G Simonneau

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

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Publications (575)3630.2 Total impact

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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; · 6.36 Impact Factor
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    ABSTRACT: Pulmonary hypertension is defined as an increase of mean pulmonary arterial pressure ≥25 mmHg at rest as assessed by right heart catheterization. According to different combinations of values of pulmonary wedge pressure, pulmonary vascular resistance and cardiac output, a hemodynamic classification of pulmonary hypertension has been proposed. Of major importance is the pulmonary wedge pressure which allows to distinguish pre-capillary (pulmonary wedge pressure ≤15 mmHg) and post-capillary (pulmonary wedge pressure >15 mmHg) pulmonary hypertension. Pre-capillary pulmonary hypertension includes the clinical groups 1 (pulmonary arterial hypertension), 3 (pulmonary hypertension due to lung diseases and/or hypoxia), 4 (chronic thrombo-embolic pulmonary hypertension) and 5 (pulmonary hypertension with unclear and/or multifactorial mechanisms). Post-capillary pulmonary hypertension corresponds to the clinical group 2 (pulmonary hypertension due to left heart diseases).
    Handbook of experimental pharmacology 01/2013; 218:3-29.
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    ABSTRACT: Pulmonary hypertension (PH) is a progressive disorder characterized by an increase in pulmonary artery pressure and structural changes in the pulmonary vasculature. Several observations indicate that growth factors play a key role in PH by modulating pulmonary artery smooth muscle cell (PA-SMC) function. In rats, established monocrotaline-induced PH (MCT-PH) can be reversed by blocking platelet-derived growth factor receptors (PDGF-R), epidermal growth factor receptors (EGF-R), or fibroblast growth factor receptors (FGF-R). All these receptors belong to the receptor tyrosine kinase (RTK) family. We evaluated whether RTK blockade by the nonspecific growth factor inhibitor, suramin, reversed advanced MCT-PH in rats via its effects on growth-factor signaling pathways. We found that suramin inhibited RTK and ERK1/2 phosphorylation in cultured human PA-SMCs. Suramin inhibited PA-SMC proliferation induced by serum, PDGF, FGF2, or EGF in vitro and ex vivo. Treatment with suramin from day 1 to day 21 after monocrotaline injection attenuated PH development, as shown by lower values for pulmonary artery pressure, right ventricular hypertrophy, and distal vessel muscularization on day 21 compared to control rats. Treatment with suramin from day 21 to day 42 after monocrotaline injection reversed established PH, thereby normalizing the pulmonary artery pressure values and vessel structure. Suramin treatment suppressed PA-SMC proliferation and attenuated both the inflammatory response and the deposition of collagen. RTK blockade by suramin can prevent MCT-PH and reverse established MCT-PH in rats. This study suggests that an anti-RTK strategy that targets multiple RTKs could be useful in the treatment of pulmonary hypertension.
    PLoS ONE 01/2013; 8(10):e77073. · 3.53 Impact Factor
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    ABSTRACT: Rational: Pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD) both display occlusive remodeling of the pulmonary vasculature responsible for increased pulmonary vascular resistances. Cytotoxic T-(CTL), Natural Killer-(NK) and Natural Killer T-(NKT) cells play a critical role in vascular remodeling in different physiological and pathological conditions. Granulysin (GNLY) represents a powerful effector protein for all these subpopulations. OBJECTIVES: To analyze the cytolytic compartment of inflammatory cells in PAH and PVOD patients. METHODS: The overall functional status of the cytolytic compartment was studied through epigenetic analysis of the GNLY gene in explanted lungs and in PBMC. Flow cytometry technology allowed analysis of specific circulating cytolytic cells and GNLY contents. A GNLY-specific ELISA allowed measurement of GNLY serum concentrations. MEASUREMENTS AND MAIN RESULTS: A decrease in GNLY demethylation in the gDNA extracted from PBMC and explanted lungs was found specifically in PVOD but not in PAH. This was associated with a decrease in populations and subpopulations of CTL and NKT, and an increase of NK populations. Despite the reduced granulysin-containing cells in PVOD patients, GNLY serum levels were higher, suggesting these cells were wasting their content. Furthermore, the increase of GNLY concentration in the serum of PVOD was significantly higher than in PAH patients. CONCLUSIONS: PVOD is characterized by alterations of circulating cytotoxic cell-subpopulations and by epigenetic dysregulation within the GNLY gene. Our findings may be helpful in the quest to develop needed diagnostic tools, including flow cytometry analyses, in order to screen for suspected PVOD in patients with pulmonary hypertension.
    American Journal of Respiratory and Critical Care Medicine 12/2012; · 11.04 Impact Factor
  • European Respiratory Review 12/2012; 21(126):267-70.
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    ABSTRACT: OBJECTIVE: To assess the survival and prognostic factors in patients with newly diagnosed incident systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) in the modern management era. METHODS: Prospectively enrolled SSc patients in the French PAH Network between January 2006 and November 2009, with newly diagnosed PAH and no interstitial lung disease, were analysed (85 patients, mean age 64.9±12.2 years). Median follow-up after PAH diagnosis was 2.32 years. RESULTS: A majority of patients were in NYHA functional class III-IV (79%). Overall survival was 90% (95% CI 81% to 95%), 78% (95% CI 67% to 86%) and 56% (95% CI 42% to 68%) at 1, 2 and 3 years from PAH diagnosis, respectively. Age (HR: 1.05, 95% CI 1.01 to 1.09, p=0.012) and cardiac index (HR: 0.49, 95% CI 0.27 to 0.89, p=0.019) were significant predictors in the univariate analysis. We also observed strong trends for gender, SSc subtypes, New York Heart Association functional class, pulmonary vascular resistance and capacitance to be significant predictors in the univariate analysis. Conversely, six-min walk distance, mean pulmonary arterial and right atrial pressures were not significant predictors. In the multivariate model, gender was the only independent factor associated with survival (HR: 4.76, 95% CI 1.35 to 16.66, p=0.015 for male gender). CONCLUSIONS: Incident SSc-associated PAH remains a devastating disease even in the modern management era. Age, male gender and cardiac index were the main prognosis factors in this cohort of patients. Early detection of less severe patients should be a priority.
    Annals of the rheumatic diseases 11/2012; · 8.11 Impact Factor
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    ABSTRACT: SESSION TYPE: Late-Breaking AbstractsPRESENTED ON: Tuesday, October 23, 2012 at 04:30 PM - 05:45 PMPURPOSE: Current oral PAH therapies have been approved based on short-term trials with exercise capacity as the primary endpoint. In this event-driven trial, the effect of macitentan, a novel dual endothelin receptor antagonist (ERA) with enhanced tissue penetration, was assessed on a primary endpoint of morbidity and mortality in PAH patients.METHODS: In this double-blind, placebo-controlled, Phase III, event-driven study, patients (≥12 years) with symptomatic PAH were randomized (1:1:1) to placebo, macitentan 3mg or macitentan 10mg, once daily. Stable background oral or inhaled PAH therapy, other than an ERA, was allowed. The primary endpoint was time from treatment initiation to first morbidity or mortality event in all randomized patients. This composite endpoint, defined as death, atrial septostomy, lung transplantation, initiation of intravenous/subcutaneous prostanoids or worsening of PAH, was blindly and independently adjudicated. Secondary endpoints included the composite of mortality due to PAH or hospitalization for PAH.RESULTS: 742 patients with PAH were randomized to placebo (n=250), macitentan 3mg (n=250) or macitentan 10mg (n=242); mean treatment duration was 85.3, 99.5 and 103.9 weeks, respectively. Macitentan reduced the risk of occurrence of morbidity and mortality events versus placebo by 30% in the 3mg group (97.5%CI:4-48%;P=0.0108) and 45% in the 10 mg group (97.5%CI:24-61%;P<0.0001). The effect of macitentan on this endpoint was observed irrespective of background PAH therapy (mainly phosphodiesterase type-5 inhibitors); risk reduction for macitentan 3mg and 10mg was 17% (95%CI:-16-41%) and 38% (95%CI:11-57%) in the presence of background PAH therapy and 47% (95%CI:15-66%) and 55% (95%CI:28-72%) in the absence of background PAH therapy. Macitentan 3mg and 10mg also reduced the risk of the secondary endpoint, mortality due to PAH/hospitalization for PAH, by 33% (97.5%CI:3-54%;P=0.0146) and 50% (97.5%CI:25-67%;P<0.0001), respectively. Macitentan was well tolerated, with similar incidences of elevated liver aminotransferases and peripheral edema across all groups. Adverse events more frequently associated with macitentan versus placebo were headache, nasopharyngitis and anemia.CONCLUSIONS: Macitentan demonstrated a significant effect on the combined endpoint of morbidity and mortality, with a favorable safety profile, in the largest and longest randomized controlled trial of therapy in PAH to date.CLINICAL IMPLICATIONS: Macitentan has the potential to improve long-term outcomes in PAH patients.DISCLOSURE: Lewis Rubin: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Lung LLC, Consultant fee, speaker bureau, advisory committee, etc.: Gilead, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: GeNoTomás Pulido: Consultant fee, speaker bureau, advisory committee, etc.: Actelion , Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Lily, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Grant monies (from sources other than industry): National Heart Insitute, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): United TherapeuticsRichard Channick: Grant monies (from industry related sources): Actelion, Consultant fee, speaker bureau, advisory committee, etc.: ActelionMarion Delcroix: Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: BayerNazzareno Galie: Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): Eli Lilly, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: BayerHossein-Ardeschir Ghofrani: Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): Ergonex, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Ergonex, Consultant fee, speaker bureau, advisory committee, etc.: Gilead, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Merck, Consultant fee, speaker bureau, advisory committee, etc.: NovartisPavel Jansa: Grant monies (from industry related sources): Actelion, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: AOP Orphan, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: BayerFranck-Olivier Le Brun: Employee: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: ActelionSanjay Mehta: Grant monies (from industry related sources): Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Takeda Nycomed, Grant monies (from sources other than industry): Heart & Stroke Foundation of Ontario/Canada (HSFO/C), Grant monies (from industry related sources): Canadian Institute of Health Research / CIHR, Grant monies (from sources other than industry): Ontario Thoracic Society (OTS), Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Canada, Consultant fee, speaker bureau, advisory committee, etc.: Takeda - Nycomed, Consultant fee, speaker bureau, advisory committee, etc.: Boehringer-Ingelheim CanadaCamilla Mittelholzer: Employee: Actelion, Shareholder: ActelionLoic Perchenet: Employee: Actelion, Shareholder: ActelionBkS Sastry: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKlineOlivier Sitbon: Grant monies (from industry related sources): GlaxoSmithKline, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): bayer, Grant monies (from industry related sources): Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: United Therapuetics, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: United Therapuetics, Consultant fee, speaker bureau, advisory committee, etc.: BayerRogerio Souza: Grant monies (from industry related sources): Actelion, Consultant fee, speaker bureau, advisory committee, etc.: ActelionAdam Torbicki: Grant monies (from industry related sources): Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: AOP Orphan Pharmaceutics, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): United Therapeutics, Grant monies (from industry related sources): AOP Orphan Pharmaceutics, Grant monies (from industry related sources): Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Bristol Myers SquibbGerald Simonneau: Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): GlaxoSmithKline, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: NovartisMacitentan is under investigation for the treatment of pulmonary arterial hypertension. SERAPHIN, the Phase 3 study reported here, is the registration trial for macitentan in this indication. University of California, San Diego, CA.
    Chest 10/2012; 142(4_MeetingAbstracts):1026A. · 7.13 Impact Factor
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    ABSTRACT: SESSION TYPE: Late-Breaking AbstractsPRESENTED ON: Tuesday, October 23, 2012 at 04:30 PM - 05:45 PMPURPOSE: Riociguat is the first member of a novel class of compounds, the soluble guanylate cyclase (sGC) stimulators. With a dual mode of action, it synergizes with endogenous nitric oxide (NO) and also directly stimulates sGC independent of NO availability. Riociguat restores the NO-sGC-cGMP pathway resulting in a significant improvement in pulmonary vascular hemodynamics and an increase in exercise ability. Here, we present results from the Phase III, multicenter, randomized, double-blind, placebo-controlled CHEST-1 study, which investigated the efficacy and safety of riociguat in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).METHODS: Patients with inoperable CTEPH (as assessed by an independent adjudication committee) or with persisting or recurrent pulmonary hypertension (PH) after pulmonary endarterectomy (PEA), and a mean pulmonary vascular resistance (PVR) >480 dyn·s/cm5 were enrolled in the trial. Treatment with supportive PH therapies was permitted but patients were treatment naïve with regards to pulmonary arterial hypertension-specific therapies. Patients were randomized to either placebo or oral riociguat, which was titrated from a starting dose of 1 mg three times daily (t.i.d.) according to systolic blood pressure (range 0.5-2.5 mg t.i.d.). The primary outcome measure was the change from baseline in 6-minute walking distance after 16 weeks of treatment. Secondary endpoints included change from baseline in PVR, functional class, time to clinical worsening, and safety and tolerability.RESULTS: The study has enrolled a total of 263 patients. Results will be available and presented at the time of the congress.CONCLUSIONS: The CHEST-1 study is the largest placebo-controlled trial to date in CTEPH and will assess the therapeutic benefit of the sGC stimulator riociguat.CLINICAL IMPLICATIONS: At present, no approved pharmacologic therapy exists for CTEPH and as a result there is an urgent unmet need in patients who are not eligible for PEA, or who have persistent or recurrent PH after PEA.DISCLOSURE: Hossein Ghofrani: Grant monies (from sources other than industry): Hossein A. Ghofrani has received sponsored grants over the past 3 years from the German Research Foundation, Excellence Cluster Cardiopulmonary Research and Germany Ministry for Education and Research, Grant monies (from industry related sources): Hossein A. Ghofrani has received industry-sponsored grants over the past 3 years from Bayer HealthCare AG, Aires, Encysive/Pfizer and Novartis, Consultant fee, speaker bureau, advisory committee, etc.: Hossein A. Ghofrani has relationships with the following drug companies: Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Novartis and GlaxoSmithKlineFriedrich Grimminger: Consultant fee, speaker bureau, advisory committee, etc.: Friedrich Grimminger has relationships with Bayer AGMarius Hoeper: Consultant fee, speaker bureau, advisory committee, etc.: Marius Hoeper has relationships with the following drug companies: Actelion, Bayer, Gilead, GlaxoSmithKline, Lilly, Novartis and PfizerNick Kim: Grant monies (from industry related sources): Nick H. Kim has received industry related grant monies from the following drug companies: Actelion, Gilead and United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Nick H. Kim has relationships with the following drug companies: Bayer (consultant), Gilead, United Therapeutics (advisory meeting)Eckhard Mayer: Consultant fee, speaker bureau, advisory committee, etc.: Eckhard Mayer has relationships with the following drug companies: Bayer Schering, Pfizer, ActelionDieter Neuser: Employee: Dieter Neuser is an employee of Bayer Pharma AGJanethe Pena: Employee: Janethe Pena is an employee of Bayer HealthCareGerald Simonneau: University grant monies: Gerald Simonneau has received university grant monies from the following drug companies: Actelion, Bayer, GlaxoSmithKline, Lilly, Novartis and Pfizer, Grant monies (from industry related sources): Gerald Simonneau has received industry related grant monies from the following drug companies: Actelion, Bayer, GlaxoSmithKline, Lilly, Novartis and Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Gerald Simonneau has relationships with the following drug companies: Actelion, Bayer, GlaxoSmithKline, Lilly, Novartis and PfizerMartin Wilkins: Grant monies (from industry related sources): Martin Wilkins has received grant monies from Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Martin Wilkins is a Chair on a research abstract panel for BayerRiociguat is an investigational new drug currently in process for registration submission to health authorities, after successful finalisation of an RCT in patients with PAH.Department of Internal Medicine, University Hospital Giessen and Marburg, Giessen, Germany.
    Chest 10/2012; 142(4_MeetingAbstracts):1023A. · 7.13 Impact Factor
  • Nazzereno Galiè, Lewis Rubin, Gérald Simonneau
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    ABSTRACT: The meeting of the Advisory Board of Experts in Pulmonary Hypertension (ABEPH) in 2011 discussed the potential development of a prognostic score for pulmonary arterial hypertension (PAH) based on parameters associated with right ventricular function. During the discussion, a shortlist of parameters derived from hemodynamic, echocardiography, magnetic resonance imaging, and biomarker analysis was developed. This shortlist is the starting point for developing a score that reflects heart function; such a score could have potential in the future clinical management of patients with PAH.
    The American journal of cardiology 09/2012; 110(6 Suppl):49S-51S. · 3.58 Impact Factor
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    ABSTRACT: A growing body of published evidence exists on the risk factors for disease progression in pulmonary arterial hypertension (PAH). The Scientific Steering Committee for the Study of Risk in PAH was established to bring together leading clinical and statistical experts in PAH and risk modelling, for the purpose of advancing the understanding of the risk of development and progression of PAH. Herein, we discuss the impact of this information on three key areas: 1) clinical decision-making; 2) policy and reimbursement; and 3) future trials and research.
    European Respiratory Review 09/2012; 21(125):234-8.
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    ABSTRACT: In chronic thromboembolic pulmonary hypertension (CTEPH) increased pulmonary vascular resistance is caused by fibrotic organization of unresolved thromboemboli. CTEPH mainly differs from pulmonary arterial hypertension (PAH) by the proximal location of pulmonary artery obliteration, although distal arteriopathy can be observed as a consequence of non-occluded area overperfusion. Accordingly, there is proportionally more wave reflection in CTEPH, impacting on pressure and flow wave morphology. However, the time constant, that is resistance times compliance, is not different in CTEPH and PAH, indicating only trivial effects of proximal wave reflection on hydraulic right ventricular load. More discriminative is the analysis of the pressure decay after pulmonary arterial occlusion, which is more rapid in the absence of significant distal arteriopathy. Structure and function of the right ventricle show a similar pattern of right ventricular hypertrophy, namely dilatation and wall thickening as well as loss of function in CTEPH as in PAH. This is probably related to similar loading conditions. Hyperventilation with hypocapnia is characteristic of both PAH and CTEPH. Ventilatory equivalents for carbon dioxide, as a function of arterial PCO2, conform to the alveolar ventilation equation in both conditions, indicating a predominant role of increased chemosensitivity. However, a slight increase in the arterial to end-tidal PCO2 gradient in CTEPH shows a contribution of increased dead space ventilation.
    European Respiratory Journal 08/2012; · 6.36 Impact Factor
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    ABSTRACT: Background: Renal replacement therapy has been suggested as a therapeutic option in the setting of acute right ventricular failure in patients with severe precapillary pulmonary hypertension. However, there are few data supporting this strategy. Objectives: To describe the clinical course and the prognosis of pulmonary hypertensive patients undergoing renal replacement therapy in the setting of acute right heart failure. Methods: This was a single-center retrospective study over an 11-year period. Data were collected from all patients with chronic precapillary pulmonary hypertension requiring catecholamine infusions for clinical worsening and acute kidney injury that necessitated renal replacement therapy. Results: Fourteen patients were included. At admission, patients had a blood urea of 28.2 mmol/l (22.3-41.2), a creatinine level of 496 µmol/l (304-590), and a mean urine output in the 24 h preceding hospitalization of 200 ml (0-650). Sixty-eight renal replacement therapy sessions were performed, 36 of which were continuous and 32 of which were intermittent. Systemic hypotension occurred in 16/32 intermittent and 16/36 continuous sessions (p = 0.9). Two patients died during a continuous session. The intensive care unit-related, 1-, and 3-month mortality was 46.7, 66.7, and 73.3%, respectively. Conclusion: Renal replacement therapy is feasible in the setting of acute right ventricular failure in patients with severe precapillary pulmonary hypertension but is associated with a poor prognosis. The best modality and timing in this population remain to be defined.
    Respiration 08/2012; · 2.92 Impact Factor
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    ABSTRACT: Backgrond: A subset of patients with heart failure with preserved ejection fraction (HFpEF) will have a marked increase in pulmonary artery pressure (PAP). Objective: To evaluate the clinical and hemodynamic characteristics of these patients in comparison to patients with idiopathic pulmonary arterial hypertension (IPAH). Methods: We reviewed the clinical and hemodynamic data of patients with HFpEF with out-of-proportion pulmonary hypertension (HFpEF-PH) and compared it to the corresponding data of age-matched patients with IPAH. Results: Twenty consecutive patients with HFpEF-PH and 20 patients with IPAH were included in the study. The mean age (±SD) was 71.3 ± 7.8 and 70.2 ± 6.7 years, respectively. The majority of the HFpEF-PH patients were postmenopausal females with at least two features of the metabolic syndrome and atrial fibrillation. Although HFpEF-PH patients fulfilled the criteria for out-of-proportion PH, with transpulmonary gradient (TPG) >12 mm Hg, the difference between the diastolic PAP and the pulmonary capillary wedge pressure (PCWP) was significantly lower compared to IPAH (6.3 ± 6.2 vs. 27.5 ± 4.8, p < 0.00001). Conclusions: Our results suggest that a diagnosis of HFpEF-PH should be suspected when severe PH occurs in an elderly postmenopausal female with one or more features of the metabolic syndrome and atrial fibrillation. Interestingly, these patients had significantly lower differences between diastolic PAP and PCWP, suggesting that the increase in TPG is mainly caused by an elevated systolic PAP, possibly as a result of increased pulmonary vascular stiffness, and not pulmonary vascular remodeling.
    Respiration 08/2012; · 2.92 Impact Factor
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    ABSTRACT: Rationale: Patients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neurohormonal systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system are up-regulated, but this may have long-term negative effects on the progression of iPAH. Objectives: Assess systemic and pulmonary RAAS activity in patients with iPAH and determine the efficacy of chronic RAAS inhibition in experimental PAH. Methods: We collected 79 blood samples from 58 patients with iPAH in the VU University Medical Center Amsterdam (between 2004 and 2010) to determine systemic RAAS activity. Measurements and Main Results: We observed increased levels of renin, angiotensin (Ang)I, and AngII, which were associated with disease progression (P < 0.05) and mortality (P < 0.05). To determine pulmonary RAAS activity, lung specimens were obtained from patients with iPAH (during lung transplantation, n = 13) and control subjects (during lobectomy or pneumonectomy for cancer, n = 14). Local RAAS activity in pulmonary arteries of patients with iPAH was increased, demonstrated by elevated angiotensin-converting enzyme activity in pulmonary endothelial cells and increased AngII type 1 (AT(1)) receptor expression and signaling. In addition, local RAAS up-regulation was associated with increased pulmonary artery smooth muscle cell proliferation via enhanced AT(1) receptor signaling in patients with iPAH compared with control subjects. Finally, to determine the therapeutic potential of RAAS activity, we assessed the chronic effects of an AT(1) receptor antagonist (losartan) in the monocrotaline PAH rat model (60 mg/kg). Losartan delayed disease progression, decreased right ventricular afterload and pulmonary vascular remodeling, and restored right ventricular-arterial coupling in rats with PAH. Conclusions: Systemic and pulmonary RAAS activities are increased in patients with iPAH and are associated with increased pulmonary vascular remodeling. Chronic inhibition of RAAS by losartan is beneficial in experimental PAH.
    American Journal of Respiratory and Critical Care Medicine 08/2012; 186(8):780-9. · 11.04 Impact Factor
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    ABSTRACT: OBJECTIVES: The study aimed to determine the optimal surgical procedure to treat pulmonary artery sarcomas responsible for pulmonary hypertension. METHODS: Between 1997 and 2010, 31 patients were treated surgically for pulmonary artery sarcomas. Sixteen patients were male; the mean age was 56 years (range, 26-78 years). Common symptoms were characteristic of acute or chronic pulmonary thromboembolic disease. Also, 21 patients experienced mild to severe pulmonary hypertension, with a mean total peripheral resistance of 473 dyn s cm(-5). Clinical presentation and preoperative work-up confirmed the suspicion of pulmonary artery sarcoma in 18 patients. The required surgical procedures included the following: pulmonary endarterectomy in 25 patients (combined with a right pneumonectomy in five and with a replacement of the main pulmonary artery by a homograft reconstruction in one), pneumonectomy only in five (three right and two left), with the use of cardiopulmonary bypass in three cases. In one patient, the right pulmonary artery only was replaced on cardiopulmonary bypass. RESULTS: Final pathology showed 26 high-grade and five intermediate-grade sarcomas. The 30-day mortality was 13% (four patients). Repeat pulmonary resection was required in two patients due to recurrent disease. Moreover, 18 patients received adjuvant therapy. Mean follow-up was 19 months (range, 1-99 months); of the 11 patients alive at follow-up, four were noted to have recurrent disease. The 1-, 3- and 5- year survival was 63, 29 and 22%, respectively. CONCLUSIONS: The prognosis of this very infrequent disease remains poor. Bilateral pulmonary endarterectomy may yield significant survival rates because it provides completeness of resection without sacrificing the pulmonary vascular bed.
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 07/2012; · 2.40 Impact Factor
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    ABSTRACT: Patients with pulmonary arterial hypertension (PAH) may exhibit reduced expiratory flows at low lung volumes, which could promote exercise-induced dynamic hyperinflation (DH). This study aimed at examining the impact of a potential exercise-related DH on the intensity of dyspnoea in patients with PAH undergoing symptom-limited incremental cardiopulmonary cycle exercise testing (CPET).Twenty-five young (38±12 yr old) non-smoking PAH patients with no evidence of spirometric obstruction and 10 age-matched non-smoking healthy subjects performed a CPET to the limit of tolerance. Ventilatory pattern, operating lung volumes [derived from inspiratory capacity (IC) measurements], and dyspnoea intensity (Borg scale) were assessed throughout CPET.IC decreased (i.e., DH) progressively throughout CPET in PAH patients (average 0.15 L), whereas it increased in all the healthy subjects (0.45 L). Among PAH patients, 15 (60%) exhibited a decrease in IC throughout exercise (average 0.50 L), whereas in the remaining 10 patients (40%) IC increased (average 0.36 L). Dyspnoea intensity and ventilation were greater in PAH patients than in controls at any stage of CPET, whereas inspiratory reserve volume was lower.We conclude that DH-induced mechanical constraints and excessive ventilatory demand occurred in these young non-smoking PAH patients with no spirometric obstruction and was associated with exertional dyspnoea.
    European Respiratory Journal 07/2012; · 6.36 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate the long-term safety and durability of efficacy of tadalafil for pulmonary arterial hypertension. Tadalafil is an oral phosphodiesterase-5 inhibitor approved for PAH treatment. In the multicenter, placebo-controlled, randomized, 16-week PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) study, tadalafil 40 mg improved exercise capacity and delayed clinical worsening. Eligible patients from PHIRST received once-daily tadalafil 20 mg (T20 mg) or 40 mg (T40 mg) (n = 357) in the double-blind, 52-week, uncontrolled extension study (PHIRST-2); 293 patients completed PHIRST-2. Durability of efficacy was explored using the 6-min walk distance (6MWD) test. Clinical worsening and changes in World Health Organization functional class were evaluated. The safety profile of tadalafil in PHIRST-2 was similar to that in PHIRST, with typical phosphodiesterase-5 inhibitor adverse events. The 6MWDs achieved in PHIRST for the subset of patients receiving T20 mg and T40 mg in both PHIRST and PHIRST-2 (406 ± 67 m [n = 52] and 413 ± 81 m [n = 59] at PHIRST-2 enrollment, respectively) were maintained at PHIRST-2 completion (415 ± 80 m [n = 51] and 410 ± 78 m [n = 59], respectively). Numerically fewer patients who were on T40 mg in PHIRST and PHIRST-2 experienced World Health Organization functional class deterioration (6% [n = 5]) compared with those randomized to T20 mg (9% [n = 7]) across both studies. Post hoc analyses showed that background bosentan use and higher 6MWD at PHIRST baseline were associated with fewer clinical worsening events. Long-term treatment with tadalafil was well tolerated in patients with pulmonary arterial hypertension. In patients receiving either T20 mg or T40 mg, the improvements in 6MWD demonstrated in the 16-week PHIRST study appeared sustained for up to 52 additional weeks of treatment in PHIRST-2. (Pulmonary Arterial Hypertension and Response to Tadalafil Study; NCT00549302).
    Journal of the American College of Cardiology 07/2012; 60(8):768-74. · 14.09 Impact Factor
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    ABSTRACT: Recent hemodynamic studies performed in large cohorts of adult patients with sickle cell disease have established the prevalence of pulmonary hypertension in this disease about 6 to 10%. Over half of these correspond to postcapillary pulmonary hypertension. Precapilliary arterial pulmonary hypertension seems to be a relatively infrequent complication of the disease. It is characterized by a different hemodynamic profile of idiopathic PAH with lower levels of pulmonary pressures and pulmonary vascular resistance. However, pulmonary vascular disease appears to have a significant impact on the functional status and vital prognosis of patients with sickle cell disease. The predictive value of echocardiography to detect pulmonary hypertension in this population is low (25-32%) when the threshold of tricuspid regurgitation velocity of 2.5m/s is used. At present, no specific treatments for pulmonary arterial hypertension is currently approved for the treatment of PAH associated with sickle cell disease due to lack of data in this specific population.
    La Presse Médicale 06/2012; · 0.87 Impact Factor
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    ABSTRACT: Idiopathic pulmonary arterial hypertension (IPAH) remains a progressive fatal disease. Palliative Potts shunt has been proposed in children displaying suprasystemic IPAH. A retrospective multicenter study was performed to evaluate Potts shunt in pediatric IPAH. Between 2003 and 2010, 8 children with suprasystemic IPAH and in World Health Organization functional class IV despite medical pulmonary arterial hypertension therapy underwent Potts shunt. Age at IPAH diagnosis ranged from 4 to 180 months (median age, 64 months). Surgical procedure was performed in a mean delay of 41.9±54.3 months (range, 4 to 167 months; median delay, 20 months) after IPAH diagnosis. Mean size of the Potts shunt was 9.25±3.30 mm. Two patients, whose medical pulmonary arterial hypertension therapy had been interrupted just after surgery, died at postoperative days 11 and 13 of acute pulmonary hypertensive crisis. After a mean follow-up of 63.7±16.1 months, the 6 children who were discharged from the hospital were alive. Functional status improved markedly in the 6 survivors, with a World Health Organization functional class I (n=4) or II (n=2) at last follow-up, consistent with significant improvement of 6-minute-walk distance (302±95 m [51%±20% of theoretical values] versus 456±91 m [68%±10% of theoretical values]; p=0.038) and decrease of brain natriuretic peptide levels (608±109 pg/mL versus 76±45 pg/mL; p=0.035). No Potts shunt was found to be restrictive at last echocardiography. Palliative Potts shunt constitutes a new alternative to lung transplantation in severely ill children with suprasystemic IPAH, carrying a prolonged survival and persistent improvement in functional capacities.
    The Annals of thoracic surgery 06/2012; 94(3):817-24. · 3.45 Impact Factor

Publication Stats

23k Citations
3,630.20 Total Impact Points

Institutions

  • 2008–2014
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      Lutetia Parisorum, Île-de-France, France
    • Armed Forces Biomedical Research Institute, France
      Bretigny, Île-de-France, France
  • 1991–2014
    • Université Paris-Sud 11
      • • Faculty of Pharmaceutical Sciences
      • • Service de Pneumologie
      • • Faculté de Médecine
      Orsay, Île-de-France, France
  • 2013
    • Mater Misericordiae University Hospital
      Dublin, Leinster, Ireland
    • University of Grenoble
      Grenoble, Rhône-Alpes, France
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 2011–2013
    • Papworth Hospital NHS Foundation Trust
      Papworth, England, United Kingdom
    • Institut Cochin
      Lutetia Parisorum, Île-de-France, France
  • 2006–2013
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 1988–2013
    • Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud
      Clamart, Île-de-France, France
  • 2012
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States
    • University of Lille Nord de France
      Lille, Nord-Pas-de-Calais, France
  • 2002–2012
    • University of Bologna
      • Institute of Cardiology
      Bologna, Emilia-Romagna, Italy
    • Universitätsklinikum Jena
      Jena, Thuringia, Germany
  • 1990–2012
    • Centre Chirurgical Marie Lannelongue
      Plessis-Robinson, Île-de-France, France
  • 2001–2011
    • University of California, San Diego
      • • Department of Medicine
      • • Division of Pulmonary and Critical Care Medicine
      San Diego, CA, United States
  • 2010
    • Centre Hospitalier Régional Universitaire de Lille
      • Division of Internal Medicine
      Lille, Nord-Pas-de-Calais, France
  • 2009–2010
    • Université Libre de Bruxelles
      Bruxelles, Brussels Capital Region, Belgium
    • Universität Heidelberg
      Heidelburg, Baden-Württemberg, Germany
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
    • Université de Montréal
      Montréal, Quebec, Canada
    • Palmelit Francia
      Montferrier, Languedoc-Roussillon, France
    • Centre Hospitalier Universitaire de Brest
      Brest, Brittany, France
  • 2006–2010
    • Université René Descartes - Paris 5
      • • Faculté de Médecine
      • • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
  • 2007
    • Columbia University
      New York City, New York, United States
  • 2002–2006
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
  • 2005
    • University of Michigan
      Ann Arbor, Michigan, United States
    • Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval)
      Québec, Quebec, Canada
    • Hôtel-Dieu de Paris – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France
  • 2004
    • Harbor-UCLA Medical Center
      Torrance, California, United States
    • CHRU de Strasbourg
      Strasburg, Alsace, France
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
  • 1999
    • Institute Mutualiste Montsouris
      Lutetia Parisorum, Île-de-France, France
    • The University of Sheffield
      • Medical School
      Sheffield, ENG, United Kingdom
  • 1997
    • Azienda Ospedaliera Niguarda Ca' Granda
      • Department of Pneumology
      Milano, Lombardy, Italy