Doyen Professeur

Emmanuel Touzé

Assesseurs Professeur

Paul Milliez

Guy Launoy

Professeur Sonia Dollfus

Evelyne Professeur

Emery

Madame Sarah

Chemtob Professeurs

Des Universités -Praticiens Hospitaliers

M Agostini

M Aide Nicolas

M Allouche

M Alves Arnaud

M Aouba Achille

M Babin

Emmanuel Oto-Rhino-Laryngologie

M Bénateau Hervé

M Benoist

Guillaume Gynécologie -Obstétrique

M Berger

Ludovic Chirurgie

M Bergot

Emmanuel Pneumologie

M Bibeau

Frédéric Anatomie

Mme Brazo

Perrine Psychiatrie

M Brouard

Jacques Pédiatrie

M Bustany

Pierre Pharmacologie

Mme Chapon

Françoise Histologie

Embryologie Mme

Clin-Godard Bénédicte

M Damaj

Ghandi Laurent Hématologie

M Dao

Manh Thông

M Defer

Gilles Neurologie

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Pascal Psychiatrie D'adultes

M Denise

Pierre P H Y S I O L O G I E

Mme Dollfus

Sonia Psychiatrie

M Dreyfus

Michel Gynécologie -Obstétrique

M Du

Cheyron Damien

Mme Émery

Evelyne Neurochirurgie

M Esmail-Beygui

Farzin Cardiologie

Mme Fauvet

Raffaèle Gynécologie -Obstétrique

M Fischer

Marc-Olivier Anesthésiologie

M Gérard

Jean-Louis Anesthésiologie

M Guillois

Bernard Pédiatrie

Mme Guittet-Baud

Lydia Epidémiologie

M Habrand

Jean-Louis Cancérologie

Radiothérapie M Hamon Mar9al

Cardiologie Mme

Hamon Michèle

M Hanouz

Jean-Luc Anesthésie

M Hulet

Christophe Chirurgie

M Icard Philippe

M Join-Lambert

Olivier

Joly-Lobbedez Mme

Cancérologie M Florence

Michael Joubert

M Endocrinologie

M Le Hello

Mme Le

Mauff Brigize

Immunologie M Lobbedez

Thierry Néphrologie

M Lubrano

Jean Chirurgie

M Mahe

Marc-André Cancérologie

M Manrique

M Marcélli

Rhumatologie M Martinaud

Olivier Neurologie

M Maurel

Jean Chirurgie

M Milliez

Paul Cardiologie

M Moreau

Sylvain Anatomie

/ Oto-Rhino- Laryngologie

M Moutel Grégoire

M Normand Hervé

M Parienti

M Pelage

Jean-Pierre Radiologie

Mme Piquet

Marie-Astrid Nutriron

M Quintyn

Jean-Claude Ophtalmologie

Mme Rat

Anne-Chris9ne Rhumatologie

M Ravasse

Philippe Chirurgie

M Repesse

Yohann Hématologie

M Reznik

Yves Endocrinologie

M Rod

Julien Chirurgie

M Roupie

Eric Médecine D'urgence Mme

Thariat Julieze

Radiothérapie M Tillou

Xavier Urologie

M Touzé

Emmanuel Neurologie

M Troussard

Xavier Hématologie

Mme Vabret

Astrid Bactériologie -Virologie

M Verdon

Renaud Maladies

Mme Verneuil

Laurence Dermatologie

M Vivien

Denis Biologie

Professeurs Associés

Des Universités

A Mi-Temps M De

L A Sayette

Vincent Neurologie

Mme Dompmartin-Blanchère

M Guillaume

M Le Bas François

M Sabatier

PRCE Rémi Cardiologie

Mme Leleu

Solveig Anglais

M Hurault De Ligny

Bruno Néphrologie

Mme Kottler

M Le Coutour Xavier

Mme Leporrier

Michel Hématologie

M Viader

Fausto Neurologie

Sarah Chemtob

M Alexandre

Joachim Pharmacologie

Mme Benhaïm

Annie Biologie

M Besnard

Mme Bonhomme

Julie Parasitologie

M Bouvier

Nicolas Néphrologie

M Coulbault

M Creveuil Chris9an

M De Boysson

Mme Dina

Julia Bactériologie -Virologie

Mme Dupont

Claire Pédiatrie

M Étard

Olivier Physiologie

M Gaberel

Thomas Neurochirurgie

M Gruchy

Nicolas Générque

M Guénolé

Fabian Pédopsychiatrie

M Hitier Mar9n

M Isnard

Christophe Bactériologie

Virologie M Justet

Aurélien Pneumologie

Mme Krieger

Sophie Pharmacie

M Legallois

Damien Cardiologie

Mme Lelong-Boulouard

Véronique Pharmacologie

Mme Levallet

Guénaëlle Cytologie

Histologie M Mittre

Hervé Biologie

M Sesboüé

Bruno P H Y S I O L O G I E

M Toutirais

Olivier Immunologie

M Veyssiere

Mme Abbate-Leray

Pascale Médecine

M Couette

Noel Mme

Jaegher De

Sophie

M Pithon

M Sainmont

Mme Schonbrodt

Mme Debruyne

Danièle Pharmacologie

Mme Derlon-Borel

Annie Hématologie

Nathalie Générque

Chirurgie maxillo-faciale et stomatologie

A Monsieur le professeur Paul Milliez, Merci de l'honneur que vous me faites d'assister à ma soutenance de thèse en tant que président de jury et de venir juger ce travail de thèse. Merci à vous pour l'enseignement reçu au sein de votre service.

A Fabien, Je te remercie pour ton immense aide et implicaRon dans ce travail de thèse ainsi que pour le partage de tes connaissance au fil des visites à l'hôpital.

A Damien, Je te remercie pour ta disponibilité dans ce travail de thèse et pour ton aide précieuse pour les staRsRques.

A Monsieur le docteur Hubert De Boysson

Merci de l'honneur que vous me faites de juger ce travail de thèse.

A mes parents et à ma soeur, Je vous remercie de m'avoir soutenu tout au long de ces dix longues années d'études et d'avoir su m'aider et m'écouter dans les moments difficiles.

A Kléa, Je te remercie de ton souRen incondiRonnel, de ton aide de tous les instants et d'être à mes côtés au quoRdien.

A mes amis rencontrés sur Cherbourg, Un grand merci pour nos soirées passées ensemble et nos bons moments qui ne se comptent plus.

A mes co-internes de cardiologie Merci à vous d'avoir été là au fil des stages de cet internat qui sera passé bien trop vite (et à nos SIRC de folie).

Figure 1: Nomogram for the predicRve value for Fabry disease. The probability of Fabry disease is esRmated on the "Total Points" axis by the sum of points for each co-variable value. The point for each co-variable is obtained by drawing a verRcal line from the variable axis to the "Points" axis.

As an example, a paRent with a Sokolov-Lyon product of 3700 (20points), a right bundle block branch (30 points), a myocardial maximal thickness of 19.5 mm (60 points) and an indexed sinus of Valsalva aorRc diameter of 22 mm/m² (50 points) has a total score of 160 points, leading to a probability of Fabry disease > 90 %. AUC: area under curve.

Introduc9on

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme α-A galactosidase. This enzyme deficiency generates a gradual accumulaRon of globotriaosylceramide (Gb3) and related glycosphingolipids in the lysosomes of many cell types, leading to a mulRsystemic disorder, including complex cardiomyopathy [START_REF] Zarate | Fabry's disease[END_REF]. The prevalence of Fabry disease is historically esRmated to be between 1/40 000 to 1/117 000 individual; however, these data likely underesRmate the true number of paRents [START_REF] Meikle | Prevalence of lysosomal storage disorders[END_REF][START_REF] Desnick | Fabry disease, an underrecognized mulRsystemic disorder: expert recommendaRons for diagnosis, management, and enzyme replacement therapy[END_REF]. Cardiac manifestaRons are mainly characterized by leg ventricular hypertrophy (LVH), which might be the predominant feature of the disease [START_REF] Yousef | Leg ventricular hypertrophy in Fabry disease: a pracRcal approach to diagnosis[END_REF]. Cardiac complicaRons are associated with high morbidity and mortality due to arrhythmia and heart failure and are currently the leading cause of death in Fabry disease [START_REF] Mehta | Natural course of Fabry disease: changing pa€ern of causes of death in FOS -Fabry Outcome Survey[END_REF][START_REF] Waldek | Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry[END_REF]. The recent guidelines of the European Society of Cardiology (ESC) on hypertrophic cardiomyopathy (HCM) have strengthened their message regarding the importance of invesRgaRng rare causes of LVH, such as Fabry disease [START_REF] Ellio€ | ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy[END_REF]. However, screening for Fabry disease remains subopRmal in non-specialized centers [START_REF] Savary | Enhancing the diagnosis of fabry disease in cardiology with a targeted informaRon: a before-ager control-impact study[END_REF]. Improvements in diagnosRc delay have not yet been achieved [START_REF] Reisin | Time delays in the diagnosis and treatment of Fabry disease[END_REF], and Fabry disease conRnues to be ogen diagnosed late ager the onset of the first clinical signs [START_REF] Eng | Fabry disease: baseline medical characterisRcs of a cohort of 1765 males and females in the Fabry Registry[END_REF][START_REF] Mehta | Fabry disease defined: baseline clinical manifestaRons of 366 paRents in the Fabry Outcome Survey[END_REF]. As the efficiency of specific Fabry therapy is heavily condiRoned by the stage of the disease [START_REF] Germain | The effect of enzyme replacement therapy on clinical outcomes in male paRents with Fabry disease: A systemaRc literature review by a European panel of experts[END_REF], both delayed diagnosis and start of treatment might result in a "loss of opportunity" for paRents. This highlights the need to conRnue to develop screening tools for daily cardiology pracRce. Contrary to amyloidosis, we sRll do not have a relevant echocardiographic tool that could differenRate Fabry disease from other more common causes of LVH [START_REF] Militaru | MulRmodality imaging in Fabry cardiomyopathy: from early diagnosis to therapeuRc targets[END_REF]. ECG remains an unavoidable first step when evaluaRng paRents with HCM [START_REF] Ellio€ | ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy[END_REF] and might suggest an underlying diagnosis [START_REF] Rapezzi | DiagnosRc work-up in cardiomyopathies: bridging the gap between clinical phenotypes and final diagnosis. A posiRon statement from the ESC Working group on myocardial and pericardial diseases[END_REF]. Nevertheless, the ECG findings considered typical for Fabry disease (i.e., short PQ interval or atrioventricular block) might be present in other causes of HCM and cannot be used alone as a specific marker of Fabry disease [START_REF] Rapezzi | DiagnosRc work-up in cardiomyopathies: bridging the gap between clinical phenotypes and final diagnosis. A posiRon statement from the ESC Working group on myocardial and pericardial diseases[END_REF]. Similarly, the Sokolov-Lyon index did not appear to be discriminatory for Fabry disease [START_REF] Namdar | Value of electrocardiogram in the differenRaRon of hypertensive heart disease, hypertrophic cardiomyopathy, aorRc stenosis, amyloidosis, and Fabry disease[END_REF]. Other validated electrocardiographic criteria for LVH were poorly invesRgated in Fabry disease.

In the present study, we aimed to evaluate: 1) the diagnosRc value of the different electrocardiographic scores of LVH in Fabry disease; and 2) the diagnosRc value for Fabry disease of a model combining ECG and echocardiographic criteria.

Methods

Popula9on

We retrospecRvely included paRents >18 years old with Fabry disease and LVH who were admi€ed was calculated according to the Dubois formula and expressed in m². History of ischemic stroke, proteinuria, and cardiovascular risk factors were recorded. Cardiac symptoms and current medicaRons, including Fabry-specific therapy, were noted. In the Fabry disease group, LVH was defined by a maximal wall thickness ≥13 mm using trans-thoracic echocardiography. In the sarcomeric HCM group, inclusion criteria were based on LVH ≥15 mm in sporadic cases, and ≥13 mm in the presence of a family history of HCM, using trans-thoracic echocardiography too.

Electrocardiogram analysis

Twelve-lead electrocardiograms at rest (speed recording of 25 mm/s, standardized calibraRon for 10 mm/mV) were separately reviewed by two readers (SS and NJ) blinded to the cause of disease. The ECG reading was performed by consensus reading. Heart rate, presence of complete right bundle block branch (RBBB), leg bundle block branch (LBBB), leg anterior fascicular block (LAH), leg posterior fascicular block (LPH), pathologic Q waves (defined by abnormal Q waves ≥40 ms in duraRon and/or ≥25% of the R wave in depth and/or ≥3 mm in depth in at least two conRguous leads except aVR [START_REF] Rapezzi | DiagnosRc work-up in cardiomyopathies: bridging the gap between clinical phenotypes and final diagnosis. A posiRon statement from the ESC Working group on myocardial and pericardial diseases[END_REF], and pre-excitaRon were noted. Corrected PQ interval (PQ interval/√RR, ms), QRS duraRon (ms), and corrected QT interval (calculated using the Baze€ formula, ms) were measured. Six electrocardiographic criteria for LVH were analyzed according to the specific American Heart

AssociaRon guidelines [START_REF] Hancock | AHA/ACCF/HRS recommendaRons for the standardizaRon and interpretaRon of the electrocardiogram: part V: electrocardiogram changes associated with cardiac chamber hypertrophy: a scienRfic statement from the American Heart AssociaRon Electrocardiography and Arrhythmias Commi€ee, Council on Clinical Cardiology; the American College of Cardiology FoundaRon; and the Heart Rhythm Society. Endorsed by the InternaRonal Society for Computerized Electrocardiology[END_REF]:

1) Sokolow-Lyon index (SV1 + RV5 or V6 ≥30 mm and ≥35 mm)

2) Cornell voltage index: RaVL + SV3 ≥20 mm for women and ≥28 mm for men In cases of voltage differences within the same lead, only the largest complex was selected.

2D transthoracic echocardiogram analysis

For each paRent, the 2D transthoracic echocardiogram was performed during the same consultaRon as the ECG and was reviewed by a senior echocardiographer. The following parameters were analyzed: leg ventricular ejecRon fracRon (LVEF) using the modified biplane Simpson's rule, LV maximal myocardial wall thickness measured from parasternal short axis view, presence of leg ventricular ouilow tract obstrucRon (LVOTO) secondary to a systolic anterior moRon, presence of right ventricular hypertrophy (RVH) defined by a myocardial thickness > 5 mm in long axis view.

Finally, the aorRc root diameters, measured at the level of the Valsalva sinuses and tubular porRon, were measured and indexed to BSA. Leg and right ventricular measurements, as well as the aorRc root diameters, were measured following the joined European AssociaRon of Echocardiography and American Society of Echocardiography guidelines [START_REF] Lang | RecommendaRons for cardiac chamber quanRficaRon by echocardiography in adults: an update from the American Society of Echocardiography and the European AssociaRon of Cardiovascular Imaging[END_REF]. Assessment of the LV wall thickness and the presence of LVOTO were defined according to the ESC-HCM guidelines [START_REF] Ellio€ | ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy[END_REF].

Sta9s9cal methods

A comparaRve analysis of paRents with Fabry disease and those with sarcomeric HCM was performed. Variables are expressed as the mean ± standard deviaRon, interquarRle ranges or as numbers and percentages. Reproducibility study of ECG tracings was performed by two observers (NJ, FL) who interpreted 10 tracings randomly taken from the sample. Inter observer and intra observer reliabiliRes were assessed using the intraclass correlaRon coefficient (ICC). The 95% confidence interval (CI) was calculated using the delta method. The staRsRcal analyses were carried out using R sogware, version 3.1.1.

Standard protocol approvals and pa9ent consents

The study conformed to the principles outlined in the DeclaraRon of Helsinki, the ethic commi€ee (CPP III Nord-Ouest) approved the research protocol.

Results

Overall 61 paRents with Fabry disease (Age: 55.6 ± 11.5 years, 57% men) were included and compared to 59 paRents with sarcomeric HCM (Age: 44.8 ± 18.3 years, 66% men). Fabry paRents were older (p < 0.001). At the Rme of the clinical evaluaRon 49 (80 %) of the Fabry paRents received a specific treatment for Fabry disease. Fabry and sarcomeric HCM paRents were comparable with respect to gender, tobacco, diabetes, cardiac symptoms, and medicaRon excepted for beta blockers and aldosterone antagonists, more frequently prescribed in the HCM group.

Hypertension, ischemic stroke, and proteinuria were significantly more prevalent in paRents with Fabry disease. The characterisRcs of our study populaRon are given in Table 1. 2.

Electrocardiogram

Echocardiogram

The mean LVEF was lower in Fabry paRents, though LVEF was conserved in both groups, and only one paRent with Fabry disease had an LVEF < 55%. The mean maximal thickness was higher in the HCM group (HCM: 21.8 ± 4.8 mm versus Fabry: 16.2 ± 3.5 mm, p < 0.001). Presence of right ventricular hypertrophy did not differ between the two groups. AorRc diameters for sinus of Valsalva and tubular aorRc diameter were higher in paRents with Fabry disease (Table 2).

Mul9variable analysis

Ager mulRvariable analysis with ECG and echocardiographic variables, only RBBB, Sokolov-Lyon product, maximal thickness wall, and indexed Valsalva sinus diameter were independently associated with Fabry disease (Table 3). These four variables were included in a regression model leading to the nomogram depicted in Figure 1.

Discussion

In the present study, we aimed to assess the value of ECG and echocardiographic parameters to discriminate Fabry disease and sarcomeric HCM. The most important finding of our analysis is the high diagnosRc performance for the diagnosis of Fabry disease when combining Sokolov-Lyon product and the presence of RBBB with maximal wall thickness and indexed aorRc diameter. Using criteria of rouRne cardiological consultaRon, we provided a simple tool that might be helpful to increase Fabry disease screening by cardiologists.

The LVH is one of the most important warning signs for the idenRficaRon of new Fabry paRents, providing cardiologists with an essenRal role in the screening of this rare condiRon. Despite increased educaRon, awareness messages, and the emergence of new cardiac imaging tools, early diagnosis remains an unmet goal, especially in non-specialized cardiomyopathies centers. MagneRc resonance imaging myocardial T1 mapping is useful for diagnosing Fabry disease in cases of LVH [START_REF] Sado | IdenRficaRon and assessment of Anderson-Fabry disease by cardiovascular magneRc resonance non contrast myocardial T1 mapping[END_REF] but is not yet widely available in all centers. The echocardiographic 'red flags', such as binary endocardium, papillary muscle hypertrophy, LVH pa€ern or LV circumferenRal strain analysis, are ogen disappoinRng or difficult to achieve in daily pracRce [START_REF] Niemann | Prominent papillary muscles in Fabry disease: a diagnosRc marker?[END_REF][START_REF] Labombarda | Loss of base-to-apex circumferenRal strain gradient: a specific pa€ern of Fabry cardiomyopathy?[END_REF][START_REF] Mundigler | The endocardial binary appearance ('binary sign') is an unreliable marker for echocardiographic detecRon of Fabry disease in paRents with leg ventricular hypertrophy[END_REF]. ECG is recommended in all paRents with HCM and might provide a clue for the diagnosis of rare eRologies of HCM, especially when interpreted in conjuncRon with echocardiography [START_REF] Rapezzi | DiagnosRc work-up in cardiomyopathies: bridging the gap between clinical phenotypes and final diagnosis. A posiRon statement from the ESC Working group on myocardial and pericardial diseases[END_REF]. Typical ECG findings in Fabry disease include PR interval shortening, increased QRS duraRon, voltage signs of LVH, repolarizaRon abnormaliRes including symmetric negaRve T waves, and various degrees of the atrio-ventricular block [START_REF] Yogasundaram | Clinical Features, Diagnosis, and Management of PaRents With Anderson-Fabry Cardiomyopathy[END_REF].

Although 'typical', none of these signs are specific of Fabry disease [START_REF] Namdar | Electrocardiographic Changes and Arrhythmia in Fabry Disease[END_REF]. Sarcomeric HCM may show the same ECG pa€erns, including LVH, negaRve T waves, and ST-segment changes [START_REF] Sakata | QT dispersion and leg ventricular morphology in paRents with hypertrophic cardiomyopathy[END_REF]. Unexplained LVH, in combinaRon with pre-excitaRon or short PR interval, can be a characterisRc of sarcomeric HCM, LAMP2, and PRKAG2 mutaRons [START_REF] Arad | Glycogen storage diseases presenRng as hypertrophic cardiomyopathy[END_REF]. In our cohort, both PQ interval and pre-excitaRon were not relevant parameters to differenRaRng Fabry disease and sarcomeric HCM. These results are in agreement with a large study of 207 Fabry paRents, where the PQ interval was not a common finding [START_REF] Namdar | PQ interval in paRents with Fabry disease[END_REF]. The increased QRS duraRon is a common marker of the electrophysiological remodeling in Fabry disease [START_REF] Yogasundaram | Clinical Features, Diagnosis, and Management of PaRents With Anderson-Fabry Cardiomyopathy[END_REF][START_REF] Kramer | Electrical changes in resRng, exercise, and Holter electrocardiography in Fabry cardiomyopathy[END_REF][START_REF] Takenaka | Terminal stage cardiac findings in paRents with cardiac Fabry disease: an electrocardiographic, echocardiographic, and autopsy study[END_REF], not only due to LVH [START_REF] Kampmann | Electrocardiographic signs of hypertrophy in fabry disease-associated hypertrophic cardiomyopathy[END_REF] but also possibly because of the deleterious metabolic effects of the progressive infiltraRon of glycosphingolipids in the conducRon Rssue [START_REF] Frustaci | Pathology and funcRon of conducRon Rssue in Fabry disease cardiomyopathy[END_REF]. We observed an unexpectedly high prevalence of RBBB in our Fabry populaRon. The more frequent right ventricular hypertrophy in Fabry paRents may be postulated to explain this finding. Besides, although speculaRve, iniRal elecRve injury of the right bundle branch by the gradual accumulaRon of Gb3 could also be evoked as another potenRal mechanism accounRng for the greater frequency of RBBB in Fabry disease. Even though RBBB was not helpful to differenRate Fabry disease and HCM in the work of Namdar et al. [START_REF] Namdar | Value of electrocardiogram in the differenRaRon of hypertensive heart disease, hypertrophic cardiomyopathy, aorRc stenosis, amyloidosis, and Fabry disease[END_REF], previous studies and case reports have reported RBBB to be a frequent intraventricular conducRon disorder in Fabry disease [START_REF] Niemann | Cross-secRonal baseline analysis of electrocardiography in a large cohort of paRents with untreated Fabry disease[END_REF][START_REF] Kramer | Electrical changes in resRng, exercise, and Holter electrocardiography in Fabry cardiomyopathy[END_REF]. In one of the first Fabry cohorts, Mehta et al. reported that RBBB was the most frequent evoluRon of the intraventricular conducRon defects [START_REF] Mehta | Simple criteria for differenRaRon of Fabry disease from amyloid heart disease and other causes of leg ventricular hypertrophy[END_REF]. Kramer et al. found RBBB in 15% of their Fabry paRents with severe myocardial fibrosis [START_REF] Kramer | Electrical changes in resRng, exercise, and Holter electrocardiography in Fabry cardiomyopathy[END_REF].

As suggested by our results and others [START_REF] Kramer | Electrical changes in resRng, exercise, and Holter electrocardiography in Fabry cardiomyopathy[END_REF][START_REF] Niemann | Cross-secRonal baseline analysis of electrocardiography in a large cohort of paRents with untreated Fabry disease[END_REF]33], LBBB and QTc prolongaRon seems to be uncommon in Fabry disease and should rather suggest others eRologies of LVH [START_REF] Namdar | Value of electrocardiogram in the differenRaRon of hypertensive heart disease, hypertrophic cardiomyopathy, aorRc stenosis, amyloidosis, and Fabry disease[END_REF][START_REF] Niemann | Cross-secRonal baseline analysis of electrocardiography in a large cohort of paRents with untreated Fabry disease[END_REF]. Among all the ECG criteria of LVH, the Sokolov-Lyon index has been the most studied in Fabry disease, despite its limitaRons. The Sokolov-Lyon index is highly specific but has low sensiRvity compared to echocardiography or MRI, especially in cases of eccentric LVH and RBBB [START_REF] Hancock | AHA/ACCF/HRS recommendaRons for the standardizaRon and interpretaRon of the electrocardiogram: part V: electrocardiogram changes associated with cardiac chamber hypertrophy: a scienRfic statement from the American Heart AssociaRon Electrocardiography and Arrhythmias Commi€ee, Council on Clinical Cardiology; the American College of Cardiology FoundaRon; and the Heart Rhythm Society. Endorsed by the InternaRonal Society for Computerized Electrocardiology[END_REF]. This may explain why the Sokolov-Lyon index did not discriminate Fabry paRents from HCM in the present and previous studies. The simple product of voltage criteria and QRS duraRon significantly improves the idenRficaRon of LVH compared to voltage criteria alone [START_REF] Okin | Electrocardiographic idenRficaRon of increased leg ventricular mass by simple voltage-duraRon products[END_REF][START_REF] Burgos | Electrocardiogram Performance in the Diagnosis of Leg Ventricular Hypertrophy in Hypertensive PaRents With Leg Bundle Branch Block[END_REF]. The interest of Sokolov-Lyon voltage product in Fabry disease was previously suggested by Kampmann et al. who found a significant correlaRon between Sokolow-Lyon voltage x QRS duraRon product (R2 = 0.52) and leg ventricular mass [START_REF] Kampmann | Electrocardiographic signs of hypertrophy in fabry disease-associated hypertrophic cardiomyopathy[END_REF]. Although the Sokolov-Lyon product might be the most appropriate ECG criteria for Fabry disease and should be systemaRcally calculated, its diagnosRc performance was inferior to the full model combining ECG and echocardiographic parameters. As there is no specific sign for Fabry disease considering both ECG and TTE, the addiRon of different ECG and echocardiographic parameters could be of interest. Using mixed criteria combining 12 lead QRS voltage < 30 mm and the raRo of interventricular septal/ posterior wall thicknesses < 1. [START_REF] Elleder | Sequelae of storage in Fabry disease--pathology and comparison with other lysosomal storage diseases[END_REF][START_REF] Monney | Ascending aorRc remodelling in Fabry disease ager long-term enzyme replacement therapy[END_REF] was proposed as potenRal factor promoRng structural aorRc wall anomalies and dilaRon of the aorta, although exact underlying mechanisms remains to be elucidated. Even though it is not considered as a marker of the disease alone, our full model assigned it an addiRonal diagnosRc value in the context of HCM with an electrical sign of LVH and RBBB. Of note, our model is compliant with TRIPOD statement [START_REF] Collins | Transparent ReporRng of a mulRvariable predicRon model for Individual Prognosis or Diagnosis (TRIPOD): the TRIPOD statement[END_REF] (eTable, Supplement). A highly sensiRve and specific model combining simple criteria available in the daily rouRne consultaRon of cardiology might prevent dramaRc delay of Fabry disease. As specific therapy efficiency appears lower when administered in an advanced stage of the disease [START_REF] Weidemann | Long-term effects of enzyme replacement therapy on fabry cardio myopathy: evidence for a be€er outcome with early treatment[END_REF], efforts must be aimed at developing diagnosRc tools, improving diagnosRc delay, and starRng specific treatment.

Limita9ons

Our work had some limitaRons. We performed a retrospecRve study dealing with a relaRvely small number of paRents with Fabry disease (although superior to most previous similar studies), which is an inherent problem with orphan diseases. We did not enroll newly diagnosed paRents. This might have affected the results of the ROC curve analysis. The studied populaRons were not matched for age which could have impacted the results, especially ECG findings. However, voltages tending to decline with increasing age, which would tend to underesRmate the value of Sokolov Lyon criteria.

Moreover, the commonly used QRS voltage criteria applied in the present study can be applied to adults older than 35 years [START_REF] Hancock | AHA/ACCF/HRS recommendaRons for the standardizaRon and interpretaRon of the electrocardiogram: part V: electrocardiogram changes associated with cardiac chamber hypertrophy: a scienRfic statement from the American Heart AssociaRon Electrocardiography and Arrhythmias Commi€ee, Council on Clinical Cardiology; the American College of Cardiology FoundaRon; and the Heart Rhythm Society. Endorsed by the InternaRonal Society for Computerized Electrocardiology[END_REF]. In this study, we have not included recent, potenRally helpful criteria, such as two-dimensional strain imaging. These modaliRes are sRll not used widely among cardiologists, and we wanted to examine the performance of simple and widely used criteria. We did not perform an external validaRon.

  Abbrevia9ons ACE: angiotensin-converRng enzyme BSA: body surface area ESC: European Society of Cardiology Gb3: globotriaosylceramide HCM: hypertrophic cardiomyopathy LVH: leg ventricular hypertrophy LAH: leg anterior fascicular block LBBB: leg bundle block branch LPH: leg posterior fascicular block LV: Leg ventricle LVEF: leg ventricular ejecRon fracRon LVOTO: leg ventricular ouilow tract obstrucRon NYHA: New-York Heart AssociaRon RBBB: right bundle block branch RVH: right ventricular hypertrophy

Figure 2 Figure 2 :

 22 Figure 2

  for rouRne follow-up to the outpaRent department of five French dedicated HCM centers between 2016 and 2019. The diagnosis of Fabry disease was confirmed by the low or missing acRvity of α-A galactosidase levels in leukocyte homogenates in men and mutaRonal analysis of the α-A galactosidase genes in both men and heterozygous women. PaRents with Fabry disease were compared with paRents with sarcomeric HCM randomly selected from two centers (CHU de Caen, CHU La PiRé-Salpêtrière) during the same period. The diagnosis of sarcomeric HCM was based on paRent and family histories, typical echocardiographic findings, clinical exclusion of other differenRal diagnoses, and geneRc analysis. The medical records of all paRents, including ECG and echocardiographic findings, were reviewed and entered into dedicated databases. Demographic details of age, gender, weight, height, and heart rate were recorded. Their body surface area (BSA)

3 )

 3 Gubner index: RD1+SV3 >25 mm 4) Romhilt-Estes score 5) Sokolow-Lyon voltage x QRS duraRon product: (SV1 + RV5 or V6) × QRS duraRon ≥3710 mm.ms. 6) Cornell voltage x QRS duraRon product: (RaVL + SV3) × QRS duraRon ≥2440 mm.ms.

Table 1 :

 1 CharacterisRcs of the study populaRon ACE: angiotensin-converRng enzyme; HCM: Hypertrophic cardiomyopathy; NYHA: New-York Heart

	Tables

Table 2 :

 2 Electrocardiographic and echocardiographic characterisRcs of the study populaRon

	Variables	Fabry (n = 61)	HCM (n=59)	p
	Electrocardiogram
	Heart rate (bpm)	64 ± 11	66 ± 15	0.66
	Corrected PQ (ms)	164 ± 49	171 ± 38	0.37
	QRS duraRon (ms)	117 ± 27	99 ± 25	< 0.001
	Corrected QT (ms)	424 ± 29	427 ± 31	0.58
	RBBB	33 (54%)	13 (22 %)	0.001
	LBBB	4 (6 %)	6 (10%)	0.69
	Leg anterior hemiblock	15 (20%)	8 (13%)	0.70
	Leg posterior hemiblock	0	0	1
	Pre excitaRon	0	1 (1.7%)	0.98
	Pathologic Q wave	10 (16.5%)	14 (23 %)	0.43
	Atrial fibrillaRon	4 (6.6 %)	1 (1.7 %)	0.38
	Le# ventricular hypertrophy indexes
	Cornell voltage criteria	19.7 ± 11	22 ± 13	0.24
	Gubner index	21 ± 14	15.6 ± 13	0.01
	Sokolov-Lyon	31.4 ± 12.4	27.8 ± 16.7	0.19
	Rohmit Estes score	7 ± 2.8	6.2 ± 3	0.07
	Sokolov-Lyon product*	3547 ± 1408	2687 ± 1791	0.004
	Cornell product*	2381 ± 1659	2290 ± 1861	0.77
	Echocardiogram
	LVEF (%)	65 ± 6	69 ± 9.5	0.01
	Myocardial maximal thickness (mm)	16.2 ± 3.5 [13-26]	21.8 ± 4.8 [13-32]	<0.001
	LVOTO	3 (5%)	15 (25 %)	<0.001
	Right ventricular hypertrophy	14 (23 %)	2 (3.4 %)	0.004
	Sinus de Valsava diameter (mm/m²)	20.5 ± 3.9	18 ± 2.5	< 0.001
	Tubular aorRc diameter (mm/m²)	18.4 ± 3	16.8 ± 2.7	0.007
	Systolic anterior moRon	4 (6.6 %)	15 (25 %)	0.01

RBBB : right bundle block branch ; LBBB : leg bundle block branch ; LAH : leg anterior hemiblock ; LPH : leg posterior hemiblock ; HCM : hypertrophic cardiomyopathy ; bpm : beat per minute ; LVOTO: leg ventricular ouilow tract obstrucRon; * leg ventricular hypertrophy index (mm) x QRS duraRon (ms); LVEF: leg ventricular ejecRon fracRon; HCM: hypertrophic cardiomyopathy

Table 3 :

 3 MulR variate analysis

	Variables	Odds Ra9o [95%CI]	p
	Sokolov-Lyon product, by 100 mm.mV	1.048 [1.015-1.087]	<0.01
	Myocardial maximal thickness, mm	0.707 [0.605-0.807]	<0.001
	Sinus de Valsava diameter, mm/m²	1.526 [1.209-20.42]	<0.01
	Right bundle branch block	12.276 [3.640-52.652]	<0.001

Table 4 :

 4 Interobserver and reproducibility and intraobserver repeatability of the ECG tracings

	Ler ventricular	Intra observer reproducibility	Inter observer reproducibility
	hypertrophy indexes	Intra Class correla9on	Intra Class Correla9on
		(95% Confident Interval)	(95% Confident Interval)
	Sokolov-Lyon	0.99 (0.96 -0.99)	0.98 (0.96 -0.99)
	Cornell	0.98 (0.92-0.99)	0.98 (0.84 -0.99)
	Gubner	0.99 (0.98 -0.99)	0.98 (0.93 -0.99)
	Rohmit Estes score	0.84 (0.38 -0.96)	0.86 (0.45 -0.96)
	Sokolov-Lyon product*	0.99 (0.96 -0.99)	0.98 (0.95 -0.99)
	Cornell product*	0.98 (0.93 -0.99)	0.98 (0.93 -0.98)

* leg ventricular hypertrophy index (mm) x QRS duraRon (ms)

  Fabry disease was built to esRmate the probability of Fabry disease based on the factors idenRfied in the mulRvariate analysis. A ROC (Receiving Operator CharacterisRc) curve was constructed to evaluate the predicRve value of the previously defined model. The developed model was tested in the specific subgroup of paRents with the Asn 215 Ser mutaRon, so called 'cardiac variant'.

ConRnuous variables were compared by the Student t-test. QualitaRve variables were compared using the Fisher test or Chi² test. A mulRvariate analysis was performed, including all variables with p ≤ 0.10 in the univariate analysis. A nomogram for the predicRve value for

  Gubner index: 21 ± 14 mm vs. 15 ± 13 mm, p = 0.01; Sokolov-Lyon product: 3547 ± 1408 vs 2687 ± 1791 mm.ms , p = 0.004). The Sokolov-Lyon voltage criterion was higher in paRents with Fabry disease, without reaching staRsRcal significance (Fabry: 31.4 ± 12.4 ms versus HCM: 27.8 ± 16.7 ms; p = 0.19). The Cornell voltage criteria, Rohmit Estes score, and Cornell product were comparable between Fabry paRents and HCM group. The results are shown in Table

	QRS duraRon was significantly higher in the Fabry group (117 ± 27 ms vs. 99 ± 25 ms, p < 0.001) and
	RBBB was more frequent in the Fabry group (54% vs. 22 %, p = 0.001). Heart rate, PQc, and QTc

intervals, LBBB, LAH, preexcitaRon, pathologic Q waves, and arrhythmia did not differ between two the groups. Regarding LVH indexes, Gubner index, and Sokolov-Lyon product were significantly higher in the Fabry group (

  [START_REF] Waldek | Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry[END_REF], Gustavsonn et al. were able to differenRate hereditary transthyreRn amyloidosis from sarcomeric HCM[START_REF] Gustavsson | Can echocardiography and ECG discriminate hereditary transthyreRn V30M amyloidosis from hypertrophic cardiomyopathy? 37[END_REF]. The unpredicted value of indexed aorRc root diameter illustrates the potenRal interest of mixed criteria. In a large cohort of paRents with Fabry disease, Barbey et al reported a dilaRon of the sinuses of Valsalva in one-third of males and 5% of females, regardless of the blood pressure level and other cardiovascular risk factors[37]. Ager mulRvariate analysis, gender, age, and interventricular thickness were strongly associated with dilaRon at the sinus of Valsalva. Progressive accumulaRon of globotriaosylceramide in vascular smooth muscle cells in the media of the aorta [37,

THESE : Valeur de l'électrocardiogramme couplée à l'échocardiographie pour différencier une maladie de Fabry d'une cardiomyopathie hypertrophique sarcomérique

  might be associated with LVH. In these rare disorders, extracardiac signs are usually the main clinical manifestaRons and strongly influenced the diagnosis orientaRon, contrary to sarcomeric HCM and cardiac variant of Fabry disease. Par délibération de son Conseil en date du 10 Novembre 1972, l'Université n'entend donner aucune approbation ni improbation aux opinions émises dans les thèses ou mémoires. Ces opinions doivent être considérées comme propres à leurs auteurs ». Le dépistage de la maladie de Fabry reste sous opRmal dans les centres non spécialisés. L'objecRf de notre étude est d'évaluer la valeur diagnosRque des scores ECG d'hypertrophie ventriculaire gauche (HVG) et la valeur diagnosRque pour le diagnosRc de la maladie de Fabry d'un score combinant des critères électriques et échocardiographiques. Méthodes : Nous avons réalisé une étude rétrospecRve mulRcentrique comparant 61 paRents a€eints d'une maladie de Fabry avec HVG à 59 paRents a€eints d'une cardiomyopathie hypertrophique sarcomérique (CMH). Six critères ECG ont été analysés : index de Sokolow-Lyon, index de Cornell, index de Gubner, score de Romhilt-Estes, produit de Sokolow-Lyon, produit de Cornell. Résultats : La durée des QRS, l'index de Gubner et le produit de Sokolow-Lyon étaient significaRvement plus élevés chez les paRents a€eints d'une maladie de Fabry. L'épaisseur maximale du VG était plus importante chez les paRents a€eints d'une CMH. Le diamètre aorRque aux sinus de Valsalva était plus grand chez les paRents a€eints d'une maladie de Fabry. Après analyse mulRvariée, le bloc de branche droit, le produit de Sokolow-Lyon, l'épaisseur maximale du VG et le diamètre aorRque était associés de façon indépendante à la maladie de Fabry. Un modèle incluant ces 4 paramètres a permis d'obtenir une courbe ROC avec une AUC à 0.918 pour la maladie de Fabry. Conclusions : Le produit de Sokolow-Lyon semble être le critère ECG le plus approprié pour disRnguer maladie de Fabry et CMH. Notre modèle combinant des paramètres simples échographiques et électrocardiographiques pourrait améliorer le dépistage et le diagnosRc de la maladie de Fabry.

	ANNEE DE SOUTENANCE : 2020
	VU, le Président de Thèse NOM ET PRENOM DE L'AUTEUR : JUNQUA Nicolas
	TITRE DE LA RESUME DE LA THESE EN FRANÇAIS :
	Conclusion
	Sokolov-Lyon product might be the most appropriate ECG criteria for Fabry disease, and should be
	systemaRcally calculated in case of HCM. We propose a combined model using ECG and
	echocardiographic parameters available in everyday cardiac rouRne consultaRon. This addiRonal tool
	might be helpful to improve screening and reduce both diagnosis and therapeuRc delay of Fabry
	disease.
	VU, le Doyen de la Faculté
	VU et permis d'imprimer
	en référence à la délibération
	du Conseil d'Université
	en date du 14 Décembre 1973
	Pour le Président
	de l'Université de CAEN et P.O
	Le Doyen

Finally, we have not included other rare diseases, such as storage disorders (protein kinase AMP-acRvated non-catalyRc subunit gamma 2 Deficiency and Danon disease), mitochondrial disease and cardiomyopathies in neuromuscular disease or Noonan's syndrome, which « Contexte : MOTS CLES : Maladie de Fabry,

cardiomyopathie hypertrophique, électrocardiogramme TITRE DE LA THESE EN ANGLAIS : The value of electrocardiogram and echocardiography to dis9nguish Fabry disease from sarcomeric hypertrophic cardiomyopathy

  Screening for Fabry disease (FD) remains subopRmal in non-specialized centers. Aims : We aimed to evaluate the diagnosRc value of electrocardiographic (ECG) scores of leg ventricular hypertrophy (LVH) and the diagnosRc value of a combined ECG and echocardiographic model for FD. Methods : We retrospecRvely reviewed the ECG and echocardiogram of 61 paRents (age: 55.6 ± 11.5 years, 57% men) with FD and LVH, and compared them to 59 paRents (age: 44.8 ± 18.3 years, 66% men) with sarcomeric hypertrophic cardiomyopathy (HCM). Six ECG criteria for LVH were specifically analyzed: 1) Sokolow-Lyon index 2) Cornell voltage index 3) Gubner index ,4) Romhilt-Estes score 5) Sokolow-Lyon voltage x QRS duraRon product and 6) Cornell voltage x QRS duraRon product. Results : Right Bundle Branch Block (RBBB) was more frequent in FD (54% vs. 22 %, p = 0.001). QRS duraRon, Gubner score, and Sokolov-Lyon product were significantly higher in FD. Maximal thickness wall (MTW) was higher in sarcomeric HCM group (21.9 ± 5.1 mm vs 15.5 ± 2.9 mm in Fabry, p < 0.001). Indexed Valsalva sinus diameter was higher in paRents with FD. Ager mulRvariable analysis RBBB, Sokolov-Lyon product, MTW and aorRc diameter were independently associated with FD. A model including these 4 parameters yielded an area under the ROC curve of 0.918 [95% Confident Interval: 0.868-0.968] for FD. Conclusion : Our model combining easy-to-assess ECG and echocardiographic parameters may be helpful to improve screening and reduce diagnosis delay of FD.

RESUME DE LA THESE EN ANGLAIS :

Background :

KEY WORDS : Fabry, hypertrophic cardiomyopathy, electrocardiogram

Remerciements