Genetic counselling in a national referral centre for pulmonary hypertension.

Genetic causes of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD) have been identified, leading to a growing need for genetic counselling.Between 2003 and 2014, genetic counselling was offered to 529 PAH and 100 PVOD patients at the French Referral Centre for Pulmonary Hypertension.Mutations in PAH-predisposing genes were identified in 72 patients presenting as sporadic PAH (17% of cases; 62 mutations in BMPR2, nine in ACVRL1 (ALK1) and one in ENG) and in 94 patients with a PAH family history (89% of cases; 89 mutations in BMPR2, three in ACVRL1 (ALK1) and two in KCNK3). Bi-allelic mutations in EIF2AK4 were identified in all patients with a family history of PVOD (n=19) and in seven patients (8.6%) presenting as sporadic PVOD. Pre-symptomatic genetic diagnosis was offered to 272 relatives of heritable PAH patients, identifying mutations in 36.4% of them. A screening programme is now offered to asymptomatic mutation carriers to detect PAH in an early phase and to identify predictors of outcomes in asymptomatic BMPR2 mutation carriers. BMPR2 screening allowed us to offer pre-implantation diagnosis to two couples with a BMPR2 mutation.Genetic counselling can be implemented in pulmonary hypertension centres.

Factors associated with diagnosis and operability of chronic thromboembolic pulmonary hypertension. A case-control study.

Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary hypertension (IPAH) share a similar clinical presentation, and a differential diagnosis requires a thorough workup. Once CTEPH is confirmed, patients who can be safely operated have to be identified. We investigated risk factors associated with CTEPH and IPAH, and the criteria for the selection of operable CTEPH patients. This case-control study included 436 consecutive patients with CTEPH and 158 with IPAH in eight European centres, between 2006 and 2010. Conditions identified as risk factors for CTEPH included history of acute venous thromboembolism (p < 0.0001), large size of previous pulmonary embolism (p = 0.0040 in univariate analysis), blood groups non-O (p < 0.0001 in univariate analysis), and older age (p = 0.0198), whereas diabetes mellitus (p = 0.0006), female gender (p = 0.0197) and higher mean pulmonary artery pressure (p = 0.0103) were associated with increased likelihood for an IPAH diagnosis. Operability of CTEPH patients was associated with younger age (p = 0.0108), proximal lesions (p ≤ 0.0001), and pulmonary vascular resistance below 1200 dyn.s.cm⁻5 (p = 0.0080). Non-operable CTEPH patients tended to be less differentiable from IPAH patients by risk factor analysis than operable patients. This study confirmed the association of CTEPH with history of acute venous thromboembolism and blood groups non-O, and identified diabetes mellitus and higher mean pulmonary artery pressure as factors suggesting an IPAH diagnosis. Non-operable CTEPH is more similar to IPAH than operable CTEPH regarding risk factors.

Independent association of urinary F2-isoprostanes with survival in pulmonary arterial hypertension.

OBJECTIVES: Within the past decade, biochemical markers have emerged as attractive tools to assess pulmonary arterial hypertension (PAH) prognosis, being noninvasive and easily repeatable.The objective of this study was to determine whether biomarkers measured at initial diagnostic right-sided heart catheterization predict 3-year all-cause mortality for incident cases of PAH independently of clinical and hemodynamic parameters. METHODS: Patients with incident PAH were enrolled between December 2003 and April 2006 in six centers from the French Network on Pulmonary Hypertension and followed for 3 years.Venous blood samples were taken during right-sided heart catheterization, and analyses were centralized. RESULTS: Among 110 enrolled patients, 11 underwent lung or heart/lung transplantation, and 27 died during follow-up. The Kaplan-Meier estimates of survival were 91%, 78%, and 75% at 1, 2, and 3 years, respectively. Plasma big endothelin-1 (hazard ratio [HR] per 1-SD increase, 1.48; 95% CI,1.14-1.92), serum troponin T . 0.01 mg/L (HR, 2.35; 95% CI, 1.05-5.29), and urinary F 2 -isoprostanes(15-F2t -isoprostane) (HR per 1-SD increase, 1.76; 95% CI, 1.31-2.36) were associated with increased unadjusted hazard of death. In multivariate analysis adjusting for patient characteristics, the level of urinary F 2 -isoprostanes was the only biomarker that remained independently associated with increased hazard of death (HR per 1-SD increase, 1.82; 95% CI, 1.28-2.60). CONCLUSIONS: This study shows that levels of urinary F 2 -isoprostane, a biomarker of lipid peroxidation,quantified at initial diagnostic right-sided heart catheterization are independently associated with mortality in a cohort of patients with incident PAH.

IgG from patients with pulmonary arterial hypertension and/or systemic sclerosis binds to vascular smooth muscle cells and induces cell contraction.

OBJECTIVES: Pulmonary arterial hypertension (PAH) is characterised by remodelling of pulmonary arteries with enhanced vascular smooth muscle cell (VSMC) contraction, migration and proliferation. The authors investigated the presence of antibodies to human VSMCs in the serum of patients with systemic sclerosis with or without PAH and idiopathic PAH (iPAH). METHODS AND RESULTS: Antibodies to VSMCs were detected by immunofluorescence in sera from healthy controls and patients with scleroderma without PAH, scleroderma-associated PAH and iPAH. Serum IgG from these patients induced contraction of VSMCs in a collagen matrix in contrast with IgG from healthy controls. Several protein spots of interest and target antigens were identified by two-dimensional immunoblotting and MS, including stress-induced phosphoprotein 1 and α-enolase. Finally, antibodies to stress-induced phosphoprotein 1 were detected by ELISA in sera from 84%, 76% and 24% of patients with scleroderma without PAH, scleroderma-associated PAH and iPAH, respectively, compared with only 3% of healthy controls. CONCLUSION: The authors have identified IgG that binds to VSMCs in the serum of patients with scleroderma and iPAH. These antibodies may be pathogenic by modulating vascular contraction. The target antigens of these antibodies are stress-induced phosphoprotein 1 and α-enolase.

Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a severe, life-limiting complication of systemic sclerosis (SSc). Guidelines recommend early detection and management of SSc-PAH. However, little is known about the impact of detection programs on patients with SSc-PAH. This study was undertaken to assess the clinical characteristics of patients with SSc-PAH at diagnosis and their long-term outcomes. METHODS: Two incident cohorts of patients with SSc-PAH from the same management era (2002/2003) were studied. The first cohort (designated the routine practice cohort) included consecutive adult patients with symptomatic SSc in whom a diagnosis of PAH was made by right-sided heart catheterization (RHC) at the time of recruitment into the French PAH Registry. The second cohort (designated the detection cohort) comprised consecutive patients with SSc who entered a systematic PAH detection program and were subsequently found to have PAH on RHC. Clinical characteristics at diagnosis of PAH and subsequent 8-year mortality were compared between the cohorts. RESULTS: There were 16 patients in each cohort. At the time of PAH diagnosis, patients in the detection cohort had less advanced pulmonary vascular disease compared with patients in the routine practice cohort, as evidenced by more patients being in New York Heart Association class I and class II, a lower mean pulmonary artery pressure and pulmonary vascular resistance index, and a higher cardiac output. Patients in the detection cohort were less likely to receive diuretics and warfarin, but there was no difference in exposure to PAH-specific therapies between the cohorts. The 1-, 3-, 5-, and 8-year survival rates were 75%, 31%, 25%, and 17%, respectively, in the routine practice cohort compared with 100%, 81%, 73%, and 64%, respectively, in the detection cohort (P = 0.0037). CONCLUSION: Compared with patients in routine clinical practice, PAH detection programs in SSc are able to identify patients with milder forms of the disease, allowing earlier management.

A hemodynamic study of pulmonary hypertension in sickle cell disease.

BACKGROUND: The prevalence and characteristics of pulmonary hypertension in adults with sickle cell disease have not been clearly established. METHODS: In this prospective study, we evaluated 398 outpatients with sickle cell disease (mean age, 34 years) at referral centers in France. All patients underwent Doppler echocardiography, with measurement of tricuspid-valve regurgitant jet velocity. Right heart catheterization was performed in 96 patients in whom pulmonary hypertension was suspected on the basis of a tricuspid regurgitant jet velocity of at least 2.5 m per second. Pulmonary hypertension was defined as a mean pulmonary arterial pressure of at least 25 mm Hg. RESULTS: The prevalence of a tricuspid regurgitant jet velocity of at least 2.5 m per second was 27%. In contrast, the prevalence of pulmonary hypertension as confirmed on catheterization was 6%. The positive predictive value of echocardiography for the detection of pulmonary hypertension was 25%. Among the 24 patients with confirmed pulmonary hypertension, the pulmonary-capillary wedge pressure was 15 mm Hg or less (indicating precapillary pulmonary hypertension) in 11 patients. Patients with confirmed pulmonary hypertension were older and had poorer functional capacity and higher levels of N-terminal pro-brain natriuretic peptide than other patients. In contrast, patients who had a tricuspid regurgitant jet velocity of at least 2.5 m per second without pulmonary hypertension and patients with a tricuspid regurgitant jet velocity of less than 2.5 m per second had similar clinical characteristics. CONCLUSIONS: In this study of adults with sickle cell disease, the prevalence of pulmonary hypertension as confirmed on right heart catheterization was 6%. Echocardiographic evaluation alone had a low positive predictive value for pulmonary hypertension. (Funded by the French Ministry of Health and Assistance Publique-Hôpitaux de Paris; ClinicalTrials.gov number, NCT00434902.).

Clinical characteristics and survival in systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease.

BACKGROUND: Pulmonary hypertension (PH) complicating systemic sclerosis (SSc)-related interstitial lung disease (ILD) is usually associated with a poor prognosis. However, data are either lacking or scarce on prognostic factors in this condition. The objectives of this study were to compare the survival of patients with ILD-associated PH (PH-ILD) or pulmonary arterial hypertension (PAH) and to determine whether the severity of PH has prognostic value in SSc-associated PH-ILD. METHODS: Consecutive patients with SSc and PH-ILD (n = 47) or PAH (n = 50) confirmed by right-sided heart catheterization were included in a cross-sectional analysis. PH was classified as mild (mean pulmonary arterial pressure [mPAP] ≤ 35 mm Hg) or moderate to severe (mPAP > 35 mm Hg). RESULTS: As compared with patients with PAH, subjects with PH-ILD were younger, were more frequently men with a history of smoking, had more frequently diffuse SSc, less frequently anticentromere antibodies, and a lower FVC/diffusing capacity of lung for carbon monoxide (DLCO) ratio. They had a worse prognosis than patients with PAH (3-year survival of 47% vs 71%, respectively; P = .07). Patients with mild PH-ILD had similar poor outcomes when compared with those with moderate to severe PH-ILD. Pericardial effusion (hazard ratio [HR], 2.44; P = .04) and lower DLCO (HR, 0.96; P = .01) were the only independent factors predictive of a poor survival in the PH-ILD group. CONCLUSIONS: Patients with SSc with PH-ILD had a different phenotype and a worse prognosis than those with SSc and PAH. Lower DLCO and presence of pericardial effusion were predictive of a poor outcome in PH-ILD, whereas mPAP seemed to have no prognostic significance.

Endothelin receptor antagonists for the treatment of pulmonary arterial hypertension.

INTRODUCTION: Endothelin is a key mediator in the pathophysiology of pulmonary arterial hypertension (PAH). Its effects are mediated through the activation of two associated receptor subtypes, termed A and B. Therapeutic strategies that modulate the activity of endothelin are, therefore, of interest to improve the functional status of patients with PAH. AREAS COVERED: The rationale for the use of endothelin receptor antagonists as a therapeutic class in PAH and pertinent data from important clinical studies are presented in this review. Areas for future research are also suggested. EXPERT OPINION: The availability of the endothelin receptor antagonist class of agents represents a significant addition to the therapeutic armamentarium which is available for the treatment of PAH. Comparative studies are warranted to establish whether selective endothelin-A receptor antagonism is more advantageous than dual receptor antagonism. Future studies of endothelin receptor antagonists will increasingly focus on the potential of a combination of different PAH therapeutic classes and will employ 'harder' clinical end points. This is of crucial importance to ensure that future developments are both worthwhile and acceptable to patients, physicians, health system payers and regulatory authorities.

Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension.

BACKGROUND: Previous studies indicate that patients with pulmonary arterial hypertension (PAH) carrying a mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene, develop the disease 10 years earlier than non-carriers, and have a more severe hemodynamic compromise at diagnosis. A recent report has suggested that this may only be the case for females and that patients with missense mutations in BMPR2 gene have more severe disease than patients with truncating mutations. METHODS: We reviewed data from all patients with PAH considered as idiopathic and patients with a family history of PAH, who underwent genetic counselling in the French PAH network between January, 1st 2004 and April, 1st 2010. We compared clinical, functional, and hemodynamic characteristics between carriers and non-carriers of a BMPR2 mutation, according to gender or BMPR2 mutation type. RESULTS: PAH patients carrying a BMPR2 mutation (n = 115) were significantly younger at diagnosis than non-carriers (n = 267) (35.8 +/- 15.4 and 47.5 +/- 16.2 respectively, p < 0.0001). The presence of a BMPR2 mutation was associated with a younger age at diagnosis in females (36.4 +/- 14.9 in BMPR2 mutation carriers and 47.4 +/- 15.8 in non-carriers, p < 0.0001), and males (34.6 +/- 16.8 in BMPR2 mutation carriers and 47.8 +/- 17.1 in non-carriers, p < 0.0001). BMPR2 mutation carriers had a more severe hemodynamic compromise at diagnosis, but this was not influenced by gender. No differences in survival and time to death or lung transplantation were found in male and female PAH patients carrying a BMPR2 mutation. No differences were observed in clinical outcomes according to the type of BMPR2 mutations (missense, truncating, large rearrangement or splice defect). CONCLUSION: When compared to non-carriers, BMPR2 mutation carriers from the French PAH network are younger at diagnosis and present with a more severe hemodynamic compromise, irrespective of gender. Moreover, BMPR2 mutation type had no influence on clinical phenotypes in our patient population.

Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era.

BACKGROUND: Novel therapies have recently become available for pulmonary arterial hypertension. We conducted a study to characterize mortality in a multicenter prospective cohort of patients diagnosed with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension in the modern management era. METHODS AND RESULTS: Between October 2002 and October 2003, 354 consecutive adult patients with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension (56 incident and 298 prevalent cases) were prospectively enrolled. Patients were followed up for 3 years, and survival rates were analyzed. For incident cases, estimated survival (95% confidence intervals [CIs]) at 1, 2, and 3 years was 85.7% (95% CI, 76.5 to 94.9), 69.6% (95% CI, 57.6 to 81.6), and 54.9% (95% CI, 41.8 to 68.0), respectively. In a combined analysis population (incident patients and prevalent patients diagnosed within 3 years before study entry; n=190), 1-, 2-, and 3-year survival estimates were 82.9% (95% CI, 72.4 to 95.0), 67.1% (95% CI, 57.1 to 78.8), and 58.2% (95% CI, 49.0 to 69.3), respectively. Individual survival analysis identified the following as significantly and positively associated with survival: female gender, New York Heart Association functional class I/II, greater 6-minute walk distance, lower right atrial pressure, and higher cardiac output. Multivariable analysis showed that being female, having a greater 6-minute walk distance, and exhibiting higher cardiac output were jointly significantly associated with improved survival. CONCLUSIONS: In the modern management era, idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension remains a progressive, fatal disease. Mortality is most closely associated with male gender, right ventricular hemodynamic function, and exercise limitation.

Pulmonary veno-occlusive disease: recent progress and current challenges.

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary arterial hypertension characterised by a progressive obstruction of small pulmonary veins that leads to elevation in pulmonary vascular resistance and right ventricular failure. Despite improved understanding and more efficacious treatment options for PAH overall, the prognosis of PVOD remains dismal. Without therapeutic intervention few patients would be expected to survive more than two years. PVOD may occur in both idiopathic and heritable forms, or develop in association with connective tissue disease, chronic respiratory disease, malignancy or bone marrow transplantation, among other causes. A widespread fibrous intimal proliferation that predominantly involves the pulmonary venules and small veins is the key histopathological hallmark. Surgical lung biopsy is considered the definitive diagnostic test but is associated with significant risk and is not recommended. Distinguishing PVOD from PAH on clinical grounds alone is generally not possible, although PVOD is characterised by a higher male/female ratio and higher tobacco exposure. Instead, non-invasive tests may be helpful and the diagnosis is usually based on an integrated assessment that incorporates high resolution computed tomography (septal lines, ground-glass opacities and lymph node enlargement), pulmonary function testing (lower DLCO), arterial blood gas analysis (lower PaO(2) at rest) and bronchoalveolar lavage (occult alveolar haemorrhage). Treatment of PVOD remains challenging as exposure to pulmonary vasodilators and PAH-specific agents may precipitate acute pulmonary oedema. Nonetheless, a number of successful outcomes describing cautious use of prostanoids, endothelin antagonists and phosphodiesterase type-5 inhibitors have been described. Unfortunately, the long term effects of these agents are variable and lung transplantation remains the treatment of choice.

Pulmonary arterial hypertension associated with systemic sclerosis in patients with functional class II dyspnoea: mild symptoms but severe outcome.

OBJECTIVE: To describe the history of SSc-associated pulmonary arterial hypertension (SSc-PAH) in patients with New York Heart Association (NYHA) functional class (FC) II dyspnoea at diagnosis. METHODS: Data at the time of diagnosis were collected and analysed retrospectively for 77 consecutive patients with SSc-PAH. RESULTS: Twelve patients (15.6%) presented with PAH and NYHA FC II dyspnoea. After a mean follow-up of 44 months, only 4 out of the 12 PAH patients remained stable in FC II, while 8 showed worsening to FC III or IV. Three patients died during the observation period; two from PAH and one from rectal cancer. Survival in patients in FC II at diagnosis was 100, 91 and 80% at 1, 2 and 3 years, respectively. CONCLUSIONS: A majority of patients with mildly symptomatic SSc-PAH in NYHA FC II at diagnosis have a severe disease with poor prognosis.

HIV-associated pulmonary arterial hypertension: survival and prognostic factors in the modern therapeutic era.

OBJECTIVES: To examine baseline characteristics and outcome, and to determine variables affecting survival in patients with pulmonary arterial hypertension (PAH) associated with HIV infection (PAH-HIV) in the modern era of highly-active antiretroviral therapy (HAART) and specific PAH therapy. DESIGN: Retrospective review of data from PAH-HIV patients without other associated risk factors for PAH, and comparison with previous series. METHODS: Data were reviewed for 77 consecutive patients treated at the French Reference Centre for Pulmonary Hypertension between October 2000 and January 2008. Results were expressed as median [1st-3rd quartile] values. RESULTS: At diagnosis of PAH, 81% patients were on HAART, 79% had a CD4+ count more than 200 cells/microl and 49% had undetectable HIV load. New York Heart Association functional class assessment was II (22%), III (69%), and IV (9%). Six-minute walk distance (6MWD) was 375 [288-421] m, and pulmonary vascular resistance was 689 [524-852] dyn s/cm(5). All patients received HAART irrespective of HIV disease stage. Specific PAH therapy was started in 50 patients and led to improvements in 6MWD and haemodynamic parameters. In patients who did not receive specific PAH therapy, 6MWD improved but haemodynamics did not change. Overall survival rate was 88% at 1 year and 72% at 3 years. On multivariate analysis, cardiac index more than 2.8 l/min per m(2) and CD4+ lymphocyte count more than 200 cells/microl were independent predictors of survival. CONCLUSION: In patients with PAH-HIV, HAART seems unable to improve haemodynamic parameters. Prognosis in PAH-HIV is mainly related to CD4+ lymphocyte count and cardiac function.

Long-term outcome of systemic sclerosis-associated pulmonary arterial hypertension treated with bosentan as first-line monotherapy followed or not by the addition of prostanoids or sildenafil.

OBJECTIVE: Data on long-term efficacy of bosentan, an oral dual ET receptor antagonist, in SSc-associated pulmonary arterial hypertension (SSc-PAH) are lacking. We aimed to describe the long-term outcome of SSc-PAH treated with first-line monotherapy bosentan followed or not by the addition of prostanoids or sildenafil. METHODS: A prospective analysis of 49 consecutive SSc-PAH patients treated with first-line bosentan was performed. New York Heart Association (NYHA) functional class, 6-min walk distance (6MWD) and haemodynamics were assessed at baseline and after 4 and 12 months. RESULTS: At 4 months, significant improvements in NYHA functional class and haemodynamics were observed with stabilization at 1 year. There was no significant improvement in 6MWD. Overall survival estimates were 80, 56 and 51% at 1, 2 and 3 years, respectively, and were significantly worse than those in a cohort of patients with idiopathic PAH (92, 89 and 79% at 1, 2 and 3 years, respectively; P < 0.0001). Twenty-three patients (47%) died after a mean follow-up of 23 (18) months. In multivariate analysis, baseline and 4-month NYHA functional class and 4-month cardiac index were independent factors associated with overall survival. CONCLUSIONS: In our cohort of consecutive SSc-PAH patients treated with first-line bosentan, improvement in NYHA functional class and haemodynamics was significant after 4 months of treatment and stabilized afterwards. One-year overall survival rate was higher than previously reported in historical series. However, long-term prognosis remains poor. Our study underlines the importance of haemodynamic evaluation 4 months after the start of treatment to provide strong parameters associated with survival-like cardiac index.

Portopulmonary hypertension: survival and prognostic factors.

RATIONALE: Portopulmonary hypertension (PoPH) can be defined as elevation of pulmonary arterial pressure and pulmonary vascular resistance in the setting of portal hypertension. Survival results in PoPH are contrasting, and prognostic factors need to be identified. OBJECTIVES: To analyze long-term survival in a large cohort of patients with PoPH with the aim of determining the independent variables affecting survival. METHODS: We retrospectively analyzed charts of all patients referred to the French Referral Center for pulmonary arterial hypertension with the diagnosis of PoPH between 1984 and 2004. MEASUREMENTS AND MAIN RESULTS: The study population comprised 154 patients; 57% male. Mean age at diagnosis was 49 +/- 11 years, 60% of patients were in New York Heart Association functional class III-IV, and mean 6-minute walk distance was 326 +/- 116 m. Hemodynamic measurements showed a mean pulmonary arterial pressure of 53 +/- 13 mm Hg, cardiac index of 2.9 +/- 0.9 L/min/m(2), and pulmonary vascular resistance of 752 +/- 377 dyn/s/cm(5). Portal hypertension was related to cirrhosis in 136 patients, with a severity assessed as follows: Child-Pugh class A 51%, Child-Pugh class B 38%, Child-Pugh class C 11%. Overall survival rates at 1, 3, and 5 yr were 88, 75, and 68%, respectively. Multivariate regression analysis individualized the presence and severity of cirrhosis and cardiac index as major independent prognostic factors. CONCLUSIONS: Prognosis in PoPH is mainly related to the presence and severity of cirrhosis and to cardiac function. The place of pulmonary arterial hypertension-specific therapies remains to be determined in the setting of PoPH.

Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation.

RATIONALE: Germline mutations in the gene encoding for bone morphogenetic protein receptor 2 (BMPR2) are a cause of pulmonary arterial hypertension (PAH). OBJECTIVES: We conducted a study to determine the influence, if any, of a BMPR2 mutation on clinical outcome. METHODS: The French Network of Pulmonary Hypertension obtained data for 223 consecutive patients displaying idiopathic or familial PAH in whom point mutation and large size rearrangements of BMPR2 were screened for. Clinical, functional, and hemodynamic characteristics, as well as outcomes, were compared in BMPR2 mutation carriers and noncarriers. MEASUREMENTS AND MAIN RESULTS: Sixty-eight BMPR2 mutation carriers (28 familial and 40 idiopathic PAH) were compared with 155 noncarriers (all displaying idiopathic PAH). As compared with noncarriers, BMPR2 mutation carriers were younger at diagnosis of PAH (36.5 +/- 14.5 vs. 46.0 +/- 16.1 yr, P < 0.0001), had higher mean pulmonary artery pressure (64 +/- 13 vs. 56 +/- 13 mm Hg, P < 0.0001), lower cardiac index (2.13 +/- 0.68 vs. 2.50 +/- 0.73 L/min/m(2), P = 0.0005), higher pulmonary vascular resistance (17.4 +/- 6.1 vs. 12.7 +/- 6.6 mm Hg/L/min/m(2), P < 0.0001), lower mixed venous oxygen saturation (59 +/- 9% vs. 63 +/- 9%, P = 0.02), shorter time to death or lung transplantation (P = 0.044), and younger age at death (P = 0.002), but similar overall survival (P = 0.51). CONCLUSIONS: BMPR2 mutation carriers with PAH present approximately 10 years earlier than noncarriers, with a more severe hemodynamic compromise at diagnosis.

Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases.

OBJECTIVE: To describe the response to first-line immunosuppressive therapy with or without pulmonary vasodilators in pulmonary arterial hypertension (PAH) associated with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MCTD). METHODS: Twenty-three consecutive patients with SLE- or MCTD-associated PAH treated with first-line immunosuppressive therapy either alone (n = 16) or in combination with pulmonary vasodilators (n = 7) were evaluated according to clinical and hemodynamic criteria before and after immunosuppressive therapy. Responders were defined as patients in New York Heart Association (NYHA) functional class I or II with hemodynamic improvement after the last pulse of cyclophosphamide. RESULTS: Among the 16 patients treated with first-line immunosuppressive therapy alone, 8 (50%) were responders. These patients had a significantly improved NYHA functional class, 6-minute walking distance, and mean pulmonary artery pressure. Patients in NYHA functional class I or II and/or a cardiac index >3.1 liters/minute/m(2) at baseline were more likely to benefit from immunosuppressive therapy. Six of the 8 nonresponders subsequently improved with pulmonary vasodilators. Among the 7 patients who were initially treated with immunosuppressive therapy and pulmonary vasodilators, 4 (57.1%) were responders. CONCLUSION: PAH associated with SLE or MCTD may respond to a treatment combining cyclophosphamide and glucocorticoids. Patients who could benefit from this immunosuppressive therapy could be those who have less severe disease at baseline. For patients with more severe disease, pulmonary vasodilators should be started, possibly in combination with immunosuppressants. In any case, clinical and hemodynamic evaluations are mandatory to monitor the response and adapt the treatment. These retrospective and uncontrolled data need to be confirmed by randomized controlled trials.

Identification of target antigens of antifibroblast antibodies in pulmonary arterial hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) may be classified as idiopathic (IPAH) or familial (FPAH) or associated with various conditions and exposures such as dexfenfluramine intake (Dex-PAH) or systemic sclerosis (SSc-PAH). Because fibroblast dysfunction has been identified in SSc and IPAH and antifibroblast antibodies (AFAs) with a pathogenic role have been detected in the serum of SSc patients, we used a proteomic approach combining two-dimensional electrophoresis and immunoblotting to identify the target antigens of AFAs in such patients. OBJECTIVES: To identify target antigens of antifibroblast antibodies in pulmonary arterial hypertension. METHODS: Sera from 24 patients with IPAH, 6 with FPAH, 6 with Dex-PAH, and 12 with SSc-PAH were collected. We pooled sera from sets of three patients with PAH classification and SSc-PAH based on autoantibody profile. Sera from 14 healthy blood donors were also pooled and used as a control. MEASUREMENTS AND MAIN RESULTS: Serum IgG antibodies in the pools of patients with IPAH (n = 8), FPAH (n = 2), Dex-PAH (n = 2), and SSc-PAH (n = 4) recognized 103 +/- 31, 63 +/- 20, 78 +/- 11, and 81 +/- 12 protein spots, respectively, whereas serum IgG antibodies from healthy control subjects recognized 43 +/- 22 protein spots. Twenty-one protein spots were specifically recognized by the serum IgG antibodies from patients with PAH. We identified 16 of the protein spots as vimentin, calumenin, tropomyosin 1, heat shock proteins 27 and 70, glucose-6-phosphate-dehydrogenase, phosphatidylinositol 3-kinase, DAP kinase, and others. These proteins are involved in regulation of cytoskeletal function, cell contraction, oxidative stress, cell energy metabolism, and other key cellular pathways. CONCLUSIONS: AFAs detected in patients with PAH recognize cellular targets playing key roles in cell biology and maintenance of homeostasis.

Therapeutic advances in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction, in situ thrombosis, and vascular remodeling of small pulmonary arteries inducing increased pulmonary arterial resistance. Conventional treatment is based on life style modification and nonspecific treatment (warfarine, diuretics, oxygen). Calcium channel blockers are vasodilatators that have been shown to be of great efficacy in a very specific subpopulation of patients with PAH. For the majority of patients, specific PAH therapies are still lacking. Numerous studies evaluating prostacyclin agonists, endothelin-receptor antagonists, and phosphodiesterase type 5 inhibitors are now available to guide therapeutic choices. Despite those important advances there is still no cure for PAH. Fortunately, research is ongoing and many drugs show promises.