Synonyms: PPH, idiopathic pulmonary arterial hypertension (IPAH), idiopathic pulmonary hypertension, plexogenic pulmonary arteriopathy, precapillary pulmonary hypertension.

This rare disorder can be defined as a sustained elevation in pulmonary artery pressure and pulmonary vascular resistance, with normal pulmonary artery wedge pressure, in the absence of a known cause. It is a diagnosis of exclusion after other possible causes of pulmonary hypertension have been excluded. It is a severe and often rapidly progressive illness in many cases.

It is thought that a hormonal or mechanical injury leads to damage to the pulmonary arterial endothelium in individuals who are genetically susceptible. The genetic abnormalities are beginning to be elucidated but, in view of the condition's rarity, large international trials will be needed before this information can be used to be therapeutically useful.¹

The injury to the pulmonary endothelium causes a tendency to in situ thrombosis in the pulmonary arterial tree, the so-called thrombotic pulmonary arteriopathy. The disease process continues through vascular scarring, endothelial dysfunction and proliferation of smooth muscle cells within the intima and media of the pulmonary arterial tree, causing progressive pulmonary arterial hypertension. This stage is known as plexogenic pulmonary arteriopathy and causes intimal fibrosis replacing normal endothelial structure.² This leads to progressive right heart strain due to obliteration of small pulmonary arterial vessels, and eventually right heart failure.

Precipitating conditions

• There is a small subset (~15–20%)² of cases that are inherited in an autosomal dominant fashion due to mutations in the BMPR2 gene (receptor in TGF-beta family).³
• There are also cases associated with hereditary haemorrhagic telangiectasia type 2, due to mutations in the ACVRL1 gene.³
• When the use of anorectic drugs to treat obesity was more widespread, there were many cases associated with their use, particularly with the drugs aminorex, fenfluramine and dexfenfluramine (now withdrawn from the market due to this and other complications).⁴
• The condition is also found at a relatively high rate in certain connective tissue disorders such as the Calcinosis, Raynaud's syndrome, (O)Esophageal dysmotility, Sclerodactyly and Telangiectasia (CREST) syndrome, progressive systemic sclerosis, Sjögren's syndrome, rheumatoid arthritis, SLE, mixed connective tissue disorder and polymyositis/dermatomyositis; how this comes about is unclear.⁵
• Pulmonary arterial hypertension (PAH) is a progressive, albeit rare, long-term complication of HIV infection, which has gained importance following the improved survival of HIV-infected patients with the use of HAART.⁶
• Despite these possible clues, there is no firm aetiological basis for the condition but abnormalities in the regulation of endothelial potassium channels that moderate vascular tone and an excess of the vasoactive and vasoproliferative properties of 5-HT are thought to be important.⁴
• It is uncertain whether cases due to these precipitants should be defined as primary or secondary pulmonary hypertension, as they may represent a different disease process or have a distinct aetiology from the pure idiopathic form.
• Serotonin is now thought to play an important role in the condition.⁷

Epidemiology

In its pure idiopathic form it is a rare disease with an approximate annual incidence of about 1–3 cases per million population.² There is a higher incidence of cases associated with connective tissue disease – about 10% of sufferers of CREST/scleroderma syndromes have the condition.⁵

Risk factors

• Female gender (F:M ratio variable at 2–9:1, depending on particular centre surveyed)²
• Tends to affect women of childbearing age – may rarely affect older women
• May also rarely affect children.

Presentation

The illness can have a very insidious onset and be hard to notice for both patients and doctors; as it cannot be diagnosed on clinical grounds alone and requires detailed investigation, it is often diagnosed late, when useful therapeutic options may be limited. It may take up to 2 years to diagnose the condition and it can progress very quickly in some cases, so it presents a significant challenge in terms of early detection.²

Symptoms

• Dyspnoea
• Generalised weakness and tiredness
• Recurrent syncope or presyncope, often related to exertion

Signs

• Right ventricular (parasternal) heave may be visible/palpable
• JVP may be elevated with prominent a and v waves
• Loud pulmonary component of second heart sound
• May be fixed or paradoxical splitting of second heart sound – very difficult to detect for most clinicians
• Murmur of pulmonary regurgitation – Graham Steell murmur
• Tricuspid regurgitation murmur – if significant right ventricular hypertrophy and dilatation present
• If significant associated tricuspid regurgitation – enlarged pulsatile liver with exaggerated hepato-jugular reflux
• Ascites and peripheral oedema – if significant right ventricular failure
• Lung fields are usually clear

Differential diagnosis

• Cor pulmonale causing secondary pulmonary hypertension
• Cardiomyopathies
• Primary right ventricular (RV) failure, e.g. following myocardial infarction
• Congestive cardiac failure
• Recurrent pulmonary emboli
• Mitral or tricuspid stenosis
• Tricuspid regurgitation
• Pulmonary stenosis
• Portal hypertension
• Pulmonary hypertension associated with connective tissue diseases
• Pulmonary hypertension associated with anorectic/stimulant drug use
• Obstructive sleep apnoea
• Hypothyroidism
• Sickle cell disease⁸

Investigations

• Routine biochemistry screen including LFTs to exclude portal hypertension
• Thyroid function tests
• Autoimmune screening – particularly anti-nuclear antibody to detect possible SLE/scleroderma-like syndrome – requires careful interpretation (up to 40% of patients with PPH will have positive antibodies but no other evidence of connective tissue disease)²
• CXR to exclude primary lung pathology – should be normal
• ECG – can show right ventricular hypertrophy and strain patterns but may be normal
• Echocardiography to assess RV function and estimate pulmonary arterial pressures
• Pulmonary function tests and cardiopulmonary exercise testing are often used
• CT of thorax to investigate other possible causes of pulmonary hypertension
• Ventilation/perfusion scanning to exclude thromboembolic cause of pulmonary arterial occlusion
• Pulmonary angiography and/or cardiac catheterisation may be needed to achieve a diagnosis but are carried out only in specialist centres
• Lung biopsy may be needed to exclude interstitial lung disease
• Polysomnography may be used to exclude obstructive sleep apnoea

Associated diseases

See precipitating conditions, above.

• Use of anorectic/stimulant drugs
• CREST syndrome/progressive systemic sclerosis
• SLE
• Sjögren's syndrome/rheumatoid arthritis
• Mixed connective tissue disorder
• Dermatomyositis/polymyositis
• Hereditary haemorrhagic telangiectasia type 2
• HIV infection
• Liver cirrhosis with portal hypertension.

Management

PPH has been an extremely difficult condition to treat, although notable advances have been made - for example, the use of combination therapies in Eisenmenger's syndrome.⁹ Although some drugs seem to have significant effects on symptoms and exercise tolerance in the short-term, there is little useful information on their effect on long-term survival in this devastating illness, an issue that future trial designs will have to address.¹⁰ Patients are best managed through regional specialist units that have the expertise to manage their severe illness, relevant complex investigations, expensive medication and clinical trial adminstration.¹¹

Anticoagulation

Retrospective studies have shown improved survival in cases of PPH that are anticoagulated but there are no RCT data available to support this therapy. Consensus is, however, that this is a useful treatment, supporting the idea that there is a thrombotic component to the illness.^2,11

Cardiosupportive therapy

Supplemental oxygen can help symptomatically with exercise tolerance. Diuretics are used to treat right heart failure and remove peripheral oedema, along with digoxin as a positive inotrope. There are no convincing trial data to support their use but consensus is that they are helpful.² 10–15% of patients with all types of pulmonary hypertension seem to respond favourably to high-dose vasodilators such as calcium-channel blockers and these drugs are used as standard therapy in PPH.¹¹

Prostacyclin analogues

Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. Various prostacyclin analogues may be used to treat the condition. Most need to be given by continuous intravenous infusion, usually through a long-term indwelling central venous catheter. There are some, such as beraprost, that are active orally, and iloprost that may be inhaled by a nebuliser, both of which show some evidence of efficacy.¹¹ A Cochrane review of intravenous prostacyclin analogues found evidence of short-term benefit (up to 12 weeks of treatment) in exercise capacity, NYHA functional class and cardiopulmonary haemodynamics. There was also some evidence that patients with more severe disease showed a greater response to treatment.¹²

Endothelin-A receptor antagonists

These drugs have been shown to have significant, beneficial pulmonary haemodynamic effects but there have been problems with hepatotoxicity with some agents such as bosentan.¹¹ One study, however, found consistent improvement in exercise capacity with long-term bosentan, except for Down's syndrome patients.¹³ A recent trial with sitaxsentan has shown a significant short-term beneficial effect.¹⁴

Phosphodiesterase-5 inhibitors

These drugs modulate the effects of nitric acid on vascular tone via their effect on cyclic GMP and appear to be relatively selective pulmonary arterial vasodilators. They are traditionally used to treat erectile dysfunction and sildenafil has been shown to have beneficial effects in PPH, being recently licensed in the US for its treatment.¹⁵

Drugs under clinical investigation¹⁶

Other drugs under current clinical investigation include serotonin antagonists, vasoactive intestinal peptide, stimulators of soluble guanylate cyclase and tyrosine kinase inhibitors.

Transplantation

Single/double-lung or cardiopulmonary transplantation may be considered in some severe cases. With pulmonary protection and immunosuppression, the long-term prognosis after lung and heart-lung transplant is good.¹⁷

Complications

• Deteriorating right heart function and right-sided cardiac failure
• Gross peripheral oedema
• Hepatic congestion and cardiac cirrhosis
• Pleural effusions
• Gross exertional dyspnoea
• Exertional syncope
• Sudden cardiac death
• Problems during childbirth including sudden death.^18,19

Prognosis

The outlook is not good with mortality at 3 years after diagnosis roughly 50%. Those who respond to prostacyclin therapy have a better outlook, as do those who are less severely affected at diagnosis, with best survival rates about 65% at 5 years.² One meta-analysis showed a reduction in mortality of 43% in response to active treatment.²⁰ The advent of pulmonary vasodilators has improved the outlook for children.²¹ Patients who do not respond to medical therapy tend to succumb to progressive right-sided heart failure if transplantation cannot be carried out.