State of the art: pulmonary hypertension

Victor J. Samillan, Andrew J. Peacock
Breathe 2014 10: 188-197; DOI: 10.1183/20734735.001214

Abstract

Key points

  • Pulmonary arterial hypertension is still a chronic and incurable disease

  • The most common mutation found in familial pulmonary arterial hypertension is a defect in the bone morphogenetic protein receptor 2 gene

  • Usually the final stage of the disease is right heart failure

Educational aims

  • To provide definitions and diagnostic methods for pulmonary hypertension

  • To provide a general classification of pulmonary hypertension

  • To provide an overview of the currently available treatments

  • To provide a future vision of next-generation treatments

Introduction

Pulmonary hypertension (PH) is characterised by an elevated pulmonary arterial pressure (PAP). PH can occur in a number of diseases and can lead to right ventricular hypertrophy and right heart failure. This arises because the right ventricle initially adapts to the afterload with increasing wall thickness and contractility but these compensatory factors are eventually insufficient and the patients die from right heart failure. The problem may be due to abnormalities in the pulmonary arteries (and thus termed pulmonary arterial hypertension (PAH)) or due to other causes (and termed PH).

One group of patients develop the disease due to a mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene. This receptor is a member of the transforming growth factor-β family and mutations were first described in a group with familial pulmonary arterial hypertension (FPAH) [1, 2]. Subsequently, the mutation was also found in some patients with idiopathic PAH without a history of FPAH [3].

Exposure to hypoxia is an important cause of PH. Acute exposure to hypoxia causes PH, which is a factor in high-altitude pulmonary oedema. Exposure to chronic hypoxia occurs in the inhabitants of locations at high altitude and also in patients with lung diseases such as chronic obstructive pulmonary disease (COPD), interstitial lung disease and sleep apnoea, and leads to chronic hypoxic PH [4].

Definition and classification

The definition of PH is an increase of the mean PAP at rest measured during right heart catheterisation (>25 mmHg). To make a diagnosis of PAH, patients must also have a pulmonary capillary wedge pressure <15 mmHg. This is an indirect method of measurement of the left atrial pressure using a balloon inflated in the pulmonary artery. Normal or low left atrial pressure excludes left heart disease. Right heart catheterisation is still necessary for the diagnosis of PH and needs to be standardised to ensure the same diagnostic criteria are applied to every patient. Patients with a PAP between 21 and 24 mmHg should be monitored carefully but we need to avoid using the term “borderline PH”, because these patients do not have PH [5].

PH was originally classified into two different groups, primary PH and secondary PH, depending on the causes and the risk factors for developing the disease [6]. At the Second World Symposium on Pulmonary Hypertension held in Evian in 1998, a new classification was proposed, which takes into account the different features of the diseases such as haemodynamic characteristics and pathological findings. Five different groups were designated: 1) PAH; 2) PH due to dysfunction of the left heart; 3) PH due to chronic lung disease and/or hypoxia; 4) chronic thromboembolic pulmonary hypertension (CTEPH); and 5) PH due to unclear mechanisms. During the recent world symposium in Nice in 2013, this classification remained broadly unchanged, except for small changes in the subclassification in each group (table 1) [7].

View this table:
Table 1 Updated clinical classification of pulmonary hypertension#

Diagnostic methods

The diagnosis of PH requires several steps, both to identify the presence of the disease and to discover its cause. One of the most difficult problems is that PH is often a multifactorial disease and we need to identify the principal cause. A summary of the process of diagnosis is shown in figure 1.

Figure 1
Figure 1

Diagnostic algorithm. PH: pulmonary hypertension; group: clinical group; TTE: transthoracic echocardiography; PFT: pulmonary function test; HRCT: high-resolution computed tomography; V/Q: ventilation/perfusion; CTEPH: chronic thromboembolic pulmonary hypertension; PVOD: pulmonary veno-occlusive disease; PCH: pulmonary capillary haemangiomatosis; RHC: right heart catheterisation; PAH: pulmonary arterial hypertension; mPAP: mean pulmonary arterial pressure; PWP: pulmonary wedge pressure; ANA: anti-nuclear antibodies; TEE: trans-oesophageal echocardiography; CMR: cardiac magnetic resonance; US: ultrasonography; LFT: liver function test; CTD: connective tissue disease; CHD: congenital heart disease; BMPR2: bone morphogenetic protein receptor 2; ALK1: activin receptor like kinase; HHT: hereditary haemorrhagic telangiectasia. Reproduced from [8] with permission from the publisher.

Clinical presentation

The most common clinical features are breathlessness and fluid retention without other cause. Breathlessness is usually quantified, and the classification system is shown in table 2. Unfortunately, because of the late diagnosis (>2 years), the symptoms often appear when the patients are in the final stage of the disease. This may be one of the reasons why the treatments do not have a high rate of success in all patients.

View this table:
Table 2 World Health Organization functional assessment classification

ECG

An ECG often gives us the first suggestion of the disease. Classical changes are right ventricular hypertrophy and strain. Right ventricular hypertrophy is found in 87% of the patients and right axis deviation in 79% of the patients with idiopathic PAH. An ECG is not a good enough tool for determining the subgroups of this disease; therefore, additional diagnostic tests are needed [8].

Echocardiography

Echocardiography is a widely available and noninvasive tool that gives us data about the presence of PH (through the presence of an increased tricuspid regurgitation, jet velocity and right ventricular dilation) and also the cause (intracardiac shunts or heart abnormalities), but is insufficiently accurate as a stand-alone measurement [10].

Chest radiography

Chest radiography may suggest the presence of PH (enlarged pulmonary artery and right ventricle) and may also suggest causes (presence of lung disease or heart dysfunction), but is also insufficient for diagnosis on its own [8].

Pulmonary function tests and arterial blood gases

Pulmonary function tests and arterial blood gas measurements are useful for identifying any abnormalities suggesting obstructive (COPD or asthma) or restrictive pulmonary disease (interstitial lung disease or chest wall abnormalities). The use of polysomnography allows a diagnosis of sleep apnoea. All these conditions can lead to PH (group 3) [8].

Right heart catheterisation and vasoreactivity

Right heart catheterisation is an intervention that is mandatory for confirmation of PH. It is performed at specialised centres. The test can confirm the severity of the PH, check for vasoreactivity and enable performance of pulmonary angiography if CTEPH is suspected. Several variables are recorded, such as cardiac output, right atrial pressure, right ventricular pressure, PAP and pulmonary artery occlusion pressure (wedge pressure) [11]. A test of vasoreactivity is performed in order to identify patients who would be candidates for calcium channel blockers. Normally, patients are given a pulmonary vasodilator such as inhaled nitric oxide and measurements are made of PAP and cardiac output. A positive test is said to have occurred when mean PAP is <40 mmHg with a rise or no change in cardiac output.

Treatments

Most of the treatments that we have available at the moment are focused on vasodilatation and a few are focused on reversing the vascular remodelling. All these treatments are used with the aim of improving certain outcomes, such as 6-min walking distance (6MWD) and right heart function, normalisation of the haemodynamic variables and change in biomarkers such as N-terminal pro-brain natriuretic peptide [12, 13].

There are three main classes of treatments: 1) endothelin receptor antagonists; 2) phosphodiesterase type 5 inhibitors [13]; and 3) prostacyclins. Two new classes of drugs, the guanylate cyclase activators and prostacyclin analogues, are just becoming available or trials are finishing and the results are awaited. A summary of treatments is shown in figure 2.

Figure 2
Figure 2

Treatment algorithm. IPAH: idiopathic pulmonary arterial hypertension; APAH: associated pulmonary arterial hypertension; WHO-FC: World Health Organization functional class; CCB: calcium channel blockers; FDA: US Food and Drug Administration; CHMP: Committee for Medicinal Products for Human Use; EMA: European Medicines Agency; s.c.: subcutaneous; ERA: endothelin receptor antagonist; PDE-5i: phosphodiesterase type 5 inhibitor; sGCS: soluble guanylate cyclase stimulators; BAS: balloon atrial septostomy. Reproduced from [14] with permission from the publisher.

Endothelin receptor antagonists

An increase in endothelin is seen in patients with PAH, although it is not known whether this is the cause or an effect of PAH [15]. There are two main endothelin receptors, A and B. Blocking endothelin receptors blocks the vasoconstrictor and mitogenic effects of endothelin. Bosentan and macitentan are dual receptor blockers, while ambrisentan is predominantly a B receptor blocker.

Ambrisentan

Ambrisentan is a nonsulfonamide propanoic acid class drug that exerts its dominant function at the level of endothelin receptor type A [14]. In the two ARIES studies (Ambrisentan in Pulmonary Arterial Hypertension, Randomised, Double-Blind, Placebo-Controlled, Multicentre, Efficacy Study), ambrisentan resulted an improvement in 6MWD in patients with idiopathic PAH and PAH associated with HIV and connective disease [16].

Bosentan

Bosentan was the first endothelin receptor inhibitor to be synthesised. Bosentan works at the level of endothelin receptors A and B. There have been five different clinical trials of bosentan. These showed improvement in different clinical outcomes, such as exercise capacity, functional class, haemodynamics and time to clinical worsening [17]. In approximately 10% of patients, treatment with bosentan caused an increase of aminotransferases. For this reason, all patients must have monthly liver function tests [14].

Macitentan

Macitentan was developed using bosentan as a model. The basic molecule of bosentan was modified to improve the action and efficacy. Macitentan has a better tissue penetration and more sustained receptor binding than bosentan. Macitentan improved the morbidity/mortality end-point in patients with PAH, in the large clinical trial SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) [18].

Phosphodiesterase type 5 inhibitors

Sildenafil

Sildenafil is the most common drug used for the treatment of PH. This was studied in the clinical trial SUPER-1 (Sildenafil Use in Pulmonary Arterial Hypertension), leading to approval by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Sildenafil is a potent phosphodiesterase 5 inhibitor that improves 6MWD and haemodynamics. The dose approved for PAH is 20 mg three times per day. Side-effects include vasodilation (flushing, headache and epistaxis) [19, 20].

Tadalafil

Tadalafil is a once-daily phosphodiesterase 5 inhibitor that produces an improvement in the exercise capacity, symptoms, time of clinical worsening and haemodynamic variables at a dose of 40 mg daily. The side-effects are similar to those of sildenafil [21].

Selexipag

Selexipag is a prostacyclin analogue that attaches to the prostacyclin receptor (IP receptor). Selexipag exerts its effect through the activation of this receptor and production of cAMP. The release of this molecule produces vasorelaxation [26]. The headline results have recently been released for a large study of selexipag in PAH (GRIPHON (Prostacyclin (PGI2) Receptor agonist In Pulmonary arterial HypertensiON)).

Prostacyclins

Prostanoids are naturally released from endothelial cells and induce vasodilatation of systemic and pulmonary vasculature and also show cytoprotective and anti-proliferative effects [8].

Epoprostenol

Epoprostenol was tested in three clinical trials in patients with idiopathic PAH and patients with PAH related to scleroderma and resulted in an improvement in the different outcomes, such as exercise capacity and haemodynamics. The route of administration for epoprostenol is intravenous. For this reason, serious adverse effects often relate to the delivery system, e.g. pump malfunction, local site infection and catheter obstruction [14].

Iloprost

Iloprost is a prostacyclin analogue that can be given by i.v. or inhaled routes. The administration of inhaled iloprost was tested in the clinical trial AIR (Aerosolised Iloprost Randomised), where it was shown that inhaling iloprost six times per day (2.5–5 μg per inhalation) improved the 6MWD [22].

Treprostinil

Treprostinil is an epoprostenol analogue that is stable at room temperature. Treprostinil can be administrated subcutaneously and orally. Several clinical trials have shown the efficacy of treprostinil. Administration by the i.v. route was approved in the USA and Europe in patients with PAH who cannot tolerate subcutaneous administration. Currently, the oral version of treprostinil is not approved for use in patients with PAH [14].

New classes of treatment: guanylate cyclase activators and prostacyclin analogues

Riociguat

Riociguat is a guanylate cyclase activator that has recently been approved by the FDA in patients with PAH and was launched on the market in April 2014. The difference between this drug and the phosphodiesterase 5 inhibitors is that riociguat enhances cGMP production whereas the phosphodiesterase 5 inhibitors prevent the breakdown of cGMP [23]. Riociguat works in combination with the available nitric oxide [24, 25]. Riociguat has shown anti-proliferative and anti-hypertrophy effects in different animal models.

The future

During recent years, it has become clear that, although symptoms and survival in PAH are much improved, we still do not have a cure for the disease. The future looks very promising, with newer pharmacological treatments that are either anti-inflammatory or anti-remodelling or both.

We now know that inflammation may contribute to PH and some groups of investigators are focusing on anti-inflammatory treatments. For example, some groups have been looking at cytokine pathways following the observation that interleukin-6 knockout mice do not develop PH [27].

We also know that remodelling of the pulmonary artery and right ventricle are the most important and challenging features when treating patients with PH. For this reason, we need to try to find treatments to stop the remodelling. A number of laboratories are examining the cellular processes that accompany pulmonary vascular remodelling. Our own laboratory has been investigating the role of stress kinases such as mitogen-activated protein kinase kinases. In the future we may be able to block their action and reverse the remodelling [28].

Educational questions

  1. How high must mean PAP be to make a diagnosis of PH?

    1. 15 mmHg

    2. 25 mmHg

    3. 120 mmHg

    4. 150 mmHg

  2. What is the most common cause of PH?

    1. Cigarette smoke

    2. Hypoxic lung diseases

    3. Mutation of the BMPR2 gene

    4. Anorexigens

  3. Which groups of PH respond to vasodilator therapy?

    1. Group I

    2. Group II

    3. Group III

    4. Group IV

    5. Group V

  4. Which is the most important end-point used to determine the benefits of PAH therapy?

    1. Improvement in the right ventricle function

    2. Improvement in the 6MWD

    3. Improvement in the breathlessness score

    4. Improvement in pulmonary haemodynamics

Suggested answers

  1. b

  2. b

  3. a

  4. a

Footnotes

  • Statement of Interest

    Andrew J. Peacock has received grants from Actelion and Bayer, and personal fees from Actelion, Bayer and GSK, outside of this work. Victor J. Samillan has received a long-term fellowship from the European Respiratory Society.

Breathe articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

References

  1. ↵
    1. Thomson JR,
    2. Machado RD,
    3. Pauciulo MW,
    4. et al
    . Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-β family. J Med Genet 2000; 37: 741–745.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Machado RD,
    2. Pauciulo MW,
    3. Thomson JR,
    4. et al
    . BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 2001; 68: 92–102.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Machado RD,
    2. Aldred MA,
    3. James V,
    4. et al
    . Mutations of the TGF-β type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 2006; 27: 121–132.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Dempsey JA,
    2. Veasey SC,
    3. Morgan BJ,
    4. et al
    . Pathophysiology of sleep apnea. Physiol Rev 2010; 90: 47–112.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Hoeper MM,
    2. Bogaard HJ,
    3. Condliffe R,
    4. et al
    . Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013; 62 Suppl. 25:D42–D50.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Simonneau G,
    2. Galiè N,
    3. Rubin LJ,
    4. et al
    . Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43 Suppl. 12:5S–12S.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Simonneau G,
    2. Gatzoulis MA,
    3. Adatia I,
    4. et al
    . Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62 Suppl. 25:D34–D41.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Galiè N,
    2. Hoeper MM,
    3. Humbert M,
    4. et al
    . Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30: 2493–2537.
    OpenUrlFREE Full Text
    1. Rubin LJ
    American College of Chest PhysiciansDiagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126 Suppl. 1:7S–10S.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Fisher MR,
    2. Forfia PR,
    3. Chamera E,
    4. et al
    . Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med 2009; 179: 615–621.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Paulus WJ,
    2. Tschöpe C,
    3. Sanderson JE,
    4. et al
    . How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007; 28: 2539–2550.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. McLaughlin VV,
    2. Gaine SP,
    3. Howard LS,
    4. et al
    . Treatment goals of pulmonary hypertension. J Am Coll Cardiol 2013; 62 Suppl. 25:D73–D81.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Peacock AJ,
    2. Crawley S,
    3. McLure L,
    4. et al
    . Changes in right ventricular function measured by cardiac magnetic resonance imaging in patients receiving pulmonary arterial hypertension-targeted therapy: the EURO-MR study. Circ Cardiovasc Imaging 2014; 7: 107–114.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Galiè N,
    2. Corris PA,
    3. Frost A,
    4. et al
    . Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013; 62 Suppl. 25:D60–D72.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Stewart DJ,
    2. Levy RD,
    3. Cernacek P,
    4. et al
    . Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease?. Ann Intern Med 1991; 114: 464–469.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Galiè N,
    2. Olschewski H,
    3. Oudiz RJ,
    4. et al
    . Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008; 117: 3010–3019.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Channick RN,
    2. Simonneau G,
    3. Sitbon O,
    4. et al
    . Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358: 1119–1123.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Pulido T,
    2. Adzerikho I,
    3. Channick RN,
    4. et al
    . Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369: 809–818.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Galiè N,
    2. Ghofrani HA,
    3. Torbicki A,
    4. et al
    . Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353: 2148–2157.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Vachiery JL,
    2. Huez S,
    3. Gillies H,
    4. et al
    . Safety, tolerability and pharmacokinetics of an intravenous bolus of sildenafil in patients with pulmonary arterial hypertension. Br J Clin Pharmacol 2011; 71: 289–292.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Pepke-Zaba J,
    2. Beardsworth A,
    3. Chan M,
    4. et al
    . Tadalafil therapy and health-related quality of life in pulmonary arterial hypertension. Curr Med Res Opin 2009; 25: 2479–2485.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Olschewski H,
    2. Simonneau G,
    3. Galiè H
    . Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347: 322–399.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Giaid A,
    2. Saleh D
    . Reduced expresion of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333: 214–221.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Ghofrani HA,
    2. Simonneau G,
    3. Rubin LJ,
    4. et al
    . Riociguat for pulmonary hypertension. N Engl J Med 2013; 369: 2266–2268.
    OpenUrlCrossRef
  25. ↵
    1. Cannon JE,
    2. Pepke-Zaba J
    . Riociguat for pulmonary hypertension. Expert Rev Clin Pharmacol 2014; 7: 259–270.
    OpenUrlPubMed
  26. ↵
    1. Simonneau G,
    2. Torbicki A,
    3. Hoeper MM,
    4. et al
    . Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J 2012; 40: 874–880.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    1. Savale L,
    2. Tu L,
    3. Rideau D,
    4. et al
    . Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res 2009; 10: 6.
    OpenUrlCrossRefPubMed
  28. ↵
    1. Mortimer HJ,
    2. Peacock AJ,
    3. Kirk A,
    4. et al
    . p38 MAP kinase: essential role in hypoxia-mediated human pulmonary artery fibroblast proliferation. Pulm Pharmacol Ther 2007; 20: 718–725.
    OpenUrlCrossRefPubMed
View Abstract
Back to top
Email
Print
Alerts
Citation Tools

State of the art: pulmonary hypertension
Victor J. Samillan, Andrew J. Peacock
Breathe Sep 2014, 10 (3) 188-197; DOI: 10.1183/20734735.001214
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To

Subjects