Elsevier

The Lancet

Volume 361, Issue 9368, 3 May 2003, Pages 1533-1544
The Lancet

Seminar
Primary pulmonary hypertension

https://doi.org/10.1016/S0140-6736(03)13167-4Get rights and content

Summary

Primary pulmonary hypertension (PPH) is a rare disorder characterised by raised pulmonary-artery pressure in the absence of secondary causes. Precapillary pulmonary arteries are affected by medial hypertrophy, intimal fibrosis, microthrombosis, and plexiform lesions. Most individuals present with dyspnoea or evidence of right heart failure. Echocardiography is the best non-invasive test to screen for suspected pulmonary hypertension. The discovery of mutations in the coding region of the gene for bone morphogenetic protein receptor 2 in patients with familial and sporadic PPH may help not only to elucidate pathogenesis but also to direct future treatment options. The pathogenesis is not completely understood, but recent investigations have revealed many possible candidate modifier genes. Without treatment, the disorder progresses in most cases to right heart failure and death. With current therapies such as epoprostenol, progression of disease is slowed, but not halted. Many promising new therapeutic options, including prostacyclin analogues, endothelin-1-receptor antagonists, and phosphodiesterase inhibitors, improve clinical function and haemodynamic measures and may prolong survival.

Section snippets

Historical perspective

The term PPH was coined by Dresdale in 1951.6 In 1954, he reported the first documented cases of familial PPH, in a mother and son with raised pulmonary-artery pressure found on right heart catheterisation.7 In 1967, an increased frequency of PPH in Europe was linked to the use of the appetite suppressant aminorex fumarate; as a result, in 1973, WHO convened an international meeting on PPH.8 The US National Institutes of Health sponsored a multicentre prospective investigation of PPH starting

Epidemiology and risk factors

The frequency of PPH in the general population is estimated at 1–2 cases per million people,8 and there are twice as many female as male patients.1, 10, 11 The disease can present at any age, but most commonly in the third decade of life in women and the fourth decade in men, with a mean age at diagnosis of 36·4 years.1 No ethnic predisposition was apparent in the National Institutes of Health registry, and the proportions by ethnic group paralleled those in the general population.1 The mean

Pathology

PPH is characterised by obstruction of small pulmonary arteries in association with plexiform lesions, medial hypertrophy, concentric laminar intimal fibrosis, fibrinoid degeneration, and thrombotic lesions (figure 2)21, 22, 23 Several pathology studies have classified patients as having either plexogenic or thrombotic arteriopathy.21, 22, 23 These analyses tried to differentiate clinical characteristics and mortality on the basis of pathology with the assumption that the two types of

Genetics

Study of families affected by PPH led to the discovery of BMPR2 as a primary gene for familial PPH on chromosome 2q33.4, 5 The heterogeneous germline mutations in BMPR2 are present in about 50% of familial PPH cases and 26% of sporadic cases and encode frameshift, partial deletion, splice-site, non-sense, and mis-sense mutations, most of which lead to premature termination of the protein.4, 5, 31, 32 Many PPH families without a mutation in the BMPR2 coding (exonic) region show linkage to the

Endothelial dysfunction

An imbalance between vasodilators and vasoconstrictors has long been thought to have a key role in the development of PPH. An early study showed increased production of thromboxane, a vasoconstrictor, and decreased formation of prostacyclin, a vasodilator, in patients with PPH.50 A subsequent study found lower expression of prostacyclin synthase in small pulmonary arteries in PPH patients than in controls.51 In addition, the overexpression of prostacyclin synthase in rodent experimental models

Clinical presentation and diagnosis

The diagnosis of many cases of PPH is delayed because symptoms overlap with those of more common diseases. Dyspnoea was the initial symptom in 60% of patients in the National Institutes of Health registry, and 98% had dyspnoea at enrolment.1 Less common symptoms included fatigue, chest pain, near-syncope, syncope, peripheral oedema, and palpitations.

Physical findings become more prevalent as right heart failure develops. Auscultation of heart sounds may reveal an increased pulmonary component (P

Anticoagulation

Anticoagulant therapy has been widely used for PPH, but the evidence supporting this approach has not come from rigorous, well-designed trials. In a retrospective, single-centre study, Fuster and colleagues found that 78 PPH patients given coumadin had better survival than 37 patients not given anticoagulant.3 In a trial designed to assess calcium-channel blockers in PPH, Rich and coworkers found that patients taking coumadin had better survival, but in that study anticoagulants were

Prostacyclin analogues

Owing to the inherent problems with epoprostenol, new prostacyclin analogues have been sought for the treatment of PPH. Beraprost, an oral analogue, in preliminary studies acutely improved haemodynamic measures in patients with PAH and had additive effects to inhaled nitric oxide.122, 123 In a retrospective, non-randomised trial, beraprost given to PPH patients maintained improvement in exercise tolerance and haemodynamic profile along with a survival benefit at 1, 2, and 3 years compared with

Experimental therapies

An established drug class, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (statins), may also be relevant to PPH therapy. These drugs prevent hypoxia-mediated downregulation of endothelial nitric oxide synthase by stabilising its mRNA,152 repress vascular smooth-muscle-cell proliferation in response to platelet-derived growth factor and vascular injury,153, 154 and attenuate hypoxic pulmonary hypertension in rats.155 We are aware of no reported trials as yet involving these agents in

Screening for disease

With the advent of many effective therapies, identification of asymptomatic carriers of BMPR2 mutations could lead to trials to prevent disease onset or progression. Exercise echocardiography to identify asymptomatic gene carriers was reported to have a sensitivity of 87·5% and specificity of 100% in two large German families with PPH.156 This approach and other non-invasive tests need independent confirmation. Another issue that needs to be addressed is requests for genetic testing by

Future directions

The pathogenetic mechanisms that result from BMPR2 mutations need to be recognised and elucidated. The identification of environmental contributors and modifying genes also requires further investigation. Once these issues are resolved, novel therapies could be developed to counteract the underlying pathogenesis perhaps at its source. In addition, screening to identify those individuals at risk of disease should allow studies to find out whether phenotypic expression can be prevented. The

Search strategy

We searched Medline from 1966 to the present for articles with the key word “pulmonary hypertension” alone or combined with other key words. These articles were appraised on the basis of the abstract and relevance to this review. We discovered many other articles after we had read the relevant papers in depth. Highest priority was given to investigations of sound scientific merit and well-constructed clinical trials.

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