Pulmonary arterial hypertension (PAH) is generally considered a rare and rapidly lethal condition with poor prognosis and few or no treatment options.1,2 However, PAH is a generic term that includes elevated pulmonary vascular resistance due to a wide range of causes (Box 1).3 PAH is defined as a mean pulmonary arterial pressure of >25 mmHg at rest and >30 mmHg with exercise. Primary pulmonary hypertension has an estimated incidence of 2 per million population (possibly higher), with PAH associated with other diseases showing a higher incidence.3 PAH is often not detected until the late and highly symptomatic stage. There is increasing recognition that PAH associated with other diseases (eg, connective tissue diseases such as scleroderma, airways diseases, interstitial lung disease and sleep apnoea) contributes to exercise intolerance and is a threat to survival. Perhaps in the past, with few treatment options, late diagnosis of PAH was not critical. With new drugs demonstrating efficacy in PAH, an active effort is required to diagnose its presence early, when these treatments may have greater effect.
Symptoms of mild-to-moderate PAH may be insidious. In the early stages, breathlessness, palpitations, fatigue and a pounding heart may be misinterpreted as lack of fitness or cardiac ischaemia. As PAH progresses, ankle oedema and later right-sided congestion (elevated jugular venous pressure, ascites, hepatomegaly, peripheral oedema) occur. Syncope is evident late in the disease. Unless the diagnosis is considered and actively sought, it may be missed.4
The most useful investigations are echocardiography and respiratory function tests. The echocardiogram may show a hypertrophied, dilated or hypokinetic right ventricle, tricuspid regurgitation and elevated pulmonary arterial pressure. The left ventricle usually contracts normally, but may be encroached upon by the enlarged right ventricle. In the absence of a tricuspid regurgitation jet, pulmonary arterial pressure cannot be determined on echocardiography and the diagnosis is not excluded using this test. Respiratory function tests show a disproportionate reduction in carbon monoxide diffusion in the lung (DLCO) (around 50% of predicted in moderate PAH), with at most a mild-to-moderate restrictive lung defect. The reduction in DLCO is greater than that seen with comparably symptomatic left heart failure.
The definitive test for PAH is right heart catheterisation, providing a direct measure of pulmonary pressures. Several Australian centres perform this as an outpatient procedure, via the right internal jugular vein under local anaesthetic. Anticoagulation does not need to be ceased and fasting is not required. Repetitive straight leg raising to increase cardiac demand may uncover early cases in which PAH is only present during exercise. The six-minute walk test is informative and safe in assessing response to treatment and has a strong independent association with mortality.5 Once PAH has been detected, a comprehensive search for causes should be undertaken (Box 2).
Patients with family history of primary PAH may have a genetic predisposition to PAH, although the predictive value of the BMPR2 gene, which has been associated with the disease, is not yet well defined.6 Up to 15% of patients with scleroderma (especially limited scleroderma) ultimately develop PAH, and annual screening with DLCO measurement and echocardiography is advisable.
PAH can be treated specifically (pulmonary thromboendarterectomy) or generically. Chronic thromboembolic pulmon-ary hypertension is increasingly recognised as an important cause of secondary PAH, for which pulmonary thrombo-endarterectomy may provide definitive treatment.7 PAH secondary to sleep apnoea may respond to continuous positive airway pressure.8 PAH complicating connective tissue disease is recognised as an independent predictor of poorer prognosis in these conditions.9 Treatment here should be along similar lines to that used in primary pulmonary hypertension.
Until recently, access to effective drug treatment for severe PAH has been very limited in Australia. Heart–lung transplantation for primary pulmonary hypertension was first performed at St Vincent's Hospital, Sydney, in 1986. This was the first putative "curative" therapy for this condition, but is now appropriate only for patients with advanced disease for whom medical therapy has failed. There is, however, an increasing selection of vasodilator and remodelling agents becoming available, providing promise of effect-ive long term medical alternatives.10-14 British guidelines for the diagnosis and treatment of PAH were recently published and treatment algorithms are under development internationally.15
The pathophysiological basis of PAH is an increase in vasoconstrictor substances (thromboxane, endothelin) and a reduction in vasodilatory substances (nitric oxide, prostacyclin) with smooth muscle cell proliferation and in situ thrombosis, resulting in structural reduction in pulmonary arterial lumen size and, ultimately, plexigenic arteriopathy.
Medical therapies for PAH (Box 3) consist of agents which modify one or more of these pathogenetic mechanisms:
anticoagulation (to prevent in situ thrombosis or thromboembolism; eg, warfarin, prostacyclin analogues);
vasodilators (eg, prostacyclin analogues, which increase intracellular cyclic AMP, calcium antagonists, endothelin antagonists, bosentan, and phosphodiesterase 5 inhibitors, which increase cyclic GMP); and
long term antifibrotic and remodelling agents (prostacyclin analogues and bosentan).
For patients refractory to vasodilator therapy, atrial septostomy may be considered. The aim of this intervention is to relieve right-sided congestion and augment systemic cardiac output. Experience with this procedure in Australia is extremely limited, but its value has been suggested in a number of small studies in other countries.24
PAH is often a lethal condition or contributes to a poor outlook, with the prognosis directly related to the severity of the associated right ventricular dysfunction.2 Once right ventricular failure ensues, the median survival for patients without treatment is short. PAH, arising secondary to other disorders, contributes to exercise intolerance and reduces survival.
With the increasing availability of effective treatment for severe pulmonary hypertension, it is important that patients are referred to centres offering the range of diagnostic and therapeutic interventions. Assessing dose response, monitoring clinical outcomes, switching agents and applying combination therapy (including different modalities) requires considerable experience to ensure optimal outcomes. Complex decisions are required in delineating patients with chronic thromboembolic pulmonary hypertension suitable for pulmonary thromboendarterectomy and the timing of listing for lung transplantation. These issues have been recently addressed in the United Kingdom where the National Health Service has designated national centres for the assessment and management of severe pulmonary hypertension.15 In addition, one centre only has been nominated to perform pulmonary thromboendarterectomy surgery, so as to ensure concentration of experience and expertise.
Historically, Australia has been unable to offer patients with PAH adequate treatment, largely because of the high cost of therapy. The performance of pulmonary thromboendarterectomy in Australia was recently shown to achieve success rates similar to international practice. Transplantation continues to be limited by donor availability.
Now, with the availability of new and effective oral agents, we can abandon the therapeutic nihilism of past decades, and offer patients effective therapies. Some of these agents allow reverse remodelling of the right ventricle within very short periods. Reverse remodelling of the pulmonary artery and the potential to reverse the entire disease process are realistic targets.
This new era of effective agents gives clinicians a sound reason to diagnose PAH, to tease out all contributing elements and to detect cases early. Trials to date have been performed in moderately to severely affected patients, but are now in progress in less ill patients. As with most cardiovascular diseases, earlier detection and intervention is likely to be rewarded with better outcomes.
1: Common causes of pulmonary arterial hypertension*
1. Pulmonary arterial hypertension
Primary pulmonary arterial hypertension:
Sporadic
Familial (up to 25%)
Pulmonary arterial hypertension related to:
Connective tissue diseases (CREST syndrome, scleroderma, mixed connective tissue disease)
HIV
Congenital heart disease, Eisenmenger's syndrome
Portopulmonary hypertension
Anorexigens
Primary pulmonary hypertension of the newborn
2. Pulmonary venous hypertension
Left heart diseases and left ventricular dysfunction
Pulmonary veno-occlusive disease
3. Disorders of the respiratory system
Chronic obstructive pulmonary disease
Interstitial lung diseases
Sleep disordered breathing
4. Chronic thromboembolic pulmonary hypertension
5. Disorders directly affecting pulmonary vasculature
* Adapted from the WHO Classification of pulmonary arterial hypertension.
2: Investigations in pulmonary arterial hypertension
Echocardiogram
Respiratory function tests: lung volumes, CO diffusion capacity
Chest x-ray
Ventilation perfusion scan
High resolution computed tomography (CT) scan of lungs
CT pulmonary angiogram
Connective tissue disease screen (antinuclear antibodies, anti-dsDNA antibodies, anti-neutrophil cytoplasmic antibodies ± antitopoisomerase [SCL-70] ± antifibrillarin [anti-RNP])
Thrombophilia screen (anticardiolipin antibody, lupus inhibitor, protein C, protein S, factor V Leiden, methyl tetrahydrofolate reductase mutation)
Sleep study
± contrast CT pulmonary angiogram
± coronary angiogram (consider >40 years old)
Right heart catheterisation for definitive diagnosis. (In PAH, mean pulmonary arterial pressure will be >25 mmHg at rest and >30 mmHg with exercise)
3: Medical therapies for pulmonary arterial hypertension
Drug class: trial results |
Drug |
References |
Level of evidence* |
Administration and dosage |
Limitations in Australia |
||||||
Anticoagulants: Associated with improved survival in primary pulmonary hypertension in responders and nonresponders to calcium-channel blockers |
Warfarin |
16 |
II |
To keep international normalised ratio (INR) in the range 2.5–4.0 |
|
||||||
Calcium-channel blockers: Improved survival and reduced symptoms in 10% of primary pulmonary hypertension patients |
Diltiazem, amlodipine, nifedipine |
16 |
II |
Oral; high dose, eg, diltiazem 900 mg daily |
Restricted to patients with preserved right ventricular function |
||||||
Prostacyclin analogues: Increased survival, reduced symptoms, improved functional class, haemodynamics and walk distance, reduced pulmonary vascular resistance |
Prostacyclin |
17–19 |
III-1 |
Continuous intravenous infusion (because of very short half-life); 22–45 ng/kg per minute |
Not reimbursed |
||||||
Iloprost |
14 |
II |
Inhaled; 20 μg 5–12 times per day |
Not reimbursed |
|||||||
Beraprost |
13 |
II |
Oral; ≥ 40 μg four times per day |
Not available |
|||||||
Treprostinil |
12 |
II |
Subcutaneous infusion; >10 ng/kg per minute |
Injection site pain, not reimbursed |
|||||||
Endothelin receptor antagonists: Improved walk distance and haemodynamics, delayed clinical worsening, improved echo parameters |
Bosentan |
10,11 |
I |
Oral; initial, 62.5 mg twice daily; target, 125 mg twice daily |
Currently available in an open label study Elevated serum transaminase levels in 3%–5% of patients |
||||||
Phosphodiesterase 5 inhibitors: Improved functional class and walk distance, reduced pulmonary arterial pressure |
Sildenafil |
20, 21 |
III-3 |
Oral; uncertain dose, 25–100 mg three times per day |
Currently in trial, possible retinal toxicity |
||||||
Medical foods: Acute reduction in pulmonary vascular resistance |
l-Arginine |
22 |
IV |
Oral (powder, capsules); 6 g per day |
Gastrointestinal side effects |
||||||
* Level of evidence according to National Health and Medical Research Council grades.23 |
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- Anne M Keogh1
- Keith D McNeil2
- Trevor Williams3
- Eli Gabbay4
- Leslie G Cleland5
- St Vincent's Hospital, Darlinghurst, NSW.
- 1 Prince Charles Hospital, Chermside, QLD.
- 2 Alfred Hospital, Prahran, VIC.
- 3 Royal Perth Hospital, Perth, WA.
- 4 Royal Adelaide Hospital, Adelaide, SA.
All the authors are members of the Australian Advisory Board, Actelion Pharmaceut-icals, Australia (manufacturer of bosentan).
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- 11. Galiè N, Hinderliter AL, Torbicki A, et al. Effects of the oral endothelin receptor antagonist bosentan on echocardiographic and Doppler measures in patients with pulmonary arterial hypertension. American Congress of Cardiology, Atlanta, USA; 17–20 March 2002. Abstract #2179.
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- 20. Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001; 104: 1218-1222.
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Abstract
Pulmonary arterial hypertension (PAH) is a heterogeneous condition with a wide range of causes.
The diagnosis is often delayed or missed.
PAH is covert in its early stages, when its detection and treatment should have the most impact.
Access in Australia to effective PAH therapies has lagged behind that in other affluent countries.
New agents for PAH, now becoming available, improve symptoms and reduce pulmonary resistance, with some demonstrating an ability to reverse remodelling of the right ventricle.
Best management of PAH is comprehensive and multidisciplinary. Centres of excellence are needed in geographically strategic areas.
Aggressive efforts must be made to diagnose PAH and to facilitate access to effective therapies.