Gérald Simonneau

European Respiratory Society, Bruxelles, Brussels Capital, Belgium

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Publications (694)4576.65 Total impact

  • Andrei Seferian · Gérald Simonneau
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a progressive disease characterised by remodelling of small pulmonary arteries leading to an increased pulmonary vascular resistance, right ventricular failure and death. Available treatments try to re-establish the equilibrium on three signalling pathways: the prostacyclin, the endothelin (ET)-1 and the nitric oxide. Prostanoids, such as epoprostenol or treprostinil have a vasodilator, antiproliferative and immunomodulatory effect and, despite the administration inconveniences, represent established therapies for severe cases of PAH. Recently oral prostacyclin receptor agonists have shown encouraging results. Many clinical studies targeting the vasoconstrictor ET-1 pathway with receptor antagonists like bosentan and ambrisentan have shown strong results, even more optimism coming from macitentan, the newest drug. Sildenafil and tadalafil, two phosphodiesterase type-5 inhibitors, have shown improved exercise capacity by increasing the nitric oxide level. Riociguat, acting on the same nitric oxide pathway, as a guanylatecyclase activator, has shown promising results in clinical trials and will be available soon. Long-awaited results for tyrosin-kinase inhibitor, imatinib, as an antiproliferative therapy in PAH have been disappointing, due to severe adverse events. In conclusion, although it remains a disease with severe prognosis, the past 20 years have represented a huge progress in terms of treatments for PAH with interesting opportunities for the future.
    European Respiratory Review 09/2013; 22(129):217-26. DOI:10.1183/09059180.00001713
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    ABSTRACT: Background: Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial. Methods: We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension. Results: A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia. Conclusions: Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. (Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179.).
    New England Journal of Medicine 08/2013; 369(9):809-18. DOI:10.1056/NEJMoa1213917 · 55.87 Impact Factor
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    ABSTRACT: Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension. In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety. By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm(-5) in the riociguat group and increased by 23 dyn·sec·cm(-5) in the placebo group (least-squares mean difference, -246 dyn·sec·cm(-5); 95% CI, -303 to -190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group). Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. (Funded by Bayer HealthCare; CHEST-1 and CHEST-2 ClinicalTrials.gov numbers, NCT00855465 and NCT00910429, respectively.)
    New England Journal of Medicine 07/2013; 369(4):319-29. DOI:10.1056/NEJMoa1209657 · 55.87 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a chronic and progressive disease leading to right heart failure and ultimately death if untreated. The first classification of PH was proposed in 1973. In 2008, the fourth World Symposium on PH held in Dana Point (California, USA) revised previous classifications. Currently, PH is devided into five subgroups. Group 1 includes patients suffering from idiopathic or familial PAH with or without germline mutations. Patients with a diagnosis of PAH should systematically been screened regarding to underlying mutations of BMPR2 gene (bone morphogenetic protein receptor type 2) or more rarely of ACVRL1 (activine receptor-like kinase type 1), ENG (endogline) or Smad8 genes. Pulmonary veno occusive disease and pulmonary capillary hemagiomatosis are individualized and designated as clinical group 1'. Group 2 'Pulmonary hypertension due to left heart diseases' is divided into three sub-groups: systolic dysfonction, diastolic dysfonction and valvular dysfonction. Group 3 'Pulmonary hypertension due to respiratory diseases' includes a heterogenous subgroup of respiratory diseases like PH due to pulmonary fibrosis, COPD, lung emphysema or interstitial lung disease for exemple. Group 4 includes chronic thromboembolic pulmonary hypertension without any distinction of proximal or distal forms. Group 5 regroup PH patients with unclear multifactorial mechanisms. Invasive hemodynamic assessment with right heart catheterization is requested to confirm the definite diagnosis of PH showing a resting mean pulmonary artery pressure (mPAP) of [greater than or equal to]25 mmHg and a normal pulmonary capillary wedge pressure (PCWP) of [less than or equal to]15 mmHg. The assessment of PCWP may allow the distinction between pre-capillary and post-capillary PH (PCWP [greater than or equal to] 15 mmHg). Echocardiography is an important tool in the management of patients with underlying suspicion of PH. The European Society of Cardiology and the European Respiratory Society (ESC-ERS) guidelines specify its role, essentially in the screening proposing criteria for estimating the presence of PH mainly based on tricuspid regurgitation peak velocity and systolic artery pressure (sPAP). The therapy of PAH consists of non-specific drugs including oral anticoagulation and diuretics as well as PAH specific therapy. Diuretics are one of the most important treatment in the setting of PH because right heart failure leads to fluid retention, hepatic congestion, ascites and peripheral edema. Current recommendations propose oral anticoagulation aiming for targeting an International Normalized Ratio (INR) between 1.5-2.5. Target INR for patients displaying chronic thromboembolic PH is between 2--3. Better understanding in pathophysiological mechanisms of PH over the past quarter of a century has led to the development of medical therapeutics, even though no cure for PAH exists. Several specific therapeutic agents were developed for the medical management of PAH including prostanoids (epoprostenol, trepoprostenil, iloprost), endothelin receptor antagonists (bosentan, ambrisentan, macitentan soon available) and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil). This review discusses the current state of art regarding to epidemiologic aspects of PH, diagnostic approaches and the current classification of PH. In addition, currently available specific PAH therapy is discussed as well as future treatments.
    Orphanet Journal of Rare Diseases 07/2013; 8(1):97. DOI:10.1186/1750-1172-8-97 · 3.36 Impact Factor
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    ABSTRACT: Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary hypertension (IPAH) share a similar clinical presentation, and a differential diagnosis requires a thorough workup. Once CTEPH is confirmed, patients who can be safely operated have to be identified. We investigated risk factors associated with CTEPH and IPAH, and the criteria for the selection of operable CTEPH patients. This case-control study included 436 consecutive patients with CTEPH and 158 with IPAH in eight European centres, between 2006 and 2010. Conditions identified as risk factors for CTEPH included history of acute venous thromboembolism (p < 0.0001), large size of previous pulmonary embolism (p = 0.0040 in univariate analysis), blood groups non-O (p < 0.0001 in univariate analysis), and older age (p = 0.0198), whereas diabetes mellitus (p = 0.0006), female gender (p = 0.0197) and higher mean pulmonary artery pressure (p = 0.0103) were associated with increased likelihood for an IPAH diagnosis. Operability of CTEPH patients was associated with younger age (p = 0.0108), proximal lesions (p ≤ 0.0001), and pulmonary vascular resistance below 1200 dyn.s.cm⁻⁵ (p = 0.0080). Non-operable CTEPH patients tended to be less differentiable from IPAH patients by risk factor analysis than operable patients. This study confirmed the association of CTEPH with history of acute venous thromboembolism and blood groups non-O, and identified diabetes mellitus and higher mean pulmonary artery pressure as factors suggesting an IPAH diagnosis. Non-operable CTEPH is more similar to IPAH than operable CTEPH regarding risk factors.
    Thrombosis and Haemostasis 05/2013; 110(1). DOI:10.1160/TH13-02-0097 · 4.98 Impact Factor
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    ABSTRACT: Background: Novel noninvasive tools may improve the management of patients with pulmonary hypertension (PH) experiencing heart failure. Major right ventricle overload leads to decreased stroke volume, which shortens left ventricular ejection time (LVET). Our arterial tonometry study tested the hypothesis that LVET carries prognostic value in patients with precapillary PH with heart failure. Methods: Clinical, biologic, and radial artery tonometry variables were prospectively obtained at admission and at day 3 to 5 in 53 consecutive patients with PH admitted to our ICU for clinical deterioration. LVET was measured from the reconstructed aortic pressure curve. Results: Overall ICU mortality (median stay, 5 days) was 17%. At admission, the LVET was shorter in patients with unfavorable outcome (median, 228 milliseconds [25th-75th percentiles, 212-278 milliseconds] vs 257 milliseconds [237-277 milliseconds], P = .032), whereas other tonometric indices were similar. The LVET at entry (237 milliseconds) had 73% sensitivity and 89% specificity for identifying death in the ICU. Other prognostic factors at admission were higher serum levels of brain natriuretic peptide (BNP) and creatinine and lower natremia. Dobutamine requirement, higher furosemide dose, and higher oxygen flow were associated with unfavorable outcome. At the second evaluation, higher serum levels of creatinine and BNP, higher furosemide dose and oxygen flow, and dobutamine or norepinephrine requirement were associated with poor outcome. The change in LVET between admission and follow-up measurement was not associated with outcome. The 90-day mortality was 28%. Conclusions: Shortened LVET at ICU admission was a prognostic factor in patients with precapillary PH with heart failure. Previously documented prognostic factors were also confirmed in this cohort.
    Chest 05/2013; 144(5). DOI:10.1378/chest.12-2659 · 7.48 Impact Factor
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    Value in Health 05/2013; 16(3):A231. DOI:10.1016/j.jval.2013.03.1175 · 3.28 Impact Factor
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    ABSTRACT: Background: The mean pulmonary artery pressure (mPAP) replaces mean systolic ejection pressure (msePAP) in the classic formula of right ventricular stroke work (RVSW) = (mPAP - RAP) × stroke volume, where RAP is mean right atrial pressure. Only the steady work is thus taken into account, not the pulsatile work, whereas pulmonary circulation is highly pulsatile. Our retrospective, high-fidelity pressure study tested the hypothesis that msePAP was proportional to mPAP, and looked at the implications for RVSW. Methods: Eleven patients with severe, precapillary pulmonary hypertension (PH) (six patients with idiopathic pulmonary arterial hypertension and five with chronic thromboembolic PH; mPAP = 57 ± 10 mm Hg) were studied at rest and during mild to moderate exercise. Eight non-PH control subjects were also studied at rest (mPAP = 16 ± 2 mm Hg). The msePAP was averaged from end diastole to dicrotic notch. Results: In the full data set (53 pressure-flow points), mPAP ranged from 14 to 99.5 mm Hg, cardiac output from 2.38 to 11.1 L/min, and heart rate from 53 to 163 beats/min. There was a linear relationship between msePAP and mPAP (r² = 0.99). The msePAP matched 1.25 mPAP (bias, -0.5 ± 2.6 mm Hg). Results were similar in the resting non-PH group and in resting and the exercising PH group. This implies that the classic formula markedly underestimates RVSW and that the pulsatile work may be a variable 20% to 55% fraction of RVSW, depending on RAP and mPAP. At rest, RVSW in patients with PH was twice as high as that of the non-PH group (P < .05), but pulsatile work fraction was similar between the two groups (26 ± 4% vs 24 ± 1%) because of the counterbalancing effects of high RAP (11 ± 5 mm Hg vs 4 ± 2 mm Hg), which increases the fraction, and high mPAP, which decreases the fraction. Conclusions: Our study favored the use of an improved formula that takes into account the variable pulsatile work fraction: RVSW = (1.25 mPAP - RAP) × stroke volume. Increased RAP and increased mPAP have opposite effects on the pulsatile work fraction.
    Chest 05/2013; 143(5):1343-1350. DOI:10.1378/chest.12-1880 · 7.48 Impact Factor
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    ABSTRACT: The performance of the right ventricle is considered as a cornerstone of the patients’ outcome in pulmonary arterial hypertension (PAH). We evaluated the prognostic value of right ventricle ejection fraction (RVEF) assessed by planar equilibrium radionuclide angiography at baseline, and of its change after initiating PAH specific therapy.Methods and MaterialsAmong 222 newly diagnosed patients with idiopathic, heritable or drug-induced PAH (1995-2011), 101 patients had a RVEF measurement at diagnosis before treatment as part of routine evaluation, 78 with a follow-up measurement 3-6 months after initiation of therapy [endothelin receptor antagonists (47%), sildenafil (27%), prostacyclin (9%), and calcium channel blockers (2%)].ResultsAfter a median follow-up of 2.6 years (range: 0.11-15.2 years), 31 deaths occurred, including 25 from a cardiovascular cause. Patients with RVEF ≥25% had a better survival than those with RVEF<25% using Kaplan Meier analysis (p<0.001). The baseline RVEF at diagnosis was associated with all-cause (hazard ratio [HR]: 0.93; p=0.002) and cardiovascular mortality (HR: 0.93; p=0.003) by univariate Cox regression. RVEF was the only independent predictor of all-cause mortality using multivariate adjusted Cox regression (HR: 0.94; p=0.024). Patients with stable or increased RVEF at 3-6 months had less cardiovascular mortality (p=0.012) by Kaplan Meier analysis than those in whom RVEF decreased despite therapy. In 75% of patients, PVR decreased after medical therapy. Seventy nine percent of those patients with decreased PVR showed a stable or increase of RV function. Conversely 53% of patients with increased PVR showed a decrease of RV function (p=0.017). In univariate analysis, RVEF was directly correlated with TAPSE, TAPSV, cardiac index and mixed venous blood saturation. Moreover, RVEF was inversely correlated with NT-pro-BNP and PVR.ConclusionsRVEF assessed with conventional planar radionuclide angiography at baseline and after initiation of PAH therapy predicts outcomes in patients with PAH.
    The Journal of Heart and Lung Transplantation 04/2013; 32(4):S105. DOI:10.1016/j.healun.2013.01.1030 · 6.65 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a rare, severe disease resulting from progressive obliteration of small-caliber pulmonary arteries by proliferating vascular cells. PAH can occur without recognized etiology (idiopathic PAH), be associated with a systemic disease or occur as a heritable form, with BMPR2 mutated in approximately 80% of familial and 15% of idiopathic PAH cases. We conducted a genome-wide association study (GWAS) based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. We detected a significant association at the CBLN2 locus mapping to 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97 (1.59-2.45; P = 7.47 × 10(-10)). CBLN2 is expressed in the lung, and its expression is higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs.
    Nature Genetics 03/2013; 45(5). DOI:10.1038/ng.2581 · 29.35 Impact Factor
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    ABSTRACT: Les récentes études hémodynamiques estiment entre 6 et 10 % la prévalence de l’hypertension pulmonaire associée à la drépanocytose de l’adulte dont plus de la moitié correspondent en réalité à des hypertensions pulmonaires postcapillaires. L’hypertension artérielle pulmonaire (HTAP) précapillaire est une complication relativement peu fréquente de cette maladie (de l’ordre de 3 à 4 % des patients). Elle se caractérise par un profil hémodynamique différent de l’HTAP idiopathique avec des niveaux de pressions pulmonaires et de résistances vasculaires pulmonaires beaucoup plus basses. Néanmoins, ce type d’atteinte vasculaire pulmonaire semble avoir un impact important sur le statut fonctionnel et le pronostic vital des patients drépanocytaires. La valeur prédictive de l’échographie cardiaque pour dépister l’hypertension pulmonaire dans cette population est basse (25 à 32 %) lorsque le seuil de vitesse d’insuffisance tricuspidienne de 2,5 m/s est utilisé. À l’heure actuelle, aucun des traitements spécifiques de l’hypertension artérielle pulmonaire n’est approuvé pour le traitement de l’HTAP associée à la drépanocytose du fait du manque de données dans cette population spécifique.
    La Presse Médicale 03/2013; 42(3):338–346. DOI:10.1016/j.lpm.2012.04.021 · 1.08 Impact Factor
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    ABSTRACT: Background: By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). Methods and results: Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥ 800 dyne·s·cm(-5) symptomatic on ≥ 2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12-52; P=0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm(-5) (95% confidence interval, -502 to - 255; P<0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation. Conclusions: Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH. Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00902174 (core study); NCT01392495 (extension).
    Circulation 02/2013; 127(10). DOI:10.1161/CIRCULATIONAHA.112.000765 · 14.43 Impact Factor
  • Joanna Pepke-Zaba · Pavel Jansa · Nick H Kim · Robert Naejie · Gerald Simonneau
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    ABSTRACT: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease with poor prognosis if not treated. The treatment of choice is surgery with pulmonary endarterectomy. However, a significant percentage of patients are deemed non-operable due to distal distribution of the disease and arteriopathy in the non-occluded areas that is indistinguishable from pulmonary arterial hypertension (PAH). The overlap in clinical presentation, pathological features and pathogenesis between PAH and CTEPH provides a compelling rationale for exploring the efficacy of PAH-targeted therapies in CTEPH. These therapies are often considered for non-operable patients and are also used in operable patients as a bridge to surgery or as post-PEA therapy for persistent pulmonary hypertension, despite the fact they are not licensed for CTEPH.Two randomised clinical trials (RCTs) have been performed in non-operable CTEPH patients. The BENEFiT study, with the endothelin receptor antagonist bosentan, did not show improvement in walking distance. Recently, the CHEST-1 trial, with the soluble guanylate cyclase stimulator riociguat, met study endpoint and demonstrated significant improvement in walking distance in patients with non-operable CTEPH.There is an urgent need for more RCTs designed to clarify whether administration of PAH-targeted therapies improves clinically meaningful endpoints in various CTEPH populations.
    European Respiratory Journal 02/2013; 41(4). DOI:10.1183/09031936.00201612 · 7.64 Impact Factor
  • Revue des Maladies Respiratoires 01/2013; 30:A132. DOI:10.1016/j.rmr.2012.10.438 · 0.62 Impact Factor
  • Revue des Maladies Respiratoires 01/2013; 30:A15. DOI:10.1016/j.rmr.2012.10.053 · 0.62 Impact Factor

Publication Stats

37k Citations
4,576.65 Total Impact Points


  • 2015
    • European Respiratory Society
      Bruxelles, Brussels Capital, Belgium
  • 2013–2015
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      Lutetia Parisorum, Île-de-France, France
  • 2002–2015
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • McGill University
      Montréal, Quebec, Canada
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1990–2015
    • Centre Chirurgical Marie Lannelongue
      Plessis-Robinson, Île-de-France, France
  • 1989–2015
    • Université Paris-Sud 11
      • • Faculty of Medicine
      • • Service de Pneumologie
      Orsay, Île-de-France, France
  • 1986–2014
    • Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud
      Clamart, Île-de-France, France
  • 2010
    • French Institute of Health and Medical Research
      • Unit of Pulmonary Hypertension: Pathophysiology and Novel Therapies
      Lutetia Parisorum, Île-de-France, France
  • 2009
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
    • Palmelit Francia
      Montferrier, Languedoc-Roussillon, France
    • Centre Hospitalier Universitaire de Brest
      Brest, Brittany, France
  • 2007–2009
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2002–2009
    • University of Bologna
      • Institute of Cardiology
      Bologna, Emilia-Romagna, Italy
  • 2006
    • Vanderbilt University
      • Division of Allergy, Pulmonary and Critical Care
      Нашвилл, Michigan, United States
    • University of Leicester
      • Department of Genetics
      Leicester, ENG, United Kingdom
  • 1984–2006
    • Hôpital Henri Mondor (Hôpitaux Universitaires Henri Mondor)
      Créteil, Île-de-France, France
  • 2005
    • Hôtel-Dieu de Paris – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France
  • 2004
    • CHRU de Strasbourg
      Strasburg, Alsace, France
  • 2001
    • Arkansas Children's Hospital
      Little Rock, Arkansas, United States
  • 1991
    • University of Tours
      Tours, Centre, France