Aux Membres

D U Jury

A Monsieur Le Docteur

Philippe De

Swardt Merci D'

Richard Et Amélie

Davy Et Manue

Manu Jeff Et Adeline

Jean Stéphane

Mi

Sibylle Katrin

Alexis Jean Pierre

Danièle

A Fabienne

Jean Enzo

Luc

Bénédicte Luiz

Mes Co-Internes

Philippe Tu Étais Mon Julien

REMERCIEMENTS

A Monsieur le Président du Jury, le Professeur Emile FERRARI. Vous me faites l'honneur de présider ce jury. Je vous remercie pour tout ce que vous m'avez apporté tant d'un point de vue professionnel : l'enseignement, la théorie, la clinique ; que d'un point de vue personnel : la rigueur et l'amour de notre métier. Je vous remercie également pour votre implication dans notre formation. Soyez assuré de mon profond respect.

A Monsieur le Professeur Pierre MARTY. Je suis particulièrement honorée que vous ayez accepté de siéger dans mon jury de thèse. Après avoir présidé la thèse de ma mère, vous aller à présent juger la mienne. Mon sujet de thèse est très éloigné de l'Histoplasmose mais j'espère vous démontrer le temps d'une soirée, que la Cardiologie est une très belle spécialité ! Merci encore pour votre disponibilité et votre aide précieuse lors de nos voyages.

A Madame le Docteur Delphine BAUDOUY. Je suis ravie de ta présence

A MA FAMILLE

A mes parents: Maman merci pour tout et surtout merci de m'avoir donné l'amour de la médecine. Papa tu as toujours cru en nous. Ta préoccupation principale était que nous ne manquions de rien. Merci également pour tes nombreux aller-retours sur Nice quand Alexia n'était pas là pour venir me soutenir! Je ne vous remercierai jamais assez pour votre soutien durant ces années difficiles ; sans vous je n'aurai jamais réussi. Vous avez mis vos vies entre parenthèses pendant nos années d'études pour que nous soyons dans les meilleures conditions pour réussir. Nous vous devons tous les 3 nos succès respectifs. Vous êtes exceptionnels.

A Medhi: nous nous sommes rencontrés juste avant de commencer l'internat et tu as été mon soutien indéfectible ces 4 dernières années. Sans toi je ne sais pas si j'aurai tenu le rythme. Merci pour ton amour, ta bienveillance et tout ce que tu fais pour moi. Tu es toujours là pour moi et tu me rends, tous les jours, la vie si merveilleusement belle et agréable. Tu es la personne la plus exceptionnelle que je connaisse. A ces magnifiques années et aux prochaines, qui seront encore plus belles. JE T'AIME.

A mes grands-parents: merci pour votre éducation, votre tendresse et votre amour. Mamo tu as été une 2 ème mère pour nous. Papo tu es le pilier de la famille. De par ta volonté et ton courage tu es la personne la plus forte que je connaisse.

Vous nous avez donné le sens des valeurs et de la famille. Je vous aime tellement. Papi : Papa m'a dit que tu aurais été ravi d'avoir un médecin dans la famille. J'espère que de là où tu es, tu es fier de moi. Mamie ton accent italien a bercé mon enfance, je me souviendrai toujours de ta force et de ton courage. Vous me manquez tellement. A mes arrière grands parents Papi Jean et Mamie Jeanne.

A mes 2 moitiés : ma grande soeur Alexia avec qui j'ai partagé tellement de choses. Toujours là, l'ainée la plus solide de nous trois. Tu es irremplaçable. Merci pour tout. Mon petit frère Arthur. Merci pour ta joie de vivre et ta bonne humeur. Merci de toujours essayer de nous faire rire. Tu as embelli nos vies. Je suis très fière de toi. (Mais tu resteras toujours notre petit bébé!!). Je n'aurai pu rêver mieux comme fratrie. Je vous aime.

A mes beaux-frères et belles-soeurs: merci d'avoir agrandi la famille! A Olivier mon grand frère depuis 10 ans merci pour ton soutien pendant les années d'internat qui n'ont pas été évidentes! A la famille Benchortane : Karim, Flora, Michaël et Sophie : ma 2 ème famille ! Merci de m'avoir accueilli à bras ouverts. Merci pour tous ces beaux moments partagés. Karim et Flora merci pour tous ces week-ends à Auron et surtout ces dimanches soirs ; bon il y avait les matchs du PSG en fond… mais c'était quand même très agréable pour lutter contre la mélancolie du dimanche soir! A Manon: la petite dernière « pièce rapportée ;) » Je suis très contente que Arthur ait rencontré une fille comme toi. Je vous souhaite de réussir vos années d'externat. On est ravi de t'avoir dans la famille. Une pensée pour Brigitte, Pierrot, Nathalie et Camille: je ne savais pas dans quelle catégorie te mettre… Co-interne (peu de temps), chef? (on s'est rencontré comme ça). Mais surtout Amie. Merci pour tout. La cardiologie m'a permis de rencontrer de très belles personnes. Merci aussi à Julien et à nos soirées jeux de société. J'espère passer encore de très bons moments avec vous 2 et voir le petit Ulysse grandir. (Ps : ne partez pas à Tahiti ! Ou Tours ! Bref, ne partez pas tout court !).

Chloé : merci pour ton amitié, j'ai passé de merveilleux moments avec toi. Merci pour ton aide et ton soutien cette année je n'oublierai pas. Je te souhaite beaucoup de bonheur avec David. Eric : au même titre que Carlo, Elise et Juliette j'ai réussi le concours de l'internat en grande partie grâce à toi. Je repense souvent à ces journées de révisions intensives; ces soirées à bosser jusqu'à minuit (et même plus…). De plus sans toi je n'aurai jamais rencontré Medhi et pour ça je pense que je ne pourrai jamais te remercier assez.

Benjamin S. : de co-interne où l'on doublait les gardes ensemble à chef ! Le temps passe vite ! Merci pour ta bonne humeur et ces fous rires qui font du bien lors des journées difficiles… Allo c'est l'interne de cardio?? IL DECALE, IL DECALLLLLEEEE !!!! Benjamin E. : de parrain de promo à co-interne. Merci pour ton aide toutes ces années. Mon co-interne de Cannes : Sam. J'ai passé un super semestre avec toi à Cannes ! En fait tous les urgentistes avec qui j'ai partagé une partie de mon internat étaient géniaux !! On devrait peut-être arrêter notre guerre avec les urgentistes ;). Je suis ravie de t'avoir rencontré.

Mes premiers co-internes à Antibes

Mes co-internes de réanimation

A L'EQUIPE DU CHU DE NICE:

A Redouane et Didier: mes 1 er chefs au CHU, merci pour votre soutien et votre aide durant ce premier semestre qui n'a pas été évident. Redouane tu as toujours été présent et bienveillant à mon égard. Merci. Didier, tu es toujours de bonne humeur et disponible. C'est tellement agréable de travailler avec toi ! Olivier: Tu n'as jamais été mon chef mais tu m'as toujours aidée ! Je n'oublierai pas la tradition rhum du vendredi soir dans ton bureau… J'ai été déçue que tu t'en ailles mais heureusement on a continué les petites pauses cafés à Tzanck ! A Dan et Nassim mes chefs de l'USIC. Merci pour votre aide permanente durant ce semestre difficile. Grâce à vous j'ai beaucoup appris dans la joie et la bonne humeur ! Julien L. : merci pour tout ce que tu m'as appris. Je suis ravie de continuer mon parcours de médecin à tes côtés.

Charlotte la dernière arrivée au CHU ! Quel plaisir de voir la cardiologie se féminiser ! Merci pour ton aide notamment pour les échos du vendredi matin. Je garde en mémoire nos soirées filles mais aussi nos petites virées parisiennes en Congrès. J'espère qu'on se refera ça cette année ! A Fabien, David, Guillaume, Pamela G., Michel merci pour votre aide et votre disponibilité tout au long de mon internat.

A Virginie l'infirmière de rééducation ; très appréciée des patients, sans toi ce travail n'aurait pas pu être réalisé. Merci.

Aux équipes paramédicales que j'ai côtoyées pendant mon internat. Aux secrétaires Carole, Coco, Boyé, Patricia. J'ai été ravie de travailler avec vous. Toujours efficaces !

A L'EQUIPE DU SERVICE DE CARDIOLOGIE D'ANTIBES

Vous m'avez accueilli dans le monde de la cardiologie, j'ai appris les bases de mon métier parmi vous.

Je pense notamment à Julien; je ne pourrai jamais te remercier suffisamment pour tout ce que tu m'as appris : la cardiologie, l'amour de ce métier et la rigueur nécessaire. Tu restes l'une des plus belles rencontres de mon internat.

A Nathaniel ; merci pour ton aide lors de mon semestre de réanimation; j'avais beaucoup entendu parler de toi et j'ai été ravie de travailler avec toi! A Folco merci pour ta bonne humeur permanente! A Maria merci pour ton aide et surtout ta

A L'EQUIPE DE LA MAISON DU MINEUR A VENCE:

Merci de m'avoir accordé votre confiance et de m'avoir fait découvrir le monde de la rééducation cardiaque.

Merci à Mme

INTRODUCTION

The health effect of exercise on cardiovascular and non-cardiovascular mortality is well known [START_REF]Systolic pulmonary artery pressure (sPAP) was estimated using the peak tricuspid regurgitation (TR) gradient (mmHg), 2. Tricuspid annular plane systolic excursion (TAPSE) (mm), 3. Tissue doppler systolic excursion velocity of tricuspid annulus S' (S'wave) (cm/s), 4. Isovolumic acceleration (IVA) (m/s 2 ), 5. Tissue doppler index mitral E/e' (RV filling pressure) 6. End-diastolic right ventricular diameter (cm), 7. Right ventricular outflow tract (RVOT) (mm), 8. Pulmonary time velocity integral (pTVI) (cm), 9. RV fractional area change (FAC) (%), 10. RV free wall peak systolic strain (%)[END_REF] . Main cardiovascular effects of exercise are; regulation of blood pressure 2,3,4,5,6 , benefits on dyslipidemias 7,8 and improvement on the sensibility to insulin 9 . Exercise is also generally associated to a significant decrease in cardiovascular events as in coronary artery disease 10 .

Right ventricular function

At rest under normal circumstances, the right ventricular (RV) systolic function only plays a modest role in the cardiac output as the left ventricular (LV) contraction and respiratory work contribute to RV contraction. During exercise; even in healthy subjects with normal pulmonary circulation; the hemodynamic load on the RV increases and becomes more important as compared to the left ventricular loading conditions. This difference is even worse in patients with pulmonary hypertension (PH) [START_REF]Systolic pulmonary artery pressure (sPAP) was estimated using the peak tricuspid regurgitation (TR) gradient (mmHg), 2. Tricuspid annular plane systolic excursion (TAPSE) (mm), 3. Tissue doppler systolic excursion velocity of tricuspid annulus S' (S'wave) (cm/s), 4. Isovolumic acceleration (IVA) (m/s 2 ), 5. Tissue doppler index mitral E/e' (RV filling pressure) 6. End-diastolic right ventricular diameter (cm), 7. Right ventricular outflow tract (RVOT) (mm), 8. Pulmonary time velocity integral (pTVI) (cm), 9. RV fractional area change (FAC) (%), 10. RV free wall peak systolic strain (%)[END_REF] . The highly compliant pulmonary vascular bed at rest may be an explanation with a low resistance and limited compliance reserve. In PH, the pulmonary vascular compliance and resistance are both impaired at rest. During exercise, because of those 3 parameters there is an increase in vascular pressure (more than in the left ventricle), to increase the cardiac output required to adapt to exercise 11 . Recent studies demonstrate that exercise-induced pulmonary hypertension 12 is an important clinical finding and we still don't know the normal range for systolic pulmonary artery pressure (sPAP) elevation during exercise in a healthy population and how it physiologically increases with age.

Pulmonary hypertension

Pulmonary hypertension (PH) is a severe cardiopulmonary disorder determined by a progressive increase in vascular pressure leading to endothelial impairment, RV failure and death 13 .

Outcomes are mostly related to right ventricular (RV) function and remodeling.

There are 5 different types of pulmonary hypertension: pulmonary arterial hypertension PAH (group 1), associated with left heart failure (group 2), chronic respiratory insufficiency (group 3), post embolic PH (group 4), unknown origin (group 5) 14,15 . In PAH symptoms and survival are closely related to RV function rather than an abnormal elevated pulmonary artery pressure (PAP) 16 . The RV function is the main determinant of the evolution in PAH. Thus, the prognosis clearly depends on the ability of the RV to adapt to elevated pulmonary artery pressure

Objectives of the study

A clinical improvement in PAH patients has been demonstrated after cardiopulmonary rehabilitation. However, many gaps in knowledge about PAH rehabilitation persist. For example the best method for rehabilitation (duration, intensity, type of exercise) is still unknown. In addition the underlying mechanism for the clinical improvement is debatable. Is it related to an improvement in RV contractile reserve / function or to the increased capacity of peripheral muscular fibers following rehabilitation ?

Thus, we aimed to assess the beneficial effect of exercise training on exercise capacity, quality of life and cardiac function in a cohort of PAH patients.

METHODS

Study design

This is a monocentric interventional cross-over study.

We included consecutive patients with PAH from our center at the university hospital in Nice (mainly cycling and initial workload was adjusted to peak VO2 at baseline); and at home daily prescribed exercises. This rehabilitation was supervised by a dedicated nurse and a physiotherapist specialized in rehabilitation and a physician was always available if needed.

Population of the study

PAH patients were recruited from our reference center of pulmonary vascular diseases at the university hospital in Nice France. Between January 2018 and March 2019, 40 consecutive patients with known PAH were screened for enrolment.

Pre-capillary PH was considered when mean pulmonary artery pressure at rest was ≥25 mmHg and pulmonary capillary wedge pressure was ≤15 mmHg (using right heart catheterization data) 32,22 . PAH patients were eligible if PAH was diagnosed by right heart catheterization, if they were stable for at least one month with no evidence of right heart failure, and if their WHO functional class was about II or III. They also had to be older than 18 years old and able to give their consent. Patients with significant left heart disease (systolic or diastolic dysfunction; left ventricular dilatation or hypertrophy, mitral or aortic valvar disease), arrhythmias or poor acoustic windows were excluded. No patient had severe tricuspid regurgitation.

Demographics and clinical evaluation (age, gender, diagnosis and etiology, baseline WHO functional class, PAH targeted advanced therapy, Brain Natriuretic Peptid (BNP) were performed at baseline. All participants were provided with written and oral information on the study. They all gave their written informed consent.

2D Echocardiographic acquisitions and measurements at rest and during stress exercise

We performed a 2D echocardiographic examination using an EPIQ-7 ultrasound system and an X5-1 transducer (Philips Medical system, Andover, MA). It included Doppler echocardiography complying with the recommendations of the American Society of Echocardiography (ASE)/ European Association for Cardiovascular Imaging (EACVI) 33,34 . A complete echocardiography, including RV strain analysis was performed in each patient 35,36 . RV myocardial strain was studied using speckletracking echocardiography of the apical long axis, obtained from the apical four chamber view during a quiet breath hold with a frame rate of 55-75/s. Two consecutive heart cycles were recorded and averaged (excluding premature beats). The offline analysis was performed using commercially available semi-automated two dimensional (2D) strain software: Tomtec Cardiac Performance Analysis (Tomtec Imaging Systems GmbH Germany 37 ) for longitudinal strain analysis. The peak RV free-wall longitudinal strain was defined as the peak negative value on the strain curve. After segmental tracking, the RV longitudinal curves were generated and the average value of longitudinal strain calculated 38,39,40,41 .

The following parameters of RV function at rest and at peak exercise were measured:

FIGURE 1: Example of 2D-strain / right ventricular speckle-tracking analysis using TomTec

(TomTec Imaging Systems GmbH, Germany)

3D Echocardiographic acquisitions and measurements at rest and during stress exercise and 3D deformation analysis

We also performed a 3D trans-thoracic echocardiography using an EPIQ-7 ultrasound system and a matrix-array X5-1 transducer (Philips Medical system, Andover, MA).

At least four 3D cine-loops of the RV were acquired from an apical 4-chamber view focused on the RV. This focused view was not an RV-focused 4-chamber view (the probe was tilted anteriorly to include the entire RV within the image). Loops were stored from full-volume acquisition over 2 heart beats, which required EKG-gating over 4 cardiac cycles during a quiet breath-hold. To allow post-processing with the dedicated software (TomTec 4D RV Function 2.0), care was taken to maximize the frame rate (≥ 20 frames per second) and to include the entire RV within the images.

Offline analysis was performed via commercial software dedicated to the RV (4D RV Function 2.0, TomTec Imaging Systems GmbH, DE). This software tracked the RV endocardial surface along the cardiac cycle using 3D speckle-tracking. It estimated the RV end-diastolic, end-systolic volumes and ejection fraction. Trabeculations and papillary muscles were included as part of the RV cavity, as recommended 42,43,19,44,45 .

Parameters of RV contractile reserve

In the following chapter Δ represents the difference between peak exercise and rest for each parameter studied.

We chose to study ΔTAPSE, Δpeak systolic strain, Δpulmonary TVI and several ratios: TAPSE/sPAP, strain/sPAP and 3D RVEF/sPAP both at rest and at peak. The correct calculation of SF-12 scores (PCS-12 and MCS-12) requires the use of special algorithms, which are controlled by a private company.

The survey was submitted to each patients before and after rehabilitation and then we used a free online algorithm to assess those two components. The algorithm we used was Ortho ToolKit.

The SF-12 version used was the SF-12 1.0. Mean Borg score before 6MWD was 1.13±1.5 out of 10 and 6.00±1.3 after. Resting oxygen saturation was 94.64±2.0% and NADIR oxygen saturation was 89.00±5.6%. The mean covered distance during the test was 393.17±99.2 meters.

FIGURE 4: SF-12 survey

After Rehabilitation

Mean Borg score before 6MWD was 1.32±1.6 out of 10 and 5.5±1.7 after. No statistical difference was found (respectively p=0.10 and p=0.44) for the effect of rehabilitation, despite a trend toward an improvement of Borg score after rehabilitation. Resting oxygen saturation was 94.80±2.4% and NADIR oxygen saturation was 88.20±4.4% indicating no significant change after rehabilitation (p=0.85 and p=0.66). Mean 6MWD distance was significantly improved after rehabilitation 425.75±96.6 meters (+32.58m p=0.02).

TABLE 4: 6 minute walk distance; comparison before and after rehabilitation

BNP and WHO functional class

The mean BNP in our population before rehabilitation was 114.67±117.7 pg/mL, whereas it

After Rehabilitation

We found an improvement in both mental and physical components. Rehabilitation led to significant changes in physical health score (p=0.006) and a trend toward an improved mental score (p=0.11). Echocardiography at rest and peak exercise: peak systolic strain at rest and sPAP at peak weren't significantly different after rehabilitation (respectively p=0.4 and p=0.32). Peak systolic strain and 3D

RVEF at peak exercise were statistically different after rehabilitation (both p=0.03). For the RV contractile reserve: ratios strain/sPAP both at peak and at rest and (strain/sPAP) weren't significant after rehabilitation (p=0.27 and p=0.60). Finally peak strain was statistically significant after rehabilitation (p=0.02) which demonstrate an improvement in RV contractile reserve. PAH patients also improved their exercise capacity; 6MWD distance (p=0.02), their peak VO2 (p=0.005), the duration of exercise (p=0.002) and their physical score (p=0.006).

  nièces adorées: Ma poupée Anna mon petit rayon de soleil de cette dernière année d'internat. A Sofia et Inès la petite dernière qui s'est fait désirer ! A Ana, Emmy et Jeanne : merci d'égayer nos vies. A mes oncles et Tantes: Pascal et Isabelle merci pour votre bienveillance et votre amour. Une pensée pour Linou. A mes cousins et cousines: Guillaume et Thomas ; les Toulousains ! Merci d'avoir animé nos repas de Noël en famille ! Je vous souhaite beaucoup de bonheur et de réussite. Fany et Jean merci pour votre soutien et votre compréhension pendant ces nombreuses années ! A Marguerite et Marc Emilien mes cousins et filleuls. A Isabelle ma marraine merci de faire partie de ma vie et de si bien t'occuper moi. J'adore passer du temps avec toi notamment lors de mes petites escapades Parisiennes. Une pensée pour Fred, Victoire et Jules. A Philipe mon parrain merci pour ton soutien, tu incarnes l'exemple même du médecin. Rigueur, travail et amour de ton métier. A la famille RICOU, BLANKERS ; Yolanda, Sander, Coralie, Arno et Paola ; on a partagé tellement de moments ensemble. Vous faites partie de la famille ! Votre père doit être tellement fier des personnes que vous êtes devenues. Je vous remercie pour tous ces voyages, soirées, anniversaires, week-ends à Orcières ! J'espère qu'il y en aura plein d'autres. A ma famille Parisienne : Michel, Francette, Isabelle, Cathy, Antoine, Chloé, Hugo, Angèle et Eva Merci pour ton soutien indéfectible. Du primaire (où l'on se battait pour la première place!!) en passant par les bancs de la prépa à Masséna pour finir toujours présent à mes côtés. Merci de m'avoir toujours donné confiance en moi! Maxime : le seul spécialiste au monde des murènes ! Merci pour ton amitié qui malgré la distance ne s'est jamais estompée. Je n'oublierai jamais Genève et le Milk… A Mikaël présent depuis la 6 ème et j'espère pendant encore de nombreuses années. Merci d'être là aujourd'hui ça me touche. Charles : Je t'ai mis dans la catégorie amis ?? ;) Merci pour ta joie de vivre et ta bonne humeur permanente ! Joanna : merci pour ton soutien et ton amitié durant toutes ces années. De médecine: Juliette : mon rayon de soleil. Merci pour tout. Toujours présente, toujours de bonne humeur, toujours à penser au bonheur des autres. Tu es la copine parfaite ! Merci pour ces années d'amitié. Merci à Bruno qui m'a sauvé la vie quand mon ordinateur a décidé de m'abandonner 1 mois avant ma thèse… ! Elise : mon autre copine, je suis tellement triste que tu sois partie à Paris. J'espère encore que tu vas revenir ! Il faut reformer la TEAM VARESE ! Merci pour tout et surtout de toujours « entretenir » notre amitié en nous retrouvant pour les week-ends et les vacances. Merci à Yoann grâce à lui on va pouvoir partir plus souvent en vacances!!! Carlo : mon petit Carlo. Comme toi il n'y en a pas 2… (et heureusement !!!). Tu me remontes toujours le moral, tu es toujours souriant et de bonne humeur. Quel bonheur d'être à tes côtés. Merci pour tout, pour ma réussite à l'internat, tous les bons moments et les voyages. David a de la chance de t'avoir.

:

  Hugo et Adil. Commencer l'internat c'est toujours une épreuve difficile mais avec vous (et n'oublions pas Etienne quand même !) ce fut un plaisir.

  Nathalie et Franck. Dudu et Momo ! Même si je ne suis pas devenue une grande réanimatrice… Je suis ravie d'avoir partagé ces 6 mois avec vous. Nath merci pour ta joie de vivre, ton énergie et ta bonne humeur permanente. Franckie merci pour tout ce que tu m'as appris ; toujours bienveillant et d'une patience à toute épreuve (ça n'a pas dû être facile avec nous 2!!). Je regrette nos petits repos de garde communs paddle/pan bagnat !! A refaire prochainement quand Nathalie revient sur le continent !! Mes co-internes de Tzanck : Eric et Carole. Eric je crois que tu es le seul cité 2 fois dans cette thèse ;) ! Carole ça m'a fait plaisir de te rencontrer et de travailler avec toi ! Bon courage pour la suite ! C'est dommage on ne se voyait pas trop la journée pendant ce stage… mais il fallait bien que certains travaillent… ! A mes autres urgentistes préférés : Fanny, Morgan et Julie !

  solidarité féminine! A Ahmed merci pour ta bienveillance. Aux Docteurs Anne Bellemain, Laurent Jacq, Alain Proton et François Bernasconi ; merci pour la confiance que vous m'avez accordée et pour tout ce que vous m'avez appris. A l'équipe paramédicale (vous êtes les meilleures!!!): notamment ma petite Lisa, Cyrielle, Laure, Charlotte, Julie, Claire (et j'en oublie…) mais également les filles des consultations Ma Josiane, Caroline et Stéphanie. Je ne me suis jamais sentie aussi bien accueillie que chez vous. Et aux secrétaires Patricia et Hafida ! A L'EQUIPE DU SERVICE DE CARDIOLOGIE DE CANNES Au Dr Tibi, vous êtes le médecin le plus respectable qu'il m'ait été donné de rencontrer durant mon internat. Merci pour tout ce que vous nous apportez. Le stage à Cannes a été de loin mon meilleur stage. Votre équipe tant médicale que paramédicale est exceptionnelle. Vous êtes un excellent médecin tout en restant un exemple d'humilité. A Nathalie Berkane ; notre Mère spirituelle à tous ! Merci pour tout ce que tu m'as appris mais également merci pour ta gentillesse et ta bienveillance à toute épreuve. A Anne Talbodec, j'ai beaucoup appris à tes côtés durant ces 6 mois. Merci. A Greg, merci pour tout ce que tu m'as appris et surtout ton aide sur les gardes ! C'était top ! Aux plus cools des cathétériseurs : Laurent B., Gilles, et Edouard. Merci pour votre accueil au bloc. Merci pour ces moments de rigolade pendant ce semestre à Cannes ! Merci également à Laurent L., Andrei et Dr Durero. A L'EQUIPE DU SERVICE DE REANIMATION D'ANTIBES Même si cela a été dur de recommencer à zéro ; ce stage à vos côtés a été extrêmement enrichissant. Je ne me suis pas découvert une grande âme de réanimatrice mais quand même… les chefs étaient très sympas, les co-internes au top, l'équipe paramédicale toujours de bonne humeur et Marie une secrétaire en or. De plus c'était l'été et nos petits cafés après le self en plein soleil étaient plutôt sympas ! J'ai passé un très bon été grâce à vous. Au Dr Tiger, merci pour vos enseignements, à Cecilia merci pour ta gentillesse et ton aide, à Jordan merci pour ton énergie communicative et ton envie d'enseigner, à Xavier le plus cool des réanimateurs toujours calme et de bonne humeur et à Anne j'ai été ravie de travailler avec toi, merci pour tout ce que tu m'as apporté durant ce stage. A L'EQUIPE DE CARDIOLOGIE, DE REANIMATION CARDIAQUE ET CHIRURGIE CARDIAQUE DE L'INSTITUT ARNAULT TZANCK (ST LAURENT DU VAR): Aux Dr Mihoubi et Elbèze, merci pour tout ce que vous m'avez appris durant ce stage. C'était une expérience très enrichissante à vos côtés. Votre dévouement dans le travail et votre rigueur sont une source d'inspiration. A Laurent, même si nous ne sommes pas trop venus en KT avec Momo merci pour ces moments passés ensemble à Tzanck et pour ton aide. On aura bien rigolé !! C'était très agréable de travailler avec toi. Aux Dr Claude Jean Mariottini, Philippe Durand et Pierre Meyer ; merci pour ce semestre à vos côtés. J'ai participé à de nombreuses procédures que je n'avais jamais eu l'occasion de voir auparavant. Ce stage a été très enrichissant pour moi surtout en fin d'internat. Aux anesthésistes et réanimateurs cardiaques : Dr Macario, Diane Lena, Julien Cady, Philippe Camarasa, Arnaud Causeret et Arnaud De La Chapelle. Merci pour tout ce que vous m'avez appris durant ces 6 mois de stage. Les visites en réa étaient très enrichissantes. Cette facette de la cardiologie est indispensable pour notre pratique future. Ps : l'hémodynamique cardiaque est beaucoup plus claire maintenant (j'ai compris que l'on pouvait remplir et diurétiquer en même temps !!) Merci également aux chirurgiens de m'avoir fait découvrir ce monde passionnant qu'est la chirurgie cardiaque et merci notamment pour leurs explications précieuses durant les interventions : Dr Stéphane Lopez, Dr Tapia et Dr Teboul.A toute l'équipe paramédicale du KT 10 lits, de la réanimation cardiaque et surtout les filles du 4 ème (sans oublier Michèle!!).

1 )

 1 Vidal, Mme Thuraine et aux Médecins Lamya Drissi, Najib Zoubir, Hélène Lescault et Françoise Nahon. Merci également aux équipes paramédicales c'est toujours un plaisir de travailler avec vous. Merci à l'ACCA pour ces réunions très enrichissantes et le soutien que vous apportez aux internes. Au Dr Ré : Merci pour tout ce que vous avez fait pour nous cette année. Vous êtes un médecin remarquable. Je n'oublierai jamais votre disponibilité dans les moments difficiles. Vous avoir rencontré m'a ouvert les yeux sur le rôle du médecin dans l'écoute du patient et la prise en charge de sa famille ce qui est primordial dans notre métier et que nous avons tendance à oublier en cardiologie. Vous êtes un exemple d'humilité et de bienveillance. NT : MERCI POUR TOUT. INTRODUCTION p. La fonction ventriculaire droite 2) L'hypertension pulmonaire 3) La réhabilitation cardio-respiratoire dans l'hypertension artérielle pulmonaire 4) La réserve contractile ventriculaire droite 5) Objectifs de l'étude IV. MATERIEL ET METHODES p. 23 1) Design de l'étude 2) Population de l'étude 3) Paramètres évalués en échocardiographie 2D 4) Paramètres évalués en échocardiographie 3D et paramètres de déformation VD 5) Paramètres de la réserve contractile ventriculaire droite 6) Échocardiographie d'effort 7) Épreuve d'effort avec VO2 8) Test de marche de 6 minutes 9) Score qualité de vie SF-12 10) Analyse statistique

FRANCE(

  CHU de NICE). This study was named REHAB-HTP (clinical trials NCT03404492). PAH patients included underwent ambulatory cardio-pulmonary rehabilitation between January 2018 and February 2019. This study was approved by the research Ethics committees, and complied with the ethical guidelines of the Helsinki Declaration (Avis du CPP du CHU Nice en date du 13/01/2018). Each patient underwent a resting echocardiography and an exercise stress echocardiography (ESE) on the same day, a cardiopulmonary exercise test (CPET), a 6-minute walk distance (6MWD), and a survey about quality of life (SF-12) before and after rehabilitation. Patients underwent 8-weeks of exercise training: 3 times a week of aerobic training in our rehabilitation center in the department of cardiology of the university hospital in Nice (Pasteur)

FIGURE

  FIGURE 2: summary of the study

  was 104.42±79.3 after, p=0.73. At baseline 66.7% patients were in WHO functional class III and 33.3% in class II. After rehabilitation, we noticed an improvement in WHO functional class (p=0.009). 7 patients (58.3%) experienced an improvement of their WHO functional class; 4 patients went from class III to class II, 2 patients from class II to class I and 1 patient from class III to I. 4 patients (33.3%) remained stable and 1 patient (8.3%) went from class II to class III.

FIGURE 7 :

 7 FIGURE 7: Box-plots comparing before and after rehabilitation.

  To assess the beneficial effect of exercise training on exercise capacity, quality of life and cardiac function as assessed by echocardiography and cardio-pulmonary exercise test.

	ABBREVIATIONS
	ASE			American Society of Echocardiography
	BNP	BACKGROUND: Pulmonary arterial hypertension (PAH) is a life-threatening condition. Brain Natriuretic Peptid
	Current ESC guidelines recommend exercise training and rehabilitation in clinically stable PAH BPM Beats Per Minute
	patients. EACVI		European Association for Cardio Vascular Imaging
	ESC			European Society of Cardiology
	ESE			Exercise Stress Echography
	CPET			Cardiopulmonary exercise test
	LV			Left Ventricle
	LVOT			Left Ventricular Outflow Tract
	mPAP			mean Pulmonary Artery Pressure
	NYHA		New York Heart Association
	PAH			Pulmonary Arterial Hypertension
	PH			Pulmonary Hypertension
	pTVI			pulmonary Time Velocity Integral
	RV			Right Ventricle
	RVEF			Right Ventricular Ejection Fraction
	RVOT			Right Ventricular Outflow Tract
	V. RV CR RESULTATS	Right Ventricular Contractile Reserve	p. 34
	RV ESV	1) Caractéristiques générales de la population à l'inclusion Right Ventricular End Systolic Volume
	RV EDV	2) Échocardiographie de repos : comparaison après réhabilitation Right Ventricular End Diastolic Volume
	3) Échocardiographie d'effort : comparaison après réhabilitation according to the maximum workload during CPET (p=0.006), CPET duration (p=0.002) and 6MWD sPAP systolic Pulmonary Artery Pressure
	4) Paramètres de la réserve contractile VD après réhabilitation Tricuspid Annular Plane Systolic Excursion distance (+32.58m, p=0.02). Anaerobic threshold and peak VO2 (+1.60mL/kg/min) improved TAPSE 5) Épreuve d'effort avec VO2 : comparaison après réhabilitation 6) Test de marche de 6 minutes : comparaison après réhabilitation significantly (p=0.03 and 0.005). Regarding imaging data, at rest, peak strain improved after WHO World Health Organization
	7) BNP et Classe fonctionnelle de dyspnée WHO après réhabilitation rehabilitation (p=0.03) whereas the RV became more dilated. RV contractile reserve, defined by the 6MWD
	8) Score qualité de vie SF-12 : comparaison après réhabilitation change in peak systolic longitudinal RV strain between rest and maximum exercise, significantly
	9) Sécurité de l'étude DISCUSSION improved (-8.08±4.8%, p=0.02). VI.	p. 44
			1) Méthode et durée de la réhabilitation
		2) Échocardiographie de repos et d'effort 3) Capacité physique déterminée par le test de marche 6 minutes et l'épreuve d'effort avec VO2 CONCLUSION: In this preliminary study, cardio-pulmonary rehabilitation led to improved
	4) Qualité de vie et classe fonctionnelle de dyspnée WHO quality of life and exercise capacity in PAH. The increased RV contractile reserve post-rehabilitation
	5) Comparaison avec la réhabilitation cardio-respiratoire dans l'insuffisance cardiaque might explain, in association with the peripheral muscular effects of exercise training, the clinical
	6) Mécanismes d'amélioration post réhabilitation benefits of rehabilitation in PAH.
			7) Limites de l'étude
	VII.	CONCLUSION	p. 48
	VIII.	BIBLIOGRAPHIE	p. 49

PURPOSE: METHODS: We prospectively included 12 clinically stable PAH patients over a 6-months period. Exercise stress echocardiography (ESE), cardio-pulmonary exercise test (CPET), SF-12 quality of life questionnaire, 6-minute walk distance (6MWD), BNP and clinical assessment were performed before and after cardio-pulmonary rehabilitation. Patients underwent 8-weeks of exercise training (3 times a week of aerobic training and at home daily prescribed exercises). RESULTS: All patients underwent ESE and CPET without any complication. Seven patients experienced a reduction in WHO functional class whereas 5 remained stable. Patients significantly improved their physical quality of life (p=0.006). They also improved their exercise capacity

  muscles structural changes (decreased in muscle fibers)21 and a poor increase in cardiac output. This low cardiac output causes lactic acidosis with early production of CO2 and lower venous oxygen saturation that can lead to severe arterial hypoxemia during exercise20 . Besides, it is known that impairment in exercise capacity influences directly the quality of life and could lead to anxiety and depression disorders 21 .Right ventricular contractile reserve (RV CR) is a new notion that remains unclear. It is the ability of the RV to adapt to elevated afterload. In a previous work (unpublished data -Mémoire de DES cardiologie Aude Missana présenté le 07 juin 2019), we established, comparing PAH patients and healthy volunteers with exercise stress echocardiography, that changes in pulmonary output,

	Right ventricular contractile reserve
	PAH therapy has evolved over the last decade. ESC guidelines 22 suggest a supportive therapy pulmonary time velocity integral (pTVI), RV peak systolic strain as well as changes in TAPSE/sPAP
	(oxygen, oral anticoagulant, diuretics, digoxin) associated to specific drug therapy: vasodilatators but mainly RV peak strain/sPAP and 3D RV ejection fraction/sPAP represent consistent and feasible
	(calcium channel blockers) and antiproliferative agents (endothelin receptor antagonists, tools to assess RV contractile reserve.
	phosphodiesterase type 5 inhibitors, guanylate cyclase stimulators, prostacyclin analogues and
	prostacyclin receptor agonists). Combination of 2 or 3 different types of drugs can be used according
	to the clinical situation.
	Nowadays, current ESC guidelines (2015) 22 recommend physical activity and supervised
	rehabilitation in clinically stable PAH patients (Class IIa, level of evidence B). This rehabilitation has
	to be performed in proper conditions, closely monitored and supervised by nurses and physicians
	specialized in PAH. The rehabilitation has to be added to a medication therapy 22,31 .

17,18,19

PAH causes dyspnea, impaired exercise performance and is associated with reduced quality of life and survival

20

. Symptoms and exercise limitation are mainly related to an excessive ventilatory response to exercise; peripheral Rehabilitation in PAH Studies about rehabilitation in PAH patients are very recent but led to new guidelines in 2015. In 2006, Mereles et al. 23 performed the first prospective randomized study to evaluate the effect of cardiopulmonary rehabilitation in PAH. They demonstrated an improvement of the 6-minute walk distance, quality of life (both physical and mental scales), WHO functional class and peak oxygen consumption. Before this study common belief was that physical training had negative impact on PAH patients and may contribute to the progression of the disease 23 and to increase the risk of sudden cardiac death. Most physicians didn't authorize their PAH patients to perform physical training. 2009 ESC guidelines about PAH suggested; mainly after Mereles et al. study that physically

deconditioned PAH patients should be considered for supervised exercise rehabilitation (Class IIa level of evidence B) but stated that more data were required before appropriate recommendations could be made.

24

Since then, additional randomized control trials (De Man et al.

25

, Grunig et al.

26,27,28

, Weinstein et al.

29

and Chan et al.

30

) have been published and demonstrated for most the same results than Mereles' study.

PICTURE 1: tilt table ergometer (CHU Nice) Cardiopulmonary exercise test (CPET)

  Exercise Stress Echocardiography with continuous monitoring of the electrocardiogram was performed on a semi recumbent cycle ergometer with lateral left inclination on a tilt table ergometer (General Electric). Measurements of RV function were performed at rest and peak exercise to quantify the RV contractile reserve. The exercise protocol was a 10 Watt (W) minimum workload with a 10W increase in workload every minute.The cardiopulmonary exercise test was performed on a cycle ergometer (General Electric) with a continuous monitoring of the electrocardiogram and blood pressure. It wasn't realized on the same day as the exercise stress echocardiography. CPET involves ventilatory measures during a gradually increase intensity exercise until limiting symptoms or exhaustion46,47,48 :

	Exercise stress echocardiography (ESE)
	1. VO2 is the respiratory oxygen uptake (in mL/min) it reflects the volume of oxygen
	consumption,
	B : Adjustment (if needed) of 2. Maximum VO2 (or peak VO2) is the maximum volume of oxygen during exercise (in
	the mL/kg/min); it reflects the functional aerobic capacity, it's the highest rate of oxygen end-diastolic RV
	endocardial border consumption during exercise. Peak VO2 values must be above 85% of the predicted
	value 48 .
	3. VCO2: carbon dioxyde production (in ml/min),	C : Adjustment (if needed) of
	the 4. Respiratory quotient (RQ) or respiratory exchange ratio which represents gas end-systolic RV
	endocardial border exchange ratio between carbon dioxide output/ oxygen uptake (VCO2/VO2). The value
	above 1 reflects a maximal exercise intensity.	D : Final result with the RV
	endocardial 5. Ventilatory anaerobic threshold (AT) or VT1 is the VO2 value measured in the first mesh, time-
	volume curve, RV volumes ventilatory threshold; it estimates the upper limit of exercise capacity which can be
	and ejection fraction sustained over a prolonged period without increasing blood lactate. AT normal values
	are around 40 to 65% of Peak VO2 48 .
	6. Pulmonary ventilation (VE) is the volume of air inhaled an exhaled during one minute
	(L/min). At rest the normal value is around 7 to 9 L/min 48 .
	7. The

ventilatory equivalent for oxygen (O2) VE/VO2 is

  This test is the mostly used to evaluate functional capacity in PAH patients. It measures the distance an individual is able to walk during six minute on a hard, flat surface. The goal is to walk as far as possible in six minutes. Outcomes measured 49,50 :

	The six-minute walk distance (6MWD)
	1. Distance covered during 6 minutes in meters
	2. Borg dyspnea scale at rest and at the end of the test (from 0 to 10; in which 10 is the
	worst)
	3. Oxygen saturation at rest and the worst value during exercise (NADIR) measured with
	pulse oximetry (in %).
	The 8 subscales range from 0 to 100 (higher scores indicating better quality of life) and are
	summarized by 2 summation scales, the physical component scale (PCS-12) and the mental
	component scale (MCS-12).
	the ratio between pulmonary
	ventilation and O2 consumption. It represents the ventilatory needed to consume an
	amount of O2 during exercise. This ratio increases when there is an inefficiently
	ventilation (normal range between 25 and 30).
	8. The ventilatory equivalent for carbon dioxide (CO2) VE/VCO2 is the ratio between
	pulmonary ventilation and CO2 production. It represents the ventilatory needed to
	eliminate an amount of CO2 produced during exercise by tissues (normal range <30).

Short Form-12 Health survey (SF-12)

The 12-item Short Form Health Survey (SF-12) is a quality of life assessment.

It is a general health questionnaire that was first published in 1995 as part of the Medical Outcomes Study (MOS). The SF-12 was created using questions drawn from each of the 8 dimensions subscales (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health) of the MOS 36 item Short Form Survey (SF-36). It is designed to have similar performance than the SF-36, while taking less time to complete.

  summarized as mean ± standard deviation for continuous variables and number of subjects (%) for categorical variables. The variables were tested by the paired data Student t-test for normally distributed variables. Otherwise, the Wilcoxon test was performed. Categorical variables were compared using Fisher's exact test. These analyses were performed using MedCalc 17.5.5 (MedCalc Software, Mariakerke, BE). In all analyses, statistical significance was defined by a p-value <0.05. PAH patients' peak VO2 was greatly impaired before rehabilitation: 13.03±3.6 mL/kg/min. The mean workload was 66.67±28.4 watts and the duration of the exercise was 6.06±2.1 minutes.

	Ventilatory equivalents were also impaired at baseline; VE/VO2 was 23.09±8.8 (normal range 25-30)
	and VE/VCO2 was 46.71±14.8 (normal range <30). PAH patients' anaerobic threshold was also
	impaired: 11.56±3.6 mL/kg/min.
	After Rehabilitation
	PAH patients both improved significantly their peak VO2 14.63±5.6 mL/kg/min
	(+1.60mL/kg/min p=0.005) and their ventilatory anaerobic threshold 13.31±4.8 mL/kg/min
	(+1.75mL/kg/min p=0.03). No statistical differences were established for the ventilatory equivalents
	respectively 26.07±9.2 (p=0.10) for the VE/VO2 and 46.38±17.5 (p=0.87) for VE/VCO2.

Rehabilitation greatly improved the duration of exercise 7.72±3.1min (p=0.006) and the intensity 80.83±35.8 watts (+14.16W, p=0.002). No significant difference was observed in clinical parameters (systolic/diastolic blood pressure and heart rate).

TABLE 3 : cardiopulmonary exercise test comparison before and after rehabilitation

 3

	Before Rehabilitation	After Rehabilitation	p
	n=12	n=12	value

  At baseline, both components were impaired; the mental score component was 44.42±11.8 and the physical score component was 49.08±7.2.

		Before Rehabilitation	After Rehabilitation	p value
		n=12	n=12
	6MWD
	Dyspnea beginning test (Borg n/10)	1.13±1.5	1.32±1.6	0.10
	Dyspnea end test (Borg n/10)	6.00±1.3	5.55±1.7	0.28
		94.64±2.0	94.80±2.4	0.70
	Nadir saturation (%)	89.00±5.6	88.20±4.4	0.66
	Distance (m)	393.17±99.2	425.75±96.6	0.02

TABLE 5 : SF-12 quality of life; comparison before and after rehabilitation Safety All

 5 patients tolerated well the exercise during the rehabilitation program and didn't experience any severe complication. No progression of the disease during rehabilitation or immediately after was observed. During the study period, 1 patient experienced dizziness while exercising in relation with high blood pressure.

		Before Rehabilitation	After Rehabilitation	p value
		n=12	n=12
	Mental score	44.42±11.8	49.08±7.2	0.11
	Physical score	38.22±11.2	43.77±8.3	0.006

SERMENT D'HIPPOCRATE

En présence des Maîtres de cette Faculté, de mes chers condisciples, et devant l'effigie d'Hippocrate :

Je promets et je jure d'être fidèle aux lois de l'honneur et de la probité, dans l'exercice de la Médecine.

Je donnerai mes soins gratuits à l'indigent, et n'exigerai jamais un salaire audessus de mon travail.

Je ne permettrai pas que des considérations de religion, de nation et de race viennent s'interposer entre mon devoir et mon patient.

Admis à 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.

RESULTS

Between January 2018 and February 2019, 40 consecutive patients with PAH were screened for enrolment. Of those, 14 PAH patients were suitable for inclusion. Two patients were lost of follow up. Finally, 12 patients with PAH participated in REHAB-HTP.

FIGURE 5: Flow chart

Population baseline characteristics:

Main characteristics of our cohort at baseline are summarized in Table 1 Peak = peak exercise test Heart rate at peak (bpm) 127.25±15.6

Systolic Blood Pressure at rest (mmHg) 121.75±20.9

Systolic Blood Pressure at peak (mmHg) 173.58±32.9

Diastolic Blood Pressure at rest (mmHg) 69.00±7.9

Diastolic Blood Pressure at peak (mmHg) 89.50±24.1

Maximum Work load (Watt) 66.67±28.4

Brain Natriuretic Peptid (BNP), (pg/mL) 114.67±111.7

Peak VO2 ( 13.03±3.6

Severe tricuspid regurgitation n(%) 0/12 (0%)

WHO functional class, n(%) I II III IV 0 (0%) 4 (33.3%) 8 (66.7%) 0 (0%) 6MWD (m) 393.17±99.2

Advanced PAH therapy n(%) Mono

RV contractile reserve parameters comparison after rehabilitation

In the following chapter Δ corresponds to the difference between peak exercise and rest for each parameter studied.

Δ ΔsPAP did not significantly differ before and after rehabilitation; respectively 41.40±22.5 mmHg and 42.67±15.8 mmHg (p=0.65).

No statistical difference in ΔTAPSE was observed after rehabilitation (3.54±4.1mm vs 3.75±3.8mm; p=0.89). Similarly no difference in Δpulmonary TVI and ΔRVEF (respectively p=0.13 and p=0.32) were found.

Ratios resting and peak TAPSE/sPAP weren't significantly different after rehabilitation (respectively p=0.57 and p=0.66). Also, no change of the difference of ratios Δ(TAPSE/sPAP) was observed after rehabilitation (p=0.73). Same results were observed for the ratios RVEF/sPAP at rest and at peak exercise and for the difference of ratios Δ(RVEF/sPAP); respectively (p=0.42, p=0.79, p=0.74).

ΔRV free wall peak systolic strain was significantly raised after rehabilitation: -8.08±4.8% vs -2.85±2.9% (p=0.02); suggesting a better increase in deformation with exercise, after rehabilitation.

Peak strain/sPAP ratios both at rest and at peak weren't significantly different after rehabilitation (respectively p=0.60 and p=0.27). Similarly, no change in the difference of ratios Δ(peak strain/sPAP) was observed after rehabilitation (p=0.45).

FIGURE 6: comparison between echocardiography at rest and peak exercise in a PAH patient:

increase in sPAP and RV dilatation with exercise. The significant results about echocardiographic parameters in our study after rehabilitation were: free wall peak systolic strain at peak exercise which was increased after rehabilitation (p=0.03), RV contractile reserve (p=0.02), 3D RVEF at peak exercise (p=0.03) and RV EDV both at rest (p=0.02) and at peak exercise (p=0.005).

In (p=0.003). In our study, PAH patients improved their 6MWD by +32.58m (p=0.02); it is less than expected compared to other rehabilitation study but even with our small sample size of population we found an improvement. Thus, it seems that rehabilitation led to more improvement in 6MWD distance than drug therapy although no control study aimed to compare drug therapy to rehabilitation. Both therapy probably have a combined and synergic beneficial effect by improving the pulmonary artery resistance and compliance.

Cardiopulmonary exercise test is less used to evaluate exercise capacity in randomized trials both about drugs and rehabilitation compared to 6MWD. For Mereles et al. rehabilitation improved peak VO2, ventilatory anaerobic threshold, achieved workload at anaerobic threshold 23 . Yuan et al.

demonstrated in their meta-analysis that the effects of exercise training on exercise capacity improved the peak VO2 (+1.49 mL/min/kg; p<0.0001) 57 and on workload (+14.88 watt p<0.0001). In Grünig's study PAH patients improved the workload by +15watts (p<0.001) and their peak VO2 by +2.1 ml/min/kg (p<0.001). Our results were similar, PAH patients improved their peak VO2 by +1.6 ml/min/kg (p=0.005) and their workload by +14.16watts.

Quality of life and WHO functional class

At baseline, all patients had a significantly compromised quality of life and PAH patients included had a WHO functional class II or III. At the end of the study, all patients perceived an improvement of their symptoms. Main studies about cardiopulmonary rehabilitation in PAH patients demonstrated an improvement in quality of life, they all used the SF-36 short form survey 23,25,28,30 . We found a significant improvement in the physical component but not in mental score. This difference may be explained by the fact that compared to other studies we didn't insist on the mental support and psychological approach during our rehabilitation program.

Rehabilitation in chronic heart

Limits of the study

Our study was a cross-over monocentric study. Our results are limited by the small sample size of our population. Given the small number of stable PAH patients, including in REHAB-HTP has been a challenge.

A selection bias has to be noticed, as our PAH patients did not represent the overall PAH population. We included PAH patients WHO functional class II or III and other authors included all PAH patients even WHO functional Class IV. We considered that a therapeutic adjustment using prostacyclin analogs was more adequate in those patients. To be included, PAH patients had to be stable for at least one month, be able and agree to perform the 8-weeks restrictive rehabilitation program, thus full-time worker were almost systematically excluded.

Our rehabilitation program was only ambulatory as compared to the main studies, thus being a potential bias. However, in the end, same findings were observed (as compared to other studies).

Thus, ambulatory rehabilitation programs could be suggested to PAH patients.

The ESE was also a limitation to our study; it was more difficult to perform and interpret than dobutamine stress but we wanted to recreate more physiological conditions to mimic exercise. We also deliberately exclude dobutamine stress echocardiography to study PAH as it could lead to severe arrhythmias.

Regarding at home daily prescribed exercises, despite being systematically interrogated, we could not be sure that patients did their homework.

We included only stable PAH patients; all were treated by a targeted PAH therapy. The effect of rehabilitation could have been underestimated by that but, according to guidelines; rehabilitation has to be added to optimal drug therapy.

During our rehabilitation, our physiotherapist resigned. This was also a bias for the 6MWD because this test can be operator dependent.

CONCLUSION

To conclude; in this preliminary study, cardio-pulmonary rehabilitation led to improved quality of life and exercise capacity in PAH. The increased RV contractile reserve post-rehabilitation might explain, in association with the peripheral and respiratory muscular effects of exercise training, the clinical benefits of rehabilitation in PAH.


Alary D Bien

Optimal insurance contracts with adverse selection and comonotonic background risk

Keywords: Adverse Selection, Background risk, Optimal Contract

In this note, we consider an adverse selection problem involving an insurance market à la Rothschild-Stiglitz. We assume that part of the loss is uninsurable as in the case with health care or environmental risk. We characterize su¢ cient conditions such that adverse selection by itself does not distort competitive insurance contracts. A su¢ ciently large uninsurable loss provides an incentive to high-risk policyholders not to mimic low-risk policyholders without distorting the optimal coverage.

Introduction

The existence of an uninsurable …nancial risk a¤ects the individual's insurance choice. Some authors have studied the impact of such background risk on the theory of insurance demand (Doherty andSchlesinger (1983, 1990) ; [START_REF] Eeckhoudt | Background Risk, Prudence, and the Demand for Insurance[END_REF] ; [START_REF] Hau | A Note on Insurance Coverage in Incomplete Markets[END_REF]).

The purpose of this note is thus to analyse the e¤ects of …nancial background risk in an adverse selection setting à la [START_REF] Rothschild | Equilibrium in Competitive Insurance Markets : An Essay on the Economics of Imperfect Information[END_REF] (abbreviated here as RS). To our knowledge, [START_REF] Crocker | Background Risk and the Performance of Insurance Markets under Adverse Selection[END_REF] are the only authors to focus on the e¤ect of a background risk on optimal insurance contracts with adverse selection. They assume that the background risk is independent of the insurable loss. This additional risk a¤ects the extent of insurance coverage because it increases the risk aversion of vulnerable agents. Crocker and Snow show that the RS deductible needed to achieve separation is lower than in the case of the standard RS model. Moreover, to achieve a separating equilibrium, the proportion of high-risk agents must be higher than in RS. Otherwise, pooling equilibrium appears. However, uninsurable losses are usually perfectly correlated with …nancial loss rather than being independent. This is the case when considering environmental risks, human capital or health: part of the losses is unobservable and/or uninsurable.

We study here the incidence of an uninsurable loss comonotonic with the insurable risk in a RS setting. In particular we characterize conditions underwhich private information does not modify the optimal contracts. Due to the comonotonic uninsurable loss, the high-risk agent balances between a higher coverage (and a higher premium) and a smaller premium (with a smaller coverage). If the agent faces a su¢ ciently large uninsurable risk, the e¤ect of coverage dominates the e¤ect of premium reduction. The present study has the following structure. The model is presented in section 2 and the private information equilibrium is characterized in section 3. Section 4 reports the conclusions.

The model

There are two possible states of nature : the "no loss" state occurs with probability p i and the "loss" state with probability 1 p i : Consumers share the same Von Neumann-Morgenstern utility function U (W ) where W denotes the wealth and W 0 the corresponding initial wealth. As in RS, there are two types of agent in the economy (i 2 fH; Lg for high and low risk) di¤ering in their loss probabilities : p H > p L . We assume that there is a proportion of high-risk agents in the total population.

In the loss state, their wealth is reduced by an amount Z i = D + i . We assume H > L = 0. Moreover we consider that only D is veri…able. 1Therefore i is uninsurable and may be considered as a background risk that is comonotonic with D.

Under competition, insurers are constrained to earn zero expected pro…t. We consider an insurance contract i ; i where i denotes the premium and i the indemnity net of the premium.

With public information (both on the probability and the loss Z i ), the optimal individual contract is given by solving

max i ; i p i U (W 0 Z i + i ) + (1 p i ) U (W 0 i )
which is subject to zero expected pro…t on each contract

(1 p i ) i p i i = 0
Since the premium is actuarially fair, it is straightforward to show that the optimal contracts provide full coverage thus implying i + i = Z i . From the zero expected pro…t constraint, we obtain i = p i Z i .

Private information equilibrium

Under private information, insurers do not observe the individual risk characteristics i.e. the probability p i and the uninsurable loss i . According to the standard explanation of screening in insurance markets, …rms use deductible to sort high and low levels of risks. If this property is valid, then L-risk type agents will accept a large deductible in order to signal their type and pay a lower premium. This is due to the fact that only H-types want to mimic L-types. L-types never choose an H-type contract which can be explained by the single crossing property. This property states that, for any contract ; the marginal rate of substitution for the H-risk type must be lower than for the L-risk type.

This property is true if the indi¤erence curve has a greater slope for the L-type agents than for the H-type agents. Hence,

p L 1 p L U 0 (W 0 ) U 0 (W 0 D + ) > p H 1 p H U 0 (W 0 ) U 0 (W 0 D H + ) (1)
As p L < p H and H > 0; this inequality always holds true.

As observed in a standard RS setting, this condition implies that the H-risk type will overvalue a monetary transfer in the bad state compared to the L-risk type agent. The H-risk type is thus willing to purchase more insurance rather than the L-risk agent. Hence, competitive contracts under full information are not incentive compatible. The H-risk agents prefer an Lrisk type's contract because they receive the same indemnity but with a lower premium. Insurers achieve separation by introducing a deductible. Thus the L-risk type agent is o¤ered a contract with limited coverage at a low unit price. Moreover the self selection constraint of L-type agents is never binding. Therefore, we focus here on incentives for H-type agents .

Note that, contrary to RS under perfect information, di¤erent contracts exhibit di¤erent indemnities. Thus it is not trivial that the self selection constraint of H risk agents is binding.

We can characterize conditions such that …rst best contracts are optimal under asymmetric information i :e: such that the H-type self selection constraint is slack.

The optimal contracts have to satisfy the following program :

max H ; H ; L ; L [p H U (W 0 D H + H ) + (1 p H ) U (W 0 H )] + (1 ) [p L U (W 0 D + L ) + (1 p L ) U (W 0 L )]
subject to zero expected pro…t on each contract

(1 p L ) L p L L = 0 (1 p H ) H p H H = 0
and the H-type agent's self selection constraint

p H U (W 0 D H + H ) + (1 p H ) U (W 0 H ) (2 H ) p H U (W 0 D H + L ) + (1 p H ) U (W 0 L )
This program is the same as the previous one except that it contains a self selection constraint. Clearly, ignoring this constraint will give rise to the same solution. Then we can characterize situations such that this condition is slack when …rst best contracts are o¤ered. Therefore, we obtain the following result.

Proposition 1 If the uninsurable loss is su¢ ciently large, the equilibrium contracts under private information correspond to the …rst best contracts.

Proof. In order to characterize the equilibrium, …rst best contracts have to satisfy the incentive-compatibility constraint :

u (w p H (D + H )) p H u (w p L D H ) (1 p H )u (w p L D) 0
Let us denote f ( H ; p L ) the left hand side of this constraint :

f ( H ; p L ) = u (w p H (D + H )) p H u (w p L D H ) (1 p H )u (w p L D)
Note that f (0; p L = p H ) = 0: If the risk type are the same, the incentivecompatibility constraint is obviously satis…ed. Departing from (0; p L = p H ) by decreasing p L we decrease f ( H ; p L ) and the incentive-compatibility constraint is no longer satis…ed since df ( H ;p L ) dp l > 0: However such a decrease may be compensated by a variation of the uninsurable loss H such that the incentive-compatibility constraint remains satis-…ed. By fully di¤erentiating the function f ( H ; p L ), we know that

df ( H ; p L ) = p H [u 0 (w p L D H ) u 0 (w p H (D + H ))] d H +D [p H u 0 (w p L D H ) + (1 p H )u 0 (w p L D)] dp L Then df ( H ; p L ) = 0 if and only if d H = D [p H u 0 (w p L D H ) + (1 p H )u 0 (w p L D)] p H [u 0 (w p L D H ) u 0 (w p H (D + H ))] dp L
However, from H = 0, we can only consider an increase in the uninsurable loss then it must be the case that d H > 0. Since dp L < 0, this will be true if and only if

p H [u 0 (w p L D H ) u 0 (w p H (D + H ))] < 0 which is equivalent to H > (p H p L ) 1 p H D = H (p L ). Note that H (p H ) = 0 then from (0; p L = p H ), we know that f (0 D [p H u 0 (w p L D H ) + (1 p H )u 0 (w p L D)] p H [u 0 (w p L D H ) u 0 (w p H (D + H ))] dp L ; p L = p H dp L ) = 0
Then, providing that H > H (p L ), we can de…ne a function H (p L ) such that f ( H ; p L ) = 0 by using the implicit function theorem. Moreover, for all H H (p L ) f ( H ; p L ) 0 meaning that the incentice-compatibility constraint is always satis…ed for the …rst best contracts.

The intuition of this result is the following. A H-risk type agent who chooses an L-risk type contract is no longer compensated for the uninsurable loss. 2 . A higher uninsurable loss decreases the wealth in the unfavourable state but increases the di¤erence between insurance premiums. However if the uninsurable loss is su¢ ciently large, the ensuing reduction in utility due to it overwhelms the bene…t of a lower premium. Therefore the H-type policyholders prefers their own type of contract.s in which their self selection constraint is never binding. Optimal contracts under asymmetric information are those of full information.

Conclusion

Crocker and Snow (2006) show that the existence of an unobservable independent background risk may close some insurance markets. However, they show that extending coverage to background risk can have a positive social value. In this paper, we focus on a perfect correlation between risks. In fact we consider that part of the loss is unobservable so it is therefore then uninsurable as in the case of health or human capital. We establish certain conditions whereby private information leads to the absence of ine¢ ciencies in competitive markets. This comonotonic background risk induces policyholders to prefer their own …rst best contract to any other contract they may choose due to private information.

As in[START_REF] Doherty | Adverse Selection When Loss Severities Di¤er: First-Best and Costly Equilibria[END_REF], we consider that applicants have di¤erent losses. Doherty and Jung show that, if losses are observed, adverse selection does not modify the …rst best contracts. Indeed, insurers may infer risk types from the loss. In our model, we assume that policyholders have the same observable loss. Then, contrary to Doherty and Jung, insurers cannot infer the type of policyholder by observing losses.

Note that it is unnecessary to assume L = 0 is not . Our result is true if H > L . In this case, the H-type agent is partially compensated for the uninsurable loss. Nevertheless, if the remaining uncovered loss is su¢ ciently large, the same argument applies.