Clermont Université

Auvergne

Mohamed Diplome D'état De Docteur

Directeurs De

Madame Paysal

Justine Docteur

Monsieur Nottin Stéphane

M M Bacin Franck -Begue

René-Jean -Beytout Jean -Boire

Jean- Paul -Bommelaer Gilles -Boucher

Jean-Louis -Cano Noël - Cassagnes

Jean -Catilina Pierre -Chamoux

Jean -Chipponi Jacques - Chollet

Philippe -Citron Bernard -Clement Gilles -Dastugue

Bernard -Dauplat Jacques -Dechelotte

Pierre -Demeocq François -De Riberolles

Charles -Deteix Patrice -Escande

Georges -Mme Fonck

Yvette -M Gentou

Claude -Mme Glanddier

Phyllis -Mm Irthum

Bernard -Jacquetin Bernard -Laveran

Henri -Lesourd Bruno - Levai

Gérard -Michel Jean-Luc -Mondie

Jean-Michel -Philippe Pierre - Planche

Jean -Mme Rigal

Danièle -Mm Rozan

Pierre -Sirot Jacques -Ribal

Jean-Pierre -Souteyrand Pierre -Tanguy

Alain -Terver Sylvain -Thieblot

Philippe -Tournilhac Michel -Vanneuville Guy - Viallet

Jean-François -Mme Veyre

Annie Professeurs Emerites

M M Aumaitre

Olivier -Avan Paul -Bazin

Jean-Etienne -Caillaud Denis -Dapoigny Michel -Dubray

Claude -Durif Franck -Eschalier

Jean-Louis -Labbe André -Mme Lafeuille

Hélène -Mm Lemery Didier -Lusson

Jean-René -Pouly Jean-Luc

Exceptionnelle M Classe

Philippe Vago

Cytogénétique M Histologie-Embryologie

Louis Boyer

M Canis

Michel Gynécologie-Obstétrique

Mme Penault-Llorca

Frédérique Anatomie

Cytologie Pathologiques

M Bignon

Yves Jean Cancérologie

Biologique M Boirie

Yves Nutrition

Humaine M Clavelou

Pierre Neurologie

M Gilain

Laurent O R L M Lemaire

Jean-Jacques Neurochirurgie

M Camilleri

Lionel Chirurgie Thoracique

M Cardio-Vasculaire

Pierre-Michel Llorca

Adultes M Psychiatrie D'

Denis Pezet

Digestive M Chirurgie

Bertrand Souweine

Médicale M Réanimation

Stéphane Chirurgie Boisgard

Orthopédique

Mme Traumatologie

Martine Duclos

M Physiologie

Jeannot Schmidt

Urgence M Médecine D'

Marc Berger

M Hématologie

Jean-Marc Garcier

M Soubrier

Martin Rhumatologie

M Abergel

Armando Hépatologie

Mme Barthelemy

Isabelle Chirurgie Maxillo-Faciale

M Ruivard

Marc Médecine

Interne Mme Jalenques

Isabelle Psychiatrie D'

Adultes M Mom

Thierry Oto-Rhino-Laryngologie

M Coudeyre

M. D'INCAN Michel Dermatologie -Vénéréologie

M Gerbaud

Laurent Epidémiologie

Mme Pickering

Gisèle Pharmacologie

Clinique M Sapin-Defour

M Verrelle

Pierre Radiothérapie

Clinique M Tauveron

Igor Endocrinologie

Maladies Métaboliques

M Richard

Ruddy Physiologie

M Bay

Jacques-Olivier Cancérologie

Mme Godfraind

Catherine Anatomie

M Laurichesse

Henri Maladies

Infectieuses Et

Tropicales M Tournilhac

Olivier Hématologie

M Chiambaretta

Frédéric Ophtalmologie

M Filaire

Marc Anatomie

Chirurgie Thoracique

M Gallot

Denis Gynécologie-Obstétrique

M Guy

Laurent Urologie

M Traore

Ousmane Hygiène

Hospitalière M Andre

Interne M Bonnet

Richard Bactériologie

Virologie M Cachin

Florent Biophysique

Médecine Nucléaire

M Costes

Frédéric Physiologie

M Futier

Emmanuel Anesthésiologie-Réanimation

Mme Heng

Anne-Elisabeth Néphrologie

M Motreff

Pascal Cardiologie

M Rabischong

Benoît Gynécologie

Obstétrique M Chabrot

M Descamps

Stéphane Chirurgie Orthopédique

Mme Traumatologique

Cécile Henquell

Virologie M Bactériologie

Christophe Pomel

Générale M Cancérologie -Chirurgie

Fabien Thaveau

Vasculaire M Chirurgie

Georges Brousse

Classe

Mme Creveaux

M Faict

Kanold Lastawiecka

Justyna Pédiatrie

M Cornelis

François Génétique

M Lesens

Olivier Maladies

Tropicales M Authier

Nicolas Pharmacologie

Médicale M Lautrette

Alexandre Néphrologie

Réanimation Médicale

M Eschalier

Romain Cardiologie

M Merlin

Etienne Pédiatrie

Mme Tournadre

Anne Rhumatologie

M Durando

Xavier Cancérologie

M Dutheil

Frédéric Médecine

Santé Au Travail

Mme Fantini

Maria Livia

Neurologie M Sakka

Laurent Anatomie -Neurochirurgie

M Bourdel

Nicolas Gynécologie-Obstétrique

M Guieze

Romain Hématologie

M Poincloux

Laurent Gastroentérologie

M Souteyrand

Géraud Cardiologie

M Evrard

Bertrand Immunologie

M Poirier

Philippe Parasitologie

Mycologie Mme

Pham Dang

Nathalie Chirurgie

Maxillo-Faciale Stomatologie

Mme Sarret

Catherine Pédiatrie

M Bouvier

Damien Biochimie

Moléculaire M Biologie

Anthony Buisson

Mme Gastroentérologie

Lucie Cassagnes

M Gagniere

Johan Chirurgie

Viscérale Et Digestive

M Jabaudon-Gandet

Matthieu Anesthésiologie-Réanimation

Médecine Péri-Opératoire

M Lebreton

Aurélien Hématologie

M Moisset

Xavier Neurologie

M Samalin

Ludovic Psychiatrie D'

Adultes M Biau

Julian Radiothérapie

M Lachal

Jonathan Pédopsychiatrie

Mme Classe

Corinne Malpuech-Brugere

Humaine Professeurs Nutrition

Associes

Mme Bottet-Mauloubier

Anne Médecine

Générale M Cambon

Benoît Médecine

Générale M Tanguy

Gilles Médecine

Générale M Bernard

Hors Classe

Mme Bouteloup

Corinne Nutrition

Mme Fogli

Anne Biochimie

Biologie Moléculaire

Mme Gouas

Laetitia Cytologie

Cytogénétique M Histologie

Julien Delmas

M Bactériologie

Frédéric Robin

Marceau Geoffroy

M Morvan

Daniel Biophysique

Traitement De L'image

Mme Goumy

Carole Cytologie

Histologie

Mme Cytogénétique

Lauren Veronese

Cytologie

Audrey Mirand

Lemlih Ouchchane

Biostatistiques

M Libert

Frédéric Pharmacologie

Médicale Mme Coste

Karen Pédiatrie

Mme Aumeran

Claire Hygiène

Hospitalière Mme

Nourrisson Céline

Parasitologie -Mycologie Mme

Pons Hanaë

M Coll

Guillaume Neurochirurgie

M Godet

Thomas Anesthésiologie-Réanimation

Classe M Moustafa

Farès Médecine D'

Urgence M Chenaf

Chouki Pharmacologie

Clinique M Aniort

Julien Néphrologie

M Clerfond

Guillaume Cardiologie

Mme Dupuy

Claire Médecine

Intensive -Réanimation Mme

Julian Valérie

Physiologie M Lahay Clément

Mme Vaillant-Roussel

M Blanchon

Loïc Biochimie

M Marchand

Fabien Pharmacologie

Médicale Mme

Vaurs-Barriere Catherine

Normale M Classe

Jean-Luc Bailly

Aubel Mme

Oncologie Corinne

Mme Moléculaire

Christelle Guillet

Humaine M Nutrition

Yannick Bidet

M Oncogénétique

Guillaume Dalmasso

Frank Pizon

Publique M Santé

Soler Cédric

M Giraudet

M Lolignier

A Notre

Jury De

Madame Le Docteur

Claire Dauphin

Monsieur Le Docteur

Romain Tresorier

Madame Le Docteur

Greze Victoria

THÈSE D'EXERCICE pour le

Vous m'avez fait l'honneur d'accepter de juger ce travail Patience, Humilité, Grandeur et Dévouement Que de vertus indispensables au quotidien que vous n'avez jamais cessé de démontrer En vous remerciant de cet enseignement et de votre disponibilité sans condition Votre passion et votre minutie ont été un véritable exemple pour moi Veuillez croire en mon immense respect et de ma reconnaissance

Results:

The longitudinal strains both at the level of the sub-endocardium and sub-epicardium was reduced in CLS compared to controls. The global MW index (MWI) was also decreased (1668 ± 266 vs 1870 ± 264 %.mmHg in CLS patients and controls, respectively, P < 0.05), especially on the apical segments. An increase of LV intraventricular mechanical dispersion was observed in CLS. However, MWW and MWE remained unchanged compared to controls.

Conclusion:

Our results strongly support that cardiac remodeling is observed in CLS, characterized by a decrease in longitudinal strains and MW and an increase in LV mechanical dispersion. Specific alteration of the apex is present, but its causes and its clinical significance remain to be explored.

INTRODUCTION

Childhood cancer is a heterogeneous group of malignancies. Among adolescents, the most common cancer groups are lymphoma (27%). Five-year cancer survival exceeds 80 % in most European and North American countries today [START_REF] Steliarova-Foucher | International incidence of childhood cancer, 2001-10: a population-based registry study[END_REF][START_REF] Erdmann | Childhood cancer: Survival, treatment modalities, late effects and improvements over time[END_REF], especially with chemotherapy, which usually combines antineoplastic drugs whose anthracyclines. The aim of current international protocols is to reduce intensity of chemotherapy without threatening survival, in order to limit its toxicity, particularly on the cardiovascular system. Indeed, cardiovascular complications are one of the leading causes of morbidity and mortality among childhood cancer survivors, especially with anthracyclines which have an almost six-fold increased risk for heart failure compared to their siblings, with an increasing incidence with prolonged survival [START_REF] Franco | Cardiac complications in childhood cancer survivors treated with anthracyclines[END_REF][START_REF] Mulrooney | Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort[END_REF][START_REF] Steinherz | Cardiac failure and dysrhythmias 6-19 years after anthracycline therapy: a series of 15 patients[END_REF]. The appearance of chemotherapeutic cardiotoxicity may indicate the interruption of treatment [START_REF] Lima | Cardiotoxicity in cancer patients treated with chemotherapy: A systematic review[END_REF][START_REF] Bloom | Cancer Therapy-Related Cardiac Dysfunction and Heart Failure[END_REF],

and therefore cardiotoxicity is an important prognostic factor.

Clinical guidelines of cardiology and oncology societies on prevention and treatment of anthracycline-induced cardiotoxicity (AIC) focused on screening for left ventricular ejection fraction (LVEF) reduction throughout the treatment [START_REF] Tarantini | ANMCO/AIOM/AICO Consensus Document on clinical and management pathways of cardio-oncology: executive summary[END_REF][START_REF] Čelutkienė | Role of cardiovascular imaging in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC)[END_REF]. Recently, the American Society of Echocardiography and European societies recommended the Global Longitudinal Strain (GLS), from speckle tracking echocardiography (STE), as a marker of myocardial dysfunction [START_REF] Tarantini | ANMCO/AIOM/AICO Consensus Document on clinical and management pathways of cardio-oncology: executive summary[END_REF][START_REF] Čelutkienė | Role of cardiovascular imaging in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC)[END_REF][START_REF] Plana | Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF][START_REF] Thavendiranathan | Use of Myocardial Strain Imaging by Echocardiography for the Early Detection of Cardiotoxicity in Patients During and After Cancer Chemotherapy[END_REF].

Indeed, it may provide an early warning sign of evolving cardiomyopathy among childhoodcancer survivors treated with anthracyclines despite their normal LVEF [START_REF] Biswas | Twoand Three-Dimensional Speckle Tracking Echocardiography: Clinical Applications and Future Directions[END_REF][START_REF] Padmanabhan | Speckle Tracking Echocardiography: Clinical Usefulness[END_REF][START_REF] Yu | Two-Dimensional Speckle Tracking Echocardiography Detects Subclinical Left Ventricular Systolic Dysfunction among Adult Survivors of Childhood, Adolescent, and Young Adult Cancer[END_REF][START_REF] Merkx | Asymptomatic systolic dysfunction on contemporary echocardiography in anthracycline-treated long-term childhood cancer survivors: a systematic review[END_REF]. However, GLS represents only one component of LV strains. A comprehensive approach to assess LV systolic function needs to combine GLS with circumferential strains [START_REF] Amedro | Use of speckle tracking echocardiography to detect late anthracycline-induced cardiotoxicity in childhood cancer: A prospective controlled cross-sectional study[END_REF], and also LV twisting mechanics [START_REF] Cheung Y Fai | Left Ventricular Twisting and Untwisting Motion in Childhood Cancer Survivors: LV Twist in Childhood Cancer Survivors[END_REF]. During systole, due to the complex orientation of the myocardial fibers, LV twists consequently to the opposing rotations of the base and the apex, which is essential to maintain efficiency of systolic function. Significant reduction of twist and untwist velocities were observed in childhood lymphoma survivors (CLS) [START_REF] Cheung Y Fai | Left Ventricular Twisting and Untwisting Motion in Childhood Cancer Survivors: LV Twist in Childhood Cancer Survivors[END_REF][START_REF] Slieker | Echocardiographic Assessment of Cardiac Function in Pediatric Survivors of Anthracycline-Treated Childhood Cancer[END_REF]. Another important feature is to propose a regional assessment of LV strain [START_REF] Amedro | Use of speckle tracking echocardiography to detect late anthracycline-induced cardiotoxicity in childhood cancer: A prospective controlled cross-sectional study[END_REF] and a differentiation of subendocardial and subepicardial layers that could provide additional information on the subtle myocardial remodeling in CLS.

Recently, Myocardial work (MW), obtained by integrating both cardiac deformation and noninvasive LV pressure has been proposed as an additional echocardiographic tool to detect subtle

LV dysfunctions [START_REF] Li | Myocardial work: The analytical methodology and clinical utilities[END_REF][START_REF] Ilardi | Myocardial Work by Echocardiography: Principles and Applications in Clinical Practice[END_REF]. In adults population, MW has already been evaluated in many diseases and previous work demonstrated its better sensitivity in predicting coronary artery disease and assess early subclinical ischemic myocardial dysfunction compared to GLS [START_REF] Edwards | Global Myocardial Work Is Superior to Global Longitudinal Strain to Predict Significant Coronary Artery Disease in Patients With Normal Left Ventricular Function and Wall Motion[END_REF].

Importantly, MW can be assessed regionally, according to a 18-segments model of the LV.

However, its global and regional assessment in CLS remains to be evaluated.

Myocardial performance can also be altered by the non-uniform contractions of LV myocardial walls, that could led to a LV dyssynchrony (LVD) characterized by an increased mechanical timing dispersion at end systole. In childhood cancer survivors, previous studies showed structural myocardial abnormalities with presence of diffuse interstitial fibrosis, and sarcomeric disruption [START_REF] Steinherz | Cardiac failure and dysrhythmias 6-19 years after anthracycline therapy: a series of 15 patients[END_REF][START_REF] Sawyer | Mechanisms of Anthracycline Cardiac Injury: Can we identify strategies for cardio-protection? Progress in cardiovascular diseases[END_REF]. Since interactions exist between myocardial fibrosis and conduction disorders [START_REF] Tham | Diffuse myocardial fibrosis by T1-mapping in children with subclinical anthracycline cardiotoxicity: relationship to exercise capacity, cumulative dose and remodeling[END_REF], we questioned a potential increase of LV mechanical dispersion in CLS. The LV mechanical dispersion, never explored in this specific population, can be assessed not only from the segmental analysis of timing of LV strains, but also from the MW. Indeed, a study of MW, which includes myocardial constructive (MCW) and wasted work (MWW), could reveal an increase in mechanical dispersion via an increase in MWW [START_REF] Harbo | One step closer to myocardial physiology: From PV loop analysis to state-of-the-art myocardial imaging[END_REF].

In this context, the objective of the study was to compare the cardiac function of CLS, with healthy age-matched controls, to determine the late effects of anthracyclines by assessing not only myocardial strain, but also MW and LV mechanical dispersion. We hypothesized that CLS treated with anthracyclines have adverse cardiac remodeling characterized by 1) a decrease of longitudinal strain, especially in the subendocardial layer, 2) a decrease of segmental and global MW, 3) increase of LV intraventricular mechanical dispersion associated with an increase of MWW.

MATERIALS AND METHODS

Study design and population

This study collected the data of our previous prospective cross-sectional case-control study run from January 2022 to May 2022 in Clermont-Ferrand University Hospital, France. 16 CLS were included and compared with 15 healthy controls, recruited from the database of the Centre d'Investigation Clinique of Clermont-Ferrand University Hospital, and matched for sex, age (± 5 years), and body mass index (BMI ± 5 kg/m²). None of the participants had cardiac medication at the time of evaluation and all were normotensive and in sinus rhythm. CLS aged between 18-25 years old were followed for childhood lymphoma post-therapeutic surveillance, and considered as recovered (i.e., free of any lymphoma medication or radiotherapy for at least one year), with no physical disability at the day of inclusion. To guarantee a late cardiac functional assessment and the absence of any progressive malignancy, only patients who have recovered of treatment for over 2 year, up to 10 years, were eligible for the study. Subjects were excluded if they had been clinically diagnosed for a running infection or undergone corticosteroid treatment within the last three months before the day of visit. Approval was granted by the Comité de Protection des Personnes Sud-Est V (no. 21.02921.000036 cat 1). Written informed consents were collected from every participant on the day of visit in line with the principles of the Declaration of Helsinki.

Anthropometrics

Height was determined using a mural stadiometer with subject barefoot (graduated in cm, precision of 0.5 cm), and weight using a digital weight scale (graduated in kg, with 0.1 kg precision), permitting calculation of BMI (body weight.body height -², with weight in kg and height in m). Blood pressure (BP) were recorded at rest, using an automatic device (General Electric Dynamap PRO 300 V2, Boston, MA, USA).

Biological data

Blood samples were collected after 12 hours fasting and at least 10 minutes resting. The two main cardiotoxicity biomarkers, troponin I and N-Terminal pro-brain natriuretic peptide (NT-proBNP), were assessed in all participants. Standard blood test as haemoglobin, C-reactive protein, thyroid hormones and albumin were also performed to identify biological anomalies, which could influence cardiac parameters.

Echographic conventional recordings

Echocardiography was carried out with the subject in the left lateral decubitus position, with

Vivid ultrasound systems (GE Healthcare, Horten, Norway) using a 3.

Two-dimensional strain analysis from STE

Cine loops were recorded in parasternal long and short axis (basal and apical) and apical (5, 4, 2, and 3 chambers) views and saved for blinded off-line analysis (EchoPAC, BT204 Version, GE Healthcare), with ECG recording. Data was normalized to percentage of systolic duration to avoid differences in heart rate and cine loops frame rates. We used an 18-segments model from apical 4-, 2-, and 3-chambers views to assess LV regional strains and time to peak (TTP) strains in accordance with the nomenclature of Lang et al [START_REF] Lang | Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF]. A segment-by-segment validation must be done to continue the analysis. When analysis was not possible or unreliable, the segment or cut was excluded from the analysis. Systolic and diastolic strain rates were then obtained from time-derivation of strains. The diastolic longitudinal strain rate (diastolic GLSrate) was used as an indicator of LV relaxation [START_REF] Wang | Global diastolic strain rate for the assessment of left ventricular relaxation and filling pressures[END_REF].

LV twisting mechanics were assessed by STE using two-dimensional images from the apical and basal short-axis planes previously stored. Basal planes were assessed regarding the mitral valve and apical planes toward the apex with no visible papillary muscles. With LV contraction, the cardiac apex and the base rotates in counterclockwise and clockwise directions, respectively, when viewed from the apex. Twist represents the mathematical difference in the rotation of the apex and base, at each percentage of systolic duration [START_REF] Notomi | Measurement of ventricular torsion by two-dimensional ultrasound speckle tracking imaging[END_REF]. Peak systolic twisting velocity was defined by the peak positive rate of torsional deformation, whereas the peak diastolic untwisting velocity was defined by the peak negative rate of torsional deformation.

Untwisting velocity is thought to be an important initial manifestation of active relaxation.

The LV mechanical dispersion was quantified by calculating the standard deviation (SD) of the TTP systolic strain in the longitudinal direction in the 18-segments model (SD18S), and the maximum delay between the segments with earliest and the latest TTP (Delta 1-18).

Myocardial work

MW was estimated using the Automatic Function Imaging (AFI) of the Echo PAC software (Version 203; GE Healthcare). MW was assessed as a function of time throughout the cardiac cycle by the combination of LV strain data (recorded on the apical 4-, 3-, and 2-chambers views)

obtained by STE and a non-invasively estimated LV pressure curve as previously described [START_REF] Russell | A novel clinical method for quantification of regional left ventricular pressure-strain loop area: a non-invasive index of myocardial work[END_REF]. The result was integrated over time to obtain MW as a function of time. MW was calculated from mitral valve closure until mitral valve opening as previously described. The valvular markers of mitral and aortic opening and closure were taken first on the doppler from peak early (E) and atrial (A) trans-mitral flow and trans-aortic, for reproducibility, and then imported into the MW analysis with a secondary modification on the 2D section for synchronization. All data are averaged on 2 cardiac cycles, synchronized with ECG, and we assumed that high and low pressure measured was equal to peak systolic and diastolic LV pressures and to be uniform throughout the ventricle. Strain and MW evaluation was done by a single investigator. The global or segmental myocardial work efficiency (MWE) depends on the MCW and MWW, and was obtained as follows:

𝑀𝑊𝐸 = 𝑀𝐶𝑊 𝑀𝐶𝑊 + 𝑀𝑊𝑊 × 100
In systole, the work performed by the myocardium during segmental shortening represents MCW (includes lengthening in isovolumic relaxation), whereas the work performed by the myocardium during stretch or segmental lengthening represents the energy loss, which is defined as MWW. For both global and segmental analyses, we constructed LV pressure-strains loops. The area of the loops represented the Myocardial work index (MWI).

Statistical analysis

All values were expressed as mean ± SD. Statistical analyses were performed using Medcalc (version 19.1, Medcalc Software). One-way analysis of variance (ANOVA) was used to compare groups, after checking the normality of distribution of each variable by the Shapiro-Wilk test. In the absence of normal distribution, the nonparametric Kruskal-Wallis test was used. Statistical significance for all analyses was assumed at p <0.05.

RESULTS

Participants characteristics

Clinical data of the two populations are presented in Table 1. The median time interval between the end of chemotherapy and patient enrolment was 7 years. CLS were treated by chemotherapy with a mean cumulative dose of anthracyclines of 160 mg.m -² with a maximal dose of 286 mg.m -² in one patient. Doxorubicine was mainly used. Mean corticosteroids was 2600 mg.m -².

Alkylant-agent and type II topo-isomerase inhibitor were used for all patients. Four Hodgkin lymphoma survivors had a total of 19.6 Gy mediastinal and cervical targeted radiation therapy (depending on diagnosis stage or relapse) and 2 beneficiated of autologous hematopoietic stem cell transplantation for relapse.

There was no significant difference between CLS and healthy controls in term of blood pressure. No patient had symptoms of heart failure. Heart rate was significantly higher in CLS compared to controls. No statistical difference was shown on troponin I and NT-proBNP, with a mean value of 51 ± 33 ng.L -1 in CLS. Haemoglobin was higher in CLS. None participant had anemia. Non-significative difference was found on CRP, negative for all, thyroid hormone nor on nutritional status estimated by albumin levels .

Left ventricular morphology and function

Data of LV morphology and function are presented in Table 2. LV posterior wall thickness, LV septum thickness, LV end-diastolic and end-systolic volume, LV mass and LV mass indexed to body surface area were comparable in both population. LVEF was significantly decreased in CLS patients but no LVEF below 60% was detected. There was no significant difference in the early to late diastolic filling ratio (E/A ratio) and E/E' ratio.

Left ventricular regional strains and myocardial work

LV strains are presented in Table 3 and Figure 1. GLS was diminished in CLS patients compared to controls, whereas no difference was observed on circumferential strains. We note a significant and similar difference in both sub-endocardium and sub-epicardium in CLS compared to controls. In CLS, the global strain rate values were significantly inferior and we note significative difference in Diastolic GLS-rate. LV twisting mechanics are presented in Table 3 and Figure 2. LV rotations and twist were similar between groups despite their patterns during the cardiac cycle appears slightly different. Peak untwisting rate, which occurred in very early diastole, was lower in CLS compared to controls.

MW data are presented in Table 4 and Figure 3. In CLS patients, the LV pressure-strain loops (PSL) was shifted to the right, consequently to the decrease of their GLS. The MWI, calculated as the area of the PSL, was significantly different between groups (1668 ± 266 vs 1870 ± 264 %.mmHg in CLS patients and controls, respectively). In CLS, segmental MWI values presented in Figure 4 were significantly lower in the apical segments, whereas no significant difference was showed in the mid and basal segments.

Left ventricular mechanical dispersion

The SD18S and the Delta1-18, markers of intraventricular mechanical dispersion, were significantly increased in the CLS group (Table 4). No difference was however observed between groups regarding the MWW, and consequently the MWE was unchanged.

DISCUSSION

The aim of our study was to compare the cardiac function of CLS with age-matched control subjects to determine the late anthracyclines cardiotoxicity using STE. In CLS, we observed 1) a reduction of longitudinal strains in a similar manner in the sub-endocardium and subepicardium, without alteration of circumferential strains and twist 2) a decrease of MW, mainly observed on segmental analysis with specific alteration in apex, 3) an increase of LV intraventricular mechanical dispersion, but without significant alteration of MWW and global MWE.

Lower longitudinal strain without alteration of circumferential strains and twist in CLS

The first result of our study was that GLS, which allows a more sensitive analysis of systolic function than LVEF, was significantly lower in CLS than in controls although they received relatively low doses of anthracyclines. Of note, whereas GLS was decreased, LV CS, rotations and twist were unchanged in CLS. The LV twist plays an important role to promote LV ejection during systole, therefore the maintenance of LV twist in CLS probably contributed to maintain their LVEF despite the decrease of the GLS. Similar pattern of impaired GLS without changes in CS was documented in young patients after chemotherapy [START_REF] Padmanabhan | Speckle Tracking Echocardiography: Clinical Usefulness[END_REF][START_REF] Amedro | Use of speckle tracking echocardiography to detect late anthracycline-induced cardiotoxicity in childhood cancer: A prospective controlled cross-sectional study[END_REF][START_REF] Slieker | Echocardiographic Assessment of Cardiac Function in Pediatric Survivors of Anthracycline-Treated Childhood Cancer[END_REF][START_REF] Çetin | Subclinical anthracyclineinduced cardiotoxicity in long-term follow-up of asymptomatic childhood cancer survivors: Assessment by speckle tracking echocardiography[END_REF], but also in patients suffering of hypertrophic cardiomyopathy [START_REF] Sun | Echocardiographic strain in hypertrophic cardiomyopathy and hypertensive left ventricular hypertrophy[END_REF]. Since sub-endocardial layer is principally composed of fibers oriented longitudinally, it has been often hypothesized that sub-endocardial layer was more sensitive to myocardial disease such as fibrosis. For example, lower CS is found in transmural myocardial infarction, differentiating it from subendocardial infarction [START_REF] Padmanabhan | Speckle Tracking Echocardiography: Clinical Usefulness[END_REF]. In adults with an AIC [START_REF] Tham | Diffuse myocardial fibrosis by T1-mapping in children with subclinical anthracycline cardiotoxicity: relationship to exercise capacity, cumulative dose and remodeling[END_REF][START_REF] Ylänen | Cardiac Magnetic Resonance Imaging in the Evaluation of the Late Effects of Anthracyclines Among Long-Term Survivors of Childhood Cancer[END_REF] previous studies observed that the late gadolinium cardiac magnetic resonance was enhanced specifically in the sub-endocardium, suggesting the presence of fibrosis. However, our results indicated that the decrease of LS was similar on both layers, that spoke in favor of an homogeneous alteration of the different zones of the myocardium rather than a specific alteration of the sub-endocardial layer.

During systole, contraction of the cardiomyocytes generates opposite rotations of the LV base and apex, inducing a LV twist. This mechanism predominantly deforms the subendocardial fiber matrix, resulting in storage of potential energy. Subsequent untwist deformation is associated with the release of restoring forces, which contributes to LV diastolic relaxation and early filling which onset and peak could be significantly delayed in diastolic heart failure [START_REF] Sengupta | Twist mechanics of the left ventricle: principles and application[END_REF].

In our study, we observed that untwisting rate was lowered in CLS despite their normal LV twist. This result has been described by others [START_REF] Cheung Y Fai | Left Ventricular Twisting and Untwisting Motion in Childhood Cancer Survivors: LV Twist in Childhood Cancer Survivors[END_REF][START_REF] Yu | Transmural strain and rotation gradient in survivors of childhood cancers[END_REF] and support that underlying mechanisms of diastolic function were altered in CLS patients with a potential decrease of LV intrinsic myocardial relaxation.

Specific decrease of apical MW in CLS

Non-invasive PSL as a surrogate of MW have been validated by many studies and distinguished itself by an overcome of EF and LS load dependency [START_REF] Abawi | The non-invasive assessment of myocardial work by pressure-strain analysis: clinical applications[END_REF][START_REF] Gao | Clinical research progress of myocardial work in assessment and prediction of coronary artery disease in noninvasive pressure-strain loop technique[END_REF][START_REF] Paysal | Left Ventricular Strains and Myocardial Work in Adolescents With Anorexia Nervosa[END_REF][START_REF] Zhan | Deterioration in myocardial work indices precedes changes in global longitudinal strain following anthracycline chemotherapy[END_REF]. Indeed, MW takes into account deformation as well as afterload through interpretation of strain in relation to dynamic noninvasive LV pressure (estimated by measurement of cuff pressures). This estimation of MW was already studied in preclinical and adults cohorts of patients [START_REF] Li | Myocardial work: The analytical methodology and clinical utilities[END_REF][START_REF] Ilardi | Myocardial Work by Echocardiography: Principles and Applications in Clinical Practice[END_REF][START_REF] Mihalcea | Myocardial work-A new tool for early detection of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy induced-cardiotoxicity in hematological patients[END_REF]. For example, MW has been assessed in ischemic cardiac disease, allowing to detect subclinical coronary artery disease without any regional wall motion abnormalities, and had more important sensitivity for myocardial oxygen consumption [START_REF] Edwards | Global Myocardial Work Is Superior to Global Longitudinal Strain to Predict Significant Coronary Artery Disease in Patients With Normal Left Ventricular Function and Wall Motion[END_REF]. In pediatric population, Zhan et al. recently demonstrated that global MWI enhanced hypertensive heart disease evaluation and cardiac dysfunction during and after chemotherapy follow-up [START_REF] Zhan | Deterioration in myocardial work indices precedes changes in global longitudinal strain following anthracycline chemotherapy[END_REF][START_REF] Zhan | Left ventricular myocardial work indices in pediatric hypertension: correlations with conventional echocardiographic assessment and subphenotyping[END_REF]. In our study, while systolic BP were similar between the two groups, the MWI was reduced in CLS, linked in a large part to their lower GLS.

The strength of our study was to assess not only global MW, but also segmental MW. Based on regional assessments on a 18-segments model of the LV, we observed that MW was specifically decreased in the apical region. To our knowledge, no previous studies assessed the segmental MWI in CLS. This result was in agreement with previous study, showing impaired LS specifically in apical segments, in a cohort of childhood-cancer survivors [START_REF] Amedro | Use of speckle tracking echocardiography to detect late anthracycline-induced cardiotoxicity in childhood cancer: A prospective controlled cross-sectional study[END_REF][START_REF] Poterucha | Changes in left ventricular longitudinal strain with anthracycline chemotherapy in adolescents precede subsequent decreased left ventricular ejection fraction[END_REF][START_REF] Okuma | Impact of persistent left ventricular regional wall motion abnormalities in childhood cancer survivors after anthracycline therapy: Assessment of global left ventricular myocardial performance by 3D speckle-tracking echocardiography[END_REF][START_REF] Yu H Kui | New threedimensional speckle-tracking echocardiography identifies global impairment of left ventricular mechanics with a high sensitivity in childhood cancer survivors[END_REF]. We also noticed a specific and significant decrease of MW on the basal inferior in CLS compared to controls, whereas other basal segments remained strictly unchanged. The clinical significance and the underlying mechanisms of this regional alteration remains unclear.

Specific segmental modifications of MW have already been showed in adult populations for precising diagnosis, or as a predictor of mortality by evaluation of its apex-to-base ratio in cardiac amyloidosis, or as short-term prognosis markers in ischemic diseases or posttherapeutic prediction response in cardiac resynchronization therapy [START_REF] Abawi | The non-invasive assessment of myocardial work by pressure-strain analysis: clinical applications[END_REF]. In our population and on the basis of preclinical in-vivo juvenile rat's study, our result can suggest starting fibrosis pattern in the apical regions in CLS [START_REF] Chakouri | Screening for in-vivo regional contractile defaults to predict the delayed Doxorubicin Cardiotoxicity in Juvenile Rat[END_REF]. Apical deterioration might be also explained by the extent of sensitivity toward the LV apical vortex, which is formed by the helical fibers that exist without any surrounding circumferential muscle [START_REF] Padmanabhan | Speckle Tracking Echocardiography: Clinical Usefulness[END_REF]. Further investigations are needed to explore the role of the apex in myocardial mechanics and its specific implication in long-term cardiac dysfunction in CCS.

Higher intraventricular mechanical dispersion in CLS

Interstitial fibrosis was detected in microscopic slides of heart tissue from patients who had cardiac transplants after AIC, without significant cardiac hypertrophy [START_REF] Bernaba | Pathology of late-onset anthracycline cardiomyopathy[END_REF]. Myocardial fibrosis having adverse effects on excitability, sarcomeric organization, and the regulation of intracellular calcium and myofilament Ca2+ sensitivity [START_REF] Chakouri | Screening for in-vivo regional contractile defaults to predict the delayed Doxorubicin Cardiotoxicity in Juvenile Rat[END_REF][START_REF] Leerink | Cardiac Disease in Childhood Cancer Survivors[END_REF], these myocardial alterations could increase mechanical dispersion and decrease myocardial efficiency. Based on segmental STE analysis, we observed that SD18S and delta 1-18, both overall indexes of LV mechanical dispersion, were significantly increased in CLS compared to controls. Others studies also showed increased systolic intraventricular dyssynchrony index in childhood-cancer survivors, with significant negative correlations with LVEF [START_REF] Cheung Y Fai | Left ventricular myocardial deformation and mechanical dyssynchrony in children with normal ventricular shortening fraction after anthracycline therapy[END_REF][START_REF] Klitsie | Assessment of intraventricular time differences in healthy children using two-dimensional speckle-tracking echocardiography[END_REF]. To complete the study of mechanical dispersion, we measured MCW and MWW to calculate MWE. In patients with increased mechanical dispersion, MWW is generally increased and consequently MWE reduced.

However, we did not significant alteration of both MWW and MWE in CLS compared to controls. These findings were nevertheless concordant with Zhan et al. showing preserved MWE [START_REF] Zhan | Deterioration in myocardial work indices precedes changes in global longitudinal strain following anthracycline chemotherapy[END_REF].

Study limitations

Our study has several limitations. First, this is a single center study including a small group of patients. However, despite the small sample size, our data clearly showed a significant impact of anthracycline on LV regional myocardial function assessed by 2D-strain echocardiography and MW. Moreover, we assessed only the late effects of anthracycline, several years after completion of therapy in CLS, and it would be interesting to have assess also the alteration of their cardiac function during the treatment. However, long-term effects of anthracyclines are known to develop even years after completion of treatment. Finally, it would be helpful to link the increase of the LV mechanical dispersion observed in CLS with a potential increase of myocardial fibrosis from magnetic resonance imaging with late gadolinium enhancement.

Conclusion

With more CLS now reaching adulthood, understanding the adverse effects of chemotherapy and particularly anthracyclines on the cardiovascular system is of major interest. Our results highlighted that the late cardiac effects of chemotherapy based on low to moderate doses of anthracyclines were characterized by a decrease of the GLS. The strength of our study was to assess the MW, a new echocardiographic tools which has been shown to be useful to detect early and subtle dysfunction in various pathologies. We observed that global MW was depressed in CLS. Based on a regional analysis, our data strongly supported that MW was diminished specifically on apical segments. Moreover, our regional analysis enabled an assessment of the intraventricular mechanical dispersion, which was higher in CLS compared to controls. All-in-one, our study strongly supported a late but subtle effect of chemotherapy based on anthracyclines in young adults. However, further studies would be helpful to evaluate the clinical significance of these cardiac remodeling and their potential long-term adverse cardiac events, in order to propose an adapted follow-up to CLS and evaluate the benefit of cardio-protective preventive therapies.

BASAL LEVEL MID LEVEL APICAL LEVEL BASAL LEVEL MID LEVEL

5

 5 MHz transducer (M4S probe), by the same, experimented, cardiologist, blinded of the status of patients. 2D echocardiographic measurements were made in accordance with the American Society of Echocardiography guidelines[START_REF] Lang | Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF]. Cine loops are stored in one R-R interval length to facilitate easy analysis. Electrocardiogram (ECG) signal is recorded for R-R interval clip storage and no ambiguous ECG complexes or leading T-waves were displayed. Interventricular septum thicknesses were measured from the parasternal long axis view. LV volumes and LVEF were assessed using the Simpsons biplane method. Stroke volume and cardiac output were assessed from a 5-chamber view and then indexed to body surface area. LV mass was estimated by the Lang formula and indexed to body surface area. Diastolic function was assessed by doppler from peak early (E) and atrial (A) trans-mitral flow velocities. Septal and lateral E' wave from tissue doppler completes this evaluation. The LV filling pressures were evaluated from the E/E' ratio.

Figure 1 .Figure 2 .Figure 3 .Figure 4 .

 1234 Figure 1. Longitudinal and circumferential strain

le Professeur Stéphane NOTTIN Madame le Docteur Justine PAYSAL

  Je vous remercie pour votre aide dans l'encadrementde ce travail Vous avez toujours été disponible, je vous remercie d'avoir tant donner de votre personne et de votre temps pour ce projet, d'avoir été patients pour les multiples relectures J'espère avoir été à la hauteur du sujet que vous m'avez confié Un mot pour Stéphane, je te connais si peu mais tu as rapidement su me mettre à l'aise et me transmettre ta passion pour la mécanique du coeur. Tu m'a transmis le sens de la recherche et de la pédagogie et se serai un honneur de poursuivre mon parcours de recherche à tes côtés. INTRODUCTION ......................................................................................................... 2. MATERIALS AND METHODS ................................................................................... . DISCUSSION ............................................................................................................... 5. Conclusion .................................................................................................................... References ............................................................................................................................ Annexes ...............................................................................................................................

	REMERCIEMENTS	TABLES AND FIGURES
	A NOTRE MAITRE ET PRESIDENT DU JURY
	MAITRES DE CONFERENCES ASSOCIES DES UNIVERSITES Monsieur le Professeur Etienne MERLIN UNIVERSITE CLERMONT AUVERGNE Professeur des Universités, Praticien Hospitalier ___________________ Mme ESCHALIER Bénédicte Médecine Générale Pédiatrie Générale Multidisciplinaire Chef de service TABLES
	PRESIDENTS HONORAIRES Mme RICHARD Amélie UNIVERSITE D'AUVERGNE M. TESSIERES Frédéric Mme ROUGE Laure Mme BERTRAND-JARROUSSE Véronique Mme VICARD-OLAGNE Mathilde M. MENINI Thibault	Médecine Générale : JOYON Louis Médecine Générale : DOLY Michel Médecine Générale : TURPIN Dominique Médecine Générale : VEYRE Annie Médecine Générale : DULBECCO Philippe : ESCHALIER Alain Médecine Générale
	PRESIDENTS HONORAIRES Vous nous faites l'honneur d'accepter la présidence de notre jury de thèse : CABANES Pierre
	UNIVERSITE BLAISE PASCAL			: FONTAINE Jacques
				: BOUTIN Christian
				: MONTEIL Jean-Marc
				: ODOUARD Albert
				: LAVIGNOTTE Nadine
	PRESIDENT DE L'UNIVERSITE			: BERNARD Mathias
	PREMIERE VICE-PRESIDENTE
	CHARGEE DU PILOTAGE ET DES MOYENS		: FOGLI Anne
	VICE PRESIDENTE CHARGEE DE LA FORMATION	: PEYRARD Françoise
	VICE-PRESIDENTE CHARGEE DE LA RECHERCHE	: PREVOT Vanessa
	DIRECTEUR GENERAL DES SERVICES		: PAQUIS François
		
		UFR DE MEDECINE
	PROFESSEURS DES UNIVERSITES DE MEDECINE GENERALE ET DES PROFESSIONS PARAMEDICALES Professeur des Universités Praticien Hospitalier
	DOYENS HONORAIRES Physiologie Expérimentale Cardiovasculaire	Pédiatrie	: DETEIX Patrice
		1ère CLASSE	: CHAZAL Jean
	DOYEN-DIRECTEUR			: CLAVELOU Pierre
	DIRECTRICE ADMINISTRATIVE M. VORILHON Philippe	: ROBERT Gaëlle Médecine Générale
	Mme LAPORTE Catherine		Médecine Générale
	PROFESSEURS DES UNIVERSITES

Ecrire n'est un plaisir que lorsqu'il s'accompagne à celui

de

penser, lequel suppose qu'on ne connaisse pas déjà la vérité. Vous êtes la source d'inspiration de ceux qui veulent se hisser. Je vous remercie de m'avoir encadrer, guider au cours de ces années, et nous avoir élevés par votre méthode Par votre humour et par vos critiques J'espère donc être digne de votre confiance Soyez assuré de mon profond respect Monsieur A Justine, merci d'avoir pensé à moi pour ce projet et d'avoir été si présente et patiente malgré les échéances. Depuis mon 1 er semestre en tant qu'interne, tu as su transmettre tes connaissances et ton intérêt pour la recherche et ton souci du détail me permettent d'accomplir ce projet aujourd'hui ! 1. 2.1 Study design and population ........................................................................................ 2.2 Anthropometrics ......................................................................................................... 2.3 Biological data ............................................................................................................ 2.4 Echographic conventional recordings .......................................................................... 2.5 Two-dimensional strain analysis from STE ................................................................. 2.6 Myocardial work ......................................................................................................... 2.7 Statistical analysis ....................................................................................................... 3. RESULTS ..................................................................................................................... 3.1 Participants characteristics .......................................................................................... 3.2 Left ventricular morphology and function ................................................................... 3.4 Left ventricular regional strains and myocardial work ................................................. 3.5 Left ventricular mechanical dispersion ........................................................................ 4

Table 1 .

 1 Baseline Characteristics of Patients and Controls....................................................

Table 2 .

 2 Left ventricular morphology and function...............................................................

Table 3 .

 3 LV and RV strains ..................................................................................................

Table 4 .

 4 Myocardial Left ventricular twisting mechanics .......................................................................

	Figure 3. Myocardial work and its components ....................................................................

work and LV mechanical dispersion .................................................... FIGURES Figure 1. Longitudinal and circumferential strain .................................................................

Figure 2.

Figure 4. Segmental Pressure

  -Strain loops ...........................................................................

	ABREVIATIONS
	AFI : Automatic Function Imaging
	AIC: anthracycline induced cardiotoxicity
	ANOVA : One-way analysis of variance
	BMI : body mass index
	BP : Blood pressure
	CLS : childhood lymphoma survivors
	ECG : Electrocardiogram
	GLS : Global Longitudinal Strain
	LVD : Left ventricular dyssynchrony
	LVEF : left ventricular ejection fraction
	MCW : myocardial constructive work
	MW : Myocardial work
	MWE: myocardial work efficiency
	MWI : myocardial work index
	MWW : myocardial wasted work

PSL : pressure-strain loops SD : standard deviation STE : speckle tracking echocardiography

	Abstract
	Background: The cardiac-induced toxicity of chemotherapy including anthracycline is well-
	described in childhood lymphoma survivors (CLS).
	Objective: Myocardial work (MW) is a new echocardiographic tool with a high sensibility to
	detect early and subtle alterations of myocardial function. We aimed to evaluate the late effects
	of anthracycline by assessing the global and segmental MW and intraventricular mechanical
	dispersion from speckle tracking echocardiography in CLS.
	Methods: Thirty-one young adults including 16 CLS and 15 age-matched healthy controls were
	enrolled in the study. All underwent a resting echocardiography including an evaluation of left
	ventricular (LV) morphology and regional myocardial function. We assessed LV longitudinal
	(differentiating sub-endocardial and sub-epicardial layers), circumferential strains and twist,
	LV myocardial regional strains and MW. LV mechanical dispersion was assessed from the time
	dispersion of LV longitudinal strain and from myocardial wasted work (MWW) and myocardial
	work efficiency (MWE).
	TTP : time to peak

Table 2 .

 2 Left ventricular morphology and function

	Patients (n = 16)	Controls (n=15)

Annexes

Je donnerai mes soins gratuits à l'indigent et je n'exigerai jamais un salaire audessus de mon travail. Admis dans l'intérieur des maisons, mes yeux ne verront pas ce qui s'y passe, ma langue taira les secrets qui me seront confiés et mon état ne servira pas à corrompre les moeurs ni à favoriser le crime.

Respectueux et reconnaissant envers mes MAÎTRES, je rendrai à leurs enfants l'instruction que j'ai reçue de leurs pères.

Que les HOMMES m'accordent leur estime si je suis fidèle à mes promesses.

Que je sois couvert d'OPPROBRE et méprisé de mes confrères si j'y manque.

JABER Mohamed

Signature