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Contemporary prognostic equations in pulmonary arterial hypertension (PAH) derived from US and French cohorts may not perform as well in the UK as a locally derived scoring scheme. The aim of the study was to develop and validate a UK risk score to predict prognosis in PAH. Baseline mortality predictors identified by multivariate Cox analysis in 182 incident PAH patients were used to derive the Scottish composite score (SCS). Its prognostic performance in an independent UK cohort was compared with the French registry and Pulmonary Hypertension Connection (PHC) registry equations using Brier scores (BS). The SCS based on age, sex, aetiology, right atrial pressure, cardiac output and 6-min walk distance predicted survival in the validation cohort (hazard ratio (HR) 1.7 per point increase; p<0.001) and provided further prognostic stratification in World Health Organization (WHO) functional class III patients (HR 1.8 per point increase; p<0.001). It was more accurate than the French registry equation in predicting 1-yr survival (BS: 0.092 versus 0.146; p=0.001) and 2-yr survival (0.131 versus 0.255; p<0.001). There was no significant difference in BS between the SCS and PHC registry equation. The SCS predicts survival and can be used to supplement WHO functional class in prognostication.

Background: Beyond their role as innate immune effectors, natural killer (NK) cells are emerging as important regulators of angiogenesis and vascular remodeling. Pulmonary arterial hypertension (PAH) is characterized by severe pulmonary vascular remodeling and has long been associated with immune dysfunction. Despite this association, a role for NK cells in disease pathology has not yet been described., Methods and Results: Analysis of whole blood lymphocytes and isolated NK cells from PAH patients revealed an expansion of the functionally defective CD56(-)/CD16(+) NK subset that was not observed in patients with chronic thromboembolic pulmonary hypertension. NK cells from PAH patients also displayed decreased levels of the activating receptor NKp46 and the killer immunoglobulin-like receptors 2DL1/S1 and 3DL1, reduced secretion of the cytokine macrophage inflammatory protein-1β, and a significant impairment in cytolytic function associated with decreased killer immunoglobulin-like receptor 3DL1 expression. Genotyping patients (n=222) and controls (n=191) for killer immunoglobulin-like receptor gene polymorphisms did not explain these observations. Rather, we show that NK cells from PAH patients exhibit increased responsiveness to transforming growth factor-β, which specifically downregulates disease-associated killer immunoglobulin-like receptors. NK cell number and cytotoxicity were similarly decreased in the monocrotaline rat and chronic hypoxia mouse models of PAH, accompanied by reduced production of interferon-γ in NK cells from hypoxic mice. NK cells from PAH patients also produced elevated quantities of matrix metalloproteinase 9, consistent with a capacity to influence vascular remodeling., Conclusions: Our work is the first to identify an impairment of NK cells in PAH and suggests a novel and substantive role for innate immunity in the pathobiology of this disease.

Objectives: Advanced age is not a barrier to cardiac surgery, with reports demonstrating excellent outcomes, but the effect of age on more complex surgery has not been studied. We assessed the outcomes of pulmonary endarterectomy (PEA) surgery in patients aged >70., Methods: A retrospective review of consecutive patients who underwent PEA between January 2006 and March 2011 at a national referral centre. The total cohort was dichotomized according to age on the day of surgery, either below or above 70 years. Outcomes were in-hospital mortality, overall survival and the length of ICU and hospital stays., Results: Four hundred and eleven patients underwent PEA during the 5-year period. The mean age was 56.9 years (range, 17-84 years). The in-hospital mortality was 14 of 308 (4.6%) for patients <70 years compared with 8 of 103 (7.8%) for patients ≥70 years (P = 0.21). The overall survival at 1, 2 and 3 years was 91.4, 89.9 and 87.7% in the <70-year old group and 85.9, 84.1 and 84.1% in the >70-year old group (log-rank test, P = 0.07), respectively. The length of ICU and in-hospital stays was longer in the >70-year old group, by 1 and 2 days, respectively (P = 0.005 and 0.001)., Conclusions: PEA surgery in patients ≥70 years is safe and carries a comparable risk of early mortality in younger patients, but there is an increase in resource use due to longer ICU and hospital stays. Advanced age should be taken into consideration when assessing suitability for PEA, but age per se should not be a contraindication to surgery.

We previously reported that osteoprotegerin (OPG) is regulated by pathways associated with pulmonary arterial hypertension (PAH), and is present at elevated levels within pulmonary vascular lesions and sera from patients with idiopathic PAH (IPAH). Since OPG is a naturally secreted protein, we investigated the relationship between serum OPG and disease severity and outcome in patients with IPAH and animal models. OPG mRNA expression was measured in pulmonary artery smooth muscle cells (PASMC) from pulmonary arteries of patients with and without IPAH. Serum concentrations of OPG were measured in a retrospective and prospective group of patients. OPG levels were compared with phenotypic data and other putative PAH biomarkers. Prognostic significance was assessed and levels compared with healthy controls. Correlation of OPG and pulmonary vascular remodeling was also performed in rodent models of PAH. OPG mRNA was significantly increased 2-fold in PASMC isolated from explanted PAH lungs compared with control. Serum OPG concentrations were markedly elevated in IPAH compared with controls. In Cohort 1 OPG levels significantly correlated with mean right atrial pressure and cardiac index, while in Cohort 2 significant correlations existed between age-adjusted OPG levels and gas transfer. In both cohorts an OPG concentration above a ROC-derived threshold of 4728 pg/ml predicted poorer survival. In two rodent models, OPG correlated with the degree of pulmonary vascular remodeling. OPG levels are significantly elevated in patients with idiopathic PAH and are of prognostic significance. The role of OPG as a potential biomarker and therapeutic target merits further investigation.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is often a sequel of venous thromboembolism with fatal natural history; however, many cases can be cured by pulmonary endarterectomy. The clinical characteristics and current management of patients enrolled in an international CTEPH registry was investigated., Methods and Results: The international registry included 679 newly diagnosed (≤6 months) consecutive patients with CTEPH, from February 2007 until January 2009. Diagnosis was confirmed by right heart catheterization, ventilation-perfusion lung scintigraphy, computerized tomography, and/or pulmonary angiography. At diagnosis, a median of 14.1 months had passed since first symptoms; 427 patients (62.9%) were considered operable, 247 (36.4%) nonoperable, and 5 (0.7%) had no operability data; 386 patients (56.8%, ranging from 12.0%- 60.9% across countries) underwent surgery. Operable patients did not differ from nonoperable patients relative to symptoms, New York Heart Association class, and hemodynamics. A history of acute pulmonary embolism was reported for 74.8% of patients (77.5% operable, 70.0% nonoperable). Associated conditions included thrombophilic disorder in 31.9% (37.1% operable, 23.5% nonoperable) and splenectomy in 3.4% of patients (1.9% operable, 5.7% nonoperable). At the time of CTEPH diagnosis, 37.7% of patients initiated at least 1 pulmonary arterial hypertension-targeted therapy (28.3% operable, 53.8% nonoperable). Pulmonary endarterectomy was performed with a 4.7% documented mortality rate., Conclusions: Despite similarities in clinical presentation, operable and nonoperable CTEPH patients may have distinct associated medical conditions. Operability rates vary considerably across countries, and a substantial number of patients (operable and nonoperable) receive off-label pulmonary arterial hypertension-targeted treatments.

The past decade has seen increased application of 18-flurodeoxyglucose positron emission tomography ((18)FDG-PET) imaging to help diagnose and monitor disease, particularly in oncology, vasculitis and atherosclerosis. Disordered glycolytic metabolism and infiltration of plexiform lesions by inflammatory cells has been described in idiopathic pulmonary arterial hypertension (IPAH). We hypothesized that increased (18)FDG uptake may be present in the lungs, large pulmonary arteries and right ventricle of patients with pulmonary hypertension, and that this uptake would be related to markers of immune activation. We imaged the thorax of 14 patients with pulmonary hypertension (idiopathic and chronic thromboembolic) and six controls by (18)FDG-PET/computed tomography (CT) and measured uptake in the lung parenchyma, large pulmonary arteries and right ventricle. (18)FDG uptake in the lungs and pulmonary arteries was normalized for venous blood activity to give a target-to-background ratio (TBR). Blood was contemporaneously drawn for high-sensitivity CRP - C-reactive protein (CRP) (hsCRP), N-Terminal Probrain natriuteric peptide (NT-ProBNP) and other inflammatory cytokines. IPAH patients had significantly higher lung parenchymal TBR (P=0.034) and right ventricle FDG uptake (P=0.007) than controls. Uptake in the main pulmonary arteries was similar in chronic thromboembolic pulmonary hypertension, IPAH and controls. There were no correlations between (18)FDG uptake and hsCRP or inflammatory cytokine levels. NT-ProBNP correlated with RV uptake in those with pulmonary hypertension (r=0.55, P=0.04). In this pilot study, we found increased (18)FDG uptake in the lung parenchyma and right ventricle of subjects with IPAH. The lung uptake might be useful as a surrogate marker of increased cellular metabolism and immune activation as underlying mechanisms in this disease. Further evaluation of the impact of targeted therapies in treatment-naïve patients and the significance of right ventricular uptake is suggested.

N-terminal pro B-type natriuretic peptide (NT-proBNP) is a product of cleavage of the cardiac prohormone pro B-type natriuretic peptide into its active form. It has proven to be a useful biomarker in left heart failure. However, studies examining the utility of serial measurements of NT-proBNP in pulmonary arterial hypertension (PAH) patients have shown mixed results. We compared three methods of predicting adverse clinical outcomes in PAH patients: the change in 6 minute walk distance (6MWD), the change in absolute levels of NT-proBNP and the change in log-transformed levels of NT-proBNP. All PAH patients presenting from March-June 2007 were screened. Patients who were clinically unstable, had abnormal renal function or hemoglobin levels or lacked a prior NT-proBNP were excluded. 63 patients were followed up for adverse clinical outcomes (defined as death, transplantation, hospitalisation for right heart failure, or need for increased therapy). Three methods were used to predict adverse events, i.e.: (a) comparing a 6MWD performed in March-June 2007 and a previous 6MWD. A decrease in 6MWD of ≥30m was used to predict clinical deterioration; (b) comparing a NT-proBNP value measured in March-June 2007 and a previous NT-proBNP. An increase in NT-proBNP of ≥250pg/ml was used to predict clinical deterioration (250pg/ml represented approximately 30% change from the baseline median value of NT-proBNP for this cohort); and (c) comparing the loge equivalents of two consecutive NT-proBNP values. We used the formula: loge(current NT-proBNP) - loge(previous NT-proBNP)=x. A value of x≥+0.26 was used to predict adverse events. This is equivalent to a 30% change from baseline, and hence is comparable to the chosen cut-off for absolute levels of NT-proBNP. A loge difference of ≥+0.26 identifies patients at risk of adverse events with a specificity of 98%, a sensitivity of 60%, a positive predictive value of 89%, and a negative predictive value of 90%. A drop in 6MWD of ≥30m has a specificity of 29%, a sensitivity of 73%, a positive predictive value of 24% and a negative predictive value of 24%. It seems possible to risk-stratify apparently stable PAH patients by following the changes in their serial log-transformed NT-proBNP values. In this small pilot study, this method was better than relying on changes in the actual levels of NT-proBNP or changes in 6MWD. This needs to be validated prospectively in a larger cohort.

Nitric oxide (NO) is an important molecule in the mammalian cardiovascular system and the elucidation of its biological role has led to the awarding of a Nobel prize in medicine. There have been many significant discoveries in NO biology over the past two decades and translation of these developments from bench to bedside has allowed an explosion of therapies for pulmonary hypertension. This article provides an overview of the NO pathway in the pulmonary circulation in maintenance of normal vascular tone as well as its dysregulation in pulmonary hypertension, and a discussion of therapies based on inhaled NO or manipulation of its downstream signaling pathways. Several therapies such as phosphodiesterase inhibitors are already in use, and various experimental therapies are also discussed.

Background: Anaemia is common in left heart failure and is associated with a poorer outcome. Many patients with pulmonary arterial hypertension (PAH) are anaemic or iron-deficient. This study was performed to investigate the prevalence of iron deficiency in PAH and to identify possible causes., Methods: All patients with idiopathic or heritable PAH diagnosed in 1995-2008 were identified. Controls were selected from patients with chronic thromboembolic pulmonary hypertension (CTEPH). Full blood counts were examined and any abnormality was investigated. Patients were excluded if they had a cause for iron deficiency. The prevalence study was based on 85 patients with idiopathic PAH and 120 with CTEPH. A separate group of 20 patients with idiopathic PAH and 24 with CTEPH with matching haemodynamics were prospectively investigated for serum factors affecting iron metabolism., Results: The prevalence study identified a point prevalence of unexplained iron deficiency of 50% in premenopausal women with idiopathic PAH compared with 8% in premenopausal women with CTEPH (p=0.002); 14% in postmenopausal women with idiopathic PAH compared with 6% in postmenopausal women with CTEPH (p=0.16); 28% in men with idiopathic PAH men compared with 2% in men with CTEPH (p=0.002); and 60% in patients with heritable PAH. The serum study showed that patients with idiopathic PAH had lower serum iron and transferrin saturations than those with CTEPH. Interleukin-6 levels correlated with iron levels (r=-0.6, p=0.006) and transferrin saturations (r=-0.68, p=0.001) in idiopathic PAH but not in CTEPH., Conclusions: The prevalence of unexplained iron deficiency is significantly higher in idiopathic PAH than in CTEPH. This may be linked to interleukin-6.

Objective: This study assessed the utility of dual-energy pulmonary CT angiography (CTA) for noninvasive assessment of regional pulmonary perfusion in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Regional perfusion abnormalities were correlated with hemodynamic parameters and structural abnormalities on pulmonary CTA., Subjects and Methods: Twenty patients with CTEPH (11 men and nine women; mean age, 61.5 years) underwent pulmonary CTA with a dual-energy technique. Right heart catheterization data were available in 15 cases. Scan parameters were as follows: tube A, 140 kV (75 mA); tube B, 80 kV (300 mA); gantry rotation, 500 milliseconds; pitch, 0.5; and collimation, 14 × 1.2 mm. An iodine map was generated via three-material-decomposition and was scored for extent of hypoperfusion. Correlation was made with mosaic attenuation pattern, extent of vascular obstruction, and right heart hemodynamics. Iodine attenuation values were analyzed within completely occluded, partially occluded, and disease-free lobes., Results: A strong correlation existed between dual-energy CT-derived perfusion and mosaic attenuation pattern when both lobar (r > 0.6; n = 20; p < 0.006) and whole-lung scores were assessed (r = 0.77; n = 20; p < 0.001). There was no statistically significant correlation between dual-energy CT perfusion and vascular obstructive index, mean pulmonary artery pressure, or pulmonary vascular resistance (p > 0.08). Of 42 completely occluded lobes, 27 (64%) had demonstrable residual perfusion (mismatching), suggesting that blood supply was maintained via systemic collaterals., Conclusion: Dual-energy CT can offer a "one-stop" assessment of anatomy and perfusion in CTEPH. The additional information provided by dual-energy CT could have a future role in helping guide patient selection for thromboendarterectomy surgery.

Objective: Pulmonary endarterectomy is a curative surgical treatment option for the majority of patients with chronic thromboembolic pulmonary hypertension. The current surgical management and postoperative outcome of patients enrolled in an international registry on chronic thromboembolic pulmonary hypertension were investigated., Methods: The registry included newly diagnosed (≤6 months) consecutive patients with chronic thromboembolic pulmonary hypertension from February 2007 to January 2009., Results: A total of 679 patients were registered from 1 Canadian and 26 European centers, of whom 386 (56.8%) underwent surgery. The median age of patients undergoing surgery was 60 years, and 54.1% were male. Previous pulmonary embolism was confirmed for 79.8% of patients. Perioperative complications occurred in 189 patients (49.2%): infection (18.8%), persistent pulmonary hypertension (16.7%), neurologic (11.2%) or bleeding (10.2%) complications, pulmonary reperfusion edema (9.6%), pericardial effusion (8.3%), need for extracorporeal membrane oxygenation (3.1%), and in-hospital mortality due to perioperative complications (4.7%). Documented 1-year mortality was 7%. Preoperative exercise capacity was predictive of 1-year mortality. Postoperative pulmonary vascular resistance predicted in-hospital and 1-year mortality. In patients evaluated within 1 year after surgery, the median pulmonary vascular resistance had decreased from 698 to 235 dyn x s x cm(-5) (95% confidence limit, 640-874 and 211-255, respectively, n = 70) and the median 6-minute walk distance had increased from 362 to 459 m (95% confidence limit, 340-399 and 440-473, respectively, n = 168). New York Heart Association functional class improved with most patients progressing from class III/IV to class I/II., Conclusions: Pulmonary endarterectomy is associated with a low in-hospital mortality rate and improvements in hemodynamics and exercise capacity., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Intravenous prostacyclin (iv PGI) and inhaled Iloprost (inh ilo) are established therapies in pulmonary arterial hypertension (PAH), however comparative data are lacking., Methods and Patients: We performed a long-term open label comparison trial of iv PGI or high dose inh ilo in 24 patients with severe PAH: 12 patients (9 female, 40 +/- 14 years, 10 idiopathic PAH, 2 PAH in connective tissue disease CTD) received iv PGI, whereas 12 patients (7 female, 43 +/- 12 years, 5 IPAH, 6 CTD, 1 porto-pulmonary hypertension) were commenced on inh ilo with a median dose of 120 μg/24 h. Haemodynamic parameters and 6 min walking distance (6MWD) at baseline did not differ between both groups., Results: After 3 months therapy, patients on iv PGI showed a significant increase in 6MWD from 220 to 280 m (p < 0.01), whereas patients on high dose inh ilo increased 6MWD from 200 to 275 m (p < 0.05). The event free follow up was 23 [1-76] months in the iv PGI2I group, and 16 [7-38] months in the high dose inh ilo group (p < 0.05). Patients with a 6MWD ≥ 300 m after 3 months therapy had a significantly longer event free follow up [16 vs. 35 months; p < 0.004]., Conclusion: In this patient population with severe pulmonary hypertension of different etiologies, event free follow up on treatment with iv PGI is significantly longer compared to high dose inh ilo. The 6MWD after 3 months treatment might be predictive for long term outcome., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: Pulmonary endarterectomy is the treatment of choice for chronic thromboembolic pulmonary hypertension. In many patients hemodynamics are normalized early after surgical intervention. However, the effect of residual pulmonary hypertension on postoperative clinical status and survival is unknown., Methods: Data were collected prospectively on all patients who underwent pulmonary endarterectomy in a continuous national series between 1997 and December 2007. Postoperatively, patients underwent scheduled reinvestigation, including functional testing and right heart catheterization, at 3 months after the operation. They were divided into 2 groups based on mean pulmonary artery pressure: group 1, less than 30 mm Hg; group 2, 30 mm Hg or greater., Results: Three hundred fourteen patients underwent pulmonary endarterectomy, survived to hospital discharge, and completed the 3-month follow-up period. At 3 months after pulmonary endarterectomy, there was a significant reduction in mean pulmonary artery pressure for the whole cohort (48±12 to 26±10 mm Hg, P<.001). However, 31% of the patients had residual pulmonary hypertension. Group 1 patients enjoyed significantly better exercise capacity and improved symptoms compared with group 2 patients. In addition, there were significantly fewer patients receiving targeted medical therapy in group 1 versus group 2 (0% vs 25%, P<.001). Conditional survival after discharge from the hospital for the whole cohort was 90.0% at 5 years and was not different between groups (90.3% for group 1 vs 89.9% for group 2, P=.36)., Conclusions: For patients undergoing pulmonary endarterectomy, survival after hospital discharge is excellent. Residual pulmonary hypertension significantly compromised symptom status and functional capacity but did not appear to adversely affect medium-term survival. The effect of targeted medical therapy in patients with residual pulmonary hypertension after pulmonary endarterectomy needs to be evaluated further., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Inflammation is a feature of pulmonary arterial hypertension (PAH), and increased circulating levels of cytokines are reported in patients with PAH. However, to date, no information exists on the significance of elevated cytokines or their potential as biomarkers. We sought to determine the levels of a range of cytokines in PAH and to examine their impact on survival and relationship to hemodynamic indexes., Methods and Results: We measured levels of serum cytokines (tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta, -2, -4, -5, -6, -8, -10, -12p70, and -13) using ELISAs in idiopathic and heritable PAH patients (n=60). Concurrent clinical data included hemodynamics, 6-minute walk distance, and survival time from sampling to death or transplantation. Healthy volunteers served as control subjects (n=21). PAH patients had significantly higher levels of interleukin-1beta, -2, -4, -6, -8, -10, and -12p70 and tumor necrosis factor-alpha compared with healthy control subjects. Kaplan-Meier analysis showed that levels of interleukin-6, 8, 10, and 12p70 predicted survival in patients. For example, 5-year survival with interleukin-6 levels of >9 pg/mL was 30% compared with 63% for patients with levels < or = 9 pg/mL (P=0.008). In this PAH cohort, cytokine levels were superior to traditional markers of prognosis such as 6-minute walk distance and hemodynamics., Conclusions: This study illustrates dysregulation of a broad range of inflammatory mediators in idiopathic and familial PAH and demonstrates that cytokine levels have a previously unrecognized impact on patient survival. They may prove to be useful biomarkers and provide insight into the contribution of inflammation in PAH.

Background: Relative area change (RAC) of the proximal pulmonary artery is a measurement of pulmonary artery distensibility and has been shown to correlate with vasoreactivity studies in patients with idiopathic pulmonary arterial hypertension. We have previously noted a relationship between invasive hemodynamic vasoreactivity testing and long-term response to sildenafil in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). We therefore set out to determine whether RAC can provide useful correlatory non-invasive data., Methods: Patients recruited to a randomized, controlled trial (RCT) of sildenafil at 40 mg 3 times daily underwent additional magnetic resonance imaging (MRI) at the baseline of the trial. Eighteen patients had an MRI that led to a diagnosis of inoperable distal CTEPH or significant residual CTEPH post-operatively. The primary end-point was improvement in 6-minute walk test (6MWT) with secondary end-points of right heart catheterization-based hemodynamics, N-terminal pro-brain natriuretic peptide (NT pro-BNP) and functional class. RAC assessed by MRI was correlated with trial end-points., Results: Fourteen subjects with baseline MRI completed the protocol. RAC was the only baseline variable that correlated at 1 year to the primary end-point of improvement in 6MWT (r = 0.7, p = 0.006), and also to a change in NT pro-BNP (r = 0.59, p = 0.03). Using a cut-off of RAC over 20% there was an 87.5% sensitivity (95% confidence interval [CI]: 45% to 100%) and a 66.7% specificity (95% CI: 22% to 96%) for an improvement in 6MWT of >40 meters., Conclusions: RAC correlates with functional response to sildenafil, as measured by the 6MWT, and improved heart function, as measured by NT pro-BNP. RAC shows potential in understanding and possibly predicting treatment response., (Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The last 10 years have seen significant advances in the understanding of the pathophysiology and treatment of pulmonary arterial hypertension (PAH). This has included new insights into the genetics, cell-signalling pathways and pathological changes seen in the small pulmonary arteries as well as the introduction of new treatments which have improved prognosis. The classification of pulmonary hypertension (PH) has also been changed several times, most recently in 2003. It now divides forms of PH into 5 broad groups according to their pathophysiology and response to treatment. This review focuses primarily on the advances that have been made in the comprehension and treatment of Group 1 (PAH); however reference is also made to other groups within the classification. Pharmacologic treatment now includes calcium-channel blockers, endothelin antagonists, prostanoids, phosphodiesterase type 5 inhibitors, anticoagulants and diuretics. There are 2 recent sets of guidelines directing treatment, one published by the American College of Chest Physicians in 2007 and the most recent published by the National Pulmonary Hypertension Centres of the UK and Ireland in 2008. The recent advances in understanding of the underlying cellular mechanisms have also opened the doorway to new potential therapies such as stem cell transplantation and the targeting of platelet-derived factors and apoptosis.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening and debilitating disease affecting up to 5% of survivors of pulmonary embolism. Diagnostic testing is important to distinguish it from other forms of pulmonary hypertension and to assess the feasibility of pulmonary endarterectomy. This review provides an up-to-date perspective on the diagnosis and assessment of the disease. Patients with CTEPH often have a history of pulmonary embolism, deep-vein thrombosis, thrombophilia, splenectomy, ventriculo-atrial shunt, inflammatory bowel disease or malignancy. Chest radiography may reveal pulmonary infarcts. CTEPH is often diagnosed as a wedge-shaped perfusion defect with normal ventilation scan during ventilation-perfusion scintigraphy, but multi-slice computed tomography angiography may be needed for differential diagnosis. Right heart catheterisation is required for diagnostic confirmation. Suitability for surgery is assessed by evaluating the number of obstructed vessels which could be disobliterated in the context of the pulmonary vascular resistance. Pulmonary vascular resistance that is out of proportion to evident obstructions is indicative of distal disease. Conventional pulmonary angiography, multi-slice computed tomography angiography and, potentially, magnetic resonance imaging can aid the decision to operate, but risk stratification systems are needed. In conclusion, CTEPH can be cured surgically, providing that patients are diagnosed and assessed using the appropriate techniques.

Rationale: Severe pulmonary arterial hypertension (PAH) is characterized by the formation of plexiform lesions and concentric intimal fibrosis in small pulmonary arteries. The origin of cells contributing to these vascular lesions is uncertain. Endogenous endothelial progenitor cells are potential contributors to this process., Objectives: To determine whether progenitors are involved in the pathobiology of PAH., Methods: We performed immunohistochemistry to determine the expression of progenitor cell markers (CD133 and c-Kit) and the major homing signal pathway stromal cell-derived factor-1 and its chemokine receptor (CXCR4) in lung tissue from patients with idiopathic PAH, familial PAH, and PAH associated with congenital heart disease. Two separate flow cytometric methods were employed to determine peripheral blood circulating numbers of angiogenic progenitors. Late-outgrowth progenitor cells were expanded ex vivo from the peripheral blood of patients with mutations in the gene encoding bone morphogenetic protein receptor type II (BMPRII), and functional assays of migration, proliferation, and angiogenesis were undertaken. measurements and main results: There was a striking up-regulation of progenitor cell markers in remodeled arteries from all patients with PAH, specifically in plexiform lesions. These lesions also displayed increased stromal cell-derived factor-1 expression. Circulating angiogenic progenitor numbers in patients with PAH were increased compared with control subjects and functional studies of late-outgrowth progenitor cells from patients with PAH with BMPRII mutations revealed a hyperproliferative phenotype with impaired ability to form vascular networks., Conclusions: These findings provide evidence of the involvement of progenitor cells in the vascular remodeling associated with PAH. Dysfunction of circulating progenitors in PAH may contribute to this process.

Background: Pulmonary arterial hypertension (PAH) is a rare, progressive lung disorder that impairs performance of daily activities and quality of life (QoL), leading to right heart failure and death. Treatment options include prostanoids, endothelin antagonists, and phosphodiesterase type 5 inhibitors (e.g., tadalafil). Currently there is no cure for PAH, but tadalafil has improved exercise capacity in these patients., Objectives: To explore the effect of tadalafil on health-related quality of life (HRQoL) measures., Research Design and Methods: The Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) clinical trial examined the efficacy and tolerability of tadalafil for the treatment of PAH. The impact of tadalafil on HRQoL and exercise capacity, as measured by 6-minute walk test (6MW test), was also examined. Change from baseline to last non-missing post-baseline was examined for the SF-36, EQ-5D, and 6MW test, along with the relationship between HRQoL and 6MW test performance., Results: Tadalafil 40 mg showed significant improvement over placebo for six of eight SF-36 domains, and EQ-5D index scores. Also, the tadalafil 40-mg group showed significant improvement over placebo on the 6MW test (p < 0.001), but no clear relationship was found between 6MW test performance and HRQoL., Conclusion: Results suggest that tadalafil 40 mg may significantly improve HRQoL and exercise capacity for PAH patients. Limitations of this study include its relatively short nature limited to 16 weeks and the relative heterogeneity of the study population.

Objective(s): To investigate the clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of adults with pulmonary arterial hypertension (PAH) within their licensed indications., Data Sources: Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched up to February 2007. Further data were obtained from dossiers submitted to NICE by the manufacturers of the technologies., Review Methods: The systematic clinical and economic reviews were conducted according to accepted procedures. Model-based economic evaluations of the cost-effectiveness of the technologies from the perspective of the UK NHS and personal social services were carried out., Results: In total, 20 randomised controlled trials (RCTs) were included in this assessment, mostly of 12-18 weeks duration and comparing one of the technologies added to supportive treatment with supportive treatment alone. Four published economic evaluations were identified. None produced results generalisable to the NHS. There was no consensus in the industry submissions on the most appropriate model structure for the technology assessment. Improvement in 6-minute walk distance (6MWD) was seen with intravenous epoprostenol in primary pulmonary hypertension (PPH) patients with mixed functional class (FC) (mainly III and IV, licensed indication) compared with supportive care (58 metres; 95% CI 6-110). For bosentan compared with supportive care, the pooled result for improvement in 6MWD for FCIII patients with mixed PAH (licensed indication) was 59 metres (95% CI 20-99). For inhaled iloprost, sitaxentan and sildenafil no stratified data for improvement in 6MWD were available. The odds ratio (OR) for FC deterioration at 12 weeks was 0.40 (95% CI 0.13-1.20) for intravenous epoprostenol compared with supportive care. The corresponding values for inhaled iloprost (FCIII PPH patients; licensed indication), bosentan, sitaxentan (FCIII patients with mixed PAH; licensed indication) and sildenafil (FCIII patients with mixed PAH; licensed indication) were 0.29 (95% CI 0.07-1.18), 0.21 (95% CI 0.03-1.76), 0.18 (95% CI 0.02-1.64) and [Commercial-in-confidence information has been removed] respectively. The incremental cost-effectiveness ratios (ICERs) for the technologies plus supportive care compared with supportive care alone, determined by independent economic evaluation, were 277,000 pounds/quality-adjusted life-year (QALY) for FCIII and 343,000 pounds/QALY for FCIV patients for epoprostenol, 101,000 pounds/QALY for iloprost, 27,000 pounds/QALY for bosentan and 25,000 pounds/QALY for sitaxentan. For the most part sildenafil plus supportive care was more effective and less costly than supportive care alone and therefore dominated supportive care. In the case of epoprostenol the ICERs were sensitive to the price of epoprostenol and for bosentan and sitaxentan the ICERs were sensitive to running the model over a shorter time horizon and with a lower cost of epoprostenol. Two RCTs directly compared the technologies against each other with no significant differences observed between the technologies. Combinations of technologies were investigated in four RCTs, with some showing conflicting results., Conclusion(s): All five technologies when added to supportive treatment and used at licensed dose(s) were more effective than supportive treatment alone in RCTs that included patients of mixed FC and types of PAH. Current evidence does not allow adequate comparisons between the technologies nor for the use of combinations of the technologies. Independent economic evaluation suggests that bosentan, sitaxentan and sildenafil may be cost-effective by standard thresholds and that iloprost and epoprostenol may not. If confirmed, the use of the most cost-effective treatment would result in a reduction in costs for the NHS. Long-term, double-blind RCTs of sufficient sample size that directly compare bosentan, sitaxentan and sildenafil, and evaluate outcomes including survival, quality of life, maintenance on treatment and impact on the use of resources for NHS and personal social services are needed.

The 4th World Symposium on Pulmonary Hypertension was the first international meeting to focus not only on pulmonary arterial hypertension (PAH) but also on the so-called non-PAH forms of pulmonary hypertension (PH). The term "non-PAH PH" summarizes those forms of PH that are found in groups 2 to 5 of the current classification of PH, that is, those forms associated with left heart disease, chronic lung disease, recurrent venous thromboembolism, and other diseases. Many of these forms of PH are much more common than PAH, but all of them have been less well studied, especially in terms of medical therapy. The working group on non-PAH PH focused mainly on 4 conditions: chronic obstructive lung disease, interstitial lung disease, chronic thromboembolic PH, and left heart disease. The medical literature regarding the role of PH in these diseases was reviewed, and recommendations regarding diagnosis and treatment of PH in these conditions are provided. Given the lack of robust clinical trials addressing PH in any of these conditions, it is important to conduct further studies to establish the role of medical therapy in non-PAH PH.

Most patients with chronic thromboembolic pulmonary hypertension are operable, and pulmonary endarterectomy is the treatment of choice. Pulmonary endarterectomy should not be delayed for medical therapy, and risk stratification helps to define patients likely to achieve the best outcome. Inoperable patients should be referred for trials of medical agents. Atrial septostomy is promising but underutilized, although better ways of ensuring an adequate, lasting septostomy still need to be determined. Indications for the procedure are unchanged, and it should be considered more frequently. Bilateral sequential lung or heart-lung transplantation is an important option for selected patients, and potential candidates who are class IV or III but not improving should be referred early to a transplantation center. Currently, there is a need for right ventricular assist devices with flow characteristics suited to the circulation of patients with pulmonary arterial hypertension. Right ventricular synchronization therapy has not yet been tested. Novel shunts (e.g., Potts anastomosis) also hold promise. All surgery for pulmonary hypertension should be performed in centers with experience in these techniques.

Several prognostic variables have previously been identified in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Specific medical conditions have also been associated with the development and prognosis of CTEPH. Using a national registry, the current authors have assessed the prognostic value of a larger number of variables and have also attempted to validate the clinical importance of previously identified aetiological factors. Baseline information for all 469 CTEPH patients diagnosed in the UK pulmonary hypertension service between January 2001 and June 2006 was collected from hospital records. Although univariate analysis confirmed the prognostic importance of pulmonary resistance, in multivariate analysis gas transfer and exercise capacity predicted pulmonary endarterectomy perioperative mortality. Cardiac index and exercise capacity independently predicted outcome in patients with nonoperable disease. Previous splenectomy was noted in 6.7% of patients, being significantly more common in patients with nonoperable than operable disease (13.7 versus 3.6%). Medical risk factors were not found to predict mortality. In a large national cohort, predictors of outcome in patients with both operable and nonoperable chronic thromboembolic pulmonary hypertension have been identified. These may be useful in planning treatment. The aetiological importance of previously identified medical risk factors has been confirmed, although the current authors were unable to validate their prognostic strength.

Rationale: Pulmonary arterial hypertension in association with connective tissue disease (CTD-PAH) has historically had a poor prognosis, with a 1-year survival rate among patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) of 45%. However, more therapies have become available., Objectives: To investigate the survival and characteristics of all patients diagnosed with CTD-PAH in the U.K. pulmonary hypertension service., Methods: National registry of all incident cases of CTD-PAH diagnosed consecutively between January 2001 and June 2006., Measurements and Main Results: Patients with CTD-PAH (429; 73% SSc-PAH) were diagnosed by a catheter-based approach. One- and 3-year survival rates were 78 and 47% for patients with isolated SSc-PAH. Survival was worse for those with respiratory disease-associated SSc-PAH (3-yr survival, 28%; P = 0.005) whereas survival among patients with exercise-induced SSc-PAH was superior (3-yr survival, 86%; P = < 0.001). Age, sex, mixed venous oxygen saturation, and World Health Organization functional class were independent predictors of survival in isolated SSc-PAH. Nineteen percent of patients with exercise-induced SSc-PAH and 39% of patients with isolated SSc-PAH who were in functional classes I and II had evidence of disease progression. The prevalence of diagnosed SSc-PAH is 2.93 per 1 million. The 3-year survival rate of 75% for those with pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH) was significantly better than that for patients with SSc-PAH (P = 0.01)., Conclusions: Survival of patients with SSc-PAH in the modern treatment era is better than in historical series. A significant proportion of patients with mild functional impairment or exercise-induced SSc-PAH have evidence of disease progression. Survival of patients with respiratory disease-associated pulmonary hypertension is inferior. SLE-PAH has a better prognosis than SSc-PAH.

Objectives: Our goal was to investigate the effect of treatment with the oral dual endothelin receptor antagonist bosentan on the hemodynamics and exercise capacity of patients with chronic thromboembolic pulmonary hypertension (CTEPH)., Background: CTEPH is characterized by vascular obstruction and remodeling, leading to increased pulmonary vascular resistance (PVR). Although pulmonary endarterectomy (PEA) is potentially curative, medical therapy is needed in patients with inoperable disease or persistent/recurrent pulmonary hypertension after PEA., Methods: The BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension) study was a double-blind, randomized, placebo-controlled study in CTEPH including patients with either inoperable CTEPH or persistent/recurrent pulmonary hypertension after PEA (>6 months after PEA). Independent coprimary end points were change in PVR as a percentage of baseline and change from baseline in 6-min walk distance after 16 weeks of treatment with bosentan or placebo. Secondary end points included change from baseline in World Health Organization functional class and other hemodynamic parameters., Results: One hundred fifty-seven patients were enrolled and randomized: 80 to placebo, 77 to bosentan. A statistically significant treatment effect (TE) of bosentan over placebo on PVR was demonstrated: -24.1% of baseline (95% confidence interval [CI]: -31.5% to -16.0%; p < 0.0001). Total pulmonary resistance (TE: -193 dynxsxcm(-5); 95% CI: -283 to -104 dyn.s.cm(-5); p < 0.0001) and cardiac index (TE: 0.3 lxmin(-1)xm(-2); 95% CI: 0.14 to 0.46 lxmin(-1)xm(-2); p = 0.0007) improved. Mean TE on 6-min walk distance was +2.2 m (95% CI: -22.5 to 26.8 m; p = 0.5449). Bosentan treatment was well tolerated., Conclusions: This study demonstrated a positive TE of bosentan on hemodynamics in this patient population. No improvement was observed in exercise capacity. Further trials are needed to define the role of medical therapy in patients with CTEPH (Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension; NCT00313222).

The aim of the present study was to validate and determine the minimal important difference (MID) and responsiveness of the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Utility Index, a new tool enabling cost utility analyses. CAMPHOR, 6-min walking test (6MWT) and New York Heart Association (NYHA) data for 869 pulmonary hypertension patients (545 (63%) female; mean+/-SD age 56.6+/-15.4 yrs) from three centres were analysed. Utility was correlated with 6MWT data and calculated by NYHA class to assess validity. Effect sizes were calculated for those with two CAMPHOR assessments. Distribution and anchor-based MIDs were calculated. Analyses were carried out in patients receiving bosentan in order to determine whether or not those remaining in NYHA class III following treatment improved. The Utility Index distinguished between adjacent NYHA classes and correlated with 6MWT results. CAMPHOR subscales and utility were as responsive as the 6MWT (effect sizes ranged 0.31-0.69 for the CAMPHOR and 0.16-0.34 for the 6MWT). The within-group MID for the Utility Index was estimated to be approximately 0.09. Patients remaining in NYHA class III experienced, on average, a significant improvement (CAMPHOR Utility Index and functioning), which exceeded the MID. The CAMPHOR Utility Index is valid and responsive to change. Patients can experience significant and important improvements even if they do not improve on the basis of traditional outcomes, such as NYHA functional class.

Objective: Chronic thromboembolic pulmonary hypertension (CTEPH) results in severe symptoms and impaired survival. Pulmonary thromboendarterectomy (PTE) is considered the gold standard treatment. Many units have reported excellent early results post PTE, but there is less information on whether benefit is sustained. We sought to determine the medium-term functional and haemodynamic outcome for patients following PTE and the longer-term survival after discharge from hospital., Methods: Data were collected prospectively on all patients who underwent PTE in the UK between 1997 and June 2006. Patients were reassessed at 3 and 12 months after operation. Follow-up over time was assessed using repeated measures ANOVA, the Friedman test or Wilcoxon signed ranks test as appropriate., Results: Two hundred and twenty-nine patients underwent PTE, survived to hospital discharge, and completed follow-up. At 3 months following operation, there was a significant reduction in mean pulmonary artery pressure (47+/-14 to 25+/-14mmHg, p<0.001), a significant increase in cardiac index (1.9+/-0.7 to 2.5+/-0.6l/minm(2), p<0.001) and a significant increase in 6-min walk distance (269+/-123 to 375+/-104m, p<0.001). At 12-month follow-up, the haemodynamic improvements were sustained and there was a further increase in 6-min walk distance (375+/-104 to 392+/-108m, p=0.004). NYHA class was significantly reduced at 3 months, with the improvement sustained at 12 months. Conditional survival following discharge from hospital was 92.5% at 5 years and 88.3% at 10 years., Conclusions: PTE is a very effective therapy for CTEPH. This is the first report from a continuous national series to fully characterise haemodynamic and functional outcome 1 year after PTE. Patients enjoy continued improvement in haemodynamic status that translates into better exercise capacity, reduced symptoms and excellent survival.

Pulmonary endarterectomy (PEA) surgery is the treatment of choice in surgically accessible chronic thromboembolic pulmonary hypertension and is potentially curative. The UK is served by seven specialist pulmonary hypertension centres and, consequently, there are regions which do not have a specialist unit. Since 2000, Papworth Hospital (Papworth Everard, UK) has been the sole PEA provider for the UK, offering the opportunity to study the national incidence of operable disease and give potential insight into factors that might affect geographical distribution within the UK. All 262 UK residents who underwent PEA surgery between April 2000 and May 2006 were included in the present study. The age-adjusted cumulative referral rates were compared between regions to test for uniformity. Overall, observed rates differed significantly from expected, with evidence of significant nonuniformity across the UK. The highest rates were observed in proximity to the nationally designated specialist centres and in particular in East Anglia and the West Midlands, nearest Papworth. These two regions differed by >2 x SD from the national mean rate. The present study demonstrates wide geographical variation in the number of patients referred for pulmonary endarterectomy surgery. This suggests that there may be patients who are not presently being offered this potentially curative option.

Background: There are currently no licensed medical therapies for inoperable chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: In this double-blind, placebo-controlled pilot study, 19 subjects with inoperable CTEPH were randomly assigned to sildenafil or placebo for 12 weeks. The primary end point was change in 6-min walking distance (6MWD). Secondary end points included changes in World Health Organization (WHO) class, cardiopulmonary hemodynamics, quality of life (QOL) scores, and N-terminal pro brain natriuretic peptide (NT-proBNP). All subjects were transferred to open-label sildenafil at the end of the study and offered repeat assessment at 12 months., Results: There were no significant differences between the two groups with respect to change in exercise capacity. However significant improvements were seen in WHO class and pulmonary vascular resistance (PVR). Seventeen subjects were eligible for reassessment at 12 months and demonstrated significant improvements in 6MWD, activity and symptom components of QOL, cardiac index, PVR, and NT-proBNP., Conclusions: Although this pilot study was insufficiently powered to test the primary end point, it did suggest beneficial effects in favor of sildenafil in several secondary end points at both 3 months and 12 months. Further larger-scale trials of sildenafil in inoperable CTEPH are required to confirm these findings and potentially increase the treatment options available for this devastating disease., Trial Registration: The study protocol was registered with the UK National Research Register database (publication ID N0542136603).

Rationale: The management of chronic thromboembolic pulmonary hypertension (CTEPH) has changed over recent years with the growth of pulmonary endarterectomy surgery and the availability of disease-modifying therapies., Objectives: To investigate the prognosis of CTEPH in a national setting during recent years., Methods: All incident cases diagnosed in one of the five pulmonary hypertension centers in the United Kingdom between January 2001 and June 2006 were identified prospectively. Information regarding baseline characteristics, treatment, and follow-up was subsequently collected from hospital records., Measurements and Main Results: A total of 469 patients received a diagnosis, of whom 148 (32%) had distal, nonsurgical disease. One- and three-year survival from diagnosis was 82 and 70% for patients with nonsurgical disease and 88 and 76% for those treated surgically (P = 0.023). Initial functional improvement in patients with nonsurgical disease was noted but did not persist at 2 years. Significant functional and hemodynamic improvements were seen in surgically treated patients with an increase in six-minute-walk distance of 105 m (P < 0.001) at 3 months. Five-year survival from surgery in the 35% of patients who survived to 3 months but had persistent pulmonary hypertension was 94%., Conclusions: The prognosis in nonsurgical disease has improved. We have confirmed the previously described good outcome in surgically treated disease. However, we have also demonstrated that the long-term prognosis for patients who have persistent pulmonary hypertension at 3 months after surgery is good. The observed improvements in outcome during the modern treatment era reinforce the importance of identifying patients with this increasingly treatable condition.

Although chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by the persistence of organised thrombus, few pro-thrombotic risk factors have been identified in subjects with the disease. The aim of the present study was to compare the prevalence of eight functionally relevant haemostatic polymorphisms between CTEPH subjects and healthy controls. Genomic DNA was isolated from 214 CTEPH subjects and 200 healthy controls, and analysed for Factor V Leiden, prothrombin guanine (G) to adenine (A) substitution at nucleotide 20210 (20210G>A), plasminogen activator inhibitor-1 4G/5G, tissue plasminogen activator 7351 cytosine (C)>thymidine (T), Factor XIII 100G>T, fibrinogen Aalpha substitution of threonine with alanine at position 312 (Thr312Ala), fibrinogen Bbeta substitution of arginine with lysine at position 448 (Arg448Lys) and fibrinogen Bbeta 455G>A polymorphisms. A significant difference was demonstrated in fibrinogen Aalpha Thr312Ala genotype and allele frequencies between CTEPH subjects and controls. The presence of the alanine allele significantly increased the risk of CTEPH. The fibrinogen Aalpha alanine 312 allele alters fibrinogen alpha-alpha chain cross-linkage and has previously been associated with both increased risk of embolisation and increased resistance to thrombolysis. An association between this polymorphism and chronic thromboembolic pulmonary hypertension, therefore, supports an embolic aetiology for this disease, and may provide a mechanism by which thrombus persists following an acute event.

Objective: Pulmonary endarterectomy is the best treatment for patients with chronic thromboembolic pulmonary hypertension. Traditionally pulmonary endarterectomy has been performed utilising deep hypothermic circulatory arrest to provide a bloodless field, but some recent reports have challenged this concept. We reviewed our experience with selective antegrade cerebral perfusion as the initial strategy of controlling bronchial collateral flow to avoid complete circulatory arrest in patients undergoing pulmonary endarterectomy., Methods: A retrospective review of all patients meeting the above criteria between July 2003 and June 2006. Selective antegrade cerebral perfusion at 20 degrees C was used as the initial means of reducing blood flow to the operative field., Results: One hundred and fifty-one patients (83 male, 68 female, mean age 56+/-16 years) were operated on using this strategy. The preoperative New York Heart Association class distribution showed the majority to be in class III or IV (142 of 151). At initial assessment, mean pulmonary artery pressure was 49+/-12 mmHg and mean pulmonary vascular resistance was 851+/-391 dynes s cm(-5). Selective antegrade cerebral perfusion was required in 145 for a total period of 63+/-24 min. Thirteen (9%) patients required conversion to deep hypothermic arrest for completion of the operation. In-hospital mortality was 22 (15%). There were no instances of focal neurological deficit. Prearranged clinical follow-up for 3 and 12 months was 97% complete with one late death by 3 months and one more by 12 months. The majority were in New York Heart Association class I or II at 3 months (102 of 115) and 12 months (65 of 74). At 3-month follow-up the mean pulmonary artery pressure was 27+/-10 mmHg and pulmonary vascular resistance was 304+/-220 dynes s cm(-5)., Conclusions: Overall results improved with era and institutional experience. The use of selective antegrade cerebral perfusion for pulmonary endarterectomy appears to be technically feasible in the majority of patients and is an alternative to complete circulatory arrest. To clarify its role further, comparison with deep hypothermic circulatory arrest in a randomised controlled trial is necessary.

Background: Sildenafil inhibits phosphodiesterase-5, enhancing cyclic guanosine monophosphate- mediated relaxation of pulmonary vasculature and is effective in treating patients with pulmonary arterial hypertension (PAH)., Methods: Patients with PAH (n = 278) received oral sildenafil (20, 40, or 80 mg three times daily) in a 12-week, double-blind, placebo-controlled study and an open-label extension. Health-related quality of life (HRQoL) was recorded by patients using the Medical Outcomes Study 36-item short form (SF-36) and EuroQol 5D (EQ-5D) questionnaires at baseline and after 12 and 24 weeks of therapy. Data are presented for patients who received sildenafil for up to 24 weeks., Results: Sildenafil-treated patients, compared with placebo-treated patients, exhibited significant improvement in exercise capacity at week 12 (p < 0.001). Increases from baseline to week 12 were observed in all SF-36 domains for sildenafil-treated patients, with statistically significant improvements, compared with placebo-treated control subjects, in physical functioning (p < 0.001), general health (p < 0.001), and vitality (p < 0.05). Statistically significant improvements were also observed for the EQ-5D current health status (p < 0.01) and utility index (p < 0.01). These benefits were maintained for 24 weeks. Treatment groups were pooled for analyses as the results for the 6-min walk distance, SF-36, and EQ-5D were not dose dependent., Conclusions: Sildenafil improves HRQoL of PAH patients. These improvements appear to be maintained for at least 24 weeks. The effects are strongest in domains addressing the physical impact of health on daily activities and patients' overall perception of health.

Background: This study aims to evaluate the role of NT-proBNP and six minute walking distance (6MWD) in the pre- and post-operative assessment of subjects undergoing pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: Subjects undergoing PEA between August 2004 and July 2006 were assessed at baseline and 3 months post-operatively with resting haemodynamics, NT-proBNP and 6MWD., Results: A number of 111 subjects underwent surgery, of which 102 were included. 15 subjects died before their 3 month assessment. Non-survivors had significantly worse preoperative NT-proBNP and 6MWD (4728 pg/mL vs 1863 pg/mL, p=0.001, 182.4 m vs 263.5 m, p=0.001). Taking pre-operative cut-off values of 1200 pg/mL for NT-proBNP and 345 m for 6MWD, both tests had high negative predictive value for predicting mortality (97.3% and 100%, respectively). Amongst survivors, peri-operative changes in NT-proBNP and 6MWD correlated with changes in total pulmonary resistance (TPR) (r=0.49, p<0.001 and r=-0.46, p<0.001). Post-operatively, both NT-proBNP and 6MWD also correlated with mPAP (r=0.65, p<0.001 and r=-0.50, p<0.001) and PVR (r=0.63, p<0.001 and r=-0.47, p<0.001). The ability of NT-proBNP to predict persistent pulmonary hypertension was significantly confounded by age, but not gender, BMI or renal function., Conclusions: Pre-operative evaluation with NT-proBNP and 6MWD helps risk-stratify patients prior to PEA. Post-operatively, both markers correlate with changes in disease burden and right ventricular function. These results suggest that both NT-proBNP and 6MWD offer effective 'bedside' tools for the long term follow up of patients with CTEPH.

Background: Although pulmonary endarterectomy (PEA) is potentially curative in chronic thromboembolic pulmonary hypertension (CTEPH), some patients have distally distributed disease that is not amenable to surgery. The aetiology and characteristics of this patient group are currently not well understood., Objectives: This study compares the baseline demographic features and outcomes in subjects with distal CTEPH, those with proximal CTEPH and those with idiopathic pulmonary arterial hypertension (IPAH) to determine whether these conditions represent separate entities or whether they exist along the same spectrum of disease., Methods: The medical history, clinical characteristics, bone morphogenetic protein receptor type II (BMPR2) mutation status and outcomes of 96 subjects with IPAH, 35 with distal CTEPH and 68 with proximal CTEPH referred to a single specialist centre between 1994 and 2005 were reviewed., Results: There were significant differences between the distal CTEPH, proximal CTEPH and IPAH groups in age (55.9 years vs 54.8 years vs 46.2 years, p<0.001), proportion who were male (43% vs 69% vs 29%, p<0.001), previous deep vein thrombosis (28.6% vs 30.9% vs 3.1%, p<0.001), positive BMPR2 status (0% vs 0% vs 15%, p = 0.018), mean pulmonary artery pressure (47.3 mm Hg vs 45.4 mm Hg vs 54.8 mm Hg, p<0.001) and total pulmonary resistance (12.9 WU vs 12.4 WU vs 18.1 WU, p<0.001). Patients with distal CTEPH and those with IPAH were managed similarly and had comparable survival characteristics (1 year survival 77% vs 86%; 3 year survival 53% vs 60%; p = 0.68)., Conclusions: Patients with distal CTEPH share certain demographic features with patients with proximal CTEPH that not only indicate a common aetiology but also help to differentiate them from patients with IPAH. Despite more favourable haemodynamic parameters in those with distal CTEPH, patients in this group had a poor long-term outcome which was similar to that of patients with IPAH.

Introduction: Although surgery is the treatment of choice for CTEPH, it is not appropriate for patients with surgically inaccessible distal disease. These patients are traditionally managed supportively, but may benefit from newer, more specific vasoactive therapies. This study examines the acute haemodynamic responses to inhaled nitric oxide (iNO) and intravenous sildenafil in this patient population., Methods: Nine patients with de novo distal CTEPH and nine with persistent pulmonary hypertension post-pulmonary endarterectomy (PEA) were enrolled. At right heart catheterisation, following baseline haemodynamic measurements, iNO was administered at 20 ppm for 10 min. Following repeat measurements, iNO was discontinued with a subsequent washout period of 10 min. Sildenafil was then administered intravenously at two doses, to achieve plasma levels equivalent to 25 mg and 50 mg orally, with further measurements obtained at the end of each infusion., Results: Significant reductions in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) were demonstrated following both iNO (-4.3 mm Hg or -10.3% p=0.001 and -101 dyn/s/cm(5) or -15.6% p<0.001) and sildenafil (-7.4 mm Hg or -16.9% p<0.001 and -188.8 dyn/s/cm(5) or -25.1% p<0.001). Individual mPAP and cardiac output (CO) responses to iNO and sildenafil correlated well, but haemodynamic changes following sildenafil were consistently more marked. There was, however, no difference in effect between the two doses of sildenafil. Although sildenafil caused significant reductions in systemic vascular resistance, the net haemodynamic effect of sildenafil remained pulmonary selective. Subgroup analysis suggested that post-PEA patients were more responsive to both iNO and sildenafil than de novo patients., Discussion: Although all but one patient failed to fulfil the formal haemodynamic response criteria typically used in idiopathic pulmonary arterial hypertension (IPAH), subjects displayed significant acute responses to both iNO and sildenafil suggesting that increased vascular tone forms an important component of distal CTEPH. It is possible that these acute haemodynamic responses may translate to improved clinical outcomes, and thus further long term trials of sildenafil in distal CTEPH are warranted.

Nebulised iloprost is established therapy of severe pulmonary hypertension; however, the effects on the bronchoalveolar compartment have not been investigated so far. We studied the short- and long-term effects of nebulised iloprost on pulmonary function tests and gas exchange in 63 patients with severe pulmonary hypertension (idiopathic n=17, chronic thromboembolism n=15, connective tissue disease n=12, congenital heart disease n=11, respiratory diseases n=8). Patients received iloprost in increasing dose up to 140 micro g iloprost/24h via an ultrasonic nebuliser. Short-term effects were assessed before and after every nebulisation: peak expiration flow decreased in mean by 1.9% (423+/-98 to 415+/-98) and percutaneous oxygen saturation increased in mean by 0.7% (90+/-6 to 91+/-5) post-nebulisation. There were no significant differences concerning underlying diagnosis or dose of nebulised iloprost. Within 3 months, 9 patients stopped treatment due to non-compliance with frequent nebulisations (n=3), or severe side effects (n=4); 2 patients with additional obstructive lung disease developed bronchoconstriction. Long-term effects were assessed by pulmonary function tests and gas exchange parameters at baseline and after 3 months treatment. There were no significant differences after 3 months therapy neither in FEV(1), FVC, TLC, residual volume nor in diffusions capacity, SO(2) at rest and during 6 min walking test, also in respect of the underlying diseases. However, there was a significant increase in 6 min walking distance (6 MWD) after 3 months (246+/-113 to 294+/-115 m, P<0.05). In conclusion, treatment with nebulised iloprost leads to functional improvement in severe pulmonary hypertension without systematic adverse short- and long-term effects on pulmonary function test or gas exchange. Patients with additional obstructive lung disease might develop bronchoconstriction. Severe side effects leading to discontinuation of treatment occurred in 9% of patients.

Pulmonary endarterectomy (PEA) is recommended as the treatment of choice for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, only a proportion of patients fulfill the criteria for surgical intervention. In addition, operated patients with CTEPH may experience a gradual hemodynamic and symptomatic decline related to a secondary hypertensive arteriopathy in the small precapillary pulmonary vessels. It has also been questioned what can be done to reduce risks from PEA surgery to improve outcome in "high risk" patients with CTEPH with substantial impairment of pulmonary hemodynamics before surgery. Such patients may benefit from preoperative reduction of pulmonary vascular resistance by means of medical therapy. Conventional medical treatments, such as anticoagulation, diuretics, digitalis, and chronic oxygen therapy, show low efficacy in the treatment of CTEPH as they do not affect underlying disease processes. Over the last decade, several novel therapies have been developed for pulmonary arterial hypertension (PAH), including prostacyclin analogs (epoprostenol, beraprost, iloprost), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan), and phosphodiesterase-5 inhibitors (sildenafil). Evidence of efficacy in PAH, coupled with studies showing histopathologic similarities between CTEPH and PAH, provides a rationale to extend the use of some of these medications to the treatment of CTEPH. However, direct evidence from clinical trials in CTEPH is limited to date. This article reviews evidence supporting, and issues surrounding, the possible use of novel PAH medications in CTEPH.

The treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). However, many patients develop a severe progressive small vessel pulmonary arteriopathy that is inaccessible to surgical intervention and is associated with poor survival. The purpose of the present study was to evaluate the medium-term efficacy and safety of the dual endothelin receptor antagonist, bosentan, in inoperable CTEPH. Forty-seven patients with inoperable CTEPH (distal disease or persistent pulmonary hypertension following PEA) underwent evaluation after 1 yr of bosentan therapy. Outcomes included assessment of 6-min walk test (6MWT), haemodynamics and World Health Organization functional classification. Monitoring of serious adverse effects and changes in therapy was undertaken. Patients showed sustained improvements in 6MWT (49+/-8 m), functional classification, cardiac index (+0.2+/-0.07 L.min(-1).m(-2)) and total pulmonary resistance (-139+/-42 dyn.s.cm(-5)). Those patients with persisting pulmonary hypertension following PEA showed the greatest improvement. One-yr survival was 96%, and bosentan was well tolerated with only one patient developing deranged liver function. Although all patients with chronic thromboembolic pulmonary hypertension should be considered for pulmonary endarterectomy, bosentan provides an alternative medical therapy to improve function and delay the progression of this devastating disease in those in whom surgery is not suitable.

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.

Rationale: Bosentan, a dual endothelin receptor antagonist, has proven efficacy in pulmonary hypertension. Due to an association with hepatic dysfunction, it is typically initiated at a sub-therapeutic dose for 4 weeks before titration to a therapeutic dose. At our institution some patients have undergone rapid titration, to potentially benefit from therapy earlier. This study assesses the impact of this practice on hepatic safety., Method: All patients initiated on bosentan therapy before April 2005 were included. Rapidly titrated patients achieved a therapeutic dose by 3 days, whereas standard titration patients were titrated at 4 weeks. All patients were monitored with monthly liver function tests., Results: 149 patients commenced bosentan, of which 55 were rapidly titrated. At baseline, the two groups were similar in age, BMI, diagnosis, 6-min walking distance, alanine aminotransferase (ALT), cardiac index and pulmonary artery pressures. The rapid group had elevated right atrial pressures (9.7 mm Hg versus 7.4 mm Hg, p = 0.016) and worse WHO functional class (p = 0.008) and included less females (31% versus 69%, p = 0.024). The incidence of hepatic dysfunction in all patients was 12.8% at 12 months. There was no statistical difference in incidence between the rapid and standard groups (4% versus 11% at 3 months, p = 0.211 and 6% versus 15% at 12 months, p = 0.219). Of all patients on bosentan, hepatic dysfunction was most significantly associated with a higher baseline ALT (p = 0.021), female sex (p = 0.003) and underlying connective tissue disease (p = 0.025). Subgroup analysis suggested these factors were not confounders when comparing rapid and standard titration., Conclusions: Rapid and standard titration of bosentan resulted in similar hepatic safety profiles. Baseline ALT, female sex and the presence of connective tissue disease increased the risk of hepatic dysfunction independent of the titration method used.

Objective: No outcome measures specific to pulmonary hypertension (PH) currently exist. The aim of the study was to develop health-related quality of life (symptoms and functioning) scales and a quality of life scale that would allow comprehensive, accurate and valid patient-reported outcome assessment in clinical studies., Methods: The content of the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) was derived from qualitative interviews conducted with 35 patients. Item reduction was based on the analysis of responses to a postal survey (n=75) and patient interviews (n=15) designed to determine face and content validity. A final postal validation study (n=91) was performed to determine reproducibility and construct validity., Results: The questionnaire was well received by participants who found it to be relevant, comprehensible and quick and easy to complete. Rasch and factor analyses were conducted to ensure unidimensionality of the final CAMPHOR scales; Overall symptoms (made up of Energy, Breathlessness and Mood subscales), Functioning and Quality of life. The CAMPHOR scales had good internal consistency (alpha=0.90-0.92) and reproducibility (test-retest correlations=0.86-0.92). They also exhibited convergent, divergent and known groups validity., Conclusions: The CAMPHOR is a valuable new instrument for assessing patient-reported outcome in PH clinical trials and routine practice.