed by tagged cardiac magnetic resonance in asymptomatic individuals: the multi-ethnic study of atherosclerosis[END_REF][START_REF] Yoneyama | Natural History of Myocardial Function in an Adult Human Population: Serial Longitudinal Observations From MESA[END_REF].

Effect of obesity

Obesity, defined as a BMI > 30 kg/m 2 was also associated with increased LV mass with a concentric LV remodeling and an increased LV mass/volume ratio. In MESA, Turkbey et al.

described a 6 ± 2 g increase in LV mass for every 10 kg increase in patient weight [START_REF] Turkbey | The impact of obesity on the left ventricle: the Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF]; in a second study Heckbert et al. showed a 12 g increase in LV mass every 10 kg increase in body surface area [START_REF] Heckbert | Traditional cardiovascular risk factors in relation to left ventricular mass, volume, and systolic function by cardiac magnetic resonance imaging: the Multiethnic Study of Atherosclerosis[END_REF]. Conversely, every 5% weight loss was associated with a 1.3% decrease in height-indexed LV mass independently of age, race, gender or BMI [START_REF] Shah | Weight loss and progressive left ventricular remodelling: The Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF].

The increase in LV end-diastolic volume per each 10-kg/m 2 increased in BMI for obese was 10 ml. For men with an average LV volume (140 ml), a 10-unit changed in BMI corresponded to a 19% increase in LV volume. Similar relationships were also observed for women [START_REF] Turkbey | The impact of obesity on the left ventricle: the Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF].

LV concentric remodeling is related to the severity of obesity with 0.04 g/mL increase in mass/volume ratio every 10 kg increase, due to a greater increase in LV mass relative to LV EDV [START_REF] Turkbey | The impact of obesity on the left ventricle: the Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF]. This relation was confirmed by another study which showed that every 5% weight loss was associated with a 1.3% decrease in LV mass/volume ratio independently of age, race, gender or BMI [START_REF] Shah | Weight loss and progressive left ventricular remodelling: The Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF]. This LV concentric remodeling was also associated with an increase in left atrium volume indexed to the body surface [START_REF] Zemrak | Left Atrial Structure in Relationship to Age, Sex, Ethnicity, and Cardiovascular Risk Factors: MESA (Multi-Ethnic Study of Atherosclerosis)[END_REF], a marker of increased LV filling pressures.

In terms of tissue composition including interstitial fibrosis, obese patients had an increase in native T1 native value (+ 45 ms) (using MOLLI sequence) [START_REF] Liu | Healthy aging of the left ventricle in relationship to cardiovascular risk factors: The Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF].

Effect of smoking and dyslipidemia

Heckbert et al. showed that smoking was not associated with significant change in LV mass, no effect on LV volume and a slight increase in mass/volume ratio [START_REF] Heckbert | Traditional cardiovascular risk factors in relation to left ventricular mass, volume, and systolic function by cardiac magnetic resonance imaging: the Multiethnic Study of Atherosclerosis[END_REF]. In the same study, they described the effect of dyslipidemia with no significant change in LV mass, LV EDV and LV stroke volume [START_REF] Heckbert | Traditional cardiovascular risk factors in relation to left ventricular mass, volume, and systolic function by cardiac magnetic resonance imaging: the Multiethnic Study of Atherosclerosis[END_REF].

In terms of tissue composition including interstitial fibrosis, there was no effect of smoking and dyslipidemia on native T1 value and ECV values in patients without prior history of cardiovascular events [START_REF] Liu | Healthy aging of the left ventricle in relationship to cardiovascular risk factors: The Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF]. In MESA, these factors were not significantly associated with the presence of scar defined by LGE.

For 10 years smoking patients, smoking causes a lower regional LV circumferential shortening(28) compared to non-smokers. Furthermore, it was reported a dose-response relationship between cigarette consumption, measured in pack-years, and regional LV dysfunction by circumferential strain [START_REF] Rosen | Hypertension and smoking are associated with reduced regional left ventricular function in asymptomatic: individuals the Multi-Ethnic Study of Atherosclerosis[END_REF].

INTERSTITIAL FIBROSIS AND REMODELING IN STAGE B HF

Stage B HF is defined by pathologic alterations of LV structure and function without symptoms of HF. Most of the structural and functional modifications assessed by CMR at this stage are predictive of HF adverse events. The following paragraphs review the link between these alterations and their predictive value on subsequent HF events (stage C HF).

However, to our knowledge, there is no data to show that any therapeutic intervention at this stage based on a CMR imaging finding prevents subsequent HF events. Table 3 summarizes the data obtained from the literature about the effects of LV remodeling, interstitial fibrosis and systolic function on the occurrence of stage C HF.

RELATIONSHIP BETWEEN LV REMODELING PARAMETERS AND SYMPTOMATIC HF

LV mass was associated with incident HF events after a median follow-up of 4 years with a hazard ratio of 1.4 per 10 g/m 2 increment. Higher LV mass at baseline (LV mass >95 th percentile) is strongly associated with incident HF with a hazard ratio of 8.6 (95% confidence interval: 3.7 to 19.9) [START_REF] Bluemke | The relationship of left ventricular mass and geometry to incident cardiovascular events: the MESA (Multi-Ethnic Study of Atherosclerosis) study[END_REF][START_REF] Jain | Cardiovascular imaging for assessing cardiovascular risk in asymptomatic men versus women: the multi-ethnic study of atherosclerosis (MESA)[END_REF]. This risk of HF occurrence was present in patients with [START_REF] Schelbert | Prevalence and prognosis of unrecognized myocardial infarction determined by cardiac magnetic resonance in older adults[END_REF] or without [START_REF] Bluemke | The relationship of left ventricular mass and geometry to incident cardiovascular events: the MESA (Multi-Ethnic Study of Atherosclerosis) study[END_REF][START_REF] Chahal | Heart failure risk prediction in the Multi-Ethnic Study of Atherosclerosis[END_REF] myocardial replacement scar. This link between LV hypertrophy and HF has been confirmed in the Framingham study and other cohorts [START_REF] Kannel | Left ventricular hypertrophy as a risk factor: the Framingham experience[END_REF][START_REF] Kannel | Left ventricular hypertrophy and risk of cardiac failure: insights from the Framingham Study[END_REF].

In MESA, LVED volume was significantly associated with incident HF events with a hazard ratio of 1.3 per 10% increment [START_REF] Bluemke | The relationship of left ventricular mass and geometry to incident cardiovascular events: the MESA (Multi-Ethnic Study of Atherosclerosis) study[END_REF]. LVED dilation (end-diastolic diameter >52 mm or >95 th percentile) was associated with HF after a median follow-up of 9.4 years with a hazard ratio of 2.2 and 7.4 in patients with preserved LVEF and reduced LVEF, respectively. Overall, LV dilation predicts incident HF independently of LVEF [START_REF] Yoneyama | Cardiovascular magnetic resonance in an adult human population: serial observations from the multi-ethnic study of atherosclerosis[END_REF]. LV eccentric remodeling (defined by high LV mass index, normal mass/volume ratio) and concentric remodeling (defined by normal LV mass index, an increased mass/volume ratio) patterns are also significantly associated with increased risk of HF as well, as compared with participants with normalshape LV [START_REF] Yeboah | Left ventricular dilation and incident congestive heart failure in asymptomatic adults without cardiovascular disease: multi-ethnic study of atherosclerosis (MESA)[END_REF]. Eccentric remodeling with increased sphericity is also significantly associated with higher NT-proBNP levels and lower LVEF [START_REF] Ambale-Venkatesh | Left ventricular shape predicts different types of cardiovascular events in the general population[END_REF].

In MESA, concentric remodeling with higher LV mass/volume ratio was associated with incident HF events with a hazard ratio of 2.3 per 10% increment [START_REF] Bluemke | The relationship of left ventricular mass and geometry to incident cardiovascular events: the MESA (Multi-Ethnic Study of Atherosclerosis) study[END_REF]. This pattern of ventricular remodeling appears to confer significant HF risk, especially when present earlier in life [START_REF] Cheng | Age-related left ventricular remodeling and associated risk for cardiovascular outcomes: the Multi-Ethnic Study of Atherosclerosis[END_REF]. This concentric remodeling has also been associated with replacement fibrosis in MESA [START_REF] Turkbey | Prevalence and Correlates of Myocardial Scar in a US Cohort[END_REF].

THE EFFECT OF LV FIBROSIS ON THE OCCURRENCE OF STAGE C HF

Interstitial fibrosis and replacement fibrosis are both predictors of HF events. Replacement (scarring) fibrosis is present in the more advanced stages of disease. It is always synonymous of cardiomyocyte death and impaired myocardial performance. It is detectable by CMR with

LGE imaging with a high degree of accuracy and reproducibility [START_REF] Sibley | T1 Mapping in cardiomyopathy at cardiac MR: comparison with endomyocardial biopsy[END_REF][START_REF] Ambale-Venkatesh | Cardiac MRI: a central prognostic tool in myocardial fibrosis[END_REF]. The simple presence of LGE has been reported in various cardiomyopathies and pathology settings [START_REF] Mewton | Assessment of myocardial fibrosis with cardiovascular magnetic resonance[END_REF]. Its presence is also systematically and independently associated with adverse cardiovascular outcomes [START_REF] Mewton | Assessment of myocardial fibrosis with cardiovascular magnetic resonance[END_REF].

In MESA, of the total 1840 participants who underwent contrast-enhanced CMR, with a mean age of 68 years, 7.9% had subendocardial or transmural LGE of myocardial infarction, and 78% of these latest were undetected by ECG or by clinical adjudication [START_REF] Turkbey | Prevalence and Correlates of Myocardial Scar in a US Cohort[END_REF]. In a recent study, Ambale-Venkatesh et al. showed that the proportion of participants with myocardial scar was significantly higher in patients with incident HF (37.5%) compared to patients without HF [START_REF] Ambale-Venkatesh | Association of myocardial fibrosis and cardiovascular events: the multi-ethnic study of atherosclerosis[END_REF].

In the MESA study, asymptomatic individuals with positive LGE had a concentric hypertrophy in women and LV dilatation in men, with altered LVEF. Conversely, individuals without myocardial scar maintained LV function [START_REF] Venkatesh | Association of longitudinal changes in left ventricular structure and function with myocardial fibrosis: the Multi-Ethnic Study of Atherosclerosis study[END_REF]. Therefore, the presence of replacement fibrosis was associated with changing LV volumes and reduced function over time even in individuals from lower-risk populations.

In MESA, interstitial fibrosis determined by T1 mapping, was significantly associated with LV function. Male subjects had a linear decline in LV systolic function with interstitial fibrosis, whereas women had a progressive decline in LV diastolic function with fibrosis [START_REF] Donekal | Interstitial fibrosis, left ventricular remodeling, and myocardial mechanical behavior in a population-based multiethnic cohort: the Multi-Ethnic Study of Atherosclerosis (MESA) study[END_REF][START_REF] Sibley | T1 Mapping in cardiomyopathy at cardiac MR: comparison with endomyocardial biopsy[END_REF]. Hence, restrictive filling with eventual diastolic dysfunction could progress to a stiffer left ventricle. In addition, men had progressively increased interstitial fibrosis with burden of CVD risk factors, while women were likely to have more interstitial fibrosis independently of cardiovascular risk factors [START_REF] Liu | Evaluation of age-related interstitial myocardial fibrosis with cardiac magnetic resonance contrast-enhanced T1 mapping: MESA (Multi-Ethnic Study of Atherosclerosis)[END_REF][START_REF] Yi | The association between cardiovascular risk and cardiovascular magnetic resonance measures of fibrosis: the Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF].

More recently, T1 mapping values were significantly associated with invasively measured LV stiffness in HFpEF patients. Additionally, ECV measurements were correlated with exercise response with impaired active relaxation [START_REF] Rommel | Extracellular Volume Fraction for Characterization of Patients With Heart Failure and Preserved Ejection Fraction[END_REF]. Schelbert et al. showed in 1174 patients with normal systolic function, that myocardial interstitial fibrosis, defined by ECV, was similarly prevalent in HFpEF patients or at risk for HFpEF, suggesting that myocardial fibrosis might precede clinical HFpEF diagnosis [START_REF] Schelbert | Temporal Relation Between Myocardial Fibrosis and Heart Failure With Preserved Ejection Fraction: Association With Baseline Disease Severity and Subsequent Outcome[END_REF]. In this report, myocardial fibrosis was associated with disease severity (peptide natriuretic levels) and adverse outcomes. Also, ECV and T1 mapping values in MESA have been shown to be significantly correlated with NT-proBNP levels. Liu et al. showed that each 1-SD increment (0.44 pg/mL) of log NTpro BNP was associated with a 0.62% increment in ECV fraction, and 4.7 ms increment in native T1 [START_REF] Liu | Association of Elevated NT-proBNP With Myocardial Fibrosis in the Multi-Ethnic Study of Atherosclerosis (MESA)[END_REF].This further confirms the link between HF events and CMR measures of interstitial fibrosis as NT-pro BNP showed an association with incident HF events after a median follow-up of 4.7 years with a hazard ratio of 2.5 per unit log increment [START_REF] Chahal | Heart failure risk prediction in the Multi-Ethnic Study of Atherosclerosis[END_REF]. The same finding was reported by Schelbert et al. [START_REF] Schelbert | Temporal Relation Between Myocardial Fibrosis and Heart Failure With Preserved Ejection Fraction: Association With Baseline Disease Severity and Subsequent Outcome[END_REF] in a HFpEF patient population.

With all these precise functional, remodeling and tissue characterization features, CMR allows an in-vivo assessment of different pathophysiology processes. The ability to scan large groups of patients or to repeat acquisitions in time in a single patient exposed to several cardiovascular risk factors offers the potential to understand the progression of disease within the myocardium. It also offers the potential to assess the effect of therapeutic interventions.

INTEGRATING CMR IN THE ROUTINE CLINICAL WORKUP OF STAGE A & B HEART FAILURE PATIENTS

Today, in routine clinical practice, the first imaging technique that is widely available for therapeutic management is echocardiography. However, this imaging technique does not provide precise tissue characterization; therefore its ability to discriminate between several mechanisms of systolic myocardial dysfunction is poor. This was illustrated by Lupon et al.

who assessed the evolution of LVEF over an 11-year period in HFpEF patients [START_REF] Lupón | Heart Failure With Preserved Ejection Fraction Infrequently Evolves Toward a Reduced Phenotype in Long-Term Survivors[END_REF]. In that study, LVEF declined significantly in 27.8% of patients with, versus 6.6% of patients without ischemic history. Thus, at one point in time, a complete assessment of myocardial functional, anatomic and underlying tissue characterization to accurately phenotype a patient with HFpEF is crucial for therapeutic management, as demonstrated above. However, several frontiers remain to be crossed beyond observational studies, before CMR becomes the first widely accepted imaging technique for the therapeutic management of HFpEF specifically, and heart failure in general. Three principal areas need to be addressed before such stage is reached.

1) Phase 2 Randomized Clinical Studies: the use of CMR imaging endpoints in interventional randomized studies for stage A and B HF patients is necessary to demonstrate, improve understanding, and set CMR at the core of patient clinical management.

The assessment of LV function and remodeling, as well as LGE by CMR, have already been well established as imaging endpoints by numerous prior phase 2 randomized clinical studies, especially in the field of acute MI [START_REF] Mewton | Assessment of myocardial fibrosis with cardiovascular magnetic resonance[END_REF][START_REF] Mewton | Postconditioning attenuates no-reflow in STEMI patients[END_REF][START_REF] Ibanez | Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial[END_REF][START_REF] Piot | Effect of cyclosporine on reperfusion injury in acute myocardial infarction[END_REF]. For stage A and B HF patients, CMR parameters such as LV mass and ECV should be used as primary endpoints in interventional studies assessing the efficacy of drugs or other interventions. Such trials in selected group of patients will consolidate the efficacy of new drugs, will put CMR assessment at the center of patient management, and at the same time create hypotheses for phase 3 studies. These types of trial were performed in the past using endomyocardial biopsy where myocardial fibrosis regression after antihypertensive treatment was first demonstrated [START_REF] Díez | Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients[END_REF][START_REF] Brilla | Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease[END_REF]. Serial assessment with CMR offers the opportunity to assess non-invasively the impact of novel interventions designed to reduce LV fibrosis, improve myocardial function and induce reverse remodeling.

In this regard, ongoing Phase 2 clinical trials such as the PIROUETTE trial (NCT02932566) are designed to examine the potentially beneficial effects of pirfenidone, a new antifibrotic agent, in HFpEF patients with ECV ≥27%.

2) Phase 3 Randomized Clinical Studies: However, the routine utilization of CMR in the assessment and management of patients with heart failure or suspected myocardial dysfunction will require the demonstration of its effectiveness in randomized clinical trials in terms of improved outcomes and/or cost-effectiveness when compared to routine clinical care. Currently, there are a few clinical trials using CMR as a screening or risk stratifying tool in patient management to improve clinical outcomes. In the CMR GUIDE trial (Cardiovascular Magnetic Resonance-GUIDEd management of light to moderate ventricular systolic dysfunction; NCT01918215) for example, HF patients with moderate systolic dysfunction and increased risk of sudden cardiac death are randomized to primary prevention implantation of a cardioverter-defibrillator or not according to their LGE status [START_REF] Selvanayagam | Cardiovascular magnetic resonance-GUIDEd management of mild to moderate left ventricular systolic dysfunction (CMR GUIDE): Study protocol for a randomized controlled trial[END_REF]. Similar studies could be performed in type A and type B HF patients, where CMR could help select specific patient phenotypes (increased LV mass index, increased ECV, presence of LGE) that are associated with a higher risk of future adverse cardiac events. These patients could then be randomized in interventional trials designed to assess the efficacy of drugs, devices or specific cardiovascular procedures.

3) Improving diagnostic accuracy/ reliability and accessibility for patients with Heart

Failure.

In order to place CMR at the center of HF patient management, CMR accessibility in routine clinical practice should improve significantly. In an ideal system, CMR assessment should be as simple as a NTproBNP measurement. This will only be possible through standardization of CMR acquisition protocols among different institutions as well as among different scanner manufacturers. CMR scanning time for patients has to be significantly reduced, and education/ training of medical and paramedical staff involved in CMR utilization needs to be improved. Imaging post processing time should also be reduced in the future. As a guideline for this paradigm shift, imaging protocols that used in multicenter phase 3 positive studies should be simple to allow the results of to be widely disseminated beyond centers of concentrated expertise. Finally, education to the practicing cardiologist should be directed at how to best use CMR to expedite care, improve clinical outcomes and the overall effectiveness of the health care system. Comorbidities and aging together with extracardiac organ involvement and acute myocardial events induce systemic inflammation with increased levels of inflammatory biomarkers (soluble interleukin 1 receptor-like 1(IL1RL1) or ST2, C-reactive protein, growth differentiation factor 15 (GDF 15) and galectin 3). This concurs with increased myocardial wall stress induced by hypertension or obesity, together with acute events (ischemic events) that cause myocardial cell death. Myocardial remodeling and interstitial fibrosis begin with endothelial dysfunction that attracts infiltrating leukocytes and produces reactive oxygen species with reduced nitric oxide (NO) bioavailability. Activated interstitial leukocytes secrete transforming growth factor beta which enhances interstitial collagen deposition. This endothelial dysfunction combined with the increased myocardial mechanical stress reduces soluble guanylate cyclase (sGC) activity, cyclic guanosine monophosphate (cGMP) content and the beneficial phosphorylation of protein kinase G (PKG) inducing cardiomyocyte stiffness and hypertrophy. Images from a young and normal patient (A); a healthy ageing patient with a concentric remodeling pattern and a slight significant increase in relative interstitial fibrosis extent (B); a patient in stage A HF with diabetes, hypertension and obesity leading to a significant LV hypertrophy and a greater increase in interstitial fibrosis (C), a patient in stage B HF with HFpEF and interstitial fibrosis becomes irreversible and diffuse, further increasing the concentric remodeling (D), and a patient in stage B HF with HFrEF and a macroscopic scar of lateral MI which causes a shift towards eccentric remodeling (E) demonstrate the spectrum of disease severity. ECV: Extracellular Volume; HF: heart failure; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; MI: myocardial infarction CENTRAL ILLUSTRATION. Left ventricular macrostructural and microstructural remodeling in healthy ageing, stage A and stage B heart failure. The normal left ventricle undergoes normal remodeling during the process of healthy ageing (upper panel). In stage A heart failure, the left ventricle is exposed to increased blood pressure, diabetes, obesity, lack of exercise (central panel), which leads to an increase in LV mass to volume ratio (concentric remodeling). In stage B heart failure, the pathophysiological processes activated in stage A continue and the microstructural and macrostructural LV remodeling become more severe (bottom panel). At this stage, two phenotypes can be individualized: the preserved ejection fraction phenotype and the reduced ejection phenotype. The latter may be linked to an MI as a consequence of the risk factors mentioned above, although there is also the case of reduced ejection phenotype with non-ischemic dilated cardiomyopathy not mentioned here

Conclusion

Figure 1 .

 1 Figure 1.

  as follows: Stage A: High risk of heart failure, but no structural heart disease or symptoms of heart failure; Stage B: Structural heart disease, but no symptoms of heart failure; Stage C: Structural heart disease and symptoms of heart failure; Stage D: Refractory heart failure requiring specialized interventions.

20 CMR

 20 could become the most useful non-invasive imaging technique to provide reliable and reproducible "imaging biomarkers" in the management of stage A & B HF patients. In this regard, CMR can provide: 1) precise definition of imaging endpoints in interventional randomized trials for stage A and B HF patients, 2) reproducible landmarks for routine monitoring of patients at risk for clinical complications, drug side effects, and clinical improvement or deterioration. 3) stratification of patients to decide upon appropriate therapy and management demonstrated in randomized clinical trials. In summary, personalized approaches based on clinically important pathophysiological mechanisms, and technical developments to further improve the robustness of imaging results are required to improve the performance of phase 3 trials to deliver "the right intervention to the right patient at the right time."(71).

Figure Legends:Figure 1 .

 1 Figure Legends:

Figure 2 .

 2 Figure 2. Representative cases of co-registered left ventricular native T1 maps, ECV and end-diastolic cine frame in short axis in healthy ageing, stage A and stage B heart failure. *Native T1 and ECV measurements performed by integrating the MI area into the measurement. Measurements of the myocardium excluding the scar zone were native T1 = 1205ms and ECV = 33.9%. Native T1 mapping (left column) and ECV mapping (middle column) quantify the wide spectrum of myocardial interstitial fibrosis ranging from healthy subjects to stage B HF through stage A HF. Cine images (right column) describe the evolution of LV remodeling at different stages.Images from a young and normal patient (A); a healthy ageing patient with a concentric remodeling pattern and a slight significant increase in relative interstitial fibrosis extent (B); a patient in stage A HF with diabetes, hypertension and obesity leading to a significant LV hypertrophy and a greater increase in interstitial fibrosis (C), a patient in stage B HF with HFpEF and interstitial fibrosis becomes irreversible and diffuse, further increasing the concentric remodeling (D), and a patient in stage B HF with HFrEF and a macroscopic scar of lateral MI which causes a shift towards eccentric remodeling (E) demonstrate the spectrum of disease severity. ECV: Extracellular Volume; HF: heart failure; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; MI: myocardial infarction

Breath-hold and motioncorrection algorithm (MOCO) (72) Motion through-plane Always check native images None (repeat acquisition)

Heart rate Arrhythmia RR length inSil reconstructions (73) Tachycardia HR > 90 bpm use recovery periods in seconds to ensure HR independent measures Sequence / setup Native and post-Gd T1 differences T1 sequence cannot measure long and short T1 with the same setup different inversion time needed to optimize T1 estimation Use optimized recommanded scheme: 5(3)3 for native T1 and 4(1)3(1)1 post-Gd (74) Men increased (26-28,75-78) (mean 80 ± 8.5 g/m 2 with 6 g/m 2 of increase)

Women no difference [START_REF] Yoneyama | Cardiovascular magnetic resonance in an adult human population: serial observations from the multi-ethnic study of atherosclerosis[END_REF][START_REF] Hudsmith | Normal human left and right ventricular and left atrial dimensions using steady state free precession magnetic resonance imaging[END_REF][START_REF] Alfakih | Normal human left and right ventricular dimensions for MRI as assessed by turbo gradient echo and steady-state free precession imaging sequences[END_REF][START_REF] Kawel-Boehm | Normal values for cardiovascular magnetic resonance in adults and children[END_REF][START_REF] Maceira | Normalized left ventricular systolic and diastolic function by steady state free precession cardiovascular magnetic resonance[END_REF] (mean 67 ± 7.5 g/m 2 with 5 g/m 2 of increase) Men increased (31,36) (mean 88 ±10.5 g/m 2 with 14 g/m 2 of increase)

Women increased (31,36) (mean 67 ±11.5 g/m 2 with 5 g/m 2 of increase) Men increased (17,28) (mean 82 ± 3.5 g/m 2 with 8 g/m 2 of increase)

Women increased (17,28) (mean 69 ± 3.5 g/m 2 with 6 g/m 2 of increase)

Men Increased (45,46) (mean 89 ± 10.5 g/m 2 with 15 g/m 2 of increase)

Women Increased (45,46) (mean 69 ±10.5 g/m 2 with 7 g/m 2 of increase)

No difference (43) (mean 71 ±10.5 g/m 2 ) Decreased (43) LV volume EDV = 147 ± 21 mL

Stroke volume = 97 ± 14 mL Decreased EDV (17,26,27,30,31,75-78) (mean 125 ± 21 mL with 22 mL of decrease)

Decreased Stroke volume (17,31,75-78) (mean 72 ± 14 mL with 25 mL of decrease)

Decreased LV EDV (37) (mean 125 mL± 28 mL with 22 mL of decrease)

Decreased Stroke volume (37) (mean 85 mL ± 21 mL with 12 mL of decrease)

Decreased LV EDV (17,28) (mean 122 mL± 21 mL with 25 mL of decrease)

Decreased Stroke volume (17,28) (mean 84 mL ± 14 mL with 13 mL of decrease)

Increased EDV (45) (mean 157 ± 21 mL with 10 mL of increase)

No difference (43) (Stroke volume mean 95.1 ± 14 mL)

Decreased LV EDV and stroke volume (43) LV Masse/Volu me Ratio MVR = 0.86 ± 0.21

Increased (17,26-28,30,34) (mean 0.89 ± 0.15 with 0.03 of increase)

Increased (36,38) (mean 0.91 ± 0.17 with 0.05 of increase)

Increased (17,28) (mean 0.93 ± 0.20 with 0.07 of increase)

Increased (43,45,46) (mean 0.89 ± 0.15 with 0.03 of increase)

No difference (43) (mean 0.89 ± 0.15 with 0.03 of increase)

No difference (43) LAVI LAVI = 32 ± 6.7 mL/m 2 Increased (47,75,80,81) (mean 39 ± 6.7mL/m 2 with 7mL/m 2 of increase)

No difference (47) Increased (47) (mean 38 ±12.2 mL/m 2 with 6mL/m 2 of increase)

No difference (47) (mean 34 ± 6.7mL/m 2 )

No difference (47) Decreased (47) (mean 31 ±6.7mL/m 2 with 1mL/m 2 of decrease)

Interstitial fibrosis

Native T1 value (MOLLI sequence) 976 ± 7 ms (23) Increased (32,33,82) (mean 988 ± 39 ms with 12 ms of increase)

Increased (31,41) (mean 1027 ± 41 ms with 51 ms of increase)

Increased (32,33,83) (mean 989 ± 45 ms with 13 ms of increase) Increased (30,31) (native T1 mean 1015 ± 45 ms with 39 ms of increase)

No difference (30,31) (native T1 mean 980 ± 42 ms)

No difference (30,31) (native T1 mean 971 ± 38 ms)

LV interstitial fibrosis ECV (%)

ECV = 25.9 ± 0.4% (30,32) Increased (32,33) (mean 28.7 ± 2.7 % with 2.8 % of increase)

Increased (31,41) (mean 26.7 ± 2.4 % with 0.8 % of increase)

Increased (32,33,83) (mean 28.2 ± 2.5 % with 2.3 % of increase)

LGE macroscopic Scar

No scar No scar (17,26-34) No scar (31,36-38,41) No scar (17,28,32,33) No scar (43,45,46) No scar (43) No scar (43) LV Function LVEF LVEF = 66 ± 4.5 % Preserved (17,26-34,78) (mean 69 ± 4.6%)

Preserved (31,36-38,41) (mean 68 ± 8.0%) Preserved (17,28,32,33) Preserved (43,45,46) Preserved (43) (mean 65 ± 4.5 %) Preserved (43) CMR strain

Longitudi nal global

No abnormality NA Decreased (36) No effect (17,28,84) Radial NA No difference (17,28,84) Circumfer ential * Decreased (17,28) Decreased (36) Decreased (17,28,85) Decreased (30,40,84) Decreased (85) in a dose-dependent manner

No difference (30,40,84) Torsion ** Increased (28) Increased (36) Increased (17,28) -Decreased (28) -

Values are Meanp ± SDp. Meanp = pooled weighted mean; SDp = pooled standard deviation All comparisons of this table were obtained against a subgroup of healthy individuals.

Measures reported from studies mixing steady-state free precession (SSFP) and fast gradient echo (GRE) sequences.

All strain data comes from MESA using tagging. ρ normal values for healthy adults ages 20 to 60 with pooled weighted mean values from references (33,75-78,80,81) .

Table 3. Effects of LV remodeling, interstitial fibrosis and systolic function on the occurrence of stage C HF

Risk of stage C HF LV Remodeling

LV mass

Increased LV mass (mean HR 8.6 and HR of 1.4 per 10 g/m 2 ) (48,49)

LV volume

Increased LV end-diastolic volume (mean HR 2.2 with preserved LVEF or HR 7.4 with reduced LVEF; and mean HR of 1.3 per 10% increment) (48) Reduced LV sphericity (mean HR 1.5) (55) LV mass/volume Ratio Higher LV mass/LV volume (mean HR of 2.3 per 10% increment) (48) Size and Function of LA Higher LAVI (mean HR 1.5 for > 32 mm 3 /m 2 ) (86) Lower LA strain( 87,88)

Interstitial fibrosis

LGE macroscopic Scar Increased (mean HR 1.5) (89)

Native T1

No difference (59) LV interstitial fibrosis ECV (%) Increased (mean HR 1.4 for ECV > 26%) (90) LV Systolic Function

CMR strain

Impaired LV circumferential shortening (mean HR 1.2) (91) Abbreviations: CMR: cardiac magnetic resonance; ECV: extracellular volume; EDV: end-diastolic volume; HF: heart failure; HR: hazard ratio; LA: left atrium; LAVI: left atrium volume corrected for the body surface area; LGE: late gadolinium enhancement; LV: left ventricle.