Gerald Simonneau - Academia.edu (original) (raw)

Papers by Gerald Simonneau

Research paper thumbnail of A prospective study of the 6 min walk test as a surrogate marker for haemodynamics in two independent cohorts of treatment-naïve systemic sclerosis-associated pulmonary arterial hypertension

Annals of the rheumatic diseases, Jan 31, 2015

Despite the wide use of the 6 min walk distance (6MWD), no study has ever assessed its validity a... more Despite the wide use of the 6 min walk distance (6MWD), no study has ever assessed its validity as a surrogate marker for haemodynamics and predictor of outcome in isolated pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH). We designed this work to address this issue. Treatment-naïve patients with SSc-PAH were prospectively included from two sources: the French PAH Network (a prospective epidemiological cohort) (n=83) and randomised clinical trials submitted for drug approval (Food and Drug Administration) (n=332). Correlations between absolute values of the 6MWD and haemodynamics at baseline, as well as between variations of 6MWD and haemodynamics during follow-up, were studied in both populations. In the French cohort, baseline cardiac output (CO) (R(2)=0.19, p=0.001) and New York Heart Association class (R(2)=0.10, p<0.001) were significantly and independently correlated with baseline 6MWD in multivariate analysis. A significant, independent, but wea...

Research paper thumbnail of Non-Invasive Determination of Cardiac Output in Pre-Capillary Pulmonary Hypertension

PLOS ONE, 2015

Cardiac output (CO) is a major diagnostic and prognostic factor in pre-capillary pulmonary hypert... more Cardiac output (CO) is a major diagnostic and prognostic factor in pre-capillary pulmonary hypertension (PH). Reference methods for CO determination, like thermodilution (TD), require invasive procedures and allow only steady-state measurements. The Modelflow (MF) method is an appealing technique for this purpose as it allows non-invasive and beatby-beat determination of CO.

Research paper thumbnail of Guidelines on diagnosis and treatment of pulmonary arterial hypertension

Research paper thumbnail of Prognostic Factors for Survival in Hiv-Associated Pulmonary Arterial Hypertension

Research paper thumbnail of Serotonin-Induced Smooth Muscle Hyperplasia in Various Forms of Human Pulmonary Hypertension

Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature ... more Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of pulmonary hypertension (PH). Serotonin (5-HT) is involved in the hyperplasia through its interactions with specific receptors and internalization by a specific plasma membrane transporter. We investigated the expression and role of the 5-HT transporter (5-HTT) and 5-HT1B, 5-HT2A, and 5-HT2B receptors in lungs and isolated PA-SMCs

Research paper thumbnail of Long-Term Safety, Efficacy And Survival Outcomes Of Pulmonary Arterial Hypertension In WHO Functional Class II Patients Treated With Bosentan

B107. BIOMARKERS AND PREDICTORS OF OUTCOMES IN PULMONARY HYPERTENSION, 2012

Research paper thumbnail of 086 Altered Endothelin-1 (ET1) synthesis and ET1 receptors expression and function in idiopathic pulmonary hypertension: influence of BMPRII mutations

Revue des Maladies Respiratoires, 2007

Introduction: Progression of idiopathic pulmonary hypertension (PH) is associated with increased ... more Introduction: Progression of idiopathic pulmonary hypertension (PH) is associated with increased serum and lung interleukin-6 (IL-6) levels. In patients with chronic obstructive pulmonary disease, we recently reported that the severity of PH was closely linked to serum IL-6 levels and was linked to polymorphism of the IL-6 gene. To investigate the role of IL-6 in hypoxic PH, we examined development of PH in IL-6-deficient (IL-6-/-) mice and questioned whether exposure to hypoxia was associated with alteration in lung IL6 and IL6 receptor expression. Methods: Male IL-6-/-mice and their wild type (IL-6+/+) controls were subjected to 2 weeks exposure to hypoxia (10% O2) or normoxia. Results: In IL6+/+ mice, IL-6 mRNA levels increased by 2 to 4 fold after 1 week hypoxia with a return to basal levels after 2 weeks. Lung IL-6 receptor and gp 130 (signal transducer of IL-6) mRNA levels also increased by 6 to 10 fold at 1 week and remained elevated at 2 weeks exposure to hypoxia. Following exposure to 2 weeks hypoxia, the increase in systolic right ventricular pressure (SRVP) was markedly lower in IL-6-/-than in IL-6+/+ mice (25,2 3,6 versus 32,6 4,1 mmHg, p < 0,001) as well as right ventricular/ left ventricular+septum weight ratio (RV/LV+S) (28,6 1,6 versus 39,3 2,6 , p < 0,001) and the percentage of muscular pulmonary vessels (26,4 ± 8,5 versus 41,4 ± 6,5%, p < 0,05). Conclusion: These data suggest a key role of IL-6 in hypoxiainduced vascular remodeling and pulmonary hypertension.

Research paper thumbnail of Role for dysregulated endothelium- derived FGF2 signaling in progression of pulmonary hypertension

Revue des Maladies Respiratoires, 2008

Pulmonary hypertension (PH) is a progressive, lethal lung disease characterized by pulmonary arte... more Pulmonary hypertension (PH) is a progressive, lethal lung disease characterized by pulmonary artery SMC (PA-SMC) hyperplasia leading to right-sided heart failure. Molecular events originating in pulmonary ECs (P-ECs) may contribute to the PA-SMC hyperplasia in PH. Thus, we exposed cultured human PA-SMC to medium conditioned by P-EC from patients with idiopathic PH (IPH) or controls and found that IPH P-ECconditioned medium increased PA-SMC proliferation more than control P-EC medium. Levels of FGF2 were increased in the medium of IPH P-ECs over controls, while there was no detectable difference in TGF-β1, PDGF-BB, or EGF levels. No difference in FGF2-induced proliferation or FGF receptor type 1 (FGFR1) mRNA levels was detected between IPH and control PA-SMCs. Knockdown of FGF2 in P-EC using siRNA reduced the PA-SMC growth-stimulating effects of IPH P-EC medium by 60% and control P-EC medium by 10%. In situ hybridization showed FGF2 overproduction predominantly in the remodeled vascular endothelium of lungs from patients with IPH. Repeated intravenous FGF2-siRNA administration abolished lung FGF2 production, both preventing and nearly reversing a rat model of PH. Similarly, pharmacological FGFR1 inhibition with SU5402 reversed established PH in the same model. Thus, endothelial FGF2 is overproduced in IPH and contributes to SMC hyperplasia in IPH, identifying FGF2 as a promising target for new treatments against PH.

Research paper thumbnail of Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension

Thorax, 2004

Dexfenfluramine associated pulmonary arterial hypertension occurring in a patient with hereditary... more Dexfenfluramine associated pulmonary arterial hypertension occurring in a patient with hereditary haemorrhagic telangiectasia related to a mutation within the endoglin gene is described. This report highlights the critical role of the TGF-beta signalling pathway in this condition.

Research paper thumbnail of Prolongation d’un traitement par antivitamine K pendant dix-huit mois versus placebo au décours d’un premier épisode d’embolie pulmonaire idiopathique traité six mois : un essai randomisé multicentrique en double aveugle. Essai « PADIS-EP »

Revue des Maladies Respiratoires, 2008

Prolongation d'un traitement par antivitamine K pendant dix-huit mois versus placebo au décours d... more Prolongation d'un traitement par antivitamine K pendant dix-huit mois versus placebo au décours d'un premier épisode d'embolie pulmonaire idiopathique traité six mois : un essai randomisé multicentrique en double aveugle. Essai « PADIS-EP » Réception version princeps à la Revue : 16.01.2008. Demande de réponse aux auteurs : 26.03.2008. Réception de la réponse des auteurs : 30.04.2008. Acceptation définitive : 28.05.2008. Investigateur principal coordinateur : Francis Couturaud, CHU de Brest ; Promoteur : CHU de Brest ; Laboratoire fabriquant la warfarine : laboratoire Macors (Auxère) ; Organisme responsable du cahier d'observation électronique : société Clininfo (Université Lyon 1) ; Gestion des INR : Clinique des Anticoagulants d'Île de France.

Research paper thumbnail of Étude ouverte comparative de l'efficacité et de la tolérance de l'introduction des AVK au 1er ou au 10e jour du traitement par énoxaparine des thromboses veineuses profondes

La Revue de Médecine Interne, 1996

Research paper thumbnail of Hypertension artérielle pulmonaire associée aux connectivites

La Revue de Médecine Interne, 2002

Research paper thumbnail of Effect of Macitentan on Hospitalizations

JACC: Heart Failure, 2015

This study sought to evaluate the effect of macitentan on hospitalization of patients with sympto... more This study sought to evaluate the effect of macitentan on hospitalization of patients with symptomatic pulmonary arterial hypertension (PAH). PAH is a progressive, life-threatening disease often requiring hospitalization. In the multicenter, double-blind, randomized, event-driven, phase III SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) trial, patients with symptomatic PAH were randomized (1:1:1) to receive placebo or 3 mg or 10 mg of macitentan. Effects of macitentan on the risk, rate, and number of hospital days for all-cause and PAH-related hospitalizations were compared with those for placebo. Risk and causes of hospitalizations unrelated to PAH were investigated. Of 742 randomized patients, 250 received placebo, 250 received 3 mg of macitentan, and 242 received 10 mg of macitentan; the overall median duration of treatment was 115 weeks. Risk of all-cause hospitalization was reduced by 18.9% (p = 0.1208) and 32.3% (p = 0.0051) in the macitentan 3-mg and 10-mg arm, respectively. Rates of all-cause hospitalizations and numbers of hospital days were reduced by 20.5% (p = 0.0378) and 30.6% (p = 0.0278), respectively, with 3 mg of macitentan and by 33.1% (p = 0.0005) and 31.0% (p = 0.0336), respectively, with 10 mg of macitentan. Risk of PAH-related hospitalizations were reduced by 42.7% (p = 0.0015) and 51.6% (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) in the macitentan 3-mg and 10-mg arms, respectively. Rate of PAH-related hospitalizations and numbers of hospital days were reduced by 44.5% (p = 0.0004) and 53.3% (p = 0.0001), respectively, with 3 mg of macitentan, and reduced by 49.8% (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) and 52.3% (p = 0.0003), respectively, with 10 mg of macitentan. Risk of non-PAH-related hospitalization was similar between treatment arms. Macitentan 10 mg significantly reduced the risk and rate of all-cause hospitalization, which was driven by reductions in the risk and rate of PAH-related hospitalization. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension; NCT00660179).

Research paper thumbnail of P16 Treatment of VTE during pregnancy with a once-daily regimen of LMWH

Thrombosis Research, 2009

Research paper thumbnail of Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis

Thorax, 2005

Pulmonary hypertension (PH) is a rare complication of sarcoidosis, although it is not uncommon in... more Pulmonary hypertension (PH) is a rare complication of sarcoidosis, although it is not uncommon in advanced disease. A retrospective series of 22 sarcoidosis patients (16 men) of mean (SD) age 46 (13) years with PH was divided into two groups depending on the absence (stage 0: n = 2, stage II: n = 4, stage III: n = 1) or presence (n = 15) of radiographic pulmonary fibrosis at the time of PH diagnosis. In both groups PH was moderate to severe and there was no response to acute vasodilator challenge. In non-fibrotic cases no other cause of PH was found, suggesting a specific sarcoidosis vasculopathy, although no histological specimens were available. In cases with fibrosis there was no correlation between haemodynamics and lung volumes or arterial oxygen tensions, suggesting other mechanisms for PH in addition to pulmonary destruction and hypoxaemia. These included extrinsic arterial compression by lymphadenopathies in three cases and histologically proven pulmonary veno-occlusive disease in the five patients who underwent lung transplantation. Ten patients received high doses of oral prednisone for PH (stage 0: n = 1, stage II: n = 4 and stage IV: n = 5); three patients without pulmonary fibrosis experienced a sustained haemodynamic response. Survival of the overall population was poor (59% at 5 years). Mortality was associated with NYHA functional class IV but not with haemodynamic parameters or with lung function. Two very different phenotypes of sarcoidosis combined with PH are observed depending on the presence or absence of pulmonary fibrosis. PH is a severe complication of sarcoidosis.

Research paper thumbnail of Treatment of pulmonary hypertension secondary to connective tissue diseases

Research paper thumbnail of Inhaled Iloprost for Severe Pulmonary Hypertension

New England Journal of Medicine, 2002

The New Eng land Jour nal of Medicine Conclusions Inhaled iloprost is an effective therapy for pa... more The New Eng land Jour nal of Medicine Conclusions Inhaled iloprost is an effective therapy for patients with severe pulmonary hypertension. (N Engl J Med 2002;347:322-9.)

Research paper thumbnail of Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension

New England Journal of Medicine, 2005

Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monopho... more Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monophosphate, thereby enhancing the cyclic guanosine monophosphatemediated relaxation and growth inhibition of vascular smooth-muscle cells, including those in the lung.

Research paper thumbnail of Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial

The Lancet, 2008

Background Treatments for pulmonary arterial hypertension have been mainly studied in patients wi... more Background Treatments for pulmonary arterial hypertension have been mainly studied in patients with advanced disease (WHO functional class [FC] III and IV). This study was designed to assess the eff ect of the dual endothelin receptor antagonist bosentan in patients with WHO FC II pulmonary arterial hypertension.

Research paper thumbnail of Effects of the oral endothelin receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension

Journal of the American College of Cardiology, 2002

The purpose of this study was to investigate the effects of bosentan (125 or 250 mg twice daily) ... more The purpose of this study was to investigate the effects of bosentan (125 or 250 mg twice daily) on echocardiographic and Doppler variables in 85 patients with World Health Organization class III or IV pulmonary arterial hypertension (PAH). BACKGROUND Bosentan, an orally active dual endothelin-receptor antagonist, improves symptoms, exercise capacity, and hemodynamics in patients with PAH.

Research paper thumbnail of A prospective study of the 6 min walk test as a surrogate marker for haemodynamics in two independent cohorts of treatment-naïve systemic sclerosis-associated pulmonary arterial hypertension

Annals of the rheumatic diseases, Jan 31, 2015

Despite the wide use of the 6 min walk distance (6MWD), no study has ever assessed its validity a... more Despite the wide use of the 6 min walk distance (6MWD), no study has ever assessed its validity as a surrogate marker for haemodynamics and predictor of outcome in isolated pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH). We designed this work to address this issue. Treatment-naïve patients with SSc-PAH were prospectively included from two sources: the French PAH Network (a prospective epidemiological cohort) (n=83) and randomised clinical trials submitted for drug approval (Food and Drug Administration) (n=332). Correlations between absolute values of the 6MWD and haemodynamics at baseline, as well as between variations of 6MWD and haemodynamics during follow-up, were studied in both populations. In the French cohort, baseline cardiac output (CO) (R(2)=0.19, p=0.001) and New York Heart Association class (R(2)=0.10, p<0.001) were significantly and independently correlated with baseline 6MWD in multivariate analysis. A significant, independent, but wea...

Research paper thumbnail of Non-Invasive Determination of Cardiac Output in Pre-Capillary Pulmonary Hypertension

PLOS ONE, 2015

Cardiac output (CO) is a major diagnostic and prognostic factor in pre-capillary pulmonary hypert... more Cardiac output (CO) is a major diagnostic and prognostic factor in pre-capillary pulmonary hypertension (PH). Reference methods for CO determination, like thermodilution (TD), require invasive procedures and allow only steady-state measurements. The Modelflow (MF) method is an appealing technique for this purpose as it allows non-invasive and beatby-beat determination of CO.

Research paper thumbnail of Guidelines on diagnosis and treatment of pulmonary arterial hypertension

Research paper thumbnail of Prognostic Factors for Survival in Hiv-Associated Pulmonary Arterial Hypertension

Research paper thumbnail of Serotonin-Induced Smooth Muscle Hyperplasia in Various Forms of Human Pulmonary Hypertension

Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature ... more Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of pulmonary hypertension (PH). Serotonin (5-HT) is involved in the hyperplasia through its interactions with specific receptors and internalization by a specific plasma membrane transporter. We investigated the expression and role of the 5-HT transporter (5-HTT) and 5-HT1B, 5-HT2A, and 5-HT2B receptors in lungs and isolated PA-SMCs

Research paper thumbnail of Long-Term Safety, Efficacy And Survival Outcomes Of Pulmonary Arterial Hypertension In WHO Functional Class II Patients Treated With Bosentan

B107. BIOMARKERS AND PREDICTORS OF OUTCOMES IN PULMONARY HYPERTENSION, 2012

Research paper thumbnail of 086 Altered Endothelin-1 (ET1) synthesis and ET1 receptors expression and function in idiopathic pulmonary hypertension: influence of BMPRII mutations

Revue des Maladies Respiratoires, 2007

Introduction: Progression of idiopathic pulmonary hypertension (PH) is associated with increased ... more Introduction: Progression of idiopathic pulmonary hypertension (PH) is associated with increased serum and lung interleukin-6 (IL-6) levels. In patients with chronic obstructive pulmonary disease, we recently reported that the severity of PH was closely linked to serum IL-6 levels and was linked to polymorphism of the IL-6 gene. To investigate the role of IL-6 in hypoxic PH, we examined development of PH in IL-6-deficient (IL-6-/-) mice and questioned whether exposure to hypoxia was associated with alteration in lung IL6 and IL6 receptor expression. Methods: Male IL-6-/-mice and their wild type (IL-6+/+) controls were subjected to 2 weeks exposure to hypoxia (10% O2) or normoxia. Results: In IL6+/+ mice, IL-6 mRNA levels increased by 2 to 4 fold after 1 week hypoxia with a return to basal levels after 2 weeks. Lung IL-6 receptor and gp 130 (signal transducer of IL-6) mRNA levels also increased by 6 to 10 fold at 1 week and remained elevated at 2 weeks exposure to hypoxia. Following exposure to 2 weeks hypoxia, the increase in systolic right ventricular pressure (SRVP) was markedly lower in IL-6-/-than in IL-6+/+ mice (25,2 3,6 versus 32,6 4,1 mmHg, p < 0,001) as well as right ventricular/ left ventricular+septum weight ratio (RV/LV+S) (28,6 1,6 versus 39,3 2,6 , p < 0,001) and the percentage of muscular pulmonary vessels (26,4 ± 8,5 versus 41,4 ± 6,5%, p < 0,05). Conclusion: These data suggest a key role of IL-6 in hypoxiainduced vascular remodeling and pulmonary hypertension.

Research paper thumbnail of Role for dysregulated endothelium- derived FGF2 signaling in progression of pulmonary hypertension

Revue des Maladies Respiratoires, 2008

Pulmonary hypertension (PH) is a progressive, lethal lung disease characterized by pulmonary arte... more Pulmonary hypertension (PH) is a progressive, lethal lung disease characterized by pulmonary artery SMC (PA-SMC) hyperplasia leading to right-sided heart failure. Molecular events originating in pulmonary ECs (P-ECs) may contribute to the PA-SMC hyperplasia in PH. Thus, we exposed cultured human PA-SMC to medium conditioned by P-EC from patients with idiopathic PH (IPH) or controls and found that IPH P-ECconditioned medium increased PA-SMC proliferation more than control P-EC medium. Levels of FGF2 were increased in the medium of IPH P-ECs over controls, while there was no detectable difference in TGF-β1, PDGF-BB, or EGF levels. No difference in FGF2-induced proliferation or FGF receptor type 1 (FGFR1) mRNA levels was detected between IPH and control PA-SMCs. Knockdown of FGF2 in P-EC using siRNA reduced the PA-SMC growth-stimulating effects of IPH P-EC medium by 60% and control P-EC medium by 10%. In situ hybridization showed FGF2 overproduction predominantly in the remodeled vascular endothelium of lungs from patients with IPH. Repeated intravenous FGF2-siRNA administration abolished lung FGF2 production, both preventing and nearly reversing a rat model of PH. Similarly, pharmacological FGFR1 inhibition with SU5402 reversed established PH in the same model. Thus, endothelial FGF2 is overproduced in IPH and contributes to SMC hyperplasia in IPH, identifying FGF2 as a promising target for new treatments against PH.

Research paper thumbnail of Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension

Thorax, 2004

Dexfenfluramine associated pulmonary arterial hypertension occurring in a patient with hereditary... more Dexfenfluramine associated pulmonary arterial hypertension occurring in a patient with hereditary haemorrhagic telangiectasia related to a mutation within the endoglin gene is described. This report highlights the critical role of the TGF-beta signalling pathway in this condition.

Research paper thumbnail of Prolongation d’un traitement par antivitamine K pendant dix-huit mois versus placebo au décours d’un premier épisode d’embolie pulmonaire idiopathique traité six mois : un essai randomisé multicentrique en double aveugle. Essai « PADIS-EP »

Revue des Maladies Respiratoires, 2008

Prolongation d'un traitement par antivitamine K pendant dix-huit mois versus placebo au décours d... more Prolongation d'un traitement par antivitamine K pendant dix-huit mois versus placebo au décours d'un premier épisode d'embolie pulmonaire idiopathique traité six mois : un essai randomisé multicentrique en double aveugle. Essai « PADIS-EP » Réception version princeps à la Revue : 16.01.2008. Demande de réponse aux auteurs : 26.03.2008. Réception de la réponse des auteurs : 30.04.2008. Acceptation définitive : 28.05.2008. Investigateur principal coordinateur : Francis Couturaud, CHU de Brest ; Promoteur : CHU de Brest ; Laboratoire fabriquant la warfarine : laboratoire Macors (Auxère) ; Organisme responsable du cahier d'observation électronique : société Clininfo (Université Lyon 1) ; Gestion des INR : Clinique des Anticoagulants d'Île de France.

Research paper thumbnail of Étude ouverte comparative de l'efficacité et de la tolérance de l'introduction des AVK au 1er ou au 10e jour du traitement par énoxaparine des thromboses veineuses profondes

La Revue de Médecine Interne, 1996

Research paper thumbnail of Hypertension artérielle pulmonaire associée aux connectivites

La Revue de Médecine Interne, 2002

Research paper thumbnail of Effect of Macitentan on Hospitalizations

JACC: Heart Failure, 2015

This study sought to evaluate the effect of macitentan on hospitalization of patients with sympto... more This study sought to evaluate the effect of macitentan on hospitalization of patients with symptomatic pulmonary arterial hypertension (PAH). PAH is a progressive, life-threatening disease often requiring hospitalization. In the multicenter, double-blind, randomized, event-driven, phase III SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) trial, patients with symptomatic PAH were randomized (1:1:1) to receive placebo or 3 mg or 10 mg of macitentan. Effects of macitentan on the risk, rate, and number of hospital days for all-cause and PAH-related hospitalizations were compared with those for placebo. Risk and causes of hospitalizations unrelated to PAH were investigated. Of 742 randomized patients, 250 received placebo, 250 received 3 mg of macitentan, and 242 received 10 mg of macitentan; the overall median duration of treatment was 115 weeks. Risk of all-cause hospitalization was reduced by 18.9% (p = 0.1208) and 32.3% (p = 0.0051) in the macitentan 3-mg and 10-mg arm, respectively. Rates of all-cause hospitalizations and numbers of hospital days were reduced by 20.5% (p = 0.0378) and 30.6% (p = 0.0278), respectively, with 3 mg of macitentan and by 33.1% (p = 0.0005) and 31.0% (p = 0.0336), respectively, with 10 mg of macitentan. Risk of PAH-related hospitalizations were reduced by 42.7% (p = 0.0015) and 51.6% (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) in the macitentan 3-mg and 10-mg arms, respectively. Rate of PAH-related hospitalizations and numbers of hospital days were reduced by 44.5% (p = 0.0004) and 53.3% (p = 0.0001), respectively, with 3 mg of macitentan, and reduced by 49.8% (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) and 52.3% (p = 0.0003), respectively, with 10 mg of macitentan. Risk of non-PAH-related hospitalization was similar between treatment arms. Macitentan 10 mg significantly reduced the risk and rate of all-cause hospitalization, which was driven by reductions in the risk and rate of PAH-related hospitalization. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension; NCT00660179).

Research paper thumbnail of P16 Treatment of VTE during pregnancy with a once-daily regimen of LMWH

Thrombosis Research, 2009

Research paper thumbnail of Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis

Thorax, 2005

Pulmonary hypertension (PH) is a rare complication of sarcoidosis, although it is not uncommon in... more Pulmonary hypertension (PH) is a rare complication of sarcoidosis, although it is not uncommon in advanced disease. A retrospective series of 22 sarcoidosis patients (16 men) of mean (SD) age 46 (13) years with PH was divided into two groups depending on the absence (stage 0: n = 2, stage II: n = 4, stage III: n = 1) or presence (n = 15) of radiographic pulmonary fibrosis at the time of PH diagnosis. In both groups PH was moderate to severe and there was no response to acute vasodilator challenge. In non-fibrotic cases no other cause of PH was found, suggesting a specific sarcoidosis vasculopathy, although no histological specimens were available. In cases with fibrosis there was no correlation between haemodynamics and lung volumes or arterial oxygen tensions, suggesting other mechanisms for PH in addition to pulmonary destruction and hypoxaemia. These included extrinsic arterial compression by lymphadenopathies in three cases and histologically proven pulmonary veno-occlusive disease in the five patients who underwent lung transplantation. Ten patients received high doses of oral prednisone for PH (stage 0: n = 1, stage II: n = 4 and stage IV: n = 5); three patients without pulmonary fibrosis experienced a sustained haemodynamic response. Survival of the overall population was poor (59% at 5 years). Mortality was associated with NYHA functional class IV but not with haemodynamic parameters or with lung function. Two very different phenotypes of sarcoidosis combined with PH are observed depending on the presence or absence of pulmonary fibrosis. PH is a severe complication of sarcoidosis.

Research paper thumbnail of Treatment of pulmonary hypertension secondary to connective tissue diseases

Research paper thumbnail of Inhaled Iloprost for Severe Pulmonary Hypertension

New England Journal of Medicine, 2002

The New Eng land Jour nal of Medicine Conclusions Inhaled iloprost is an effective therapy for pa... more The New Eng land Jour nal of Medicine Conclusions Inhaled iloprost is an effective therapy for patients with severe pulmonary hypertension. (N Engl J Med 2002;347:322-9.)

Research paper thumbnail of Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension

New England Journal of Medicine, 2005

Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monopho... more Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monophosphate, thereby enhancing the cyclic guanosine monophosphatemediated relaxation and growth inhibition of vascular smooth-muscle cells, including those in the lung.

Research paper thumbnail of Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial

The Lancet, 2008

Background Treatments for pulmonary arterial hypertension have been mainly studied in patients wi... more Background Treatments for pulmonary arterial hypertension have been mainly studied in patients with advanced disease (WHO functional class [FC] III and IV). This study was designed to assess the eff ect of the dual endothelin receptor antagonist bosentan in patients with WHO FC II pulmonary arterial hypertension.

Research paper thumbnail of Effects of the oral endothelin receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension

Journal of the American College of Cardiology, 2002

The purpose of this study was to investigate the effects of bosentan (125 or 250 mg twice daily) ... more The purpose of this study was to investigate the effects of bosentan (125 or 250 mg twice daily) on echocardiographic and Doppler variables in 85 patients with World Health Organization class III or IV pulmonary arterial hypertension (PAH). BACKGROUND Bosentan, an orally active dual endothelin-receptor antagonist, improves symptoms, exercise capacity, and hemodynamics in patients with PAH.