Pulmonary arterial hypertension: an update

Patients with PAH can complain of dyspnoea, exercise intolerance, chest pain, dizziness and syncope, all symptoms that are also common in other cardiopulmonary disorders. For that reason, the diagnosis of PAH is often delayed. In the advanced stage signs of right heart failure are present in most of the patients. A decreased peripheral oxygen saturation due to a decreased cardiac output and in some cases a right-to-left shunt through a patent foramen ovale and physiological intrapulmonary shunts can develop. Furthermore, there can be clinical signs of the associated disease.

The ECG can show signs of right ventricular hypertrophy (RVH) and right atrial (RA) dilation. On chest X-ray central pulmonary arterial dilatation and a rarification of the peripheral blood vessels can be seen (Fig. 2). However, neither tests have adequate sensitivity and specificity to be a screening tool.

Echocardiography is the principal screening tool for PH. However, it has important limitations in accuracy of estimating pulmonary pressure. Although there are data showing a good correlation between echocardiographic findings and invasive measurements, there are also several studies reporting significant differences [17‐19]. Another limitation is the fact that a measurement of the tricuspid regurgitation (TR)velocity to estimate PAP is not possible in a significant proportion of patients due to lack of TR or a poor acoustic window. In addition to PAP estimation indirect signs of elevated PAP such as pulmonary regurgitation velocity, acceleration time of the antegrade Doppler signal across the pulmonary valve and signs of right ventricular (RV) pressure overload or failure should always be documented to increase accuracy of the method (Fig. 3a-d). In patients with symptoms and increased risk for developing PAH, additional invasive evaluation is necessary, also in case of normal echocardiographic findings. Nevertheless echocardiography remains the non-invasive key investigation and also plays an important role in classification of PH by excluding or identifying systolic or diastolic left heart dysfunction and valve disease or congenital heart disease as associated condition and gives important prognostic information [20, 21]. The presence of pericardial effusion and a tricuspid annual excursion (TAPSE) <15 are predictors of worse outcome in PAH.

In pulmonary function tests PAH patients normally show no or no more than mild restriction or obstruction at peripheral airway level. But the diffusion capacity of the lung for carbon monoxide (DLCO) is often severely reduced. Although a low DLCO can also be the result of interstitial lung disease or emphysema, the combination of a very low DLCO with a lack of restriction or obstruction is very suspicious for PAH conditions, especially PVOD and collagen vascular disease.

In cardiopulmonary exercise tests PAH patients can show reduction in VO2max and increase in ventilatory inefficiency (VE/VCO2); furthermore early lactate acidosis, decreased end-expiratory CO2 and reduced O2 pulse are common, but none of those changes are specific for PAH. However, exercise tests have an important role in the follow-up in PAH patients as VO2 max and also a simple 6-minute walk test (6 MWD) are important prognostic markers [22]. A peak VO2 <12 ml/min/kg or a 6 MWD <300 m are predictors of clinical decline and mortality. Shah et al. could show an independent relation between exercise capacity and PVR, RA pressure and CO, the last two reflecting RV function, the strongest predictor of poor outcome in PAH [23].

In patients with PH, (HR)CT can show a dilated proximal pulmonary artery, abnormal pulmonary vessels, RV dilation and abnormal septal position. It can rule out emphysema or interstitial lung disease and can give important information for the diagnosis of PVOD [24]. CT angiography is necessary if a ventilation/perfusion scan can not sufficiently rule out thromboembolic lung disease.

MRI can not serve as a screening tool for PAH due to the insufficient accuracy of estimating pulmonary pressure and the availability of MRI. However, MRI is an important upcoming diagnostic tool in PAH as it is currently considered to be the non-invasive gold standard for evaluation of the right ventricle [25]. It allows a distinct visualisation of the right ventricle, evaluation of RV mass, septal bowing as a consequence of RV pressure or volume overload, and systolic and diastolic volumes of the right and left ventricle, which gives important information not only about compromised RV function but also about interventricular dependency (Fig. 4). As decline of RV function is a key predictor of mortality, MRI provides essential information about the stage of the disease and supports therapeutic decisions.

Right heart catheterisation (RHC) is always required to confirm the diagnosis of PAH and to assess haemodynamics. In the same procedure vasoreactivity tests should be performed, which are indicated in PAH to identify patients who might benefit from long-term therapy with calcium channel blockers. The procedure has a low risk in experienced centres (mortality 0.055%) [26]. The agent of choice in acute vasoreactivity testing is inhaled nitric oxide (NO), because it has the lowest risk profile. Epoprostenol or adenosine intravenously can be used as an alternative. Response to a vasoreactivity test is defined as decrease of the mean PAP by ≥10 mmHg reaching a value ≤40 mmHg without decreasing cardiac output [27]. RHC should be repeated in patients with clinical deterioration for the evaluation of treatment escalation or timing of (heart)lung transplantation. Right atrial pressure and cardiac output are established prognostic markers.

BNP/NT-proBNP levels reflect the severity of RV dysfunction and are predictors of outcome. A NT-proBNP cut-off point at 1400 pg/mL was predictive of a 3-year outcome in 55 patients with severe precapillary PH [28]. But larger studies are needed to confirm or optimise the cut-off value for different subgroups of PAH.

All patients with PAH should be treated in multidisciplinary teams in expert centres [1]. Treatment of the associated disease should be optimised in cooperation with the treating specialists. There are several restrictions and potential life-threatening conditions to avoid. It cannot be stressed enough that general precautionary measurements in daily life have an important impact on survival in PAH. Pregnancy is contraindicated in all PAH patients. Patients should avoid staying at high altitude level (>1500 m). PAH is a high-risk factor for surgery. Surgery, if unavoidable, should therefore take place in cooperation with a PH centre. Fluid restriction and diuretics are indicated when right heart failure develops. Beta-blockers are not indicated. Calcium channel blockers (CCB) are only allowed in patients who have responded to invasive vasoreactivity testing. Anticoagulation is indicated (INR 2.0–3.0) to prevent in-situ thrombosis in IPAH, heritable PAH, and PAH due to anorexigens. However, it should be weighted against the risk of bleeding in other PAH subgroups and individually [1, 29]. Oxygen therapy is advised in case of pO2 <8 kPa (60 mmHg) [1].

In the last decade advanced medication targeting the pulmonary vascular tone has become available and could essentially contribute to a better outcome in patients with PAH. Currently there are three groups with different pathophysiological pathways available: prostanoids, endothelin receptor antagonists (ERA) and phosphodiasterase-5 inhibitors (PDE-5 inhibitors). All three groups reached the status of established PAH therapy. However, most of the studies were conducted in patients with IPAH, heritable PAH, drug-induced PAH and PAH associated with connective tissue disease. The data are limited in CHD-PAH. There is one randomised study available for the subgroup with Eisenmenger physiology[30] and PAH-CHD patients are sometimes small subgroups in larger randomized studies with PAH. Data are even more limited in PAH associated with HIV [31], portopulmonary PAH [32], haemolytic anaemia and schistosomiasis. Randomised studies are lacking in these subgroups. There is currently not enough evidence that advanced PAH drugs improve outcome in other forms of PH than PAH (group 2 to 5 of PH classification).

As a substitute for the lack of endogenous prostacyclin, which is produced by endothelial cells, prostacyclin (epoprostenol) was introduced 1984 as a continuous infusion for the treatment of PAH. In 1996, before the era of oral PAH drugs began, a randomised study could document that the use of epoprostenol improved clinical status, haemodynamics and survival compared with conventional therapy [33]. For use in patients with functional class IV it is still the only drug with a level of evidence A and therefore the drug of choice. An important disadvantage is the need for continuous administration of the drug through a central venous line with a portable infusion pump. Catheter-related complications (infection, thrombosis) as well as emergency situations with rebound PH caused by accidental discontinuation of the drug are often reported. In the meantime prostacyclin analogues have been developed which can be administered intravenously, subcutaneously, orally or by inhalation. Two of them are currently available in the Netherlands: trepostinil and iloprost. Trepostinil has a longer half-life and can be administered subcutaneously. In a placebo-controlled study improvement of symptoms and haemodynamics could be shown [34]. However, the subcutaneous administration is associated with pain at the injection site in 85% of the cases and requires frequent change of injection sites, local anaesthetics or even discontinuation of the drug. Iloprost can be administered through inhalation and acts selectively on pulmonary artery vessels in ventilated regions of the lung. A randomised trial showed significant clinical improvement compared with placebo [35]. However, iloprost has to be inhaled 6–9 times per day (30 min per session) to reach an effect comparable with other prostanoids.

PAH is characterised by elevated plasma and tissue levels of endothelin-1, a strong vasoconstrictor and inductor of smooth muscle cell proliferation. It acts by binding to endothelin receptors (ETA and ETB). Bosentan is a dual receptor antagonist, blocking both receptors. Several randomised clinical studies show that bosentan has beneficial effects on exercise capacity, haemodynamics and the time to clinical worsening [36‐39]. The drug is usually well tolerated. One important side effect is an increase of liver enzyme levels in approximately 10% of the cases. So treatment with bosentan requires monthly monitoring of liver function. Sometimes dose reduction and in rare cases discontinuation of the drug is necessary.

Ambrisentan, a selective ETA receptor antagonist, is also associated with a significant clinical improvement in randomised trials [40], although data about ambrisentan are more limited. Of note, in studies with ambrisentan only very few patients presented with an increase of liver enzymes. Still, monitoring of liver function tests is mandatory in all patients treated with ERA. Another selective ETA receptor antagonist, sitaxentan, was withdrawn from the market in December 2010 because of complications caused by increase of liver enzymes. Other side effects of ERA can be peripheral oedema, and pharmacological interaction for instance with coumarins. Furthermore, pregnancy is contraindicated because of the potential teratogenicy of ERA.

The inhibition of phosphodiesterase-5 causes an increase of cyclic-GMP, which induces vasodilation and inhibits pulmonary artery remodelling. It also has a positive inotropic effect on the hypertrophic right ventricle. The first PDE-5 inhibitor approved for treatment of PAH was sildenafil. A placebo-controlled trial [41] shows a significant but not dose-dependent increase in the 6 MWD for sildenafil (in an oral dose of 20, 40 and 80 mg 3 times per day respectively) in 278 patients with mostly IPAH. A randomised controlled trial with tadalafil shows improvement in 6 MWD and a slight increase in time to clinical worsening compared with a placebo group [42]. Tadalafil was approved in 2009 and can be administered in a single oral daily dose. PDE-5 inhibitors must not be combined with other NO donors such as nitrates, because this combination can induce extreme hypotension. Furthermore, the use of protease inhibitors such as ritonavir and indinavir can increase the bioactivity of PDE-5 inhibitors, which has to be taken into account when treating patients with PAH associated with HIV infection. Other possible side effects are visual disorders (such as photosensitivity and colour changes), flushes, and headache and muscle pain.

Diagnosis of PAH and initiation of therapy with advanced PAH medication has to be the beginning of an intensive and well-structured care. Depending on the WHO functional class initial therapy normally starts with one medical substance according to the guidelines [1]. The medication for advanced PAH that is available in the Netherlands is listed in Table 2. Short-term follow-up is indicated (every 3–4 months). Depending on clinical condition and diagnostic tests, which consist of laboratory tests, exercise tests, echocardiography and, if necessary right heart catheterisation, medical therapy has to be increased when treatment goals are not reached [43, 44] (see criteria of stable or unstable disease: Table 3). In addition C-reactive protein and heart rate, two simply obtainable parameters, have recently been shown to contain prognostic information in PAH [45, 46] and can be used alongside. Several forms of combination therapy are established [38, 47, 48] or are currently under investigation. Combination therapy as initial therapy has been discussed, but is not yet an established therapy. If a PAH patient is not responding or even deteriorating under PAH medication the diagnosis of PVOD should be considered, especially, when the patient tends to develop lung oedema under therapy.

In patients who are unstable despite optimised combination therapy atrioseptostomy can be considered. After passing the atrium septum, by using the Brockenbrough procedure, a small right-to-left shunt is created by balloon inflation to unload the right ventricle at the cost of lower arterial saturation. The size of the shunt is guided by arterial saturation. A pre-interventional RA pressure >20 mmHg and arterial saturation <90% are contraindications for the procedure, which should only be performed in experienced centres considering the high risk [49].

Despite the good results of disease stabilisation with medical combination therapy, PAH remains a disease with a poor prognosis. Listing for lung or heart/lung transplantation in time and close cooperation with a transplantation centre is essential. A recent study shows that mortality of PAH patients on the waiting list for lung transplantation is disproportionate, whereas the outcome after transplantation is similar to other conditions (COPD, idiopathic pulmonary fibrosis) [50].