Pulmonary arterial hypertension: a new era in management

Pulmonary arterial hypertension (PAH) is generally considered a rare and rapidly lethal condition with poor prognosis and few or no treatment options.1,2 However, PAH is a generic term that includes elevated pulmonary vascular resistance due to a wide range of causes (Box 1).3 PAH is defined as a mean pulmonary arterial pressure of >25 mmHg at rest and >30 mmHg with exercise. Primary pulmonary hypertension has an estimated incidence of 2 per million population (possibly higher), with PAH associated with other diseases showing a higher incidence.3 PAH is often not detected until the late and highly symptomatic stage. There is increasing recognition that PAH associated with other diseases (eg, connective tissue diseases such as scleroderma, airways diseases, interstitial lung disease and sleep apnoea) contributes to exercise intolerance and is a threat to survival. Perhaps in the past, with few treatment options, late diagnosis of PAH was not critical. With new drugs demonstrating efficacy in PAH, an active effort is required to diagnose its presence early, when these treatments may have greater effect.

Symptoms of mild-to-moderate PAH may be insidious. In the early stages, breathlessness, palpitations, fatigue and a pounding heart may be misinterpreted as lack of fitness or cardiac ischaemia. As PAH progresses, ankle oedema and later right-sided congestion (elevated jugular venous pressure, ascites, hepatomegaly, peripheral oedema) occur. Syncope is evident late in the disease. Unless the diagnosis is considered and actively sought, it may be missed.4

The definitive test for PAH is right heart catheterisation, providing a direct measure of pulmonary pressures. Several Australian centres perform this as an outpatient procedure, via the right internal jugular vein under local anaesthetic. Anticoagulation does not need to be ceased and fasting is not required. Repetitive straight leg raising to increase cardiac demand may uncover early cases in which PAH is only present during exercise. The six-minute walk test is informative and safe in assessing response to treatment and has a strong independent association with mortality.5 Once PAH has been detected, a comprehensive search for causes should be undertaken (Box 2).

Patients with family history of primary PAH may have a genetic predisposition to PAH, although the predictive value of the BMPR2 gene, which has been associated with the disease, is not yet well defined.6 Up to 15% of patients with scleroderma (especially limited scleroderma) ultimately develop PAH, and annual screening with DLCO measurement and echocardiography is advisable.

PAH can be treated specifically (pulmonary thromboendarterectomy) or generically. Chronic thromboembolic pulmon-ary hypertension is increasingly recognised as an important cause of secondary PAH, for which pulmonary thrombo-endarterectomy may provide definitive treatment.7 PAH secondary to sleep apnoea may respond to continuous positive airway pressure.8 PAH complicating connective tissue disease is recognised as an independent predictor of poorer prognosis in these conditions.9 Treatment here should be along similar lines to that used in primary pulmonary hypertension.

Until recently, access to effective drug treatment for severe PAH has been very limited in Australia. Heart–lung transplantation for primary pulmonary hypertension was first performed at St Vincent's Hospital, Sydney, in 1986. This was the first putative "curative" therapy for this condition, but is now appropriate only for patients with advanced disease for whom medical therapy has failed. There is, however, an increasing selection of vasodilator and remodelling agents becoming available, providing promise of effect-ive long term medical alternatives.10-14 British guidelines for the diagnosis and treatment of PAH were recently published and treatment algorithms are under development internationally.15

PAH is often a lethal condition or contributes to a poor outlook, with the prognosis directly related to the severity of the associated right ventricular dysfunction.2 Once right ventricular failure ensues, the median survival for patients without treatment is short. PAH, arising secondary to other disorders, contributes to exercise intolerance and reduces survival.

With the increasing availability of effective treatment for severe pulmonary hypertension, it is important that patients are referred to centres offering the range of diagnostic and therapeutic interventions. Assessing dose response, monitoring clinical outcomes, switching agents and applying combination therapy (including different modalities) requires considerable experience to ensure optimal outcomes. Complex decisions are required in delineating patients with chronic thromboembolic pulmonary hypertension suitable for pulmonary thromboendarterectomy and the timing of listing for lung transplantation. These issues have been recently addressed in the United Kingdom where the National Health Service has designated national centres for the assessment and management of severe pulmonary hypertension.15 In addition, one centre only has been nominated to perform pulmonary thromboendarterectomy surgery, so as to ensure concentration of experience and expertise.