Marc Humbert

Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud), Lutetia Parisorum, Île-de-France, France

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Publications (348)2095.41 Total impact

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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; · 2.40 Impact Factor
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  • European respiratory review : an official journal of the European Respiratory Society. 12/2014; 23(134):469-475.
  • Pascal Chanez, Marc Humbert
    European respiratory review : an official journal of the European Respiratory Society. 12/2014; 23(134):405-7.
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    ABSTRACT: Background:Inflammation may contribute to the pathobiology of pulmonary arterial hypertension (PAH). Deciphering the PAH fingerprint on the inflammation orchestrated by dendritic and T cells (DC and LT), key driver and effector cells respectively of the immune system, may allow the identification of immunopathological approaches to PAH management. Methods:We performed immunophenotyping of monocyte-derived DC (MoDC) and circulating lymphocytes from idiopathic PAH (iPAH) and control patients by flow-cytometry. Using the same technique, we performed cytokine profiling of both populations following stimulation and/or coculture. We tested the immunomudulatory effects of the glucocorticoid (dexamethasone/Dex) on this immunophenotype and cytokine profile. We confirmed, the immune polarization of PAH patients in blood DNA, by an epigenetic approach. Results:The profile of membrane costimulatory molecules of PAH-MoDCs was similar to controls. However, PAH-MoDCs retained higher levels of the T cell activating molecules CD86 and CD40 after Dex pretreatment than controls. This was associated with an increased expression of IL-12p40 and a reduced migration toward CCL21. Moreover, both with and without Dex, PAH-MoDCs induced a higher activation and proliferation of CD4+ T cells, associated with a reduced expression of IL-4 (Th2 response) and a higher expression of IL-17 (Th17 response). Purified PAH CD4+ T cells expressed higher level of IL-17 after activation than controls. Lastly, there was significant hypomethylation of the IL-17 promoter in the PAH blood DNA as compared to controls. Conclusions:As previously demonstrated in other chronic inflammatory and autoimmune conditions, we have highlighted Th17 immune polarization in PAH patients for the first time. Inflammation may contribute to the pathobiology of pulmonary arterial hypertension (PAH). Deciphering the PAH fingerprint on the inflammation orchestrated by dendritic and T cells (DC and LT), key driver and effector cells respectively of the immune system, may allow the identification of immunopathological approaches to PAH management. We performed immunophenotyping of monocyte-derived DC (MoDC) and circulating lymphocytes from idiopathic PAH (iPAH) and control patients by flow-cytometry. Using the same technique, we performed cytokine profiling of both populations following stimulation and/or coculture. We tested the immunomudulatory effects of the glucocorticoid (dexamethasone/Dex) on this immunophenotype and cytokine profile. We confirmed, the immune polarization of PAH patients in blood DNA, by an epigenetic approach. The profile of membrane costimulatory molecules of PAH-MoDCs was similar to controls. However, PAH-MoDCs retained higher levels of the T cell activating molecules CD86 and CD40 after Dex pretreatment than controls. This was associated with an increased expression of IL-12p40 and a reduced migration toward CCL21. Moreover, both with and without Dex, PAH-MoDCs induced a higher activation and proliferation of CD4+ T cells, associated with a reduced expression of IL-4 (Th2 response) and a higher expression of IL-17 (Th17 response). Purified PAH CD4+ T cells expressed higher level of IL-17 after activation than controls. Lastly, there was significant hypomethylation of the IL-17 promoter in the PAH blood DNA as compared to controls. As previously demonstrated in other chronic inflammatory and autoimmune conditions, we have highlighted Th17 immune polarization in PAH patients for the first time.
    Chest 11/2014; · 7.13 Impact Factor
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    ABSTRACT: Mutations in the BMPR2 gene encoding bone morphogenetic protein receptor type II (BMPRII) is the main genetic risk factor for heritable pulmonary arterial hypertension (PAH). The suspected mechanism is considered to be a defect of BMP signaling. The BMPRII receptor exists in a short isoform without a cytoplasmic tail, which has preserved BMP signaling. A cohort-study compared age at PAH diagnosis and severity between patients carrying a BMPR2 mutation affecting the cytoplasmic tail of BMPRII and affected carriers of a mutation upstream of this domain. We identified 171 PAH affected carriers with a mutatedBMPR2 gene. Twenty-three were carriers of a point mutation located on the cytoplasmic tail of BMPRII. This population was characterized by having an older age at diagnosis compared to other BMPR2mutation carriers (43.2±12.1 and 35.7±14.6 years; p=0.040), a lower pulmonary vascular resistance (13.3±3.5 and 17.4±6.7; p=0.023) and a higher proportion of acute vasodilator responders with a long-term response to calcium channel blockers (8.7% and 0%, p=0.02). No statistically differences were observed in survival. An in vitro assay showed that mutations located in the cytoplasmic tail led to normal activation of the Smad pathway, whereas activation was abolished in the presence of mutations located in the kinase domain. Patients carrying a mutation affecting the cytoplasmic tail of BMPRII were characterized by an older age at diagnosis compared to other BMPR2 mutation carriers, less severe hemodynamic characteristics, and a greater chance of being a long-term responder to calcium channel blockers. Further investigations are needed to better understand the consequences of theseBMPR2 mutations in BMPRII signaling pathways, and their possible role in pulmonary arterial remodeling.
    Chest 11/2014; · 7.13 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a devastating life-threatening disorder characterized by elevated pulmonary vascular resistance leading to elevated pulmonary arterial pressures, right ventricular failure, and ultimately death. Vascular endothelial cells mainly produce and secrete endothelin (ET-1) in vessels that lead to a potent and long-lasting vasoconstrictive effect in pulmonary arterial smooth muscle cells. Along with its strong vasoconstrictive action, ET-1 can promote smooth muscle cell proliferation. Thus, ET-1 blockers have attracted attention as an antihypertensive drug, and the ET-1 signaling system has paved a new therapeutic avenue for the treatment of PAH. We outline the current understanding of not only the pathogenic role played by ET-1 signaling systems in the pathogenesis of PH but also the clinical pharmacology of endothelin receptor antagonists (ERA) used in the treatment of PAH.
    American journal of cardiovascular drugs : drugs, devices, and other interventions. 11/2014;
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    ABSTRACT: Isolated cases of pulmonary arterial hypertension (PAH) in patients treated with interferon (IFN) α or β have been reported in the literature. The aim of this study was to describe all consecutive cases of PAH patients with a history of IFN exposure identified in the French reference centre for severe pulmonary hypertension between 1998 and 2012. A total of 53 patients with PAH and a history of IFN therapy were identified. 48 patients had been treated with IFNα for chronic hepatitis C. Most of them had portal hypertension (85%) and 56% had HIV co-infection. Five additional patients had been treated with IFNβ for multiple sclerosis. The diagnosis of PAH was made within 3 years after IFN therapy in 66% of patients. Repeated haemodynamic assessment was available in 13 out of 16 patients exposed to IFN after the diagnosis of PAH. Increased pulmonary vascular resistance >20% was observed in 11 out of 13 cases (median 43% increase; IQR 32-67%). In five of these patients, IFN withdrawal resulted in spontaneous haemodynamic improvement. This retrospective analysis suggests that IFN therapy may trigger PAH. However, most of these patients had other risk factors for PAH. A prospective case-control study is necessary to definitively establish a link between IFN exposure and PAH.
    The European respiratory journal. 10/2014;
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    ABSTRACT: Background:Pulmonary arterial hypertension (PAH) is a rare and ultimately fatal disorder of the pulmonary vasculature. There is increasing interest in the worldwide characteristics of PAH patients, although data coming from the southern hemisphere remain scarce. The objective of this study was to describe a cohort of incident PAH patients from a large reference center in Brazil. Methods:All consecutive patients diagnosed with PAH by right heart catheterization between 2008 and 2013 were included in the study. Results:A total of 178 newly diagnosed PAH patients were enrolled in the study (mean age of 46 yr, female/male ratio of 3.3:1 and 45.5% in functional class III or IV). IPAH, CTD and Sch-PAH accounted for 28.7, 25.8 and 19.7% of all cases, respectively. The patients were treated with PDE5 inhibitors (66%), ERAs (27%) or a combination of both (5%). For the PAH group as a whole, the estimated survival rate 3 years after diagnosis was 73.9%. The prognosis for the CTD patients was worse than that for the IPAH and Sch-PAH patients (p=0.03). Conclusions:The distribution of PAH etiologies and the baseline characteristics in our registry clearly differ from the previously published European and USA-based registries. These differences highlight the importance of regional registries and also raise questions regarding the need to better account for such differences in future clinical trials.
    Chest 10/2014; · 7.13 Impact Factor
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    ABSTRACT: Background Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. Methods In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. Results The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. Conclusions Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521 .).
    New England Journal of Medicine 09/2014; · 54.42 Impact Factor
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    ABSTRACT: IgE is central to the pathophysiology of allergic asthma. Omalizumab, a humanized anti-IgE mAb, specifically binds free IgE and interrupts the allergic cascade by preventing binding of IgE with its high-affinity FcεRI receptors on mast cells, antigen-presenting cells, and other inflammatory cells. The clinical efficacy of omalizumab has been well documented in a number of clinical trials that involve adults, adolescents, and children with moderate-to-severe and severe allergic asthma. In these studies, omalizumab reduced exacerbations, asthma symptoms, inhaled corticosteroid and rescue medication use, and improved quality of life relative to placebo or best standard of care. Similar benefits have been reported in observational studies in “real-world” populations of patients. Results from recent pooled data from randomized clinical trials and from a large prospective cohort study provide reassurance about the long-term safety of omalizumab. Omalizumab dosing is individualized according to body weight and serum-IgE level, and recent adjustments to the dosing algorithm in Europe have enabled more patients to be eligible for treatment. Ongoing and future research is investigating the optimal duration of therapy, accurate predictors of response to treatment, and efficacy in nonatopic asthma as well as other IgE-mediated conditions.
    The Journal of Allergy and Clinical Immunology: In Practice. 09/2014;
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    European heart journal. 08/2014;
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    ABSTRACT: Chronic thromboembolic pulmonary hypertension is a rare but underdiagnosed disease. The development of imaging played a crucial role for the screening and the decision of operability over the past few years. Indeed, chronic thromboembolic pulmonary hypertension is the only type of pulmonary hypertension with a potential curative treatment: pulmonary endarterectomy. It is a complexe surgical procedure performed under cardiopulmonary bypass with deep hypothermia and circulatory arrest. The aim of the procedure is to completely remove the scar tissue inside the pulmonary arteries down to the segmental and sub-segmental levels. Compared to lung transplantation, which carries a postoperative mortality of 15-20% and a 5-year survival of 50%, pulmonary endarterectomy is a curative treatment with a postoperative mortality of less than 3%. However, lung transplantation remains an option for young patients with inoperable distal disease or after pulmonary endarterectomy failure. Considering that medical history of deep venous thrombosis or pulmonary embolism is lacking in 25 to 50%, the diagnosis of chronic thromboembolic pulmonary hypertension remains challenging. The lung V/Q scan is useful for the diagnosis showing ventilation and perfusion mismatches. Lesions located at the level of the pulmonary artery, the lobar or segmental arteries may be accessible to surgical removal. The pulmonary angiogram with the lateral view and the pulmonary CT scan help to determine the level of the intravascular lesions. If there is a correlation between the vascular obstruction assessed by imaging and the pulmonary resistance, pulmonary endarterectomy carries a postoperative mortality of less than 3% and has a high rate of success. If the surgery is performed at a later stage of the disease, pulmonary arteriolitis developed mainly in unobstructed territories and participated in the elevated vascular resistance. At this stage, postoperative risk is higher.
    Presse medicale (Paris, France : 1983). 08/2014;
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    The European respiratory journal. 08/2014;
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    ABSTRACT: Limited numbers of operated patients with chronic thromboembolic pulmonary hypertension (CTEPH) are refractory to pulmonary endarterectomy (PEA) and experience persistent pulmonary hypertension (PH). We retrospectively assessed lung histology available from nine patients with persistent PH (ineffective PEA (inPEA) group) and from eight patients transplanted for distal CTEPH inaccessible by PEA (noPEA group). Microscopically observed peculiarities were compared with the histology of a recently developed CTEPH model in piglets. Pre-interventional clinical/haemodynamic data and medical history of patients from the inPEA and noPEA groups were collected and analysed. Conspicuous remodelling of small pulmonary arteries/arterioles, septal veins and pre-septal venules, including focal capillary haemangiomatosis, as well as pronounced hypertrophy and enlargement of bronchial systemic vessels, were the predominant pattern in histology from both groups. Most findings were reproduced in our porcine CTEPH model. Ink injection experiments unmasked abundant venular involvement in so-called small vessel or microvascular disease, as well as post-capillary bronchopulmonary shunting in human and experimental CTEPH. Microvascular disease is partly due to post-capillary remodelling in human and experimental CTEPH and appears to be related to bronchial-to-pulmonary venous shunting. Further studies are needed to clinically assess the functional importance of this finding.
    European Respiratory Journal 08/2014; · 6.36 Impact Factor
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    ABSTRACT: Patients with pulmonary arterial hypertension (PAH) must be referred to expert centers (reference center and competences centers in the French PAH network). Despite progresses in the knowledge of PAH pathophysiology, it is still a devastating disease needing an aggressive approach of therapy to improve long-term outcomes. The target of current therapies is endothelial dysfunction of pulmonary arteries. Continuous intravenous infusion of epoprostenol remains the only recommended therapy for the most severe patients with PAH. If treatment goals are not met, a sequential combination therapy is recommended (i.e. combination of drugs targeting different dysfunctional pathways). Lung transplantation remains the only curative treatment of PAH.
    Presse medicale (Paris, France : 1983). 08/2014;
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    ABSTRACT: After lung transplantation, increased left ventricular (LV) filling can lead to LV failure, increasing the risk of post-operative complications and mortality. LV dysfunction in pulmonary arterial hypertension (PAH) is characterized by a reduced LV ejection fraction and impaired diastolic function.
    Journal of the American College of Cardiology 07/2014; 64(1):28-37. · 14.09 Impact Factor
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    ABSTRACT: Idiopathic pulmonary arterial hypertension (IPAH) is an incurable condition leading to right ventricular failure and death and inflammation is postulated to be associated with vascular remodelling. Interleukin (IL)-33, a member of the "alarmin" family can either act on the membrane ST2 receptor or as a nuclear repressor, to regulate inflammation. We show, using immunohistochemistry, that IL-33 expression is nuclear in the vessels of healthy subjects whereas nuclear IL-33 is markedly diminished in the vessels of IPAH patients. This correlates with reduced IL-33 mRNA expression in their lung. In contrast, serum levels of IL-33 are unchanged in IPAH. However, the expression of the soluble form of ST2, sST2, is enhanced in the serum of IPAH patients. Knock-down of IL-33 in human endothelial cells (ECs) using siRNA is associated with selective modulation of inflammatory genes involved in vascular remodelling including IL-6. Additionally, IL-33 knock-down significantly increased sST2 release from ECs. Chromatin immunoprecipitation demonstrated that IL-33 bound multiple putative homeodomain protein binding motifs in the proximal and distal promoters of ST2 genes. IL-33 formed a complex with the histone methyltransferase SUV39H1, a transcriptional repressor. In conclusion, IL-33 regulates the expression of IL-6 and sST2, an endogenous IL-33 inhibitor, in primary human ECs and may play an important role in the pathogenesis of PAH through recruitment of transcriptional repressor proteins.
    Biochemical and Biophysical Research Communications 07/2014; · 2.28 Impact Factor

Publication Stats

10k Citations
2,095.41 Total Impact Points

Institutions

  • 2008–2014
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      • Service de Pneumologie
      Lutetia Parisorum, Île-de-France, France
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Paris, Ile-de-France, France
    • University of Geneva
      • Division of Paediatrics
      Genève, GE, Switzerland
  • 2002–2014
    • Université Paris-Sud 11
      • • Faculty of Pharmaceutical Sciences
      • • Faculté de Médecine
      • • Service de Pneumologie
      Orsay, Île-de-France, France
    • Centre Chirurgical Marie Lannelongue
      Plessis-Robinson, Île-de-France, France
  • 2013
    • Catholic University of Louvain
      Walloon Region, Belgium
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Papworth Hospital NHS Foundation Trust
      Papworth, England, United Kingdom
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany
    • University of Grenoble
      Grenoble, Rhône-Alpes, France
    • Mater Misericordiae University Hospital
      • Department of Respiratory Medicine
      Dublin, Leinster, Ireland
  • 2006–2013
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud
      Clamart, Île-de-France, France
    • Academisch Medisch Centrum Universiteit van Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2012
    • University of Michigan
      Ann Arbor, Michigan, United States
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
    • University of Lille Nord de France
      Lille, Nord-Pas-de-Calais, France
    • Icon Clinical Research Inc
      North Wales, Pennsylvania, United States
    • Université du Droit et de la Santé Lille 2
      Lille, Nord-Pas-de-Calais, France
  • 2011
    • Institut Cochin
      Lutetia Parisorum, Île-de-France, France
    • University College London
      • Centre for Rheumatology
      London, ENG, United Kingdom
  • 2008–2011
    • University of Zurich
      Zürich, Zurich, Switzerland
  • 2006–2011
    • Centre Hospitalier Régional Universitaire de Lille
      • Division of Internal Medicine
      Lille, Nord-Pas-de-Calais, France
  • 2010
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
    • Université de Bretagne Occidentale
      Brest, Brittany, France
    • University of São Paulo
      • Department of Cardio-Pulmonary
      São Paulo, Estado de Sao Paulo, Brazil
    • University of California, Los Angeles
      • Division of Rheumatology
      Los Angeles, CA, United States
  • 2009
    • Palmelit Francia
      Montferrier, Languedoc-Roussillon, France
    • Lille Catholic University
      Lille, Nord-Pas-de-Calais, France
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, MD, United States
    • Medical University of Bialystok
      Belostok, Podlasie, Poland
  • 2007–2009
    • CHRU de Strasbourg
      Strasburg, Alsace, France
  • 2002–2009
    • University of Bologna
      • Institute of Cardiology
      Bologna, Emilia-Romagna, Italy
  • 2001
    • WWF United Kingdom
      Londinium, England, United Kingdom
  • 1997
    • National Heart, Lung, and Blood Institute
      Maryland, United States