David J Fox
BMSc(Hons) MB(Hons) MRCP
Rajdeep S Khattar
Manchester Heart Centre Manchester Royal Infirmary
Pulmonary arterial hypertension (PAH) is the most serious and potentially devastating chronic disorder of the pulmonary circulation. Although there is no universally agreed definition of PAH, generally accepted haemodynamic criteria consist of a sustained elevation in pulmonary arterial pressure of greater than 25mmHg at rest or 30mmHg following exercise, with a mean pulmonary- capillary wedge pressure and left ventricular end-diastolic pressure of less than 15mmHg.(1) A recently revised classification of PAH, based on the diverse aetiology and pathogenesis of the disease, is given in Table 1.(2)
Mechanisms of disease
In the pulmonary circulation, there is a homeostatic balance between a variety of mediators that influence vascular tone, cellular growth and coagulation. Pulmonary endothelial cell dysfunction or injury causes an imbalance in these factors, promoting vasoconstriction, smooth muscle cell and endothelial cell proliferation, and thrombosis. A variety of genetic and environmental triggers may lead to the endothelial cellular injury that promotes these changes. Irrespective of the underlying aetiology, the histological appearance of lung tissue in each of these conditions is similar.
Although PAH may be asymptomatic in its early stages, exertional dyspnoea virtually occurs in all patients as the disease progresses. Fatigue and weakness are also common, and a minority of patients may report angina or syncope. As PAH may be associated with a variety of conditions, evidence of a related illness should be considered. Orthopnoea and paroxysmal nocturnal dyspnoea are suggestive of pulmonary congestion due to left-sided heart disease. Raynaud’s phenomenon, arthralgias and nonspecific systemic symptoms should raise the possibility of an underlying connective tissue disorder. A history of snoring or apnoea warrants evaluation for sleep-disordered breathing. The appearance of peripheral oedema and abdominal distension indicates advanced disease with the development of right ventricular failure and tricuspid regurgitation. Classical physical signs of PAH include a loud pulmonary component of the second heart sound and the presence of a left parasternal heave suggestive of right ventricular hypertrophy. The murmurs of pulmonary and tricuspid regurgitation and signs of right ventricular failure indicate advanced disease. Other physical signs may provide insights into the underlying aetiology.
Doppler echocardiography is the most useful non-invasive screening test for the detection of PAH.(3) In addition to providing a quantitative assessment of PA pressure, echocardiography can delineate right atrial and ventricular enlargement and can exclude underlying conditions such as significant left heart disease and congenital heart disease. If PAH remains unexplained, serological testing for connective tissue disease and HIV infection should be performed. Ventilation-perfusion scanning may be performed to exclude chronic pulmonary thromboembolism, and pulmonary function testing and arterial blood gas sampling should be performed to consider the possibility of underlying chronic airway or parenchymal lung disease. However, it should be remembered that even in patients with idiopathic PAH or chronic pulmonary thromboembolic disease, about 20% of patients have a restrictive defect (lung volumes <80% of predicted). Notably, PAH also occurs in diseases such as sickle-cell disease and chronic liver and renal disease. Ingestion of appetite suppressants, tryptophan and contaminated rapeseed oil have all been associated with the development of PAH. Because of its inherent risks, lung biopsy is not recommended unless diagnosis can only be made by histological examination. Right heart catheterisation remains the gold standard for assessment of pulmonary haemodynamics.
The absence of identifiable secondary causes of PAH should prompt the need for genetic testing. Mutations in the bone morphogenetic protein receptor II (BMPR2) gene have been identified in approximately 50% of patients with a family history of PAH and 25% of those thought to have sporadic idiopathic PAH (IPAH).(4)
Acute vasodilator testing is central to formulating the treatment strategies for IPAH, as those who demonstrate significant reductions in PA pressure may respond to oral calcium channel blockers.(5) The short-acting vasodilators intravenous epoprostenol and inhaled nitric oxide are the preferred agents for vasodilator testing. Patients who demonstrate a significant response to vasodilator testing should be given nifedipine, amlodipine or diltiazem depending on baseline heart rate; verapamil should be avoided because of its negative inotropic effect.
As hypoxaemia is a potent pulmonary vasoconstrictor, supplemental oxygen shoud be used as necessary in patients with IPAH to maintain oxygen saturations at >90% at all times. Diuretics and digoxin may be given in patients with right heart failure, and respiratory tract infections should be treated aggressively.
Microscopic thrombosis has been demonstrated in IPAH, and patients with right ventricular failure and venous stasis are at an increased risk for pulmonary thromboembolism. Consequently, oral anticoagulation is recommended, with demonstrated proven survival benefit.(6)
There is evidence to suggest that a relative deficiency of prostacyclin, a potent vasodilator with antiplatelet effects, may contribute to the pathogenesis of PAH. Recent randomised controlled trials with the use of the prostacyclin analogue epoprostenol have demonstrated a beneficial effect on exercise capacity, haemodynamics and quality of life in patients with moderate-to-severe PAH.(7) However, epoprostenol therapy is complicated by the need for continuous intravenous infusion. This limitation has led to the development of prostacyclin analogues with alternative routes of delivery. Treprostinil is one such agent, which can be given subcutaneously. However, a problem associated with this drug has been pain and erythema at the infusion site, making administration of the target dose difficult to achieve. The use of the inhaled prostacyclin analogue iloprost is an alternative option, and based on available data it appears a safe, effective and well-tolerated treatment for severe PAH. Its main disadvantage is the relatively short duration of action, requiring the use of six to nine inhalations per day.
Endothelin-1 is a potent vasoconstrictor that may contribute to the increase in vascular tone and pulmonary vascular hypertrophy associated with PAH. The endothelin-receptor antagonists bosentan and sitaxsentan have undergone randomised controlled clinical trials in moderate to severely symptomatic patients with PAH, showing improvements in exercise capacity and haemodynamics after 3–4 months of treatment.(8) However, both drugs are associated with the risk of hepatotoxicity and important drug interactions.
Several phosphodiesterase inhibitors, including dipyridamole, cause potent pulmonary vasodilatation in animal models of acute and chronic PAH. However, the clinical use of dipyridamole has been limited by the lack of potency and selectivity and by systemic side-effects. Several reports of non-randomised single-centre studies using sildenafil for the treatment of PAH suggest promise for this agent with relatively few side-effects.(9) However, randomised controlled trials are needed to compare the efficacy of sildenafil with other agents. Thus far, the use of combination therapies with different mechanisms of action has not been formally evaluated in clinical trials.
The rationale for surgical therapies in PAH is based on the identification of subsets of patients in whom a specific procedure is indicated. The three main forms of surgical treatment are atrial septostomy, pulmonary thromboendarterectomy and lung transplantation. The aim of atrial septostomy is to create a left-to-right shunt to decompress the right ventricle and increase systemic blood flow. However, the procedure carries significant periprocedural morbidity and mortality, limiting its use to patients with severe PAH unresponsive to treatment and requiring palliation, or as a bridge to transplantation. Pulmonary thromboendarterectomy may be indicated in selected patients with chronic pulmonary thromboembolism. In the current era, the use of prostacyclin analogues has reduced the need for lung transplantation; transplant surgery should not be considered until medical therapy has failed.
PAH is an uncommon condition that occurs as an idiopathic process or is associated with a variety of underlying disorders. Echocardiography plays a central role in the detection of PAH, and subsequent investigation to look for underlying causes is of paramount importance. The last decade has seen major advances in the medical treatment of PAH. The complexity of the treatment options necessitates referral to a specialist centre, and further research should lead to continued improvements in the management of this condition.
- Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998;352:719-25.
- Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension.J Am Coll Cardiol 2004;43:S5-S12.
- Currie PJ, Seward JB, Chan KL, et al.Continuous wave Doppler determination of Stiebellehner L, Petkov Vright ventricular pressure: a simultaneous Doppler-catheterization study in 127 patients. J Am Coll Cardiol 1985;6:750-6.
- Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The international PPH Consortium. Nat Genet 2000;26:81-4.
- Sitbon O, Brenot F, Denjean A, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension:a dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med 1995;151:384-9.
- Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984;70:580-7.
- 7. Sitbon O, Humbert M, Nunes H, et al. Long term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780-8.
- 8. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension.N Engl J Med 2002;346:896-903.
- Stiebellehner L, Petkov V, et al. Long term treatment with oral sildenafil in addition to continous IV epoprostenol in patients with pulmonary arterial hypertension. Chest 2003;123:1293-5.