Volume 3, Issue 1, Pages 1-9 (2010)

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ABSTRACT

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Secondary pulmonary hypertension

Abstract

Most cases of pulmonary arterial hypertension (PAH) are not idiopathic, but rather are attributable to other disorders. This fact has become increasingly apparent following the recent establishment of centralised PAH registries in several countries. Yet, this “secondary” PAH has been the subject of even less research than idiopathic PAH, itself an orphan disease par excellence. Secondary PAH is heterogeneous: prognosis and response to vasodilator therapy differs substantially between various forms of secondary PAH, partly as a function of underlying pathophysiology, and cannot simply be extrapolated from data derived from idiopathic PAH.

This article reviews the commonest secondary causes of PAH, focusing on epidemiology, risk factors, clinical presentation, treatment options, prognosis, and the role of screening. PAH secondary to chronic hypoxia, congenital heart disease, connective tissue disorders, liver disease, appetite suppressants and stimulants, and HIV infection are all considered. Strengths and limitations of available screening tests for PAH are discussed.

Keywords: Pulmonary arterial hypertension, Systemic sclerosis, Portopulmonary hypertension, Echocardiography

Article Outline

• Abstract

• 1. Introduction

• 2. Diagnostic tests

• 2.1. Echocardiography

• 2.2. Transfer coefficient (DLCO)

• 2.3. Six minute walk test

• 3. Pulmonary hypertension as a complication of hypoxaemia

• 3.1. Chronic obstructive pulmonary disease (COPD)

• 3.2. Sleep disordered breathing

• 3.3. Idiopathic pulmonary fibrosis (IPF)

• 3.4. Other interstitial lung diseases

• 3.5. Sarcoidosis

• 3.6. Prognosis

• 3.7. Langerhans cell histiocytosis (LCH)

• 3.8. Lymphangioleiomyomatosis (LAM)

• 4. Connective tissue diseases

• 4.1. Pathophysiology of PAH-CTD

• 4.2. Treatment of PAH-CTD

• 4.2.1. Prostacyclin analogues

• 4.2.2. Endothelin-1 receptor antagonists

• 4.2.3. Immunosuppression

• 4.3. Prognosis of PAH-CTD

• 5. Portopulmonary hypertension

• 6. Hereditary haemorrhagic telangiectasia (HHT)

• 7. Stimulants and appetite suppressants

• 8. Human immunodeficiency virus (HIV) infection

• 9. Screening

• 10. Conclusion

• Conflict of interest

• CME section

• Educational questions

• References

• Copyright

Educational aims

•To review the pathophysiology and clinical features of the commonest causes of secondary pulmonary arterial hypertension (PAH).

•To review the evidence for efficacy of the available treatment modalities for PAH, when applied to secondary PAH.

•To understand the strengths and limitations of invasive and noninvasive screening tests for PAH.

•To understand with which frequency and for which conditions screening is recommended.

•To develop an understanding of prognosis of the various forms of secondary PAH.

1. Introduction

Pulmonary arterial hypertension (PAH) is defined as a resting mean pulmonary artery pressure (PAP)≥25mmHg, with normal left atrial pressure. The incidence of PAH has been estimated at 15 cases per million, of which two thirds are ‘secondary’ PAH.1 Prevalence estimates for the various types of secondary PAH have frequently been made on the basis of echocardiographic studies. Echocardiography is probably oversensitive for the diagnosis of PAH,2, 3 and right heart catheterisation (RHC) remains the gold standard. The recent establishment of national registries of RHC-confirmed PAH in France and the United Kingdom are allowing more accurate epidemiologic and prognostic information about secondary PAH to come to light.1, 4

The World Symposium on Pulmonary Hypertension (Venice, 2003) divides PH into five pathophysiological categories.5 Our review focuses on secondary causes of pulmonary arterial hypertension (category 1), including collagen vascular diseases, HIV infection and anorexigen use. We also review PH related to chronic hypoxia (category 2), and some miscellaneous conditions including sarcoidosis. In the interests of space and brevity, pulmonary venous hypertension and chronic thromboembolic disease are not reviewed.

2. Diagnostic tests

2.1. Echocardiography

Echocardiography is the test most frequently used to investigate for suspected PAH. It is noninvasive, and is usually more readily available than RHC. However, it is probably oversensitive for PAH2, 3 and cannot distinguish between arterial and venous hypertension.

At present echocardiography is the best noninvasive test for diagnosis of PAH, but echocardiographic findings (positive or negative) need to be interpreted in combination with clinical clues such as disproportionately poor exercise capacity, low transfer coefficient (DLCO) or clinical right heart failure.

2.2. Transfer coefficient (DLCO)

A DLCO that is lowered out of proportion to the degree of lung disease is widely recognised as suggestive of PAH.6 This pattern can also occur in mixed obstructive and restrictive lung disease. A reduced DLCO has been associated with increased risk of PAH in idiopathic pulmonary fibrosis (IPF),7 systemic sclerosis (SSc)8 and sarcoidosis.9

Current British Thoracic Society guidelines recommend annual pulmonary function tests (PFTs) in SSc, proceeding to echocardiography if the DLCO is declining or is disproportionately impaired.6 In ILD, consideration of PAH is also recommended where there is a disproportionate reduction in DLCO.

2.3. Six minute walk test

The six minute walk test (6MWT) provides both useful prognostic information and an objective baseline measure of functional limitation which can then be followed to observe its response to therapeutic interventions. Parameters derived from the 6MWT have been commonly used to provide endpoints in therapeutic trials in PAH. Though development of secondary PAH is known to lower six minute walk distance (6MWD),10, 11, 12 the role of the 6MWT in diagnosing PAH remains largely uninvestigated. A study in sarcoidosis reported that oxygen saturation<90% on 6MWT predicted PAH more accurately than 6MWD, and advocated using a combination of 6MWT and echocardiography to screen for PAH in this patient group.9 6MWT may be impractical as a diagnostic test in those PAH-associated conditions that are marked by musculoskeletal disability or poor peripheral perfusion, such as scleroderma.13

3. Pulmonary hypertension as a complication of hypoxaemia

3.1. Chronic obstructive pulmonary disease (COPD)

Among patients with COPD, mild PAH is common14 and correlates with decline in FEV1. However a subpopulation of patients have PAH disproportionate to the severity of airflow obstruction.14, 15 Postulated mechanisms include emphysematous destruction of the pulmonary vascular bed, hyperviscosity, in situ thrombosis, and vascular remodelling due to hypoxic vasoconstriction or chronic inflammation.16

COPD accounted for 0.8% of cases of PAH in a retrospective study at a PAH referral centre.17 Among patients with COPD referred for lung transplant, 7.4% had disproportionate PAH.14 Among 998 patients with COPD who underwent RHC, only 2.7% had pulmonary artery pressure (PAP)>40mmHg, and only 1.1% had PAH with COPD as the only identifiable cause.15 PAH of any degree is an adverse prognostic indicator in COPD,18 possibly because it usually reflects more advanced lung disease.

Echocardiography is relatively insensitive for COPD-associated PAH, due probably to the increased distance that ultrasound waves must penetrate. In a group of patients with advanced lung disease (mostly COPD), echocardiography could only estimate right ventricular systolic pressure (RVSP) in 44% of cases, and this modality misclassified 48% of patients as having PAH.19 As echocardiography cannot rule PAH-COPD in or out, clinicians must consider other clues such as disproportionate impairment of DLCO, 6MWD, or clinical right heart function.

Some researchers have studied the role of exhaled biomarkers in diagnosis of PAH complicating COPD. Levels of endothelin-1 (ET-1) in exhaled breath condensate and plasma were increased, and levels of exhaled nitric oxide reduced, in patients with PAH-COPD compared to other patients with COPD and healthy controls. Moreover, ET-1 levels correlated with PAP and inversely correlated with FEV1.20

There are few studies of treatment of PAH-COPD. Long term nifedipine was not beneficial.21 Pulmonary vasodilators may worsen hypoxaemia by counteracting hypoxic vasoconstriction and diverting blood flow to poorly ventilated areas of lung, as reported in a recent observational study.22 Inhalational delivery may avoid this problem23: indeed, an randomised trial of 3 months of inhaled nitric oxide showed haemodynamic improvements in severe COPD.24

A case of favourable response to bosentan has been reported25; however bosentan showed no beneficial effects and worsened gas exchange in an randomised trial among patients with severe COPD.26 Long-term sildenafil was not associated with any improvement in haemodynamics or 6MWD in a cohort of 5 patients.27 For the time being, use of pulmonary vasodilators in PAH-COPD should be avoided outside the context of clinical trials.28

3.2. Sleep disordered breathing

Sleep disordered breathing (SDB) encompasses a variety of disorders including obstructive and central sleep apnoea, and nocturnal alveolar hypoventilation due to obesity (obesity hypoventilation syndrome) or other mechanical respiratory abnormalities. True PAH in the setting of SDB is presumed to be caused by hypoxic vasoconstriction. In addition, a high proportion of patients with obstructive sleep apnoea (OSA) have abnormal left ventricular filling, which may cause pulmonary venous hypertension.29

Prevalence estimates of PAH in OSA range between 17–53%.30, 31, 32, 33 Most PAH attributed to OSA appears to be mild: a systematic review found that the mPAP was <30mmHg in all published studies.34 There are few reported estimates of SDB prevalence in PAH: one small study found that nocturnal oxygen desaturation was very common in idiopathic pulmonary arterial hypertension (IPAH), whereas apnoeas and hypopnoeas were rare.35 Desaturation was associated with diurnal hypoxaemia, desaturation with exercise, and higher A-a gradients. Diurnal hypoxaemia and nocturnal desaturation have been identified as risk factors for PAH in SDB in a number of studies.30, 31, 36, 37 Body mass index (BMI) is a risk factor in some studies30, 31, 36 but not others.32, 37 Apnoea–hypopnoea index is a risk factor in a minority of studies.29, 31, 32

Successful treatment of OSA with CPAP usually lowers PAP,29, 36, 38 even in severe cases.39 No published studies have examined clinical outcomes in the treatment of PAH-SDB.

The American College of Chest Physicians currently recommends that “assessment for SDB” is undertaken in all patients with PAH.34 Polysomnography is recommended only if there is clinical suspicion of OSA however. Conversely, screening for PAH in patients with OSA is not recommended.

3.3. Idiopathic pulmonary fibrosis (IPF)

Information in the prevalence of PAH in IPF is scant, with reported estimates of up to 84% in echocardiographic studies,40, 41 but lower prevalences of 8.1% using RHC.42 PAH also correlates poorly with lung function test results,7 suggesting that it is not simply a consequence of severe lung disease.

PAH appears to worsen prognosis in IPF, with a recent retrospective study reporting 1 year mortality of 61.2%, versus 19.9% in patients without PAH.43

Bosentan has been trialled in IPF, but patients with PAH were excluded.44 In a small open-label trial of IV epoprostenol and sildenafil, oxygenation was worsened by epoprostenol and improved by sildenafil.45 Another open-label study of sildenafil in IPF showed improvement in 6MWD.46 Inhaled iloprost and inhaled nitric oxide resulted in improved haemodynamics in another small study.47

Overall, the use of vasodilators in IPF is not currently justified outside of clinical trials. It is recommended that patients awaiting lung transplantation for IPF have regular echocardiography to monitor RV function in the event of developing PAH.

3.4. Other interstitial lung diseases

Interstitial lung disease may be idiopathic (the idiopathic interstitial pneumonias, IIP) or secondary to other conditions such as connective tissue diseases.

PAH associated with ILD may be a consequence of the hypoxia, interstitial fibrosis, vascular remodelling and hyperviscosity that complicate these conditions as they advance. Additionally, and especially in the case of secondary ILD, PAH may represent a separate consequence of the underlying systemic process causing ILD. Studies in IPF suggest that PAH risk is independent of lung function impairment.7

3.5. Sarcoidosis

Prevalence estimates for PAH in sarcoidosis have ranged from 1–28%.48 Most of these estimates have been based on echocardiography, but echo findings seem to correlate acceptably with RHC in sarcoidosis.49

Most patients listed for lung transplantation for sarcoidosis have PAH on RHC.50 Risk factors may include lung function impairment (especially total lung capacity), male gender, and more severe changes on chest X-ray.48

Sarcoidosis can cause pulmonary hypertension in several ways. PAH as a nonspecific consequence of progressive hypoxia and fibrosis associated with interstitial lung disease seems to account for most cases,49, 51, 52 but not all. Several published cases describe extrinsic compression of large vessels by mediastinal lymphadenopathy or mediastinal fibrosis.53 Granulomatous vasculitis is a common histopathological finding and seems to preferentially involve veins.49, 54

A subgroup of patients may respond to immunosuppressive therapy in the absence of vasodilators: there are several reports of success with corticosteroids.49, 55, 56, 57 Corticosteroid responsiveness may confound attempts to study the effects of pulmonary vasodilators in sarcoidosis, as most of the study population will receive concomitant immunosuppressants.

In a retrospective analysis of 22 patients with sarcoidosis-associated PAH who were treated with vasodilator therapy, improved haemodynamics and exercise capacity were seen.58 Most patients had advanced pulmonary fibrosis, and most also received immunosuppressive therapy. In another retrospective study, long-term haemodynamic improvements were seen with sildenafil, though exercise capacity was unchanged.59 Sustained haemodynamic and functional improvements were seen in small cohorts treated with bosentan,60, 61, 62 IV epoprostenol,63 and inhaled nitric oxide.64

PAH caused by compression of large vessels has been successfully treated with stenting.65

3.6. Prognosis

The prognosis of sarcoidosis-associated PAH appears somewhat better than IPAH, although this may depend on which pathophysiological mechanism is causing the patient's PAH. In one cohort of patients, 3 year transplant-free survival was 74%.58 Unsurprisingly the presence of PAH worsens prognosis among patients awaiting lung transplantation for sarcoidosis.

Screening patients with sarcoidosis for PAH using 6MWD has been advocated.9 This seems reasonable in patients with advanced lung disease; in other cases the prevalence of PAH is still unknown, and may not be high enough to justify screening in asymptomatic patients.

3.7. Langerhans cell histiocytosis (LCH)

Severe PAH appears to be ubiquitous in advanced LCH: PAH was present in 92% of cases of LCH referred for lung transplantation and was moderate to severe in 73%.66 One study found severe PAH in all tested patients.67 Severity of PAH appears to be independent of lung function.67, 68 Histology shows a proliferative vasculopathy affecting muscular arteries, veins and venules; plexiform lesions were not reported.67

A case of moderately severe LCH-associated PAH improved with corticosteroid therapy and smoking cessation.69 Overall little has been published about successful treatment of PAH in this condition.

3.8. Lymphangioleiomyomatosis (LAM)

A cross-sectional echocardiographic study in LAM reported a prevalence of PAH of 7% at rest, rising to 47% with exercise,70 but there is no published literature of treatment success.

4. Connective tissue diseases

The establishment of PAH registries has allowed estimates of the prevalence of connective tissue disease-associated pulmonary hypertension (PAH-CTD); in the United Kingdom it is estimated at 4.23 per million, with an incidence of 1.55/million/year.4 The estimate from the French national registry is lower at 0.4/million/year.1 The strongest association is with scleroderma, which accounts for 76% of PAH-CTD in the French registry.1 PAH affects 3–16% of patients with scleroderma,2, 71, 72, 73, 74 independent of the presence of ILD.75 PAH is also common in systemic lupus erythematosus (SLE)1 and mixed connective tissue disease (MCTD).72, 74, 76

Reported risk factors include Raynaud's syndrome,75, 77, 78, 79, 80 hypocomplementaemia,81 cryoglobulinaemia,81 anti-Ro,75 anti-RNP 75, 82 and anticardiolipin78, 83, 84, 85 antibodies, and rheumatoid factor positivity.75 In systemic sclerosis, anti-Scl 70 antibodies may be associated with a lower risk of PAH.8

The similarity of the pathologic lesion in PAH-CTD and IPAH, the female predominance among patients with IPAH, and the association of IPAH with autoantibodies and autoimmune conditions86, 87, 88 has led to speculation that IPAH might be an autoimmune disease. This would be supported by examples of patients who initially present with “idiopathic” PAH, then proceed to develop other features of a connective tissue disease; however opportunities to observe this have until now been limited by the shortened life expectancy of patients with PAH. This situation may change with more widespread use of pulmonary vasodilator therapy. Observations of a therapeutic response to immunosuppressive therapy alone add further weight to this hypothesis.89, 90

4.1. Pathophysiology of PAH-CTD

Endothelial cells produce endothelin-1, nitric oxide (NO) and prostacyclin (PGI, epoprostenol). There is substantial evidence suggesting that endothelial cells are dysfunctional in PAH-CTD. Expression of endothelial nitric oxide synthase (eNOS) is reduced in PAH,91 and among patients with scleroderma expression of eNOS is also reduced.92

Levels of endothelin-1, a potent vasoconstrictor, promoter of fibrosis and smooth muscle mitogen with a central role in IPAH pathogenesis, are increased in scleroderma93 and SLE,79, 94 where higher levels are associated with increased risk of PAH.

Anti-endothelial cell antibodies (AECA) have been reported in association with PAH in SSc,95 MCTD85, 96 and SLE,97 and higher AECA serum levels are associated with increased risk of PAH.95 AECA may be pathogenic: exposure to AECA caused healthy endothelial cells to increase E-selectin expression96 and endothelin-1 secretion.97

Anti-fibrillarin antibodies are reported in association with PAH-SSc and PAH-SLE.83, 98 Anti-tissue plasminogen activator antibodies are associated with increased risk of PAH in SSc,99 and are also more common in IPAH.100 Anti-fibrillin-1 antibodies are common in scleroderma.101

4.2. Treatment of PAH-CTD

In general, treatment practices have been extrapolated from IPAH. The prevalence of pulmonary veno-occlusive disease may be increased in patients with PAH-CTD,102 so extra care is required to exclude evidence of this condition when starting vasodilator therapy.

4.2.1. Prostacyclin analogues

Patients with PAH-CTD treated with IV epoprostenol have shown improvements in functional class, 6MWD, and haemodynamics in short term open-label studies.103, 104, 105 Longer-term studies of IV prostacyclin and inhaled iloprost have suggested clinical and haemodynamic benefits in PAH-CTD and SSc.106, 107

In a post hoc analysis of a double-blind randomised trial of IV treprostinil versus placebo, patients with PAH-CTD (50% scleroderma, 28% SLE, 22% MCTD) showed haemodynamic improvements, a marginal increase in 6MWD, and no improvement in Borg dyspnoea score.108 No benefit was seen from beraprost in a short term randomised trial.109

4.2.2. Endothelin-1 receptor antagonists

In cohort studies, long term treatment with the nonselective endothelin-1 receptor antagonist bosentan improved exercise capacity and RVSP,110 and was associated with 92% 48-week survival.111

In a subgroup analysis of an open-label randomised trial of sitaxsentan versus bosentan, patients with PAH-CTD had better 1-year survival with sitaxsentan and were less likely to withdraw from sitaxsentan than bosentan.112

4.2.3. Immunosuppression

There have been several case reports and case series describing physiological and clinical responses of PAH-CTD to various forms of immunosuppression alone.75, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125

4.3. Prognosis of PAH-CTD

A review of hospital discharge records from Scotland found a median survival of 5.9 years in males and 4.9 years in females.126

Pulmonary involvement is the leading cause of death in scleroderma127 and MCTD.128 1-year survival in PAH-SSc is only 78%.4 Survival in PAH associated with polymyositis, SLE and MCTD appears to be better with reported 3-year survival of 100%, 74% and 63% respectively.4

Negative prognostic factors reported in PAH-CTD include sPAP>60mmHg, DLCO<35% predicted, elevated mean right atrial pressure, shorter time between diagnoses of CTD and PAH, and presence of ILD.129, 130 Favourable factors include younger age, female sex, better WHO functional class, and higher mixed venous oxygen saturation.4

5. Portopulmonary hypertension

Portopulmonary hypertension (PAH-PH) is defined as pulmonary arterial hypertension in the setting of portal hypertension.131 Prospective studies indicate 1–6% of portal hypertension is complicated by PAH.132, 133, 134 Portal hypertension accounted for 10.4% of secondary PAH in the French registry1; most patients were male, though this probably reflects the overwhelming male predominance among cirrhotic patients, and there may in fact still be a female preponderance.131, 135 Other risk factors may include autoimmune hepatitis135 and mutations in oestrogen signalling pathways.136

PAH-PH is more commonly confirmed using RHC than most other forms of PAH, owing to its importance as a prognostic factor in liver transplantation. Echocardiography again appears oversensitive, with reported PPV of 59–65%.133, 137 A benign hyperdynamic circulatory state is common in liver disease and cannot be distinguished from PAH-PH on echocardiographic grounds. Nevertheless echocardiographic screening is advocated where liver transplantation is being contemplated, provided diagnoses are confirmed by RHC.138

The pathogenesis of PAH-PH is unclear, and may involve endothelial shear stress, or the effects of vasoconstrictors moving from the portal to the pulmonary circulation.139 Endothelin-1 levels are elevated in the pulmonary circulation of patients with PAH-PH140; however they will often have a better haemodynamic profile than IPAH owing to elevated systemic prostacyclin and nitric oxide levels that typify portal hypertension.141, 142 This may render some forms of vasodilator therapy less effective or even hazardous in PAH-PH.143

Intravenous epoprostenol has been associated with haemodynamic benefits in short-term144 and long-term107 open-label studies. A case series showing deterioration in portal hypertension with worsening splenomegaly after epoprostenol administration has also been published.143

Patients with severe PAH-PH have shown improved functional capacity and haemodynamics in two retrospective cohort studies of long term bosentan treatment.145, 146 Bosentan appeared to have greater beneficial effects than inhaled iloprost on symptoms, haemodynamics, and survival. There are case reports of successful use of sildenafil147 and combination therapy with iloprost, sildenafil and bosentan.148

The prognostic implications of PAH-PH are unclear. Some retrospective studies have suggested a poor outcome,149 others have not.132 Published estimates of 3-year survival range between 38–89%131, 149, 150; presence and severity of cirrhosis emerged as negative prognostic factors.131

6. Hereditary haemorrhagic telangiectasia (HHT)

HHT is a common autosomal dominant disorder where mutations in genes of the TGFβ receptor family lead to mucocutaneous telangiectasia and visceral arteriovenous malformations. Individuals with HHT may develop PAH as a result of the high-output circulatory state associated with multiple arteriovenous malformations,151 or as an isolated phenomenon clinically similar to IPAH. The latter presentation is strongly associated with mutations in the gene for activin receptor-like kinase-1 (ACVRL1).152, 153

True PAH is probably a rare complication of HHT.154 An echocardiographic screening study found evidence of PAH in 12% of patients with HHT; however only one patient underwent confirmatory RHC, so the significance of this result is unclear. It seems likely that where HHT is accompanied by significant arteriovenous shunt, pulmonary arterial pressures will be mildly elevated on echocardiography due to hyperdynamic circulatory state.

Little has been published on the treatment of HHT-associated PAH. Cases of successful treatment with long term IV prostacyclin155 and bosentan156 have been reported.

7. Stimulants and appetite suppressants

In the 1970s, a European epidemic of PAH associated with use of the amphetamine-like appetite suppressant aminorex led to the withdrawal of that agent.157 A decade later, the serotonin reuptake inhibitor fenfluramine was also implicated in causing PAH.158 This was confirmed in a case-control study which found an odds ratio of 23.1 among patients using fenfluramine derivatives for over 3 months.159 Fenfluramine was withdrawn from sale in 1997. Pathogenesis of anorexigen-associated PAH is probably through elevation of circulating levels of serotonin, a pulmonary vasoconstrictor and smooth muscle mitogen. Use of other stimulants has also been associated with risk of PAH, including amphetamine, methamphetamine and cocaine.160

Anorexigen-associated PAH accounted for 9.5% of cases of RHC-confirmed PAH in a national French registry.1 77% of cases were due to fenfluramine derivatives. The role of echocardiographic screening for PAH and valvular disease in individuals exposed to anorexigens is unclear. One published study found evidence of PAH in 6.7% of screened women, though confirmatory RHC was not performed.161

Once established, anorexigen-associated PAH appears to follow a similar clinical course to IPAH,162 leading some commentators to suggest that anorexigens precipitate rather than cause PAH.162 This is supported by the detection of BMPR2 mutations in 9–22.5% of patients with anorexigen-associated PAH.162, 163

8. Human immunodeficiency virus (HIV) infection

HIV infection is a moderately strong risk factor for PAH; about 0.5% of HIV-positive individuals have PAH.164 HIV infection accounted for 6.2% of cases of secondary PAH in the French registry data reported by Humbert et al.1 Most patients were male. Pathological studies show plexiform arterial lesions, as in IPAH.165

HIV infection is associated with immune deficiency and dysregulation, and HIV-infected lymphocytes and macrophages secrete inflammatory cytokines. Additionally, several connections have been made between viral antigens and pathogenesis of PAH. The gp120 viral envelope protein stimulates endothelial cells and macrophages to secrete endothelin-1.166 Nef antigen is found in endothelial cells from HIV-positive patients,167 and seems to induce those cells to proliferate.167 Macaques infected with a Nef-expressing strain of simian immunodeficiency virus develop plexiform lesions.167 The tat viral protein also activates endothelial cells, stimulates angiogenesis, and suppresses BMPR2 gene expression in vitro.168

A genotyping study of HIV-positive patients with PAH found an increased frequency of HLA-eDR6 and HLA-DR52 alleles,169 a finding also noted in diffuse infiltrative lymphocytosis syndrome (DILS), an uncommon immune response to HIV infection which bears some similarities to Sjögren syndrome.

There is little published literature specific to the treatment of HIV-associated PAH (PAH-HIV). A cohort study of bosentan showed improvements in 6MWD, haemodynamics and functional class at 4 months that were maintained beyond 12 months of followup.170

PAH-HIV appears to run a more aggressive course than IPAH, with a 1 year survival of 51–73% and median survival of 1.3 years.171 PAH is the cause of death in 72% of patients with PAH-HIV.171 A CD4 count<200 confers a worse prognosis, and highly active antiretroviral therapy may reduce the incidence of PAH-HIV by maintaining immunocompetence.172, 173

9. Screening

The role of screening is unresolved for many of the conditions discussed above. Criteria that must be satisfied in order to justify a screening programme include evidence that early detection improves outcome, existence of a reasonably accurate screening test, and a risk of the condition that is high enough to compensate for the expense and personal risk associated with screening procedures.174 Currently screening for secondary PAH is specifically advocated in scleroderma,175, 176 congenital heart disease with left-to-right shunt, and portal hypertension where liver transplantation is being considered.176, 177 A recent consensus statement advocates screening with echocardiography in any disease where PAH is a known complication, proceeding to RHC for patients with TR velocity >=2.8m/s and normal right atrial pressure.176

Screening relies on a clear definition of the disorder of interest. This is complicated in PAH: first, by the increase in normal pulmonary artery pressures with age,178 and second, by the recognised phenomenon of “proportionate” mild or moderate pulmonary hypertension in association with many cardiorespiratory disorders.6 This “proportionate” pulmonary hypertension may not adversely affect prognosis, although few of the prognostic studies we have reviewed have stratified for degree of pulmonary hypertension. The point where proportionate pressures become disproportionate has not been defined.6

Owing to the risks and resource limitations associated with right heart catheterisation, echocardiography has been the test most commonly used to screen for PAH. The problem of false positives in echocardiographic diagnosis of PAH is well recognised.2, 3, 19, 133, 137 This has led to interest in other screening modalities. Several studies have examined exhaled nitric oxide (ENO) as a screening test. Three groups have reported that ENO levels are elevated overall in scleroderma compared with healthy controls, but lowered in PAH-SSc.179, 180, 181 An inverse correlation between ENO and PAP was also reported.180, 181 A small study of IPAH and anorexigen-associated PAH found that ENO levels normalised after 3 months of bosentan therapy.182

Computed tomography/magnetic resonance pulmonary angiography is also promising, with pulmonary artery distensibility showing high sensitivity and specificity for PAH.183, 184

The vasoactive hormone brain natriuretic peptide (BNP) and its N-terminal fragment (N-terminal pro-BNP) correlate with haemodynamic parameters and functional status in PAH,185, 186, 187, 188, 189 and may predict prognosis43, 185, 188 and response to therapy190 in at least some forms of secondary PAH. The role of BNP or NT-proBNP as a screening test for PAH, alone or in combination with echocardiography, warrants further research.

10. Conclusion

Pulmonary hypertension is a serious and increasingly recognised complication of many respiratory and systemic diseases. Diagnosis is difficult, as echocardiography, while sensitive, is a poorly specific test for PAH. To avoid unnecessarily exposing patients to the risks of RHC, the combination of echocardiography with other noninvasive screening tests should continue to be explored. BNP, ENO and CT/MR pulmonary angiography each show signs of promise in this regard.

Development of PAH is generally associated with poor prognosis, and secondary PAH is the leading cause of death in some of the conditions reviewed. For most of the available treatment modalities, evidence of efficacy is minimal or nonexistent, though this situation is gradually improving.

Conflict of interest

The authors have no conflicts of interest to declare.

CME section

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Educational questions

Answer the following questions:

1.In pulmonary arterial hypertension secondary to chronic obstructive pulmonary disease (COPD), which one of the following statements is true?

a.Moderate or severe PAH is a very common finding in end stage COPD

b.While large randomised trials are lacking, the balance of available evidence suggests that pulmonary vasodilators are beneficial

c.For a patient with COPD and an FEV1 of 65% predicted, a DLCO of 30% predicted is disproportionately low and suggests the presence of PAH

d.All patients with severe COPD should be screened for pulmonary hypertension with annual transthoracic echocardiography.

2.The most widely recommended noninvasive screening test for PAH in systemic sclerosis is:

a.6

minute walk test looking at desaturation, dyspnoea, and distance walked

b.DLCO

c.Brain natriuretic peptide

d.Transthoracic echocardiography

3.In sarcoidosis, which one of the following statements is true?

a.PAH is a very common complication in end stage pulmonary sarcoidosis

b.There is no relationship between severity of interstitial lung disease and risk of PAH.

c.Most cases are due to compression of pulmonary vessels by intrathoracic lymphadenopathy and mediastinal fibrosis

d.While immunosuppression is often effective for sarcoidosis, it is not effective in treating associated PAH

4.In PAH associated with connective tissue disorders, which one of the following statements is true?

a.Among patients with systemic sclerosis, PAH is now the leading cause of death.

b.Mixed connective tissue disorder is the CTD accounting for the greatest number of cases of PAH.

c.The presence of antibodies to Scl-70 indicates increased risk of PAH.

d.Female sex is associated with a worse prognosis.

5.In PAH associated with HIV infection, which one of the following statements is true?

a.The gag viral protein may play a role in pathogenesis by suppressing expression of the BMPR2 gene product.

b.Prognosis correlates with CD4 count.

c.More of this patient group will die from opportunistic infections than from PAH.

d.In countries where highly active antiretroviral therapy (HAART) is widely available, PAH is now the leading cause of death among HIV-positive individuals.

References

1. 1Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Pulmonary arterial hypertension in france: results from a national registry. Am J Respir Crit Care Med. 2006;173:1023–1030. CrossRef

2. 2Hachulla E, Gressin V, Guillevin L, Carpentier P, Diot E, Sibilia J, et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum. 2005;52:3792–3800. MEDLINE

3. 3Penning S, Robinson KD, Major CA, Garite TJ. A comparison of echocardiography and pulmonary artery catheterization for evaluation of pulmonary artery pressures in pregnant patients with suspected pulmonary hypertension. Am J Obstet Gynecol. 2001;184:1568–1570. Abstract | Full Text | Full-Text PDF (57 KB) | CrossRef

4. 4Condliffe R, Kiely DG, Peacock AJ, Corris PA, Gibbs JSR, Vrapi F, et al. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med. 2009;179:151–157. CrossRef

5. 5Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43:5S–12S. MEDLINE

6. 6Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM, Harrison NK, et al. Interstitial lung disease guideline: the British thoracic society in collaboration with the thoracic society of Australia and New Zealand and the Irish thoracic society. Thorax. 2008;63(Suppl. 5):v1–58. CrossRef

7. 7Nathan SD, Shlobin OA, Ahmad S, Urbanek S, Barnett SD. Pulmonary hypertension and pulmonary function testing in idiopathic pulmonary fibrosis. Chest. 2007;131:657–663. MEDLINE | CrossRef

8. 8Steen V, Medsger TA. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003;48:516–522. MEDLINE | CrossRef

9. 9Bourbonnais JM, Samavati L. Clinical predictors of pulmonary hypertension in sarcoidosis. Eur Respir J. 2008;32:296–302. CrossRef

10. 10Baughman RP, Sparkman BK, Lower EE. Six-minute walk test and health status assessment in sarcoidosis. Chest. 2007;132:207–213. CrossRef

11. 11Anthi A, Machado RF, Jison ML, Taveira-Dasilva AM, Rubin LJ, Hunter L, et al. Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension. Am J Respir Crit Care Med. 2007;175:1272–1279. CrossRef

12. 12Villalba WO, Sampaio-Barros PD, Pereira MC, Cerqueira EM, Leme CA, Marques-Neto JF, et al. Six-minute walk test for the evaluation of pulmonary disease severity in scleroderma patients. Chest. 2007;131:217–222. MEDLINE | CrossRef

13. 13Garin MC, Highland KB, Silver RM, Strange C. Limitations to the 6-minute walk test in interstitial lung disease and pulmonary hypertension in scleroderma. J Rheumatol. 2009;36:330–336.

14. 14Thabut G, Dauriat G, Stern JB, Logeart D, Levy A, Marrash-Chahla R, et al. Pulmonary hemodynamics in advanced copd candidates for lung volume reduction surgery or lung transplantation. Chest. 2005;127:1531–1536. MEDLINE | CrossRef

15. 15Chaouat A, Bugnet AS, Kadaoui N, Schott R, Enache I, Ducolone A, et al. Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;172:189–194. CrossRef

16. 16Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in copd. Eur Respir J. 2008;32:1371–1385.

17. 17Stevens D, Sharma K, Szidon P, Rich S, McLaughlin V, Kesten S. Severe pulmonary hypertension associated with copd. Ann Transplant. 2000;5:8–12. MEDLINE

18. 18Oswald-Mammosser M, Weitzenblum E, Quoix E, Moser G, Chaouat A, Charpentier C, et al. Prognostic factors in copd patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure. Chest. 1995;107:1193–1198. MEDLINE | CrossRef

19. 19Arcasoy SM, Christie JD, Ferrari VA, Sutton MSJ, Zisman DA, Blumenthal NP, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med. 2003;167:735–740. CrossRef

20. 20Carratu P, Scoditti C, Maniscalco M, Seccia TM, Gioia GD, Gadaleta F, et al. Exhaled and arterial levels of endothelin-1 are increased and correlate with pulmonary systolic pressure in copd with pulmonary hypertension. BMC Pulm Med. 2008;8:20. CrossRef

21. 21Saadjian AY, Philip-Joet FF, Vestri R, Arnaud AG. Long-term treatment of chronic obstructive lung disease by nifedipine: an 18-month haemodynamic study. Eur Respir J. 1988;1:716–720. MEDLINE

22. 22Blanco I, Gimeno E, Munoz PA, Gomez FP, Pizarro S, Gistau C, et al. Sildenafil in pulmonary hypertension associated with copd. [abstract] Am J Respir Crit Care Med. 2009;179:A1046.

23. 23Hegewald MJ, Elliott CG. Sustained improvement with iloprost in a copd patient with severe pulmonary hypertension. Chest. 2009;135:536–537. CrossRef

24. 24Vonbank K, Ziesche R, Higenbottam TW, Stiebellehner L, Petkov V, Schenk P, et al. Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe copd. Thorax. 2003;58:289–293. MEDLINE | CrossRef

25. 25Cottin V, Khouatra C, Lazor R, Canu P, Cordier J-F. Pulmonary hypertension therapy and copd: still many questions to be answered. Eur Respir J. 2009;33:450–452author reply 452–53. CrossRef

26. 26Stolz D, Rasch H, Linka A, Valentino MD, Meyer A, Brutsche M, et al. A randomised, controlled trial of bosentan in severe copd. Eur Respir J. 2008;32:619–628. CrossRef

27. 27Chapman TH, Wilde M, Sheth A, Madden BP. Sildenafil therapy in secondary pulmonary hypertension: is there benefit in prolonged use?. Vascul Pharmacol. 2009;.

28. 28Hoeper MM. Treating pulmonary hypertension in copd: where do we start?. Eur Respir J. 2008;32:541–542. CrossRef

29. 29Arias MA, Garcia-Rio F, Alonso-Fernandez A, Martinez I, Villamor J. Pulmonary hypertension in obstructive sleep apnoea: effects of continuous positive airway pressure: a randomized, controlled cross-over study. Eur Heart J. 2006;27:1106–1113. CrossRef

30. 30Bady E, Achkar A, Pascal S, Orvoen-Frija E, Laaban JP. Pulmonary arterial hypertension in patients with sleep apnoea syndrome. Thorax. 2000;55:934–939. MEDLINE | CrossRef

31. 31Chaouat A, Weitzenblum E, Krieger J, Oswald M, Kessler R. Pulmonary hemodynamics in the obstructive sleep apnea syndrome. Results in 220 consecutive patients. Chest. 1996;109:380–386. MEDLINE | CrossRef

32. 32Krieger J, Sforza E, Apprill M, Lampert E, Weitzenblum E, Ratomaharo J. Pulmonary hypertension, hypoxemia, and hypercapnia in obstructive sleep apnea patients. Chest. 1989;96:729–737. MEDLINE | CrossRef

33. 33Niijima M, Kimura H, Edo H, Shinozaki T, Kang J, Masuyama S, et al. Manifestation of pulmonary hypertension during rem sleep in obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 1999;159:1766–1772.

34. 34Atwood CW, McCrory D, Garcia JGN, Abman SH, Ahearn GS, of Chest Physicians AC . Pulmonary artery hypertension and sleep-disordered breathing: Accp evidence-based clinical practice guidelines. Chest. 2004;126:72S–77S. MEDLINE | CrossRef

35. 35Rafanan AL, Golish JA, Dinner DS, Hague LK, Arroliga AC. Nocturnal hypoxemia is common in primary pulmonary hypertension. Chest. 2001;120:894–899. MEDLINE | CrossRef

36. 36Alchanatis M, Tourkohoriti G, Kakouros S, Kosmas E, Podaras S, Jordanoglou JB. Daytime pulmonary hypertension in patients with obstructive sleep apnea: the effect of continuous positive airway pressure on pulmonary hemodynamics. Respiration. 2001;68:566–572. MEDLINE | CrossRef

37. 37Laks L, Lehrhaft B, Grunstein RR, Sullivan CE. Pulmonary hypertension in obstructive sleep apnoea. Eur Respir J. 1995;8:537–541. MEDLINE

38. 38Sajkov D, Wang T, Saunders NA, Bune AJ, Mcevoy RD. Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2002;165:152–158.

39. 39Ogawa A, Emori T, Sumita W, Watanabe A, Fujio H, Miyaji K, et al. Continuous positive airway pressure ameliorated severe pulmonary hypertension associated with obstructive sleep apnea. Acta Med Okayama. 2006;60:191–195.

40. 40Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest. 2006;129:746–752. MEDLINE | CrossRef

41. 41Nadrous HF, Pellikka PA, Krowka MJ, Swanson KL, Chaowalit N, Decker PA, et al. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest. 2005;128:2393–2399. MEDLINE | CrossRef

42. 42Hamada K, Nagai S, Tanaka S, Handa T, Shigematsu M, Nagao T, et al. Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis. Chest. 2007;131:650–656. MEDLINE | CrossRef

43. 43Song JW, Song JK, Kim DS. Echocardiography and brain natriuretic peptide as prognostic indicators in idiopathic pulmonary fibrosis. Respir Med. 2009;103:180–186. Abstract | Full Text | Full-Text PDF (185 KB) | CrossRef

44. 44King E, Behr J, Brown K, du Bois M, Lancaster L, de Andrade A, et al. Build-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;.

45. 45Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet. 2002;360:895–900. Abstract | Full Text | Full-Text PDF (88 KB) | CrossRef

46. 46Collard HR, Anstrom KJ, Schwarz MI, Zisman DA. Sildenafil improves walk distance in idiopathic pulmonary fibrosis. Chest. 2007;131:897–899. MEDLINE | CrossRef

47. 47Olschewski H, Ghofrani HA, Walmrath D, Schermuly R, Temmesfeld-Wollbruck B, Grimminger F, et al. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med. 1999;160:600–607.

48. 48Handa T, Nagai S, Miki S, Fushimi Y, Ohta K, Mishima M, et al. Incidence of pulmonary hypertension and its clinical relevance in patients with sarcoidosis. Chest. 2006;129:1246–1252. MEDLINE | CrossRef

49. 49Nunes H, Humbert M, Capron F, Brauner M, Sitbon O, Battesti JP, et al. Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis. Thorax. 2006;61:68–74. MEDLINE | CrossRef

50. 50Shorr AF, Helman DL, Davies DB, Nathan SD. Pulmonary hypertension in advanced sarcoidosis: epidemiology and clinical characteristics. Eur Respir J. 2005;25:783–788. MEDLINE | CrossRef

51. 51Haque AK, Gokhale S, Rampy BA, Adegboyega P, Duarte A, Saldana MJ. Pulmonary hypertension in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol. 2002;33:1037–1043. Abstract | Full Text | Full-Text PDF (309 KB) | CrossRef

52. 52Sulica R, Teirstein AS, Kakarla S, Nemani N, Behnegar A, Padilla ML. Distinctive clinical, radiographic, and functional characteristics of patients with sarcoidosis-related pulmonary hypertension. Chest. 2005;128:1483–1489. MEDLINE | CrossRef

53. 53Damuth TE, Bower JS, Cho K, Dantzker DR. Major pulmonary artery stenosis causing pulmonary hypertension in sarcoidosis. Chest. 1980;78:888–891. MEDLINE | CrossRef

54. 54Takemura T, Matsui Y, Saiki S, Mikami R. Pulmonary vascular involvement in sarcoidosis: a report of 40 autopsy cases. Hum Pathol. 1992;23:1216–1223. MEDLINE | CrossRef

55. 55Davies J, Nellen M, Goodwin JF. Reversible pulmonary hypertension in sarcoidosis. Postgrad Med J. 1982;58:282–285. MEDLINE | CrossRef

56. 56Mangla A, Fisher J, Libby DM, Saddekni S. Sarcoidosis, pulmonary hypertension, and acquired peripheral pulmonary artery stenosis. Cathet Cardiovasc Diagn. 1985;11:69–74. MEDLINE | CrossRef

57. 57Rodman DM, Lindenfeld J. Successful treatment of sarcoidosis-associated pulmonary hypertension with corticosteroids. Chest. 1990;97:500–502. MEDLINE | CrossRef

58. 58Barnett CF, Bonura EJ, Nathan SD, Ahmad S, Shlobin OA, Osei K, et al. Treatment of sarcoidosis-associated pulmonary hypertension: a two-center experience. Chest. 2008;.

59. 59Milman N, Burton CM, Iversen M, Videbaek R, Jensen CV, Carlsen J. Pulmonary hypertension in end-stage pulmonary sarcoidosis: therapeutic effect of sildenafil?. J Heart Lung Transplant. 2008;27:329–334. Abstract | Full Text | Full-Text PDF (266 KB) | CrossRef

60. 60Baughman RP. Pulmonary hypertension associated with sarcoidosis. Arthritis Res Ther. 2007;9(Suppl 2):S8. CrossRef

61. 61Foley RJ, Metersky ML. Successful treatment of sarcoidosis-associated pulmonary hypertension with bosentan. Respiration. 2008;75:211–214. CrossRef

62. 62Sharma S, Kashour T, Philipp R. Secondary pulmonary arterial hypertension: treated with endothelin receptor blockade. Tex Heart Inst J. 2005;32:405–410. MEDLINE

63. 63Fisher KA, Serlin DM, Wilson KC, Walter RE, Berman JS, Farber HW. Sarcoidosis-associated pulmonary hypertension: outcome with long-term epoprostenol treatment. Chest. 2006;130:1481–1488. MEDLINE | CrossRef

64. 64Preston IR, Klinger JR, Landzberg MJ, Houtchens J, Nelson D, Hill NS. Vasoresponsiveness of sarcoidosis-associated pulmonary hypertension. Chest. 2001;120:866–872. MEDLINE | CrossRef

65. 65Hamilton-Craig CR, Slaughter R, McNeil K, Kermeen F, Walters DL. Improvement after angioplasty and stenting of pulmonary arteries due to sarcoid mediastinal fibrosis-case report. Heart Lung Circ. 2008;.

66. 66Dauriat G, Mal H, Thabut G, Mornex JF, Bertocchi M, Tronc F, et al. Lung transplantation for pulmonary langerhans' cell histiocytosis: a multicenter analysis. Transplantation. 2006;81:746–750. MEDLINE | CrossRef

67. 67Fartoukh M, Humbert M, Capron F, Maitre S, Parent F, Le Gall C, et al. Severe pulmonary hypertension in histiocytosis x. Am J Respir Crit Care Med. 2000;161:216–223.

68. 68Harari S, Brenot F, Barberis M, Simmoneau G. Advanced pulmonary histiocytosis x is associated with severe pulmonary hypertension. Chest. 1997;111:1142–1144. MEDLINE | CrossRef

69. 69Benyounes B, Crestani B, Couvelard A, Vissuzaine C, Aubier M. Steroid-responsive pulmonary hypertension in a patient with langerhans' cell granulomatosis (histiocytosis x). Chest. 1996;110:284–286. MEDLINE | CrossRef

70. 70Taveira-DaSilva AM, Hathaway OM, Sachdev V, Shizukuda Y, Birdsall CW, Moss J. Pulmonary artery pressure in lymphangioleiomyomatosis: an echocardiographic study. Chest. 2007;132:1573–1578. CrossRef

71. 71Koh ET, Lee P, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol. 1996;35:989–993. MEDLINE

72. 72Kondo H. Autoimmune aspects of pulmonary hypertension in collagen vascular diseases. Intern Med. 2003;42:1163–1164. MEDLINE | CrossRef

73. 73Mukerjee D, George DS, Coleiro B, Knight C, Denton CP, Davar J, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis. 2003;62:1088–1093. MEDLINE | CrossRef

74. 74Wigley FM, Lima JAC, Mayes M, McLain D, Chapin JL, Ward-Able C. The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the uncover study). Arthritis Rheum. 2005;52:2125–2132. MEDLINE | CrossRef

75. 75Launay D, Mouthon L, Hachulla E, Pagnoux C, de Groote P, Remy-Jardin M, et al. Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease. J Rheumatol. 2007;34:1005–1011.

76. 76Prakash UB. Respiratory complications in mixed connective tissue disease. Clinics in Chest Medicine. 1998;19:733–746ix. MEDLINE | CrossRef

77. 77Chen CH, Chen HA, Wang HP, Liao HT, Chou CT, Huang DF. Pulmonary arterial hypertension in autoimmune diseases: an analysis of 19 cases from a medical center in northern Taiwan. J Microbiol Immunol Infect. 2006;39:162–168. MEDLINE

78. 78Li EK, Tam LS. Pulmonary hypertension in systemic lupus erythematosus: clinical association and survival in 18 patients. J Rheumatol. 1999;26:1923–1929.

79. 79Shen JY, Chen SL, Wu YX, Tao RQ, Gu YY, Bao CD, et al. Pulmonary hypertension in systemic lupus erythematosus. Rheumatology International. 1999;18:147–151. MEDLINE | CrossRef

80. 80Shen M, Zhang F, Zhang X. Pulmonary hypertension in primary biliary cirrhosis: a prospective study in 178 patients. Scand J Gastroenterol. 2009;44:219–223. CrossRef

81. 81Vassiliou VA, Moyssakis I, Boki KA, Moutsopoulos HM. Is the heart affected in primary sjogren's syndrome? An echocardiographic study. Clin Exp Rheumatol. 2008;26:109–112.

82. 82Kasukawa R, Nishimaki T, Takagi T, Miyawaki S, Yokohari R, Tsunematsu T. Pulmonary hypertension in connective tissue disease. Clinical analysis of sixty patients in multi-institutional study. Clin Rheumatol. 1990;9:56–62. MEDLINE | CrossRef

83. 83Asherson RA, Hackett D, Gharavi AE, Harris EN, Kennedy HG, Hughes GR. Pulmonary hypertension in systemic lupus erythematosus: a report of three cases. J Rheumatol. 1986;13:416–420.

84. 84Nishimaki T, Aotsuka S, Kondo H, Yamamoto K, Takasaki Y, Sumiya M, et al. Immunological analysis of pulmonary hypertension in connective tissue diseases. J Rheumatol. 1999;26:2357–2362.

85. 85Vegh J, Szodoray P, Kappelmayer J, Csipo I, Udvardy M, Lakos G, et al. Clinical and immunoserological characteristics of mixed connective tissue disease associated with pulmonary arterial hypertension. Scand J Immunol. 2006;64:69–76. MEDLINE | CrossRef

86. 86Morse JH, Antohi S, Kasturi K, Saito S, Fotino M, Humbert M, et al. Fine specificity of anti-fibrillin-1 autoantibodies in primary pulmonary hypertension syndrome. Scand J Immunol. 2000;51:607–611. MEDLINE | CrossRef

87. 87Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107:216–223. MEDLINE

88. 88Rich S, Kieras K, Hart K, Groves BM, Stobo JD, Brundage BH. Antinuclear antibodies in primary pulmonary hypertension. J Am Coll Cardiol. 1986;8:1307–1311. Abstract | Full-Text PDF (526 KB) | CrossRef

89. 89Bellotto F, Chiavacci P, Laveder F, Angelini A, Thiene G, Marcolongo R. Effective immunosuppressive therapy in a patient with primary pulmonary hypertension. Thorax. 1999;54:372–374. MEDLINE | CrossRef

90. 90Ogawa A, Nakamura K, Matsubara H, Fujio H, Ikeda T, Kobayashi K, et al. Prednisolone inhibits proliferation of cultured pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension. Circulation. 2005;112:1806–1812. CrossRef

91. 91Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333:214–221. MEDLINE | CrossRef

92. 92Romero LI, Zhang DN, Cooke JP, Ho HK, Avalos E, Herrera R, et al. Differential expression of nitric oxide by dermal microvascular endothelial cells from patients with scleroderma. Vasc Med. 2000;5:147–158. CrossRef

93. 93Morelli S, Ferri C, Polettini E, Bellini C, Gualdi GF, Pittoni V, et al. Plasma endothelin-1 levels, pulmonary hypertension, and lung fibrosis in patients with systemic sclerosis. Am J Med. 1995;99:255–260. Full-Text PDF (702 KB) | CrossRef

94. 94Matsuda J, Tsukamoto M, Gohchi K, Saitoh N, Miyajima Y, Kazama M. Effect of total-body cold exposure on plasma concentrations of von willebrand factor, endothelin-1 and thrombomodulin in systemic lupus erythematosus patients with or without raynaud's phenomenon. Acta Haematologica. 1992;88:189–193. MEDLINE | CrossRef

95. 95Negi VS, Tripathy NK, Misra R, Nityanand S. Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension. J Rheumatol. 1998;25:462–466.

96. 96Bodolay E, Csipo I, Gal I, Sipka S, Gyimesi E, Szekanecz Z, et al. Anti-endothelial cell antibodies in mixed connective tissue disease: frequency and association with clinical symptoms. Clin Exp Rheumatol. 2004;22:409–415.

97. 97Yoshio T, Masuyama J, Mimori A, Takeda A, Minota S, Kano S. Endothelin-1 release from cultured endothelial cells induced by sera from patients with systemic lupus erythematosus. Ann Rheum Dis. 1995;54:361–365. MEDLINE | CrossRef

98. 98Tormey VJ, Bunn CC, Denton CP, Black CM. Anti-fibrillarin antibodies in systemic sclerosis. Rheumatology (Oxford, England). 2001;40:1157–1162. MEDLINE | CrossRef

99. 99Fritzler MJ, Hart DA, Wilson D, Garcia-De La Torre I, Salazar-Paramo M, Vazquez-Del Mercado M, et al. Antibodies to fibrin bound tissue type plasminogen activator in systemic sclerosis. J Rheumatol. 1995;22:1688–1693.

100. 100Morse JH, Barst RJ, Fotino M, Zhang Y, Flaster E, Gharavi AE, et al. Primary pulmonary hypertension, tissue plasminogen activator antibodies, and hla-dq7. Am J Respir Crit Care Med. 1997;155:274–278.

101. 101Tan FK, Arnett FC, Antohi S, Saito S, Mirarchi A, Spiera H, et al. Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin-1, in patients with scleroderma and other connective tissue diseases. J Immunol. 1999;163:1066–1072. MEDLINE

102. 102Dorfmuller P, Humbert M, Perros F, Sanchez O, Simonneau G, Muller KM, et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol. 2007;38:893–902. Abstract | Full Text | Full-Text PDF (626 KB) | CrossRef

103. 103Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med. 2000;132:425–434. MEDLINE

104. 104Humbert M, Sanchez O, Fartoukh M, Jagot JL, Sitbon O, Simonneau G. Treatment of severe pulmonary hypertension secondary to connective tissue diseases with continuous iv epoprostenol (prostacyclin). Chest. 1998;114:80S–82S. MEDLINE | CrossRef

105. 105Robbins IM, Gaine SP, Schilz R, Tapson VF, Rubin LJ, Loyd JE. Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus. Chest. 2000;117:14–18. MEDLINE | CrossRef

106. 106Launay D, Hachulla E, Hatron PY, Goullard L, Onimus T, Robin S, et al. Aerosolized iloprost in crest syndrome related pulmonary hypertension. J Rheumatol. 2001;28:2252–2256.

107. 107McLaughlin VV, Genthner DE, Panella MM, Hess DM, Rich S. Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series. Ann Intern Med. 1999;130:740–743. MEDLINE

108. 108Oudiz RJ, Schilz RJ, Barst RJ, Galie N, Rich S, Rubin LJ, et al. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest. 2004;126:420–427. MEDLINE | CrossRef

109. 109Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002;39:1496–1502. Abstract | Full Text | Full-Text PDF (121 KB) | CrossRef

110. 110Cozzi F, Montisci R, Marotta H, Bobbo F, Durigon N, Ruscazio M, et al. Bosentan therapy of pulmonary arterial hypertension in connective tissue diseases. Eur J Clin Invest. 2006;36(Suppl. 3):49–53. MEDLINE | CrossRef

111. 111Denton CP, Pope JE, Peter H-H, Gabrielli A, Boonstra A, van den Hoogen FHJ, et al. Long-term effects of bosentan on quality of life, survival, safety and tolerability in pulmonary arterial hypertension related to connective tissue diseases. Ann Rheum Dis. 2008;67:1222–1228. CrossRef

112. 112Benza RL, Barst RJ, Galie N, Frost A, Girgis RE, Highland KB, et al. Sitaxsentan for the treatment of pulmonary arterial hypertension: a 1-year, prospective, open-label observation of outcome and survival. Chest. 2008;134:775–782. CrossRef

113. 113Castro GWR, Appenzeller S, Bertolo MB, Costallat LTL. Isolated pulmonary hypertension secondary to rheumatoid arthritis. Clin Rheumatol. 2006;25:901–903. MEDLINE | CrossRef

114. 114Ribeiro JM, Lucas M, Victorino RM. Remission of precapillary pulmonary hypertension in systemic lupus erythematosus. J R Soc Med. 2001;94:32–33. MEDLINE

115. 115Pines A, Kaplinsky N, Goldhammer E, Olchovsky D, Frankl O. Corticosteroid responsive pulmonary hypertension in systemic lupus erythematosus. Clin Rheumatol. 1982;1:301–304. MEDLINE | CrossRef

116. 116Groen H, Bootsma H, Postma DS, Kallenberg CG. Primary pulmonary hypertension in a patient with systemic lupus erythematosus: partial improvement with cyclophosphamide. J Rheumatol. 1993;20:1055–1057.

117. 117Tanaka E, Harigai M, Tanaka M, Kawaguchi Y, Hara M, Kamatani N. Pulmonary hypertension in systemic lupus erythematosus: evaluation of clinical characteristics and response to immunosuppressive treatment. J Rheumatol. 2002;29:282–287.

118. 118Jais X, Launay D, Yaici A, Le Pavec J, Tcherakian C, Sitbon O, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum. 2008;58:521–531. CrossRef

119. 119Johnson SR, Gladman DD, Urowitz MB, Ibañez D, Granton JT. Pulmonary hypertension in systemic lupus. Lupus. 2004;13:506–509. MEDLINE | CrossRef

120. 120Dahl M, Chalmers A, Wade J, Calverley D, Munt B. Ten year survival of a patient with advanced pulmonary hypertension and mixed connective tissue disease treated with immunosuppressive therapy. J Rheumatol. 1992;19:1807–1809.

121. 121Ferri C, Emdin M, Storino FA, Giuggioli D, Longombardo G, Greco F, et al. Isolated pulmonary hypertension in diffuse cutaneous systemic sclerosis successfully treated with long-term plasma exchange. Scand J Rheumatol. 2000;29:198–200. MEDLINE | CrossRef

122. 122Gonzalez-Lopez L, Cardona-Muñoz EG, Celis A, la Torre IG-d, Orozco-Barocio G, Salazar-Paramo M, et al Therapy with intermittent pulse cyclophosphamide for pulmonary hypertension associated with systemic lupus erythematosus. Lupus. 2004;13:105–112. MEDLINE | CrossRef

123. 123Nakagawa N, Osanai S, Ide H, Nishigaki Y, Takahashi S, Nakano H, et al. Severe pulmonary hypertension associated with primary sjogren's syndrome. Intern Med. 2003;42:1248–1252. MEDLINE | CrossRef

124. 124Zhang X, Zeng X. Severe pulmonary hypertension in pediatric primary sjogren syndrome: a case report. J Clin Rheumatol. 2007;13:276–277. CrossRef

125. 125Tatsukawa H, Nagano S, Umeno Y, Oribe M. A case of primary sjogren's syndrome with severe pulmonary hypertension and glomerular damage. Ryumachi. 2003;43:564–568. MEDLINE

126. 126Peacock AJ, Murphy NF, McMurray JJV, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension. Eur Respir J. 2007;30:104–109. CrossRef

127. 127Arroliga AC, Podell DN, Matthay RA. Pulmonary manifestations of scleroderma. J Thorac Imaging. 1992;7:30–45. MEDLINE | CrossRef

128. 128Burdt MA, Hoffman RW, Deutscher SL, Wang GS, Johnson JC, Sharp GC. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. 1999;42:899–909. MEDLINE | CrossRef

129. 129Johnson SR, Swinton JR, Granton JT. Prognostic factors for survival in scleroderma associated pulmonary arterial hypertension. J Rheumatol. 2008;35:1584–1590.

130. 130Hachulla E, Launay D, Mouthon L, Sitbon O, Berezne A, Guillevin LF, et al. Is pulmonary arterial hypertension really a late complication of systemic sclerosis?. Chest. 2009;.

131. 131Le Pavec J, Souza R, Herve P, Lebrec D, Savale L, Tcherakian C, et al. Portopulmonary hypertension: survival and prognostic factors. Am J Respir Crit Care Med. 2008;178:637–643. CrossRef

132. 132Castro M, Krowka MJ, Schroeder DR, Beck KC, Plevak DJ, Rettke SR, et al. Frequency and clinical implications of increased pulmonary artery pressures in liver transplant patients. Mayo Clin Proc. 1996;71:543–551. MEDLINE

133. 133Colle IO, Moreau R, Godinho E, Belghiti J, Ettori F, Cohen-Solal A, et al. Diagnosis of portopulmonary hypertension in candidates for liver transplantation: a prospective study. Hepatology. 2003;37:401–409. MEDLINE | CrossRef

134. 134Hadengue A, Benhayoun MK, Lebrec D, Benhamou JP. Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology. 1991;100:520–528. Abstract

135. 135Kawut SM, Krowka MJ, Trotter JF, Roberts KE, Benza RL, Badesch DB, et al. Clinical risk factors for portopulmonary hypertension. Hepatology. 2008;48:196–203. CrossRef

136. 136Roberts KE, Fallon MB, Krowka MJ, Brown RS, Trotter JF, Peter I, et al. Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease. Am J Respir Crit Care Med. 2009;179:835–842. CrossRef

137. 137Krowka MJ, Swanson KL, Frantz RP, McGoon MD, Wiesner RH. Portopulmonary hypertension: results from a 10-year screening algorithm. Hepatology. 2006;44:1502–1510. MEDLINE | CrossRef

138. 138Murray KF, Carithers RL, AASL D. Aasld practice guidelines: evaluation of the patient for liver transplantation. Hepatology. 2005;41:1407–1432. MEDLINE | CrossRef

139. 139Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet. 2004;363:1461–1468. Abstract | Full Text | Full-Text PDF (437 KB) | CrossRef

140. 140Benjaminov FS, Prentice M, Sniderman KW, Siu S, Liu P, Wong F. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut. 2003;52:1355–1362. MEDLINE | CrossRef

141. 141Battista S, Bar F, Mengozzi G, Zanon E, Grosso M, Molino G. Hyperdynamic circulation in patients with cirrhosis: direct measurement of nitric oxide levels in hepatic and portal veins. J Hepatol. 1997;26:75–80. Abstract | Full-Text PDF (711 KB) | CrossRef

142. 142Sitzmann JV, Campbell K, Wu Y, Clair CS. Prostacyclin production in acute, chronic, and long-term experimental portal hypertension. Surgery. 1994;115:290–294. MEDLINE

143. 143Findlay JY, Plevak DJ, Krowka MJ, Sack EM, Porayko MK. Progressive splenomegaly after epoprostenol therapy in portopulmonary hypertension. Liver Transpl Surg. 1999;5:362–365. MEDLINE

144. 144Krowka MJ, Frantz RP, McGoon MD, Severson C, Plevak DJ, Wiesner RH. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): a study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology. 1999;30:641–648. MEDLINE | CrossRef

145. 145Hoeper MM, Halank M, Marx C, Hoeffken G, Seyfarth HJ, Schauer J, et al. Bosentan therapy for portopulmonary hypertension. Eur Respir J. 2005;25:502–508. MEDLINE | CrossRef

146. 146Hoeper MM, Seyfarth HJ, Hoeffken G, Wirtz H, Spiekerkoetter E, Pletz MW, et al. Experience with inhaled iloprost and bosentan in portopulmonary hypertension. Eur Respir J. 2007;30:1096–1102. CrossRef

147. 147Makisalo H, Koivusalo A, Vakkuri A, Hockerstedt K. Sildenafil for portopulmonary hypertension in a patient undergoing liver transplantation. Liver Transpl. 2004;10:945–950. MEDLINE | CrossRef

148. 148Austin MJ, McDougall NI, Wendon JA, Sizer E, Knisely AS, Rela M, et al. Safety and efficacy of combined use of sildenafil, bosentan, and iloprost before and after liver transplantation in severe portopulmonary hypertension. Liver Transpl. 2008;14:287–291. CrossRef

149. 149Kawut SM, Taichman DB, Ahya VN, Kaplan S, Archer-Chicko CL, Kimmel SE, et al. Hemodynamics and survival of patients with portopulmonary hypertension. Liver Transpl. 2005;11:1107–1111. MEDLINE | CrossRef

150. 150Humbert M, Segal ES, Kiely DG, Carlsen J, Schwierin B, Hoeper MM. Results of european post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J. 2007;30:338–344. CrossRef

151. 151Bhatia S, Morrison JF, Bower TC, McGoon MD. Pulmonary hypertension in the setting of acquired systemic arteriovenous fistulas. Mayo Clin Proc. 2003;78:908–912. MEDLINE | CrossRef

152. 152Olivieri C, Lanzarini L, Pagella F, Semino L, Corno S, Valacca C, et al. Echocardiographic screening discloses increased values of pulmonary artery systolic pressure in 9 of 68 unselected patients affected with hereditary hemorrhagic telangiectasia. Genet Med. 2006;8:183–190. MEDLINE | CrossRef

153. 153Trembath R. Mutations in the tgf-beta type 1 receptor, alk1, in combined primary pulmonary hypertension and hereditary haemorrhagic telangiectasia, implies pathway specificity. J Heart Lung Transplant. 2001;20:175. Full Text | Full-Text PDF (80 KB) | CrossRef

154. 154Cottin V, Dupuis-Girod S, Lesca G, Cordier JF. Pulmonary vascular manifestations of hereditary hemorrhagic telangiectasia (rendu-osler disease). Respiration. 2007;74:361–378. CrossRef

155. 155Minai OA, Rigelsky C, Eng C, Arroliga AC, Stoller JK. Long-term outcome in a patient with pulmonary hypertension and hereditary hemorrhagic telangiectasia. Chest. 2007;131:984–987. MEDLINE | CrossRef

156. 156Bonderman D, Nowotny R, Skoro-Sajer N, Adlbrecht C, Lang IM. Bosentan therapy for pulmonary arterial hypertension associated with hereditary haemorrhagic telangiectasia. Eur J Clin Invest. 2006;36(Suppl. 3):71–72. CrossRef

157. 157Michelakis ED, Weir EK. Anorectic drugs and pulmonary hypertension from the bedside to the bench. Am J Med Sci. 2001;321:292–299. MEDLINE | CrossRef

158. 158Douglas JG, Munro JF, Kitchin AH, Muir AL, Proudfoot AT. Pulmonary hypertension and fenfluramine. Br Med J (Clin Res Ed). 1981;283:881–883. MEDLINE

159. 159Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International primary pulmonary hypertension study group. N Engl J Med. 1996;335:609–616. MEDLINE | CrossRef

160. 160Chin KM, Channick RN, Rubin LJ. Is methamphetamine use associated with idiopathic pulmonary arterial hypertension?. Chest. 2006;130:1657–1663. MEDLINE | CrossRef

161. 161Bowen RL, Foreyt JP, Poston WS, Miller CC, Hyman D, Pendleton VR, et al. Echocardiographic assessment of patients receiving long-term treatment with anorexiant medications. Endocr Pract. 1999;5:17–23.

162. 162Souza R, Humbert M, Sztrymf B, Jais X, Yaici A, Le Pavec J, et al. Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases. Eur Respir J. 2008;31:343–348. CrossRef

163. 163Humbert M, Deng Z, Simonneau G, Barst RJ, Sitbon O, Wolf M, et al. Bmpr2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J. 2002;20:518–523. MEDLINE | CrossRef

164. 164Sitbon O, Lascoux-Combe C, Delfraissy JF, Yeni PG, Raffi F, De Zuttere D, et al. Prevalence of hiv-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med. 2008;177:108–113. CrossRef

165. 165Mehta NJ, Khan IA, Mehta RN, Sepkowitz DA. Hiv-related pulmonary hypertension: analytic review of 131 cases. Chest. 2000;118:1133–1141. MEDLINE | CrossRef

166. 166Kanmogne GD, Primeaux C, Grammas P. Induction of apoptosis and endothelin-1 secretion in primary human lung endothelial cells by hiv-1 gp120 proteins. Biochem Biophys Res Commun. 2005;333:1107–1115. CrossRef

167. 167Marecki JC, Cool CD, Beckey VE, Voelkel NF, Flores SC. Hiv-1 nef protein is present a the site of plexiform lesions in patients with hiv-related pulmonary hypertension, and induces a program of altered endothelial cell growth and survival in vitro. Proc Am Thoracic Soc. 2006;3:A476.

168. 168Caldwell RL, Gadipatti R, Lane KB, Shepherd VL. Hiv-1 tat represses transcription of the bone morphogenic protein receptor-2 in u937 monocytic cells. J Leukoc Biol. 2006;79:192–201. MEDLINE | CrossRef

169. 169Morse JH, Barst RJ, Itescu S, Flaster ER, Sinha G, Zhang Y, et al. Primary pulmonary hypertension in hiv infection: an outcome determined by particular hla class ii alleles. Am J Respir Crit Care Med. 1996;153:1299–1301.

170. 170Degano B, Yaici A, Le Pavec J, Savale L, Jais X, Camara B, et al. Long-term effects of bosentan in patients with hiv-associated pulmonary arterial hypertension. Eur Respir J. 2009;33:92–98. CrossRef

171. 171Nunes H, Humbert M, Sitbon O, Morse JH, Deng Z, Knowles JA, et al. Prognostic factors for survival in human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2003;167:1433–1439. CrossRef

172. 172Pugliese A, Isnardi D, Saini A, Scarabelli T, Raddino R, Torre D. Impact of highly active antiretroviral therapy in hiv-positive patients with cardiac involvement. J Infect. 2000;40:282–284. MEDLINE | CrossRef

173. 173Zuber J-P, Calmy A, Evison JM, Hasse B, Schiffer V, Wagels T, et al. Pulmonary arterial hypertension related to hiv infection: improved hemodynamics and survival associated with antiretroviral therapy. Clin Infect Dis. 2004;38:1178–1185. CrossRef

174. 174Obuchowski NA, Graham RJ, Baker ME, Powell KA. Ten criteria for effective screening: their application to multislice ct screening for pulmonary and colorectal cancers. AJR Am J Roentgenol. 2001;176:1357–1362.

175. 175British Cardiac Society Guidelines and Medical Practice Committee . Recommendations on the management of pulmonary hypertension in clinical practice. Heart. 2001;86(Suppl. 1):I1–13.

176. 176National Pulmonary Hypertension Centres of the UK and Ireland . Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Heart. 2008;94(Suppl. 1):i1–41.

177. 177Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:40S–47S. MEDLINE

178. 178Lam CS, Borlaug BA, Kane GC, Enders FT, Rodeheffer RJ, Redfield MM. Age-associated increases in pulmonary artery systolic pressure in the general population. Circulation. 2009;.

179. 179Kharitonov SA, Cailes JB, Black CM, du Bois RM, Barnes PJ. Decreased nitric oxide in the exhaled air of patients with systemic sclerosis with pulmonary hypertension. Thorax. 1997;52:1051–1055. MEDLINE | CrossRef

180. 180Malerba M, Radaeli A, Ragnoli B, Airo' P, Corradi M, Ponticiello A, et al. Exhaled nitric oxide levels in systemic sclerosis with and without pulmonary involvement. Chest. 2007;132:575–580. CrossRef

181. 181Rolla G, Colagrande P, Scappaticci E, Chiavassa G, Dutto L, Cannizzo S, et al. Exhaled nitric oxide in systemic sclerosis: relationships with lung involvement and pulmonary hypertension. J Rheumatol. 2000;27:1693–1698.

182. 182Girgis RE, Champion HC, Diette GB, Johns RA, Permutt S, Sylvester JT. Decreased exhaled nitric oxide in pulmonary arterial hypertension: response to bosentan therapy. Am J Respir Crit Care Med. 2005;172:352–357. CrossRef

183. 183Bogren HG, Klipstein RH, Mohiaddin RH, Firmin DN, Underwood SR, Rees RS, et al. Pulmonary artery distensibility and blood flow patterns: a magnetic resonance study of normal subjects and of patients with pulmonary arterial hypertension. Am Heart J. 1989;118:990–999. MEDLINE | CrossRef

184. 184Revel MP, Faivre JB, Remy-Jardin M, Delannoy-Deken V, Duhamel A, Remy J. Pulmonary hypertension: Ecg-gated 64-section ct angiographic evaluation of new functional parameters as diagnostic criteria. Radiology. 2009;250:558–566. CrossRef

185. 185Bernus A, Wagner BD, Accurso F, Doran A, Kaess H, Ivy DD. Brain natriuretic peptide levels in managing pediatric patients with pulmonary arterial hypertension. Chest. 2009;135:745–751. CrossRef

186. 186Ciurzynski M, Bienias P, Lichodziejewska B, Kurnicka K, Szewczyk A, Glinska-Wielochowska M, et al. Non-invasive diagnostic and functional evaluation of cardiac involvement in patients with systemic sclerosis. Clin Rheumatol. 2008;27:991–997. CrossRef

187. 187Lammers AE, Hislop AA, Haworth SG. Prognostic value of b-type natriuretic peptide in children with pulmonary hypertension. Int J Cardiol. 2009;135:21–26. Abstract | Full Text | Full-Text PDF (253 KB) | CrossRef

188. 188Leuchte HH, El Nounou M, Tuerpe JC, Hartmann B, Baumgartner RA, Vogeser M, et al. N-terminal pro-brain natriuretic peptide and renal insufficiency as predictors of mortality in pulmonary hypertension. Chest. 2007;131:402–409. MEDLINE | CrossRef

189. 189Leuchte HH, Holzapfel M, Baumgartner RA, Neurohr C, Vogeser M, Behr J. Characterization of brain natriuretic peptide in long-term follow-up of pulmonary arterial hypertension. Chest. 2005;128:2368–2374. MEDLINE | CrossRef

190. 190Simeoni S, Lippi G, Puccetti A, Montagnana M, Tinazzi E, Prati D, et al. N-terminal pro-bnp in sclerodermic patients on bosentan therapy for pah. Rheumatol Int. 2008;28:657–660. CrossRef

a Department of Medicine, Building 599, University of Auckland, Grafton, Auckland, New Zealand

b Greenlane Respiratory Services, Auckland City Hospital, Park Road, Grafton, Auckland, New Zealand

Corresponding author. Tel.: +64 9 3074949; fax: +64 9 6310712.

1 Tel.: +64 9 9237290. Email: p.sexton@auckland.ac.nz.

PII: S1755-0017(10)00002-3

doi:10.1016/j.rmedc.2010.01.001

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