Group 1.1/1.2 Idiopathic and heritable PAH

Idiopathic PAH describes a sporadic disease with neither a family history of PAH nor an identified risk factor. When PAH occurs in a familial context, germline mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, a member of the transforming growth factor beta (TGF- ß) signaling family, can be detected in about 70% of cases [6, 7]. More rarely, mutations in activin receptor like kinase type 1 (ACVRL1 or ALK1) or endoglin genes, also coding for members of the TGF-ß signaling family, have been identified in patients with PAH, predominantly with coexistent hereditary hemorrhagic telangiectasia. Some authors suggested that mutations of genes encoding for Smads proteins (Smad8, Smad1 and Smad5), which are other members of the TGF-ß signaling pathway, or mutations in caveolin-1 gene may predispose to PAH [8–10].

BMPR2 mutations have also been detected in 11–40% of apparently idiopathic cases with no family history [11, 12]. Indeed, the distinction between idiopathic and familial PAH with BMPR2 mutations is artificial, as all patients with a BMPR2 mutation have heritable disease. In addition, BMPR2 mutations were identified in only 70-80% families with PAH. Thus, it was decided to abandon the term “familial PAH” in favor of the term “heritable PAH”, including idiopathic PAH with germline mutations and familial cases with or without identified mutations [13, 14].

Group 1.3 Drug- and toxin-induced PAH

Aminorex, fenfluramine derivatives and toxic rapeseed oil represent the only identified “definite” risk factors for PAH [5, 16]. Souza et al. have demonstrated that this subgroup of PAH shares clinical, functional, hemodynamic, and genetic features with idiopathic PAH, suggesting that fenfluramine exposure represents a potential trigger for PAH without influencing its clinical course [17].

Two prospective epidemiologic investigations, the SNAP (Surveillance of North American Pulmonary Hypertension) and the SOPHIA (Surveillance of Pulmonary Hypertension in America) study, were conducted in the USA [18, 19]. These investigations included retrospectively 559 and 1335 patients with PH, respectively, and confirmed the previously described association between idiopathic PAH and the use of fenfluramine. In the SNAP study, the odds ratio of developing PH was 7.5 for the use of fenfluramine more than six months of treatment [18].

The agent benfluorex is structurally and pharmacological related to fenfluramine and may be also considered as an anorectic agent. Frachon and co-workers [20] showed a significantly higher prevalence of unexplained valvular heart disease in patients taking benfluorex compared to controls. In addition, Savale and co-workers demonstrated recently that exposure to benfluorex is suggested to be a trigger in the development of PAH [21]. Benfluorex was withdrawn from the market in 2009.

The SOPHIA study examined intake of a variety of nonselective monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, antidepressants and anxiolytics. No increased risk of developing PAH was observed [19].

Amphetamine use represents a “likely” risk factor, although they are frequently used in combination with fenfluramine. A recent retrospective study suggested a relationship with the use of methamphetamine (inhaled, smoked, oral, or intravenous) and the occurrence of PAH [22]. Methamphetamine use is now considered a “very likely” risk factor for the development of PAH.

Recently published data from the French registry of pulmonary hypertension suggested that dasatinib, a tyrosine kinsase inhibitor (TKI), may induce precapillary PAH [23]. Several cases of precapillary PH in chronic myelogenous leukemia patients treated with dasatinib have been reported.

Group 1.4.1 PAH associated with connective tissue diseases

PAH associated with connective tissue diseases (CTD) represents an important clinical subgroup, in which systemic sclerosis represents the major cause of CTD associated PAH. The prevalence of PAH has been well established only for systemic sclerosis (SSc). Prospective studies using echocardiography as a screening method and RHC for confirmation found a prevalence of PAH between 7–12% [24, 25]. PH due to lung fibrosis [26], diastolic left heart dysfunction [27] and primary cardiac involvement [28] are also frequent in the setting of pulmonary hypertension in these patients, emphasizing the importance of a systemic evaluation with RHC to accurately classify the underlying mechanism of PH.

Group 1.4.2 HIV infection

PAH is a rare complication of HIV infection [29, 30]. HIV-associated PAH has clinical, hemodynamic, and histologic characteristics broadly similar to those seen in idiopathic PAH. Epidemiologic data in the early 1990s, a time when therapy with highly active antiretroviral therapy was not yet available, indicated a prevalence of 0.5% [31]. The prevalence of HIV-associated PAH was evaluated more recently and showed a stable prevalence of 0.46% [32].

Group 1.4.3 Porto-pulmonary hypertension

Porto-pulmonary hypertension (POPH) is defined by the development of PAH associated with increased pressure in the portal circulation [33, 34]. Prospective hemodynamic studies have shown that 2-6% of patients with portal hypertension had PH [35, 36]. However, RHC is mandatory for the diagnosis of portal PH, as several mechanisms may increase pulmonary artery pressure in the setting of advanced liver disease: hyperdynamic circulatory state with high cardiac output, fluid overload and diastolic dysfunction. Pulmonary vascular resistance (PVR) is usually normal in these cases.

Group 1.4.4 Congenital heart diseases

A significant proportion of patients with congenital heart disease (CHD), in particular those with systemic-to-pulmonary shunts, will develop PAH if left untreated. Eisenmenger's syndrome is defined as CHD with an initial large systemic-to-pulmonary shunt that induces progressive pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis [37, 38]. It represents the most advanced form of PAH associated with CHD. It has been reported that a large proportion of patients with CHD develop some degree of PAH [39–41]. The prevalence of PAH associated with congenital systemic-to-pulmonary shunts in Europe and North America has been estimated between 1.6 and 12.5 cases per million adults, with 25-50% of this population affected by Eisenmenger’s syndrome.

Group 1.4.5 Schistosomiasis

In the Dana Point classification, PH associated with schistosomiasis was included in Group 1. Recently, it has been demonstrated that PH associated with schistosomiasis may have a similar clinical presentation and histological findings as idiopathic PAH [42, 43]. The mechanism of PAH in patients with schistosomiasis is probably multifactorial including portal PH, a frequent complication of this disease [44] and local vascular inflammation, whereas mechanical obstruction by schistosoma eggs seems to play a minor role. More than 200 million people are infected and 4–8% of them will develop hepatosplenic disease. Then, PAH associated with schistosomiasis represents a frequent form of PAH in countries where the infection is endemic. Data from a recent study based on invasive hemodynamics evidenced the prevalence of PAH in patients with hepatosplenic disease of 4.6%; also important was the prevalence of post-capillary hypertension (3%) reinforcing the need of invasive hemodynamics for the specific diagnosis of PAH in schistosomiasis [45].

Group 1.4.6 Chronic hemolytic anemia

The chronic hemolytic anemias represent a subcategory of PAH. There has been increasing evidence that PAH is a complication of chronic hereditary and acquired hemolytic anemias, including sickle cell disease [46, 47], thalassemia [48], hereditary spherocytosis [49], stomatocytosis [50], and microangiopathic hemolytic anemia [51].

PH has been reported most frequently in patients with sickle cell disease, however the prevalence of PAH is not yet clearly established. The prevalence of PH in sickle cell disease is undoubtedly much lower than 32% as suggested by echocardiography [47]. Recently, a prospective epidemiologic studies using echocardiographic screening and direct hemodynamic confirmation were conducted in 398 outpatients with sickle cell disease at referral centers in France [52]. In this study, the prevalence of a tricuspid regurgitant jet velocity of at least 2.5 m per second measured by echocardiography was 27%. In contrast, the prevalence of pulmonary hypertension confirmed on catheterization was only 6%, suggesting that echocardiographic evaluation alone had a low positive predictive value for PH in this population. Indeed, the precise mechanism of PAH in sickle cell disease remains uncertain.

Group 5.1 Hematologic disorders

PH has been reported in chronic myeloproliferative disorders including polycythemia vera, essential thrombocythemia, and chronic myeloid leukemia [79, 80]. Several mechanisms may be implicated in PH associated with chronic myeloproliferative disorders including high cardiac output, asplenia, direct obstruction of pulmonary arteries by circulating megakaryocytes [81], CTEPH [82], portal PH, and congestive heart failure. Splenectomy as a result of trauma or as a treatment for hematologic disorders may increase the risk of developing PH [83]. As described above, dasatinib use may be one cause of PAH, particularly in chronic myeloid leukemia [23].

Group 5.2 Systemic disorders

The second subgroup includes systemic disorders, including sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis or vasculitis.

PH is a well recognized complication of sarcoidosis [84], with a reported prevalence of 1–28% [84]. PH is multifactorial and usually attributed to the destruction of capillary bed by the fibrotic process and/or the result of chronic hypoxemia [85]. However, the severity of PH is frequently out of proportion to the degree of parenchymal lung disease and blood gas abnormalities, suggesting specific pulmonary vascular involvement [86]. Such mechanisms may include extrinsic compression of large pulmonary arteries by lymph node enlargement, and granulomatous infiltration of the pulmonary vasculature, especially the pulmonary veins, which sometimes mimic PVOD [87].

Pulmonary Langerhans cell histiocytosis is an uncommon cause of infiltrative and destructive lung disease. Severe PH is a common feature in patients with end stage disease [88] and PH in these patients is usually related to chronic hypoxemia and/or abnormal pulmonary mechanics. Histopathologic examination has shown severe diffuse pulmonary vasculopathy involving predominantly intralobular pulmonary veins and, to a lesser extent, muscular pulmonary arteries [89].

Lymphangioleiomyomatosis is a rare multisystem disorder predominantly affecting women, characterized by cystic lung destruction, lymphatic abnormalities, and abdominal tumors. PH is relatively uncommon in patients with lymphangioleiomyomatosis [90]. Recently, a series of 20 cases of lymphangioleiomyomatosis associated PH has been reported showing that PH is usually moderate in this setting and associated with pulmonary function impairment [91].

Neurofibromatosis type 1, also known as von Recklinghausen’s disease, is an autosomal-dominant disease. The disease is occasionally complicated by systemic vasculopathy. A series of cases of PH have been reported in the setting of Neurofibromatosis type-1 [92].

Group 5.3 Metabolic disorders

PH has been reported in a few cases of type Ia glycogen storage disease, a rare autosomal-recessive disorder caused by a deficiency of glucose-6-phosphatase [93–95]. The mechanisms of PH are uncertain but portocaval shunts, atrial septal defects, severe restrictive pulmonary function defects or thrombosis are thought to play a role. In one case, autopsy findings revealed the presence of plexiform lesions [96].

Gaucher’s disease is a rare disorder characterized by a deficiency of lysosomal B glucosidase, which results in an accumulation of glucocerebroside in reticuloendothelial cells. In a study of 134 patients with Gaucher’s disease who were systematically screened by echocardiography, PH was not uncommon [97]. In this setting, several potential mechanisms for PH have been suggested, including interstitial lung disease, chronic hypoxemia, capillary plugging by Gaucher cells and splenectomy [97, 98].

The association between thyroid diseases and PH has been reported in some studies [99]. A prospective study of 63 consecutive adult patients with PAH found a prevalence of autoimmune thyroid disease, including both hypothyroidism and hyperthyroidism, in 49%, suggesting that these conditions may share a common immunogenetic susceptibility [100].

Group 5.4 Miscellaneous conditions

The last subgroup includes a number of miscellaneous conditions, including tumoral obstruction, fibrosing mediastinitis or chronic renal failure on dialysis.

A progressive obstruction of proximal pulmonary arteries leading to PH may be observed in tumor obstruction when a tumor grows into the central pulmonary arteries with additional thrombosis. Such cases are due principally to pulmonary artery sarcomas, which occur rarely but are usually rapidly fatal [101–103]. The differential diagnosis with CTEPH can be difficult and CT angiography may be useful to differenciate an obstruction by tumor or thrombotic material. Occlusion of the microvasculature by metastatic tumor emboli represents a cause of rapidly progressive PH.

Fibrosing mediastinitis have been mainly reported in sarcoidosis, tuberculosis, histoplasmosis and after radiotherapy. Fibrosing mediastinitis may be associated with severe PH due to compression of both pulmonary arteries and veins.

Lastly, PH has been reported in patients with end-stage renal disease maintained on long-term hemodialysis. Based on echocardiographic studies, the prevalence of PH in this patient population is estimated up to 40% [104]. PH in these patients may be explained by high cardiac output (resulting from the arteriovenous access, anemia and fluid overload) and potential diastolic and systolic left heart dysfunctions. Furthermore, hormonal and metabolic modification associated with end-stage renal disease might lead to dysfunction of normal pulmonary vascular tone.

Isolated medial hypertrophy

This abnormality of the vessel wall can be observed in all subgroups of PAH and may even be encountered in other forms of PH, e.g. in mitral valve stenosis. The lesion corresponds to a smooth muscle cell proliferation and / or recruitment within the tunica media; the histological criterion of hypertrophy / hyperplasia is fulfilled, when the diameter of a single medial layer, delimited by its internal and external elastic lamina, exceeds 10 per cent of the arteries cross-sectional diameter (Figure 2A). Isolated hypertrophy of the medial layer may be considered as an early and even reversible event as it has been shown in PH due to hypoxia in high altitude [171]. However, medial hypertrophy is usually associated with other PAH-lesions.

Concentric and eccentric non-laminar intimal fibrosis

Fibrotic lesions of the intimal layer are frequent in PAH-diseased lungs. The intima may be thickened by proliferation and recruitment of fibroblasts, myofibroblasts and other connective tissue cells, and consequently by the interstitial deposition of collagen (Figure 2B, C). In a purely descriptive approach, this thickening may be uniform and concentric, or focally predominating and eccentric. However, the eccentric intimal thickening is frequently observed in cases with thrombotic events and could represent residues of wall-adherent, organized thrombi. Thrombotic lesions, or so called in situ thrombosis, are a frequent pattern in different PAH-subgroups: organization and recanalization of totally occluding thrombotic material may lead to bizarre, fibrotic multi-channel lesions (so called “colander-like” lesions) which can be easily confounded with proliferative complex lesions (see below) (Figure 2D). Frequently, adventitial fibrosis is associated to intimal modifications (Figure 2A, B).

Concentric laminar intimal fibrosis

This morphologically conspicuous phenotype of intimal fibrosis is also known as “onion-skin” or “onion-bulb” lesion. Numerous concentrically arranged fibrotic layers occlude the arterial lumen of small (diameter: 100–200 μm) arteries (Figure 2E). The scary, cell-lacking morphology of this lesion is frequently found in patients suffering from idiopathic PAH and PAH associated to CTD [172]. Nevertheless, immunohistochemical analysis reveals fibroblasts, myofibroblasts and smooth muscle cells.

Complex lesions

The pathological classification of the World Symposium meetings in Venice and in Dana Point comprises three patterns, plexiform lesion, dilation lesion and arteritis. The plexiform lesion probably represents the most illustrious form of vascular lesions in PAH and affects various vascular compartments: focal intimal thickening of small pulmonary arteries, preferably beyond branching points and exuberant endothelial cell proliferation, leading to the formation of capillary-like, sinusoidal channels on a smooth muscle cell and collagen-rich matrix within the native arterial lumen and resulting in obstruction [173, 174]. This glomeruloid-like arterial zone feeds into dilated, vein-like congestive vessels, which are perceivable at low magnification (Figure 2F). The latter vein-like vessels are also known as dilation lesions and may predominate the histological pattern (Figure 2G). Classical arteritis with transmural inflammation and fibrinoid necrosis, as first described by Heath and Edwards for PAH associated to congenital cardiac disease (Eisenmenger), is not a regular finding in PAH [175]. Nevertheless, perivascular inflammatory infiltrates of diseased pulmonary arteries in PAH-patients, consisting mainly of T- and B-lymphocytes, dendritic cells, mast-cells and macrophages can be regularly found [141, 148, 176] (Figure 2H). It has not been elucidated until now, whether this inflammatory pattern is of pathogenetic importance, or if it represents a pure epiphenomenon within disease evolution. The reported evidence of proinflammatory mediators, so called chemokines, released by altered endothelial cells of PAH-lungs strongly indicates a self-supporting and self-amplifying process [145, 177].

Venous and venular lesions (Pulmonary veno-occlusive disease and pulmonary hemangiomatosis)

A clear-cut differentiation between pre-and post-capillary pulmonary vascular lesions is sometimes difficult to make: lesions frequently concern veins and arteries in lungs of patients with PVOD, and vice-versa veins may be strongly involved in some subgroups of PAH. This is not contradictory because the clinical approach to ‘difficult-to-treat’ PAH-groups may be similar to clinical management of PVOD and PVOD-patients are frequently treated – under great precaution – with pulmonary arterial dilators, e.g. prostanoids. Recent reports, for example, indicate that CTD associated PAH, classically being considered as pre-capillary PH, simultaneously displays a PVOD-like pattern in histology [178, 179]. Like in PVOD, the observed post-capillary lesions concern septal veins and pre-septal venules and usually consist of a loose and pauci-cellular and cushion-like intimal fibrosis that may totally occlude the lumen. A muscularization of both, septal veins and pre-septal venules may be observed (Figure 3A, B). Importantly, occult pulmonary hemorrhage regularly occurs in patients displaying PVOD. This particularity, which is certainly due to the post-capillary bloc, is of diagnostic importance, as bronchio-alveolar lavage can reveal an occult hemorrhage. The degree of hemorrhage can be evaluated semi-quantitatively and qualitatively using the Golde Score, which takes number and Perls-Prussian-Blue staining-degree of intra-alveolar siderophages into consideration (Figure 3C) [180]. Pulmonary capillary hemangiomatosis has been historically described as an aggressive capillary proliferation with patchy distribution within the pulmonary parenchyma: alveolar septa are thickened by 3 to 4 capillary layers, and infiltration of venous and bronchiolar structures with secondary occlusion may be present (Figure 3D). It is thought, that a clinically relevant post-capillary bloc is owed to this angiomatoid expansion. Occult hemorrhage or hemosiderosis, therefore, is frequently found [181]. However, Lantuejoul and co-workers have shown in a remarkable retrospective histological analysis, that capillary hemangiomatosis-pattern is virtually always present in PVOD, and vein-remodelling is constantly observed in case with a primary diagnosis of PCH [54]. The authors suggest the possibility, that PVOD and PCH might be the same disease, with a vein- or a capillary-predominating pattern. We fully support this view, and in our experience from the French National PH Reference Center, no clinical distinction is made between both conditions.

Physical activities

Peripheral vasodilatation or increased cardiac demand will put PAH patient at risk of acute cardiac failure and syncope. Thus, we traditionally advise against extreme physical activity. Patients are taught to stay active while adapting effort according to their symptoms. Nevertheless, the appropriate level of physical activity is difficult to define. To date, only few studies have evaluated to effect of cardio-respiratory rehabilitation in PAH. One of this program involved three weeks of inpatient rehabilitation followed by three month training at home with phone call supervision. No modification on cardiac hemodynamic was observed on echocardiography but 6-MWD and quality of life were improved. As proposed in ERS/ESC guidelines, more data are required before appropriate recommendations can be made [15].

Altitude and hypoxia

As hypoxic vasoconstriction may be an aggravating factor in PAH, stays at altitude above 1500-2000 meters without supplemented oxygen and air flight in unpressurized cabin should be avoided [15]. Chronic hypoxia (PaO2 <60 mmHg) warrants oxygen therapy for symptoms and to avoid PAH deterioration.

Pregnancy and contraception

The hemodynamic and hormonal modifications occurring during pregnancy and peripartum period can lead to severe, and sometimes fatal, right heart failure [197, 198]. Pregnancy is considered to be associated with high rate of mortality (30-50%) in PAH patients [15]. Thus, pregnancy is contraindicated in women affected by PAH. Consequently, contraception is strongly recommended in PAH women of childbearing age [197, 198]. Combined estrogen-progestin oral contraceptive is theoretically contraindicated because their pro-thrombotic activity. Therefore, mechanical contraception (intra-uterine device for example) or surgical sterilization should be proposed. Nethertheless, pregnancy should be managed with specific PAH therapies and planned elective delivery in expert centres [15].

Anaesthesia and surgery

Hypotension induced by anaesthetic drugs, and hemodynamic insults following surgical and anaesthetic interventions are generally poorly tolerated by PAH patients, with a high procedural morbidity and mortality. Consequently, it is recommended in general that PAH patients avoid unnecessary procedures. When required, these should be highly planned with the multidisciplinary team, either within, or in close liaison with, the expert centers, in order to coordinate surgical and medical interventions [199].

Proscribed drugs

Vasoconstrictors used in cold medication to relieve nasal congestion should be avoided in PAH patients. Beta-blockers have been shown to be deleterious to PAH patients because they prevent the important adaptive physiologic response that allows preservation of adequate cardiac output. To discontinue such drugs in a patient with PAH may lead, by itself, to important clinical and hemodynamic improvement [200].

Diuretics

Diuretics are one of the most important treatments in the setting of PAH because right heart failure leads to fluid retention, hepatic congestion, ascites and peripheral edema. Right ventricular overload is part of clinical symptoms and has been associated with a poor prognosis in PAH [201]. Diuretics and salt-free diet relieve hypervolemia and associated symptoms. Whether this strategy improves prognosis is unknown. Dose adjustment of diuretics is needed, based on clinical and hemodynamic findings. Renal function and blood chemistry should be monitored to avoid renal failure or dyskalemia [192].

Oral anticoagulation

Pathology specimens from PAH patients may show in situ thrombosis and thrombi recanalisation. Only few studies support anticoagulation treatment in PAH (mostly retrospective or not randomized) [202, 203]. Current recommendations propose oral anticoagulation aiming for targeting an International Normalized Ratio (INR) between 1.5 and 2.5. Although the somewhat sparse evidence base is derived exclusively from idiopathic, heritable and PAH due to anorexigens, anticoagulation has been generalised to all patient groups, given the absence of contraindication. Anticoagulation is usually not recommended in porto-pulmonary hypertension because of the risk of esophageal variceal haemorrhage. In patients with systemic sclerosis, oral anticoagulation can be difficult to manage because of their high risk of bleeding, especially from the gastrointestinal tract. Variceal ligation is a preventive option in these cases. Long-term oral anticoagulation is essential in CTEPH with an INR which is recommended to be between 2 and 3.

Digitalis

Digoxin has been suggested as part of PAH therapy in the past because it produces an acute increase in cardiac output [204], although its efficacy is unknown in PAH. Therefore it is usually proposed in PAH associated with atrial tachyarrhythmias [192].

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.

Macitentan

Macitentan, also called ACT-064992, is a novel, highly potent, tissue-targeting dual ET-1 receptor antagonist characterized by a high lipophilicity [247]. Macitentan has been tested in the largest, long-term, event-driven randomized, controlled study (SERAPHIN, Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve clinical outcome) [246]. The Seraphin study was designed to evaluate the efficacy and safety of macitentan through the primary endpoint of time to first morbidity and all-cause mortality event in 742 patients with symptomatic PAH. Patients were treated for up to three and a half years.

Macitentan has met its primary endpoint, decreasing the risk of a morbidity/mortality event over the treatment period versus placebo. Secondary efficacy endpoints, including change from baseline to month six in 6-MWD, change from baseline to month six in NYHA FC and time – over the whole treatment period - to either death due to PAH or hospitalization due to PAH, also showed a dose-dependent effect. Treatment with macitentan in this study was well tolerated; headache, nausea and vomiting were reported as minor adverse events [248]. The safety set comprised 741 patients, who received at least one dose of study treatment (placebo, 3 mg or 10 mg). The number of adverse events reported and patients discontinuing treatment due to adverse events was similar across all groups. Similar elevations of liver aminotransferases greater than three times the upper limit of normal were observed in all groups. In addition, no difference was observed between macitentan and placebo in terms of fluid retention (edema). A decrease in hemoglobin - reported as an adverse event - was observed more frequently on macitentan than placebo, with no difference in treatment discontinuation between groups.

Vardenafil

Vardenafil is another PDE5 inhibitor. Recently published data from a prospective, randomised study including 66 patients with PAH suggests improvement in 6-MWD and hemodynamic parameters after 3 months of treatment with vardenafil as compared to placebo. Side effects are not reported and proposed dosage is 5 mg twice daily [249]. However, further studies are needed.

Riociguat

Endothelium-derived NO regulates vascular homeostasis through pulmonary arteries SMC relaxation via the activation of the second messenger cGMP. The clinical benefits associated with the PDE-5 inhibitor class has led to interest in testing whether other agents that modulate NO signaling might be similarly beneficial in PAH. Riociguat is a first-in-class drug that augments cGMP biosynthesis through direct stimulation of the enzyme soluble guanylate cyclase (sGC) promoting vasodilatation by direct stimulation of sGC in an NO-independent fashion, and by sensitization of sGC to low endogenous NO levels [250].

A phase I randomized placebo-controlled study in 58 healthy male subjects were given riociguat orally was designed to test the safety profile, pharmacokinetics and pharmacodynamics of single oral doses of riociguat (0.25–5 mg). A proof-of-concept study was conducted to investigate oral riociguat in patients with moderate to severe PH in a two-part, non-randomized, open-label, single center trial [251]. Riociguat was well tolerated in doses up to 2.5 mg, whereas 5 mg caused asymptomatic hypotension in one patient. Therefore the 2.5 mg dose was used in the second part of the trial to demonstrate efficacy. Riociguat significantly reduced mPAP, PVR and systemic vascular resistance and increased cardiac index [251]. Results from a multicenter, open-label, uncontrolled phase II trial involving 75 patients with PAH (n = 33) and chronic thrombo-embolic PH (n = 42) showed that 12 weeks of oral riociguat given 3 times daily conferred improvements in symptoms, NYHA FC, exercise capacity, NT-proBNP level, and pulmonary hemodynamics [252]. Riociguat is also under investigation in other form of PH as PH associated with chronic obstructive pulmonary disease, with interstitial lung disease or with left ventricular dysfunction [253–255].

The Phase III, double-blind, randomized, placebo-controlled PATENT-1 study investigated the efficacy and safety of riociguat in patients with symptomatic PAH [256]. Treatment-naïve patients and patients pre-treated with ERAs or prostacyclin analogues were eligible. Riociguat was titrated from a starting dose of 1 mg three times daily (t.i.d.) [range 0.5–2.5 mg t.i.d.]. The primary outcome was the change from baseline in 6-MWD at week 12. Secondary endpoints included the change from baseline in pulmonary vascular resistance (PVR), NT-proBNP, NYHA FC, clinical worsening, living with PH questionnaire and Borg dyspnea score. A total of 445 patients were randomized. Preliminary analysis showed a significant increase in 6-MWD from baseline of 35.8 m with riociguat versus placebo (95% CI 20.1–51.5 m, p < 0.0001). Predefined exploratory analyses indicated that riociguat improved 6-MWD in pretreated patients (+35.7 m [95% CI 15.0–56.3 m]) as well as treatment naïve patients (+38.4 m [95% CI 14.5–62.3 m]). Significant improvements were also seen in PVR (p < 0.0001), NT-proBNP (p < 0.0001), functional class (p = 0.003), clinical worsening (p = 0.0046), living with PH questionnaire (p = 0.002) and Borg dyspnea score (p = 0.002). Riociguat was well tolerated and had a favorable safety profile. Thus, riociguat may represent a new treatment option for patients with PAH. An open-label extension study (PATENT-2) will evaluate the long-term safety of riociguat in patients with PAH.

Selexipag

Selexipag is an orally active prodrug metabolized to the highly selective prostacyclin IP receptor agonist ACT-333679 (previously known as MRE-269), which has a half-life of over 6 h [257]. With in high selectivity for the IP receptor over other prostanoid receptors (at least 130-fold selectivity), selexipag can be distinguished from beraprost or iloprost currently used in the management of PAH [258]. With no affinity for the prostaglandin E receptor 3 (EP3), selexipag exerts similar vasodilatory activity on both large and small pulmonary arterial branches [259] and its relaxant efficacy is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease such as ET-1 [260]. Preclinical study results showed that twice-daily administration of selexipag attenuates right ventricular hypertrophy, improves pulmonary hemodynamics, and significantly increases survival in MCT-treated PH rats [259].

A phase II study, involving 43 PAH patients showed that treatment with selexipag for 17 weeks conferred significant improvements in PVR (−30.3% versus placebo) compared with placebo [261]. Treatment with selexipag was well tolerated by most patients in this study. Adverse events were consistent with the known side effect profile of IPr agonism such as headache, pain in extremity, pain in jaw, nausea, and diarrhea. These side effects decreased over time in patients treated with selexipag [261].

A phase III randomized trial GRIPHON [262] to examine the effect of selexipag on morbidity and mortality in PAH is underway and will afford more information regarding efficacy and safety of selexipag.

Tyrosine kinase inhibitors

One of the most promising targets in PAH is platelet-derived growth factor (PDGF). PDGF has been implicated in endothelial cell dysfunction and proliferation and migration of smooth muscle cells. It has been suggested that PDGF may play a role in PAH [263–265]. Pulmonary vascular remodelling in different animal models of PAH was shown to regress with the administration of imatinib mesylate (Gleevec®), a PDGF receptors antagonist approved for the treatment of chronic myeloid leukaemia [266]. Moreover, case reports suggest a beneficial effect of imatinib among severe PAH patients and a first randomized (imatinib vs placebo), double-blind, 24 weeks Phase II study was performed in 59 PAH patients in NYHA functional class II to IV receiving specific PAH therapies [267]. The primary endpoint (6-MWD after 24 weeks) was not different between 2 groups (+22 m in imatinib group as compared to placebo) even if a significant improvement of hemodynamic parameters was observed, especially among the patients with the most severe hemodynamic compromise [267]. This preliminary study does not allow concluding on the potential benefits of imatinib in PAH, but led to development of a phase III clinical trial (IMPRES) evaluating imatinib in a randomized controlled double-blind trial of 24-week, in 202 severe PAH patients treated with at least two PAH specific drugs. After 24 weeks, a significant improvement in the primary endpoint, 6MWD, was observed (+32 m in imatinib group vs. placebo) as well as an improvement of secondary endpoints including hemodynamic parameters [268]. However, several cases of subdural hematoma were reported in patients treated with imatinib: 2 cases in the double-blind period of 24 weeks and 7 supplemental cases in an open-label extension phase of the study. The mechanism of these subdural hematomas is not elucidated and the high incidence observed may be partly favored by anticoagulation recommended for PAH patients. Subdural hematoma is a complication of imatinib previously reported in other settings where it has been used, including oncology or pulmonary fibrosis. Netherless, this complication has rarely been reported in previous clinical trials in PAH or in registries. In addition, it has been demonstrated that tyrosine kinase inhibitors, including imatinib, may have possible cardiac adverse effects on long term use that might limit its benefice in PAH [269]. According to these results, the benefit/risk ratio of imatinib in PAH was not considered to be sufficient and to date, the use imatinib was not recommended in PAH.

Balloon atrial septostomy

The presence of a right-left shunt, secondary to congenital cardiac malformation, or a patent foramen oval, among patients with severe PAH, seems to carry a better prognosis [270]. Atrioseptostomy is an artificial communication interauricular to decrease the right heart volume, subjected to a high after load secondary to increased pulmonary resistances [271]. The surgical creation of a right-left shunt decreases right auricular pressure and increases systemic blood flow, later on, reduction in right ventricular wall tension is expected [271]. Thus, in spite of arterial desaturation induced by the shunt, oxygen delivery is improved [271]. Atrioseptostomy has however never been studied in controlled clinical trials. However, several experienced teams reported their data and it seems that immediate mortality is high, reaching 14% during the first week, particularly in the case of severe desaturation and right heart failure [105, 271–273]. Among patients who survived, clinical improvement with regression of symptoms and gain of functional capacity can be observed. Atrioseptostomy should only be carried out in centers with significant experience, both in performance of atrioseptostomy and management of PAH patients, especially post interventional. The impact of balloon atrial septostomy on long term survival has not been established in RCTs [271, 274].

Lung transplantation

Lung transplantation was historically the treatment of choice for severe PAH and remains treatment of choice if medical treatments are insufficient [197]. However, this particularly heavy surgery can be proposed only to a minority of patients suffering from PAH. Moreover, long-term benefits remain disappointing with approximately 50% survival at 5 years [275]. Early mortality is mainly related to infectious complications whereas late mortality reflects mostly chronic rejection such as obliterating bronchiolitis. Mono-pulmonary transplantation had good long-term results [276, 277], but most centers currently prefer bi-pulmonary transplantation which has less post-operative complications [278]. Cardiopulmonary transplantation may be necessary for patients presenting with terminal right heart failure or complex congenital heart disease [279]. In conclusion, PAh is a rare group of diseases that shares broadly similar pathological features, pathophysiology and clincal presentation. The discovery of the central role of endothelial dysfunction leads to the development of specific PAH therapies including prostanoids, endothelin receptor antagonists and PDE-5 inhibitors. Even these therapeutic advances, no cure of the disease can be achieved and the prognosis remains unsatisfactory.