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Biomedical subjects

G Simonneau

Publications and source records attributed to G Simonneau.

At least 55 records · Page 3Linked to original sources
PubMed2002

[Pulmonary hypertension associated with connective tissue diseases].

PURPOSE: Pulmonary hypertension is a rare but well-known life-threatening complication of connective tissue diseases. The aim of this article is to analyse the available literature and to report the experience of a pulmonary vascular diseases centre about this complication. CURRENT KNOWLEDGE AND KEY POINTS: Scleroderma and its limited variant, the CREST syndrome (calcification, Raynaud phenomenon, esophageal dysmotility, sclerodactily, telangiectasia), is the most common connective tissue disease affected by pulmonary hypertension. Dyspnea is the main symptom and is frequently severe. Echocardiography is an excellent exam to detect pulmonary hypertension. However, right heart catheterization is necessary to confirm the diagnosis of pulmonary hypertension and to test vasoreactivity with a potent vasodilator such as nitric oxide. Pulmonary hypertension is less severe in patients with connective tissue diseases perhaps because of an earlier diagnosis. A significantly lower proportion of patients presents an acute vasodilator response, suggesting an early constitution of irreversible pulmonary vascular lesions. Continuous intravenous epoprostenol therapy seems to be less effective as compared with patients with primitive pulmonary hypertension and does not improve survival. So, we observed dramatic improvement in rare cases after immunosuppressive therapy. FUTURE PROSPECTS AND PROJECTS: New treatments with oral, subcutaneous or inhaled stable prostacyclin analogs or with an endothelin receptor antagonist are currently being evaluated. The role of immunosuppressive therapy has to be defined.

Antihypertensive Agents↗
PubMed2002

Plasminogen activation by blood monocytes and alveolar macrophages in primary pulmonary hypertension.

The pathophysiology of primary pulmonary hypertension (PPH) remains poorly understood. Vascular wall remodeling and endothelial dysfunction reflected by modifications in plasma fibrinolytic proteins and von Willebrand factor have been well documented in PPH. We hypothesize that endothelial mediators, produced in excess in PPH patients, may stimulate migrating mononuclear cells and thereby modulate alveolar macrophage function; in particular, the plasminogen activation system. Components of the fibrinolytic system were therefore studied in plasma, blood monocytes and alveolar macrophages obtained from bronchoalveolar lavage in 10 patients with PPH and in four controls. Compared with controls, PPH patients had elevated plasma levels of tissue-type plasminogen activator (15.6 +/- 9.9 versus 5.5 +/- 3 ng/ml) and plasminogen activator inhibitor-1 (27.8 +/- 23 versus 16.4 +/- 12 ng/ml). In contrast, binding and activation of plasminogen by single-chain urokinase-type plasminogen activator (scu-PA) at the surface of blood monocytes and alveolar macrophages were not different from those of control values. Dissociation constants (K(d)) for binding of scu-PA and plasminogen to alveolar macrophages were similar in both PPH (4.7 +/- 1.5 and 0.88 +/- 0.3 micromol/l, respectively) and control (6.7 +/- 0.1 and 1.02 +/- 0.12 micromol/l, respectively) groups. These results indicate that in PPH patients the fibrinolytic activity of alveolar macrophages is normal, whereas endothelial fibrinolytic proteins are abnormally elevated in plasma.

Adult↗
PubMed2002

Pulmonary arterial hypertension and type-I glycogen-storage disease: the serotonin hypothesis.

A case of pulmonary arterial hypertension in a patient with type-Ia glycogen-storage disease, a rare autosomal recessive disorder caused by a deficiency of glucose-6-phosphatase is reported in this study. It has been suggested that the occurrence of pulmonary arterial hypertension in type-Ia glycogen-storage disease could be due to an abnormal production of vasoconstrictive amines such as serotonin. To test this hypothesis, plasma serotonin concentrations were prospectively measured in 13 patients with type-Ia glycogen-storage disease, one patient with severe pulmonary hypertension and type-Ia glycogen-storage disease, 16 patients displaying severe pulmonary arterial hypertension, and 26 normal healthy controls. Elevated plasma serotonin concentrations were found in patients with either severe pulmonary arterial hypertension (38.8+/-7.3 nmol x L(-1)) or type-Ia glycogen-storage disease (36.8+/-11.5 nmol x L(-1)), as compared with controls (8.8+/-0.6 nmol x L(-1), p<0.001). Plasma serotonin was dramatically elevated in the patient with type-Ia glycogen-storage disease and pulmonary arterial hypertension (113.4 nmol x L(-1)). It is concluded that type-Ia glycogen-storage disease may be another condition in which abnormal handling of serotonin is one event in a multistep process leading to severe pulmonary arterial hypertension.

Adolescent↗
PubMed2002

BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives.

This study investigated whether patients developing pulmonary arterial hypertension (PAH) after exposure to the appetite suppressants fenfluramine and dexfenfluramine have mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, as reported in primary pulmonary hypertension. BMPR2 was examined for mutations in 33 unrelated patients with sporadic PAH, and in two sisters with PAH, all of whom had taken fenfluramine derivatives, as well as in 130 normal controls. The PAH patients also underwent cardiac catheterisation and body mass determinations. Three BMPR2 mutations predicting changes in the primary structure of the BMPR-II protein were found in three of the 33 unrelated patients (9%), and a fourth mutation was found in the two sisters. No BMPR2 mutations were identified in the 130 normal controls. This difference in frequency was statistically significant. Moreover, the mutation-positive patients had a somewhat shorter duration of fenfluramine exposure before illness than the mutation-negative patients, a difference that was statistically significant when the two sisters were included in the analysis. In conclusion, the present authors have detected bone morphogenetic protein receptor 2 mutations that appear to be rare in the general population but may combine with exposure to fenfluramine derivatives to greatly increase the risk of developing severe pulmonary arterial hypertension.

Adolescent↗
PubMed2002

[Pulmonary hypertension and obesity].

Obesity is a morbid condition with hemodynamic consequences affecting the systemic and pulmonary circulations leading to a risk of pulmonary hypertension. Data in the literature do not argue in favor of a direct relationship between pulmonary hypertension and obesity. These two conditions appear to be two distinct entities, the different co-morbidities observed in obesity favoring pulmonary hypertension. Certain co-morbidities, for instance use of anorexic agents, exhibit a clear relationship with pulmonary hypertension. There is also a possible relationship with left ventricular failure, hypoxemia, and other respiratory disorders (including obstructive sleep apnea), hypothyroidism, and thomboembolism.

Aminorex↗
PubMed2001

[Economic assessment of the use of tinzaparin in the treatment of acute pulmonary embolism in France].

OBJECTIVE: This pharmacoeconomic study was conducted to determine the cost of using tinzaparin, a low-molecular-weight heparin (LMWH), administered intravenously, in comparison with non-fractionated heparin (NFH) for the treatment of acute pulmonary embolism (PE) in France. METHODS: A decision algorithm indicating the therapeutic schedules and their consequences was constructed from data collected during a large-scale multicentric study and from data obtained from interviews with French physicians implicated in the treatment of pulmonary embolism. This model was used to estimate costs and to compare per patient expenditures for the two therapeutic schedules. RESULTS: Cost of instituting treatment per patient (excluding costs common to both schedules) was 202 euros for NFH and 77 euros for tinzaparin (delta 125 euros in favor of tinzaparin). Including follow-up costs for the 90 day analysis period, tizaparin reduced costs by 123 euros per patient (211 versus 334 euros for patients treated with NFH). Taking into account the sole cost of management of the two critical events that occurred during NFH or tinzaparin (8 first days) treatment, tinzaparin reduced costs by 137 euros per patient (112 euros versus 249 euros respectively). CONCLUSION: Tinzaparin reduced health care costs for pulmonary embolism due to easier administration, less complex laboratory tests, and personnel time savings. The robustness of the results was confirmed by the sensitivity analysis.

Acute Disease↗
PubMed2001

Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.

BACKGROUND: Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension. METHODS: In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat. FINDINGS: In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups. INTERPRETATION: Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

Antihypertensive Agents↗
PubMed2001

Role of nitric oxide in hepatopulmonary syndrome in cirrhotic rats.

The hepatopulmonary syndrome (HPS) is characterized by intrapulmonary vascular dilatations and an increased alveolar-arterial oxygen difference (AaPO(2)). Exhaled nitric oxide (NO) concentrations are elevated, suggesting that pulmonary NO overproduction may be the mechanism underlying HPS. We investigated whether common bile duct ligation in rats results in lung NO overproduction and whether normalization of NO synthesis by a 6-wk course of N(G)-nitro-L-arginine methyl ester (L-NAME) (5 mg x kg(-)(1) x d(-)(1)) prevents HPS. Untreated cirrhotic rats showed increases in AaPO(2) and in cerebral uptake of intravenous (99m)Tc-labeled albumin macroaggregates (indicating intrapulmonary vascular dilatations), with decreases in pulmonary vascular resistance and in pulmonary vasoconstriction induced by angiotensin II and hypoxia. Increases were found in exhaled NO; pulmonary total and calcium-dependent NO synthase (NOS) activities; and pulmonary expression of inducible and, to a lesser extent, endothelial NOS. Accumulation of intravascular macrophages accounted for the inducible NOS expression. L-NAME normalized AaPO(2), brain radioactivity, pulmonary vascular resistance, reactivity to hypoxia and angiotensin II, exhaled NO, and NOS activities. These findings suggest that HPS and the associated reduced response to pulmonary vasoconstrictors seen in untreated cirrhotic rats are related to increased pulmonary NO production dependent primarily on increases in the expression and activities of inducible NOS within pulmonary intravascular macrophages.

Animals↗
PubMed2001

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension.

Activin Receptors↗
PubMed2001

Pulmonary artery pulse pressure and wave reflection in chronic pulmonary thromboembolism and primary pulmonary hypertension.

OBJECTIVES: The purpose of this time-domain study was to compare pulmonary artery (PA) pulse pressure and wave reflection in chronic pulmonary thromboembolism (CPTE) and primary pulmonary hypertension (PPH). BACKGROUND: Pulmonary artery pressure waveform analysis provides a simple and accurate estimation of right ventricular afterload in the time-domain. Chronic pulmonary thromboembolism and PPH are both responsible for severe pulmonary hypertension. Chronic pulmonary thromboembolism and PPH predominantly involve proximal and distal arteries, respectively, and may lead to differences in PA pressure waveform. METHODS: High-fidelity PA pressure was recorded in 14 patients (7 men/7 women, 46 +/- 14 years) with CPTE (n = 7) and PPH (n = 7). We measured thermodilution cardiac output, mean PA pressure (MPAP), PA pulse pressure (PAPP = systolic - diastolic PAP) and normalized PAPP (nPAPP = PPAP/MPAP). Wave reflection was quantified by measuring Ti, that is, the time between pressure upstroke and the systolic inflection point (Pi), deltaP, that is, the systolic PAP minus Pi difference, and the augmentation index (deltaP/PPAP). RESULTS: At baseline, CPTE and PPH had similar cardiac index (2.4 +/- 0.4 vs. 2.5 +/- 0.5 l/min/m2), mean PAP (59 +/- 9 vs. 59 +/- 10 mm Hg), PPAP (57 +/- 13 vs. 53 +/- 13 mm Hg) and nPPAP (0.97 +/- 0.16 vs. 0.89 +/- 0.13). Chronic pulmonary thromboembolism had shorter Ti (90 +/- 17 vs. 126 +/- 16 ms, p < 0.01) and higher deltaP/PPAP (0.26 +/- 0.01 vs. 0.09 +/- 0.07, p < 0.01). CONCLUSIONS: Our study indicated that: 1) CPTE and PPH with severe pulmonary hypertension had similar PA pulse pressure, and 2) wave reflection is elevated in both groups, and CPTE had increased and anticipated wave reflection as compared with PPH, thus suggesting differences in the pulsatile component of right ventricular afterload.

Adult↗
PubMed2001

Pathobiology of pulmonary hypertension. The role of platelets and thrombosis.

With the rare exceptions of PAH associated with antiphospholipid antibodies, genetic platelet dysfunction, or inherited deficiencies of antithrombotic pathways, the thrombotic lesions are secondary, but frequently occurring, in most cases of primary or secondary PAH. Pulmonary arterial hypertension is associated with thrombotic lesions and persistent vasoconstriction and structural remodeling of PA. Activated platelets interact with the PA wall and may contribute to the functional and structural alterations of pulmonary vessels by releasing vasoactive factors and mitogenic mediators.

Animals↗
PubMed2001

Risk factors for pulmonary arterial hypertension.

The present limitations in knowledge of the potential risk factors for PPH undoubtedly are attributable to the facts that PPH is a rare disease with an unknown pathogenesis and lacking large case series. Moreover, definite epidemiologic data are rare and ideally should be obtained from epidemiologic surveys such as large case-control studies. The increased incidence of the disease in young women, the familial cases, the association with autoimmune disorders, and the recent discovery that mutation of the PPH1 gene may not be restricted to familial PPH support the hypothesis that the development of pulmonary hypertension likely implies an individual susceptibility or predisposition, which is probably genetically determined. It is also now commonly believed that the development of pulmonary hypertension in some of these predisposed individuals could be hastened or precipitated by various expression factors (some of them yet unrecognized), such as ingestion of certain drugs or diets, portal hypertension, or HIV infection.

Altitude↗
PubMed2001

Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension.

Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of primary pulmonary hypertension (PPH). Here we found that PA-SMCs from patients with PPH grow faster than PA-SMCs from controls when stimulated by serotonin or serum and that these effects are due to increased expression of the serotonin transporter (5-HTT), which mediates internalization of indoleamine. In the presence of 5-HTT inhibitors, the growth stimulatory effects of serum and serotonin were markedly reduced and the difference between growth of PA-SMCs from patients and controls was no longer observed. As compared with controls, the expression of 5-HTT was increased in cultured PA-SMCs as well as in platelets and lungs from patients with PPH where it predominated in the media of thickened pulmonary arteries and in onion-bulb lesions. The L-allelic variant of the 5HTT gene promoter, which is associated with 5-HTT overexpression and increased PA-SMC growth, was present in homozygous form in 65% of patients but in only 27% of controls. We conclude that 5-HTT activity plays a key role in the pathogenesis of PA-SMC proliferation in PPH and that a 5HTT polymorphism confers susceptibility to PPH.

Adolescent↗
PubMed2000

Improvement of von Willebrand factor proteolysis after prostacyclin infusion in severe pulmonary arterial hypertension.

BACKGROUND: The presence of dysfunctional von Willebrand factor (vWF) in pulmonary arterial hypertension (PAH) was suggested to be related to increased proteolysis. METHODS AND RESULTS: In 10 patients with severe PAH, we studied the proteolysis of plasma vWF (vWF levels, multimeric distribution, proteolytic pattern, and cleaving protease activity) and hemodynamic variables (mean pulmonary artery pressure, cardiac index, and total pulmonary vascular resistance) at baseline and 30 days after initiation of continuous prostacyclin infusion. At baseline, vWF levels were significantly increased, vWF proteolysis was excessive, and vWF-cleaving protease activity remained normal. These biological abnormalities were reversible and paralleled the improvement of hemodynamics under vasodilator treatment with prostacyclin. CONCLUSIONS: The excessive proteolysis of vWF in PAH is likely to be related to an increased susceptibility of vWF to proteases induced by high shear rates rather than to an enhanced release of enzymes.

ADAM Proteins↗
PubMed2000

Rapid diagnosis of infectious pleural effusions by use of reagent strips.

Reagent strips have not yet been tested for use in the diagnosis of infectious pleural effusions. A reagent strip was used to evaluate 82 patients with pleural effusions: 20 patients had transudative effusions, 35 had infectious exudative effusions (empyema in 14 and parapneumonic effusion in 21), and 27 had noninfectious exudative effusions. Pleural fluid protein, as evaluated by the reagent strip, proved accurate for the detection of exudative effusions (sensitivity, 93.1%; specificity, 50%; positive predictive value, 84.3%; negative predictive value, 71.5%; odds ratio [OR], 6.77; and 95% confidence interval [CI], 1.87-24). The reagent strip leukocyte esterase test effectively detected infectious exudative effusions (sensitivity, 42.8%; specificity, 91.3%; positive predictive value, 88.2%; negative predictive value, 51.2%; OR, 4.46; and 95% CI, 1.2-16.4). Pleural pH was significantly predicted by the reagent strip but was of no assistance in categorization of exudative effusions as infectious or noninfectious. Compared with physical, laboratory, and microbiological data, the reagent strip was as accurate for estimation of percentages of infectious and noninfectious exudative effusions. Thus, reagent strips may be a rapid, easy-to-use, and inexpensive technique for discriminating transudative from exudative pleural effusions and for categorizing exudative pleural effusions as infectious or noninfectious.

Adult↗
PubMed2000

Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis.

BACKGROUND: A high frequency of asymptomatic pulmonary embolism (PE) has been reported in patients with deep venous thrombosis (DVT) in studies of a limited number of patients using varying criteria for lung scan assessment. OBJECTIVES: To estimate the frequency of PE using systematic lung scans in a large group of outpatients with DVT and to compare the results using varying lung scan assessment criteria. METHODS: An international multicenter study comparing 2 different regimens of low-molecular-weight heparin nadroparin in DVT: perfusion lung scans were performed in 622 outpatients with no clinical indication of PE and with proximal DVT confirmed by venography. Three hundred seventy-nine of these patients underwent ventilation lung scans. High-probability (HP) scans for PE were assessed separately using either ventilation scans or chest radiographs to define mismatched perfusion defects. RESULTS: Perfusion scans showed abnormalities in 82% of the patients; 59% had segmental defects and 30% had normal scans or scans with a very low probability of PE. Depending on the criteria used, 32% to 45% had HP scans for PE; these percentages were higher in young patients. No relationship was found between extent of thrombosis and HP scans. The estimated frequency of silent PE was 39.5% to 49.5%. During a 3-month follow-up period during which the patients received therapy, the rate of PE recurrence was low (1.3%) and did not differ between patients with baseline HP scans and those with normal scans. CONCLUSIONS: Regardless of what interpretative criteria are used for assessing lung scans in PE, the frequency of silent PE is 40% to 50% in patients with DVT. A baseline lung scan may easily detect PE in these patients but is not useful for predicting early thromboembolic recurrences that may occur during therapy.

Adolescent↗