European Respiratory Society
Pulmonary Hypertension

Pulmonary hypertension plays an increasingly important role in contemporary medicine. It may present as discrete disease or as complication of a broad spectrum of other conditions, such as connective tissue disease, congenital heart disease, liver disease, lung disease or left heart disease. All of these forms have different features and their management is never the same. This Monograph aims to provide an in-depth overview of our current understanding of the various forms of pulmonary hypertension, their diagnosis and their treatment.

  • European Respiratory Society Monograph
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    Correspondence: T. Higenbottam, TranScrip Partners LLP, 400 Thames Valley Park Drive, Reading RG6 1PT, UK. Email:

    The history of pulmonary vascular disease has followed a remarkable course. It epitomises all that is good in medicine’s development. Early history involved description of the clinical presentation and natural history of the disease. These approaches were enhanced by the introduction of measurements such as chest radiography, ECGs and right heart catheterisation(RHC). A major advance occurred with detailed work on the structural abnormalities from histopathology. Finally, attempts to classify the different forms of pulmonary vascular disease were made.

    The structural and physiological observations and advances in vascular pharmacology allowed the “modern” treatments to be introduced: prostacyclin (PGI2), bosentan, sildenafil and inhaled nitric oxide (NO). Each had a place and analogues.

    We are now entering a new phase, which has benefited from lung transplant surgery giving access to patients’ lung cells for studies of mechanisms. Advances in genetics and the ability to identify the mutations that result in heritable pulmonary arterial hypertension (PAH) have pinpointed the target mechanisms for new therapies. This is not “controlling the pathophysiological abnormalities” but introducing therapies that may reverse the structural abnormalities of the disease. PAH is leading a modern revolution in medicine’s development.

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    Correspondence: A. Vonk Noordegraaf, Dept of Pulmonology, VU University Medical Center, Boelelaan 1117, 1007 MB Amsterdam, The Netherlands. Email:

    Pulmonary hypertension (PH) is a haemodynamic state that can be encountered in many different diseases. Sometimes, PH is caused by characteristic changes in small pulmonary arteries and treatment with pulmonary-specific vasodilators is indicated only in those cases (classified as pulmonary arterial hypertension (PAH)). In other conditions associated with PH, these treatments can be dangerous and alternative therapeutic approaches may be required. Because the choice of treatment is critically dependent on a correct classification of the disease, updated European Respiratory Society (ERS)/European Society of Cardiology (ESC) guidelines provide a systematic roadmap for the diagnosis of PH. Even with these guidelines, it can sometimes still be difficult to come to the right conclusion. In this chapter, we illustrate the diagnostic pitfalls using clinical cases from the Pulmonary Hypertension Center at the VU University Medical Center (Amsterdam, the Netherlands).

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    Correspondence: N. Galiè, Institute of Cardiology, University of Bologna, via Massarenti 9, 40138-Bologna, Italy. Email:

    The progress made in the medical treatment of pulmonary arterial hypertension (PAH) in the past 15 years is unique, particularly for a rare and severe condition. To date, seven drugs belonging to three pharmacological classes (endothelin receptor antagonists (ERA), phosphodiesterase type-5 inhibitors (PDE-5 I) and prostanoids) administered by four different routes (oral, inhaled, subcutaneous and intravenous) have been approved by the Food and Drug Administration and the European Medicines Agency. All three classes of drug exert both vasodilator and antiproliferative effects, and interfere with the endothelial dysfunction abnormalities observed in PAH patients. Modern drug therapy, including combination therapy, leads to a significant improvement in PAH patients' symptomatic status and a slower rate of clinical deterioration. Despite this finding, PAH remains a chronic disease without a cure. In addition, the medical and interventional treatments for more advanced cases are still invasive and prone to significant side-effects. Future candidate compounds on phase III drug development are as follows: macitentan, a novel dual ERA with tissue penetration properties; selexipag, an orally available selective prostacyclin receptor agonist; riociguat, a soluble guanylate cyclase stimulator; and imatinib, a tyrosine kinase inhibitor.

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    Correspondence: P.M. Hassoun, Johns Hopkins University, Division of Pulmonary and Critical Care Medicine, 1830 East Monument Street, Baltimore, MD 21205, USA. Email:

    Pulmonary arterial hypertension (PAH) is a common complication of connective tissue diseases (CTD) and a leading cause of death in this population. Despite significant advances in therapy for PAH, particularly for idiopathic PAH (IPAH), the response to treatment in patients with CTD associated with PAH, mainly in scleroderma-associated PAH (SSc-PAH), has been quite disappointing. This chapter reviews the epidemiology, clinical manifestations, pathophysiology and currently available therapies for CTD-associated PAH with a particular focus on SSc-PAH, animal models of disease, and newly identified potential targets for therapy for this devastating syndrome.

  8. Page 58
    Correspondence: M.J. Krowka, 200 1st Street SW, Mayo Clinic, Rochester, MN 55905, USA. Email:

    Portopulmonary hypertension (POPH) is an uncommon pulmonary vascular consequence of portal hypertension. It presents as exertional dyspnoea and may lead to right heart failure and death if untreated. There is no relationship between the existence and degree of POPH and the severity of advanced liver disease. Due to the spectrum of pulmonary haemodynamic changes associated with hepatic dysfunction, screening by transthoracic echocardiography and confirmation by right heart catheterisation (RHC) is necessary for accurate diagnosis and therapeutic considerations. Despite the lack of controlled studies, pulmonary vasomodulation therapies in POPH can significantly improve pulmonary haemodynamics and right ventricular (RV) function. The potential to “cure” POPH, at least haemodynamically, with a combination of pulmonary vasomodulation therapy and liver transplantation appears to be an attainable goal in a cohort of POPH patients yet to be optimally characterised. Controlled, multicentre studies and long-term follow-up post-liver transplantation are needed.

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    Correspondence: D. Bonnet, Pediatric Cardiology, Hôpital Necker Enfants Malades, 149, rue de Sevres, 75015 Paris, France. Email:

    Pulmonary hypertension (PH) associated with congenital heart disease (CHD) is a heterogeneous condition that ranges from systolic hypertension with massive pulmonary blood flow in infantile left-to-right shunts, to Eisenmenger’s syndrome. The rapid progress that has been made in this field is essentially due to the availability of new pulmonary arterial hypertension (PAH) drugs, which can be used in patients only previously managed with supportive therapy. The successes and limitations of the new therapies have allowed further definition of the subtypes of PH associated with CHD. The emergence of a system of classification for the condition indicates the complexity of a problem that is highly significant in terms of morbidity and mortality. Manipulating the variety of clinical forms of PAH and PAH associated with CHD has increased knowledge about the pathophysiology of these conditions. This new information will certainly improve patient management and outcome.

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    Correspondence: H.W. Farber, The Pulmonary Center, Boston University School of Medicine, Boston, MA 02116, USA. Email:

    With the advent of highly active antiretroviral therapy (HAART), there have been significant reductions in infectious complications with HIV; however, the prevalence of HIV-associated pulmonary arterial hypertension (HIV-PAH) has not changed. HIV-PAH can occur at any point during the disease and no definitive association with CD4 count or viral load has been observed. The aetiology and pathogenesis of HIV-PAH remains poorly characterised, although a number of observations in a simian immunodeficiency virus (SIV) model and in vitro studies support a pathogenic role for HIV proteins. Although there are no randomised controlled trials of treatment for HIV-PAH, therapies are currently similar to those employed for other forms of PAH; however, there are potential interactions between PAH medications and antiretrovirals and potential effects on hepatic function. Nonetheless, limited series of patients treated with epoprostenol or bosentan have demonstrated acute and chronic benefits of pulmonary vasodilators in patients. As HIV-infected patients are living longer, HIV-PAH is likely to become a more frequent complication, despite the increased access to HAART.

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    Correspondence: S. Takatsuki, Pediatric Cardiology, Children's Hospital Colorado, 13123 East 16th Avenue, B100, Aurora, CO 80045, USA. Email:

    This review provides an overview of recent advances in the pathobiology, classification, and treatment strategies of paediatric pulmonary hypertension (PH). Current registries have begun to provide differences in aetiology and clinical course between adult and paediatric forms of PH. For example, in the majority of patients, PH in children is idiopathic or associated with congenital heart disease (CHD); PH associated with connective tissue disease (CTD) is rare in children. Recent studies of paediatric PH have highlighted unique aspects of the pathogenesis and challenging treatments in idiopathic pulmonary arterial hypertension (IPAH) or associated pulmonary arterial hypertension. Although treatment with new selective pulmonary vasodilators offers haemodynamic and functional improvement in paediatric populations, treatments in children still depend on results from larger adult studies and experience of clinicians treating children. Future studies are required for development of specific strategies for children with PH.

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    Correspondence: I.M. Lang, Dept of Cardiology, Medical University of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria. Email:

    Chronic thromboembolic pulmonary hypertension (CTEPH) results from mechanical obstruction of (major) pulmonary vessels by non-resolving thromboemboli. If left untreated, the condition is fatal due to increased right ventricular afterload and right heart failure. Recent advances in the understanding of misguided thrombus resolution, small-vessel pulmonary arteriopathy and the identification of CTEPH risk factors have introduced novel disease concepts. In this chapter, we assemble the relevant literature into a picture of the old and new views of CTEPH evolution. Moreover, the role of established as well as experimental diagnostic tools is reviewed, with an emphasis on imaging techniques that allow visualisation of perfusion defects and differentiation between thromboembolic and non-thromboembolic pulmonary vascular disease. Finally, therapeutic options are discussed. Pulmonary endarterectomy (PEA) is the treatment of choice in patients with confirmed CTEPH. After successful PEA, patients are considered cured, since a vast majority nearly normalise their haemodynamic parameters and exercise capacity. Data on medical treatment of the condition and evidence-based knowledge are put into perspective with current clinical practice.

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    Correspondence: Y. Adir, Pulmonary Division, Lady Davis Carmel Medical Center, 7 Michal St, Haifa, 34362 Israel. Email:

    Left heart disease (LHD) is probably the most frequent cause of pulmonary hypertension (PH). Although in the past, rheumatic mitral valve stenosis has been the most common cause of this condition, PH-LHD mainly results from heart failure related to systolic and/or diastolic dysfunction of the left ventricle (LV) and is associated with elevated left-sided cardiac filling pressures. Most patients have a passive increase in pulmonary arterial pressure (Ppa) due to backward transmission of the elevated left atrial pressure, while a small subset develop severe PH with elevated transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR). When present, PH is usually associated with a poor prognosis and increased mortality. Optimising heart failure regimens and corrective valve surgery are the cornerstones of the treatment of PH in LHD. Although PH-LHD may evolve to right ventricular (RV) failure and is associated with some changes in the pulmonary vascular bed similar to pulmonary arterial hypertension (PAH), there are no data to support the use of PAH-specific therapies in the setting of PH-LHD. However, recent studies have suggested the usefulness of sildenafil, a phosphodiesterase type-5 inhibitor (PDE-5 I). This chapter addresses the epidemiology, pathophysiology, risk factors and treatment controversies of PH-LHD.

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    Correspondence: A. Chaouat, Département de Pneumologie, Hôpital de Brabois, CHU de Nancy, Allée du Morvan, 54500 Vandoeuvre-lès-Nancy, France. Email:

    Mild-to-moderate pulmonary hypertension (PH) is a common complication of advanced chronic obstructive pulmonary disease (COPD). The presence of PH is associated with an increased risk of acute exacerbation and decreased survival.

    Patients with COPD may present with severe elevation of pulmonary artery pressure (mean pulmonary artery pressure >35–40 mmHg). This is observed in end-stage disease, left heart disease or another COPD-associated respiratory disorder. A small proportion of patients may develop severe PH without any concomitant heart or lung disease other than COPD. These patients have unusual cardiopulmonary abnormalities with moderate airflow limitation, severe hypoxaemia, hypocapnia, a very low diffusing capacity of the lung for carbon monoxide and pulmonary haemodynamic characteristics similar to those of idiopathic pulmonary arterial hypertension (IPAH). Survival in this latter population of COPD is severely compromised. Right heart catheterisation (RHC) is mandatory when severe PH is suspected.

    Management of PH in COPD relies on ruling out comorbidities, optimising therapy for COPD and long-term oxygen therapy. Specific treatment developed for IPAH should not be prescribed in COPD patients outside controlled trials or experienced PAH centre.

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    Correspondence: V. Cottin, Hôpital Louis Pradel, Service de Pneumologie, 28 Avenue Doyen Lepine, F-69677 Lyon Cedex, France. Email:

    There is a growing body of evidence that pulmonary hypertension (PH) is relatively common in patients with idiopathic pulmonary fibrosis (IPF). PH in IPF is associated with increased dyspnoea, decreased exercise capacity, greater oxygen requirements, lower diffusing capacity of the lung for carbon monoxide (DL,CO) and reduced survival. Pulmonary haemodynamics do not correlate with pulmonary function testing. The pathogenesis is complex and multifactorial, and includes lung destruction, intrinsic vascular abnormalities, hypoxia, alterations in mediators, dysregulation of neovascularisation and microvascular injuries. Additionally, comorbidities, particularly concomitant emphysema, thromboembolic events, cardiac diastolic dysfunction and obstructive sleep apnoea (OSA) may increase the risk of PH in IPF. No screening recommendations are available but right heart catheterisation (RHC) is the diagnostic procedure of choice. As yet, no studies of pulmonary vasoactive agents have demonstrated clinical efficacy; however, further trials are sorely needed. If PH therapy is considered on a case-by-case basis, particular attention must be paid to the potential benefits and possible risks, particularly worsening of gas exchange.

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    Correspondence: A. Tazi, Service de Pneumologie, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, 75475, Paris cedex 10, France. Email:

    Pulmonary Langerhans’ cell histiocytosis (PLCH) is an uncommon disorder of unknown aetiology that predominantly affects young adult smokers. In patients with advanced disease, who develop airway obstruction and extensive cystic lesions on high-resolution computed tomography (HRCT), pre-capillary pulmonary hypertension (PH) is frequently observed, though no clear relationship exists between PH and extent of parenchymal lung disease and/or hypoxia. This observation suggests that alternate or additional pathomechanisms contribute to an intrinsic pulmonary vasculopathy that involves both the pre-capillary arterioles and post-capillary venous compartment, in addition to possible pulmonary veno-occlusive disease (PVOD)-like lesions.

    Patients with PLCH who develop PH have a particularly poor prognosis and early referral for lung transplantation assessment is recommended. Encouraging recent data suggest that agents licensed for use in pulmonary arterial hypertension (PAH) (group 1 of the PH classification) confer improvements in pulmonary haemodynamics and are generally well tolerated. Further investigation into the use of medical therapy in this population is warranted.

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    Correspondence: H. Nunes, Service de Pneumologie, Hôpital Avicenne, 125 rue de Stalingrad, 93009 Bobigny, France. Email:

    Pulmonary hypertension (PH) affects approximately 6% of unselected patients with sarcoidosis but its prevalence is much higher in advanced pulmonary fibrosis. Although destruction of the distal capillary bed and resultant hypoxaemia are central, the underlying mechanisms are multifactorial: left heart dysfunction, specific pulmonary vasculopathy (which can cause pulmonary veno-occlusive disease), local increased vasoreactivity, extrinsic vascular compression and portal hypertension. As a result, some patients exhibit ‘‘disproportionate’’ PH, i.e. more severe than expected from the level of functional impairment. There is no validated screening algorithm for the detection of sarcoidosis-associated PH but recent studies have underlined the role of right heart catheterisation (RHC) to exclude post-capillary PH, which is frequently underestimated by echocardiography. PH is associated with a significantly increased morbidity and mortality in sarcoidosis. The cornerstone of management is supportive therapy and lung transplantation in otherwise eligible patients. Rare cases with nonfibrotic pulmonary disease respond to corticosteroids. Published data on the efficacy and safety of pulmonary arterial hypertension (PAH) agents are scarce and discrepant, requiring further studies.

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    Correspondence: D. Montani, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie, Hôpital Bicêtre, Assistance Publique –Hôpitaux de Paris, Université Paris-Sud, Le Kremlin-Bicêtre, France. Email:

    In the recent classification of pulmonary hypertension (PH), pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH) were grouped as a single subcategory within pulmonary arterial hypertension (PAH) because of specific similarities in their diagnosis, prognosis and management. These diseases are characterised by predominant involvement of small pulmonary veins (PVOD) or capillaries (PCH), and cannot be distinguished from idiopathic PAH (IPAH) by their clinical or haemodynamic presentation. Only histopathological examination can confirm the diagnosis, but lung biopsies are high-risk procedures and are not recommended. A less invasive approach combining computed tomography (CT) of the chest, carbon monoxide diffusion and bronchoalveolar lavage (BAL) may be helpful to screen PVOD or PCH patients. These patients have a poor prognosis and were at risk of developing pulmonary oedema with specific PAH therapy. Thus, lung transplantation remains the treatment of choice for PVOD and PCH. In patients with the most severe disease, the cautious use of specific PAH therapy can be proposed as a bridging therapy while the patient awaits a lung transplant.

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    Correspondence: N.S. Hill, Pulmonary, Critical Care and Sleep Division, Pulmonary Hypertension Center, Tufts Medical Center, Tupper 3, 800 Washington Street #257, Boston, MA 02111, USA. Email:

    Obesity is an increasingly recognised global health problem. Obesity, insulin resistance and hyperlipidaemia are commonly referred to as the metabolic syndrome, which has long been implicated in the pathogenesis of systemic vascular disorders. The link between obesity and pulmonary vascular diseases, however, is a more recent debate that includes three aspects: 1) obesity as an active contributor in the pathogenesis of pulmonary arterial hypertension (PAH) of World Health Organization (WHO) group 1; 2) the association of pulmonary vasculopathy with obesity, in the setting of obesity cardiomyopathy (this entity belongs to the pulmonary hypertension (PH) of WHO group 2); and 3) PH in the setting of obesity hypoventilation syndrome (OHS), which is part of WHO group 3. In this chapter, we will review the current understanding in pathophysiology and clinical manifestations of these three pulmonary vascular disorders.

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    Correspondence: K.M. Olsson, Dept of Respiratory Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Email:

    Pulmonary arterial hypertension (PAH) most commonly occurs in females of childbearing age. Specific advanced therapies have been developed for PAH during the last decade that have improved quality of life and outcome for patients with PAH. However, despite these recent advances, pregnancy in females with PAH is associated with a high maternal mortality. Therefore, current guidelines strongly discourage pregnancy and recommend an effective method of contraception in females of childbearing age with PAH. If this fails, early pregnancy termination is advised. Those patients who choose to continue with the pregnancy must be treated early with targeted PAH therapies including prostanoids and/or phosphodiesterase type-5 inhibitors (PDE-5 I). In addition, the care of the pregnant females with PAH requires a highly planned, multidisciplinary approach, preferably in a dedicated pulmonary hypertension (PH) referral centre. This allows formulation of an agreed and documented management strategy for planned delivery and post-partum monitoring.

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    Correspondence: L. Price, Pulmonary Hypertension Service and Adult Intensive Care Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Email:

    Pulmonary hypertension (PH) is an independent risk factor for perioperative complications, including death. Physiological challenges during anaesthesia and surgery can precipitate an increase in pulmonary vascular resistance (PVR) and/or worsen right ventricular (RV) function, which may lead to pulmonary hypertensive crises and acute RV failure, the cause of most perioperative complications and mortality. Certain types of cardiothoracic procedures are at increased risk of perioperative PH, with mortality related to RV failure exceeding 80%. In patients with pre-existing PH, retrospective single-centre studies suggest the mortality risk from general surgical procedures ranges from 7% to 18%, with a morbidity of 14–42%. Most studies are, however, limited by small numbers and the grouping of heterogeneous procedures and patient groups. The presence of pre-operative RV dysfunction, lower exercise tolerance and increased New York Heart Association (NYHA) functional class are pre-operative indicators of worse outcomes; operative factors include long duration or surgery, as well as high-risk or emergency surgery. Herein, perioperative management and planning, including management of PH crises, will be discussed.

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    Correspondence: S. Gaine, Dept of Respiratory Medicine, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland. Email:

    Pulmonary hypertension (PH) is a devastating disease for which effective therapies have only recently become available. Currently available treatments are based on three therapeutic pathways and drug classes: prostacyclin analogues, endothelin receptor antagonists (ERAs) and phosphodiesterase type-5 inhibitors (PDE-5 I). While the use of these drugs often confers improvements in important clinical parameters, the prognosis for most PH patients remains poor and more effective approaches are required. Potential novel therapeutic strategies include agents that demonstrate enhanced targeting of pathways that are the focus of existing treatments (i.e. prostacyclin, nitric oxide (NO) and endothelin pathways) and agents that act on entirely new targets. In this regard, the “Holy Grail” of drug development remains the identification of compounds that are capable of reversing the pathological remodelling that is characteristic of PH, thereby restoring normal pulmonary vascular structure and function. Looking beyond pharmacotherapy, research efforts examining the potential role of endothelial progenitor cells as a treatment alternative for PH are also underway. This chapter highlights agents at different stages of clinical development that may become part of the future PH therapeutic armamentarium.

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    Correspondence: J. Gottlieb, Dept of Respiratory Medicine, Hannover Medical School, OE6870, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Email:

    Lung transplantation (LTx) now offers an effective therapy for patients with end-stage pulmonary vascular disease. Debate continues as to which transplant operation should be performed for such patients. The major practical problem facing LTx at this time is a shortfall in suitable donor organs compared with the number of potential recipients. The shortfall in donor organs has led to the successful introduction of lungs from non-heartbeating donors. In the early post-operative period, primary graft dysfunction remains a major problem and, in the long term, chronic lung allograft dysfunction and infections are the leading causes of death. Extracorporeal membrane oxygenation (ECMO) may improve the perioperative management of pulmonary arterial hypertension (PAH) patients following LTx.

    Patients who have received lung transplants and remain free of chronic lung allograft dysfunction enjoy an excellent standard of life, with normal or near-normal restoration of activities and good prospects for prolonged survival.

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    Correspondence: L.J. Rubin, University of California, San Diego School of Medicine, 9300 Campus Point Dr, M/C 7372, La Jolla, CA 92037, USA. Email:

    Over the past 20 years remarkable progress has been achieved in our understanding of the pathogenesis of pulmonary arterial hypertension (PAH), and in developing targeted treatment for this life-threatening disease. However, despite these achievements, the outcomes of PAH remain poor and delays in diagnosis and initiation of treatment contribute to the unacceptable outcomes. Through global efforts to study this rare disease, we envisage that the next few years will lead to new modalities to facilitate noninvasive diagnosis and monitor the course of disease, as well as novel treatment strategies based on further unravelling the pathogenic processes responsible for its development and progression.