PAH-specific therapies
Better understanding in pathophysiological mechanisms of PH over the past quarter of a century has led to the development of medical therapeutics, even though no cure for pulmonary arterial hypertension exists. Several specific therapeutic agents were developed for the medical management of PAH including prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors. Furthermore, emerging treatments such as tyrosine kinase inhibitors, soluble guanylate cyclase activators (riociguat) and prostacyclin receptor agonists (selexipag) are currently being evaluated in PAH.

Prostanoids 
Endothelium-derived prostaglandin I2 (PGI2), or prostacyclin, is an arachidonic acid produced by endothelial cells. Prostacyclin is a powerful systemic and pulmonary vasodilator and an inhibitor of platelet aggregation through the increase in intracellular cyclic adenosine monophosphate (cAMP) [206,207]. Moreover, prostacyclin plays an important role in antiproliferative, antithrombotic, antimitogenic and immunomodulatory activity [208]. Prostanoids are a family of prostacyclin analogues available in intravenous, subcutaneous, or inhaled form.
Epoprostenol In the 1980s, intravenous epoprostenol was the first prostanoid evaluated in PAH [209]. As the half-life of epoprostenol is <5 minutes, it requires an indwelling central venous catheter which is connected to an infusion pump for continuous intravenous administration. Treatment with epoprostenol is complex, uncomfortable and expensive and cannot be considered as an ideal treatment despite its evident clinical benefit. Common side effects associated with treatment include headache, flushing, jaw pain and gastrointestinal disturbance [201,210]. The efficacy of continuous i.v. administration of epoprostenol has been tested in three unblinded RCTs in idiopathic PAH [207,211] and PAH associated with systemic sclerosis [212].
Barst and colleagues [183] showed improvement in exercise capacity with an increase in 6-MWD of 47meters after 12 months of epoprostenol treatment in 81 patients with idiopathic PAH. Moreover, a significant improvement of survival was observed (no death at three months of treatment in the group with epoprostenol against 8 deaths in the group receiving conventional treatment including diuretics and anticoagulants [213]. Long-term persistence of efficacy has also been shown [201,214] in idiopathic PAH, as well as in other associated PAH [215,216] and in non operable CTEPH [217]. Long term effectiveness has never been evaluated prospectively but retrospective analysis comparing patients treated by intravenous epoprostenol with data from patients treated with conventional therapy find meaningful clinical benefit for patients in NYHA FC III or IV [201,214,218,219]. Functional class, hemodynamic parameters and long term survival were all improved in the group treated with i.v. epoprostenol.
Epoprostenol had initially been proposed as a bridging therapy for lung transplantation but it is currently regarded as the treatment of choice for patients in NYHA FC IV. If treatment with epoprostenol is necessary, it will be started at low dose of 2-4 ng/kg/min and is gradually increased to 10-16 ng/kg/min according to side effects [201]. Treatment interruption secondary to pump dysfunction or the rupture of the catheter, although rare, can induce serious adverse events [201]. Because of its route of administration, central venous catheter bloodstream infections can occur, and should be systematic searched in the context of unexplained clinical deterioration.
Treprostinil Due to complications related to the central venous catheter used for the i.v. administration of epoprostenol, other prostacyclin agonists have been developed. Treprostinil is a prostacyclin analogue which benefits from a longer half-life of 58–83 minutes by subcutaneous administration [220]. It is delivered by a minipump similar to those used for insulin [221]. A multicenter randomized trial evaluated subcutaneous administrated treprostinil versus placebo over three months in patients in NYHA functional class II-IV suffering from idiopathic PAH, PAH related to CHD with a shunt or PAH associated with CTD [221]. Patients treated with treprostinil increased 6-MWD and had benefits like quality of life, pulmonary hemodynamics and improvement of clinical symptoms. Unfortunately, local side-effects such as pain and inflammation at the injection site are present in the majority of patients treated with treprostinil which often lead to limitation of increasing dose or treatment cessation. Intravenous treprostinil is only licensed for the use in the USA and provides the advantage of less frequent need for drug reservoir replacement [220]. Inhaled treprostinil was examined in a placebo-controlled TRIUMPH-1 study [222], but results of this formulation were not convincing and this product is not yet licensed outside the USA.
Inhaled Iloprost Iloprost is a prostacyclin analogue administered by inhalation or the intravenous route. The pulmonary vasodilating effects of inhaled iloprost lasts nearly 45 minutes, therefore six to nine inhalations daily are needed, with each of them requiring approximately 30 minutes [223,224]. Common side effects of treatment were cough, flushing, jaw pain and headache [223]. In the AIR study [223] conducted in at 37 European pulmonary hypertension centers, study participants (idiopathic PAH, PAH associated to systemic sclerosis, anorexigen associated PAH or non operable CTEPH) in functional class III or IV were assessed during a three month period. Patients received a daily inhalation of 2.5 μg or 5.0 μg of iloprost 6 or 9 times a day or placebo. After 3 months of treatment, 17% of patients receiving iloprost reached the combined endpoint of improvement in functional class and 10% gain in 6-MWD as compared to 5% in the placebo group.

Endothelin receptors antagonists 
Endothelin-1 (ET-1) is a potent vasoconstrictor and therefore plays an important role in the pathogenesis of PAH. In addition, it is responsible for smooth muscle cell proliferation [158]. Elevated ET-1 plasma levels are found in patients suffering from PAH and are correlated with poor prognosis. There are two existing isoforms of ET-1 receptors: endothelin A (ETRA) and endothelin B (ETRB). Activation of ETRA and ETRB on pulmonary artery smooth muscle cells induce proliferation and vasoconstriction, whereas activation of ETRB on pulmonary endothelial cells leads to release of NO and prostacyclin and participate to the clearance of circulating ET-1.
Bosentan Bosentan is an oral active dual ETRA and ETRB antagonist. Bosentan has been evaluated in PAH (idiopathic, associated with CTD, and Eisenmenger’s syndrome) in five RCT’s (Pilot, BREATHE-1, BREATHE-2, BREATHE-5, and EARLY) that have shown improvement in exercise capacity, functional class, haemodynamic, echocardiographic and Doppler variables, and time to clinical worsening [107,225-228]. The first placebo-controlled study included 32 patients affected by idiopathic PAH or scleroderma presenting with PAH showing significant exercise improvement with a gain of 76 meters after three months of treatment with bosentan as compared to placebo [225].
The BREATHE 1 study confirmed the efficacity of treatment with Bosentan in more than 200 assessed patients in NYHA functional class III or IV compared to placebo in a three month trial. After three months of treatment with bosentan, improvements in NYHA functional class were observed in 42% of patients receiving bosentan compared with 30% in the placebo arm. 6-MWD was improved overall to 44 meters in favor of bosentan. Furthermore, delayed time to clinical worsening was also noted as well as better results in dynpnea scores [226]. One accepted common side effect of treatment is increase in liver enzymes; this is why monthly monitoring of liver transaminases is mandatory in all patients receiving bosentan. Treatment is started at a dose of 62.5 mg twice a day and increased to the dose of 125 mg twice daily after one month of treatment.
Subsequently published data of treatment with bosentan suggested persistent improvements in pulmonary hemodynamics, exercise capacity and modified NYHA functional class and possibly survival rate of patients [229-231]. Results from the EARLY study (double-blind, randomised controlled 6 months trial) showed that the effect of the dual endothelin receptor antagonist bosentan in patients with mildly symptomatic PAH could be beneficial for PAH patients in NYHA functional class II [228].
Ambrisentan Ambrisentan is a selective ETA receptor antagonist administrated once daily at a dose of 5 mg or 10 mg. Two large RCTs (ARIES I and II, i.e. Ambrisentan in Pulmonary Hypertension, Randomized, Double blind, Placebo-controlled Multicenter, Efficacy Studies I and II) have demonstrated efficacy on symptoms, haemodynamics and time to clinical worsening of patients with idiopathic PAH and associated to CTD and HIV infection [232]. An extension study of the ARIES study is the recently published ARIES-E study by Klinger and colleagues [233]. They followed patients for a mean period of 60 weeks in where patients underwent hemodynamic evaluation. The authors concluded that treatment with ambrisentan leads to hemodynamic stability in PAH patients.

Phosphodiesterase type-5 inhibitors 
NO is a potent pulmonary arteries SMC relaxant that disposed vasodilator activity through up-regulation of its associated down-stream signalling molecule, cyclic GMP (cGMP), metabolism of which is dependent on the activation of a number of PDEs [208]. Phosphodiesterase type 3, 4 and 5 are the three main types of this enzyme found in pulmonary artery contractive cells. PDE-5 is the most abundantly expressed isoform in pulmonary circulation which was confirmed by several experimental investigations showing a beneficial effect of PDE-5 inhibitors on vascular remodelling and vasodilatation [234,235].
Sildenafil Sildenafil is an oral PDE-5 inhibitor that is available in Europe since 2005 for PAH patients in functional class II-III whereas this drug is licensed in Canada and the USA for patients in functional class II-IV. Basis for the authorization of this drug in the setting of PAH was a large randomized, placebo-controlled trial in which different doses of sildenafil were assessed in 278 patients presenting with idiopathic PAH, PAH related to CTD or congenital systemic to pulmonary shunts surgically corrected. The majority of study patients were in functional class II-III. After three months of treatment, the mean placebo-adjusted changes in 6-MWD for 20 mg, 40 mg and 80 mg doses of sildenafil were 45 meters, 46 meters and 50 meters, respectively. Furthermore, significant hemodynamic and functional class improvements were noted in every sildenafil group as compared to placebo. Common side effects of treatment with sildenafil include headache, flushing and dyspepsia but no hepatic enzymes increase was noted as compared with endothelin receptor antagonists. Long term extension data from 222 patients who completed one year of sildenafil monotherapy with a dose of 80 mg three times daily showed encouraging results with a gain in 6-MWD, suggesting a durable treatment effect [236]. However, sildenafil approval in Europe is currently limited to 20 mg three times a day. No data is currently available on the long-term efficacy of this lower dosage.
Tadalafil Another PDE-5 inhibitor is tadalafil which was granted for use in patients with PAH in Europe and North America in 2009. Galiè and colleagues [237] assessed in the PHIRST trial 405 randomly assigned patients who were either treatment naïve or already receiving bosentan therapy to placebo or one of the several proposed doses of tadalafil 2.5 mg or 10 mg or 20 mg or 40 mg once daily for a period of three months. At study completion, patients receiving tadalafil showed an overall mean placebo-correlated increase in 6-MWD of 33 meters [208]. Thus, this increase was dose-dependent, with only the 40 mg dose achieving the prespecified value for statistical significance for improvement. Data analysis of comparative hemodynamic data from 93 patients who underwent repeat RHC has significant reduction in mPAP and PVR under treatment with tadalafil. Barst and co-authors [238] underlined favourable effects with tadalafil 40 mg among patients receiving background bosentan, although improvements were less marked compared with treatment naïve cohort.