Elsevier

The Lancet

Volume 352, Issue 9129, 29 August 1998, Pages 719-725
The Lancet

Seminar
Primary pulmonary hypertension

https://doi.org/10.1016/S0140-6736(98)02111-4Get rights and content

Summary

Primary pulmonary hypertension (PPH) is a progressive disease characterised by raised pulmonary vascular resistance, which results in diminished right-heart function due to increased right ventricular afterload. PPH occurs most commonly in young and middle-aged women; mean survival from onset of symptoms is 2–3 years. The aetiology of PPH is unknown, although familial disease accounts for roughly 10% of cases, which suggests a genetic predisposition. Current theories on pathogenesis focus on abnormalities in interaction between endothelial and smooth-muscle cells. Endothelial-cell injury may result in an imbalance in endothelium-derived mediators, favouring vasoconstriction. Defects in ion-channel activity in smooth-muscle cells in the pulmonary artery may contribute to vasoconstriction and vascular proliferation. Diagnostic testing primarily excludes secondary causes. Catheterisation is necessary to assess haemodynamics and to evaluate vasoreactivity during acute drug challenge. Decrease in pulmonary vascular resistance in response to acute vasodilator challenge occurs in about 30% of patients, and predicts a good response to chronic therapy with oral calcium-channel blockers. For patients unresponsive during acute testing, continuous intravenous epoprostenol (prostacyclin, PGI2) improves haemodynamics and exercise tolerance, and prolongs survival in severe PPH (NYHA functional class III–IV). Thoracic transplantation is reserved for patients who fail medical therapy. We review the progress made in diagnosis and treatment of PPH over the past 20 years.

Section snippets

Definition and classification

Pulmonary hypertension is clinically defined as a mean pulmonary arterial pressure of more than 25 mm Hg at rest or 30 mm Hg during exercise.4 Although there are many causes and ways of classing the disorder,5 pulmonary hypertension is usually classed as either primary or secondary on clinical grounds. A diagnosis of primary pulmonary hypertension is made when all types of secondary pulmonary hypertension have been excluded on clinical grounds (figure 1).

Epidemiology

The estimated annual incidence of PPH in European and US studies is 1–2 cases per million people per year in the general population, and necropsy studies have shown a prevalence of 1300 per million.6 The incidence of PPH among users of appetite suppressants may be as high as 25–50 per million per year.7

The mean age at diagnosis of PPH is 36 years, although it can occur at any age,8 and the mean age at diagnosis is slightly higher in male than in female patients. There is a female excess of PPH

Pathology

The normal pulmonary artery is a compliant structure with few muscle fibres, which allows the pulmonary vascular bed to function as a high-flow, low-pressure circuit. The vascular pathological features of PPH are not unique or diagnostic, and include smooth-muscle hypertrophy, intimal hyperplasia, and in-situ thrombosis (figure 2). More complex lesions can occur, including arteritis and the characteristic plexogenic lesion—an aneurysmal dilatation of an arterial branch distal to an obstructed

Aetiology and pathogenesis

The aetiology of PPH is unknown. Current concepts of pathogenesis envisage individual susceptibility and a triggering stimulus as the initiating factors for pulmonary vascular injury and repair. Only small proportions of people in high-risk groups (users of appetite suppressants and HIV-1-infected people) develop pulmonary hypertension. The occurrence of PPH within families suggests genetic susceptibility. The inheritance pattern is autosomal dominant with a female-to-male ratio of two to one,10

Symptoms and diagnostic tests

The earliest symptom in most cases of PPH is the gradual onset of shortness of breath after physical exertion. This shortness of breath is non-specific and is frequently ascribed to a lack of physical fitness. Thus, diagnosis of PPH is commonly dezlayed, sometimes for more than 2 years after the onset of symptoms.8 Other common signs and symptoms include chest pain from right-ventricular ischaemia, near syncope or syncope, tiredness, and peripheral oedema. Raynaud's phenomenon, which is

Management

Although there is no cure for PPH, there have been advances in both medical and surgical treatment. Physical activity should be limited, and medications that can aggravate pulmonary hypertension should be avoided—vasoactive decongestants, cardiodepressant antihypertensive drugs such as β-adrenergic blockers, and agents that interfere with warfarin or potentiate the degree of anticoagulation, such as non-steroidal anti-inflammatory drugs. Places with low concentrations of ambient oxygen, such as

Medical therapy

The rationale for vasodilator therapy is based on the premise that vasoconstriction to varying degrees is a feature of PPH. Almost every type of vasodilator has been tried in the past, but there have been no prospective randomised trials of oral vasodilator therapy for PPH. Non-controlled studies have shown improved haemodynamics, exercise tolerance, and survival in some patients treated with oral vasodilators. However, the cardiopulmonary haemodynamic changes that will occur with vasodilator

Surgical therapy

The poor prognosis of PPH has encouraged the development of transplantation techniques: the first successful heart-lung transplantation was done on a patient with PPH. However, experience with pulmonary thromboendarterectomy for chronic thromboembolic disease has shown that right-ventricular dysfunction was reversible when normal pulmonary-artery pressures were restored. Single or bilateral lung transplantation is now done for patients with severe PPH, and heart-lung transplantation is reserved

Prognosis

The prognosis for untreated PPH is poor. In a series of 137 cases from the UK, the median survival time was 3·4 years.37 Among 200 patients enrolled on the US National Institutes of Health Registry, the mean life expectancy was 2·5 years from diagnosis of PPH. Research in France gave similar results.38 The National Institutes of Health study showed 64% survival at 1 year and 48% survival at 3 years. The results were not affected by age, age at onset, sex, symptom duration, a positive test for

Future directions

New therapeutic approaches in PPH are directed at targeting pathogenetic mechanisms and improving drug delivery. The encouraging results with epoprostenol in patients with advanced non-vasoconstrictive PPH suggest that the idea that PPH is irreversible should be re-examined. Treatments now being developed include thromboxane-synthesis inhibitors and receptor antagonists, specific phosphodiesterase inhibitors, endothelin-receptor antagonists, and prostacyclin analogues. Cicaprost, an oral

References (39)

  • H Connolly et al.

    Valvular heart disease associated with fenfluramine-phentermine

    N Engl J Med

    (1997)
  • L Rubin

    ACCP consensus statement: primary pulmonary hypertension

    Chest

    (1987)
  • P Wood

    Pulmonary hypertension with special reference to the vasoconstrictive factor

    Br Heart J

    (1958)
  • P McDonnell et al.

    Primary pulmonary hypertension and cirrhosis: are they related?

    Am Rev Respir Dis

    (1983)
  • L Abenhaim et al.

    Appetite-suppressant drugs and the risk of primary pulmonary hypertension: International Primary Pulmonary Hypertension study group

    N Engl J Med

    (1996)
  • S Rich et al.

    Primary pulmonary hypertension: a national prospective study

    Ann Intern Med

    (1987)
  • JE Loyd et al.

    Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension

    Am J Respir Crit Care Med

    (1995)
  • J Loyd et al.

    Familial primary pulmonary hypertension: clinical patterns

    Am Rev Respir Dis

    (1984)
  • S Hatano et al.
  • Cited by (487)

    • Group 3 PH: Clinical Features and Treatment

      2021, Encyclopedia of Respiratory Medicine, Second Edition
    • Exercise Training in Pulmonary Hypertension

      2021, Encyclopedia of Respiratory Medicine, Second Edition
    View all citing articles on Scopus
    View full text