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Biomedical subjects

Gerald Simonneau

Publications and source records attributed to Gerald Simonneau.

At least 19 recordsLinked to original sources
PubMed2007

Endothelin-1/endothelin-3 ratio: a potential prognostic factor of pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare condition characterized by elevated pulmonary artery pressure leading to right-heart failure and death. Endothelin (ET)-1 has been shown to play a significant pathogenic role in PAH. ET-3 has not yet been investigated in PAH. METHODS: ET-1 and ET-3 plasma concentrations were measured in 33 PAH patients prior to any specific PAH therapy and in 9 control subjects. In PAH patients, hemodynamic parameters measured by right-heart catheterization, 6-min walk distance (6MWD), New York Heart Association (NYHA) functional class, and time until lung transplantation or death were recorded. RESULTS: In patients with PAH, levels of ET-1 were increased while those of ET-3 were decreased, as compared to control subjects (p < 0.005 for both comparisons). ET-1/ET-3 ratio varied little in control subjects, while it increased threefold in PAH patients (p < 0.0001). ET-1 correlated positively with right atrial pressure (RAP), indexed total pulmonary resistance, and negatively with cardiac index and venous saturation of oxygen (Svo(2)). ET-3 correlated positively with 6MWD. ET-1/ET-3 ratio correlated positively with RAP, negatively with Svo(2) and 6MWD, and was also associated with NYHA functional class. ET-1/ET-3 ratio was associated with prognosis in this sample of PAH patients treated with specific therapies. CONCLUSIONS: PAH is characterized by elevated ET-1 and ET-1/ET-3 ratio and decreased ET-3 plasma concentrations. All of them correlate with hemodynamic and clinical markers of disease severity. ET-1/ET-3 ratio might be a novel prognostic factor in PAH. These preliminary data should be validated in a large prospective multicenter cohort of PAH patients.

Adult↗
PubMed2006

Angiopoietin/Tie2 pathway influences smooth muscle hyperplasia in idiopathic pulmonary hypertension.

RATIONALE: Angiopoietins are involved in blood vessel maturation and remodeling. OBJECTIVES: One consequence of endothelium-specific tyrosine kinase-2 (Tie2) receptor activation by angiopoietin-1 (Ang1) is the release of endothelium-derived growth factors that recruit vascular wall cells. We investigated this process in idiopathic pulmonary arterial hypertension (iPAH). METHODS: Ang1, Ang2, and total and phosphorylated Tie2 expression (mRNA and protein) was evaluated in human lung specimens and in cultured pulmonary artery smooth muscle cells (PA-SMCs) and pulmonary endothelial cells (P-ECs) isolated from patients with iPAH and control subjects. Media collected from Ang1-treated P-ECs were assessed for their PA-SMC growth-promoting effect. MEASUREMENTS AND MAIN RESULTS: Tie2 receptor was fourfold higher in lungs and P-ECs from patients with iPAH than in those from control subjects, with a parallel increase in phosphorylated lung Tie2 receptor. In contrast, Ang1 and Ang2 expression in lungs, P-ECs, and PA-SMCs did not differ. Incubation of PA-SMCs with medium collected from P-EC cultures induced marked proliferation, and this effect was stronger when using P-ECs from patients with iPAH than from control subjects. Ang1 pretreatment of P-ECs from either patients or control subjects induced a further increase in PA-SMC proliferation. Fluoxetine, an inhibitor of the mitogenic action of serotonin, reduced the growth-promoting effect of P-EC media. Ang1 added to P-ECs from patients with iPAH increased the production of endothelin-1 (ET-1) and serotonin, but not of platelet-derived growth factor-BB or epidermal growth factor, and increased the amount of mRNA encoding tryptophan hydroxylase-1 (the rate-limiting enzyme of serotonin synthesis), preproET-1, and ET-1-converting enzyme. CONCLUSIONS: The Ang1/Tie2 pathway is potentiated in iPAH, contributing to PA-SMC hyperplasia via increased stimulation of endothelium-derived growth factors synthesis by P-ECs.

Angiopoietin-1↗
PubMed2006

Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia.

BACKGROUND: The mechanism of pulmonary artery smooth muscle cell (PA-SMC) hyperplasia in idiopathic pulmonary artery hypertension (iPH) may involve both an inherent characteristic of PA-SMCs and abnormal control by external stimuli. We investigated the role of pulmonary microvascular endothelial cells (P-ECs) in controlling PA-SMC growth. METHODS AND RESULTS: Serum-free medium of quiescent P-ECs elicited marked PA-SMC proliferation, and this effect was greater with P-ECs from patients with iPH than from control subjects and greater with PA-SMCs from these patients than from control subjects. Fluoxetine, which inhibits serotonin-induced mitogenesis by blocking the serotonin transporter, and p-chlorophenylalanine, which inhibits serotonin synthesis by blocking tryptophan hydroxylase (TPH), caused a similar 60% reduction in the growth-promoting effect of P-EC media, whereas endothelin receptor blockers had no effect. Assays of TPH activity in P-EC medium based on p-chlorophenylalanine-sensitive 5-hydroxytryptophan accumulation or serotonin determination indicated serotonin synthesis by P-ECs and an increase in this TPH-dependent process in iPH. Expression of the tph1 gene encoding the peripheral form of the TPH enzyme was increased in lungs and P-ECs from patients with iPH. Lung TPH1 immunostaining was confined to the pulmonary vessel intima. CONCLUSIONS: P-ECs produce paracrine factors governing PA-SMC growth. Serotonin, the main P-EC-derived growth factor, is overproduced in iPH and contributes to PA-SMC hyperplasia.

Aged↗
PubMed2006

Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is clinically characterized by a sustained elevation in mean pulmonary artery pressure leading to significant morbidity and mortality. The disorder is typically sporadic, and in such cases the term idiopathic PAH (IPAH) is used. However, cases that occur within families (familial PAH (FPAH)) display similar clinical and histopathological features, suggesting a common etiology. Heterozygous mutations of a type II member of the TGF-beta cell signaling superfamily known as BMPR2 on chromosome 2q33 have been identified in many kindreds with FPAH, yet display both reduced penetrance and sex bias. This report presents the compilation of data for 144 distinct mutations that alter the coding sequence of the BMPR2 gene identified in 210 independent PAH subjects. This large data set characterizes the extent of sequence variation and reveals that the majority (71%) of mutations in FPAH and IPAH comprise nonsense, frameshift, and splice-site defects, and gene rearrangements. These predict premature termination of the transcript with likely loss through the process of nonsense-mediated decay (NMD). A total of 44 missense mutations were identified that substitute amino acid residues at highly conserved sites within recognized functional domains of the mature receptor. We assess this category of mutations in the context of their heterogeneous effects on cell signaling when assayed by in vitro cell-based systems. Disease-causing mutation hot-spots within BMPR2 are summarized. Taken together, these observations are likely to aid in the development of targeted mutation detection strategies relevant for patient management. Finally, we examine the age- and sex-dependent reduced penetrance of BMPR2 mutations by reviewing bmpr2 animal models and the requirement for additional genetic and/or environmental modifiers of disease. In conclusion, these data provide compelling genetic evidence that haploinsufficiency is the predominant molecular mechanism underlying disease predisposition, and support the concept of a critical threshold of signaling activity below which disease may be precipitated.

Bone Morphogenetic Protein Receptors, Type II↗
PubMed2006

BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension.

Mutations of the BMPR2 gene predispose to pulmonary arterial hypertension (PAH), a serious, progressive disease of the pulmonary vascular system. However, despite the fact that most PAH families are consistent with linkage to the BMPR2 locus, sequencing only identifies mutations in some 55% of familial cases and between 10% and 40% of cases without a family history (idiopathic or IPAH). We therefore conducted a systematic analysis for larger gene rearrangements in panels of both familial and idiopathic PAH cases that were negative on sequencing of coding regions. Analysis of exon dosage across the entire gene using Multiplex Ligation-dependent Probe Amplification identified nine novel rearrangements and enabled full characterization at the exon level of previously reported deletions. Overall, BMPR2 rearrangements were identified in 7 of 58 families and 6 of 126 IPAH cases, suggesting that gross rearrangements underlie around 12% of all FPAH cases and 5% of IPAH. Importantly, two deletions encompassed all functional protein domains and are predicted to result in null mutations, providing the strongest support yet that the predominant molecular mechanism for disease predisposition is haploinsufficiency. Dosage analysis should now be considered an integral of part of the molecular work-up of PAH patients.

Bone Morphogenetic Protein Receptors, Type II↗
PubMed2006

Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension.

BACKGROUND & AIMS: It has been suggested that beta-blockers might be harmful in pulmonary arterial hypertension. However, no study has evaluated the effect of beta-blockers in these patients. The aim of this study was to investigate the effect of beta-blockers on exercise capacity and pulmonary hemodynamics in patients with portopulmonary hypertension receiving beta-blockers for the prophylaxis of variceal bleeding. METHODS: Ten consecutive patients with moderate to severe portopulmonary hypertension (mean pulmonary artery pressure of 52 [10] mm Hg) underwent a 6-minute walk test and a right heart catheterization at baseline and 2 (1) months after beta-blocker withdrawal. RESULTS: Following beta-blocker withdrawal, 9 of 10 patients increased their 6-minute walked distance with a mean increase in the whole group of 79 (78) meters (P = .01). Cardiac output increased by 28% (P < .01) with no change in mean pulmonary artery pressure, resulting in a 19% decrease in pulmonary vascular resistance (P < .01). Increases in cardiac output were related to a 25% increase in heart rate (P < .01), whereas stroke volume was unchanged (P = .65). The improvements in exercise tolerance were associated with increases in chronotropic response (maximal heart rate minus resting heart rate) from 18 (9) to 34 (12) beats/min (P < .01) during the 6-minute walk test. CONCLUSIONS: In patients with moderate to severe portopulmonary hypertension, beta-blockers are associated with significant worsening in exercise capacity and pulmonary hemodynamics. These deleterious effects support the contraindication of beta-blockers in patients with portopulmonary hypertension.

Adrenergic beta-Antagonists↗
PubMed2006

Current understanding of the role of bosentan in inoperable chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension may occur in the context of incomplete lysis of acute pulmonary emboli, resulting in the obstruction of pulmonary blood flow, as well as progressive right ventricular dysfunction and failure. The treatment of choice for this condition is surgical removal of the obstructing material. However, in many patients, surgery is not possible due to either an unfavourable distribution of the disease, the development of a concurrent small vessel pulmonary arteriopathy, or the presence of significant comorbid conditions. There is increasing evidence that the medical therapies that are used in other forms of pulmonary hypertension may also be effective in inoperable chronic thromboembolic pulmonary hypertension. This article examines the rationale for the use of the oral dual endothelin receptor antagonist bosentan in this life-threatening condition.

Antihypertensive Agents↗
PubMed2005

Serotonin transporter polymorphisms in familial and idiopathic pulmonary arterial hypertension.

RATIONALE: Serotonin is a pulmonary vasoconstrictor and smooth muscle cell mitogen. The serotonin transporter (SERT) is abundant in pulmonary vascular smooth muscle. Compared with the short (S) allele, the long (L) SERT promoter allele is associated with increased SERT transcription and more severe pulmonary hypertension in a cohort of patients with chronic obstructive pulmonary disease, and was more prevalent in a cohort with idiopathic pulmonary arterial hypertension (IPAH), compared with control subjects. OBJECTIVE: We hypothesized that the SERT L allele would associate with an earlier age at diagnosis and/or shorter survival interval in pulmonary arterial hypertension (PAH) than the S allele. METHODS: SERT promoters from 166 familial PAH (FPAH), 83 IPAH, and 125 control subjects were sequenced. One hundred twenty-seven of the patients with FPAH had a known mutation in bone morphogenetic protein receptor 2 (BMPR2). RESULTS: The mean age at diagnosis was 35.8 yr in patients with FPAH and 41.1 yr in patients with IPAH (p = 0.02). There were no significant differences in distribution of the LL, LS, or SS genotypes in IPAH, FPAH, or unaffected BMPR2 mutation carriers. In FPAH, the LL genotype was associated with an earlier age at diagnosis (p < 0.02). CONCLUSIONS: In patients with IPAH, these SERT genotypes do not correlate with age at diagnosis or survival interval. In patients with FPAH, the LL genotype correlates with an earlier age at diagnosis than SL or SS, although survival among the groups was similar. The correlation of the SERT promoter polymorphism with age at diagnosis in FPAH suggests a possible relationship between the SERT and BMPR2.

Adult↗
PubMed2005

Influence of donor characteristics on outcome after lung transplantation: a multicenter study.

BACKGROUND: The liberalization of lung-donor criteria and the use of marginal donors have been advocated to face the current shortage of donors in lung transplantation. However, the impact of donor characteristics on the outcome of lung transplantation is still largely unknown. We aimed to determine, on a large cohort of patients, the effect of donors characteristics on short- and long-term outcome of lung transplantation METHODS: Between 1988 and 1998, a total of 785 adult patients underwent single-lung transplantation (n = 270), bilateral-lung transplantation (n = 251), and heart-lung transplantation (n = 264) in 7 centers in France. We constructed several multivariate models to assess the relationship between donor characteristics and early gas exchange, duration of mechanical ventilation, and long-term survival after lung transplantation. RESULTS: Among donor characteristics, donor gas exchange before harvest was found to be significantly associated with recipient early gas exchange, duration of mechanical ventilation, and long-term survival after adjustment for potential confounding variables. Moreover, nonlinear modeling showed a steep increase in the relative risk of death when donor PaO2/FiO2 before harvest was below 350 (hazard ratio 1.43; 95% confidence interval 1.10-1.85; p = 0.01). Donor and recipient sex mismatch were also found to be significantly associated with long-term survival. CONCLUSIONS: Although liberalization of lung-donor criteria may be considered to overcome the shortage of lung donors, our data suggest that the violation of the gas-exchange criterion should be avoided.

Adult↗
PubMed2005

Idiopathic pulmonary hypertension: what did we learn from genes?

Pulmonary arterial hypertension (PAH) is an uncommon disorder. PAH can be idiopathic, associated with other conditions or clustered in families. Indeed, at least 6% of individuals diagnosed with so-called "primary" pulmonary hypertension have a family history of the disorder. Familial PAH segregates as an autosomal dominant trait but with markedly reduced penetrance. Defects within bone morphogenetic protein receptor type II gene (BMPR2), coding for a type II receptor member of the transforming growth factor beta (TGF-beta) family, have been shown to underlie familial PAH. Germline BMPR2 mutations have been detected in at least 60% of the families studied to date. Disease-associated mutations are predicted to interrupt the BMP-mediated signalling pathway predisposing to proliferation of cells within small pulmonary arteries. Several lines of evidence point to the potential requirement of additional factors, either environmental or genetic, in the pathogenesis of the disease. In addition, a proportion of idiopathic PAH as well as anorexigen-associated PAH turn out to have an inherited basis, as demonstrated by detection of germline BMPR2 mutations. Analysis of other genes encoding TGF-beta receptor proteins, led to the demonstration that PAH in association with hereditary hemorrhagic telangiectasia, an autosomal dominant vascular dysplasia, can involve other TGF-beta receptor subtypes. These observations support the hypothesis that mutations in the TGF-beta superfamily may be a trigger for pulmonary vascular remodeling. Nevertheless, PAH pathobiology remains unclear and genomic approaches may identify additional molecular determinants for this disorder.

Bone Morphogenetic Protein Receptors, Type II↗
PubMed2004

Clinical classification of pulmonary hypertension.

In 1998, during the Second World Symposium on Pulmonary Hypertension (PH) held in Evian, France, a clinical classification of PH was proposed. The aim of the Evian classification was to individualize different categories sharing similarities in pathophysiological mechanisms, clinical presentation, and therapeutic options. The Evian classification is now well accepted and widely used in clinical practice, especially in specialized centers. In addition, this classification has been used by the U.S. Food and Drug Administration and the European Agency for Drug Evaluation for the labeling of newly approved medications in PH. In 2003, during the Third World Symposium on Pulmonary Arterial Hypertension held in Venice, Italy, it was decided to maintain the general architecture and philosophy of the Evian classification. However, some modifications have been proposed, mainly to abandon the term "primary pulmonary hypertension" and to replace it with "idiopathic pulmonary hypertension"; to reclassify pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis; to update risk factors and associated conditions for pulmonary arterial hypertension and to propose guidelines in order to improve the classification of congenital systemic-to-pulmonary shunts.

Genetic Predisposition to Disease↗
PubMed2004

Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension.

The numerous controlled clinical trials performed recently in pulmonary arterial hypertension (PAH) can allow us to abandon a clinical-based treatment strategy and adopt an evidence-based therapy. Both uncontrolled and controlled clinical trials with different compounds and procedures are reviewed and compared in order to define the efficacy-to-side-effect ratio of each treatment. A grading system for the level of evidence of treatments based on the number of favorable controlled clinical trials performed with a given compound is adopted; a treatment algorithm based on the evidence derived by clinical trials is proposed. It includes drugs approved by regulatory agencies for the treatment of patients with PAH and/or drugs available on the market for other indications. The algorithm is restricted to patients in New York Heart Association (NYHA) functional class III or IV because they represent the largest population included in controlled clinical trials. In addition, the different treatments have been evaluated mainly in sporadic, idiopathic PAH and in PAH associated with scleroderma or to anorexigen use. Extrapolation of these recommendations to the other PAH subgroups should be done with caution. Oral anticoagulation is proposed for all patients, whereas diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia, respectively. High doses of calcium channel blockers are indicated only in the minority of patients who are responders to acute vasoreactivity testing. Nonresponders to acute vasoreactivity testing, or responders who remain in NYHA functional class III, should be considered candidates for treatment with either an endothelin receptor antagonist or a prostanoid. Continuous intravenous administration of epoprostenol is proposed as rescue treatment in NYHA functional class IV patients. Phosphodiesterase-V inhibitors should be considered in patients who have failed or are not candidates to other therapies. Combination therapy can be attempted in selected cases. Both balloon atrial septostomy and lung transplantation are indicated for refractory patients or where medical treatment is unavailable.

Algorithms↗
PubMed2004

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 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 from patients with primary PH (n=14), pulmonary veno-occlusive disease (n=4), or secondary PH (SPH, n=8) and nonpulmonary hypertensive control subjects. Whereas strong immunostaining for the three receptor types and 5-HTT was seen in remodeled pulmonary vessels from patients in all PH categories, only 5-HTT expression was increased in lungs and cultured PA-SMCs from patients versus controls. The increased growth response of PA-SMCs from patients with primary PH, pulmonary veno-occlusive disease, or SPH to 5-HT or serum was entirely attributable to 5-HTT overexpression, because 5-HTT inhibitors but not 5-HT receptor antagonists abolished 5-HT mitogenic activity and reduced the serum-induced growth response to similar levels in patients as in controls. The L-allelic variant of the 5-HTT gene promoter, which is associated with 5-HTT overexpression, was present homozygously in 14 of 25 (56%) lung transplantation patients with SPH but in only 27% of controls. Polymorphism of the 5-HTT gene promoter was only partly responsible for the increased 5-HTT expression in PH, because PA-SMCs from patients exhibited higher 5-HTT levels than same-genotype cells from controls and no additional promoter sequence alterations were found. We conclude that 5-HTT overexpression is a common pathogenic mechanism in various forms of PH.

Adolescent↗
PubMed2004

Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.

Pulmonary arterial hypertension (PAH) is often difficult to diagnose and challenging to treat. Untreated, it is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. The past decade has seen remarkable improvements in therapy, driven largely by the conduct of randomized controlled trials. Still, the selection of most appropriate therapy is complex, and requires familiarity with the disease process, evidence from treatment trials, complicated drug delivery systems, dosing regimens, side effects, and complications. This chapter will provide evidence-based treatment recommendations for physicians involved in the care of these complex patients. Due to the complexity of the diagnostic evaluation required, and the treatment options available, it is strongly recommended that consideration be given to referral of patients with PAH to a specialized center.

Antihypertensive Agents↗
PubMed2004

Surgical treatments/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.

While considerable advances have been achieved in the medical treatment of pulmonary arterial hypertension (PAH) over the past decade, surgical and interventional approaches continue to have important roles in those patients for whom medical therapy is unavailable or has been unsuccessful. These techniques include pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension, thoracic transplantation, and atrial septostomy. This chapter will provide evidence-based recommendations for the selection and timing of surgical and interventional treatments of PAH for physicians involved in the care of these complex patients.

Evidence-Based Medicine↗