Résultats De L'

Expérience Grenobloise

Thèse Présentée Pour L'

Obtention Du

Titre De

Docteur En

Médecine Diplôme D'

État Thomas

Barret Thèse

Soutenue Publiquement

Devant Le Jury

Président Composé De

M Le Professeur

Bruno Degano

Me Le Docteur

Hélène Bouvaist

Directrice De Thèse

Gérald Vanzetto

Christophe Pison Me Le Docteur

Cécile Rocca

Christelle

Morgane Florence

Maryline, Emmanuelle, Greg « Lac »)

Dimitri

Raphaëlle

Morgane, Souhaila, Noémie, Elodie, Laura, Aurore… David

Apporté Vous M'avez Énormément

A L'équipe Du

B A Gaël

Dr Au

Jouve A Thomas

Guy

Carole Schwebel

Dr Marianne Noirclerc

Dr Merel Dit Greg

Dr Laurence Poletti

Christophe Sébastien

Audrey

Sandrine

Lyon Au Pr

Dr Hélène Thibault

Dr Martine Barthelet

Sophie Thivolet

Dr Marion Au

Dr Sophie Rosset

A Lamoureux

Marie

LA READAPTATION CARDIAQUE DANS LA PRISE EN CHARGE DE L'HYPERTENSION ARTERIELLE PULMONAIRE ET DE L'HYPERTENSION PULMONAIRE THROMBOEMBOLIQUE CHRONIQUE

L'UFR de Médecine de Grenoble n'entend donner aucune approbation ni improbation aux opinions émises dans les thèses ; ces opinions sont considérées comme propres à leurs auteurs.

[Données à caractère personnel

Madame le Docteur Cécile Rocca,

Merci de me faire l'honneur de juger ce travail. Tes remarques pertinentes m'ont grandement aidé. Merci de m'avoir accueilli de ton service, où c'est avec grand plaisir que je travaille à tes côtés. Je te remercie de la confiance que tu m'as renouvelée. Tu as toute ma reconnaissance et ma profonde considération.

A mes co-internes, sans qui la vie hospitalière n'aurait pas la même saveur,

A ma promo. Je ne sais pas si l'on peut en rêver de meilleure :

A Antoine, dit Michel, grâce à toi la visite à l'USIC n'a pas son pareil. Polyvalent, tu es le meilleur dribbleur de Côte d'Or que je connaisse, et tu portes la nuque longue comme personne. « Sacré Michel ! Toujours le mot pour rire ».

A Anne, tu as été un soutien primordial dans les moments de galère des premiers mois d'internat. J'ai hâte de pouvoir répondre à ton invitation et découvrir enfin celui qui fait ton bonheur à la maison.

A Lauriane, tu es la seule à avoir le droit de m'appeler « tomtom » et la seule capable de faire une relève entière à l'USIC en me montrant des photos de ta fille. Tu es un peu spéciale pour moi et c'est un vrai plaisir à chaque fois de te revoir.

A Léa. Si j'ai un regret c'est celui de n'avoir jamais été dans le même stage que toi. Mais ça ne m'a pas empêché d'apprécier tes qualités humaines et professionnelles. Je te souhaite que du bonheur dans ta nouvelle vie de docteur.

A ceux qui m'ont montré la voie, aujourd'hui devenus d'éminents cardiologues : Nicolas, Adrien, Katell, Thomas, Johanne, Marjorie, Océane, Wassima, Lisa… A ceux qui suivent : Victor (dit professeur Mathieu), Sara, Elodie, Lucie, Arnaud, Benjamin, Estelle, Guillaume, Antoine, Charles-Eric, Laura, Robin, Lou, Rémi, … A Olivier et Emilien venus se perdre en cardiologie adulte.

Aux internes de l'internat. A Elsa, pour être simplement qui tu es. A Valentine.

A Maïty, Evelyne, Donatien pour m'avoir fait découvrir la kiz, et la via ferrata.

A Catherine, Antoine, Morgane, pour votre bonne humeur dans ce monde mystérieux où les glomérules peuvent prendre la forme de « pain à cacheter », et où l'on sait se serrer les coudes.

A Alison, Louis, Quentin, Florian, Sophie, Hélène, Salomé, Malik. Pour ces moments inoubliables à vivre une montagne russe d'émotions, avec des rires le plus le souvent. Je t'en veux toujours, Florian, d'avoir eu, à une relève, cette vision qui t'a permis de voir une idylle naissante, avant tout le monde.

A Carolina, Pernelle, un jour on sera des pro de l'impro c'est sûr ! A Alexis, plus attiré par le bloc d'escalade que par le bloc note ou le bloc opératoire.

A Ahmad, tu forces le respect par ta gentillesse, tes compétences et ton travail.

A Gaultier, et nos colloques improvisés sur le Strain de l'oreillette gauche.

A Jessica, délicate et adorable, tu as su mener de front la thèse et le mariage, et je te souhaite le meilleur pour la suite.

A mes co-internes de Dijon, Chalon-sur-Saône ou Auxerre. A Grégoire, Pauline, Maxime, Julien, Lucie que j'ai quittés trop vite. A Alexis, Carole, Céline, Marion, Emilie (et à nos pauses thé-Mario Kart), Karim, Pierre, Michel, Jérémy, … Aux externes, Florian, Quentin (pour cette virée à Lyon), Nathan, Quentin (pour avoir égayé votre passage à l'USIC), Jade(-Marie) (merci d'avoir joué les entremetteuses), Ariane (et Adrien) et à nos parties d'escape futures, Léa (l'alliance parfaite entre les potins et la cardiologie), Safa (pour avoir amené un peu de philosophie dans nos discussions), Léa, et tant d'autres… A Sven, ouvert, érudit, sportif et sans doute la plus belle personne que j'ai jamais connue ; je pense à toi là où tu es.

A mes amis de fac et plus encore,

A Johan. Parfois la vie force des rencontres improbables. Tu avais écrit un jour que tu seras toujours de mon côté ; saches que tu peux me compter à tes côtés éternellement. Même si je n'ai pas souvent appliqué tes conseils à ton grand désespoir, c'est un bonheur les écouter et de pouvoir discuter avec un esprit éclairé. A Barcelone, à Montélimar, aux Cowboys ou au ski, je n'ai que des bons souvenirs en tête. Et j'ai hâte d'en créer d'autres avec toi.

A tes parents. A Pauline, et sa bonne humeur rayonnante.

A Rachid, vent de fraîcheur s'il en est.

A Antoine. Je ne te l'ai jamais caché, tu as toujours été un modèle pour moi. En toutes circonstances, tu sais te dépasser : que ça soit à la fac, au surf, aux jeux de société, … Ton enthousiasme est communicatif, et c'est un vrai plaisir de partager des moments avec toi au goûter, en soirée ou en vacances (même si tu parles quand même toujours autant à la coinche). Je te souhaite le meilleur dans votre nouvelle maison et cette nouvelle vie qui s'offre à vous.

A Juliette, toujours charmante et accueillante ; Antoine a bien de la chance de t'avoir à ses côtés. Les yeux dans les yeux, vous croquez la vie à pleines dents tendrement, et ça fait chaud au coeur.

A Jonathan. Ta disponibilité, ton humour, ton goût pour les mots et le sport sont le cocktail idéal pour passer de bons moments. Toujours partant pour de nouvelles expériences culinaires ou culturelles, c'est un plaisir de les partager avec toi. Après tant d'années à Lyon, il te suffirait d'adopter le quart d'heure lyonnais pour vivre comme les locaux (mais je ne suis pas sûr que ça change). Dove fare un buon aperitivo a Roma ? Maintenant je sais : à Trastevere avec toi. A presto.

A Geoffrey, pour ta franchise et ton authenticité. A un moment donné, je suis quand même bien obligé de remercier la Drôme de me permettre des rencontres aussi sincères qu'extraordinaires.

A Thomas, dit « Nounours », pour ta gentillesse et nos poutines en sortant de gynéco.

A mon groupe de sous-conf salvateur : Guillaume, Anne, Camille.

A Audric, pour le temps passer à l'ENS à réviser.

A Bénédicte. Merci de m'avoir supporté pendant deux années probablement parmi les plus déstabilisantes.

A ma famille, ou tout comme,

A mes parents. Merci pour votre amour et votre soutien sans faille. Vous avez bien voulu me supporter depuis le début et jusqu'au bout (et même durant mon dernier semestre à Lyon). Si j'en suis là aujourd'hui c'est aussi grâce à vous. Je suis fier d'être votre fils.

A Noémie. Parfois, j'ose imaginer avoir été un modèle pour toi, mais ce serait trahir ton intelligence et ta personnalité. Même si tu restes ma petite soeur chérie, le temps passe si vite et je suis fière de ton parcours.

A Laurie. Depuis le début, tu as toujours été là quand il le fallait, et je ne t'en remercierai jamais assez. Ta sensibilité, ta rigueur et ta combativité, me laissent admiratif. Tu es indispensable.

A Simon. Enfant, je me suis longtemps efforcé de te ressembler, en vain. Aujourd'hui quand je te vois, j'ai encore mes yeux de petit frère et je reste impressionné par le chemin que tu as parcouru. Merci aussi à Elodie, ta super femme, qui contribue grandement à votre bonheur.

A Magali. A Julien. Merci de compléter cette formidable fratrie. Merci d'être là, même quand vous êtes loin. A Lionel. A Mélisa. Merci pour votre bonne humeur et votre gentillesse.

A mes neveux et nièces : Laly, Flore et Adam qui m'ont soutenu psychologiquement jusque dans la dernière ligne droite, en acceptant volontiers de jouer à cache-cache, miaou-miaou ou mistigri avec moi. Cybélia, Macéo, Goran, Guilhem, et leur accent chantant.

A mes grands-parents, qui sont et resteront un modèle pour moi.

A ma marraine Christelle. Passionnée et passionnante, ton ouverture d'esprit et ton ouverture aux autres font de toi une personne en or.

A mon parrain Luc. Une personne extraordinaire, que je connais trop peu. Malgré tout, je sais que je peux compter sur toi, et j'aimerais passer plus de temps avec toi. A Paulette A Amandine. Je mesure la chance que j'ai de t'avoir rencontrée, et plus encore de te savoir auprès de moi. Merci pour tes sourires, ta patience, ton soutien sans faille, et ton enthousiasme. (2). And yet, reduced exercise capacity in PH is common and associated with anxiety disorders, depression, skeletal muscle dysfunction and compromised quality of life (3,4).

Since then, more studies in rather small cohorts of patients with PAH and CTEPH have shown beneficial effects of exercise training as add-on to medical therapy by improving symptoms, exercise capacity and quality of life, with reassuring data on safety (5-8).

Definition of pulmonary hypertension

Normal mean pulmonary artery pressure (mPAP) at rest is 14.0±3.3 mmHg; this value is slightly influenced by age and posture, and independent of sex and ethnicity (9) Since the 1st World Symposium on Pulmonary Hypertension (WSPH) organised by the WHO in 1973, pulmonary hypertension is defined by a resting mPAP ≥25 mm Hg measured by right heart catheterisation in the supine position (10)(11)(12).

During the 6 th WSPH in 2018, the task force members suggested mPAP >20 mmHg as above the upper limit of normal (above the 97.5 th percentile), and the need for PVR ⩾3WU to define the presence of pre-capillary PH (groups 1, 3 and 4, some patients from group 5, and exceptionally patients from group 2 with combined pre-and post-capillary PH) (13).

Different groups of pulmonary hypertension

PH is classified into five groups based on the aetiology, or pathophysiological features:

-Group 1, pulmonary arterial hypertension (PAH) comprises patients with precapillary pulmonary hypertension due to distinct underlying disorders who share a similar angioproliferative vasculopathy in the pulmonary arterioles, leading to endothelial and smooth muscle proliferation and dysfunction, inflammation and thrombosis (14,15).

PAH comprises various different pathologies, such as idiopathic, heritable, druginduced PAH (e.g. anorexigenic agents), as well as PAH associated with concomitant diseases such as connective tissue disease, HIV infection, portal hypetension, or congenital heart disease. Since the 3rd WSPH held in 2003, pre-capillary PH of group 1 (PAH) has been defined by the presence of mPAP ⩾25 mmHg with a normal pulmonary artery wedge pressure (PAWP)⩽15 mmHg and elevated pulmonary vascular resistance (PVR) ⩾3 Wood Units (WU) and the absence of other causes of pre-capillary PH, (e.g. hypoxemia or chronic parenchymal lung diseases or chronic thromboembolic disease) (10,11).

-Group 2 is classified as pulmonary hypertension due to left heart disease.

-Group 3 includes PH due to lung diseases and/or hypoxia.

-Group 4 includes those with PH due to pulmonary artery obstructions, such as chronic thromboembolic PH.

-Group 5 is pulmonary hypertension due to miscellaneous disorders that cannot be attributed to one other group (for example pulmonary hypertension in the context of haematological disorders).

b. CTEPH

In the various registries, CTEPH is mostly diagnosed between 50 and 70 years-old, with males and females being equally affected [START_REF] Hoeper | Chronic thromboembolic pulmonary hypertension[END_REF][START_REF] Galiè | ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)[END_REF][START_REF] Ghofrani | Riociguat for the treatment of chronic thromboembolic pulmonary hypertension[END_REF].

Studies determined that the incidence of CTEPH was 1,0-8,8% of all survivors of acute pulmonary embolism [START_REF] Dentali | Incidence of chronic pulmonary hypertension in patients with previous pulmonary embolism[END_REF][START_REF] Becattini | Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism[END_REF][START_REF] Pengo | Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism[END_REF][START_REF] Ribeiro | Pulmonary embolism: oneyear follow-up with echocardiography doppler and five-year survival analysis[END_REF], with a calculated average incidence of 4% in Europe and USA [START_REF] Opitz | Chronic thromboembolic pulmonary hypertension[END_REF].

In European registries, the reported annual chronic thromboembolic pulmonary hypertension incidence rates is 0,9-5,7 cases per million adults per year (16,19,[START_REF] Condliffe | Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension[END_REF][START_REF] Kramm | Incidence and characteristics of chronic thromboembolic pulmonary hypertension in Germany[END_REF]. But this number is much fewer than the expected annual incidence (16).

Up to 25% of patients with CTEPH have no history of acute pulmonary embolism [START_REF] Pepke-Zaba | Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry[END_REF], the symptoms are relatively unspecific, and physicians are ill-informed about the disease; this is why CTEPH is certainly underdiagnosed [START_REF] Gopalan | Diagnosis of chronic thromboembolic pulmonary hypertension[END_REF]. The calculated incidence including diagnosed and undiagnosed disease ranges from 30 to 50 cases per million inhabitants per year in the USA and Europe. The projection model indicated that incidence of CTEPH will continue to increase over the next decade (37).

Risks factors a. PAH

The idiopathic form of the disease concerns mostly women of childbearing age. There is an inherited form of PAH. Several gene mutations have been identified; the most common coding for bone morphogenetic protein receptor type II (BMPR2) cause up to 80% of the heritable PAH population (despite an incomplete penetrance about 20%), and 20% of cases of sporadic idiopathic disease [START_REF] Larkin | Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension[END_REF][START_REF] Soubrier | Genetics and genomics of pulmonary arterial hypertension[END_REF]. In comparison, activin receptor-like kinase 1 (ALK1), mothers against decapentaplegic homolog 9 (SMAD9) and endoglin 1 (ENG) concern only 5% of cases of heritable disease (15).

Lupus, scleroderma, cirrhosis, and HIV infection are strongly associated with PAH. Some drugs, methamphetamine and cocaine use increase the risk for developing this disease [START_REF]Pulmonary Arterial Hypertension Symptoms, Causes and Risk Factors[END_REF].

b. CTEPH

Multiple risk factors have been linked to CTEPH, such as prior splenectomy, autoimmune or hematological disorders (e.g., lupus or antiphospholipid syndrome), cancer, ventriculoatrial shunts, chronic inflammatory disorders (such as osteomyelitis and Crohn's disease), thyroid replacement therapy, and non-O blood group [START_REF] Bonderman | Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension[END_REF][START_REF] Jaïs | Splenectomy and chronic thromboembolic pulmonary hypertension[END_REF][START_REF] Bonderman | Risk factors for chronic thromboembolic pulmonary hypertension[END_REF][START_REF] Simonneau | The pathophysiology of chronic thromboembolic pulmonary hypertension[END_REF][START_REF] Blauwet | Surgical pathology of pulmonary thromboendarterectomy: a study of 54 cases from 1990 to 2001[END_REF].

The higher incidence of chronic thromboembolic disease in Japanese patients compared with patients from USA, and the predominance of CTEPH among women, suggest that race, sex, or environmental exposure may play a key role in this condition [START_REF] Jaff | Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association[END_REF].

Pathophysiology

Pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH) share similar physiological outcome, in which remodelling of the pulmonary vascular bed is responsible for the rise in pulmonary vascular resistance (PVR), leading to progressive right ventricular failure and functional decline.

a. PAH

The pathobiology of PAH is complex and incompletely understood. Latest advances have led to a better understanding of the key components underlying this inadequate accumulation of pulmonary vascular cells within the arterial walls leading to vascular remodeling causing a partial occlusion of small pulmonary arteries, and high pulmonary arterial pressure (15).

Among the under lying molecular and cellular mechanisms, some play critical roles in the pathogenesis of the disease [START_REF] Bordenave | Nouveau regard sur la physiopathologie de l'hypertension artérielle pulmonaire[END_REF][START_REF] Hemnes | Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled[END_REF] :

pulmonary endothelial dysfunction, in particular vascular stiffness (by increased wall thickness, smooth muscle cells proliferation and changes in the type and quantity of extracellular matrix proteins ( 49)), and endothelial-to-mesenchymal transition (involved by the formation of neo-intimal vascular lesions in the pulmonary arteries caused by increased proliferation of endothelial cells (EC) and smooth muscle cells (SMC) ( 50)).

alterations of the inter-cell communications within the pulmonary arterial walls,

alteration of the inflammatory component: vascular cells can respond to inflammatory stimuli by enhanced proliferation and migration and reduced apoptosis; responsible for the exaggerated perivascular infiltration of inflammatory cells (B-and T-lymphocytes, mast cells, dendritic cells, macrophages, etc.) [START_REF] Humbert | Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives[END_REF].

loss of BMPR2 (bone morphogenic protein receptor type 2) activity increases apoptosis in vascular cells, leading to vascular remodeling and ultimately PAH (15,[START_REF] Morrell | Cellular and molecular basis of pulmonary arterial hypertension[END_REF] However, there are many other complex and often interacting pathways involved in the development of PAH.

b. CTEPH

The pathophysiology of CTEPH is complex and multifactorial; including pulmonary artery obstruction by non-resolved thrombi, and pulmonary microvasculopathy. But it remains still not completely understood.

The following factors have been related to failure of thrombus resolution, and development of CTEPH: inflammation; genetic factors leading to fibrinolysis resistance; reduced fibrinolytic capacity; increased hypercoagulability; impaired angiogenesis; small vessel disease [START_REF] Yaoita | Thrombin-Activatable Fibrinolysis Inhibitor in Chronic Thromboembolic Pulmonary Hypertension[END_REF][START_REF] Robbins | Update on chronic thromboembolic pulmonary hypertension[END_REF].

Clinical presentation

The cardinal symptom of PH is progressive exercise dyspnea (11); but symptoms of PH remain non-specific: dyspnea upon exertion, fatigue, weakness, chest pain, lightheadedness/syncope with exertion, anorexia and, less frequently, cough. Progressive right-sided heart failure occurs in late stage of disease. Rarely, haemoptysis, hoarseness (unilateral vocal chord paralysis) and arrhythmias may characterise PH [START_REF] Frost | Diagnosis of pulmonary hypertension[END_REF].

Physical examination is often without abnormalities, when PH is compensated. Findings may include loud heart sound (P2 component), murmur of tricuspid regurgitation, and signs of rightsided heart failure as jugular venous distension, hepatojugular reflux, ascites, hepatomegaly and splenomegaly, peripheral oedema [START_REF] Frost | Diagnosis of pulmonary hypertension[END_REF]. In some cases, clinical examination may suggest an underlying cause of PH.

Regarding CTEPH, about 25% of patients have no history of acute pulmonary embolism [START_REF] Pepke-Zaba | Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry[END_REF], and there are no specific symptoms of CTEPH. For this reason, CTEPH diagnosis is often delayed : mean delay from onset of symptoms to diagnosis of CTEPH was 18 ± 26 months [START_REF] Held | Chronic thromboembolic pulmonary hypertension: Time delay from onset of symtoms to diagnosis and clinical condition at diagnosis[END_REF].

Thus, patients may be asymptomatic for several years before presenting progressive dyspnoea on exertion, exercise intolerance, fatigue or depression [START_REF] Held | Chronic thromboembolic pulmonary hypertension: Time delay from onset of symtoms to diagnosis and clinical condition at diagnosis[END_REF] ; then syncope and oedema occurs in late stages of disease progression. [START_REF] Gopalan | Diagnosis of chronic thromboembolic pulmonary hypertension[END_REF].

Diagnosis

In the case of clinical suspicion of pulmonary hypertension, an echocardiography is performed in search of elevation of peak tricuspid regurgitation velocity over PH. If the diagnosis of left heart or lung diseases is confirmed, the appropriate treatment for these illnesses should be considered.

In the contrary case, a V/Q lung scan should be performed for the differential diagnosis between CTEPH and PAH.

b. CTEPH

Even though there is no clear recommendation, a screening by echocardiography could be considered up to 2 years after acute pulmonary embolism [START_REF] Jaff | Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association[END_REF].

CTEPH is defined as symptomatic pulmonary hypertension with persistent pulmonary perfusion defects despite a 3-month anticoagulant therapy [START_REF] Gall | An epidemiological analysis of the burden of chronic thromboembolic pulmonary hypertension in the USA, Europe and Japan[END_REF].

Imaging plays a central role in CTEPH diagnosis: ventilation/perfusion lung scintigraphy (V/Q scan) shows segmental perfusion defects without matching ventilation abnormalities.

Thereafter presence of specific imaging findings on computed tomography pulmonary angiography (CTPA), cardiovascular magnetic resonance imaging (MRI) or conventional pulmonary angiography (CPA) will define the diagnosis of CTEPH [START_REF] Galiè | ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)[END_REF][START_REF] Nishiyama | Chronic pulmonary embolism: diagnosis[END_REF] 9. Treatment a. PAH Treatment includes supportive therapies (as anticoagulants when indicated, diuretics, supplemental oxygen, psychosocial support, genetic counselling, appropriate birth control, supervised physical exercise) (15,[START_REF] Galiè | ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)[END_REF], and disease-targeted drugs, consisting of vasodilators agents (5).

Until 2001, epoprostenol was the only medicaton available to treat PAH, and mainly used as a bridge to transplantation [START_REF] Sitbon | Initial dual oral combination therapy in pulmonary arterial hypertension[END_REF].

The pathogenesis of PAH involves dysfunction of three key pathways: the nitric oxide pathway, the prostacyclin pathway, and the endothelin pathway (59), cf. annex 1.

This three relevant signaling pathways represent therapeutic targets for the medical treatment options [START_REF] Rosenkranz | Pulmonary hypertension: current diagnosis and treatment[END_REF], with several drugs currently approved for the treatment of pulmonary arterial hypertension (61):

the endothelin receptor antagonists ambrisentan, bosentan, and macitentan;

the phosphodiesterase-5 inhibitors sildenafil and tadalafil;

the soluble guanylate cyclase stimulator riociguat;

the prostacyclin analogues beraprost (in Japan and South Korea only), epoprostenol, iloprost and treprostinil;

the prostacyclin receptor agonist selexipag.

Adverse effects occur with all of the specific medication [START_REF] Humbert | Treatment of pulmonary arterial hypertension[END_REF].

Over the past few decades, the development of effective medical drugs and the use of combination therapy to target multiple pathogenic pathways simultaneously have considerably improved the prognosis of patients with PAH [START_REF] Benza | An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry[END_REF], and also improved symptoms, exercise capacity, and quality of life [START_REF] Sitbon | Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study[END_REF].

Whereas previous guidelines recommended initial monotherapy, followed by regular assessments, and initiation of combination therapy when treatment goals were not met (61), the current ESC/ERS guidelines recommend initial combination therapy:

-Newly diagnosed PAH patients with low or intermediate risk receive initial or early combination therapy comprising an endothelin receptor antagonist (ERA) with a phosphodiesterase-5 (PDE5) inhibitor or a soluble guanylate cyclase (sGC) stimulator [START_REF] Galiè | Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension[END_REF][START_REF] Pulido | Macitentan and morbidity and mortality in pulmonary arterial hypertension[END_REF][START_REF] Lajoie | Combination therapy versus monotherapy for pulmonary arterial hypertension: a meta-analysis[END_REF].

-High-risk PAH patients receive a recommended triple treatment with an ERA, a PDE5

inhibitor or an sGC stimulator, and an intravenously administered prostacyclin analog [START_REF] Galiè | ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)[END_REF].

The treatment response and clinical assessment must performed every 3-6 months [START_REF] Galiè | ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)[END_REF]. The treatment strategy depends on the individual response: if the patient has not achieved the primary treatment goal, that is attainment of the low-risk category after the initial treatment, the next step is dual or triple combination therapy (11).

Sitbon and al. showed that initial oral dual combination therapy of an ERA plus a PDE5

inhibitor was associated with significant improvements in functional class, exercise capacity and dyspnea [START_REF] Sitbon | Initial dual oral combination therapy in pulmonary arterial hypertension[END_REF]. Simultaneously, signs of right heart failure and levels of brain natriuretic peptide (BNP) were significantly reduced, suggesting a reduction in clinical worsening. This strategy was also accompanied by significant improvements in 6MWD and haemodynamic parameters, including reductions in pulmonary vascular resistance (PVR) and mPAP.

In patients with severe PAH, the triple combination therapy is a way to improve the long-term benefits [START_REF] Sitbon | Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study[END_REF].

Despite the currently available treatment, many patients remain symptomatic with reduced exercise capacity, quality of life, or develop right heart failure [START_REF] Van De Veerdonk | Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy[END_REF].

Current specific PAH therapy do not specifically target inflammation and pulmonary vascular remodeling, which are likely new targets of the next therapeutic innovation. It requires a better identification of the pathobiological mechanisms underlying, b. CTEPH Surgical pulmonary endarterectomy is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension [START_REF] Galiè | ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)[END_REF]. Among them 50 to 70% are operable [START_REF] Pepke-Zaba | Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry[END_REF]. The perioperative mortality at experienced centres is 2 to 4% [START_REF] Madani | Pulmonary endarterectomy: recent changes in a single institution's experience of more than 2,700 patients[END_REF][START_REF] Cannon | Dynamic Risk Stratification of Patient Long-Term Outcome After Pulmonary Endarterectomy: Results From the United Kingdom National Cohort[END_REF]. Approximately half of the patients had a post-operative mPAP ≤25 mmHg [START_REF] Cannon | Dynamic Risk Stratification of Patient Long-Term Outcome After Pulmonary Endarterectomy: Results From the United Kingdom National Cohort[END_REF]. In around 20% of patients treated surgically, the residual pulmonary hypertension is clinically significant and has to be treated [START_REF] Cannon | Dynamic Risk Stratification of Patient Long-Term Outcome After Pulmonary Endarterectomy: Results From the United Kingdom National Cohort[END_REF].

For patients who are not candidates for surgery, interventional balloon pulmonary-angioplasty is an emerging treatment option to recanalize obliterated pulmonary vessels at subsegmental level [START_REF] Hoeper | Chronic thromboembolic pulmonary hypertension[END_REF].

Riociguat is the only drug approved for patients with inoperable chronic thromboembolic pulmonary hypertension or residual postoperative disease. Other classes of drugs might be used with a lower grade of recommendation. ( 61 31% to 50% develop persistent/recurrent pulmonary hypertension after undergoing PEA [START_REF] Humbert | Risk assessment in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension[END_REF][START_REF] Jenkins | Pulmonary endarterectomy: the potentially curative treatment for patients with chronic thromboembolic pulmonary hypertension[END_REF]. More recently, balloon pulmonary angioplasty (BPA) may be considered in patients who are technically non-operable or carry an unfavourable risk/benefit ratio for PEA [START_REF] Galiè | ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)[END_REF].

However, without surgical intervention survival is poor and proportional to the degree of pulmonary hypertension and right ventricular dysfunction: in 1982, CTEPH patients had an estimated 5-year survival of 30% if mPAP was greater than 40 mmHg, and 10% if mPAP was more than 50 mmHg [START_REF] Riedel | Longterm follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data[END_REF].

With new treatment options, including BPA, the prognosis of non-operated patients with CTEPH improved. Indeed, recent studies estimate a 1-year survival over 90%, a 3-year survival of 85%, [START_REF] Delcroix | Risk assessment in medically treated chronic thromboembolic pulmonary hypertension patients[END_REF][START_REF] Taniguchi | Predictors of survival in patients with not-operated chronic thromboembolic pulmonary hypertension[END_REF], and a 5-year survival around 60% [START_REF] Delcroix | Risk assessment in medically treated chronic thromboembolic pulmonary hypertension patients[END_REF].

In these patients, baseline NYHA FC, RAP, 6MWD, BPA therapy and diagnosis period (2006-2012 vs 2013-2016) were predictors of survival [START_REF] Taniguchi | Predictors of survival in patients with not-operated chronic thromboembolic pulmonary hypertension[END_REF].

There is currently no established risk assessment strategy to guide treatment decisions in patients with CTEPH. However, a recent study suggested that that an abbreviated version of the ERS/ESC risk stratification may be applicable (with the method from Kylhammar et al.) to predict mortality in non-operated and medically treated CTEPH patients [START_REF] Delcroix | Risk assessment in medically treated chronic thromboembolic pulmonary hypertension patients[END_REF]. In a similar way as PAH mortality risk, variables closely linked to the mortality risk were 6MWD, WHO FC, BNP/NT-proBNP.

Exercise training and pulmonary hypertension a. Exercise training and rehabilitation

Chronic cardiorespiratory disorders as PAH lead to physical inactivity, skeletal muscle dysfunction and compromised quality of life (4). In addition, patients with PAH were advised, for decades, to avoid physical exercise which has been thought to carry a high risk of sudden cardiac death and exacerbate right heart failure. Indeed, it was commonly believed that physical activity may have a negative impact on patients by increasing pulmonary remodeling and contributing to the progression of PH (1). In PH population reduced exercise capacity is associated with depression and anxiety disorders (3).

In the guidelines of 2009, because of a lack of efficacy data, rehabilitation was considered only in special circumstances, such as in deconditioned PAH patients, in a highly supervised setting with avoidance of distressing and excessive physical activity (2).

However, there is some evidence from left heart failure that regular physical activity improve endothelial function, exercise capacity, and quality-of-life parameters, and may be beneficial even in severe disease [START_REF] Hambrecht | Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure[END_REF]. Physical training reduce vascular oxidative stress and exert beneficial vascular effects in part by increasing activity of endothelial nitric oxide synthase [START_REF] Kojda | Dysfunctional regulation of endothelial nitric oxide synthase (eNOS) expression in response to exercise in mice lacking one eNOS gene[END_REF].

Since then, additional studies have been performed that provided evidence of improvements of symptoms and exercise performance with reassuring data on safety (6,7). However, it must be emphasised that the patients in these studies were all in a stable condition on advanced drug therapy, under close supervision in PAH expert centres and the training was specially designed for PAH patients.

In the updated guidelines of 2015 ( 26 In PAH patients, skeletal muscle dysfunction has been reported with muscle atrophy, reduced capillary density, decreased oxidative enzyme activity, reduced exercise capacity and muscle strength, fewer type IIa fibres. In few studies, exercise training significantly improve these alterations in muscle tissue and muscle function (8,[START_REF] Mainguy | Effects of a Rehabilitation Program on Skeletal Muscle Function in Idiopathic Pulmonary Arterial Hypertension[END_REF][START_REF] Keusch | Rehabilitation in patients with pulmonary arterial hypertension[END_REF].

Exercise training also improves lung performance with better pulmonary perfusion, oxygen uptake and inhibition of smooth muscle cells [START_REF] Keusch | Rehabilitation in patients with pulmonary arterial hypertension[END_REF]. In addition, it decreases insulin resistance that have been reported more prevalent in PAH population [START_REF] Hansmann | Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferatoractivated receptor-gamma activation[END_REF].

A recent study showed that aerobic exercise promotes a significant increase in H2O2/VEGF/p-Akt signal for pulmonary physiological angiogenesis [START_REF] Colombo | Exercise training contributes to H2O2/VEGF signaling in the lung of rats with monocrotalineinduced pulmonary hypertension[END_REF].

In

d. Evidence and effects of rehabilitation in pulmonary hypertension patients

In healthy people and chronically ill patients, a higher daily physical activity lead to a better survival than less active controls [START_REF] Ruiter | Iron deficiency is common in idiopathic pulmonary arterial hypertension[END_REF][START_REF] Van Empel | Iron deficiency in patients with idiopathic pulmonary arterial hypertension[END_REF].

Previous studies in rather small cohorts of patients with idiopathic pulmonary arterial hypertension (IPAH) and inoperable chronic thromboembolic pulmonary hypertension

e. Safety and adverse events

The rapid deterioration of right ventricle function leading to hemodynamic impairment, the occurrence of arrhythmias and syncope have been considered as the major risks of an exercise programme in patients with severe PAH (103,104).

Side effects in specialist centres under expert supervision were relatively rare. Actually, no study has reported an increased incidence of major adverse events in PAH patients undergoing a monitored and personalised exercise training (105)

Of the 6 RCTs analyzed by Morris et al., one study reported a single adverse event, where a participant stopped exercise training due to lightheadedness (101). In one of the largest studies (183 patients), a total of 13.6% of their participants had adverse events. Almost half of these patients suffered acute respiratory infections that had to be treated with antibiotics and forced the transitory suspension of the training programme. Severe adverse events, such as syncope/pre-syncope or supra-ventricular arrhythmias, occurred only in 4.4% of the patients.

No signs of clinical worsening of right heart failure were detected during their hospitalisation, and no severe adverse episodes occurred when the patients continued the exercise training at home (between hospital discharge and the planned follow-up, 15 weeks later) (7). The metaanalysis including 16 prospective intervention studies with 469 PH patients, reported dizziness, presyncope, palpitation, hypotension and oxygen desaturation in 4,7% of training patients (onethird were not related to exercice). No major adverse events, such as progression of symptoms, right heart failure, or death, were observed among the patients during the training period. On median follow-up of 29.5 months (21-36 months), the survival rate was 91%, and the transplant-free survival rate was 89%. [START_REF] Pandey | Efficacy and Safety of Exercise Training in Chronic Pulmonary Hypertension: Systematic Review and Meta-Analysis[END_REF] PH patients are often not aware of their own physical limits and may tend to overexercise. They have to be supervised and taught to recognise their physical limits, to prevent dangerous adverse effects of exercise. To minimize the risk, some safety precautions must be adopted when starting an exercice training programme. In the previous studies, it is required that PH patients are in clinically stable condition on optimised PH targeted therapy for at least 2 months [START_REF] Marra | Principles of Rehabilitation and Reactivation: Pulmonary Hypertension[END_REF].

Training should be initiated with very low workloads (between 40 and 80% of peak exercise capacity), as well, dumbbell training must be practiced with low weights involving single muscle groups only. Oxygen saturation and heart rate have to be closely monitored (SpO2 >85%, HR <120 per minute). Especially for severe patients, it is recommended to start the rehabilitation programme in an inpatient setting, where both supervision during training and observation just after is possible [START_REF] Keusch | Rehabilitation in patients with pulmonary arterial hypertension[END_REF].

f. Other components of rehabilitation

Patients with PH have to face many life stress factors, such as physical limitation, contraindications to have a pregnancy, high cost of treatment, unemployment, etc. Mental disorders (such as anxiety and depression) are more prevalent in this population, and closely related to the functional disability: the percentages of major depression higher in WHO FC IV patients (45%) than for the WHO FC I (7.7%) (3). That is why, goals of PH treatment should include quality of life as a major targets to reach (106), and many studies have pointed out that the rehabilitation programme, in addition to medical therapy, may improve depression and anxiety symptoms in patients with PH (5,105,(107)(108)(109)(110).

Rehabilitation is a global approach that not only consists of exercise training, but also includes a multidisciplinary team (including cardiology and respiratory medicine physicians, specialised nurses, radiologists, access to psychological and social work support), which provides informations, counselling and therapeutic interventions, during individual or small groups. It is a way to improve physical and emotional status. Moreover, during theirs stays patients may benefit from specific PH-drug titration: side effects are not uncommon, and could limit an increase in the dose if the titration is feared or not well tolerated by outpatients. A progressive titration when appropriate with management of side effects is a way to achieve optimal medical therapy.

Conclusions

Supervised rehabilitation in PH patients should be recommended, in addition to optimal medical treatment with PH targeted drugs, if performed in a highly experienced team under expert supervision. The pathomechanisms are not fully understood yet, but many studies agree in the favorable effects of training programme: it leads to significant improvements in symptoms, exercise capacity and quality of life.

This programme should be implemented by centres experienced in both PH patient care and rehabilitation. Some safety precautions must be adopted in order to avoid adverse events: among other things, patients have to be in stable condition on optimised medical therapy, and closely monitored during the exercise training. Despite the few studies so far, there is no published guidelines available detailing how exercise rehabilitation should be carried out. . And yet, reduced exercise capacity in PH is common and associated with anxiety disorders, depression, skeletal muscle dysfunction and compromised quality of life (3,4).

Introduction

Since then, more studies in rather small cohorts of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) have shown beneficial effects of ET as add-on to medical therapy by improving symptoms, exercise capacity and quality of life, with reassuring data on safety (5)(6)(7)(8). However, it must be emphasised that the patients in these studies were all in a stable condition on optimised PAH-targeted drug therapy (such as endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, prostacyclin analogues, calcium-channel blockers, and guanylate cyclase stimulators) for at least 2 or 3 months, under close supervision in highly specialised PAH expert centres, and the training was specially designed for PAH patients.

In the updated guidelines of 2015 ( 9 (PASP) were estimated from tricuspid regurgitation velocity. Furthermore, the right heart catheterization (RHC) before and after rehabilitation, when available, were analyzed.

Rehabilitation programme

Patients were supervised either in a day hospital, or in a classical hospitalisation stay, by an expert care team composed of cardiologist physicians, nurses, pharmacists, dietician, physiotherapists, psychologist, social worker.

It is important to consider potential limiting factors (orthopedic or rheumatologic limitation, sequelae of stroke...) requiring a programme adaptation. Exercise testing are performed (cardiac stress test, cardiopulmonary exercise testing, or 6-minute walk) to establish the training programme at the beginning.

During rehabilitation, PH-specific drug therapy could not be introduced, but doses could be adapted.

The exercise training programme consists of :

- o treadmill walking, if the patient was not able to practice bicycle ergometer training (most often for rheumatological problems). The first session lasted 10 to 20 minutes with a speed of 2 km/h with 0% incline, then duration, speed and incline were increased progressively.

-Respiratory therapy, including breathing techniques, Yoga, and strengthening of respiratory muscles; during 30 minutes twice a day 5 days a week, -Some patients practice dumbbell training of single muscle groups (8 to 10 moves, 10 times with low weights: 500gr to 1 kg) in order to improve muscle mass and stamina.

-Outside supervised walk, 30 minutes daily, 5 days a week.

Heart rate, oxygen saturation and rating of perceived exertion were monitored during bicycle ergometer training or treadmill. Patients with or without oxygen therapy at baseline who had oxygen desaturation less than 90% during exercise, received a higher oxygen flow or had oxygen therapy introduction. When patients' heart rate reaches more than 120 beats per minute, or oxygen saturation fell to <85%, training was reduced. The perceived exertion should not excess 4 from the Borg rating of perceived exertion CR10 scale (somewhat hard exertion),

otherwise training was reduced or stopped. The subjective evaluation and experience of the care team also matters. As a consequence, physicians and physiotherapists could adapt the programme to each individual case.

It is important for PH patient to avoid hard exertion, and carrying of heavy loads. The team must be very careful about history of syncope or other cardiac symptoms (palpitations, chest pain, dizziness, lightheadedness...). If it is, a watchful supervision is needed.

Risk assessment and outcomes

To facilitate treatment decision for patients with PAH, the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) for the diagnosis and treatment of pulmonary hypertension (9) proposed a dynamic risk stratification strategy (cf annex 1) and recommend regular risk assessment at expert PH centres using clinical, echocardiographic, exercise, biochemical, and hemodynamic parameters.

These risk stratification groups are applicable at the time of diagnosis, and during follow-up for prognostication. Patients can be categorized as low-, intermediate-, or high-risk, with an estimated 1-year mortality of <5%, 5-10%, and >10%, respectively. The goal of PAH treatment is achieving and maintaining a low-risk profile. Studies showed that this risk assessment accurately predicted the risk of death or lung transplantation in newly diagnosis-PAH patients at the time of diagnosis and during the follow-up. The number of low-risk criteria achieved during the first year of follow-up is also associated with better prognosis than the number of low-risk criteria present at baseline (11). Some studies suggest that the ESC/ERS risk assessment may be applicable in patients with medically treated CTEPH (12,13).

However, most of the variables used in risk assessment are based on expert opinion with low levels of evidence, therefore more studies are needed to check the accuracy of this risk assessment during the follow-up. Moreover, the effect of exercise training on risk assessment is has not yet been fully established. Adverse events were recorded during the study period. Transplant-free survival time was calculated from the beginning of rehabilitation to the date of last follow-up, death or lung transplantation, for survival analyses. In patients who died, we provided the most likely cause of death, without independent adjudication.

Statistics

Statistical analyses were performed using Excel and Medistica.pvalue.io. The difference of the mean grade at baseline and at follow-up was calculated. Survival was analyzed using Kaplan-Meier method and log-rank test. Survival was compared between the different risk groups as assessed at follow-up. P<0.05 was considered statistically significant. Continuous data are presented as mean +/-standard deviation.

Results

Between o Concerning the treadmill programme, the speed ranged between 0,8 to 5,5 km/h (average speed: 3,3 km/h) with 0% to 14% incline (average incline when applicable: 6,4%). The mean numbers of sessions per patient was 12,2.

-Patients pursued respiratory group therapy (during 30 minutes twice a day 5 days a week), and most of them went for the outside supervised walk (30 minutes daily 5 days a week, weather permitting). 15 patients practiced dumbbell training of single muscle groups with low weights. The weights ranged between 0,5 to 5,5 kg for upper limb (if we do not consider the higher value, the mean weight was 1,25 kg), and between 0,5 to 13 kg for lower limb (if we do not consider the higher value, the mean weight was 1,45 kg). The mean numbers of sessions per patient was 8,9.

-Among patients in rehabilitation, 6 patients were not in condition to perform endurance exercice training because of a severe exercise intolerance: In these 6 patients, 4 pursued respiratory group therapy; among them 1 practiced dumbbell training, and 2 were able to have an individual supervised walk.

-No patients had PH-specific therapy introduction during the rehabilitation, but 12 patients had specific-drug titration and among them 2 had balloon pulmonary angioplasty. 8 PAH-patients was under continuous intravenous prostacyclin during their stays. Diuretics was also adjusted: during the rehabilitation, diuretics were stopped for 4 patients, the dose were decreased for 9 patients, and increased for 4 patients, finally 2 patients had introduction of diuretics. So, the mean dose of furosemide was lowered from 96,02 to 89,3 mg per day.

-At baseline, 29,3% of patients were in the "low risk", 68,3% in the "intermediate risk", and 2,4% in the "high risk" group. After rehabilitation, 51,2% of patients were in the "low risk", 46,3% in the "intermediate risk", and 2,4% in the "high risk" group. -Even for the 6 patients who did not benefit from endurance training, the mean risk assessment grade improved from 2,29 at baseline to 2,10 at follow-up. However, this difference of -0,19 points is not statistically significative (95% CI, -0,63 to 0,25).

-Adverse events occurred in 21,9 % of the patients: sepsis that had to be treated with antibiotics (n=3) (including 2 acute respiratory infections), digestive disorders (n=2) due to adverse effects of PAH specific therapy titration, desaturation during exercise training (n=2). Other events were minor as palpitations (n=1), dizziness (n=1). Among these adverse events, the majority was not linked with physical activity. In our study, a total of 21,9% of participants suffered adverse events, the majority of which was not linked with physical activity. No major adverse events such as progression of right heart failure or death, were reported. In one of the largest studies from the highly expert centre of Heidelberg (183 patients), a total of 13,6% of their participants had adverse events (7). A metaanalysis including 16 prospective intervention studies, reported adverse events in 11,3% of participants (6,6% infections, plus 4,7% minor side effects such as dizziness, presyncope, syncope, palpitations, hypotension, or oxygen desaturation) (16). From these experiences, lowdose exercise and respiratory training programme under expert supervision with oxygenotherapy (when needed), is relatively safe, with no major adverse events.

In our study, the expert PH centre defined the treatment then rehabilitation centre could adapt the doses. No patients had specific-therapy introduction during the rehabilitation, but 21 patients had had a therapeutic titration during the month prior to rehabilitation, and 12 patients had specific PH-drug titration during their stay, nevertheless we had no major adverse event.

Therefore the selection of PH patients is crucial to guaranty the safety of the rehabilitation, but patients do not have to be in clinically stable condition on optimised PH targeted therapy for at least 2 months (as can be seen from rehabilitation studies). Exercise training is a beneficial therapy with a good safety profile when closely supervised, in participants who were assessed in a PH expert centre before beginning the rehabilitation. After a median observational follow-up of 33 months (IQR 10,5-60,0), 31 (75%) patients had no clinical event, which was defined as first occurrence of any of the following event: death or heart-lung transplantation. 8 patients died, and 2 had a transplantation. Causes of death were right heart failure (n=1), sudden death (n=2), severe hypoxemia (n=2), cancer (n=2) and unknown (n=1). It is interesting to note, patients who remained or reached a "low risk" profile after rehabilitation, have a better prognosis (p<0,01). Therefore, changes in the risk category, seem to be an accurate predictor of long-term survival.

In our study, the survival rate was 80,5%, after a median follow-up of 33,0 months (IQR 10,5-60,0). It is similar to large cohorts of newly diagnosed patients:

-The cohort from Boucly et al. in 2017, 1017 PAH patients were enrolled from the French registry (mean age 57 years, 59% female, 75% idiopathic PAH). After a median followup of 34 months, 238 (23%) patients had died (11).

-The cohort from Delcroix et al. in 2017, 561 newly diagnosed inoperable CTEPH patients from COMPERA registry. Overall survival estimates of 75% at 3 years (13) -A meta-analysis of 16 prospective intervention studies with a median follow-up of 29,5 months (range, 21-36 months), the proportion of participants alive was 91% (12 deaths), and the proportion of participants with transplant-free survival was 89% (16).

Our study has limitations requiring cautious interpretation of our findings. Indeed, the present study was a retrospective trial (without placebo-controlled, nor double-blind design), and limited by the small number of patients, and by the population heterogeneity of group 1 (including those with IPAH, heritable PAH, anorexigen-induced PAH, congenital heart disease, and portopulmonary hypertension) and group 4 PH patients (including postoperative patients (PEA or BPA) and inoperable patients). Patients belonged to group 1 or 4 PH, therefore, the benefits of exercise training observed may not be applicable to patients with other classes of pulmonary hypertension. Due to retrospective trial design, it is subject to missing values, in particular in patients who had no haemodynamic reassessment or were not followed by our PH expert centre. Finally, it may me mentioned that, in the early 2010's, the use of combination therapy in patients with PAH was less developed due to the lack of evidence; this way the prognosis of early enrolled patients may be more pejorative.

Germany have 39 PH expert centres, but only one PH rehabilitation centre in Heidelberg (20).

Most published studies were conducted in this highly specialised rehabilitation centre under close expert supervision (5,21) With our study, we wanted to evaluate the feasibility, beneficial effects and safety of the rehabilitation of patients with PAH or CTEPH, with one of the largest cohort in France, and by this way we want to promote the development of PH reeducation in France.

Exercise training should not be initiated in a non-supervised and not adequately monitored setting. From our data, we can formulate and suggest different components of the rehabilitation programme in patients with PAH or CTEPH: the supportive therapy is started when needed, and patients must be referred to specialised PH expert centres to confirm the diagnosis. After that, the expert centre must evaluate clinical status of patients, and also determine the PHtargeted strategy with or without rehabilitation. The treatment must be introduced before But despite all of this, a standardised programme not flexible is not realistic, because programme have to be constantly adapted by the care team for each patient. To this end, it is essential to have a daily cooperation between physicians and physical therapists (or other professionals) to ensure safety in rehabilitation. Résultats : 41 patients ont été inclus (âge moyen, 59,6 +/-18,1 ans). La réadaptation a permis une amélioration du score de risque (différence moyenne, -0,25, 95% CI, -0,45 to -0,07), de la classe fonctionnelle NYHA et de paramètres hémodynamiques tels que la PAPm (-6,3 mmHg, 95% CI, -2,3 to -0,3) et la pression auriculaire droite. La distance parcourue au test de marche de 6 minutes progresse au-delà de différence minimale pertinente (33 m), mais n'est pas statistiquement significative (53,1 m, 95% CI, -17,7 to 123,9). 21,9% des participants ont souffert d'effets indésirables non majeurs, dont la majorité n'est pas liée à l'exercice physique. Methods : All consecutive patients with PAH or CTEPH admitted in a French rehabilitation centre between March 2010 and May 2019 were evaluated retrospectively on functional, biological parameters, and haemodynamics. We also apply a recently validated abbreviated versions of the ESC/ERS pulmonary hypertension risk stratification.

Results : 41 patients were included (mean age 59,6 +/-18,1 years-old). The rehabilitation programme improved the risk assessment grade (-0,25 point, 95% CI, -0,45 to -0,07), the NYHA functional class and haemodynamic parameters including mPAP (-6,3 mmHg, 95% CI, -12,3 to -0,3) and right atrial pressure. The 6-minute walk distance improvement exceeded by far the minimal important difference of 33 m, but was not statistically significative (53,1 m, 95% CI, -17,7 to 123,9). 21,9% of participants suffered adverse events, the majority of which was not linked with physical activity, and no major adverse events (progression of right heart failure or death) were reported.

Conclusion : Among patients with PAH or CTEPH, the rehabilitation programme, in a supervised setting, as add-on to medical therapy is relatively safe and effective to improve functional capacity, hemodynamic parameters, and risk assessment grade.

KEYWORDS: Physical exercise, Pulmonary hypertension, Pulmonary arterial hypertension, Chronic thromboembolic pulmonary hypertension, Rehabilitation programme SECTION: Cardiology

1 . 2 . 3 . 4 .

 1234 INTRODUCTION ................................................................................................................................ DEFINITION OF PULMONARY HYPERTENSION ........................................................................ DIFFERENT GROUPS OF PULMONARY HYPERTENSION ........................................................ EPIDEMIOLOGIC DATA...................................................................................................................

  ), specialised PAH rehabilitation is recommended for patients in stable clinical condition with the best standard of pharmacological treatment, with the notion that supervised rehabilitation should be implemented by centres experienced in both PAH patient care and rehabilitation of compromised patients (class IIa recommendation, evidence level B). Optimised pharmacological treatment is defined as single or combination therapy with PAH-targeted drug therapy such as calcium-channel blockers, prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and guanylate cyclase stimulator. The guidelines also clearly suggest that such an expert centre should consist of a multidisciplinary team including cardiology and respiratory medicine physicians, clinical nurse specialist, radiologists, psychological and social work support. Furthermore, it is recommended for expert referral centres to have a direct link to adult congenital heart disease units, pulmonary endarterectomy surgeons and a lung transplantation programme. Expert referral centres are requested to follow at least 50 patients with PAH or chronic thromboembolic pulmonary hypertension (CTEPH), and should have two new referrals per months.b. Mechanisms of exercise training in PAH patientsThe exact pathophysiological mechanisms by which exercise leads to beneficial effects are not yet fully understood.In mice, exercise training was able to prevent hypoxia-induced pulmonary vascular remodeling, and improved exercise capacity and pulmonary haemodynamics[START_REF] Weissmann | Structural and functional prevention of hypoxia-induced pulmonary hypertension by individualized exercise training in mice[END_REF]. The effect of exercise training on physical capacity was more important in mice who received drug treatment (sildenafil). The effects were not associated with changes in the expression of the nitric oxide, phosphodiesterase 5, or soluble guanylate cyclase pattern, which belongs to targeted pathways for PAH therapy. These results suggest that exercise training might be complementary to pharmacological treatment, affecting molecular pathways not yet identified.In other rat and mice experiments, it has been shown an attenuation of acute vasoconstriction in response to hypoxia, a reduction in right ventricular pressure and pulmonary artery diameter, and a better right ventricle capillary density[START_REF] Colombo | Effects of exercise on monocrotaline-induced changes in right heart function and pulmonary artery remodeling in rats[END_REF][START_REF] Favret | Exercise training improves lung gas exchange and attenuates acute hypoxic pulmonary hypertension but does not prevent pulmonary hypertension of prolonged hypoxia[END_REF] In patients with chronic heart failure and PAH, exercise training has been shown to reduce inflammation and TNF-level, which is involved in the development of PAH[START_REF] Huber | The pathogenesis of pulmonary hypertensionan update[END_REF][START_REF] Gielen | Anti-inflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure[END_REF][START_REF] Harbaum | Acute effects of exercise on the inflammatory state in patients with idiopathic pulmonary arterial hypertension[END_REF].

  summary, exercise training impacts angiogenesis, muscular strengh, right ventricle contractility, ventilatory efficiency, hormonal, and immune system, and may improve symptoms, exercise capacity, quality of life and hemodynamics. c. Different components of the rehabilitation programme with pulmonary arteriel hypertension (PAH) Since 2006, several published studies conducted rehabilitation in PAH patients with different training protocols, but there is no consensus on how to train PH patients. Most published studies were conducted in the PAH centre of Heidelberg in Germany (5,98): they established a training programme, which started as a 3-week inpatient training followed by a home-based training with individualised instructions and supervised by the respective expert centre. Before the rehabilitation and right after, patients are evaluated in the PAH centre and were stable and compensated under optimized medical therapy (such as endothelin antagonists, iloprost, sildenafil, calcium channel blockers, anticoagulants, diuretics, and supplemental oxygen) for at least 2-3 months before entering the study. The initial exercise training intensity was also assessed. During the following 3 weeks of in-hospital rehabilitation, the physicians for rehabilitation stay in contact with the PAH experts. The training consists of interval bicycle ergometer training with a lower workload (0 to 10W) for 30 seconds and a higher workload for 1 minute (20 to 35W) for 10 to 25 minutes per day in a supervised and monitored setting. The training intensity was increased (eg, up to 35 to 50 W) with respect to the individual tolerability and improvement. Training intensity was limited by peak heart rate (HR) (not more than 120 bpm), oxygen saturation (not less than 85%), and subjective physical exertion. If needed training was reduced. Furthermore, 60 minutes of walking, 30 minutes of dumbbell training of single muscle groups with low weights (500 to 1000 g) and 30 minutes of respiratory training were performed 5 days a week. Patients was also educated in perceiving their physical limits, and all patients were advised to avoid heavy exercise. Other centres have also used treadmill walking for 30 to 45 minutes under similarly intensive supervision (99). And thus, most published studies used aerobic exercise training with low workload (intensity titrated between 40 to 80% of peak exercise capacity or about 60-80% of the HR achieved during a baseline exercise test) (95) under close supervision by PAH experts, in patients who were clinically stable and treated with optimized PAH drug therapy without signs of overt right heart failure.

  Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are subtypes of pre-capillary pulmonary hypertension (PH). In these conditions, remodeling of the pulmonary vascular bed with an obliterative vasculopathy is responsible for the rise in pulmonary arterial pressure and pulmonary vascular resistance (PVR), and without treatment ultimately leads to right ventricular failure and death. Despite advances in drug therapy with improvements in the short-term survival of patients with PAH, the condition remains incurable. But the recent development of effective medical therapies and the use of combination therapy have considerably improved the prognosis of patients, but also functional capacity and haemodynamics. By contrast, CTEPH is potentially curable by surgery (pulmonary endarterectomy), or interventional balloon pulmonary angioplasty when indicated. For decades, exercise training has not been recommended for patients with pulmonary arterial hypertension (PAH) due to the fear of a possible risk of sudden cardiac death, arising from worsening hemodynamics and deterioration in right heart function during exercise. It was commonly believed that physical training may contribute negatively to the evolution and progression of PH (1). Because of a lack of efficacy data, supervised exercise rehabilitation was first recommended from 2009 ESC/ERS pulmonary hypertension Guidelines but only in deconditioned PAH patients in a highly supervised setting with avoidance of excessive physical activity (exercise training (ET) remained in class IIa recommendation with a level of evidence B) (2)

  ), supervised PAH rehabilitation is recommended for stable patients with the best standard of pharmacological treatment and in stable clinical condition and should be implemented by centres experienced in both PAH patient care and rehabilitation of patients (class IIa recommendation, evidence level B). However, there is no published guidelines available detailing how exercise rehabilitation should be carried out. Therefore, this recommendation is limited by the gaps in the knowledge about the optimal method of rehabilitation, programme duration, and intensity of the exercise training.Patients are often unaware of their own physical limits and, especially for PH patients, it is essential to supervise exercise training when needed during the follow-up and to avoid overexercise to prevent adverse effects of exercise. Also, rehabilitation not only consists of exercise training, but also includes a multidisciplinary team (including cardiology and respiratory medicine physicians, specialised nurses, radiologists, access to psychological and social work support), which provides informations, counselling and therapeutic interventions. To facilitate treatment decision for patients with PAH, the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) for the diagnosis and treatment of pulmonary hypertension (9) and the 2018 Proceedings of the 6th World Symposium on Pulmonary Hypertension (10) proposed a dynamic risk stratification strategy, and recommend regular risk assessment at expert PH centres using clinical, echocardiographic, exercise, biochemical, and hemodynamic parameters. However, the effect of exercise training on risk assessment is has not yet been fully established. We apply the risk assessment criteria from the 2015 ESC/ERS guidelines to a retrospective cohort of patients with PAH or CTEPH who practice rehabilitation with exercise training programme.The study aimed to evaluate the feasibility of the rehabilitation of patients with PAH or CTEPH, in real life like practiced in a French centre, and to assess the evolution of the risk stratification of these patients. Finally, we evaluate the safety and beneficial effects of cardiac rehabilitation and exercise training in patients; and if data are encouraging, we want to promote the development of PH reeducation in France and identify which patients would benefit from rehabilitation.

  Endurance training: o low-intensity bicycle ergometer training (e.g 5 to 50 watts) in a supervised and monitored setting; up to 30 minutes once or twice a day, 5 days a week. The training intensity was increased with respect of the individual tolerability and improvement. The first session lasted 10 to 25 minutes, with an initial intensity which corresponds to 50% of the maximum load reached in the initial effort test,with or without interval training (a lower workload for 30 seconds and a higher workload for 1 minute (eg, 20 to 35 W)). The sessions' length was increased progressively to 30 minutes. The workload was also raised progressively (+5W), according to patient's exercise tolerance and pulse rate (target heart rate corresponding to 60% to 80% of the maximum heart rate).

Following a strategy proposed

  by KYLHAMMAR et al., an abbreviated version of the 2015 ESC/ERS pulmonary risk stratification strategy was performed : we collect 8 variables recommended for PAH risk stratification in the 2015 ESC/ERS treatment guidelines (WHO functional class, 6MWD, NT-pro BNP, right atrial (RA) area, pericardial effusion, cardiac index, RAP, SvO2) (14). The cut-off values proposed in the guidelines were graded from 1 to 3 (1: low risk, 2: intermediate risk and 3: high risk). If a 6-min walking test (6MWT) was registered as non-achievable due to clinical condition, it was assigned a grade of 3. The sum of all grades was divided by the number of available variables, which gave a mean grade for each patient. Then it was rounded to the nearest integer, which was used to define the patient's risk group from 1 to 3 where 1= 'Low risk', 2= 'Intermediate risk', and 3= 'High risk'. Risk stratification were made from baseline assessments and from follow-up assessments, which allows to analyze the evolution of the risk assessment.

o 1

 1 patient presented tachycardia by atrial fibrillation with clinical signs of global heart failure (55-year-old PAH patient). o 2 patients presented recent signs of severe left heart failure, which required oxygen therapy (61-year-old PAH patient and 77-year-old CTEPH patient).o 2 patients did not totally recovery from recent interventions with complications (15 days after pulmonary endarterectomy with postoperative pneumopathy, and 5 days after balloon pulmonary angioplasty lung with reperfusion edema with clinical signs of heart failure which required oxygen therapy) (71-year-old CTEPH patient, and 83-year-old CTEPH patient).o 1 patient suffered from worsening of the general state as the disease progresses over 8 years, despite multiple treatment attempts (therapeutic failure in a 85year-old patient).

Figure 4 :

 4 Figure 4: Survival (alive free from heart-lung transplantation) (A) : survival in the study population (B) : survival based on follow-up risk group (p<0,01)

  . They established a 3-week inpatient training programme followed by a home-based training. During the in-hospital rehabilitation, the physicians stay in daily contact with the PH experts. Patients received optimized PH-targeted medical treatment over at least 2 months before starting the programme in order to provide a good safety profile, and medication remained unchanged during the study period. In comparison, France have fewer PH centre (24 in metropolitan France and 2 in french overseas departments) (cf Annex 2) (22), and throughout the country, practices are disparate in term of rehabilitation programme among patients with PH.

  entering the rehabilitation programme. Exercise trainings should be implemented by rehabilitation centres experienced in frail patients reeducation (e.g. patients with severe heart failure), and which are working in close collaboration with PH expert care centre. For safety reasons, exercise training could be started in an in-hospital setting, especially if patients are vulnerable (e.g. elderly people, patients with sign of right heart failure, low exercise capacity, WHO FC IV, comorbidities, high dose of diuretics or oxygen therapy). If the safety process is respected, participants no need to be all in a stable condition on optimised PAH-targeted drug therapy. At first, the rehabilitation centre determines initial exercise training intensity, and counsel patients and trainers. The physical approach consists of low-intensity training in a close supervised and monitored setting, low-dose dumbbell training, and respiratory therapy. Patients need to be trained how to perceive their own physical limits and to perform exercise training at home in a safe way.

  The reeducation not only consists of exercise and respiratory training; in fact the multidisciplinary approach allows to offer therapeutic education, information, supervised exercise training, psychological, and nutritional support if needed, and social service. PH patients have to face various difficulties and stress factors in everyday life, such as physical disabilities, contraindications to have a pregnancy, high cost of treatment, and unemployment.Many studies highlighted that the rehabilitation program could serve as an adjuvant to manage depression and anxiety in this patients[START_REF] Vecchia | Exercise training in pulmonary arterial hypertension[END_REF] LAREADAPTATION CARDIAQUE DANS LA PRISE EN CHARGE DE L'HYPERTENSION ARTERIELLE PULMONAIRE ET DE L'HYPERTENSION PULMONAIRE THROMBOEMBOLIQUE CHRONIQUE : RÉSULTATS DE L'EXPÉRIENCE GRENOBLOISE RESUME Introduction : Alors que l'activité physique a longtemps été déconseillée chez les patients atteints d'une hypertension pulmonaire, des études récentes ont montré que la réadaptation en centre expert pouvait avoir un rôle bénéfique dans la prise la prise en charge de l'hypertension artérielle pulmonaire (HTAP), et l'hypertension pulmonaire thromboembolique chronique (HTP-TEC). Méthodes : Tous les patients porteurs d'HTAP ou HTP-TEC, admis en rééducation cardiaque entre mars 2010 et mai 2019, ont été évalués de façon rétrospective sur des paramètres fonctionnels, biologiques, et hémodynamiques. Une version abrégée récemment validée de la stratification du risque a été appliquée.

  Conclusion : Chez les patients atteints d'HTAP ou HTP-TEC, la réadaptation pratiquée en milieu supervisé, associée au traitement médical spécifique, permet une amélioration des capacités fonctionnelles, des paramètres hémodynamiques et du pronostic estimé, sans complication majeure. MOTS-CLES : exercice physique, hypertension pulmonaire, hypertension artérielle pulmonaire, hypertension pulmonaire thromboembolique chronique, réadaptation cardiaque FILIÈRE : Cardiologie et Maladies Vasculaires REHABILITATION IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION AND CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION : RESULTS FROM THE GRENOBLE EXPERIENCE ABSTRACT Introduction : For decades, patients with pulmonary hypertension (PH) were advised to avoid exercise in fear of deterioration in right heart function. Since then, recent studies have reported that rehabilitation programme in expert centres may have a specific role in the management of pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH).

  Chaque moment partagé ensemble est un bonheur de plus. Tu m'as déjà tellement apporté, pourtant je me dis que le meilleur est à venir. Je t'aime, tout simplement. « Privé de nourriture, tu t'imagines bien qu'au troisième jour de marche… mon coeur, ça n'allait plus très fort… Eh bien ! le long d'une pente verticale, sur laquelle je progressais, suspendu au-dessus du vide, creusant des trous pour loger mes poings, voilà que mon coeur tombe en panne. Ça hésite, ça repart. Ça bat de travers. Je sens que s'il hésite une seconde de trop, je lâche. Je ne bouge plus et j'écoute en moi. Jamais, tu m'entends ? Jamais en avion je ne me suis senti accroché d'aussi près à mon moteur, que je ne me suis senti, pendant ces quelques minutes-là, suspendu à mon coeur. Je lui disais : Allons, un effort ! Tâche de battre encore… Mais c'était un coeur de bonne qualité ! Il hésitait, puis repartait toujours… Si tu savais combien j'étais fier de ce coeur ! » Dans la chambre de Mendoza où je te veillais, tu t'endormais enfin d'un sommeil essoufflé. Et je pensais : « Si on lui parlait de son courage, Guillaumet hausserait les épaules. Mais on le trahirait aussi en célébrant sa modestie. Il se situe bien au-delà de cette qualité médiocre. S'il hausse les épaules, c'est par sagesse. Il sait qu'une fois pris dans l'événement, les hommes ne s'en effraient plus. Seul l'inconnu épouvante les hommes. Mais, pour quiconque l'affronte, il n'est déjà plus l'inconnu. Surtout si on l'observe avec cette gravité lucide. Le courage de Guillaumet, avant tout, est un effet de sa droiture. » Sa véritable qualité n'est point là. Sa grandeur c'est de se sentir responsable. Responsable de lui, du courrier et des camarades qui espèrent. Il tient dans ses mains leur peine ou leur joie. Responsable de ce qui se bâtit de neuf, là-bas, chez les vivants, à quoi il doit participer. Responsable un peu du destin des hommes, dans la mesure de son travail. Il fait partie des êtres larges qui acceptent de couvrir de larges horizons de leur feuillage. Être homme, c'est précisément être responsable. C'est connaître la honte en face d'une misère qui ne semblait pas dépendre de soi. C'est être fier d'une victoire que les camarades ont remportée. C'est sentir, en posant sa pierre, que l'on contribue à bâtir le monde.

	PART I:
	PULMONARY ARTERIAL HYPERTENSION, CHRONIC
	THROMBOEMBOLIC PULMONARY HYPERTENSION AND
	REHABILITATION: A REVIEW
	Antoine de Saint Exupéry, Terre des hommes.
	A propos de son ami Henri Guillaumet qui est arrivé à regagner la civilisation, après un atterrissage
	forcé dans la Cordillère des Andes et six jours éprouvants passés dans le froid et la neige

Table of contents

 of

Figure 1: Clinical classification of pulmonary hypertension updated from Simonneau et al. (13) 1: PAH

	1.1 Idiopathic PAH
	1.2 Heritable PAH
	1.3 Drug-and toxin-induced PAH
	1.4 PAH associated with:
	1.4.1 Connective tissue disease
	1.4.2 HIV infection
	1.4.3 Portal hypertension
	1.4.4 Congenital heart disease
	1.4.5 Schistosomiasis
	1.5 PAH long-term responders to calcium channel blockers
	1.6 PAH with overt features of venous/capillaries (PVOD/PCH) involvement
	1.7 Persistent PH of the newborn syndrome
	2: PH due to left heart disease
	2.1 PH due to heart failure with preserved LVEF
	2.2 PH due to heart failure with reduced LVEF
	2.3 Valvular heart disease
	2.4 Congenital/acquired cardiovascular conditions leading to post-capillary PH
	3

: PH due to lung diseases and/or hypoxia

	3.1 Obstructive lung disease
	3.2 Restrictive lung disease
	3.3 Other lung disease with mixed restrictive/obstructive pattern
	3.4 Hypoxia without lung disease
	3.5 Developmental lung disorders
	4

: PH due to pulmonary artery obstructions

	4.1 Chronic thromboembolic PH
	4.2 Other pulmonary artery obstructions
	5

: PH with unclear and/or multifactorial mechanisms

	a. PAH
	The reported incidence of pulmonary arterial hypertension in the developed world is 1,1-7,6
	per million adults per year; the prevalence of pulmonary arterial hypertension is 6,6-26,0 per
	million adults (16-19)
	Pulmonary arterial hypertension has been thought to affect mainly younger people, mostly
	females (20). This consideration is particularly true for heritable PAH, which affects twice as
	many women as men (21) and the average age at the time of diagnosis was approximately 50
	years (22).
	More recently, in Germany the average age of patients at the time of diagnosis was 64 years
	(22), and in UK 29% of the patients with newly diagnosed PAH were over the age of 70 years
	(23); reinforcing the notion that the phenotype and the age of patients with PAH were
	continuous to change. Advancing age has been identified as an independent risk factor for
	mortality in this population (24).
	5.1 Haematological disorders
	5.2 Systemic and metabolic disorders
	5.3 Others
	5.4 Complex congenital heart disease
	PAH: pulmonary arterial hypertension; PVOD: pulmonary veno-occlusive disease; PCH: pulmonary capillary
	haemangiomatosis; LVEF: left ventricular ejection fraction.
	4. Epidemiologic data
	Because the diagnosis requires an invasive procedure (right heart catheterization), the
	epidemiology of pulmonary hypertension is difficult to study. Therefore, large-scale population
	studies are based on echocardiography because invasive tests for epidemiological studies would
	not be ethical.

  . PAH In case of PH suspicion, the diagnosis process have to rule out all other causes of PH, in particular most common clinical groups of PH [group 2 and group 3], then distinguishes group 4, and finally concluded the PAH's accountability (26). Indeed, if transthoracic echocardiography is compatible with PH, the clinician needs to collect clinical history, symptoms, physical signs, ECG, chest radiograph, pulmonary function tests and chest CT to identify the presence of group 2 (left heart diseases) or group 3 (lung diseases)

3.4m/s or over 2.8m/s associated with right heart overload. But to confirm the diagnosis of pulmonary hypertension right heart catheterisation is mandatory. Diagnostic criteria for PAH and CTEPH include a resting mean pulmonary arterial pressure greater than or equal to 25 mmHg. Measurement of pulmonary arterial occlusion pressure (PAOP) is necessary to exclude post-capillary pulmonary hypertension. a

  )10. Prognosis and risk assessment PH is characterized by a progressive increase in pulmonary vascular resistance, leading to right heart failure and premature death[START_REF] Simonneau | Clinical classification of pulmonary hypertension[END_REF][START_REF] Rubin | Primary pulmonary hypertension[END_REF].During follow-up, achieving and maintaining a low-risk profile is the recommended goal of PAH treatment. However, the accuracy of this risk assessment has not been fully established and most of cutoffs are based on expert opinion, with low levels of evidence.

	Since then, abbreviated versions of the 2015 ESC/ERS risk stratification strategy have been
	a. PAH evaluated retrospectively in newly diagnosed PAH (74-77):
	-Boucly et al. (2017) studied a retrospective incident cohort of patients with PAH, and
	Over the past decades, the life expectancy of PAH patients has increased with a 3-year survival showed the risk of death or lung transplantation was accurately determined using a
	rate of 70 to 80% now (24), compared with 40% in the 1980s (11). Before the late 1990s, simple quantification of the number of low-risk criteria present at diagnosis, and, most
	treatments for PAH patients consisted of supportive therapy, and was focused on symptoms importantly, achieved during the first year of follow-up for WHO FC, 6MWD, right
	related to right heart failure, with a median survival of 2.8 years in 1986 (95% Cl, 1.9 to 3.7 atrial pressure (RAP) and cardiac index. In the analysis, attaining only two or less low-
	b. CTEPH
	Unlike others forms of PH, CTEPH is potentially curable. Pulmonary endarterectomy (PEA) is
	According to these guidelines, certain low-risk features are associated with better prognosis in the treatment choice for patients who are surgical candidates (82) : however, up to 50% of
	PAH, such as no sign right heart failure, a WHO FC I or II, a 6MWD >440 m, an haemodynamic patients are considered inoperable because of an inaccessible and/or distal thromboembolism,
	assessment with a right atrial pressure (RAP) <8 mmHg and a cardiac index ⩾2.5 L/min/m². or serious comorbidities (34).

years)

[START_REF] Alonzo | Survival in patients with primary pulmonary hypertension. Results from a national prospective registry[END_REF]

. Recent data from the United States-based registry assessing pulmonary arterial hypertension disease management (REVEAL registry) showed a median survival of 7 years presumably due to a combination of significant advances in treatment strategies and patient support strategies

(15,[START_REF] Benza | An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry[END_REF]

. Despite improvements in the short-term survival of patients with PAH, the condition remains incurable

[START_REF] Galiè | ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)[END_REF]

. The 2015 ESC/ERS (European Society of Cardiology/European Respiratory Society) guidelines (26) and the 2018 Proceedings of the 6th World Symposium on Pulmonary Hypertension (73) recommend regular risk assessment at expert PH centres using a series of variables to stratify patients into low, intermediate and high-risk categories (corresponding to an estimated one-year mortality rate of <5%, 5-10% and >10% respectively), cf Annex 2. This assessment is meant to be applicable in patients with newly diagnosed PAH and at any time during the course of the disease, and aims to facilitate treatment decisions. It includes clinical features (e.g. World Health Organization (WHO) functional class (FC), right ventricular function), exercise testing (e.g., 6-minute walking test (6MWT), cardiopulmonary exercise testing), imaging (echocardiography, cardiac magnetic resonance imaging), haemodynamics (right atrial pressure, cardiac index, mixed venous oxygen saturation), and biomarkers (BNP and NT-proBNP).

Also, BNP levels <50 ng/L or NT-proBNP <300 ng/L are considered to be low-risk features. risk criteria at follow-up had a worse long-term prognosis than those with three or four low-risk criteria

[START_REF] Boucly | Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension[END_REF]

.

-Kylhammar et al. (

2017

) proposed a method whereby 8 criteria (6MWD, WHO FC, NT-proBNP, right atrial area, pericardial effusion, RAP, cardiac index, and SvO2) are graded from 1 to 3 (1=low, 3=high) using the ESC/ERS risk stratification. The rounded mean of these grades is then used to define patient risk status

[START_REF] Kylhammar | A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension[END_REF]

. -Hoeper et al. (2017) evaluated an abbreviated version of the risk stratification model in newly diagnosed PAH patients (from the COMPERA web-based PH registry) using 6 variables (6MWD, WHO FC, NT-proBNP/BNP, RAP, cardiac index, and SvO2) and the same analysis method as Kylhammar et al. Among them, 6MWD, WHO FC, BNP/NT-proBNP and SvO2 were closely linked to the mortality risk (75).

Two studies in PH have demonstrated that the presence of anaemia is indicative of a poor prognosis

[START_REF] Hampole | Usefulness of red cell distribution width as a prognostic marker in pulmonary hypertension[END_REF][START_REF] Krasuski | Association of anemia and long-term survival in patients with pulmonary hypertension[END_REF]

. Furthermore, iron deficiency is prevalent in patients with IPAH and is associated with disease severity

[START_REF] Ruiter | Iron deficiency is common in idiopathic pulmonary arterial hypertension[END_REF][START_REF] Van Empel | Iron deficiency in patients with idiopathic pulmonary arterial hypertension[END_REF]

.

  (CTEPH) have shown beneficial effects of exercise training as add-on to disease targeted medical therapy by increasing exercise capacity and quality of life(5,8). The effects were observed in different forms of pulmonary vascular diseases, such as idiopathic PAH, CTEPH and PH due to respiratory or left heart diseases(7). The improvement in exercise capacity was

	recorded with an improvement in 6MWD, VO2 peak, cardiac output (100), muscle strength and
	muscle endurance. Also, physical and mental quality of life scores measured with the SF-36
	questionnaire improved significantly, especially in the domains of physical functioning, general
	health perception, vitality, social functioning, role emotional and mental health (6).
	A meta-analysis in 2015, including 16 prospective intervention studies with 469 PH
	participants, observed a 53.3 m improvement in 6MWD at 15 weeks with exercise training on
	pooled analysis (weighted mean difference, 53.3 m; 95% CI, 39.5-67.2). Exercise training was
	also associated with significant improvement in pulmonary arterial systolic pressure (weighted
	mean difference, -3.7 mm Hg; 95% CI, -5.4 to -1.9), peak oxygen uptake (weighted mean
	difference, 1.8 mL/kg per minute; 95% CI, 1.4-2.3), and quality of life as measured on SF-36
	questionnaire subscale scores. (99)
	63 points higher
	(0.80 to 8.47 points, n = 33, 2 RCTs) and for the SF-36 mental component score 4.17 points
	higher (0.01 to 8.34 points; n = 33; 2 RCTs).
	Ehlken et al. (102) evaluated the effect of training on morbidity and mortality of PAH patients
	(n=58) compared with a retrospective control group (n=46) treated with usual care and
	optimized PAH therapy. During a mean follow-up of 24 ± 12 months, 25.8% of the patients
	receiving exercise training had adverse events, a rate much lower when compared to the control
	patients (54,4%). The incidence of clinical worsening was also lower. The 1-and 2-year

In 2017, a review of randomized controlled trials (RCTs) assesses the efficacy and safety of exercise-based rehabilitation for people with PH (most participants were Group I pulmonary artery hypertension) (101). They study 6 RCTs with 206 participants included. Study duration ranged from 3 to 15 weeks. Exercise programmes included both inpatient-and outpatient-based rehabilitation. The mean 6MWD following exercise training was 60.12 metres higher than control (30.17 to 90.07 metres, n = 165, 5 RCTs), the mean peak oxygen uptake was 2.4 ml/kg/minute higher (1.4 to 3.4 ml/kg/min, n = 145, 4 RCTs). The health-related quality of life also improved with a mean change for the SF-36 physical component score 4.

survival rates were better in the exercise training group compared to the control group (100% and 95% vs. 93% and 88%, respectively; P<0.05).

  2010 and 2019, 41 patients were included (mean age 59,6 +/-18,1 years-old). The majority of patients were female (60,9 %), with PAH (n= 23 (56,1%)). Patients with CTEPH were 43,9% (n=18). Most patients had no clinical signs of right heart failure (83%) and were in

TABLE 2 Detailed demographics and baseline characteristics of the patients according to their PH group PAH CTEPH

 2 Endurance training consists of low-intensity bicycle ergometer training and/or treadmill walking. 19 patients had bicycle ergometer training and treadmill walking. 13 patients had only bicycle ergometer training. 2 patients had only treadmill walking. The training intensity was increased with respect of the individual tolerability and improvement.

	Subjects, n	23	18
	Age, years	50,9 (+/-16,5)	70,8 (+/-13,0)
	Female gender, %	56,5	66,7
	Clinical signs of right heart failure, %	17,4 (n=4)	16,7 (n=3)
	WHO FC I/II/III/IV, n	0/11/9/3	0/5/9/3 (unknown =1)
	6MWD, m (when done)	407 (+/-191) (NP= 2)	367 (+/-105) (NP = 4)
	NT-pro-BNP, ng/L	1753 (+/-2776)	2298 (+/-2658)
	Echocardiography
	RA area, cm²	21,4	25,3
	Pericardial effusion, %	4,5	0
	Heamodynamics
	RAP, mmHg	9,3	9,6
	mPAP, mmHg	49,6	39,9
	Cardiac index, L/min/m²	2,47	2,26
	SvO2, %	63,1	58,4
	Supportive therapy
	Anticoagulants, %	60	100
	Diuretics, %	69,6	61,1
	Supplemental oxygen, %	17	50
	Therapy
	No specific therapy, %	0	44
	Monotherapy, %	17	17
	Dual therapy, %	48	39
	Triple therapy, %	35	0
	Group 4 intervention
	PEA, n	/	6
	BPA, n	/	7
	PEA and BPA, n	/	1
	No intervention, n	/	4
	Stability on optimised medical therapy
	< 3 months, % (mean, days)	65 (18,4)	83 (23,4)
	> 3 months, % (mean, days)	35 (292,5)	17 (290)
	-The mean length of stay (except the weekend day when there was not reeducation
	session) was 20,3 days (+/-9,2), which corresponds to almost 4 weeks.

-

TABLE 3 Detailed demographics and baseline characteristics of the patients according to the type of hospitalisation Day hospital patients

 3

	Conventional hospital
	patients

Stability on optimised medical therapy < 1 months, n (%) < 3 months, n (%)

		4 (28,6)	12 (66,7)
		8 (57,1)	15 (81,5)
	Time from diagnosis, months	31,5	35,9

TABLE 4 Baseline and final characteristics of the 41 patients Study population at start of rehabilitation Study population at end of rehabilitation Clinical signs of right heart failure, n (%

 4

	)	7 (17)	2 (4,9)
	WHO FC I/II/III/IV, n	0/16/18/6 (unknown = 1)	0/29/9/3
	Mean WHO FC	2,75 (+/-0,70)	2,36 (+/-0,61) *
	Mean risk assessment grade	1,76	1,51 *
	6MWD, m (when done)	391,1 (+/-161) (NP=6)	444,2 (+/-143) (NP=4) (NS)
	Biology
	NT-pro-BNP, ng/L	1973,6	1510,3 (NS)
	Hemoglobin, g/dL	13,3	13,5 (NS)
	Créatinine, µmol/L	91,21	86,2 (NS)
	Bilirubin	9,54	9,58 (NS)
	Echocardiography
	LVEF, %	60,7	61,8 (NS)
	TAPSE, mm	17,8	19,0 (NS)
	RA area, cm²	22,7	21,1 (NS)
	Pericardial effusion, n (%)	1 (2,5)	3 (7,3) (NS)
	Heamodynamics
	RAP, mmHg	9,44 (+/-5,2)	5,9 (+/-3,2) *
	mPAP, mmHg	45.2 (+/-12,4)	38.9 (+/-10.3) *
	Cardiac index, L/min/m²	2,37 (+/-0,77)	2,78 (+/-0,83) (NS)
	SvO2, %	63,2 (+/-9,2)	66,3 (+/-9,1) (NS)
	Supportive therapy
	Anticoagulants, n (%)	32 (78,0)	32 (78,0)
	Diuretics, n (%)	27 (65,9)	25 (61,0)
	Supplemental oxygen, n (%)	13 (31,7)	11 (26,8)
	Number of specific therapy 0/1/2/3, n	8/7/18/8	8/7/18/8
	Therapeutic intervention
	Therapeutic titration during the month
	prior to rehabilitation, n (%)	21 (51)	/
	Drug titration, n (%)	/	12 (29,3)
	Ballon pulmonary angioplasty, n (%)	/	2 (4,8)

Remerciements

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Methods

Patients selection

This monocentric study was a retrospective analysis of data from consecutive PAH patients and CTEPH patients admitted in our cardiac rehabilitation centre. All patients were previously hospitalised in PH expert centre, with whom we work closely. Right heart catheterization was performed in all patients, then the expert centre ascertained the PAH or CTEPH diagnosis, decided on the therapy project, started the drug titration if required, and could refer patients to our rehabilitation centre if clinically stable, even if the treatment titration was still in progress.

Patients meeting inclusion criteria were enrolled between March, 2010 and May, 2019. The observational period ended in September, 2019. Follow-up time was calculated from the date of the rehabilitation.

Study population

Eligible patients included adults aged over 18 years with confirmed diagnosed PAH of any aetiology and CTEPH by the expert PH centre, then admitted for a cardiac rehabilitation.

Patients were not supposed to be stable and compensated under optimized medical therapy before entering the study. But for safety reasons, the clinical and functional status were assessed by PH expert centre, before referring the patient either in rehabilitation day hospital or in a classical rehabilitation hospitalisation stay.

In addition to PH-specific drug therapy if needed, patients also received standard supportive therapy that include oral anticoagulants, diuretics, oxygen, and iron substitution.

Outcome measures

Before the rehabilitation and during the follow-up, most of patients have regular evaluation in the expert PH centre and the rehabilitation centre. Functional status and clinical signs of right heart failure was assessed. Thereby, a 6-minutes walking test was carried out before exercise training programme and at the end, when clinically possible. In the same way as biology. Also, an echocardiography was performed before entering the rehabilitation and right after (if the echocardiography was not available at the end of exercise training programme, the first echocardiography during the follow-up was considered  The mean risk assessment grade at baseline was 1,76 (grade scale from 1 to 3). At follow-up, it was 1,51. Which means that the risk assessment grade evolves favorably after rehabilitation, with a statistically significative difference of -0,25 points (95% CI, -0,45 to -0,07).

-The WHO functional class was improved by the rehabilitation: with rehabilitation the number of patients with WHO functional class II increased from 16 to 29. In the same time, the numbers of patients with WHO functional class III or IV decreased respectively from 18 to 9, and from 6 to 3. One patient's status at start rehabilitation was unknown. The mean WHO functional class at baseline was 2,75, and it was significantly improved at the end of the rehabilitation to 2,36 (-0,39, 95% CI, -0,68 to -0,10).

Discussion

The present study is a retrospective study from consecutive diagnosed PAH patients and CTEPH patients who benefited from cardiac rehabilitation in our rehabilitation centre.

According to the actual PH guidelines, treatment decisions should be based on risk assessments, and the main objective of PH therapy is achieving or maintaining a low-risk profile. This treatment goal was achieved in the majority of our patients: following risk stratification proposed by KYLHAMMAR et al. there was 29% low-risk profile patients at the beginning, and 51% at follow-up. The rehabilitation programme seems to be beneficial, even to frail patients, and also to patients who did not practice endurance training. The effect of exercise and respiratory training was associated with significative improvements in risk assessment grade, WHO/NYHA functional class, and haemodynamic parameters (mPAP and RAP). Only few patients performed cardiopulmonary exercise testing, that is a reason why the evolution of VO2 and workload at the anaerobic threshold was not analysed. With such a small patient cohort, the mean 6MWD improvement from baseline was 53,1 m and was not significative in our study, but exceeding the minimum clinically important difference of 33 m by far (15). However, the absolute value is comparable to others studies : a meta-analysis, including 16 prospective intervention studies with 469 PH participants, observed up to 53 m improvement in 6MWD at 15 weeks with exercise training on pooled analysis (weighted mean difference, 53,3 m; 95% CI, 39,5-67,2) (16). In comparison, some therapy randomized controlled trials showed significative effects with lower improvements : patients who received initial dual therapy with ambrisentan (10 mg) plus tadalafil (40 mg), in the AMBITION trial, had a 48,98 m median change from baseline after 24 weeks (17). In the SERAPHIN trial, at month 6, the 6-minute walk distance had increased by a mean of 12,5 m in the group that received 10 mg of macitentan (18). In the GRIPHON trial, at week 26, the 6-minute walk had increased by 4,0 m from baseline in the selexipag group (maximum dose, 1600 μg twice daily) (19).

When comparing the type of hospitalisation (day hospitalisation or conventional hospitalisation), it is noted that patients who benefit from rehabilitation during day hospitalisation, are less frail than inpatients at baseline: they are younger, have no sign of right heart failure, have a better 6MWD and functional class (with no WHO FC IV), have less diuretics or oxygen therapy, have better biological and hemodynamic parameters, and are more likely to be in a stable condition on optimised PH targeted medical therapy.

Conclusion

In our study, the rehabilitation programme improved functional capacity, and hemodynamic parameters in patients with PAH or CTEPH. The 6-minute walk distance improvement exceeded by far the minimal important difference (MID) of 33 m, but was not statistically significative in our study. Also, the results of this study suggest that rehabilitation improves the risk assessment grade, even in frail patients or in patients who are not in stable condition on optimised medical therapy. In addition, it helps patients to remain or reach "low-risk" profile, which is associated with a better survival. Moreover, in a supervised setting, it is safe with no major adverse events.

We are still waiting for specific recommandations about exercise in PH, but in the meantime rehabilitation programmes must be suggested as a secure and effective tool with synergistic effect with specific-PH therapy, to improve exercise capacity in PAH and CTEPH patients.

These data are encouraging and warrant further randomized trials to develop the optimal training component.

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