Marc Humbert

Université Paris-Sud 11, Orsay, Île-de-France, France

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Publications (417)2512.88 Total impact

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    ABSTRACT: The French Pulmonary Hypertension Network (FPHN) registry and the Registry to Evaluate Early And Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) have developed predictive models for survival in pulmonary arterial hypertension (PAH). In this collaboration, we assess the external validity (or generalisability) of the FPHN ItinérAIR-HTAP predictive equation and the REVEAL risk score calculator. Validation cohorts approximated the eligibility criteria defined for each model. The REVEAL cohort comprised 292 treatment-naïve, adult patients diagnosed <1 year prior to enrolment with idiopathic, familial or anorexigen-induced PAH. The FPHN cohort comprised 1737 patients with group 1 PAH. Application of FPHN parameters to REVEAL and REVEAL risk scores to FPHN demonstrated estimated hazard ratios that were consistent between studies and had high probabilities of concordance (hazard ratios of 0.72, 95% CI 0.64-0.80, and 0.73, 95% CI 0.70-0.77, respectively). The REVEAL risk score calculator and FPHN ItinérAIR-HTAP predictive equation showed good discrimination and calibration for prediction of survival in the FPHN and REVEAL cohorts, respectively, suggesting prognostic generalisability in geographically different PAH populations. Once prospectively validated, these may become valuable tools in clinical practice. Copyright ©ERS 2015.
    European Respiratory Journal 04/2015; DOI:10.1183/09031936.00004414 · 7.13 Impact Factor
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    ABSTRACT: Pulmonary hypertension (PH) is a common complication of numerous diseases, including left-sided heart diseases and chronic lung diseases and/or hypoxia, where PH is associated with exercise limitation and a worse prognosis. Other forms of PH include pulmonary arterial hypertension (PAH), chronic thromboembolic PH (CTEPH), and PH with unclear multifactorial mechanisms. Over the past decade, it has been documented that systolic pulmonary artery pressure (sPAP) may help estimate mean pulmonary artery pressure (mPAP) in adults with high accuracy and reasonably good precision (mPAP = 0.61 sPAP + 2 mm Hg). This strong linear relationship between sPAP and mPAP was unexpected from a classic physiologic point of view. Consistent results have been obtained from independent teams using either high-fidelity micromanometer-tipped PA catheters or fluid-filled catheters. Overall, the strong link between sPAP and mPAP has been documented over a wide range of PAPs, heart rate, cardiac output, wedge pressure, and causes of PH, during changes in posture and activity, and irrespective of patient's sex, age, and BMI. A review of available invasive data confirms that patients with CTEPH and idiopathic PAH matched for their mPAP exhibit essentially similar sPAP. Pressure redundancy may be explained by the dependence of PA compliance upon mPAP. The 25 mm Hg threshold used to define PH accurately corresponds to an sPAP of 38 mm Hg. Although the limits of the echocardiographic estimation of sPAP are widely documented, results from invasive studies may furnish an evidence-based sPAP-derived mPAP value, potentially useful in the multiparameter echocardiographic approach currently used to diagnose and follow patients with PH.
    Chest 04/2015; 147(4):943-50. DOI:10.1378/chest.14-1755 · 7.13 Impact Factor
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    ABSTRACT: Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH. In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ⩽5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to pulmonary hypertension susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH (pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-hypertension PH. We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH. Copyright ©ERS 2015.
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    ABSTRACT: In the absence of a disease-modifying treatment for systemic sclerosis (SSc), the management of the main causes of morbidity and mortality is essential to offer the best possible patient care. Accordingly, early diagnosis and treatment of lung involvement plays a central role. Several new agents against pulmonary artery hypertension (PAH) have driven a notable progress in managing this complication in the recent years. Prostacyclin derivates, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, or guanylate cyclase stimulators are used today in single or combined therapy to improve the prognosis of PAH patients. Regarding interstitial lung disease (ILD) cyclophosphamide remains the most evidence-based therapy for SSc ILD. Small-scale interventional or observational studies support mycophenolate mofetil for either first-line or maintenance therapy after an initial course of cyclophosphamide. Observational studies also show promising results for biologic agents like Rituximab, and autologous stem cell transplant appears to be an option for severe and carefully selected cases. Moreover, nintedanib and pirfenidone have been shown to be effective in recent studies for idiopathic lung fibrosis. Randomized controlled trials are needed to test the effects of these potential therapies in SSc-ILD. The development of targeted therapies for lung involvement in SSc, together with the increasing knowledge regarding patient selection and management of the available drugs, will help to improve care of SSc patients with lung involvement.
    03/2015; 1(1):51-67. DOI:10.1007/s40674-014-0011-2
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    ABSTRACT: Endothelial cell (EC) dysfunction plays a central role in the pathogenesis of pulmonary arterial hypertension (PAH), promoting vasoconstriction, smooth muscle proliferation, and inflammation. This study sought to test the hypothesis that nebivolol, a β1-antagonist and β2,3-agonist, may improve PAH and reverse the PAH-related phenotype of pulmonary ECs (P-EC). We compared the effects of nebivolol with metoprolol, a first-generation β1-selective β-blocker, on human cultured PAH and control P-EC proliferation, vasoactive and proinflammatory factor production, and crosstalk with PA smooth muscle cells. We assessed the effects of both β-blockers in precontracted PA rings. We also compared the effects of both β-blockers in experimental PAH. PAH P-ECs overexpressed the proinflammatory mediators interleukin-6 and monocyte chemoattractant protein-1, fibroblast growth factor-2, and the potent vasoconstrictive agent endothelin-1 as compared with control cells. This pathological phenotype was corrected by nebivolol but not metoprolol in a dose-dependent fashion. We confirmed that PAH P-EC proliferate more than control cells and stimulate more PA smooth muscle cell mitosis, a growth abnormality that was normalized by nebivolol but not by metoprolol. Nebivolol but not metoprolol induced endothelium-dependent and nitric oxide-dependent relaxation of PA. Nebivolol was more potent than metoprolol in improving cardiac function, pulmonary vascular remodeling, and inflammation of rats with monocrotaline-induced pulmonary hypertension. Nebivolol could be a promising option for the management of PAH, improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function. Until clinical studies are undertaken, however, routine use of β-blockers in PAH cannot be recommended. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
    Journal of the American College of Cardiology 02/2015; 65(7):668-680. DOI:10.1016/j.jacc.2014.11.050 · 15.34 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a disorder in which mechanical obstruction of the pulmonary vascular bed is largely responsible for the rise in mean pulmonary arterial pressure, resulting in a progressive functional decline despite current available therapeutic options. The fundamental pathogenetic mechanisms underlying this disorder include pulmonary vasoconstriction, in situ thrombosis, medial hypertrophy, and intimal proliferation, leading to occlusion of the small to mid-sized pulmonary arterioles and the formation of plexiform lesions. Several predisposing or promoting mechanisms that contribute to excessive pulmonary vascular remodeling in PAH have emerged, such as altered crosstalk between cells within the vascular wall, sustained inflammation and dysimmunity, inhibition of cell death, and excessive activation of signaling pathways, in addition to the impact of systemic hormones, local growth factors, cytokines, transcription factors, and germline mutations. Although the spectrum of therapeutic options for PAH has expanded in the last 20 years, available therapies remain essentially palliative. However, over the past decade, a better understanding of new key regulators of this irreversible pulmonary vascular remodeling has been obtained. This review examines the state-of-the-art potential new targets for innovative research in PAH, focusing on (1) the crosstalk between cells within the pulmonary vascular wall, with particular attention to the role played by dysfunctional endothelial cells; (2) aberrant inflammatory and immune responses; (3) the abnormal extracellular matrix function; and (4) altered BMPRII/KCNK3 signaling systems. A better understanding of novel pathways and therapeutic targets will help in the designing of new and more effective approaches for PAH treatment.
    Chest 02/2015; 147(2):529-37. DOI:10.1378/chest.14-0862 · 7.13 Impact Factor
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    European Respiratory Journal 02/2015; 45(2):297-300. DOI:10.1183/09031936.00221914 · 7.13 Impact Factor
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    ABSTRACT: Comité de la ESC para la elaboración de Guías de Práctica Clínica (CPG): José Luis Zamorano (Presidente) (España), Stephan Achenbach (Alemania), Helmut Baumgartner (Alemania), Jeroen J. Bax (Países Bajos), Héctor Bueno (España), Veronica Dean (Francia), Christi Deaton (Reino Unido), Çetin Erol (Turquía), Robert Fagard (Bélgica), Roberto Ferrari (Italia), David Hasdai (Israel), Arno Hoes (Países Bajos), Paulus Kirchhof (Alemania/Reino Unido), Juhani Knuuti (Finlandia), Philippe Kolh (Bélgica), Patrizio Lancellotti (Bélgica), Ales Linhart (República Checa), Petros Nihoyannopoulos (Reino Unido), Massimo F. Piepoli (Italia), Piotr Ponikowski (Polonia), Per Anton Sirnes (Noruega), Juan Luis Tamargo (España), Michal Tendera (Polonia), Adam Torbicki (Polonia), William Wijns (Bélgica), Stephan Windecker (Suiza)
    Revista Espa de Cardiologia 01/2015; DOI:10.1016/j.recesp.2014.12.002 · 3.34 Impact Factor
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    ABSTRACT: Riociguat is a soluble, guanylate cyclase stimulator, approved for pulmonary arterial hypertension. In the 12-week PATENT-1 study, riociguat was well tolerated and improved several clinically relevant end-points in patients with pulmonary arterial hypertension who were treatment naïve or had been pretreated with endothelin-receptor antagonists or prostanoids. The PATENT-2 open-label extension evaluated the long-term safety and efficacy of riociguat. Eligible patients from the PATENT-1 study received riociguat individually adjusted up to a maximum dose of 2.5 mg three times a day. The primary objective was to assess the safety and tolerability of riociguat; exploratory efficacy assessments included 6-min walking distance and World Health Organization (WHO) functional class. Overall, 396 patients entered the PATENT-2 study and 324 (82%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in PATENT-2 was similar to that observed in PATENT-1, with cases of haemoptysis and pulmonary haemorrhage also being observed in PATENT-2. Improvements in the patients', 6-min walking distance and WHO functional class observed in PATENT-1 persisted for up to 1 year in PATENT-2. In the observed population at the 1-year time point, mean±sd 6-min walking distance had changed by 51±74 m and WHO functional class had improved in 33%, stabilised in 61% and worsened in 6% of the patients versus the PATENT-1 baseline. Long-term riociguat was well tolerated in patients with pulmonary arterial hypertension, and led to sustained improvements in exercise capacity and functional capacity for up to 1 year. Copyright ©ERS 2015.
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    ABSTRACT: -The vascular remodeling responsible for pulmonary arterial hypertension (PAH) involves predominantly accumulation of α-smooth muscle actin (α-SMA)-expressing mesenchymal-like cells in obstructive pulmonary vascular lesions. Endothelial-to-mesenchymal transition (EndoMT) may be a source of those α-SMA-expressing cells. -In situ evidence of EndoMT in human PAH was obtained, using confocal microscopy of multiple fluorescent stainings at the arterial level, and using transmission electron microscopy (TEM) and correlative light and electron microscopy (CLEM) at the ultrastructural level. Findings were confirmed by in vitro analyses of human PAH and control cultured pulmonary artery endothelial cells (PAEC). In addition, the mRNA and protein signature of EndoMT was recognized at the arterial and lung level by quantitative RT-PCR and Western blot analyses. We confirmed our human observations in established animal models of pulmonary hypertension (MCT and SuHx). After establishing the first genetically modified rat model linked to BMPR2 mutations (BMPR2(Δ140Ex1/+) rats), we demonstrated that EndoMT is linked to alterations in signaling of BMPR2, a gene that is mutated in 70 % of cases of familial PAH and in 10-40 % of cases of idiopathic PAH. We identified molecular actors of this pathological transition, including twist overexpression and vimentin phosphorylation. We demonstrated that rapamycin partially reversed the protein expression patterns of EndoMT, improved experimental PAH and decreased the migration of human PAEC, providing the proof-of-concept that EndoMT is druggable. -EndoMT is linked to alterations in BPMR2 signaling and is involved in the occlusive vascular remodeling of PAH, which findings may have therapeutic implications.
    Circulation 01/2015; DOI:10.1161/CIRCULATIONAHA.114.008750 · 14.95 Impact Factor
  • European Respiratory Journal 01/2015; 45(1):1-6. DOI:10.1183/09031936.00201614 · 7.13 Impact Factor
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    ABSTRACT: Right ventricle ejection fraction (RVEF) evaluated with magnetic resonance imaging is a strong determinant of patient outcomes in pulmonary arterial hypertension. We evaluated the prognostic value of RVEF assessed with conventional planar equilibrium radionuclide angiography at baseline and change 3-6 months after initiating pulmonary arterial hypertension-specific therapy. In a prospective cohort of newly diagnosed patients with idiopathic, heritable or anorexigen-associated pulmonary arterial hypertension, RVEF was measured at baseline (n=100) and 3-6 months after initiation of therapy (n=78). After a median follow-up of 4.1 years, 41 deaths occurred, including 35 from cardiovascular causes. Patients with a (median) baseline RVEF >25% had better survival than those with a RVEF <25% using Kaplan-Meier analysis (p=0.010). RVEF at baseline was an independent predictor of all-cause and cardiovascular mortality in adjusted Cox regression model (p=0.002 and p=0.007, respectively; HR 0.93 for both). Patients with stable or increased RVEF at 3-6 months had a trend for improved all-cause survival (HR 2.43, p=0.086) and had less cardiovascular mortality (HR 3.25, p=0.034) than those in whom RVEF decreased despite therapy. RVEF assessed with conventional planar equilibrium radionuclide angiography at baseline and change in RVEF 3-6 months after therapy initiation independently predict outcomes in patients with pulmonary arterial hypertension. Copyright ©ERS 2015.
    European Respiratory Journal 12/2014; DOI:10.1183/09031936.00158014 · 7.13 Impact Factor
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    ABSTRACT: Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
    American Journal Of Pathology 12/2014; 185(2). DOI:10.1016/j.ajpath.2014.10.021 · 4.60 Impact Factor
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    ABSTRACT: Right ventricular (RV) response to exercise or pharmacological stress is not well documented in pulmonary hypertension (PH). We investigated the relationship between RV reserve and ventricular-arterial coupling. Surgical ligation of the left pulmonary artery was performed in 13 Large White piglets (PH group), thereafter weekly embolisations of the right lower lobe were performed for 5 weeks. A control group of six piglets underwent sham procedures. Right heart catheterisation and echocardiography were performed at week 6. Pressure-volume loops were recorded before and after dobutamine infusion. Induction of experimental PH resulted in a higher mean±sd pulmonary artery pressure (34±9 versus 14±2 mmHg; p<0.01) and in a lower ventricular-arterial coupling efficiency (0.66±0.18 versus 1.24±0.17; p<0.01) compared with controls at 6 weeks. Dobutamine-induced relative changes in RV stroke volume index (SVI) and end-systolic elastance were lower in the PH group (mean±sd 47±5% versus 20±5%, p<0.01, and 81±37% versus 32±14%, p<0.01, respectively). Change in SVI was strongly associated with resting ventricular-arterial coupling (R(2)=0.74; p<0.01). RV reserve was associated with ventricular-arterial coupling in a porcine model of chronic pressure overload. Copyright ©ERS 2014.
    European Respiratory Journal 12/2014; DOI:10.1183/09031936.00081314 · 7.13 Impact Factor
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    Circulation 12/2014; 130(24):2189-208. DOI:10.1161/CIRCULATIONAHA.114.006974 · 14.95 Impact Factor
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    ABSTRACT: Palliative Potts shunt has been proposed in children with suprasystemic pulmonary arterial hypertension (PAH). A retrospective multicentre study was performed to assess short- and long-term outcomes after Potts shunt. From 2003 to 2014, 24 children underwent a Potts shunt [19 surgical, median age: 7.7 years (1.5-17 years), median weight: 19.5 kg (10.2-47 kg) and 5 transcatheter, median age: 8.1 years (2.3-9.7 years), median weight: 22 kg (12.5-31 kg)] for drug-refractory PAH. For the first time in humans, we performed an unidirectional valved Potts anastomosis in a child with infrasystemic PAH on intravenous epoprostenol who experienced repeated central line infections. Severe postoperative complications occurred in 6 patients (25.0%, all from the surgical group) including 3 early deaths (12.5%) related to low cardiac output. After a median follow-up (FU) of 2.1 years (range, 3 months to 14.3 years, ≥8 years in 7 patients), World Health Organization (WHO) functional class was dramatically improved in the 21 survivors, all being in WHO-functional class 1 or 2 (P < 0.05); none experienced syncope during the FU; none had overt right ventricular failure; mean 6-min walk distance improved from 42.3 ± 10.0% to 81.2 ± 9.7% of adjusted values for age and sex (P < 0.001), BNP/NT-proBNP levels normalized in all; and weaning of intravenous epoprostenol was obtained in all patients who received triple combination as pre-Potts anastomosis therapy. Finally, all survivors caught up to normal growth curves. Arterial oxygen saturation gradient between upper and lower limbs persisted at the last FU (94.7 ± 3.6% vs 81.6 ± 5.1%, P < 0.001). One patient required double lung transplantation 6 years after a surgical Potts shunt. Palliative Potts shunt allows prolonged survival and dramatic, long-lasting improvement in functional capacities in children with severe, drug-refractory PAH. The Potts shunt might be considered as a first surgical or interventional step in the management of children with severe, drug-refractory PAH, leaving the door open for further lung transplantation, if needed. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 12/2014; 47(3). DOI:10.1093/ejcts/ezu445 · 2.81 Impact Factor
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    ABSTRACT: To investigate the usefulness of a self-reported respiratory health transition question over 10 years through reliability, ability to capture long-term asthma trajectory and predictive ability. In two 20-year cohorts (Asthma-E3N, n = 16,371, 61-88 years; EGEA, n = 1254, 27-82 years), perceived 10-year change in respiratory health ("Overall, in the last 10 years, do you think that your bronchial or respiratory health has changed?" if yes: "Has it improved/deteriorated?") was studied in relation with change in respiratory medication dispensation and lung function, with change in asthma status measured over the same period of time, and with subsequent asthma-related outcomes. Perceived deterioration (14% in Asthma-E3N) was associated with increased dispensations of respiratory medications over time (from 17% with >2 dispensations in 2004 to 26% in 2010). Report of perceived deterioration (13% in EGEA) was related to a lung function decline steeper by 9.3 mL/year as compared to perceived improvement. In both cohorts, change (improvement or deterioration) was more often perceived by participants with than without asthma (>45% vs <20%) and was dominant among participants with persistent current asthma (77%). Perceived deterioration was related to poorer asthma control 7 years later and to higher use of oral corticosteroids in the following 18 months. The proposed simple self-reported respiratory health transition question over 10 years allows predicting part of the long-term trajectory of asthma. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Respiratory Medicine 12/2014; DOI:10.1016/j.rmed.2014.11.010 · 2.92 Impact Factor
  • Pascal Chanez, Marc Humbert
    European Respiratory Review 12/2014; 23(134):405-7. DOI:10.1183/09059180.00009614
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Publication Stats

14k Citations
2,512.88 Total Impact Points

Institutions

  • 2002–2015
    • Université Paris-Sud 11
      • • Faculty of Medicine
      • • Service de Pneumologie
      Orsay, Île-de-France, France
  • 1993–2015
    • Centre Chirurgical Marie Lannelongue
      Plessis-Robinson, Île-de-France, France
  • 2014
    • Aix-Marseille Université
      Marsiglia, Provence-Alpes-Côte d'Azur, France
  • 2013–2014
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      Lutetia Parisorum, Île-de-France, France
  • 2002–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2005–2013
    • Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud
      Clamart, Île-de-France, France
  • 2001–2013
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Imperial College London
      Londinium, England, United Kingdom
  • 2012
    • Royal Free London NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2011–2012
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • Universitair Ziekenhuis Ghent
      Gand, Flanders, Belgium
  • 2010
    • Université de Bretagne Occidentale
      Brest, Brittany, France
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
    • University of California, Los Angeles
      • Division of Rheumatology
      Los Angeles, CA, United States
  • 2009
    • University of Bologna
      • Institute of Cardiology
      Bologna, Emilia-Romagna, Italy
    • Palmelit Francia
      Montferrier, Languedoc-Roussillon, France
    • Medical University of Bialystok
      Belostok, Podlasie, Poland
    • Centre Hospitalier Régional Universitaire de Lille
      Lille, Nord-Pas-de-Calais, France
  • 2007
    • CHRU de Strasbourg
      Strasburg, Alsace, France
    • University of São Paulo
      • Department of Cardio-Pulmonary
      San Paulo, São Paulo, Brazil
  • 2006
    • Academisch Medisch Centrum Universiteit van Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Polytech Paris-UPMC
      Lutetia Parisorum, Île-de-France, France
    • Hôpital Henri Mondor (Hôpitaux Universitaires Henri Mondor)
      Créteil, Île-de-France, France
  • 1995–1997
    • National Heart, Lung, and Blood Institute
      Maryland, United States