SeminarPrimary pulmonary hypertension
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)
- et al.
Primary pulmonary hypertension: clinical and haemodynamic study
Am J Med
(1951) - et al.
Increased plasma serotonin in primary pulmonary hypertension
Am J Med
(1995) - et al.
Attenuated K+ channel gene transcription in primary pulmonary hypertension
Lancet
(1998) - et al.
Comparison of progressive exercise performance of normal subjects and patients with primary pulmonary hypertension
Chest
(1987) - et al.
Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension
Lancet
(1991) - et al.
Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin)
Lancet
(1984) Primary pulmonary hypertension: case series from the United Kingdom
Chest
(1994)Primary pulmonary hypertension: case series from France
Chest
(1994)- et al.
Medical and surgical treatment options for pulmonary hypertension
Am J Med Sci
(1998) Ueber sklerose der Lungen arterie
Dtsch Archiv Klin Med
(1891)
Valvular heart disease associated with fenfluramine-phentermine
N Engl J Med
ACCP consensus statement: primary pulmonary hypertension
Chest
Pulmonary hypertension with special reference to the vasoconstrictive factor
Br Heart J
Primary pulmonary hypertension and cirrhosis: are they related?
Am Rev Respir Dis
Appetite-suppressant drugs and the risk of primary pulmonary hypertension: International Primary Pulmonary Hypertension study group
N Engl J Med
Primary pulmonary hypertension: a national prospective study
Ann Intern Med
Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension
Am J Respir Crit Care Med
Familial primary pulmonary hypertension: clinical patterns
Am Rev Respir Dis
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