Pulmonary Hypertension

oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

Pulmonary hypertension is an increase in mean pulmonary arterial pressure, which can be caused by or associate with a wide variety of conditions (see below).

Idiopathic pulmonary arterial hypertension is a rare disorder that 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.

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.[1] This leads to progressive right heart strain due to obliteration of small pulmonary arterial vessels, and eventually right heart failure.[2]

Pulmonary hypertension (PH) is a haemodynamic and pathophysiological condition defined as an increase in mean pulmonary arterial pressure (PAP) ≥25 mm Hg at rest as assessed by right heart catheterisation.

Pulmonary arterial hypertension is a clinical condition characterised by the presence of precapillary PH in the absence of other causes of precapillary PH such as PH due to lung diseases, chronic thromboembolic PH, or other rare diseases (see 'Classification', below). PAH includes different forms that share a similar clinical picture and virtually identical pathological changes of the lung microcirculation.

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In its pure idiopathic form it is a rare disease with an approximate annual incidence of about 2-6 cases per million population.[1] 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).[1]
  • Tends to affect women of childbearing age - may rarely affect older women.
  • May also rarely affect children.

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 two 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.[1]

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 are present.
  • If significant associated tricuspid regurgitation - enlarged pulsatile liver with exaggerated hepato-jugular reflux.
  • Ascites and peripheral oedema - if there is significant right ventricular failure.
  • Lung fields are usually clear.
  • Routine biochemistry screen including LFTs (portal hypertension).
  • TFTs.
  • Autoimmune screening - particularly antinuclear antibody to detect possible SLE/scleroderma-like syndrome - requires careful interpretation (up to 40% of patients with primary pulmonary hypertension (PPH) will have positive antibodies but no other evidence of connective tissue disease).[1]
  • CXR to exclude other lung diseases but this is not useful for diagnosing PH.
  • ECG – can show right ventricular hypertrophy and strain patterns but may be normal.
  • Echocardiography to assess right ventricular function and estimate pulmonary arterial pressures.
  • Pulmonary function tests
  • Exercise testing: a six-minute walk is often used to test for aerobic capacity and severity of PH but it lacks specificity.
  • High-resolution CT of the thorax to investigate other possible causes of PH.
  • 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.
  • Management of any underlying cause.
  • 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.[7]
  • 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.[8]
  • Atrial septostomy is a palliative procedure that may provide some benefit to patients whose condition is deteriorating.[1]
  • 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.[9]

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.[1][9]

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.[1]
  • 10-15% of patients with all types of PH seem to respond favourably to high-dose vasodilators such as calcium-channel blockers and these drugs are used as standard therapy in PPH.[9]

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.[9]
  • 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.[10]

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.[9]
  • One study, however, found consistent improvement in exercise capacity with long-term bosentan, except for Down's syndrome patients.[11]
  • A trial with sitaxsentan has shown a significant short-term beneficial effect.[12]

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 licensed in the USA for its treatment.[13]

Drugs under clinical investigation[14]

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.[15]

  • For untreated PPH, the estimated three-year survival rate is approximately 41%.
  • One study of long-term continuous intravenous prostacyclin therapy found that three-year survival increased to approximately 63%.[1]
  • One meta-analysis showed a reduction in mortality of 43% in response to active treatment.[18]
  • The advent of pulmonary vasodilators has improved the outlook for children.[19]
  • Patients who do not respond to medical therapy tend to develop progressive right-sided heart failure if transplantation cannot be carried out.

Further reading & references

  1. Oudiz RJ; Pulmonary Hypertension, Medscape, Sep 2012
  2. McLaughlin VV, Archer SL, Badesch DB, et al; ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009 Apr 28;119(16):2250-94. doi: 10.1161/CIRCULATIONAHA.109.192230. Epub 2009 Mar 30.
  3. Guidelines on diagnosis and treatment of pulmonary hypertension, European Society of Cardiology (2009)
  4. Pulmonary Hypertension, Primary, 1, PPH1; Online Mendelian Inheritance in Man (OMIM)
  5. Galie N, Manes A, Farahani KV, et al; Pulmonary arterial hypertension associated to connective tissue diseases. Lupus. 2005;14(9):713-7.
  6. Rosenzweig EB, Barst RJ; Pulmonary arterial hypertension in children: a medical update. Indian J Pediatr. 2009 Jan;76(1):77-81. Epub 2009 Apr 18.
  7. Beghetti M, Galie N; Eisenmenger syndrome a clinical perspective in a new therapeutic era of pulmonary arterial hypertension. J Am Coll Cardiol. 2009 Mar 3;53(9):733-40.
  8. Rich S; The current treatment of pulmonary arterial hypertension: time to redefine success. Chest. 2006 Oct;130(4):1198-202.
  9. Peacock AJ; Treatment of pulmonary hypertension. BMJ. 2003 Apr 19;326(7394):835-6.
  10. Paramothayan NS, Lasserson TJ, Wells AU, et al; Prostacyclin for pulmonary hypertension in adults. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD002994.
  11. Duffels MG, Vis JC, van Loon RL, et al; Effect of bosentan on exercise capacity and quality of life in adults with pulmonary arterial hypertension associated with congenital heart disease with and without Down's syndrome. Am J Cardiol. 2009 May 1;103(9):1309-15. Epub 2009 Mar 13.
  12. Barst RJ, Langleben D, Badesch D, et al; Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol. 2006 May 16;47(10):2049-56. Epub 2006 Apr 24.
  13. Reffelmann T, Kloner RA; Cardiovascular effects of phosphodiesterase 5 inhibitors. Curr Pharm Des. 2006;12(27):3485-94.
  14. Olsson KM, Hoeper MM; Novel approaches to the pharmacotherapy of pulmonary arterial hypertension. Drug Discov Today. 2009 Mar;14(5-6):284-90. Epub 2009 Jan 20.
  15. Toyoda Y, Thacker J, Santos R, et al; Long-term outcome of lung and heart-lung transplantation for idiopathic pulmonary arterial hypertension. Ann Thorac Surg. 2008 Oct;86(4):1116-22.
  16. Carro-Jimenez EJ, Lopez JE; Primary pulmonary hypertension and pregnancy. Bol Asoc Med P R. 2005 Oct-Dec;97(4):328-33.
  17. Madden BP; Pulmonary hypertension and pregnancy. Int J Obstet Anesth. 2009 Apr;18(2):156-64. Epub 2009 Feb 14.
  18. Galie N, Manes A, Negro L, et al; A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009 Feb;30(4):394-403. Epub 2009 Jan 20.
  19. De Wolf D; Clinical practice: pulmonary hypertension in children. Eur J Pediatr. 2009 May;168(5):515-22. Epub 2009 Jan 16.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Sean Kavanagh
Current Version:
Peer Reviewer:
Prof Cathy Jackson
Document ID:
3176 (v24)
Last Checked:
14/01/2013
Next Review:
13/01/2018