Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive, fatal disease. We studied 674 consecutive adult patients who were prospectively enrolled in the French PAH registry (121 incident and 553 prevalent cases). Two survival analyses were performed. First, the cohort of 674 patients was followed for 3 yrs after study entry and survival rates described. Then, we focused on the subset with incident idiopathic, familial and anorexigen-associated PAH (n = 56) combined with prevalent patients who were diagnosed <3 yrs prior to study entry (n = 134). In the cohort of 674 patients, 1-, 2-, and 3-yr survival rates were 87% (95% CI 84-90), 76% (95% CI 73-80), and 67% (95% CI 63-71), respectively. In prevalent idiopathic, familial and anorexigen-associated PAH, 1-, 2-, and 3-yr survival rates were higher than in incident patients (p = 0.037). In the combined cohort of patients with idiopathic, familial and anorexigen-associated PAH, multivariable analysis showed that survival could be estimated by means of a novel risk-prediction equation using patient sex, 6-min walk distance, and cardiac output at diagnosis. This study highlights survivor bias in prevalent cohorts of PAH patients. Survival of idiopathic, familial and anorexigen-associated PAH can be characterised by means of a novel risk-prediction equation using patients' characteristics at diagnosis.

Pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) is currently classified as a subgroup of pulmonary arterial hypertension (PAH) and accounts for 5-10% of cases initially considered to be idiopathic PAH. PVOD has been described as idiopathic or complicating other conditions, including connective tissue diseases, HIV infection, bone marrow transplantation, sarcoidosis and pulmonary Langerhans cell granulomatosis. PVOD shares broadly similar clinical presentation, genetic background and haemodynamic characteristics with PAH. Compared to PAH, PVOD is characterised by a higher male/female ratio, higher tobacco exposure, lower arterial oxygen tension at rest, lower diffusing capacity of the lung for carbon monoxide, and lower oxygen saturation nadir during the 6-min walk test. High-resolution computed tomography (HRCT) of the chest can be suggestive of PVOD in the presence of centrilobular ground-glass opacities, septal lines and lymph node enlargement. Similarly, occult alveolar haemorrhage is associated with PVOD. A noninvasive diagnostic approach using HRCT of the chest, arterial blood gases, pulmonary function tests and bronchoalveolar lavage could be helpful for the detection of PVOD patients and in avoiding high-risk surgical lung biopsy for histological confirmation. PVOD is characterised by a poor prognosis and the possibility of developing severe pulmonary oedema with specific PAH therapy. Lung transplantation is the treatment of choice. Cautious use of specific PAH therapy can, however, be helpful in some patients.

Long-term effects of bosentan in patients with HIV-associated pulmonary arterial hypertension.

Bosentan has proven 4-month efficacy in patients with HIV-associated pulmonary arterial hypertension (PAH-HIV). Herein, the long-term outcome of unselected PAH-HIV patients treated with first-line bosentan is described. Data for 59 consecutive World Health Organization (WHO) functional class II-IV PAH-HIV patients treated with first-line bosentan between May 2002 and July 2007 were analysed. HIV status, 6-min walk distance and haemodynamics were assessed at baseline, after 4 months and every 6-12 months thereafter. After 4 months, 6-min walk distance increased from 358+/-98 to 435+/-89 m and pulmonary vascular resistance decreased from 737+/-328 to 476+/-302 dyn x s x cm(-5). At the final evaluation (29+/-15 months), 6-min walk distance remained stable and pulmonary vascular resistance decreased further to 444+/-356 dyn x s x cm(-5). Haemodynamics normalised in 10 patients. At their last evaluation, these 10 patients were in WHO functional class I, with a 6-min walk distance of 532+/-52 m. Overall survival estimates were 93, 86 and 66% at 1, 2 and 3 yrs, respectively. Bosentan was safe when combined with highly active antiretroviral therapy, with no negative impact on HIV infection control. The present data confirm the long-term benefits of bosentan therapy in HIV-associated pulmonary arterial hypertension patients with improvements in symptoms, 6-min walk distance and haemodynamics, and with favourable overall survival.

Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases.

The aim of the present study was to describe a large cohort of fenfluramine-associated pulmonary arterial hypertension (fen-PAH) and its possible prognostic markers. The records of all patients with a diagnosis of fen-PAH evaluated at the present authors' centre from 1986-2004 were retrospectively studied. Baseline clinical and haemodynamic data were collected, as well as survival times. The median duration of fenfluramine exposure was 6 months, with a median of 4.5 yrs between exposure and onset of symptoms. Nine (22.5%) out of 40 patients evaluated resulted positive for the presence of germline bone morphogenetic protein receptor (BMPR) type 2 mutations. In these patients, the duration of exposure to fenfluramine was significantly lower than in patients without mutation. The median survival was 6.4 yrs, without significant difference between fen-PAH and a control group of idiopathic and familial pulmonary arterial hypertension patients referred to the present authors' centre during the same time frame and treated identically. Duration of fenfluramine exposure showed no relation to survival, while cardiac index was the only independent predictor of multivariate analysis. Fenfluramine-associated pulmonary arterial hypertension shares clinical, functional, haemodynamic and genetic features with idiopathic pulmonary arterial hypertension, as well as overall survival rates. Therefore, the present authors conclude that fenfluramine exposure characterises a potent trigger for pulmonary arterial hypertension without influencing its clinical course.

[Pulmonary arterial hypertension due to tumor emboli]. / Hypertension artérielle pulmonaire postembolique tumorale.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is rare in the presence of malignancy and tumour embolisation is one of several possible pathological mechanisms. CASE REPORTS: We report our experience of 5 clinical cases and undertake a literature revue of the pathophysiological mechanisms and of the possible diagnostic and therapeutic approaches. CONCLUSIONS: Neoplastic PAH due to tumour micro-emboli is rare and the diagnosis difficult to establish. Cytological examination of pulmonary arterial blood could allow early institution of appropriate chemotherapy and lead to an improvement in the grave prognosis of this condition.

[Genetics of pulmonary arterial hypertension: recent data and practical applications]. / Génétique de l'hypertension artérielle pulmonaire: données récentes et applications pratiques.

INTRODUCTION: Pulmonary arterial hypertension (PAHT) is defined as an increase of mean pulmonary artery pressure above 25 mmHg at rest, or 30 mmHg on exercise, due to obliteration of small calibre pulmonary arteries by proliferation of endothelial cells and smooth muscle. Beside idiopathic PAHT and that associated with other conditions, a familial form has been identified. STATE OF THE ART: Family studies have shown an association between mutations of the BMPR2 gene and PAHT phenotypes. The products of this gene appear to be involved in vascular homeostasis and its mutations are the basis of a loss this function and, in consequence, proliferation of pulmonary vascular cells. PERSPECTIVES: Certain characteristics, such as incomplete penetrance and genetic anticipation, lead to a complex relationship between genotype and phenotype and make genetic counselling difficult. Other members of the extended family of TGF-beta receptors are implicated in the development of the Osler-Rendu syndrome, but may also be associated with the development of PAHT. CONCLUSION: Progress in genetics allows better understanding of the pathophysiology of this disease and could lead to new therapeutic possibilities.

[Pulmonary hypertension: from genetics to treatments]. / Hypertension artérielle pulmonaire: de la génétique aux traitements.

Pulmonary hypertertension (PHT) is a rare disease defined by increased resistance of the pulmonary arteries inevitably leading to right heart failure if specific treatment is not given. This disease can occur sporadically (idiopathic or primary PHT), within a familial context (familial PHT, BMPR2 gene mutation), or occur as a complication of other diseases (connective tissue disease, congenital cardiomyopathy, human immunodeficiency virus infection, portal hypertension, use of anorexigenic agents). The incidence of primary PHT is 2 million cases per year, probably an underestimation due to the low specificity of clinical signs, predominantly exercise-induced dyspnea. Recent therapeutic advances (prostacyclin and endothelin receptor antagonists administered in continuous infusion) have improved the prognosis of this orphan disease. Inhaled iloprost and type 5 phosphodiesterase inhibitors should be evaluated for this indication. Lung transplantation is reserved for patients unresponsive to medical treatment.

[Biomarkers as prognostic factors in pulmonary arterial hypertension. Rationale and study design]. / Evaluation pronostique de biomarqueurs dans l'hypertension artérielle pulmonaire. Justification et plan expérimental.

CURRENT SITUATION: Pulmonary arterial hypertension (PAH) is a serious disease. Its prognostic is based on the functional status quantified by the NYHA class and the 6-min walking test, and the hemodynamic data. The algorithms of treatment are solely based on the hemodynamic data and the functional status. The main objective is to test whether basal concentrations of isoprostanes, Big endotheline 1, ADMA, high sensitivity CRP, NT-Pro-BNP and cardiac troponin T are a 3-year prognostic factor in PAH using a combined criterion: death from any cause and pulmonary or cardiopulmonary transplantation. MATERIALS AND METHODS: This is a multicenter, prospective, prognostic, single blinded study (plasma and urinary samples being blinded). The study started in november 2003, running for 2 years, with a 3 year follow-up for each patient. The main inclusion criterion is PAH. The data analysis will use a multivariable Cox model, taking into account the functional and hemodynamic parameters. EXPECTED RESULTS: This study will determine whether any of the biomarkers tested provides additional prognostic information in PAH in addition to the functional and hemodynamic parameters.