Pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a chronic and progressive disease leading to right heart failure and ultimately death if untreated. The first classification of PH was proposed in 1973. In 2008, the fourth World Symposium on PH held in Dana Point (California, USA) revised previous classifications. Currently, PH is devided into five subgroups.

Group 1 includes patients suffering from idiopathic or familial PAH with or without germline mutations. Patients with a diagnosis of PAH should systematically been screened regarding to underlying mutations of BMPR2 gene (bone morphogenetic protein receptor type 2) or more rarely of ACVRL1 (activine receptor-like kinase type 1), ENG (endogline) or Smad8 genes. Pulmonary veno occusive disease and pulmonary capillary hemagiomatosis are individualized and designated as clinical group 1′.

Group 2 ‘Pulmonary hypertension due to left heart diseases’ is divided into three sub-groups: systolic dysfonction, diastolic dysfonction and valvular dysfonction.

Group 3 ‘Pulmonary hypertension due to respiratory diseases’ includes a heterogenous subgroup of respiratory diseases like PH due to pulmonary fibrosis, COPD, lung emphysema or interstitial lung disease for exemple.

Group 4 includes chronic thromboembolic pulmonary hypertension without any distinction of proximal or distal forms.

Group 5 regroup PH patients with unclear multifactorial mechanisms. Invasive hemodynamic assessment with right heart catheterization is requested to confirm the definite diagnosis of PH showing a resting mean pulmonary artery pressure (mPAP) of ≥ 25 mmHg and a normal pulmonary capillary wedge pressure (PCWP) of ≤ 15 mmHg.

Definition and classification

Pulmonary arterial hypertension (PAH) is defined by right-heart catheterization (RHC) showing precapillary pulmonary hypertension with a mean pulmonary artery pressure (mPAP) of >25 mmHg and a normal pulmonary artery wedge pressure (PCWP) of <15 mmHg [1,2]. The classification of pulmonary hypertension (PH) has gone through a series of changes since the first classification proposed in 1973 which designated only two categories, primary pulmonary hypertension or secondary PH, depending on the presence or absence of identifiable causes or risk factors [3,4]. In 1998, a second World Symposium on PH was held in Evian (France) and this classification attempted to create categories of PH that shared similar pathogenesis, clinical features and therapeutic options [5]. This classification allowed defining homogenous groups of patients to conduct clinical trials and to obtain approval for specific PAH therapies worldwide. In 2003, the third World Symposium on PH (Venice, Italy) did not propose major changes. However, the terms idiopathic PAH, familial PAH, and associated PAH were introduced. The other prominent change was to move pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from separate categories into a single subcategory of PAH.

In 2008, the fourth World Symposium on PH held in Dana Point (California, USA) and the consensus of an international group of experts was to revise previous classifications in order to accurately reflect published data, as well as to clarify some areas that were unclear. In 2013, the fifth World Symposium on PH held in Nice (France) and proposed only minor modifications, however, since the definite conclusions of this symposium were not yet published, we presented the Dana Point classification of PH (Table 1).

Table 1

Table 1

Diagnostic classification of pulmonary hypertension

1. Pulmonary arterial hypertension (PAH)1.1 Idiopathic
1.2 Heritable
1.3 Drugs and toxins induced
1.4 Associated with (APAH):
  1.4.1 Connective tissue disease
  1.4.2 Infection with human immunodeficiency virus
  1.4.3 Portal hypertension
  1.4.4 Congenital heart disease
  1.4.5 Schistosomiasis
  1.4.6 Chronic haemolytic anaemia
1.5 Persistent pulmonary hypertension of the newborn
2. Pulmonary hypertension with left heart disease2.1 Systolic dysfunction
2.2 Diastolic dysfunction
2.3 Valvular disease
3. Pulmonary hypertension due to lung diseases and/or hypoxia3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental abnormalities
4. Chronic thromboembolic pulmonary hypertension 
5. PH with unclear and/or multifactorial mechanisms5.1 Haematological disorders: myeloproliferative disorders, splenectomy.
5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis
This classification was adapted from (Simonneau et al. [16])

Epidemiology

Information relative to the natural history of PAH was derived from a national registry conducted in the USA in the early 1980s, which included 187 patients with idiopathic PAH followed for up to 5 years. This study characterized the disease and confirmed its poor prognosis with a median survival of 2.8 years [105,106]. Better understanding of pathophysiological mechanisms of PAH has led to the development of novel therapeutic strategies in the last decade which improved quality of life, exercise capacity and survival of these PH patients [107].

In France, a national multicenter registry prospectively collected data from 674 adults with PAH from October 2002 to October 2003 and followed these patients during a 3-year period [108]. This prospective study has shown more up to date data on the epidemiology of PAH. This registry has confirmed the female predominance in most subtypes of PAH with a female/male sex ratio (SR) of 1.9 for all PAH patients, and particularly in idiopathic PAH (SR 1.6), familial PAH (SR 2.2) and anorexigen-associated PAH (SR 14.9) [108]. The mean age of PAH patients in this cohort was 50 years with a quarter of patients older than 60 years underlining the possibility of developing PAH in all ages. In this assessed cohort, 39.2% of patients had idiopathic PAH and 3.9% familial PAH. In the subgroup of PAH, where PAH was associated with other conditions, 15.3% had connective tissue disease, 11.3% congenital heart diseases, 10.4% portal hypertension, 9.5% anorexigen-related PAH and 6.2% HIV infection [108]. In France, the low estimation of the prevalence of PAH and idiopathic PAH are respectively of 15 cases and 5.9 cases/million adult inhabitants. The low estimation of PAH incidence is 2.4 cases/million adult inhabitants/year. This study conducted five years after the withdrawal of fenfluramine derivatives underlines that anorexigen-associated PAH remains an important medical problem nowadays.

Recent prospective data in consecutive patients with idiopathic, familial or anorexigen-associated PAH patients followed-up for a period of three years (56 incident and 298 prevalent cases) showed better survival rates than historical cohort. For incident cases, estimated survival rates were 85.7%, 69.6% and 54.5% at one, two and three year of follow-up, respectively. In combined mixed population (incident patients and prevalent patients diagnosed within three years before study entry), estimated one, two and three year survival was 82.9%, 67.1% and 58.2%, respectively. Parameters significantly associated to improved survival were female gender, preserved 6-MWD and normal cardiac output on RHC [109].

Data from the REVEAL registry (US Registry to Evaluate Early and Long-Term PAH Disease Management) are similar concerning the one year survival rate estimated to 91%. Variables independently associated with increased mortality included pulmonary vascular resistance >32 Wood units, NYHA functional class IV, men older than 60 years and familiy history of PAH [110].

Genetics

It is now well known that PAH can be either sporadic or clustered in families [111-114]. In 1954, Dresdale published a detailed description of a family that included three related subjects with severe PAH of unknown aetiology. Because of physician’s awareness of the familial occurrence of the disease, other cases of familial PAH were described. The National Institute of Health Registry (NIH Registry) provided the first estimate of this condition, and evaluated that at least 6% of individuals diagnosed with sporadic PAH have a family history of the disorder. In the French PAH registry, 26 cases of familial PAH were identified in the cohort of 674 patients, which corresponds to a prevalence of 3.9% of all cases of PAH and a proportion of 7.3% of familial PAH in the subgroup of idiopathic, familial or anorexigen-associated PAH [108].

Studies of genealogies of familial PAH advanced our understanding that the disease segregates an autosomal dominant trait with a markedly reduced penetrance, since only 10-20% of necessary carriers of the mutation will develop PAH [115,116]. In 2000, linkage analysis in PAH affected families found mutations within the bone morphogenetic protein receptor type 2 gene (BMPR2) [117,118]. BMPR2 gene encodes for a type 2 receptor member of the transforming growth factor beta (TGF-β) family. Nowadays, germline BMPR2 mutations are detected in 58-74% of PAH patients with a family history of the disease, and in 3.5-40% of so called idiopathic PAH patients [6,11,108,119-123]. The observation of the development of PAH in patients displaying hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vascular dysplasia, allowed us to identify two other PAH predisposing genes: ACVRL1 (Activin A receptor type II-like kinase 1) and ENG (endoglin) genes. Mutations in these two genes are infrequent in PAH but are frequently identified in HHT [120,124-130].

Moreover, recent reports described two PAH patients carriers of a mutation in Smad8 gene, one PAH patient carrier of a Smad1 mutation and one PAH patient carrier of a Smad5 mutation [8,9]. BMPR2 gene, ACVRL1, ENG, Smad8, Smad1 and Smad5 genes are encoding proteins which are involved in the TGF-β signaling pathway. More recently, using whole exome sequencing in a large PAH family, Austin et al. demonstrated the involved of mutations in caveolin-1 gene in the development of PAH [10] They confirmed their findinds identifying a caveolin-1 mutation in an unrelated PAH patient. Caveolin-1 protein is necessary for the formation of calveola, which are crucial for joining membrane receptors and initiating cellular signaling cascade such as TGF-β signalling pathway. This supports the hypothesis that mutations in genes involved in the TGF-β signaling pathway may be a trigger for pulmonary vascular remodeling. Moreover, this signaling pathway controls growth, differentiation and apoptosis of various cell types like pulmonary vascular endothelial cells (ECs) and smooth muscle cells (SMCs). Thereby, mutations in genes involved in the TGF-β signaling pathway may be responsible for abnormal proliferation of pulmonary vascular SMCs and may promote ECs apoptosis, which might lead to the selection of apoptosis resistant cells and formation of plexiform lesions, the hallmark of idiopathic PAH [131,132].


Pathophysiology

PAH is a disease which affects small pulmonary arteries. It is characterized by vascular obstruction leading to progressive increase in vascular resistance. This increases right ventricular afterload and consequently results in right ventricular failure. Intima and media proliferation and its consequent pulmonary vascular obstruction are considered to be the key element in the pathogenesis of PAH. Vasoconstriction, vascular remodeling and thrombosis are factors that increase pulmonary vascular resistance in PAH [107,137]. These processes involve a multitude of cellular and molecular elements (Figure 1).

Figure 1
Pathophysiology of PAH.
 The pulmonary vascular remodeling responsible for PAH is the consequence of closely intertwined predisposing and acquired factors. Thoses pathological elements affect all three layers of precapillary pulmonary arteries leading to intimal hyperplasia, medial thickening and adventitial remodeling/fibrosis. Intra- but also extra-pulmonary cells, such as inflammatory and progenitor cells, are suspected to play a role in this remodeling. This increases right ventricular afterload and consequently results in right ventricular failure.

Cellular factors

Proliferation of smooth muscular cells in the small peripheral pulmonary arteries is a common characteristic in all forms of PAH. In hypoxic models, fibroblasts of the adventitia migrate to the media and intima, where proliferation and production of matrix proteins are observed [138]. Neovascularization, mainly of the adventitia, occurs concomitantly to the thickening of the vascular walls [139].

In response to certain stimuli, endothelial cells abnormally proliferate to form plexiform lesions in several forms of PAH. Plexiform lesions consist of endothelial cells, matrix proteins and fibroblasts and obliterate the vascular lumen [140]. The stimuli for endothelial proliferation is still unknown but several factors have been incriminated such as hypoxia, inflammation, shear stress, drugs, viral infections and genetic susceptibility. Extrapulmonary cells may also participate in the vascular remodeling responsible for PAH. Indeed, fibrocytes and c-kit + cells are mobilized from the bone marrow, and may differentiate into vascular cells and/or produce pro-angiogenic factors to participate in the pathogenesis of PAH [141,142]. The CXCL12/CXCR4 axis may play an important role in the pulmonary recruitment of these circulating progenitors and can be therapeutically targeted [143].

Molecular factors

Many authors consider pulmonary vasoconstriction as an early event in the process of PAH. Vasoconstriction has been associated with an abnormal function or expression of potassium channels and with endothelial dysfunction [107]. Endothelial dysfunction results in a decreased production of vasodilators such as nitric oxide (NO) and prostacyclin and an increased production of vasoconstrictors such as endothelin-1 [153].

Prostacyclin (prostaglandin I2) is a potent pulmonary vasodilator that acts via the cyclic adenosine monophosphate (cAMP) pathway. It inhibits the proliferation of smooth muscle cells and decreases platelet aggregation. Production of prostacyclin is reduced in endothelial cells of patients with PAH [154]. PAH therapy based on prostacyclin and its derivates have proven efficacy both hemodynamically and in clinical trials. NO is also a pulmonary vasodilator which acts via the cyclic guanosine monophosphate (cGMP) pathway. To increase pulmonary vasodilatation dependant on NO, a recent therapeutic strategy has targeted type 5 phosphodiesterase which degrades cGMP. Sildenafil or tadalafil, type 5 phosphodiesterase inhibitors, have proven their efficacy in patients with PAH [155]. Vasoactive intestinal peptide (VIP) is a neurotransmitter that has systemic and pulmonary vasodilator properties. It also inhibits smooth cell proliferation and decreases platelet aggregation and acts via the activation of the cAMP and cGMP systems [156]. Low plasmatic concentrations of VIP have been measured in pulmonary arteries of patients with PAH.

Histopathology: vascular changes

Vascular remodelling in pulmonary arterial and venous hypertension typically involves the small pulmonary vessels. Muscular arteries of less than 500 μm display a thickening within the intimal, medial and adventitial compartment. When involved, pulmonary veins of the interlobular septa and smallest preseptal venules show fibrous obliteration and / or muscularization. Even the smallest vascular level may be involved: patients with pulmonary venous hypertension frequently present focal proliferation of alveolar capillaries. The different histological pattern is presented here below.

Arterial lesions

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.

Figure 2
Pulmonary arteries of the muscular type displaying obstructive arteriopathy in lungs of patients with PAH. A Medial hypertrophy with smooth muscle cell proliferation and pronounced adventitial fibrosis. Magnification x200, Weigert-hematoxylin-phloxine-saffron staining (WHPS). B Concentric non-laminar intimal fibrosis comprising numerous myofibroblasts (arrows). C Eccentric intimal fibrosis corresponding to organized thrombotic material. Br: bronchus, Ar: pulmonary artery. Magnification x100, HES staining. D Thrombotic lesion, so called “colander-like lesion”, with partial recanalization by microvessels. Note the similarity to plexiform lesions (F). Magnification x100, HES. E Concentric laminar intimal fibrosis, so called „onion-skin lesion“. Magnification × 200, HES. F Plexiform lesion with proliferation of small sinusoid-like vessels on a fibrotic matrix. Note surrounding dilated vessels. Magnification x100, HES. G Multiple dilation lesions being the sentinel of the centrally located plexiform lesion. Magnification × 40, Elastica-van-Gieson staining (EvG). H The same plexiform lesion after immunohistochemical staining with anti-CD3, a T-lymphocytic marker. Note the perivascular distribution of the inflammatory infiltrate. Magnification x100.

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).

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). 

Figure 3
Pulmonary veins with obstructive venopathy in lungs of patients with PVOD and a case of pulmonary capillary hemangiomatosis. A Longitudinally dissected septal vein with asymmetric intimal and partially occlusive fibrosis. Note the intra-alveolar hemorrhage due to the post-capillary block on the upper half of the photograph. Magnification × 100, EvG. B Pre-septal venule with occlusive intimal fibrosis. Magnification × 100, EvG. C Bronchio-alveolar lavage in a PVOD-patient. Perls-Prussian-Blue staining. Note the siderophages displaying gradually different color-shades (see text). Magnification × 400. D Excessively proliferating alveolar capillaries in a patient with pulmonary capillary hemangiomatosis. Note protrusion of ectatic lumina into the alveoli. Magnification × 200, anti-CD31 staining.

Clinical description

Symptoms and clinical signs of PH

There is no pathognomonic clinical sign of PH. Clinical presentation is related either to right heart failure or to associated diseases. Persistant dyspnea on exertion is the most frequent symptom; and it is present in almost patients even in the presence of mild hemodynamic abnormalities [1,182]. Dyspnea usually starts insiduously and is often neglected by patients which explain the delay of around two years in establishing the diagnosis of PH. The New York Heart Association (NYHA) provides a classification system for the clinicial evaluation of dyspnoea. Four categories are proposed to classify patients in functional classes (FC) based on how much they are limited during physical activity; the limitations/symptoms are in regard to normal breathing (Table 3).

Table 3

Modified New York Heart Association (NYHA) classification for pulmonary hypertension

CLASS IPatients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope.
CLASS IIPatients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain, or near syncope.
CLASS IIIPatients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain, or near syncope.
CLASS IVPatients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.

However, at time of diagnosis, 70% of patients are in NYHA FC III or IV. Chest pain, light-headedness and syncope may occur, particularly during physical efforts and are major signs of disease severity. Palpitations are frequent during physical efforts and may reveal true cardiac arrhythmias. Other symptoms of PAH include fatigue and weakness. Hemoptysis may complicate PAH and could be life-threatening, justifying embolization of dilated bronchial arteries. Hoarseness of the voice may occasionally be noted and is due to compression of the left laryngeal nerve by the dilated pulmonary artery (Ortner’s syndrome).

Diagnostic methods

The diagnostic process of PAH requires a series of investigations that are intended to make the diagnosis, to clarify the clinical class of PH and the underlying type of PAH and to evaluate the functional and hemodynamic impairment [183]. The detection of PH requires investigations including electrocardiogram, chest radiograph and trans-thoracic echocardiogram. Other conditions which can induce PH will be identified by tests such as pulmonary function tests, arterial blood gases, ventilation and perfusion lung scan, high resolution computed tomography (HR-CT) of the chest and pulmonary angiography. Additional investigations are required for evaluation of PAH severity including exercise testing and hemodynamics. Additional imaging may clarify underlying lung abnormalities. Finally, right heart catheterisation confirms the definite diagnosis.

Management of PAH

General measures

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].

Non specific drugs

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].

Calcium channel blockers

Calcium channel blockers (CCB) are indicated in patients with a positive vasodilatation challenge test after inhaled NO. CCB are vasodilators and were initially introduced in the 1980’s as part of PAH therapy to counteract vasoconstriction that has traditionally been assumed to be a preponderant mechanism in PAH. In the 1990’s, Rich and colleagues showed in an open prospective study that high dose of calcium channel blockers (nifedipine 90 to 240 mg/day or diltiazem 360 to 900 mg/day) significantly improve prognosis in patients with an acute vasodilation response [203]. Sitbon et al. showed that only 12.6% out of the patients could be treated by CCB according to criteria’s establish by Rich and co-workers [203]. Moreover, only half of them maintained actual long-term benefit defined as NYHA FC I or II at one year without the need for additional treatment [205]. In this study, a decrease in mean PAP > 10 mmHg to reach a value < 40 mmHg, with a stable or increased cardiac output, during acute vasodilator test was predictive of long-term response to CCB. Contrarily, CCB must be avoided in the absence of acute vasoreactivity because of the risk of significantly reduced cardiac output and systemic blood pressure [205]. The choice of CCB is based upon the patient’s heart rate; nifedipine and amlodipine were preferred in the presence of relative bradycardia and diltiazem in the presence of tachycardia. Doses of CCB used in this setting are relatively high, 120-240 mg de nifedipine, 240-270 mg for diltiazem, and up to 20 mg for amlodipine [15]. If the patient does not show a correct response (NYHA FC I or II with marked hemodynamic improvement), additional PAH specific therapy should be added. Of note, CCB is contraindicated in PVOD because of the high-risk of life threatening pulmonary edema, even in the presence of acute vasodilator response that can be observed in the same proportion as in idiopathic PAH [53].

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 [107,225228]. 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 [229231]. 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.


Authors’ contributions

DM, SG, PD, FP, BG, GG, XJ, LS, EAM, LCP, MH, GS, OS participated in drafting the manuscript. All authors read and approved the final manuscript.


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