An overview of the 6th World Symposiumon Pulmonary Hypertension

Nazzareno Galiè1, Vallerie V. McLaughlin2, Lewis J. Rubin3 andGerald Simonneau4,5

Affiliations: 1Dept of Experimental, Diagnostic and Specialty Medicine-DIMES, Alma Mater Studiorum,University of Bologna, Bologna, Italy. 2The University of Michigan, Cardiovascular Medicine, Ann Arbor, MI,USA. 3University of California, San Diego, School of Medicine, La Jolla, CA, USA. 4Univ. Paris–Sud, AP-HP,Centre de Référence de l’Hypertension Pulmonaire Sévère, Service de Pneumologie, Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Hôpital de Bicêtre, Le Kremlin Bicêtre, France. 5INSERMUMR_S999, LabEx LERMIT, Hôpital Marie Lannelongue, Le Plessis Robinson, France.

Correspondence: Nazzareno Galiè, Dept of Experimental, Diagnostic and Specialty Medicine (DIMES), AlmaMater Studiorum, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. E-mail: nazzareno.galie@unibo.it

@ERSpublicationsState of the art summary on diagnosis, prognosis, therapy and future perspectives of pulmonaryhypertension http://ow.ly/8MHN30mGtqs

Cite this article as: Galiè N, McLaughlin VV, Rubin LJ, et al. An overview of the 6th World Symposium onPulmonary Hypertension. Eur Respir J 2019; 53: 1802148 [https://doi.org/10.1183/13993003.02148-2018].

Since 1973 the World Symposia on Pulmonary Hypertension (WSPH) proceedings have summarised thescientific advances and future needs in this field through the efforts of multiple task forces, each focusingon a different aspect of pulmonary hypertension (PH) [1]. The 6th WSPH comprised 124 experts, dividedinto 13 task forces, that began their work in January 2017 and presented their consensus opinions to anaudience of 1376 participant attendees between February 27 and March 1, 2018 in Nice, France. A newlycreated task force dedicated to patients’ perspectives, including representatives of patients’ associationsworldwide, was added for the 6th WSPH.

The task forces continued their work after the 6th WSPH to incorporate participants’ input during theplenary session discussions into the 13 manuscripts published in the current issue of the EuropeanRespiratory Journal. The publication process, which in the past had been performed after each worldsymposium and included editors and blinded peer-review and revisions, has been modified with theseproceedings in order to improve the quality and the timeliness of these state-of-the art articles. The keypoints included in each task force’s manuscript, representing both current achievements and startingpoints for future research in the field of the pulmonary vascular science, are summarised below.

The task force on pathology and pathobiology summarised the most advanced achievements in the cellularand molecular basis and pathology of pulmonary vascular remodelling associated with various forms ofPH [2]. The manuscript reports new insights on specific pulmonary vascular lesions, including plexiformlesions, complex lesions and venous and venular lesions. Recent advances in cellular abnormalities arediscussed, such as dysfunction of the pulmonary vascular endothelium, accumulation of pulmonary arterysmooth muscle cells and adventitial fibroblasts, and dysregulation of the innate and adaptive immunesystem. Finally, multiple molecular mechanisms are explored and considered as emerging therapeutictargets that may constitute the rationale for future clinical studies.

The genetics and genomics task force estimated that about 25–30% of patients diagnosed with idiopathicpulmonary arterial hypertension have an underlying Mendelian genetic cause for their condition and

Received: Nov 10 2018 | Accepted: Nov 13 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

https://doi.org/10.1183/13993003.02148-2018 Eur Respir J 2019; 53: 1802148

| | EDITORIALWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

should be classified as heritable pulmonary arterial hypertension [3]. The article reports links betweenmutations and disease, and factors affecting disease penetrance. Genetic counselling and testing,management of healthy mutation carriers and psychosocial considerations and reproductive options arealso discussed. Advances in DNA sequencing technology may facilitate genomic studies in large cohortsand potentially lead to a molecular classification of the disease. This may help identify novel targets fornew drugs, expanding our therapeutic options.

The task force on the pathophysiology of the right ventricle and of the pulmonary circulation has revisitedthe pathophysiological description of the cardio-pulmonary unit (consisting of both the right ventricleand the pulmonary vascular system) in order to improve clinical data interpretation [4]. A betterunderstanding of right heart haemodynamic data as well as imaging data of the right ventricle obtained byechocardiography or magnetic resonance imaging is also provided. Provocative tests such as exercise andfluid loading are addressed, and the need for additional outcome studies to clarify the clinical relevance ofan “abnormal” response is outlined. Finally, an update is provided on the latest insights in the pathobiologyof right ventricular failure, including key pathways of molecular adaptation of the pressure-overloadedright ventricle.

One of the most significant (and controversial) recommendations from the 6th WSPH has been the proposalby the task force on haemodynamic definitions and clinical classification, to reconsider the haemodynamicdefinition of PH [5]. Based on data from normal subjects, the normal mean pulmonary arterial pressure(mPAP) at rest is approximately 14.0±3.3 mmHg [6]. Two standard deviations above this mean value wouldindicate that a mPAP >20 mmHg is the threshold for abnormal pulmonary arterial pressure (above the97.5th percentile). However, this level of mPAP is not sufficient to define pulmonary vascular disease, sinceit could be due to increases in cardiac output or pulmonary artery wedge pressure (PAWP). The task forcehas therefore proposed including a pulmonary vascular resistance (PVR) ⩾3 WU into the definition ofpre-capillary PH associated with mPAP >20 mmHg, irrespective of aetiology. Future trials should assess theefficacy of pulmonary arterial hypertension (PAH) medications (currently approved based on a mPAP⩾25 mmHg) in patients with mPAP from 21 to 24 mmHg and PVR ⩾3 WU. Due to limited data, the taskforce declined to identify a clinically useful definition of exercise PH, encouraging additional outcome studiesinstead. The clinical classification of PH was simplified, maintaining the traditional five-group structure.A new entity entitled “PAH long-term responders to calcium channel blockers” was introduced to group 1.

The task force on PH diagnosis has revised the diagnostic algorithm, providing a methodical approachfor diagnosis of patients with suspected PH both prior to and following referral to expert centres [7].In addition, expedited referral has been recommended for high-risk or complex patients, as well as patientswith confounding comorbidities. Updated screening procedures in asymptomatic patients with conditionsassociated with a high PH prevalence have been proposed, together with a review of current diagnostictools and emerging diagnostic technologies.

The task force on clinical risk stratification and medical therapy in PAH patients has provided an updateof all data available on these topics [8]. The strong relationship between risk stratification, initial treatmentstrategy and follow-up treatment escalations has been emphasised and serves as the rationale for atreatment strategy that is based on disease severity as assessed by a multi-parametric risk stratificationapproach. Clinical, exercise, right ventricular function and haemodynamic parameters and biomarkers arecombined to define a low-, intermediate- or high-risk status based on the expected 1-year mortality. Thecomprehensive treatment algorithm provides an overview of initial strategies, including monotherapy (in aminority of patients), and double or triple combination therapy. Further treatment escalation is required incase low-risk status (considered as treatment goal) is not achieved in structured follow-up assessments.

The task force on right ventricular assistance and lung transplantation has presented a comprehensiveintensive care approach for patients with PH and right-sided heart failure, including treatment of factorscausing or contributing to heart failure, careful fluid management and strategies to reduce right ventricularafterload and improve cardiac function [9]. Extracorporeal membrane oxygenation should be considered incandidates for lung transplantation (bridge to transplant) or, occasionally, in patients with a reversible causeof right-sided heart failure (bridge to recovery). For patients with advanced disease, lung transplantationremains an important treatment option. Patients should be referred to a transplant centre when they remainin an intermediate- or high-risk category despite receiving maximal PAH therapy. In experienced centres,the 1-year survival rates after lung transplantation for PH now exceeds 90%.

The task force on clinical trial design and new therapies for PAH has reviewed the progress in clinical trialdesign and end-points achieved over the past two decades, highlighting the crucial collaboration betweeninternational experts, industry and regulatory agencies [10]. New drug targets have been proposed andare summarised, including genetics, epigenetics, DNA damage, growth factors, metabolism, inflammationand immune modulation, oestrogen signalling, oxidative and hypoxic stress, serotonin and humoral

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modulation. Additional strategies such as pulmonary artery denervation and stem cell therapies are alsodiscussed. The task force also addressed the challenges facing future PAH clinical trials and has outlinedthe characteristics for phase 1, 2 and 3 registration studies.

New defining criteria for the different haemodynamic types of PH that occur with left heart disease (LHD)has been proposed by the task force on PH due to left heart disease [11]. After consideration of thechanges in the general definition of PH [5], the proposed haemodynamic definition of PH in LHD was:1) isolated post-capillary PH: PAWP >15 mmHg and mPAP >20 mmHg and PVR <3 WU; 2) combinedpost- and precapillary PH: PAWP >15 mmHg and mPAP >20 mmHg and PVR ⩾3 WU. The importanceof the differential diagnosis between idiopathic PAH and PH due to heart failure with preserved leftventricular ejection fraction has been emphasised. A pre-test probability score for PH-LHD may help inthe differential diagnosis. The nomenclature of PAH with cardiovascular risk factors should be preferredover any other, to account for their co-existence without suggesting that these risk factors are de facto thecause of the pulmonary vascular disease. The diagnostic relevance of provocative tests such as fluid loadingand exercise were also discussed, together with the uncertainties over their clinical meaning. Finally, sincemulticentre randomised trials using PAH therapies in PH-LHD have not demonstrated benefit and haveraised safety concerns, their use is still not recommended by the task force in PH-LHD.

The task force on PH due to chronic lung disease points out that PH frequently complicates the course ofpatients with various forms of chronic lung disease (CLD-PH) [12]. CLD-PH is invariably associatedwith reduced functional ability, impaired quality of life, greater oxygen requirements and an increasedrisk of mortality. The different aetiologies are discussed and the haemodynamic profile is compared withthe combination of physiological and imaging assessment. An updated definition and severity grading ofCLD-PH is also provided. The risk-to-benefit ratio of PAH approved drugs in CLD-PH patients has beenrevisited in depth. Although such therapy cannot be endorsed given the current lack of efficacy evidenceand in the face of serious safety concerns, future studies in this area are strongly encouraged.

The task force on chronic thromboembolic pulmonary hypertension (CTEPH) has provided an overviewof the state-of-the-art diagnostic and treatment modalities in this rapidly evolving field [13]. The newentity of chronic thromboembolic disease (CTED) has been characterised by similar symptoms andperfusion defects to CTEPH, but without PH at rest. CTEPH treatment recommendations should not yetbe applied to CTED, since additional prospective studies are needed. Digital subtraction pulmonaryangiography had been considered the gold standard for characterising vessel morphology in CTEPH,but is being challenged by advances in noninvasive modalities. Computed tomography pulmonaryangiography is currently widely used for assessment of operability. Pulmonary endarterectomy (PEA) isthe treatment of choice, and patient operability should be evaluated by an expert multidisciplinary CTEPHteam including a PEA surgeon, PH expert, balloon pulmonary angioplasty (BPA) interventionist andradiologist. BPA, an emerging procedure in non-operable patients, requires specific training of dedicatedinterventionists. The level of expertise of the CTEPH team should be evaluated based on the centre’snumber of procedures performed and the outcome results. Medical therapy has a supporting role toimprove symptoms and haemodynamics.

The task force on paediatric PH has revised a number of aspects of this specific field [14]. The definitionof PH is consistent with the newly proposed definition in adults [5]. The use of cardiac catheterisation as adiagnostic modality and haemodynamic assessment of PAH, including acute vasoreactivity testing, areaddressed. The common clinical classification for both adults and children has been integrated withmodifications in order to highlight aspects of paediatric disorders and better address specific features ofpaediatric PH within the core of the existing classification. Several features of paediatric PH, including theprominence of neonatal PAH, especially in preterm infants and those with developmental lung diseasesand novel genetic causes of paediatric PAH, are highlighted. Although a lack of clinical trial data for theuse of PAH-targeted therapy in this population persists, emerging data are improving the identification ofappropriate targets for goal-oriented therapy in children. Such data will likely improve future clinical trialdesign to enhance outcomes in paediatric PAH. Specific paediatric interventional management of PAH,including the Potts shunt, were also discussed.

The importance of the patients’ perspective has been outlined by a newly created task force [15]. Despiterecent progress in patients’ involvement in the PH field, patient surveys indicate that more can be done toimprove this aspect. The relevance of health-related quality of life has been outlined, and specificquestionnaire use may improve direct clinical care. Patients should be provided with access to accreditedspecialist centres that provide a multidisciplinary approach including narrative medicine, shared decisionmaking, palliative care and participation in education. The role of patients’ associations in supportingpatients and carers, lobbying for access to best care and treatments, providing input in to the developmentof clinical trials and registries, and focusing on the patient perspective have also been highlighted.

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Conflict of interest: N. Galiè reports grants and personal fees from Actelion, Bayer, GSK and Pfizer, and personal feesfrom MSD, outside the submitted work. V.V. McLaughlin reports grants and personal fees from Actelion, Acceleron,Arena and Bayer, personal fees from Caremark and United Therapeutics, and grants from Gilead and Sonovie, duringthe conduct of the study. L. Rubin reports personal fees from Actelion, Arena, Bellerophon, SoniVie and Roivant,during the conduct of the study. G. Simonneau reports grants, personal fees and non-financial support from ActelionPharmaceuticals, Bayer Healthcare, Merck and GlaxoSmithKline.

References1 Galiè N, Simonneau G. The Fifth World Symposium on Pulmonary Arterial Hypertension. J Am Coll Cardiol

2013; 62: Suppl. 25, D1–D3.2 Humbert M, Guignabert C, Bonnet S, et al. Pathology and pathobiology of pulmonary hypertension: state of the

art and research perspectives. Eur Respir J 2019; 53: 1801887.3 Morrell NW, Aldred MA, Chung WK, et al. Genetics and genomics of pulmonary arterial hypertension.

Eur Respir J 2019; 53: 1801899.4 Vonk Noordegraaf A, Chin KM, Haddad F, et al. Pathophysiology of the right ventricle and of the pulmonary

circulation in pulmonary hypertension: an update. Eur Respir J 2019; 53: 1801900.5 Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of

pulmonary hypertension. Eur Respir J 2019; 53: 1801913.6 Kovacs G, Berghold A, Scheidl S, et al. Pulmonary arterial pressure during rest and exercise in healthy subjects

A systematic review. Eur Respir J 2009; 34: 888–894.7 Frost A, Badesch D, Gibbs JSR, et al. Diagnosis of pulmonary hypertension. Eur Respir J 2019; 53: 1801904.8 Galiè N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy of pulmonary arterial

hypertension. Eur Respir J 2019; 53: 1801889.9 Hoeper MM, Benza RL, Corris P, et al. Intensive care, right ventricular support and lung transplantation in

patients with pulmonary hypertension. Eur Respir J 2019; 53: 1801906.10 Sitbon O, Gomberg-Maitland M, Granton J, et al. Clinical trial design and new therapies for pulmonary arterial

hypertension. Eur Respir J 2019; 53: 1801908.11 Vachiéry J-L, Tedford RJ, Rosenkranz S, et al. Pulmonary hypertension due to left heart disease. Eur Respir J 2019;

53: 1801897.12 Nathan SD, Barbera JA, Gaine SP, et al. Pulmonary hypertension in chronic lung disease and hypoxia. Eur Respir J

2019; 53: 1801914.13 Kim NH, Delcroix M, Jais X, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2019; 53:

1801915.14 Rosenzweig EB, Abman SH, Adatia I, et al. Paediatric pulmonary arterial hypertension: updates on definition,

classification, diagnostics and management. Eur Respir J 2019; 53: 1801916.15 McGoon MD, Ferrari P, Armstrong I, et al. The importance of patient perspectives in pulmonary hypertension.

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Pathology and pathobiology of pulmonaryhypertension: state of the art andresearch perspectives

Marc Humbert 1,2,3, Christophe Guignabert 1,2, Sébastien Bonnet4,5,Peter Dorfmüller 1,2,6, James R. Klinger7, Mark R. Nicolls8,9,10,Andrea J. Olschewski11,12, Soni S. Pullamsetti 13,14, Ralph T. Schermuly 15,Kurt R. Stenmark16 and Marlene Rabinovitch8,9,10

Number 1 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

@ERSpublicationsState of the art and research perspectives in the cellular and molecular basis and pathology ofpulmonary vascular remodelling associated with various forms of pulmonary hypertensionhttp://ow.ly/cjwp30mgzmH

Cite this article as: Humbert M, Guignabert C, Bonnet S, et al. Pathology and pathobiology of pulmonaryhypertension: state of the art and research perspectives. Eur Respir J 2019; 53: 1801887 [https://doi.org/10.1183/13993003.01887-2018].

ABSTRACT Clinical and translational research has played a major role in advancing our understandingof pulmonary hypertension (PH), including pulmonary arterial hypertension and other forms of PH withsevere vascular remodelling (e.g. chronic thromboembolic PH and pulmonary veno-occlusive disease).However, PH remains an incurable condition with a high mortality rate, underscoring the need for abetter transfer of novel scientific knowledge into healthcare interventions. Herein, we review recentfindings in pathology (with the questioning of the strict morphological categorisation of various forms ofPH into pre- or post-capillary involvement of pulmonary vessels) and cellular mechanisms contributingto the onset and progression of pulmonary vascular remodelling associated with various forms of PH.We also discuss ways to improve management and to support and optimise drug development in thisresearch field.

Received: Oct 04 2018 | Accepted: Oct 08 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

https://doi.org/10.1183/13993003.01887-2018 Eur Respir J 2019; 53: 1801887

| SERIESWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

IntroductionPulmonary hypertension (PH) encompasses a group of severe clinical entities, such as pulmonary arterialhypertension (PAH) and chronic thromboembolic PH (CTEPH), in which loss and obstructiveremodelling of the pulmonary vascular bed is responsible for the rise in pulmonary arterial pressure andpulmonary vascular resistance (PVR), resulting in progressive right heart failure and functional decline.Pulmonary vascular remodelling in PAH is not only characterised by an accumulation of different vascularcells in the pulmonary arterial wall (pulmonary artery smooth muscle cells (PA-SMCs), endothelial cells,fibroblasts, myofibroblasts and pericytes), but also by loss of pre-capillary arteries and by an exaggeratedperivascular infiltration of inflammatory cells (B- and T-lymphocytes, mast cells, dendritic cells,macrophages, etc.). Because current PAH treatments do not specifically target pulmonary vascularremodelling and inflammation, there is an urgent need to better identify the pathobiological mechanismsunderlying the progressive narrowing of the pulmonary arterial lumen and perivascular inflammation andthe loss of vessels in order to support therapeutic innovation aimed at reversing these features andregenerating normal pulmonary vessels.

Recent advances in pathology and laboratory medicineGeneral considerationsIn addition to stiffening of large elastic main, lobar and segmental pulmonary arteries, PH can beattributed to lesions mainly occurring in distal muscular-type arteries, ranging in diameter from 500 µmdown to 70 µm in humans (medial hypertrophy/hyperplasia, intimal and adventitial fibrosis, and (in situ)thrombotic lesions, plexiform lesions) (figure 1). They can be clearly differentiated from pulmonary veinsdue to their topography within the lung, since they are always neighboured by an airway (bronchiole), aswell as through their microscopic anatomy, which includes a neatly defined tunica media that is delimitedby the internal and the external elastic lamina. Small pre-capillary pulmonary arteries ranging in diameterfrom 70 µm down to 20 µm in humans (arterioles) are also involved in all groups of human andexperimental PH, through processes of loss and obliteration, abnormal muscularisation, and perivascularinflammation (figure 2). In contrast to the muscular-type arteries, they can only be indirectlydistinguished from small post-capillary venules of the same size, through serial section tracing, or, iffeasible, injection techniques with dye or beads. The capillary compartment that arises from the arteriolarmicrovasculature and that represents the largest vascular surface within the lung is also frequentlyinvolved. There is also accumulating evidence supporting the involvement of the post-capillary pulmonaryvenous vasculature in all PH groups with varying degrees of intensity. In PH due to left heart disease andchronic respiratory disease, post-capillary involvement is likely to be explained at least in part byparenchymal destruction and inflammation in patients with lung fibrosis and emphysema, and by chronicelevation in post-capillary pressure in left heart failure where PH is associated with global pulmonaryvascular remodelling. Interestingly, the severity of PH in heart failure correlates with venous and smallindeterminate vessel intimal thickening, resembling the pattern observed in pulmonary veno-occlusivedisease (PVOD) [1]; larger pulmonary veins running within the interlobular septa may appear

Affiliations: 1Faculté de Médecine, Université Paris-Sud and Université Paris-Saclay, Le Kremlin-Bicêtre,France. 2INSERM UMR_S 999, Le Plessis-Robinson, France. 3AP-HP, Service de Pneumologie, Centre deRéférence de l’Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire (DHU) ThoraxInnovation (TORINO), Hôpital de Bicêtre, Le Kremlin-Bicêtre, France. 4Pulmonary Hypertension ResearchGroup, Centre de Recherche de l’Institut de Cardiologie et de Pneumologie de Quebec, Quebec City, QC,Canada. 5Dept of Medicine, Université Laval, Quebec City, QC, Canada. 6Pathology Dept, Hôpital MarieLannelongue, Le Plessis-Robinson, France. 7Division of Pulmonary, Critical Care and Sleep Medicine, Dept ofMedicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA.8Cardiovascular Institute, Dept of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.9Division of Pulmonary and Critical Care Medicine, Dept of Medicine, Stanford University School of Medicine/VA Palo Alto, Palo Alto, CA, USA. 10The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford,CA, USA. 11Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria. 12Institute of Physiology,Medical University of Graz, Graz, Austria. 13Max Planck Institute for Heart and Lung Research Bad Nauheim,Bad Nauheim, Germany. 14Justus-Liebig University Giessen, Excellence Cluster Cardio Pulmonary Institute(CPI), Giessen, Germany. 15University of Giessen and Marburg Lung Centre (UGMLC), Justus-Liebig UniversityGiessen and Member of the German Center for Lung Research (DZL), Excellence Cluster Cardio PulmonaryInstitute (CPI), Giessen, Germany. 16Developmental Lung Biology and Cardiovascular Pulmonary ResearchLaboratories, University of Colorado, Denver, CO, USA.

Correspondence: Marlene Rabinovitch, Cardiovascular Institute, Dept of Pediatrics, Stanford University Schoolof Medicine, 269 Campus Drive, CCSR Building, Room 1215A, Stanford, CA 94305-5162, USA. E-mail:marlener@stanford.edu

Correspondence:Marc Humbert, Université Paris-Sud, Service de Pneumologie, Hôpital Bicêtre, AP-HP,78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France. E-mail: marc.humbert@aphp.fr

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“arteriolised”, mimicking the exact microscopic anatomy of muscular-type pulmonary arteries.In apparently pure pre-capillary forms of PH, such as PAH and CTEPH, the mechanisms of post-capillaryinvolvement are not obvious, since the post-capillary vessels, in theory, should be shielded from increasedpre-capillary pressure by the arterial and capillary compartment [2].

New interpretation of specific pulmonary vascular lesionsPlexiform lesions/complex lesionsComplex pulmonary arterial lesions comprise different elements, such as onion-skin lesions, plexiformcore lesions and dilation lesions, which are commonly observed in close topographic association (figure1a–c). However, the pathophysiological significance of these typical vascular changes in PAH has yet to beelucidated. In this regard, recent reports suggest that systemic vessels, such as the vasa vasorum andbronchial arteries running within the adventitia of pulmonary arteries or within the peribronchialconnective tissue, respectively, could be involved in the plexiform vasculopathy (figure 1c). Analysis ofserial sections from PAH patients with digital three-dimensional reconstruction supports a shuntinghypothesis, where plexiform lesions appear to represent anastomosing structures between bronchialmicrovessels and pulmonary arteries and veins [3]. Shunting between the bronchial and pulmonaryvasculature has been described by means of morphometric analysis of explanted lung tissue sections fromPAH patients, including idiopathic PAH (IPAH) and heritable PAH (HPAH) due to a BMPR2 (bonemorphogenetic protein receptor type 2) mutation [4]. Hypertrophy and dilatation of bronchial arteries andincrease in bronchial microvessel density in BMPR2 mutation carriers correlated with pulmonary venousremodelling [4]. Moreover, large fibrous vascular structures (“SiMFis” (singular millimetric fibrovascularlesions)) appear to connect the systemic vasculature to pulmonary arteries and veins (figure 1d). A

a) b) c) d)

e) f) g) h)

i) j)

FIGURE 1 Representative vascular lesions typically detected in lungs of patients with pulmonary arterial hypertension (PAH). a–c) Plexiformlesions. Note that the plexiform core can be in a, b) the para-arterial position, appearing connected to the adventitia, or c) even within theperimeters of the latter, possibly indicating an involvement of the systemic vasculature (vasa vasorum). d) Atypical fibrovascular lesions (alsoreferred to as “SiMFis” (singular millimetric fibrovascular lesions)) of millimetric size (note the scale bar) that can be found in PAH, mostly in itshereditary bone morphogenetic protein receptor type 2-related form. e) Recent thrombotic lesion that shows fresh fibrin at its core and abeginning organising process involving numerous fibroblasts in its periphery (arrows). f ) Fully organised thrombotic lesion (“colander-like lesion”)with several recanalisation vessels, vaguely reminiscent of a plexiform lesion. g) Concentric, non-laminar fibrosis of the intima; the media(arrows) is only slightly thickened (note the lymphocyte-rich infiltrate in the lower periphery of the vessel). h) Eccentric, cushion-like fibrosis ofthe intima, commonly interpreted as an organised thrombotic lesion. i) Hyperplasia of the media and collagen-rich fibrosis of the adventitia(arrows). j) Concentric laminar fibrosis of the intima (“onion-skin lesion”) due to the concentrically arranged multiple fibrous layers that lead tothe progressive obstruction of the pulmonary artery.

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functional role for the hypertrophic systemic vasculature in PAH that would allow short-circuiting aprimary pulmonary arterial obstruction (figure 3) has yet to be confirmed.

Venous and venular lesionsA substantial proportion of PH patients display pulmonary venous and venular remodelling (figure 2e)[4]: lungs from PAH patients with scleroderma often exhibit PVOD-like pathology [5], and CTEPH lungscommonly show pulmonary veins and venules abnormalities [2]. CTEPH is of particular interest in thiscontext. Although the primary insult, i.e. chronic thromboembolic occlusion of elastic and musculararteries, occurs on the pre-capillary side of the pulmonary vasculature and contributes to increased PVR,remodelling of microvessels is also present, affecting pre-capillary arterioles and post-capillary venules [2,6]. Importantly, bronchial arterial hypertrophy is associated with pulmonary venous remodelling inCTEPH, supporting the concept that systemic lung vessels associated with bronchopulmonary anastomosescould contribute to these changes [2].

In PVOD, pulmonary vascular lesions are thought to predominate on the post-capillary side, but arteriesare also involved [7]. Post-capillary lesions affecting septal veins and pre-septal venules frequently consistof loose, fibrous remodelling of the intima that may totally occlude the lumen. The walls of septal veinsand pre-septal venules may show smooth muscle cell hyperplasia and can be difficult to distinguish fromabnormally muscularised arterioles <70 µm in diameter in PVOD lungs [7]. Post-capillary remodelling isfrequently associated with pulmonary capillary angioectasia and capillary angioproliferation with doublingand tripling of the alveolar septal capillary layers that may be focally distributed (pulmonary capillaryhaemangiomatosis). See figure 2b–d and f.

Recent advances in cellular abnormalities and emerging therapeutic targetsDysfunction of pulmonary vascular endotheliumIn PAH, the term pulmonary endothelial dysfunction has been used to denote impairment ofendothelial-dependent vasodilatation in favour of vasoconstriction, but it also refers to reducedanticoagulant properties, active metabolic changes, reactive oxygen species production, increasedexpression of adhesion molecules (E-selectin, intercellular adhesion molecule 1 (ICAM1) and vascular celladhesion molecule 1 (VCAM1)), and a local unadapted release of different chemokines, cytokines andgrowth factors (figure 4). These latter changes result in impairments in angiogenesis and repairmechanisms that play primary roles in pulmonary vascular remodelling [8]. It is now well established thatcultured pulmonary endothelial cells from patients with PAH maintain in vitro several abnormalphenotypic features more or less pronounced, perhaps reflecting different subpopulations. Among them,

a) b) c) d)

e) f)

FIGURE 2 Representative vascular lesions typically detected in the microvasculature, capillaries and post-capillary vessels (pulmonary veins) inlungs of patients with pulmonary arterial hypertension (PAH) or pulmonary veno-occlusive disease (PVOD). a) Microvessels (arteries or venules)presenting some mild inflammatory and fibrous remodelling (patient with PAH). b) Representative image of α-smooth muscle actinimmunostaining in lungs of a patient with PVOD, highlighting substantial muscularisation of the pulmonary vasculature. c) Roundish,well-delimited area of interstitial thickening in a patient with PVOD; these areas are distributed in a patchy fashion throughout the lungs ofpatients with PVOD and probably correspond to typical ground-glass opacities on computed tomography scan. d) At higher magnification, theinterstitial thickening in (c) is due to focal multiplication of alveolar capillaries that form multiple layers within the alveolar septa; the termcapillary haemangiomatosis-like foci describes this patchy interstitial pattern. e) Muscular hyperplasia and fibrous remodelling in pulmonaryseptal veins of a patient with PAH. f) Fibrous intima thickening of small septal veins in a patient with PVOD.

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decreased capacity for vascular tube formation in vitro, heightened aerobic glycolysis, and loss of someendothelial cell markers and acquisition of several mesenchymal cell markers have been described [9–11].In PAH, a pro-inflammatory phenotype of pulmonary endothelial cells characterised by an increase insurface expression of E-selectin, ICAM1 and VCAM1 together with an excessive release of various keycytokines and chemokines has been reported [12]. Some features can be reproduced in endothelial cellsgrown from induced pluripotent stem cells (iPSCs) derived from the skin of the same patients [13, 14].Various stimuli, such as high glucose, insulin resistance, disturbed blood flow and oxidative stress, can leadto endothelial dysfunction. However, the cause and the underlying mechanisms responsible fordysfunction of the pulmonary endothelium in PAH are still incompletely understood.

Recent studies have focused on two key modulators of endothelial structure and function that initiate andperpetuate pulmonary vascular remodelling associated with PH/PAH, i.e. fluid flow-induced high shearstress as well as low oxygen tension (chronic hypoxia). Normally, vascular endothelial cells respond tohigh shear stress by losing their cobblestone appearance and elongating in the direction of flow. Failure toadapt these morphological changes is associated with an increased tendency toward vascular remodelling.Interestingly, pressure off-loading by pulmonary artery banding has been reported to prevent and evenreverse occlusive vascular remodelling in the Sugen hypoxia rat model [15]. This observation is consistentwith findings from more recent studies showing that microvascular pulmonary endothelial cells, but notproximal pulmonary artery endothelial cells, isolated from PAH patients exhibit delayed morphologicaladaptation to high shear stress in vitro [16]. Chronic hypoxia also gives rise to structural remodelling ofthe pulmonary vasculature in experimental and human PH. Recent studies have supported this notion byshowing that pulmonary vascular endothelial cells from plexiform lesions in patients with PAH have

Systemic vascular plexus

Bronchopulmonary

anastomosesPulmonary artery with

constricting lesion

Muscular hyperplasia

and intimal fibrosis

Pulmonary vein

FIGURE 3 Impact of hypertrophic systemic vasculature in pulmonary arterial hypertension (PAH): anexplanatory approach. The pulmonary artery (top centre, blue) is covered by a systemic vascular plexus,comprising systemic arterial (red) and venous (blue) vessels and microvessels. The systemic plexusanastomoses with the pulmonary artery, the capillary bed and the pulmonary vein (bottom left, red): thesebronchopulmonary anastomoses appear to bypass an occlusive PAH lesion, represented by medial thickeningand intimal fibrosis (centre). Eventually, the increased systemic blood flow into arterioles, capillaries and thepulmonary vein leads to structural changes of the latter: muscular hyperplasia and focal intimal fibrosiswithin the pulmonary vein are observed. Reproduced and modified from [4] with permission.

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decreased expression of prolyl-4 hydroxylase 2 (PHD2), an enzyme that facilitates the degradation of thehypoxic-inducible factor HIF1 and HIF2 hypoxia sensors. Furthermore, mice with endothelial cell-targeteddisruption of the gene for PHD2 (EGLN1) develop obliterative pulmonary vascular remodelling andcomplex lesions as found in human PAH [17]. A combination of amphetamine and hypoxia can increaseendothelial propensity to apoptosis and cause DNA damage by interfering with the normal metabolicfunction of HIF1α in switching to a glycolytic state [18]. Dasatinib can induce PAH and has also emergedas a modulator of pulmonary endothelial function: dasatinib at high doses induces pulmonary endothelialcell dysfunction via increased production of reactive oxygen species, thereby increasing the susceptibility topleural effusions and PH in rodents [19–21]. A better understanding of the molecular mechanismsunderlying endothelial adaptation to high shear stress and chronic hypoxia will greatly enhance ourunderstanding of the pathogenesis of PH/PAH, and may aid in identifying new therapeutic strategies.Additional insights into the altered pulmonary endothelial communication with both resident vascularcells (PA-SMCs, myofibroblasts, pericytes) and circulating cells (immune cells) are also a prerequisite for abetter understanding of PH/PAH pathogenesis.

The endothelium is also critical for the development of a functional vascular network that is dependentupon signals exchanged between the different cell types responsible for coordinating this process. Inexperimental and human PH/PAH, angiogenesis is disturbed with loss and progressive obliteration ofpre-capillary arteries leading to a pattern of pulmonary vascular rarefaction (“dead-tree” picture), even ifseveral pro-angiogenic factors are overabundant and/or overactive and an overexpression of Notch3signalling in PA-SMCs has been reported. Therefore, further studies are needed to identify how theendothelial microenvironment, at the cell–cell and cell–matrix interfaces, impairs pulmonary endothelialintegrity and its regenerative angiogenic capacity in PH/PAH. In this context, a better knowledge of thecontribution of circulating cells and resident vascular progenitors should be determined [22–28]. Indeed,pericytes are important not only for vessel maturation and stabilisation, but also for the prevention ofendothelial sprout formation and endothelial proliferation required for the production of a new functionalvasculature. In experimental and human PH/PAH, the total number of pulmonary pericytes in distalpulmonary arteries increases substantially during disease progression [26] and defects in pericyte functionhave been demonstrated [28]. Isolated pericytes from PAH patients exhibit reduced levels of genes crucialfor the Wnt/planar cell polarity pathway and fail to associate with endothelial cells during tube formationas assessed in Matrigel tube formation assays [28].

It is now clearly established that abnormal BMPR2 signalling can adversely impact endothelial barrierfunction, DNA lesion persistence related to impaired DNA repair [29], metabolism, mitochondrial fissionand fusion [30, 31], and also inflammation and its resolution [32–34]. Therefore, much effort should be

Normal pulmonary artery

PAH pulmonary artery

Functional pulmonary

endothelium

Dysfunctional pulmonary endothelium

in PAH:

• Altered secretion of pulmonary

vasodilatators and vasoconstrictors

• Changes in proliferative capacity

and sensitivity to apoptosis

• Pro-inflammatory phenotype

• Smooth muscle-like mesenchymal

phenotype

• Decreased tube formation

• Changes in migratory potential

• Changes in metabolic processes

FIGURE 4 Phenotypic signature of dysfunctional pulmonary vascular endothelium in pulmonary arterialhypertension (PAH).

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made to better understand the interplay between the BMPR2 signalling system and the process ofpulmonary vascular remodelling.

Accumulation of PA-SMCs and adventitial fibroblastsIn PAH, the pulmonary arterial microenvironment and the presence of several inherent intrinsicabnormalities and dysregulated signals are known to partly explain the progressive accumulation ofresident PA-SMCs and adventitial fibroblasts. In recent years, pre-clinical and early-stage clinical effortshave highlighted emerging targets in PAH pathophysiology. As in endothelial cells, DNA damage responsepathways are critically implicated in PA-SMC and fibroblast survival in PAH. In both human andexperimental PH/PAH the decrease in BRCA1 (breast cancer 1) protein following BMPR2 downregulationis associated with the upregulation of poly(ADP ribose) polymerase 1 (PARP1) in response to the increasein DNA damage insults [35]. The upregulation of PARP1 in PAH PA-SMCs allows them to cope with theenvironmental stresses by damping DNA damage consequences, adapting their mitochondrial functionsinto a survival mode [36, 37]. Inhibition of PARP1 in experimental PH models has shown greater efficacythan the combination of current standard of care, and thus the US Food and DrugAdministration-approved PARP1 inhibitor olaparib is under clinical investigation in PAH (ClinicalTrials.gov identifier NCT03251872). Another advance derives from observations of a downregulation ofmiRNA-124 leading to an upregulation of the RNA splicing factor polypyrimidine tract binding protein 1(PTBP1) in both fibroblasts and endothelial cells in the PH vasculature [38, 39]. PTBP1, along with othermembers of the heterogeneous nuclear ribonucleoprotein family of splicing factors, has been demonstratedto regulate splicing of pyruvate kinase muscle (PKM) isoforms. Increases in PTBP1 lead to increasedaccumulation of the PKM2 isoform, which in its dimeric (unactivated state) promotes glycolysis,proliferation and apoptosis resistance even in aerobic environments. Restoration of a normal PKM2/PKM1ratio using pharmacological inhibitors attenuated fibroblast and endothelial cell proliferation in vitro andin vivo. In addition, it has been found that tumour necrosis factor-α (TNF-α) inhibits BMPR2 expressionand promotes post-translational cleavage via the “a disintegrin and metalloproteases” ADAM10 andADAM17 in PA-SMCs, favouring BMP-mediated proliferation via alternative activin receptors [40].Furthermore, exposure of PA-SMCs to high glucose increases expression of SMURF1, an E3ubiquitin-protein ligase that dampens BMP signalling, and decreases phospho-Smad1/5/8, mimickingsignalling patterns in mutation-negative PAH-derived PA-SMCs, which are normalised by blockingglucose uptake [41]. Similarly, Smad3 depletion in PA-SMCs and in pulmonary endothelial cells wasfound to contribute to the heightened proliferation and migration, which was attenuated by inhibition ofmyocardin-related transcriptional factor [42].

Other promising targets have also been recently identified in this context and include, among others:leukotriene B4 (LTB4), interleukin-6 (IL-6) and leptin receptors, as well as the transcriptional corepressorC-terminal binding protein 1 (CtBP1), transforming growth factor-β, peroxisome proliferator-activatedreceptor-γ (PPAR-γ), mammalian target of rapamycin complex 1 (mTORC1) and Forkhead box O1(FoxO1) pathways [43–47]. In PAH, it is also established that the dynamic and unadapted remodelling ofthe extracellular matrix forms a permissive milieu that not only favours cell motility, proliferation,apoptosis, and differentiation of resident vascular cells and recruitment of inflammatory cells, but can alsohave a considerable effect on vessel stiffness [48–51]. Owing to their close locations, and because there areseveral lines of evidence that indicate the existence of a complex interrelationship between pulmonaryarterial cells and perivascular monocytes and macrophages [52, 53], a more complete understanding ofthese complex interrelationships is needed.

Dysregulation of the innate and adaptive immune systemIn experimental PH, perivascular inflammatory infiltrates of mixed inflammatory cells often precede thestructural pulmonary vascular remodelling, supporting the notion that maladaptation of the inflammatoryand immune systems exists and contributes to remodelling. Consistent with this notion, small lymphoidaggregates to large accumulations of lymphocytes resembling highly organised lymphoid follicles can beobserved in lungs of patients with PAH. Similarly, it is now established that circulating levels ofinflammatory mediators correlate with a worse clinical outcome in PAH and that alterations of circulatingcell subsets can be observed [54–56]. As a result, therapies that directly modulate inflammatory processeshave become a recent focus of clinical studies in PAH.

The fact that steroid or aspirin treatment is not effective in IPAH and HPAH, and that prostacyclin, whichhas anti-inflammatory properties [57], does not reverse the pulmonary vascular remodelling underscoresthe fact that additional insights into the roles played by the immune cells and key cytokines/chemokinesare a prerequisite for developing novel therapeutic strategies. Recent investigations provide evidence thatpulmonary vascular cells are important local sources of soluble signals in PAH that contribute topulmonary vascular remodelling. Indeed, PA-SMCs, endothelial cells, fibroblasts and myofibroblasts from

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patients with PAH exhibit a marked pro-inflammatory signature characterised by heightened expression ofvarious cytokines and chemokines, and of key inflammatory cell adhesion molecules, such as ICAM1. Theexcessive local secretion of IL-1, IL-6, LTB4, macrophage migration inhibitory factor, leptin and TNF-α,and the inactivation of FoxO1, play an integral role in mediating the structural and functional changes inthe pulmonary vasculature in PAH [12, 40, 43–46, 58].

Impaired T-regulatory cell function, T-helper 17 cell immune polarisation [59] and dendritic cellrecruitment in pulmonary vascular lesions have been demonstrated in tissues from PAH patients,supporting maladaptation of the immune response. Accordingly, circulating autoantibodies are commonlydetected in PAH patients without evidence of an associated autoimmune condition. Furthermore,lymphoid neogenesis in PH/PAH lungs has been reported. Moving forward, a better understanding of themechanisms leading to alteration in the balance between immunity and tolerance in PAH may allow theidentification of immunopathological approaches to PAH management.

Additional contributing factors to the dysregulation of the innate and adaptive immune system in PAHinclude, among others: shear stress, chronic exposure to hypoxia, dysregulation in BMPR2 signalling,ageing of the pulmonary circulation, metabolic derangements, dysfunctional or distressed mitochondria,circulating autoantibodies and immune complexes. Indeed, environmental or genotoxic stresses favourpulmonary vascular remodelling through the activation of vascular, inflammatory and immune cells.Recently, perivascular immune complexes containing the antiviral protein SAMHD1 (SAM domain andHD domain-containing protein 1) has been found to be an innate immune response to an unexplainedelevation in sequences and protein products of the human endogenous retrovirus K observed in PAHperivascular macrophages and circulating monocytes [60]. These abnormalities, in addition to others, mayperpetuate a dysregulated immune and inflammatory response (figure 5). Unadapted immunity andinflammation appear to play an active role in pulmonary endothelial dysfunction and vascular remodellingin PH/PAH, and are also likely to have a detrimental effect on cardiac function. However, there aresubtleties and complexities that require further investigation to determine whether and whichanti-inflammatory strategies will be best suited to treat PAH.

The prominent roles of autoimmunity and inflammation in the pathogenesis of PAH warrant futureclinical studies of newer biological agents that can target specific inflammatory pathways. Several clinicaltrials are currently exploring the efficacy and safety of different anti-inflammatory agents in PAH; theseinclude, among others: rituximab, a chimeric anti-human CD20 (ClinicalTrials.gov identifierNCT01086540) in patients with systemic sclerosis-associated PAH; tocilizumab, a humanised anti-IL-6

Dysregulated immune responsesImmune cell

infiltration

Lymphoid

neogenesis

Innate responses

NK cytotoxic cells

Macrophages/monocytes

Neutrophils

Granulocytes

Mast cells

Adaptive responses

Dendritic cells

B-lymphocytes CD20+

T-lymphocytes CD30+

Cytotoxic CD8+

NK T-cells

Autoimmunity

Th1 Th2 Th17

Treg

Local recruitment

Feedback regulation

Soluble factors:

Cytokines/chemokines

Complement

Granulysin

Antibodies

Autoantibodies

Normal pulmonary artery

PAH pulmonary artery

FIGURE 5 Schematic representation of immune disturbance associated with pulmonary arterial hypertension(PAH) and pulmonary vascular remodelling. NK: natural killer; Th: T-helper; Treg: T-regulatory.

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receptor antibody (ClinicalTrials.gov identifier NCT02676947) in PAH patients; FK506, an inhibitor ofcalcineurin and a binding partner of FKBP12 (12-kDa FK506-binding protein) that has also been shownto upregulate BMPR2 expression; and the elastase inhibitor produced as a recombinant protein.

Recent advances in molecular mechanisms and emerging therapeutic targetsAlthough much remains to be understood, decades of extensive studies have related PAH pathobiology togenetic, epigenetic and environmental factors (viruses, drugs, toxins, hypoxia and inflammation) that cancause or accelerate irreversible remodelling of the pulmonary vascular bed. We propose that the genetic,epigenetic and environmental factors lead to deregulation of growth factors, ion channels, hormones andcytokines that subsequently activate a complex cascade of signalling pathways causing abnormalities invascular cell phenotype, including proliferation, differentiation/de-differentiation and inflammation. Thissuggests that transcriptional dysregulation in the pulmonary vasculature can be an early event that shapesthe pulmonary vascular transcriptome, causing both depletion and ectopic activation of gene products thateventually lead to aberrant cellular processes and consequently adverse vascular remodelling [61]. Howcells sense and respond to environmental triggers that lead to transcriptional dysregulation remains acentral question of pulmonary vascular research. Recent studies are providing new insights that include:the role of non-receptor kinases; the potential of ion channels to control pulmonary arterial tone andvascular remodelling processes; the disruption in the activity of gene expression regulators (i.e.transcription factors and transcriptional coregulators); the epigenetic processes resulting in aberrantactivation of chromatin-remodelling proteins, non-coding and microRNAs; and the severe metabolicperturbations that affect transcription, post-transcriptional processes and signalling pathways (figure 6).

Dysregulation of receptor and non-receptor kinase signallingIn PH/PAH, altered expression and function of different growth factors and their respective receptortyrosine kinases (e.g. fibroblast growth factor 2, vascular endothelial growth factor, platelet-derived growthfactor, epidermal growth factor and nerve growth factor) together with inflammatory mediators (e.g.cytokines, chemokines, circulating autoantibodies and immune complexes) contribute to the phenotypicalterations of resident pulmonary vascular cells, and their accumulation in the wall of distal pulmonaryarteries has been implicated.

Emerging ion channel targetsThe identification of heterozygous loss-of-function mutations in the KCNK3 (potassium channelsubfamily K member 3) gene that encodes TWIK-related acid-sensitive potassium channel 1 (TASK1) as a

Vascular remodelling

Gene expression

Anti-proliferative,

anti-inflammatory

gene expression

Transcription factors/

coregulators

Chromatin/

epigenetic modulators

Cofactor/

substrate

Pro-proliferative,

pro-inflammatory

metabolic gene expression

Metabolic state

Growth factors Ion channels

NutrientsMechanical

strain

Hypoxia

Inflammation

Genetic

predisposition

FIGURE 6 Cross-talk between transcription factors, epigenetics and metabolism in pulmonary hypertension.Growth factors, ion channels, hormones and cytokines activate the classical signalling pathways anddownstream transcriptional factors, which will recruit chromatin-modifying enzymes to local chromatin. Onthe other hand, nutrient levels and cell metabolism will affect levels of the metabolites, which are requiredsubstrates of chromatin-modifying enzymes that use these metabolites to modify both histones and DNA.Variations in these inputs will determine epigenome remodelling and transcription, and subsequentlyvascular remodelling.

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cause for PAH has revived interest in the concept of channelopathy [62]. In addition to voltage-gatedpotassium channels, different types of transient receptor potential channels, calcium sensor proteins andcalcium-activated chloride channels have been implicated in PAH pathogenesis [63–67]. The dysregulationof potassium channels could have a central role in the immediate and long-term regulation of pulmonaryvascular function in PAH [68, 69]. This notion is consistent with the fact that restoration of potassiumchannel function can prevent or reverse experimental PH. For example, in vivo pharmacological activationof KCNK3 has beneficial effects in monocrotaline-induced PH [69]. Interestingly, endothelin, serotonin(5-HT), oxidative stress, BMPR2, docosahexaenoic acid and growth factors such as platelet-derived growthfactor are known modulators of potassium channel activities [70]. Furthermore, inhibition of voltage-gatedpotassium channels could represent one potential mechanism involved in some drug-induced PH [19, 71].The current challenge is to identify small molecules or specific strategies to restore the expression and/oractivity of these ion channels in PAH dysfunctional pulmonary vasculature.

Key transcription factors and transcriptional coregulatorsNumerous transcription factors and transcriptional coactivators (defined as a type of protein that itself hasno DNA-binding activity, but can bind to a transcription factor to augment or repress the transcriptionfactor’s ability to activate gene expression) have been implicated in PH and right ventricular dysfunction.Some of the transcription factors include PPAR-γ, myocyte enhancer factor 2 (MEF2), FoxO, p53, KLF4,HIFs, CCAAT-enhancer binding proteins (CEBPs), Runt-related transcription factor 2 (RUNX2), activatorprotein 1 (AP-1), CtBP1, FoxM1, PKM2, NF-κB, β-catenin, the Twist family basic helix–loop–helixtranscription factor 1 (TWIST1) and SLUG (figure 7) [45, 51, 72–77]. FoxO1 isoform inactivation isinvolved in the pro-proliferative and apoptosis-resistant phenotype of PA-SMCs, and is a knowndownstream mediator of different growth factors and inflammatory mediators [45]. Furthermore, therelated transcription factor FoxM1 promotes PA-SMC accumulation in PH [77], suggesting that targetingthe FoxO–FoxM1 axis could be a viable strategy for treatment of PH. Transcription factor coactivatorshave also been recently implicated in PH pathophysiology. These include PKM2 and CtBP1 [39, 72].Importantly, normalising metabolic activity via metabolic inhibitors such as 2-deoxyglucose or directlyreducing CtBP1 expression attenuates PH fibroblast proliferation and apoptosis resistance [72].

Abnormalities in other transcription factors, such as Notch3, signal transducer and activator oftranscription 3 (STAT3), and the HIPPO central component large tumour suppressor 1 (LAST1) [78], andin various growth factors, underlie phenotypic changes in pulmonary vascular cells in PAH. For example,loss of PPAR-γ in pulmonary endothelial cells leads to a deficient complex with β-catenin and this resultsin reduced apelin, causing impaired pulmonary endothelial cell survival and angiogenesis [79]. Similarly,Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) are also emergingas key regulators of cell growth and migration in PAH and link mechanical stimuli to dysregulatedvascular metabolism [80]. A comparison of two rat strains, F344 and WKY, which differ in their responseto chronic hypoxia, highlighted the gene Slc39a12 that encodes the zinc transporter ZIP12 as anothermajor regulator of hypoxia-induced pulmonary vascular remodelling [81]. Although a more completeunderstanding of the overall risk–benefit ratio of these different strategies needs to be evaluated, these datareveal the potential therapeutic interest for targeting particular transcription factors and/or transcriptionfactor coactivators in PH/PAH.

PPAR-γ1, MEF2,

FoxO1, p53, KLF4

Hypoxia Shear stress Cytokines

Ion channels Growth factors Chemokines

Anti-proliferative,

anti-inflammatory

gene expression

HIF, CEBP, RUNX, AP-1,

CtBP1, FoxM1, PKM2, NF-κB,

β-catenin, TWIST1, SLUG

Pro-proliferative,

pro-inflammatory

metabolic gene expression

Transcription

factors

PH development/progression

FIGURE 7 Role of transcription factors and transcriptional coregulators in the pathogenesis of pulmonaryhypertension (PH). See main text for definitions. Multiple pathological stimuli, such as hypoxia, shear stress,oxidative stress, mitogens and inflammation (cytokines and chemokines), trigger downstream signallingcascades, which modulate the recruitment and activation of transcription factors and transcriptionalcoregulators that determine the stimulus-specific transcriptional responses in PH.

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Emerging roles for epigenetic dysregulationAltered DNA methylation of superoxide dismutase 2 and granulysin genes, histone H1 levels, aberrantexpression levels of histone deacetylases (HDACs) and bromodomain-containing protein 4, anddysregulated microRNA and long-non-coding RNA networks together suggest multiple levels of epigeneticinvolvement in PAH pathogenesis. Recently, clinical interest in HDAC inhibition in PAH has beenregenerated through the discovery that the cytosolic HDAC6 is implicated in both pulmonary arterialremodelling and right ventricular failure. Its inhibition using a HDAC6-specific inhibitor could be tested[82]. Therefore, a complete understanding of the mechanisms involved in altered gene expression indiseased cells [61] is vital for the design of novel therapeutic strategies. Mice lacking sirtuin 3 (SIRT3), amitochondrial deacetylase, develop spontaneous PH. Interestingly, these mice have increased acetylationand inhibition of many mitochondrial enzymes and complexes, suppressing mitochondrial function.Moreover, a loss-of-function SIRT3 polymorphism is associated with PAH [83]. These studies suggest thatmitochondrial products such as 2-hydroxyglutarate, α-ketoglutarate, citrate or acetyl-CoA may regulatetranscription factors and epigenetic mechanisms. This metabolism–epigenetics axis facilitates adaptation toa changing environment in the pulmonary vasculature and right ventricle, providing a potential noveltherapeutic target. In summary, an integrative understanding of the interplay between the molecular,metabolic, genetic and epigenetic rewiring in PH/PAH is far from complete, but conceptual themes arebeginning to emerge.

Metabolic remodelling and mitochondrial dysfunctionAberrant signalling in pulmonary vascular cells that contributes to PH/PAH development and progressionmay be the cause or consequence of metabolic dysregulation. Several metabolic and signalling pathwayscould be interesting targets for PH/PAH therapy, and those being investigated involve modulation of HIF1and the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway,mitochondrial phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), the HIPPO and p53signalling pathways, and inhibition of pyruvate dehydrogenase kinase (PDK), an inhibitor of themitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation).Restitution of oxidative metabolism with the use of dichloroacetate in PAH patients might be efficacious ina subset of patients [84]. Lack of clinical response was associated with the presence of functional variantsof SIRT3 and UCP2 (uncoupling protein 2) that predict reduced PDH function independent of PDK andgreater resistance to dichloroacetate [84]. Recently, accumulation of mitochondrial heat shock protein 90has been found to contribute to the heightened aerobic glycolysis and to the mitochondrial stress responsein cultured PA-SMCs from PAH patients [85]. Even if further investigations are required to betterunderstand the contribution of different inflammatory processes, high shear stress, chronic hypoxia andcertain hormones in these metabolic dysregulations, and to identify additional and novel mechanistictargets, the use of metabolism-based therapies may be promising for PH/PAH.

Current and future perspectivesAnimal model systems that mimic specific processes contributing to PH could be valuable to discover newtreatment targets and to study their contribution to the disease pathogenesis at early and late phases.However, it is also clear that pulmonary vascular lesions experimentally induced do not recapitulate thefull spectrum of the human disease, and there are interspecies, age, sex and environment differences in theresponses to stimuli used to promote PH in these different models. In addition, there are differences inthe anatomical and functional development of the immune system in animals compared with humans.The use of human tissue samples or iPSCs to derive endothelial cells or SMCs from PAH patients shouldthus complement animal studies in providing a path to move PAH treatment into the clinic. While thereare clearly limits to model PH, there are several measures that should improve predictive utility andtranslational efficiency: 1) define the research problem as precisely as possible; 2) identify the strengthsand weaknesses of each currently available PH model; and 3) identify how they may best be used.Improvements can be made in randomising animals, consideration of both sexes, and blindingobservations related to haemodynamic and structural end-points [86–88].

Considerable advances are possible by interrogating large datasets to find novel pathways, criticaltranscription factors, microRNAs, biomarkers and metabolic mediators of PAH as well as points ofintersection that can help develop better targeted therapies. Bioinformatic approaches with establisheddatasets can generate a PAH signature and an anti-signature that can be used to find novel or repurposedtherapies, as well as to deliver them. In addition to consideration of shear stress levels, the nature of thecell matrix and the nature of cell interactions need to be incorporated. For this reason, engineering systemsthat use all three layers of the vessel wall and that mimic the extracellular matrix produced by these cellswill be most informative. New opportunities such as three-dimensional printing can now produceextensive vascular networks.

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Translating exciting pre-clinical discoveries into clinical testing presents special challenges for a raredisease like PAH. First, because of the limited number of subjects, new approaches, gleaned from thelaboratory, must be used as adjuvants on top of standard-of-care therapy. An additional challenge forresearchers is to find common pathways or pathophysiological processes to safely target all forms of PH/PAH. In this line of investigation, analyses of data from publicly available databases of “PAH-omics” data(most commonly transcriptomes) and from pooled PAH registries could represent promising approachesto discover common modules of genes that reveal new therapies. Another appealing approach could be tomove away from common pathways to, instead, phenotype patients into “responder” and “non-responder”groups. Here, the challenge is discovering patient groups, within a group that is already small to start with,who are particularly well suited to adjuvant therapy.

Conflict of interest: M. Humbert reports personal fees from Actelion and Merck, and grants and personal fees fromBayer and GSK, outside the submitted work. C. Guignabert has nothing to disclose. S. Bonnet has nothing to disclose.P. Dorfmüller reports personal fees from MSD, Bayer, Actelion and Roche, outside the submitted work. J.R. Klingerreports grants for animal study of extra cellular vesicles from United Therapeutics, outside the submitted work. M.R.Nicolls has nothing to disclose. A.J. Olschewski has nothing to disclose. S.S. Pullamsetti has nothing to disclose.R.T. Schermuly has nothing to disclose. K.R. Stenmark reports grants from ContraFect, personal fees for advisory boardwork from Pfizer, New York, personal fees for membership of a steering Committee Member (Entelligence AwardsProgram) from Actelion, and personal fees for scientific advisory board work from Janssen Research and Development,outside the submitted work. M. Rabinovitch reports use of FK506 for the treatment of PAH. The Board of Trustees ofLeland Stanford Junior University, assignee. Patent PCT/US2012035793.

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58 Parpaleix A, Amsellem V, Houssaini A, et al. Role of interleukin-1 receptor 1/MyD88 signalling in thedevelopment and progression of pulmonary hypertension. Eur Respir J 2016; 48: 470–483.

59 Hautefort A, Girerd B, Montani D, et al. T-helper 17 cell polarization in pulmonary arterial hypertension. Chest2015; 147: 1610–1620.

60 Saito T, Miyagawa K, Chen SY, et al. Upregulation of human endogenous retrovirus-K is linked to immunity andinflammation in pulmonary arterial hypertension. Circulation 2017; 136: 1920–1935.

61 Rhodes CJ, Im H, Cao A, et al. RNA sequencing analysis detection of a novel pathway of endothelial dysfunctionin pulmonary arterial hypertension. Am J Respir Crit Care Med 2015; 192: 356–366.

62 Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl JMed 2013; 369: 351–361.

63 Song S, Ayon RJ, Yamamura A, et al. Capsaicin-induced Ca2+ signaling is enhanced via upregulated TRPV1channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH. Am J Physiol Lung Cell MolPhysiol 2017; 312: L309–L325.

64 Fernandez RA, Wan J, Song S, et al. Upregulated expression of STIM2, TRPC6, and Orai2 contributes to thetransition of pulmonary arterial smooth muscle cells from a contractile to proliferative phenotype. Am J PhysiolCell Physiol 2015; 308: C581–C593.

65 Song S, Carr SG, McDermott KM, et al. STIM2 (stromal interaction molecule 2)-mediated increase in restingcytosolic free Ca2+ concentration stimulates PASMC proliferation in pulmonary arterial hypertension.Hypertension 2018; 71: 518–529.

66 Hong Z, Chen KH, DasGupta A, et al. MicroRNA-138 and microRNA-25 down-regulate mitochondrial calciumuniporter, causing the pulmonary arterial hypertension cancer phenotype. Am J Respir Crit Care Med 2017; 195:515–529.

67 Allawzi AM, Vang A, Clements RT, et al. Activation of anoctamin-1 limits pulmonary endothelial cellproliferation via p38-MAPK-dependent apoptosis. Am J Respir Cell Mol Biol 2018; 58: 658–667.

68 Lambert M, Boet A, Rucker-Martin C, et al. Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunctionassociated with pulmonary hypertension. Cardiovasc Res 2018; 114: 880–893.

69 Antigny F, Hautefort A, Meloche J, et al. Potassium channel subfamily K member 3 (KCNK3) contributes to thedevelopment of pulmonary arterial hypertension. Circulation 2016; 133: 1371–1385.

70 Nagaraj C, Tang B, Nagy BM, et al. Docosahexaenoic acid causes rapid pulmonary arterial relaxation via KCachannel-mediated hyperpolarisation in pulmonary hypertension. Eur Respir J 2016; 48: 1127–1136.

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72 Li M, Riddle S, Zhang H, et al. Metabolic reprogramming regulates the proliferative and inflammatory phenotypeof adventitial fibroblasts in pulmonary hypertension through the transcriptional corepressor C-terminal bindingprotein-1. Circulation 2016; 134: 1105–1121.

73 Calvier L, Chouvarine P, Legchenko E, et al. PPARgamma links BMP2 and TGFbeta1 pathways in vascularsmooth muscle cells, regulating cell proliferation and glucose metabolism. Cell Metab 2017; 25: 1118–1134.

74 Kapitsinou PP, Rajendran G, Astleford L, et al. The endothelial prolyl-4-hydroxylase domain 2/hypoxia-induciblefactor 2 axis regulates pulmonary artery pressure in mice. Mol Cell Biol 2016; 36: 1584–1594.

75 Ball MK, Waypa GB, Mungai PT, et al. Regulation of hypoxia-induced pulmonary hypertension by vascularsmooth muscle hypoxia-inducible factor-1alpha. Am J Respir Crit Care Med 2014; 189: 314–324.

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Genetics and genomics of pulmonaryarterial hypertension

Nicholas W. Morrell1, Micheala A. Aldred2, Wendy K. Chung3,C. Gregory Elliott4, William C. Nichols5, Florent Soubrier 6,Richard C. Trembath7 and James E. Loyd8

Number 2 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals,Cambridge, UK. 2Indiana University School of Medicine, Indianapolis, IN, USA. 3Columbia University MedicalCenter, New York, NY, USA. 4Intermountain Medical Center and University of Utah, Salt Lake City, UT, USA.5Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. 6Dept of Genetics, Hopital Pitié-Salpêtrière, Paris, France. 7Division of Genetics and Molecular Medicine, School of Basic and MedicalBiosciences, King’s College London, London, UK. 8Vanderbilt University Medical Center, Nashville, TN, USA.

Correspondence: Nicholas W. Morrell, Dept of Medicine, University of Cambridge School of Clinical Medicine,Box 157, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0QQ, UK. E-mail: nwm23@cam.ac.uk

Correspondence: James E. Loyd, Division of Allergy, Pulmonary and Critical Care Medicine, Dept of Medicine,Vanderbilt University Medical Center, 1611 21st Avenue South, T-1218 Medical Center North, Nashville, TN37232, USA. E-mail: jim.loyd@vanderbilt.edu

@ERSpublicationsState of the art and research perspectives in genetics and genomics of pulmonary hypertension andinsights into pathobiology http://ow.ly/dkkq30mgDo2

Cite this article as: Morrell NW, Aldred MA, Chung WK, et al. Genetics and genomics of pulmonaryarterial hypertension. Eur Respir J 2019; 53: 1801899 [https://doi.org/10.1183/13993003.01899-2018].

ABSTRACT Since 2000 there have been major advances in our understanding of the genetic andgenomics of pulmonary arterial hypertension (PAH), although there remains much to discover. Based onexisting knowledge, around 25–30% of patients diagnosed with idiopathic PAH have an underlyingMendelian genetic cause for their condition and should be classified as heritable PAH (HPAH). Here, wesummarise the known genetic and genomic drivers of PAH, the insights these provide into pathobiology,and the opportunities afforded for development of novel therapeutic approaches. In addition, factorsdetermining the incomplete penetrance observed in HPAH are discussed. The currently availableapproaches to genetic testing and counselling, and the impact of a genetic diagnosis on clinicalmanagement of the patient with PAH, are presented. Advances in DNA sequencing technology are rapidlyexpanding our ability to undertake genomic studies at scale in large cohorts. In the future, such studieswill provide a more complete picture of the genetic contribution to PAH and, potentially, a molecularclassification of this disease.

Received: Oct 05 2018 | Accepted: Oct 09 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

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| SERIESWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

IntroductionFor half a century after the mid-1900s, when cardiac catheterisation first provided clinicians the ability tosafely measure pulmonary haemodynamics, idiopathic pulmonary arterial hypertension (IPAH, then termedprimary pulmonary hypertension (PPH)) was recognised as a lethal pulmonary vascular disease ofenigmatic origin. Near the turn of this century, new understanding was developed of the specific geneticpredisposition in families with PAH and that information was a driver to revise the classification of PAH bythe 3rd World Symposium on Pulmonary Hypertension in 2003. Since 2000, investigators have contributedincreasing knowledge of the genetics and genomics of PAH. Technological advances in genetic sequencinghave enabled inexpensive and rapid sequencing of the coding regions of the genome (whole exomesequencing (WES)), or the whole genome (whole genome sequencing (WGS)), in families and large cohortsof patients (figure 1). Insights from human genetics are increasing our understanding of the pathobiology ofPAH, identifying new potential drug targets, and informing the care of patients and their families.

State of the artMendelian inheritanceThere is a family history of PAH in 6–10% of patients not associated with other underlying disorders [1].In 2000, genetic analysis of such families identified heterozygous germline mutations in BMPR2, the geneencoding bone morphogenetic protein receptor type 2, a member of the transforming growth factor-β(TGF-β) superfamily [2, 3]. Subsequently, mutations were also identified in IPAH [4]. It is now wellestablished that around 70–80% of families with PAH and 10–20% of IPAH cases are caused by mutationsin BMPR2 [5].

Sequencing of genes encoding BMP receptor signalling intermediaries led to the identification of raresequence variants in SMAD1, SMAD4 and SMAD9 [6, 7]. The identification of additional SMAD9mutations in large cohorts has confirmed its role in PAH [8]. In addition, exome sequencing ofBMPR2-negative individuals with more than one family member diagnosed with PAH revealed mutationsin CAV1, which encodes caveolin-1 and functions to physically colocalise BMP receptors [9]. A raremutation in CAV1 has been associated with both lipodystrophy and PAH in a young child. KCNK3(potassium channel subfamily K member 3) mutations were also identified by exome sequencing andencode a potassium channel that contributes to the membrane potential to determine pulmonary vasculartone [10]. Array comparative hybridisation and sequencing in childhood and (rarely) adult-onset PAHidentified deletions and loss-of-function mutations in TBX4 (T-box 4), a gene that is also associated withsmall patella syndrome [11]. Mutations in TBX4 are among the most common genetic causes of PAH inchildren and suggest that PAH is at least in part a developmental lung disease when it presents early in life[12, 13]. The recognition that severe PAH can also occur in families segregating hereditary haemorrhagictelangiectasia (HHT) implicated ACVRL1 (activin receptor-like kinase 1 (ALK1)) and ENG (endoglin)mutations in PAH [14–16].

Recently, a large survey was undertaken in a collaborative European cohort of adult-onset (>18 years)patients with IPAH, familial PAH (FPAH) and anorexigen-associated PAH [8]. This study of over 1000

Chromosome 2locus identified

Linkage analysis in families and Sanger sequencing

2nd WSPHEvian,France1998

3rd WSPHVenice,

Italy2003

4th WSPHDana Point,

CA, USA2008

5th WSPHNice,

France2013

6th WSPHNice,

France2018

Sequencing ofcandidate genes

Whole exome sequencing

Whole genome sequencing

BMPR2ALK1 ENG SMAD9

SMAD1CAV1

KCNK3TBX4

EIF2AK4 New genes

FIGURE 1 The history of genetic discovery in pulmonary arterial hypertension. WSPH: World Symposium onPulmonary Hypertension.

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patients confirmed the presence of causal mutations in BMPR2 (15.3%), TBX4 (1.3%), ACVRL1 (0.9%),ENG (0.6%), SMAD9 (0.4%) and KCNK3 (0.4%). No pathogenic coding variants in CAV1, SMAD1 orSMAD4 were identified, possibly due to the rarity of mutations in these genes in adults. The same studyidentified mutations in new PAH genes: ATP13A3 (ATPase 13A3; 1.1%), SOX17 (SRY-box 17; 0.9%),AQP1 (aquaporin 1; 0.9%) and GDF2 (growth differentiation factor 2/BMP9; 0.8%), and suggestedadditional genes that will require further validation. Mutations in all of these genes are autosomaldominantly inherited and exhibit reduced penetrance, meaning that some individuals who carry amutation do not manifest PAH. In IPAH cases, the mutation may be inherited from an unaffected parentor occur de novo. Where parental samples are available, determining that a mutation occurred de novo canbe helpful in establishing pathogenicity. Among paediatric IPAH patients without mutations in known riskgenes, exome sequencing revealed a 2-fold enrichment of de novo predicted deleterious variants. De novovariants in novel genes may explain 19% of paediatric-onset IPAH cases [12]. The incomplete penetranceobserved for PAH genes suggests that additional genetic, epigenetic and/or environmental factorscontribute to disease risk/progression.

In 2014, biallelic mutations in EIF2AK4, a gene encoding eukaryotic translation initiation factor 2α kinase 4,were identified as a cause of heritable pulmonary capillary haemangiomatosis (PCH) [17] and pulmonaryveno-occlusive disease (PVOD) [18]. PVOD and PCH are rare and pathologically distinct forms of PAH.Heritable PVOD and PCH are autosomal recessive and nearly completely penetrant, unlike other forms ofPAH. Individuals diagnosed with apparently sporadic PVOD or PCH may also carry biallelic EIF2AK4mutations in up to 25% of cases [17, 18]. Detection of biallelic pathogenic EIF2AK4 mutations establishes aprecise and accurate molecular diagnosis of PVOD/PCH without requiring a lung biopsy [19].

A summary of the genes reported to date in patients with HPAH is shown in table 1. A high level ofevidence needs to be established for the causal role of mutations in a particular gene before it is used inclinical screening and management.

Common genetic variationThe role of common genetic variation contributing to the aetiology or clinical course of PAH is less welldefined. To date only one genome-wide association study has been published to identify variantsassociated with PAH (n=625 cases). This study detected a significant association at the CBLN2 (cerebellin2 precursor) locus mapping to 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97(p=7.47 × 10−10) [20]. Another large study evaluated associations between polymorphisms in genescomprising the endothelin signalling pathway and clinical outcomes in 715 PAH patients of Europeandescent in the STRIDE study (sitaxsentan). An association was identified between a single nucleotidepolymorphism (rs11157866) in the G-protein γ subunit gene GNG2 and a combined improvement infunctional class and 6-min walk distance [21]. In a smaller study, levels of serum endostatin, a potentantiangiogenic protein with the capacity to induce endothelial cell apoptosis and inhibit endothelial cellproliferation, correlated with poor functional status and was a strong predictor of mortality in group 1patients. In contrast, a missense variant (rs12483377) in COL18A1, which encodes endostatin, wasassociated with lower circulating protein and reduced mortality [22]. Abnormalities of mitochondrialmetabolism are now well recognised in PAH. A recent study suggests that variants in the mitochondrialgenome may influence the risk of developing PAH, with a lower rate of disease associated with haplogroupL, the oldest ancestral human haplogroup [23]. Lastly, in a study of 2761 healthy adults, variants inoestradiol metabolism (CYP1B1 (cytochrome P450 1B1)) and androgen receptor genes were associatedwith right ventricular function [24]. Given the significant sex disparities in PAH and previous evidencethat CYP1B1 variants may modulate disease penetrance in BMPR2 mutation carriers [25], these variantswarrant further study regarding a possible role in right ventricular remodelling in PAH.

TABLE 1 Classification of pulmonary arterial hypertension genes according to level of evidencethat they play a causal role in the disease

Higher level of evidence Lower level of evidence

BMPR2; EIF2AK4; TBX4; ATP13A3; GDF2; SOX17;AQP1; ACVRL1; SMAD9; ENG; KCNK3; CAV1

SMAD4; SMAD1; KLF2; BMPR1B; KCNA5

Evidence includes de novo mutation, cosegregation studies, association with replication and functionalstudies.

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Pathobiology links between mutations and diseasePAH mutations and disease pathobiologyBMPR2 is expressed on the surface of a wide number of cells, but it is particularly highly expressed on thepulmonary vascular endothelium, where it forms a complex with the type I receptors, ALK1 or ALK2. TheALK1/BMPR2 receptor complex signals specifically in response to the circulating BMP ligands, BMP9 andBMP10, utilising ENG as a coreceptor [26, 27]. ALK1 and ENG are also highly expressed in thepulmonary endothelium, and this requirement for high levels of BMPR2/ALK1 signalling in thepulmonary endothelium may contribute to the lung-specific effects of BMPR2 mutations. BMP9 (encodedby GDF2) functions as a circulating vascular quiescence factor, protects endothelial cells from apoptosisand excessive proliferation, and inhibits vascular permeability. Loss of BMPR2 also favours endothelialdysfunction and promotes endothelial-to-mesenchymal transition. Given that mutations in ALK1 andENG (usually associated with HHT) can also cause PAH, the genetic evidence strongly suggests that thepulmonary endothelial cell is an important initiating cell type in PAH pathobiology. Nevertheless, loss ofBMPR2 function in other cell types (e.g. smooth muscle cells, fibroblasts and immune cells) may alsocontribute to disease pathobiology. For example, pulmonary artery smooth muscle cells with BMPR2mutations are hyperproliferative and resistant to the growth-suppressive effects of BMPs, through loss ofantiproliferative Smad1/5 signalling [28].

Other less common PAH mutations are also related to the BMP pathway. Smad8 (encoded by the SMAD9gene) is a downstream mediator of BMP signalling, together with Smad1 and 5. Heterozygous mutationsof SMAD9 have relatively little effect on canonical BMP signalling through Smad4, presumably due toredundancy with Smad1/5 function [29]. However, in relation to a Smad4-independent pathway thatpromotes microRNA maturation [30], SMAD9 mutations lead to significant loss of function, suggestingthat microRNAs regulated in this manner may play an important role in PAH pathogenesis [29]. Similarresults were seen in a case with congenital heart disease (CHD)-associated PAH in which pulmonaryartery endothelial cells carried a somatic heterozygous deletion of SMAD9 [31].

EIF2AK4, also known as general control non-derepressible 2 (GCN2), is a serine/threonine protein kinasethat phosphorylates the α subunit of eukaryotic initiation factor 2, which plays a key role in modulatingamino acid metabolism in response to nutrient deprivation. EIF2AK4 senses amino acid deficiencythrough binding to uncharged transfer RNA. The molecular and cellular mechanisms by which loss offunction of this kinase promotes the development of PVOD/PCH is under active investigation. In theEif2ak4−/− mouse, an increased inflammatory response to stress was observed in the intestine, secondaryto decreased autophagy and increased oxidative stress and its effect on inflammasome activation andinflammation [32]. It remains to be demonstrated if similar mechanisms are involved in the intimalfibrosis and endothelial cell proliferation observed in the lung vessels of heritable PVOD. Alternatively,EIF2AK4 biallelic loss of function leads to decreased TRIB3 (Tribbles-like protein 3), whosedownregulation has been shown to inhibit BMP-mediated cellular response [33]. Under this hypothesis,EIF2AK4 loss of function would have similar consequences to BMPR2 or SMAD9 mutations by decreasingBMP signalling.

CAV1 is a major constituent protein of caveolae (flask-shaped invaginations of the plasma membrane) andis highly expressed in endothelial cells. BMP receptors are localised in caveolae, as well as other regions ofthe plasma membrane, and studies suggest that caveolae are required for initiation of BMP signalling [34].Loss of CAV1 decreases BMPR2 membrane localisation and signalling [35]. Conversely, BMPR2 mutationscan lead to caveolar trafficking defects and intracellular localisation [36]. Lastly, it is notable that even inthe absence of a heritable mutation, expression levels of BMPR2 and CAV1 are reduced in PAH lungtissues [37, 38].

Factors affecting disease penetranceDespite the fact that pathogenic BMPR2 mutations clearly cause PAH, the penetrance of the diseasephenotype is incomplete. The best estimate is that penetrance in male carriers is around 14%, whereas infemales it is around 42% [39]. Thus, female sex is the single most important factor influencing thepenetrance of BMPR2 mutations in PAH, possibly driven by oestrogen metabolism [25]. Additional factorsinfluencing penetrance may be genetic, epigenetic and/or environmental. Genetic factors may include theexpression level of wild-type BMPR2 from the unaffected allele [40], genetic variants affecting theexpression levels of TGF-β [41] or alternative splicing of BMPR2 [42]. Studies in induced pluripotent stemcells derived from affected and unaffected BMPR2 mutation carriers have suggested that geneticbackground, specifically differences in expression of BMP pathway-modifying genes, might contribute topenetrance [43]. Additional large-scale longitudinal studies of affected and unaffected mutation carriers arerequired to more systematically search for genetic and environmental modifiers of penetrance.

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Although no study has yet addressed potential environmental factors influencing the penetrance ofBMPR2 mutations in human cohorts, studies suggest that inflammatory mediators, e.g. lipopolysaccharide[44], tumour necrosis factor-α (TNF-α) [45] and 5-lipoxygenase [46], can drive the development of PH ingenetically modified mice and in patient-derived pluripotent stem cells [47]. TNF-α directly suppressesBMPR2 mRNA and protein expression. In addition, epigenetic mechanisms such as hypermethylation ofthe BMPR2 promoter may play a role [48]. Several microRNAs have also been shown to target BMPR2mRNA to modify expression levels of the protein, including miR-21 [49] and miR-17-92 [50].

Another factor that may contribute to penetrance is somatic mutation within lung vascular cells [51].Several groups have identified DNA damage in endothelial and smooth muscle cells from PAH lungs incomparison with controls [51–53]. Loss of BMPR2 was associated with a deficiency of DNA repair [54],but increased DNA damage was also evident in cells from IPAH and associated PAH cases, and may beinduced by environmental exposures such as methamphetamine use [55]. Further studies are needed tounderstand the role of DNA damage within the lung and its contribution to disease pathogenesis.

Genetic counselling/testing and management of healthy mutation carriersGenetic counsellingMutations in PAH genes have been identified in IPAH and FPAH, anorexigen-associated PAH, PVOD/PCH, and in children with IPAH and PAH associated with CHD. There is a medicolegal duty to informall patients in these groups about the possibility of a genetic condition and that family members couldcarry a mutation that increases the risk of PAH, allowing for screening and early diagnosis. Even if genetictesting is not performed, family members should be made aware of early signs and symptoms to ensurethat a timely and appropriate diagnosis is made. If a mutation is identified in a patient, the symptomaticpatient should be reclassified as HPAH.

Genetic education and counselling should be performed prior to genetic testing for PAH to address thecomplex issues of incomplete penetrance, questions of surveillance for genetically at-risk family members,reproductive questions, concerns about genetic discrimination, as well as psychosocial issues of guilt andblame that can accompany genetically based diseases. Pre-test genetic education of the affected individualcan be performed by PAH providers and/or genetic professionals, and is facilitated by focused educationalvideos (e.g. www.youtube.com/watch?v=36rlvtj_Qrs). In-depth genetic counselling with genetic professionalsincluding genetic counsellors or medical geneticists is critical prior to genetic testing for asymptomaticfamily members. Families should also be referred to a genetic counsellor and/or clinical geneticist if theywish to consider reproductive options. The genetic counselling experience of a national reference centre onPAH shows the potential interest in genetic testing in asymptomatic family members [56].

Genetic testing in the family should begin with an affected individual whenever possible to identify therelevant mutation in the family. Otherwise, a negative genetic test result in unaffected family members isnot informative. If the familial mutation is known and an unaffected family member tests negative for thatmutation, the risk of PAH for that person is the same as the general population (around 1 per 1000000 inNorth America). This can provide great psychological relief to that family member and they can forgoevaluations to screen for PAH.

Genetic testingGenetic testing can help to explain the aetiology of the disease and stratify risk for other family membersand for future children. Clinical genetic testing is available in North America and Europe, and materialcan be sent to American or European genetic laboratories from other parts of the world. The current costof testing ranges from approximately USD1000 to USD1500 to analyse the first member of a family. Oncethe family-specific mutation is known, testing other family members costs USD300–500 in the USA. Theexact number of genes included, cost of testing and insurance coverage for testing varies by country andinsurer. The most commonly cited reason for genetic testing for PAH is to provide information to andabout children, and interest in testing is especially high for paediatric-onset PAH [57].

Targeted sequencingAs the number of genes associated with PAH increases, it has become arduous to test for each of thesegenes individually. The advent of next-generation sequencing has enabled the development of gene panelsto interrogate several genes simultaneously. Several different technologies and platforms are available, andmany are now offered on a clinical basis (www.ncbi.nlm.nih.gov/gtr/conditions/C0152171/). In addition,several of these genes can be analysed for dosage changes to detect deletions or duplications of one ormore exons. Such mutations are common in BMPR2 and TBX4. An appropriate methodology, such asmultiplex ligation-dependent probe amplification, should be used since these types of mutations are not

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readily detected by sequencing. It is important to check the genes included in the panel at the time oftesting since the composition changes as genetic discoveries advance.

Whole exome sequencing and whole genome sequencingIf an up-to-date panel of PAH genes fails to identify a pathogenic variant in a patient with familial PAHor in a child, WES may be appropriate to identify potentially novel genes. In the case of paediatric-onsetPAH, testing should ideally include the child and both parents to allow for facile identification of de novovariants. This trio approach was used to identify both the CAV1 and KCNK3 genes [9, 10]. The largest trioanalyses suggest that 19% of childhood-onset IPAH is due to de novo mutations [12]. Exome sequencing issignificantly more expensive than panel gene testing and should be ordered by a genetic professional whocan discuss the option of learning about incidental or secondary findings, currently comprised of 59 genesrecommended by the American College of Medical Genetics and Genomics that are medically actionableand potentially life saving, including genes for hereditary cancer and sudden cardiac death [58].

On the horizon is the use of WGS, which enables the identification of variants in the non-coding regionsin a patient’s genome, but is not yet routinely used on a clinical basis. Exome and genome sequencinghave the advantage of iterative reanalysis over time as novel genes are identified.

Interpretation of sequencing dataThe main problem with WES and WGS is the large number of variants identified in any individual.Interpreting the functional consequences of missense and non-coding variants is particularly challenging.Therefore, identifying potentially pathogenic variants in novel genes requires filtering out commonvariants based upon large databases of reference allele frequencies and bioinformatic prediction of thelikely functional effects. Segregation studies within families can sometimes clarify a variant of uncertainsignificance (VUS), especially if the variant is de novo or if it segregates with PAH in other affected familymembers [58], while appreciating that penetrance is usually incomplete and that carriers may beunaffected. Only genetic variants classified as pathogenic or likely pathogenic (not VUS) can be used togenetically risk stratify unaffected family members.

Psychosocial considerations and reproductive optionsGenetic test results may cause more harm than good in some individuals because there is currently noeffective way to prevent or differentially treat hereditary forms of PAH and because of the incompletepenetrance of mutations. Identifying a mutation in a family can be associated with feelings of guilt in theparent who has passed on a mutation to their child. There are also concerns about genetic discriminationin employment and insurance. Legal safeguards against genetic discrimination vary by country. In theUSA, the Genetic Information Nondiscrimination Act protects insured members against discrimination incoverage or cost of health insurance and protects against discrimination in employment, but not againstdiscrimination in life, long-term care or disability insurance based upon a genetic predisposition. Incountries with universal healthcare, the concerns about genetic discrimination are not as great and genetictesting uptake rates have been higher.

Reproductive options for those who carry pathogenic mutations include adoption, use of donor gametes,pre-natal testing, in vitro fertilisation (IVF) with pre-implantation genetic diagnosis or not consideringPAH genetic status. Accessibility and insurance coverage for IVF and pre-implantation genetic diagnosisvary by country, but coverage is often not readily available due to the cost to the patient.

Practical application of genetics and genomicsWhat is the utility of genetic diagnosis in PAH patients?Pathogenic PAH mutations associate with disease characteristics that influence treatment and prognosis.For example, HPAH associated with BMPR2 or ACVRL1 mutations presents at a younger age, with moresevere haemodynamic abnormalities, and a very low probability of acute vasoreactivity, as well as reducedsurvival in the current treatment era [59, 60]. Patients with a heritable form of PVOD are also younger atpresentation than non-mutation carriers, but there is no significant difference in the event-free survival at3 years [61].

Several studies have clearly shown that detection of pathogenic EIF2AK4 mutations is especially useful.The diagnosis of PVOD/PCH challenges PH clinicians, radiologists and pathologists. Identification ofbiallelic EIF2AK4 mutations allows confirmation of heritable PVOD/PCH without a lung biopsy andidentifies a unique form of PAH that not only does not respond well to current PAH medication, but alsopredisposes to pulmonary oedema when these medications are administered [61]. A subgroup ofindividuals diagnosed with IPAH or HPAH may also carry biallelic pathogenic EIF2AK4 mutations. Theseindividuals are characterised by presenting under the age of 50 years with a diffusing capacity of the lung

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for carbon monoxide (DLCO) <50% of predicted [62–64]. Thus, we suggest that clinicians test youngerPAH patients who have a low DLCO for EIF2AK4 mutations in order to guide treatment and for riskassessment in family members [63].

Findings from genomic studies are also starting to be used to better understand the disease process andtherapeutic responses. HEMNES et al. [65] identified a peripheral blood RNA expression signature inpatients with a PAH subphenotype responsive to calcium channel blocker therapy, suggesting anon-invasive approach to predict drug responsiveness. Using WES, genetic variants that may underlie thissubphenotype were also identified [66]. As discussed previously, common genetic variants have beenassociated with risk of PAH, survival and/or pharmacogenomic response to therapy. Most recently, it wasshown that common functional variants in SIRT3 and UCP2 might predict the response to inhibition ofpyruvate dehydrogenase kinase by dichloroacetate in a phase 2 clinical trial in PAH [67], paving the wayfor future precision medicine studies with this drug.

From genes to therapiesMolecular pathways highlighted by genetic studies are now the subject of several novel therapeuticapproaches (figure 2). LONG et al. [68] reported the beneficial effects of BMP9 administration inheterozygous BMPR2 knockout mice, suggesting that compensating for BMPR2 haploinsufficiency byincreasing dose of the ligand might constitute a targeted therapy for human PAH. At the receptor level,approaches include translational readthrough of nonsense mutations using ataluren to restore full-lengthprotein [69] or slowing down lysosomal degradation of BMPR2 with chloroquine to increase receptordensity at the cell surface [70, 71]. Both approaches effectively restored BMP signalling in vitro andlysosomal blockade reversed PH in experimental models. Inhibition of TNF-α with etanercept not only

BRE

Target genes

Stabilise BMPR2:hydroxychloroquine,etanercept

Readthrough nonsense mutations:ataluren

Relieve inhibition of BMP signalling: FK506

Smad8 Smad5

Smad4

Smad1P

PP

PP

P

FKBP12

BMPR2

BMP9/10CAV1

Direct receptor agonism: BMP9Enhance receptorrecruitment: elafin

Recover K+ channelfunction: ONO-RS-082

ALK1 Endoglin KCNK3

PP

FIGURE 2 From genes to therapies: precision medicine approaches in pulmonary arterial hypertension (PAH).BMP(R): bone morphogenetic protein (receptor); BRE: BMP-responsive element; CAV1: caveolin-1; FKBP12:12-kDa FK506-binding protein. BMP signalling in endothelial cells is mediated by the ligands BMP9 andBMP10 via the ALK1/BMPR2 receptor complex. Endoglin serves as an accessory receptor. Signalling ismediated by phosphorylation of the receptor Smads (Smad1, 5 and 8), which then associate with Smad4 andtranslocate to the nucleus, regulating genes that contain BREs in their promoters. CAV1 facilitates receptorcolocalisation, while KCNK3 encodes a potassium channel that contributes to pulmonary vascular tone. Genesthat are mutated in heritable PAH are in bold. Potential therapeutic approaches targeted to these pathwaysinclude: exogenous administration of BMP9 ligand, increasing availability of functional BMPR2 receptors(hydroxychloroquine, etanercept), promoting readthrough of nonsense mutations to restore functional BMPR2or Smad8 protein (ataluren), enhancing downstream signalling by relieving FKBP12 inhibition of BMP type 1receptors (FK506), promoting CAV1-mediated receptor recruitment (elafin), or recovering KCNK3 channelconductance (ONO-RS-082).

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targets inflammation, but can reduce receptor shedding and proteosomal degradation of BMPR2 [45].Elafin acts via CAV1 to promote receptor recruitment and enhance BMP signalling, reversing experimentalPH [72]. Downstream of BMPR2, FK506 was found to increase BMP signalling and to reverseexperimental PH, by binding FK-binding protein 12, an inhibitor of BMP signalling [73]. Phase 2a clinicaltrials have established safety and tolerability of low-dose FK506 in PAH [74]. Beyond the BMP pathway,KCNK3 mutations lead to reduced potassium channel conductance, which, at least for some mutations,can be recovered by the phospholipase A2 inhibitor ONO-RS-082 [10]. These studies underline theconsiderable progress that has been made in translating basic genetic studies into potential therapeuticmodalities. While direct correction of the underlying mutations remains challenging at present, rapidadvances in gene-editing technologies may make targeted mutational correction within the lungvasculature a realistic prospect in the future.

Proposed future directionsThese different genomic approaches highlight potential paths forward for using molecular medicine toimprove PAH patient care. Several large-scale genetics/genomics studies are currently underway in theUSA and Europe. Of note, the US National Biological Sample and Data Repository for PAH (the “PAHBiobank”; www.pahbiobank.org) is generating genetic data (targeted DNA sequencing, WES andgenome-wide single nucleotide polymorphisms) for 3000 group 1 PAH patients. The BRIDGE Project inthe UK includes PAH as one of the rare diseases for which WGS data are being generated (https://bridgestudy.medschl.cam.ac.uk/pah.shtml). Over 1250 IPAH/familial PAH patients from Europe are beinganalysed to investigate the underlying genetic variation contributing to the disease. In addition, the USNational Institutes of Health PVDOMICS initiative aims to define new molecular classifications across thetraditional World Health Organization groups by combining deep clinical phenotyping with multiple“omics” analyses [75]. It is only through such cohorts and initiatives that we will begin to have adequatepower to discover the range of genetic factors underlying PAH to provide a more complete genomicunderstanding of the disease. Ideally, this will lead to the identification of additional novel targets for newdrugs. It also may facilitate prevention strategies for PAH and the prediction of prognosis based on agenetic classification of PAH.

Conflict of interest: N.W. Morrell reports grants and personal fees from Morphogen-IX, outside the submitted work.M.A. Aldred reports grants from the NIH, during the conduct of the study. W.K. Chung has nothing to disclose.C.G. Elliott reports personal fees for steering committee work from Bayer and Bellerophon, grants and personal fees forregistry and data safety monitoring from Actelion, and was a consultant for end-point adjudication for Lung LLC, withfees paid to his employer (Intermountain Healthcare), outside the submitted work. W.C. Nichols has nothing todisclose. F. Soubrier has nothing to disclose. R.C. Trembath has nothing to disclose. J.E. Loyd has nothing to disclose.

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Pathophysiology of the right ventricleand of the pulmonary circulation inpulmonary hypertension: an update

Anton Vonk Noordegraaf1, Kelly Marie Chin2, François Haddad3,Paul M. Hassoun4, Anna R. Hemnes5, Susan Roberta Hopkins6,Steven Mark Kawut7, David Langleben8, Joost Lumens9,10 and Robert Naeije11,12

Number 3 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1Amsterdam UMC, Vrije Universiteit Amsterdam, Pulmonary Medicine, Amsterdam CardiovascularSciences, Amsterdam, The Netherlands. 2Division of Pulmonary and Critical Care Medicine, University ofTexas Southwestern, Dallas, TX, USA. 3Division of Cardiovascular Medicine, Stanford University and StanfordCardiovascular Institute, Palo Alto, CA, USA. 4Division of Pulmonary and Critical Care Medicine, JohnsHopkins University, Baltimore, MD, USA. 5Division of Allergy, Pulmonary and Critical Care Medicine, VanderbiltUniversity Medical Center, Nashville, TN, USA. 6Dept of Medicine, University of California, San Diego, La Jolla,CA, USA. 7Penn Cardiovascular Institute, Dept of Medicine, and Center for Clinical Epidemiology and Biostatistics,Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 8Center for Pulmonary VascularDisease, Cardiology Division, Jewish General Hospital and McGill University, Montreal, QC, Canada. 9MaastrichtUniversity Medical Center, CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands.10Université de Bordeaux, LIRYC (L’Institut de Rythmologie et Modélisation Cardiaque), Bordeaux, France.11Dept of Cardiology, Erasme University Hospital, Brussels, Belgium. 12Laboratory of CardiorespiratoryExercise Physiology, Faculty of Motor Sciences, Université Libre de Bruxelles, Brussels, Belgium.

Correspondence: Anton Vonk Noordegraaf, Amsterdam UMC, Vrije Universiteit Amsterdam, PulmonaryMedicine, Amsterdam Cardiovascular Sciences, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.E-mail: a.vonk@vumc.nl

@ERSpublicationsState of the art and research perspectives in pathophysiology of the right ventricle and of the pulmonarycirculation in pulmonary hypertension with theoretical and practical aspects http://ow.ly/18v830mgLiP

Cite this article as: Vonk Noordegraaf A, Chin KM, Haddad F, et al. Pathophysiology of the right ventricleand of the pulmonary circulation in pulmonary hypertension: an update. Eur Respir J 2019; 53: 1801900[https://doi.org/10.1183/13993003.01900-2018].

ABSTRACT The function of the right ventricle determines the fate of patients with pulmonaryhypertension. Since right heart failure is the consequence of increased afterload, a full physiologicaldescription of the cardiopulmonary unit consisting of both the right ventricle and pulmonary vascular systemis required to interpret clinical data correctly. Here, we provide such a description of the unit and itscomponents, including the functional interactions between the right ventricle and its load. This physiologicaldescription is used to provide a framework for the interpretation of right heart catheterisation data as well asimaging data of the right ventricle obtained by echocardiography or magnetic resonance imaging. Finally, anupdate is provided on the latest insights in the pathobiology of right ventricular failure, including keypathways of molecular adaptation of the pressure overloaded right ventricle. Based on these outcomes, futuredirections for research are proposed.

This article has supplementary material available from erj.ersjournals.com

Received: Oct 05 2018 | Accepted: Oct 09 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

https://doi.org/10.1183/13993003.01900-2018 Eur Respir J 2019; 53: 1801900

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The cardiopulmonary unit: more than a sum of its partsThe function of the right ventricle is of great clinical importance in severe pulmonary hypertension (PH)since it determines the outcome of the disease [1, 2]. Given the fact that right heart failure in PH is theconsequence of increased (arterial) afterload and not the mere consequence of a myocardial disease, a fulldescription of the cardiopulmonary unit is required in the study of right heart failure (figure 1a and b).The cardiopulmonary unit is composed of two main functional subsystems, i.e. the right ventricle and thepulmonary vasculature, each having their own intrinsic characteristics (figure 1b). The ventricularpressure–volume loop analysis is central in understanding right ventricular physiology, while pressure–flowanalysis is central in understanding pulmonary haemodynamics. For the right ventricle, intrinsiccharacteristics include contractility, chamber stiffness and, although perhaps less established, the timeconstant of ventricular relaxation (τ), which are all load independent; for the pulmonary vascular system,resistance and compliance provide intrinsic characteristics of the steady and pulsatile load.

The interaction between the intrinsic ventricular characteristics and load results in global function, and iscommonly described by cardiac output (CO) and ejection fraction (EF), on the one hand, and pressure(mean, systolic and diastolic pressure), on the other hand. The pressure gradient over the pulmonarycirculation also falls into this category. Energy transfer of right ventricular to arterial load is a special formof interaction for which we reserve the term “coupling”. The concept of coupling is particularly importantin physiologically describing the continuum of ventricular adaptation in pulmonary arterial hypertension(PAH): well-adapted right ventricles often have preserved ventriculo-arterial coupling, while maladaptedright ventricles have varying degrees of altered ventriculo-arterial coupling (figure 2). These concepts willbe discussed in more detail in the following section.

This distinction between intrinsic characteristic of a subsystem and global function or systemcharacteristics has important physiological implications. For example, despite the decrease in rightventricular EF (RVEF) in patients with PAH, right ventricle contractility as measured by ventricularelastance (i.e. end-systolic elastance (Ees)) is usually increased and not decreased [3].

DefinitionsThe current section presents some definitions that may help standardise important concepts relevant tothe field of right ventricular adaptation and right heart failure.

• Right heart failure in PH can be defined as a clinical syndrome characterised by decreased rightventricular function that leads to insufficient blood flow and/or elevated filling pressures at rest orduring physiologically demanding conditions, such as exercise, developmental growth or pregnancy.The cardinal symptoms of right heart failure include dyspnoea and fatigue as well as congestion. Theseverity of heart failure is often subcategorised according to New York Heart Association (NYHA)Functional Class and by the degree of congestion.

Intr

insi

cSy

stem

b) CPS: characterisationa) CPS: function Ventilation/perfusion matchingDiffusion capacity, distension, recruitment

Ventriculo-arterialcoupling

Perfusion–metabolism/MVO2

Atrio-ventricularinteractions

Synchrony

Lungs

LA

LV

Cardiac dynamic Pulmonary circulation

Pressure–volume

relationship

Pressure–flow

relationship

Heart rate: HR

Contractility: Ees

Relaxation: τDiastolic stiffness: Eed

Vascular resistance: PVR

Arterial compliance: PAC

Arterial elastance: Ea

Systemicorgans

Pressures

• RV pressures

• PAP

• PAWP

Volumes

• RV volumes

• Stroke volume

• EF

Flows

• CO

• Pulmonary

flow

Coupling

• Ees/Ea

RV

RA

Interventricular and interatrial interactions

Abdomino-CPS interactions

FIGURE 1 The cardiopulmonary system (CPS): a) function and b) characterisation. MVO2: myocardial oxygen consumption; RV: right ventricle; RA:right atrium; LA: left atrium; LV: left ventricle; Ees: end-systolic elastance; τ: time constant of ventricular relaxation; Eed: end-diastolic elastance;PVR: pulmonary vascular resistance; PAC: pulmonary arterial compliance; Ea: arterial elastance; PAP: pulmonary arterial pressure; PAWP:pulmonary arterial wedge pressure; EF: ejection fraction; CO: cardiac output. Subsystems (or units: heart, respectively its load) are characterisedby their intrinsic function, which can be derived from the ventricular pressure–volume relationship and the pulmonary pressure–flow relationship.The system parameters result from cardiopulmonary interaction.

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• Right ventricular adaptation in PH represents a continuum with an adapted right ventricle at one endand a maladapted ventricle at the other end. An adapted right ventricle in PH is characterised by aslightly dilated right ventricle with preserved stroke volume (SV), systolic function and normal fillingpressures, whereas a maladapted right ventricle is characterised by a dilated right ventricle withreduced SV, systolic function and increased filling pressures. As will be discussed in the followingsection, adapted ventricles usually have preserved ventriculo-arterial coupling, while maladaptedventricles usually have uncoupled ventricles (figure 2).

• Subsystem function (intrinsic properties of the cardiac or pulmonary vascular system): description of theright ventricle in a load-independent manner (Ees and end-diastolic elastance (Eed)) or pulmonaryvascular load in a manner independent of right ventricular function (pulmonary arterial vascularresistance (PVR), or arterial elastance (Ea), and pulmonary arterial compliance (PAC)).

• System function results from the interaction of the two subsystems, i.e. the ventricular pump and itsafterload. Interaction results in SV, CO, pressure and functional imaging parameters derived byechocardiography or cardiovascular magnetic resonance imaging (CMR). Descriptions of systolicfunction as RVEF or SV/right ventricular end-systolic volume (ESV) are also the result of functionalinteraction and not surrogates for coupling.

• Coupling: the condition that occurs when right ventricular function is adapted to the pulmonaryvascular load such that energy transfer is most efficient. This coupling is described by systolic andarterial elastance, Ees/Ea (figures 1b and 2).

Although this article focuses on the right ventricle, it is noteworthy that ventricular interdependency playsan important role in PH. Not only the right ventricle but also the left ventricle is involved in PH since theright ventricle and left ventricle have the septum in common, are encircled with common myocardialfibres and are within a (not acutely) distensible pericardium (figure 1a) [4, 5]. This ventricularinterdependency becomes visible in PH as rapid leftward bowing of the septum during early left ventriclediastole. This typical septal motion abnormality has been shown to be a consequence of a prolongedcontraction of the right ventricle free wall relative to that of the septum and the left ventricle free wall,causing interventricular relaxation dyssynchrony [6, 7]. As such, the septum acts as a whistleblower of aright–left ventricular tissue load imbalance, reflecting right ventricular tissue overload in the setting of PH.This rapid early-diastolic leftward motion of the septum is also associated with septal and left ventricularmyocardial stretch during late right ventricular ejection [8], causing mechanical inefficiency of the rightventricle and contributing to left ventricular underfilling [9] and atrophy [10]. The septal curvature is auseful metric in PH, reflecting both the interventricular pressure gradient and relative interventricular size,as well as dyssynchrony of contraction [7].

Assessment of the right ventricle in a load-independent mannerRight ventricular function can be characterised by the pressure–volume relation (figure 2) [11], andmeasurement of right ventricular volumes and pressures are therefore useful for the assessment of the

0

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RV coupled(Ees/Ea within normal range)

RV uncoupled(Ees/Ea reduced)

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P

Ees

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50

60

RV

pres

sure

mm

Hg

RV volume mL0 50 100 150 200

Reverse remodellingProgression

Ees Ea Ees Ea Ea

FIGURE 2 Right ventricular (RV) pressure–volume analysis. Pressure–volume loops at three different stages:normal (blue), pulmonary hypertension (green) and right ventricular failure (purple). Ees: end-systolicelastance; Ea: arterial elastance; τ: time constant of ventricular relaxation. P=α(eβV−1) describes the diastolicpressure–volume relation. Reproduced and modified from [11] with permission.

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right ventricle in PH, particularly for physiological studies. A schematic overview of an approach to rightventricle phenotyping, integrating structural imaging, haemodynamics, molecular imaging and biomarkersis given in supplementary figure S1a.

SystoleEes of the ventricle is a load-independent description of the right ventricle and the current referencemeasure of contractility; it depends on the contractile force of the myocyte and cardiac muscle mass(hypertrophy) [12, 13].

The derivation of Ees is based on the pressure–volume loop (figure 2). The best method to assess Ees is todecrease ventricular filling, e.g. by partial vena cava occlusion, and analyse the series of loops that result[14]. Connection of the end-systolic pressure (Pes)–volume points results in the Pes–volume relation and itsslope is Ees. Since this approach is invasive and not widely available in the clinic, single-beat methods havebeen developed [13, 15]. Ees can be increased 5-fold in PAH patients, reflecting that the right ventricle isperforming at a high contractile state [16]. In addition, the elastance response to pharmacological (usuallydobutamine) or physiological stress (exercise) can be useful to assess contractile reserve. In the normalright ventricle, Ees usually increases significantly with exercise [3]. In the pressure overloaded rightventricle, although the baseline is higher than normal, the degree of increase is blunted with exercise orfollowing dobutamine infusion [3, 17]. Contractile reserve at exercise is absent in more advanced diseasestates or might even decrease [3].

DiastoleIn practice, right atrial pressure and central venous pressure are often used as surrogates for diastolicproperties of the right ventricle; right atrial pressure has been consistently related to outcome in PAHstarting with the original US National Institutes of Health registry study in 1991 [18]. Usingload-independent metrics has the advantage of allowing a better understanding of the responsiveness tovolume status or change in filling conditions. Eed of the ventricle is a load-independent representation ofthe diastolic function and is best described by a diastolic elastance curve determined by multiple pressure–volume loops obtained by decreased loading by partial vena cave occlusion. The relation is curvilinear andthe most adequate description is obtained by fitting the relation with an exponential curve through thediastolic pressure–volume points, with the formula P=α(eβV−1), where α and β are curve-fitting constants(figure 2) [11, 19]. A single-beat method has been developed to determine Eed [20, 21]. Eed now can becalculated as Eed=αβeβVed, where Ved is the end-diastolic volume (EDV) [21]. The so-defined diastolicstiffness predicts outcome in PAH as well as the more complex β calculation [21].

Right ventricular diastolic function is closely associated with disease severity [20], but also with Ees [21, 22].Right ventricle diastolic stiffness in severe PH is accompanied by fibrosis and specific biological alterations,such as reduced titin phosphorylation [20]. Although Eed is related to Ees, diastolic adaptability remainsvariable in patients with PH and whether it may serve as a biomarker of pending right ventricle failure isnot completely resolved.

Assessment of the pulmonary circulation in a heart-independent mannerPulmonary vascular resistanceWhen analysing the pulmonary circulation, it is useful to distinguish a steady and pulsatile component ofthe load. These main components of arterial load are PVR and total PAC. In the pulmonary system thesetwo components are inversely related (see later). PVR is calculated as PVR=(mPAP−PAWP)/CO, wheremPAP is the mean pulmonary arterial pressure and PAWP is the pulmonary arterial wedge pressure. Ameasure of total load can also be estimated from the pressure–volume loop (figure 2) as Ea=Pes/SV. It hasbeen proposed to use Ea∼mPAP/SV when Pes is not available [23]; however, this approximation should beused with caution since, especially in higher pressures ranges, Pes is underestimated by mPAP [24].

Pulmonary capillary flow is a dynamic process. In basal states, flow through an individual capillary isintermittent. Capillary recruitment occurs when the probability of a given capillary carrying flow increases.Capillary recruitment and distension both play a role in the lung’s accommodation of pulmonary arterialblood flow. At basal or moderately increased blood flows, capillary recruitment is predominant [25, 26].At very high regional flows or pressures, after local full recruitment, capillary distension is predominant[26–29]. The local pattern of capillary recruitment/distension may vary regionally in the lung, with gravity,arterial and post-capillary venous pressures, airway pressures, and disease states all having effects [30–34].

Examining the pulmonary circulation as a whole, since in the (healthy) pulmonary circulation the arteries andveins are distensible, the assumption that the pulmonary vascular pressure difference–flow relationship is linearand crosses the origin is inaccurate. The simple formula then no longer holds and PVR can be described usingtwo parameters: α (the pulmonary circulatory distensibility coefficient) and R0 (a reference resistance usually

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assumed to be the resistance at rest) [35, 36]. While α may be relevant for the detection of early pulmonaryvascular remodelling and relates to exercise capacity, right ventricular function and outcome [37], it requiresaccurate measurement of pulmonary vascular pressure and flow at rest and at exercise. It therefore cannot becurrently recommended as part of standard haemodynamic evaluation of patients referred for PH.

Pulmonary arterial complianceThe pulsatile load of the pulmonary circulation is most often evaluated using PAC. The best method tocalculate PAC is based on a two-element Windkessel model with flow waveform and resistance as inputs toestimate the compliance value that best predicts systolic and diastolic pressures, the so-called “pulse pressure”(PP) method [38]. A simpler and accepted method to derive PAC is SV/PP [39]. This ratio assumes that theSV is buffered in the large elastic arteries in systole, without any peripheral outflow. However, there is acontinuous flow toward the periphery, reducing the vascular volume increase during ejection, resulting in anoverestimation of the true PAC [40]. It has been shown in intact experimental animals at various severities ofinduced PH that SV/PP overestimates PAC by 60–80% [40, 41]. This overestimation probably depends onpatient status. CMR-determined proximal arterial compliance amounts to around 20% of PAC [42], showingthe greater contribution of the smaller vessels compared with the systemic arterial vasculature.

Time constant of the pulmonary circulationIn the previous sections we described the steady and pulsatile components separately; however, as alreadymentioned, these are closely related by an inverse relationship. The PAP decay curve in diastole isdetermined by PVR and PAC. The combined effect can be formulated by the product of PVR and PAC.The unit of this product is time and, therefore, is called the arterial time constant (RC-time) [43].

The inverse relationship between PVR and PAC was first reported in 1971 [44]. A series of studies showedrecently that PVR and PAC are inversely related, and RC-time is constant over a wide range of severities,aetiologies and treatments of PH (figure 3) [41, 45, 46]. It is noteworthy that RC-time is decreased when PAWPincreases in patients with heart failure [47, 48]. The fact that PVR takes the wedge pressure into account,whereas compliance, calculated as SV/PP, does not, gives rise to an altered RC-time in post-capillary PH.

Owing to the inverse relationship between PVR and PAC, the dynamic range in PAC will be greater inpatients with mild pulmonary vascular disease (PVD) (zone A in figure 3), while the dynamic range inPVR will be greater in patients with more advanced PVD (zone B in figure 3). Therefore, PAC may be moresensitive to detect changes in PVD in the early phase of disease. Moreover, several studies using linearprediction models found that PAC is an independent predictor of outcome in PAH [49–52] over a widerange of PVR [53, 54]. Another implication of this remarkable structural characteristic of the pulmonaryvasculature is that it dictates the reported tight correlation between systolic PAP (sPAP), diastolic PAP(dPAP) and mPAP in normal subjects and in patients with PH of all possible aetiologies [55, 56],independently of PAWP (figure 4) [57]:

sPAP ¼ 1:61 �mPAP

and

dPAP ¼ 0:62�mPAP

PAC

mL·

mm

Hg–

1

0

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4

6

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10 RC-time constant=PVR×PAC

Zone A: greater dynamic range in complianceZone B: greater dynamic range in resistance

PAWP <10 mmHg

PAWP >20 mmHg

Increasing PAWP

A

B

PVR mmHg·s·mL–10.50.0 2.01.0 1.5

FIGURE 3 The resistance–compliance relationship: the relationship between pulmonary vascular resistance(PVR) and pulmonary arterial compliance (PAC) is characterised by a constant value of RC-time (i.e. the productof PVR×PAC). PAWP: pulmonary arterial wedge pressure. Reproduced and modified from [11] with permission.

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The first relation implies that mPAP can be calculated from Doppler echocardiographic estimates of sPAPby the formula:

mPAP ¼ 0:62 � sPAP

The mPAP calculated in this way provides an estimate of mPAP in patients referred for diagnosticwork-up of PH [58]. In echocardiography-based studies, different thresholds for right ventricular systolicpressure (e.g. 30, 35 or 40 mmHg) have been used for defining PH. According to the formula, a rightventricular systolic pressure of 40 mmHg would best approximate a mPAP of 25 mmHg assuming a mildright ventricular outflow tract gradient and an insonation angle <15°.

Assessment of the cardiopulmonary unitFunctional interactionIn the clinic, the description of right ventricular function in relation to its load is of high prognostic value.Most imaging parameters as measured by echocardiography or CMR reflect system function of theinteraction of the right ventricle and the vascular load. At present no recommendations on the mostrelevant measurements of right ventricular function can be made. Further clinical research is needed,preferably multicentre and prospective, with an a priori established list of variables of interest. It shouldnot be overlooked that adequate measurements do not only qualify based on their prognostic capability orprediction of clinical worsening; they should be reproducible and easy to assess in PH centres of expertise.

However, there is ample evidence that direct or indirect measurements of right ventricular EDV and ESV,derivation of SV, and filling pressures contain the foremost prognostic information. This can be explainedby the pressure–volume loops derived from the adapted and failing right ventricle. In the adapted rightventricle, increased afterload in PH leads to hypertrophy and an increased contractility with more or lesspreserved dimensions and SV [2, 4, 11, 59], whereas in progressive right ventricular failure, the rightventricle progressively dilates and decreases its SV.

It should be noted that SV/ESV is inversely related to RVEF, as indicated by the formula SV/ESV=EF/(1−EF).Indeed, VANDERPOOL et al. [22] showed this inverse relation exists in patients with PH [22]. Thus, both SV/ESV and RVEF contain similar prognostic information, and should be considered as parameters of functionalinteraction, not coupling. RVEF and SV/ESV have been shown to be equally predictive of outcome in patientswith PAH [60]. Rigorously defined cut-off values for shortened survival are 0.35 for EF [60, 61] and 0.54 forSV/ESV [22, 60]. Although theoretically RVEF and SV/ESV should have similar predictive potential, due tothe hyperbolic relationship between the two, the latter may be more sensitive to early changes [62]. Thenagain, it is more difficult to determine ESV in an accurate manner. A large-scale head-to-head comparison ofthese two parameters may resolve this matter.

CouplingCoupling implies efficiency of energy transfer from the ventricle to the arterial load and can be calculatedas the ratio Ees/Ea. The value will be between 1 and 2 if maximal energy transfer from ventricle to loadoccurs (figure 2).

010

30

50

70

90

mPAP=1.29×dPAP+5.3 mmHgR2=0.89, p<0.001

mPAP=0.60×sPAP+2.0 mmHgR2=0.94, p<0.001

mPA

P m

mH

g

sPAP or dPAP mmHg0 20 40 60 80 100 120 140

FIGURE 4 The mean, systolic and diastolic pulmonary arterial pressure (mPAP, sPAP and dPAP) relationships:relative values of pressures in the pulmonary circulation are tightly related. Reproduced and modified from[57] with permission.

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Coupling has been reported in PAH patients, with single-beat calculation of the Ees/Ea ratio from CMRmeasurements of right ventricular volumes and right heart catheterisation (RHC) measurements of rightventricular pressures [63]. Single-beat determinations of Ees/Ea have been implemented in experimentalanimal studies to show, for example, that acutely administered prostacyclin has no intrinsic inotropic effect[64] and that β-blocker agents may either deteriorate (acutely) [11] or improve (chronically) [64] rightventriculo–arterial coupling.

Compared with controls, in PH the Ees/Ea was decreased, indicating insufficient contractility adaptation(“homeometric”) and impending right ventricular failure. Results have been confirmed in small cohorts ofpatients with either PAH or chronic thromboembolic PH, and in one case report of a patient with asystemic-like pressured right ventricle [3, 65–68]. In these studies, Ees/Ea was measured either by thesingle-beat method [3, 63, 65, 67] or using multiple pressure–volume loops obtained by decreasing venousreturn through a Valsalva manoeuvre [66, 68]. Ees/Ea was either maintained or decreased at rest, butconsistently decreased at exercise. Decreased Ees/Ea at exercise was accompanied by an increase in rightventricular EDV [68].

Coupling is maintained at resting conditions for as long as the ventricle can adapt (figure 2). Only in thelate stages of pressure overload does uncoupling occur [11, 21]. Therefore, coupling is not a sensitiveparameter to identify an early disease state. Although coupling measured at exercise might contain moreimportant clinical information, the complexity of these measurements will limit clinical use.

Practical assessment of pulmonary haemodynamicsSingle variables such as PAPs, SV and CO are the result of the interaction of the right ventricle to its load.This implies that from a single variable, e.g. CO, no quantitative information can be obtained on either ofthe subsystems, i.e. the heart or the arterial load. For this reason, a change in PAP at exercise cannot beconsidered as a measure of right ventricular contractility.

Measuring the pressures correctlyMeasurements of PAP and PAWP during rest and especially at exercise are technically challenging becauseof respiratory pressure swings. To avoid spurious increases in PAWP at end-expiration during exercisecaused by dynamic hyperinflation and/or decrease in lung volume, it is preferable to average the reading ofpulmonary vascular pressure curves over several respiratory cycles [69]. The 2015 European Society ofCardiology/European Respiratory Society PH guidelines recommend measurements at end-expiration atrest, as is standard procedure in most catheterisation laboratories, but allow for averaging over severalrespiratory cycles during exercise when respiration-related phasic changes become excessive [1, 70].

Provocation of the pulmonary circulationProvocative testing of the pulmonary circulation with exercise or a fluid challenge has been used by somecentres in clinical practice for decades, but has only recently been standardised.

ExerciseThe upper limit of normal of mPAP during an incremental dynamic exercise challenge is now wellestablished at 30 mmHg at CO <10 L·min−1 (figure 5), which corresponds to a total pulmonary resistance

ΔP/ΔCO=6.1R2=0.92

ΔP/ΔCO=3.6R2=0.99 ΔP/ΔCO=2.2

R2=0.99

ΔP/ΔCO=0.8R2=0.99

ΔP/ΔCO=3.0

NormalScleroderma without PHScleroderma borderline PHPAH

0

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CO L·min–1

mPA

P m

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g

0 3010 20

FIGURE 5 The mean pulmonary arterial pressure (mPAP)–cardiac output (CO) relationships: the ratio of ΔP/ΔCOin health and disease. PH: pulmonary hypertension; PAH: pulmonary arterial hypertension. Reproduced andmodified from [71] with permission.

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(TPR=mPAP/CO) of 3 WU [37, 71, 72]. It has been recently proposed that exercise-induced increases inmPAP >30 mmHg at CO <10 L·min−1 be called “exercise PH” [69].

The cause of “exercise PH” is either an upstream transmission of increased PAWP, such as in heart failure,or an increase in PVR, such as in PVD, disturbed lung mechanics or hypoxia [37, 69, 71]. This differentialdiagnosis relies on a clinical probability and eventual invasive measurements of PAWP and left ventricularend-diastolic pressure. The upper limit of normal of PAWP during exercise is generally thought to bebetween 15 and 20 mmHg, but higher values can be recorded in athletes capable of very high CO and inelderly subjects [73]. Some consider 20 mmHg as a reasonable upper limit of normal [74]. However, ahigher cut-off value of 25 mmHg has been proposed for the diagnosis of heart failure [75]. As for mPAP,a flow-corrected measure may be more appropriate, but there has been no study specifically addressingthis. Since TPR normally decreases by up to 30% during exercise, the PAWP/CO slope should not exceed2 mmHg·L−1·min−1. Mean PAWP/CO slopes around 1 mmHg·L−1·min−1 have been reported in controlgroups of studies on exercise testing in heart failure patients [71, 74, 75].

Fluid challengeA fluid challenge will induce a rapid rise in PAWP in any condition associated with altered left ventriculardiastolic compliance or mitral valvulopathy [76]. Fluid loading increases PAWP in healthy volunteers as afunction of age, sex, amount infused and infusion rate [77]. There is an emerging consensus to infuse500 mL of saline in 5–10 min as the best compromise between safety and stress efficacy, with 18 mmHg asthe optimal PAWP cut-off to separate abnormal from normal [76–80]. This was recently underpinned by areport on 212 patients referred for PH who were challenged with 7 mL·kg−1 of saline given in <5 min(corresponding to 0.5 L for a 70-kg patient) [80]. To limit the number of healthy outliers [80], a cut-offvalue of 20 mmHg might be preferable. Both exercise and fluid loading increase systemic venous return,but exercise has additional effects, including sympathetic nervous system activation, intrathoracic pressurechanges and mixed venous or arterial hypoxaemia. These differences probably impact on their respectiveefficacies for diagnosis of latent disease [81].

The emerging role of non-invasive assessment of right ventricular functionThe role of right ventricular function estimated by non-invasive methods such as echocardiography(two-dimensional, three-dimensional, speckle tracking-derived echocardiography) or CMR is emergingrapidly in observational studies and has been reviewed elsewhere [82]. Speckle-derived strain technologyallows measurements of regional strains by either method and demonstrates heterogeneity of rightventricular strain depending on the region (e.g. apical versus mid or basal region) and occasionallysignificant differences between disease aetiologies, such as idiopathic PAH (IPAH) and systemic sclerosis(SSc)-associated PAH. Recent larger studies in echocardiography have demonstrated that right ventricularlongitudinal strain or indices of right ventricular end-systolic remodelling in combination with N-terminalpro-brain natriuretic peptide and NYHA Functional Class provide good discrimination of outcome inPAH [83, 84].

Imaging modalities may be incorporated into large multicentre clinical trials in PH using compositemorbidity and mortality end-points, which would be ideal settings to validate potential rightventricle-based surrogate end-points. Since CMR has greater sensitivity and reproducibility thanultrasound, and can detect an efficacy signal with a small sample size in a relatively short period of time,validation of specific right ventricle surrogate CMR markers (e.g. RVEF, right ventricular mass, rightventricular mass index; left ventricle size and function) in the setting of smaller phase 2 trials would beuseful to help identify potentially promising therapies. This could allow the creation of prediction scoresconstructed from a hierarchically organised series of identified independent predictors.

Recent insights in the pathobiology of right ventricular failureSince the 5th World Symposium on Pulmonary Hypertension report in 2013 [2], there have been majoradvances in understanding the underlying pathobiology of right ventricular remodelling and failure. Thisknowledge has been derived both from animal models, reviewed elsewhere [85], and, importantly, fromhuman tissue. Recent work has focused on several main themes and a thorough review of the completebreadth of right ventricular failure mechanisms is beyond the scope of the current article.

First, there has been an expansion of the understanding that genetic features may affect right ventricularstress responses. It is well recognised that patients with heritable forms of PAH (HPAH) have poorersurvival than their IPAH counterparts, but recent work has demonstrated that this is related to moresevere right ventricular failure in HPAH due to BMPR2 (bone morphogenetic protein receptor type 2)mutation despite similar levels of afterload, suggesting a genetic contribution to right ventricular failure[86]. In a different series of investigations, BMPR2 mutation was shown to promote lipotoxicity in the

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BMPR2 mutant right ventricle in rodents, in humans and in cultured cardiomyocytes with overexpressionof mutant BMPR2 [87–89]. More recently, POTUS et al. [90] demonstrated downregulation of miR-126 inhuman tissue and the monocrotaline model of right ventricular failure, with subsequent reduction inangiogenesis. Taken together, these data suggest a role for genetic regulation of right ventricular failureand may be used to develop new models of right ventricular failure.

The effect of sex hormones on the right ventricle has gained further attention. Male sex is known to be anindependent risk factor for poor survival [91] and JACOBS et al. [92] found that despite a similar burden ofPVD, male patients lack improvement in RVEF regardless of treatment, while their female counterpartsimproved RVEF. FRUMP et al. [93] demonstrated using the Sugen hypoxia models that oestrogen improvesright ventricular function and bioenergetics, and reduces proapoptotic signalling and inflammatorycytokine expression, perhaps suggesting a protective role for oestrogen underlying the clinically recognisedsex differences.

There is improved understanding of right ventricle metabolism with recent findings that right ventricularfailure is characterised by reduced fatty acid oxidation in addition to increased glycolysis [87, 88, 94, 95].Presently, it is unknown if enhanced fatty acid oxidation or improved glucose oxidation would mostsuccessfully improve right ventricular function. Finally, there is a new perception of the contribution ofaltered cytoskeletal function in the right ventricle. Pulmonary artery banding was used to induce rightventricular hypertrophy and dysfunction in rats, resulting in increased myocardial stiffness with increasedfibrosis- and myofibril-mediated stiffness [96]. Using the monocrotaline model, PRINS et al. [97] foundabnormal t-tubule architecture associated with reduced junctophillin-2 expression. Colchicine amelioratedthese findings, perhaps suggesting a new therapeutic avenue for the failing right ventricle. Taken together,these studies present new data on the role of the cytoskeleton and myocardial fibrosis in promoting rightventricular dysfunction.

Animal models of right ventricular failure related to group 2 PH should be developed and may require a“multiple-hit” rather than “single-hit” approach in order to more adequately reproduce the clinicalsyndrome [98].

Finally, insight into the pathophysiology of right ventricular function is also emerging from human rightventricle biopsies. Isolated cardiomyocytes thus obtained may allow for deep phenotyping and mechanisticinvestigations of specific pathways. Using this approach in patients with end-stage PAH undergoing heart–lung transplantation, and comparing with non-failing donors, RAIN et al. [20] demonstrated increasedfibrosis and stiffening of right ventricle sarcomeres in conjunction with decreased titin phosphorylation inPAH. A recent study by HSU et al. [99], using right ventricle biopsies obtained during RHC underechocardiographic guidance, revealed that patients with SSc-PAH have depressed sarcomeric function,which is manifested by a significant decline in maximal force (Fmax) calcium dependence compared withnon-PAH patients, while the opposite (i.e. increased calcium-activated Fmax) was demonstrated forpatients with IPAH, in line with data obtained by RAIN et al. [20] in (non-scleroderma) PAH patients.Collectively, these findings may explain the significant differences in outcomes and survival in these twogroups of patients.

Future directionsA summary of future directions is given in supplementary figure S1b.

Our insights into the role of the right ventricle in PH have considerably improved over recent years. Theseinsights allow for a full assessment of right ventricular function and pulmonary vascular load based onpressure and volume measurements in patients. Such an assessment permits us to test the differentialeffects of future drugs on the right ventricle and pulmonary vasculature. Use of CMR should beimplemented in PAH clinical trials and clinical practice when possible. Molecular imaging should be usedto translate from bench to bedside (and vice versa). Novel approaches are necessary to show the clinicalvalue of echocardiography for predicting response and tailoring therapy.

Currently, the clinical relevance of an abnormal exercise pulmonary haemodynamic response is largelyunknown and requires long-term follow-up studies. If PH is present, diuretics and atrioseptostomy are theonly options available to treat the right ventricle, mainly by reducing wall tension [100].

Better characterisation of normal right ventricular function, early dysfunction and irreversible failure isneeded. Growing insights into how to prevent right ventricular failure at a biological level need to betranslated to the clinic via well-designed trials. If right ventricular failure is present, the role of inotropicagents is unknown. Based on the finding that contractile reserve of the right ventricle is absent in advanceddisease, the effectiveness of inotropic drugs in end-stage right ventricular failure needs to be re-evaluated.Finally, the optimal medical care of patients in end-stage right heart failure needs to be defined.

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Conflict of interest: A. Vonk Noordegraaf reports grants and speaker fees from Actelion, MSD and GSK, outside thesubmitted work. K.M. Chin reports personal fees for consulting work on clinical trials from Actelion, grants (paid toinstitution) from Ironwood and Sonivie, personal fees for consulting work for a clinical registry from University ofCalifornia San Diego, and research grants from the NIH, outside the submitted work. F. Haddad has nothing todisclose. P.M. Hassoun has nothing to disclose. A.R. Hemnes reports personal fees from Actelion, Bayer, Complexa andUnited Therapeutics, and grants from the CMREF and NIH, outside the submitted work; and in addition has a patentissued: Annamometer (oral mechanism for detection of end-tidal CO2; not referenced in this work). S.R. Hopkins isfunded by the NIH via research grants to study the pulmonary circulation. S.M. Kawut reports non-financial travelsupport from the ATS and Pulmonary Hypertension Association, grants from Actelion, United Therapeutics, Gilead,Lung Biotech, Bayer and Mallinkrodt, and grants and non-financial support from the CMREF, outside the submittedwork and paid to his university; and has served in an advisory capacity (for grant review and other purposes) forUnited Therapeutics, Akros Pharmaceuticals, GSK and Complexa, Inc., without financial support or in-kind benefits.D. Langleben reports grants, personal fees and non-financial support from Actelion and Bayer, personal fees fromUnited Therapeutics and Merck, and grants from Northern Therapeutics, outside the submitted work. J. Lumens hasnothing to disclose. R. Naeije has nothing to disclose.

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Haemodynamic definitions and updatedclinical classification of pulmonaryhypertensionGérald Simonneau1,2, David Montani 1,2, David S. Celermajer3,Christopher P. Denton4, Michael A. Gatzoulis5, Michael Krowka6,Paul G. Williams7 and Rogerio Souza 8

Number 4 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1Université Paris-Sud, AP-HP, Centre de Référence de l’Hypertension Pulmonaire, Service dePneumologie, Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Hôpital de Bicêtre, LeKremlin-Bicêtre, France. 2INSERM UMR_S999, LabEx LERMIT, Hôpital Marie Lannelongue, Le Plessis-Robinson, France. 3Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. 4Centre forRheumatology, Royal Free Campus, University College London, London, UK. 5Adult Congenital Heart Centreand National Centre for Pulmonary Hypertension, Royal Brompton and Harefield NHS Trust, and the NationalHeart and Lung Institute, Imperial College London, London, UK. 6Transplant Center, Mayo Clinic, Rochester,MN, USA. 7Center of Chest Disease and Critical Care, Milpark Hospital, Johannesburg, South Africa.8Pulmonary Circulation Unit, Pulmonary Division, Heart Institute (InCor), Hospital das Clinicas da Faculdadede Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil.

Correspondence: Gérald Simonneau, Service de Pneumologie, Centre de Référence de l’HypertensionPulmonaire, CHU de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre Cedex, France.E-mail: gerald.simonneau@aphp.fr

@ERSpublicationsState of the art and research perspectives of haemodynamic definitions and clinical classification ofpulmonary hypertension http://ow.ly/TJeR30mgWKj

Cite this article as: Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions andupdated clinical classification of pulmonary hypertension. Eur Respir J 2019; 53: 1801913 [https://doi.org/10.1183/13993003.01913-2018].

ABSTRACT Since the 1st World Symposium on Pulmonary Hypertension (WSPH) in 1973, pulmonaryhypertension (PH) has been arbitrarily defined as mean pulmonary arterial pressure (mPAP) ⩾25 mmHg atrest, measured by right heart catheterisation. Recent data from normal subjects has shown that normal mPAPwas 14.0±3.3 mmHg. Two standard deviations above this mean value would suggest mPAP >20 mmHg asabove the upper limit of normal (above the 97.5th percentile). This definition is no longer arbitrary, but basedon a scientific approach. However, this abnormal elevation of mPAP is not sufficient to define pulmonaryvascular disease as it can be due to an increase in cardiac output or pulmonary arterial wedge pressure. Thus,this 6th WSPH Task Force proposes to include pulmonary vascular resistance ⩾3 Wood Units in thedefinition of all forms of pre-capillary PH associated with mPAP >20 mmHg. Prospective trials are requiredto determine whether this PH population might benefit from specific management.

Regarding clinical classification, the main Task Force changes were the inclusion in group 1 of a subgroup“pulmonary arterial hypertension (PAH) long-term responders to calcium channel blockers”, due to thespecific prognostic and management of these patients, and a subgroup “PAH with overt features of venous/capillaries (pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis) involvement”, due toevidence suggesting a continuum between arterial, capillary and vein involvement in PAH.

Received: Oct 06 2018 | Accepted: Oct 09 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

https://doi.org/10.1183/13993003.01913-2018 Eur Respir J 2019; 53: 1801913

| SERIESWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

IntroductionThe main objectives of our Task Force were to reassess haemodynamic definitions and the clinicalclassification of pulmonary hypertension (PH).

Regarding definitions, we addressed two questions:

1) Should we redefine PH and pre-capillary PH?2) Should exercise PH be reintroduced as part of the PH definition?

The other topic was to update the clinical classification, adopting some basic principles: 1) to maintain thegeneral architecture of the current classification of PH for adults and children, 2) to provide only relevantmodifications, and 3) to simplify the core of the classification

Haemodynamic definitionsDefinition of PHIn 1961, a report of the World Health Organization (WHO) Expert Committee on Chronic CorPulmonale mentioned clearly that the mean pulmonary arterial pressure (mPAP) does not normallyexceed 15 mmHg when the subject is at rest in a lying position, and that the value was little affected byage and never exceeded 20 mmHg [1].

Since the 1st World Symposium on Pulmonary Hypertension (WSPH) organised by the WHO in Genevain 1973, PH has been defined as mPAP ⩾25 mmHg measured by right heart catheterisation (RHC) in thesupine position at rest [2]. The Geneva WHO meeting was devoted to primary PH, a severe form of PH,some years after an outbreak related to the intake of the anorexic drug aminorex [3]. In the report of themeeting, it was recognised that this upper limit of normal mPAP of 25 mmHg was somewhat empiricaland arbitrarily defined [2]. However, this conservative cut-off value allowed physicians to discriminatesevere PH due to primary PH from other forms of PH (mainly due to lung diseases) characterised by alower mPAP. This definition remained unchanged during the subsequent WSPH meetings from 1998 to2013 [4–6], at least in part to preclude potential overdiagnosis and overtreatment of PH.

What is actually the upper limit of normal mPAP?In 2009, KOVACS et al. [7] analysed all available data obtained by RHC studies in healthy individuals todetermine normal values of mPAP at rest and exercise. Data from 1187 normal subjects from 47 studieswere analysed. mPAP at rest was 14.0±3.3 mmHg; this value was independent of sex and ethnicity, andwas only slightly influenced by age and posture. Considering this mPAP of 14 mmHg, two standarddeviations would suggest mPAP >20 mmHg as above the upper limit of normal (i.e. above the 97.5thpercentile). This definition is, therefore, no longer arbitrary, but based on a scientific approach.

A value of mPAP used in isolation is not accurate enough to characterise a clinical conditionWhatever the mPAP cut-off value considered for defining PH (⩾25 or >20 mmHg), it is important toemphasise that this value used in isolation cannot characterise a clinical condition and does not define thepathological process per se. PAP elevation may indeed have several different causes with differentmanagement and outcomes, including increase in cardiac output (CO), left-to-right cardiac shunts,elevation of pulmonary arterial wedge pressure (PAWP) in left heart disease (LHD) and hyperviscosity.This abnormal elevation may also be due to pulmonary vascular disease (PVD) associated with structuralchanges of small pulmonary arteries. In the present clinical classification of PH, pre-capillary PH concernspatients from groups 1, 3 and 4, some patients from group 5, and rarely patients from group 2 withcombined pre- and post-capillary PH.

To identify pre-capillary PH suggesting the presence of PVD, an above normal elevation ofpulmonary vascular resistance should be included in the definitionIncluding pulmonary vascular resistance (PVR=(mPAP–PAWP)/CO) in the definition of pre-capillary PHis essential, allowing discrimination of elevation of PAP due to PVD from those due to elevation of PAWPor due to high CO. Since the 3rd WSPH held in 2003, pre-capillary PH of group 1 (pulmonary arterialhypertension (PAH)) has been defined by the presence of mPAP ⩾25 mmHg with a normal PAWP⩽15 mmHg and elevated PVR ⩾3 Wood Units (WU) [4–6]. This cut-off value of PVR ⩾3 WU is alsoquite arbitrary since some recent data suggest that PVR >2 WU could be also considered abnormal [6]. Inthis sense, the use of a cut-off value of PVR ⩾3 WU is conservative, suggesting the presence of a manifestpre-capillary PH. This value of PVR ⩾3 WU is considered clinically relevant in different clinical situations,suggesting the presence of a significant PVD, e.g. it is already used as the threshold value for which thecorrection of congenital systemic-to-pulmonary shunts becomes questionable [8]. Moreover, it has beenshown that elevated PVR ⩾3 WU was associated with a poor survival after heart transplantation [9].During the 6th WSPH in 2018, for patients of group 2, the Task Force on PH due to LHD recommended

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a PVR cut-off value ⩾3 WU to define patients with a pre-capillary component [10], so-called combinedpre- and post-capillary PH, that is associated with a worse prognosis.

We propose including PVR ⩾3 WU not only in the definition of pre-capillary PH of group 1, but also inthe definition of all forms of pre-capillary PH.

In patients with PH due to chronic obstructive pulmonary disease, those with severe PH (>40 mmHg)have a marked increase in PVR (around 10 WU); more often these patients have a mild PH (mPAP 20–30 mmHg), associated with lower PVR but remaining generally >3 WU [11], and this is also the case forpatients with idiopathic pulmonary fibrosis [12]. In these different chronic lung diseases, even a modestelevation in mPAP (20–29 mmHg) was associated with a poor prognosis [13].

In chronic thromboembolism (group 4), a large international registry reported haemodynamic findings ofsevere pre-capillary PH with a mPAP of 47 mmHg and a mean PVR of 8.9 WU [14]. In this setting, evenin patients with mild elevation of mPAP (20–24 mmHg), PVR is generally >3 WU.

Outcome of patients with PVD and mPAP 21–24 mmHgAccumulating data indicate that many patients with PVD associated with an increase in mPAP but belowthe former threshold value defining PH (⩾25 mmHg) are at risk of disease progression.

In systemic sclerosis, outcome data of patients with mPAP at diagnosis between 21 and 24 mmHg havebeen recently published. In 2013, a single-centre cohort study of 228 patients with systemic sclerosis whounderwent RHC for suspicion of PH was reported [15]. mPAP 21–24 mmHg was documented in 86patients at baseline; of these, 38 underwent a second RHC during the follow-up (median follow-up48±35 months) and 16 of these (42%) developed overt PH (mPAP ⩾25 mmHg). The mean mPAP andPVR at baseline of these 16 patients was 22±2 mmHg and 2.9±0.6 WU, respectively; at follow-up, meanmPAP and PVR increased to 31±6 mmHg and 6.9±1.7 WU, respectively. Patients with so-called borderlinemPAP at diagnosis were more likely to develop overt PAH than patients with mPAP ⩽20 mmHg(p<0.001; hazard ratio (HR) 3.7). Incident development of PAH was not benign in this cohort, with fivedeaths during follow-up despite the subsequent introduction of dual oral combination therapy and/or i.v.prostacyclin.

More recently, a two-centre cohort study identified 21 patients with systemic sclerosis and a mPAP atbaseline of 21–24 mmHg [16]; these patients underwent a second RHC with a median follow-up of3 years. At baseline, mean mPAP and PVR were 22±1 mmHg and 2.3±0.8 WU, respectively. At follow-up,mPAP and PVR increased to 25±4 mmHg and 3.2±1.6 WU, respectively. Among them, seven patients(33%) developed overt PH (three PAH, three pre-capillary PH associated with interstitial lung disease andone PH due to LHD) ( J.G. Coghlan, Cardiology Dept, Royal Free Hospital, London, UK; personalcommunication).

In 2017, an Austrian group [17] published a series of 547 patients with unexplained dyspnoea and/or atrisk of PH who underwent RHC. Manifest PH (mPAP ⩾25 mmHg) was confirmed in 290 patients,borderline PH (mPAP 21–24 mmHg) in 64 cases and 193 cases were considered as “normal” with mPAP⩽20 mmHg; among them, 137 patients were defined as “lower normal” with mPAP ⩽15 mmHg. Themedian follow-up time of this cohort was 45.9 months; overall 161 patients (29%) died during thefollow-up. In the multivariate model, considering age and comorbidities, both borderline PH and manifestPH were significantly associated with poor survival compared with the “lower normal” group with HR 2.37(95% CI 1.14–4.97; p=0.022) and HR 5.05 (95% CI 2.79–9.12; p<0.001), respectively. At baseline, the groupwith mPAP 21–24 mmHg had a median PVR of 2.7 WU and 36% of these patients had PVR >3 WU.

Another instance where pre-capillary PH can be diagnosed at an earlier stage is chronic thromboembolism, asin this setting exercise limitation can occur in the absence of overt PH at rest due to the increase in dead-space ventilation resulting in a decreased ventilatory efficiency. Recently, two cohorts of 42 and 23 patients,respectively, have been reported with extensive persistent thromboembolic occlusions but without PH [18, 19].At diagnosis, mPAP was 15–24 mmHg and PVR was 2–3 WU. These patients underwent pulmonaryendarterectomy (PEA) and experienced significant improvement in WHO Functional Class, exercise capacityand quality of life, with no in-hospital mortality at 6 months. This form of chronic thromboembolismcorresponded to 4% and 7% of the overall population treated with PEA in these two centres.

Summary and perspectivesA mPAP of 20 mmHg should be considered as the upper limit of normal value. This new definition hasbeen recently proposed by others [20–22]. However, this abnormal elevation of mPAP in isolation is notsufficient to define PVD as it can be due to an increase in CO or PAWP.

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Pre-capillary PH is best defined by the concomitant presence of mPAP >20 mmHg, PAWP ⩽15 mmHgand PVR ⩾3 WU (table 1), emphasising the need for RHC with mandatory measurement of CO andaccurate measurement of PAWP.

For many years, the diagnosis of PH was based on an arbitrary value of mPAP ⩾25 mmHg, probablybecause of understandable concern about overdiagnosis and overtreatment. Actually, the main cause ofoverdiagnosis and treatment of pre-capillary PH is the failure to confirm the diagnosis by RHC.

Conversely, the other side of this dilemma could be to undertreat some patients with abnormal elevationof PAP but not meeting the classical definition of PH. Today, there is growing evidence that in somePVDs (mainly PAH associated with systemic sclerosis, chronic thromboembolism and chronic lungdiseases) patients with even a modest elevation in mPAP (21–24 mmHg) are symptomatic with exerciselimitation and may have poor outcome. Nevertheless, a change in the haemodynamic definition of PH dueto PVDs does not imply treating these additional patients, but highlights the importance of closemonitoring in this population. Prospective trials are required to determine whether this PH populationmight benefit from specific management.

Definition of exercise PHIn 2004, PH was defined as resting mPAP >25 mmHg or exercise mPAP >30 mmHg [8]. At the 4thWSPH in 2008, however, the “exercise” part of the definition was removed [23]. This was largely due touncertainties concerning the interrelationships between normal ageing, CO changes with exercise andpulmonary vascular physiology. This question was revisited again at the 6th WSPH in 2018.

Why might exercise PH be relevant?A rise in resting PH pressure is a late event in the natural history of PVDs, because of microvascular“reserves”. PAP rises only when ⩾50% of the microcirculation has been lost [24]. Much effort has beendirected towards detecting PVD at an earlier (and potentially more treatable) stage. Intuitively,“unmasking” PVD by increasing CO to demonstrate increased resistance is a logical idea. Furthermore, PHpatients first develop symptoms on exercise.

A number of studies have tried to unmask PVD by “stressing” the pulmonary circulation, by lung flowredistribution with upright posture [25] or by increasing CO [26]. This has led to the concept of“multipoint mPAP–CO” curves, where the rate of rise of mPAP with increasing CO has been informative(figure 1). In general, mPAP rises by ⩾1 mmHg per litre of CO in normal subjects; PVD patients have arise of ⩾3 mmHg per litre of CO, reflecting increased resistance [27]. Generating such data is, however,challenging as exercise RHC measurements are time consuming, difficult, and potentially complicated byerrors due to rapid respiratory cycles and inaccuracies in exercise CO and PAWP measures. Thus,generating mPAP–CO graphs for individual patients is impractical as a clinical routine.

Why might defining exercise PH and PAH be difficult?A number of variables impact on the “normal” change of mPAP with exercise, which in turn complicatesany attempt to establish a threshold for “exercise PH” as a pathological condition. Physiological changesoccur with normal ageing [7] and mPAP also does rise with increasing CO; therefore in subjects (e.g. elite

TABLE 1 Haemodynamic definitions of pulmonary hypertension (PH)

Definitions Characteristics Clinical groups#

Pre-capillary PH mPAP >20 mmHg 1, 3, 4 and 5PAWP ⩽15 mmHg

PVR ⩾3 WU

Isolated post-capillary PH (IpcPH) mPAP >20 mmHg 2 and 5PAWP >15 mmHg

PVR <3 WU

Combined pre- and post-capillary PH (CpcPH) mPAP >20 mmHg 2 and 5PAWP >15 mmHg

PVR ⩾3 WU

mPAP: mean pulmonary arterial pressure; PAWP: pulmonary arterial wedge pressure; PVR: pulmonaryvascular resistance; WU: Wood Units. #: group 1: PAH; group 2: PH due to left heart disease; group 3: PHdue to lung diseases and/or hypoxia; group 4: PH due to pulmonary artery obstructions; group 5: PH withunclear and/or multifactorial mechanisms.

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athletes) who can raise their CO to 30–40 L·min−1 at peak exercise, mPAP can exceed previous “upperlimits” of normal [28]. The greatest difficulty, however, is in using exercise to deduce the presence of PVD,because exercise also causes a rise in PAWP. Thus, if PVR=(mPAP–PAWP)/CO, one must measureexercise PAWP to deduce the pathogenesis of an abnormally high exercise-related PAP. As LHD is thecommonest cause of resting PH and left atrial pressure rises abnormally with exercise in subjects withLHD, measuring changes in PAWP (or left atrial pressure) with exercise becomes the critical determinantfor assessing PVR, in breathless patients with exercise PH.

This lack of diagnostic discrimination power (whether exercise PH is due to LHD or to PVD) has beenexplored by HERVE et al. [29]. Although total pulmonary resistance >3 mmHg per litre of CO distinguishedhealthy controls from those with LHD or PVD, it was impossible to distinguish LHD from PVD patientswith confidence (figure 2). It should be noted that accurate measurement of exercise PAWP is technicallychallenging, related to the exaggerated respiratory swings in PAWP and in part to difficulties in “wedging”a balloon catheter adequately during vigorous exertion.

Summary and perspectivesAlthough there is intuitive appeal to measuring exercise haemodynamics to detect PVD at an earlier stagethan can be revealed by measurements at rest, too many uncertainties persist to allow the reintroductionof a clinically useful definition of exercise PH. More information is required concerning normal changes

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FIGURE 1 The slope of the mean pulmonary arterial pressure (mPAP)–cardiac output (CO) relationship isdifferent in normal control versus pulmonary arterial hypertension (PAH) subjects. Reproduced and modifiedfrom [26] with permission.

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FIGURE 2 Knowledge of the mean pulmonary arterial pressure (mPAP)–cardiac output (CO) relationship does notallow distinction between left heart disease (LHD) and pulmonary vascular disease (PVD) patients; knowledgeof exercise pulmonary arterial wedge pressure is also required. TPR: total pulmonary resistance; WU: WoodUnits. Reproduced from [29] with permission.

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with ageing, high CO and especially about distinguishing exercise-elated changes in PAWP (due to LHD)from changes due to PVD. We believe that these will be fruitful areas for future investigation.

Updated clinical classification of PHThe general purpose of clinical classification of PH is to categorise clinical conditions associated with PHbased on similar pathophysiological mechanisms, clinical presentation, haemodynamic characteristics andtherapeutic management. A comprehensive and simplified version of the clinical classification of PH inchildren and adults is presented in table 2. For patients with PAH associated with congenital heart disease,the four subgroups (Eisenmenger syndrome, left-to-right shunts, coincidental or small defects andpost-operative/closed defects) remain the same [30] as the indications for defect closure (see the Task Forcearticle in this issue of the European Respiratory Journal [31]). The updates of groups 2, 3 and 4 are presentedin the respective Task Force articles in this issue of the European Respiratory Journal [10, 32, 33].

Update of group 1: PAHGroup 1.3: Drug- and toxin-induced PAHWe propose simplifying the characterisation of PAH associated with drugs and toxins into two subgroupsto help physicians to identify drugs requiring specific surveillance. “Definite association” includes drugswith data based on outbreaks, epidemiological case–control studies or large multicentre series. “Possibleassociation” is suggested by multiple case series or cases with drugs with similar mechanisms of action.Based on recent data, the association of PAH with two drugs and toxins (amphetamines/methamphetamines and dasatinib) is now considered definite (table 3).

ZAMANIAN et al. [34] reported a large series of 90 cases of PAH associated with methamphetamine-associated PAH; these subjects were less likely to be female, had more haemodynamic compromise atdiagnosis and had poorer outcomes than IPAH. This analysis confirmed an association between

TABLE 2 Updated clinical classification of pulmonary hypertension (PH)

1 PAH1.1 Idiopathic PAH1.2 Heritable PAH1.3 Drug- and toxin-induced PAH (table 3)1.4 PAH associated with:1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart disease1.4.5 Schistosomiasis

1.5 PAH long-term responders to calcium channel blockers (table 4)1.6 PAH with overt features of venous/capillaries (PVOD/PCH) involvement (table 5)1.7 Persistent PH of the newborn syndrome

2 PH due to left heart disease2.1 PH due to heart failure with preserved LVEF2.2 PH due to heart failure with reduced LVEF2.3 Valvular heart disease2.4 Congenital/acquired cardiovascular conditions leading to post-capillary PH

3 PH due to lung diseases and/or hypoxia3.1 Obstructive lung disease3.2 Restrictive lung disease3.3 Other lung disease with mixed restrictive/obstructive pattern3.4 Hypoxia without lung disease3.5 Developmental lung disorders

4 PH due to pulmonary artery obstructions (table 6)4.1 Chronic thromboembolic PH4.2 Other pulmonary artery obstructions

5 PH with unclear and/or multifactorial mechanisms (table 7)5.1 Haematological disorders5.2 Systemic and metabolic disorders5.3 Others5.4 Complex congenital heart disease

PAH: pulmonary arterial hypertension; PVOD: pulmonary veno-occlusive disease; PCH: pulmonary capillaryhaemangiomatosis; LVEF: left ventricular ejection fraction.

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methamphetamine/amphetamine use and PAH-related hospitalisation (relative risk 2.64, 95% CI 2.18–3.2;p<0.001). Interestingly, pathological assessment demonstrated characteristic vascular changes similar toIPAH, including angiomatoid plexiform lesions, but also proliferative capillaries, as described inpulmonary capillary haemangiomatosis (PCH) or pulmonary veno-occlusive disease (PVOD). Dasatinib isa second-generation tyrosine kinase inhibitor and has been reported to be associated with PAH; the lowestestimate of incident PAH occurring in patients exposed to dasatinib in France was 0.45% [35].Dasatinib-induced PAH frequently improves after discontinuation, but persists in over one-third ofpatients [35, 36].

Over the last 5 years, new drugs have been identified or suspected as potential risk factors for PAH.Several cases of deterioration or relapse of dasatinib-associated PAH after bosutinib initiation have beenreported [37–39]; these cases were also characterised by an improvement of PAH after withdrawal ofbosutinib. Cases of severe portopulmonary hypertension have occurred with novel strategies ofdirect-acting antivirals, including sofosbuvir for hepatitis C virus infection [40, 41]. Leflunomide, adisease-modifying antirheumatic drug, has been associated with several cases of PAH [42–44]. Recently,cases of potentially reversible PAH associated with natural indigo (Qing-Dai), an unapproved Chineseherbal drug, have been reported from the Japan Pulmonary Hypertension Registry [45, 46]. The activepharmaceutical ingredient of Qing-Dai is indirubin, which could induce apoptosis of pulmonaryendothelial cells in vitro [46].

Group 1.5: PAH long-term responders to calcium channel blockersAlthough remodelling of small pulmonary arteries is the main pathological finding in PAH, pulmonaryvasoconstriction also plays an important role in PAH pathophysiology, particularly in vasoreactive patients.

In a series of 64 patients published in 1992, RICH et al. [47] reported that patients with an acutevasodilator response to calcium channel blockers (CCBs) had dramatically improved survival when treatedwith long-term CCBs. In 2005, SITBON et al. [48] demonstrated in a large series of 557 PH patients thatacute vasodilator response may be observed in 12.5% of idiopathic PAH (IPAH), and overall 6.8% ofpatients have a long-term clinical and haemodynamic improvement on CCBs. This study identified thebest criteria to identify acute vasodilator response, i.e. a reduction of mPAP ⩾10 mmHg to reach anabsolute value of mPAP ⩽40 mmHg with an increased or unchanged CO. For vasoreactivity testing,inhaled nitric oxide at 10–20 ppm is the preferred agent, but i.v. epoprostenol, i.v. adenosine or inhalediloprost can be used as alternatives (table 4). Long-term response to CCBs was defined by clinical

TABLE 3 Updated classification of drugs and toxins associated with PAH

Definite Possible

Aminorex CocaineFenfluramine PhenylpropanolamineDexfenfluramine L-tryptophanBenfluorex St John’s wortMethamphetamines AmphetaminesDasatinib Interferon-α and -βToxic rapeseed oil Alkylating agents

BosutinibDirect-acting antiviral agents against hepatitis C virusLeflunomideIndirubin (Chinese herb Qing-Dai)

TABLE 4 Definitions of acute and long-term response

Acute pulmonary vasoreactivity# for patients withidiopathic, hereditable or drug-induced PAH

Reduction of mPAP ⩾10 mmHg to reach an absolute value of mPAP ⩽40 mmHgIncreased or unchanged cardiac output

Long-term response to CCBs New York Heart Association Functional Class I/IIWith sustained haemodynamic improvement (same or better than achievedin the acute test) after at least 1 year on CCBs only

PAH: pulmonary arterial hypertension; mPAP: mean pulmonary arterial pressure; CCB: calcium channel blocker. #: nitric oxide (10–20 ppm) isrecommended for performing vasoreactivity testing, but i.v. epoprostenol, i.v. adenosine or inhaled iloprost can be used as alternatives.

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improvement (New York Heart Association Functional Class I or II) and sustained haemodynamicimprovement after at least 1 year on CCBs only (same or better than achieved in the acute test and usuallyto obtain mPAP <30 mmHg with an increased or normal CO) (table 4). Pulmonary vasoreactivity testingfor identification of patients suitable for CCB treatment is recommended only for patients with IPAH,heritable PAH or drug-induced PAH. In all other forms of PAH and PH the results can be misleading andlong-term responders are rare [49].

Pathophysiology of PAH with vasoreactivity is largely unknown. Recently, Hemnes and co-workers haveshown that PAH with vasoreactivity was characterised by a specific blood signature (microarray of culturedlymphocytes) and different gene variants (whole exome sequencing) compared with IPAH [50, 51]. Theseresults suggest a specific entity with a distinct clinical course, characterised by significantly betterprognosis, unique management and different pathophysiology (table 2).

Group 1.6: PAH with overt features of venous/capillaries (PVOD/PCH) involvementSignificant pulmonary venous and/or capillary involvement has been reported in many conditions whichare known causes of PAH, such as systemic sclerosis. In the previous classification, PVOD/PCH wascharacterised as a distinct subgroup.

PVOD/PCH and PAH share similar causes and associated conditions even if some of them are morefrequently associated with more pronounced venous/capillary involvement (table 5). Heritable forms ofPVOD/PCH have been recognised in consanguineous families with a recessive transmission, due tobiallelic mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene [52–54].Occupational exposure to organic solvents, particularly to trichloroethylene, has been associated with thedevelopment of pre-capillary PH with significant venous and capillary involvement [55].

Diagnosis of significant pulmonary venous/capillary involvement (PVOD/PCH) may be strongly suspectedbased on pulmonary function tests (decreased diffusion capacity of the lung for carbon monoxide (DLCO)frequently <50% of theoretical values), arterial blood gases (severe hypoxaemia) and high-resolutioncomputed tomography of the chest (septal lines, centrilobular ground-glass opacities/nodules andmediastinal lymph node enlargement) (table 5) [53, 54, 56]. More pronounced pulmonary venous/capillaryinvolvement is associated with a poor prognosis, a limited response to PAH therapy and a risk ofpulmonary oedema with these treatments [53, 57].

PAH and PVOD/PCH usually share a broadly similar haemodynamic profile and clinical presentation. Ofnote, significant pulmonary arterial remodelling has been described in biallelic EIF2AK4 mutation carriers[58] and muscular remodelling of pulmonary septal veins can be observed in BMPR2 (bonemorphogenetic protein receptor type 2) mutation carriers [59]. What matters in practice are the clinicalconsequences of pulmonary venous/capillary involvement in pre-capillary PH. We therefore suggest thatPAH and PVOD/PCH belong to a spectrum of PVDs rather than representing two clear-cut distinctentities. We propose including “PAH with overt features of venous/capillaries (PVOD/PCH) involvement”in the revised PAH (group 1) of the updated PH classification (table 2).

Update of group 5: PH with unclear and/or multifactorial mechanismsSince the basis of our classification system was established in 1998, group 5 has passed through significantchanges. Initially describing “disorders directly affecting the pulmonary vasculature”, then named“miscellaneous” during the 3rd WSPH in 2003 [60], and finally reaching its current presentation, thisgroup includes forms of PH with unclear and/or multifactorial mechanisms [30, 61]. From the beginning,

TABLE 5 Signs evocative of venous and capillary (pulmonary veno-occlusive disease/pulmonarycapillary haemangiomatosis) involvement

Pulmonary function tests Decreased DLCO (frequently <50%)Severe hypoxaemia

Chest HRCT Septal linesCentrilobular ground-glass opacities/nodules

Mediastinal lymph node enlargement

Response to PAH therapy Possible pulmonary oedema

Genetic background Biallelic EIF2AK4 mutations

Occupational exposure Organic solvent (trichloroethylene)

DLCO: diffusing capacity of the lung for carbon monoxide; HRCT: high-resolution computed tomography;PAH: pulmonary arterial hypertension.

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this group has represented less-studied forms of PH, in comparison with other groups; nevertheless, manyof the PH forms currently in group 5 represent a significant part of the yet unrecognised worldwideburden of PH [62].

One of the central characteristics of the clinical conditions included in group 5 is that there is noidentified predominant mechanism driving the development of PH and there may be multiplepathophysiological phenomena involved in this process (table 7). In this update of the classification,changes were considered only for the subtypes in which a definite relocation was supported by theavailable literature.

Group 5.1: Haematological disordersChronic haemolytic anaemia is clearly associated with an increased risk of PH [63]. Since the 5th WSPHin 2013, little has been added to the current understanding of the numerous presentations of PH in sicklecell disease (SCD). However, it is clear that in this setting PH is frequently multifactorial, includingelevated CO, LHD, thromboembolic disease, altered blood viscosity and PVD due to endothelialdysfunction, mainly due to nitric oxide depletion [64–67]. More recently, restrictive cardiomyopathy hasbeen better recognised and described in clinical and experimental studies [68]. These data reinforce theutmost importance of this particular form of PH and the need for continuous investigation in this field[64, 65]. In addition, over recent years, significant data have been generated regarding another importantchronic haemolytic anaemia, i.e. β-thalassaemia. A better understanding about the risk factors for majorcomplications of the disease, including PH, has been derived from significant cohorts [69]. Furthermore,DERCHI et al. [70] evaluated the prevalence of PH through invasive haemodynamic evaluation, similarly towhat has been done in SCD [71–73]. In their cohort of 1309 patients that underwent screening evaluation,pre-capillary PH was confirmed in 2.1% of the cases, while a post-capillary profile was found in 0.3% [70].Older age and splenectomy were clear risk factors associated with PH. Although this study providedimportant information regarding the significance of PH in this clinical condition, more data concerningthe histopathology of vascular involvement as well as about pathophysiological mechanisms of PHdevelopment in these patients are still needed to better address potential management strategies.

TABLE 7 Pulmonary hypertension with unclear and/or multifactorial mechanisms

5.1 Haematological disorders Chronic haemolytic anaemiaMyeloproliferative disorders

5.2 Systemic and metabolicdisorders

Pulmonary Langerhans cell histiocytosisGaucher diseaseGlycogen storage diseaseNeurofibromatosisSarcoidosis

5.3 Others Chronic renal failure with or without haemodialysisFibrosing mediastinitis

5.4 Complex congenital heartdisease

See the Task Force article by ROSENZWEIG et al. [31] in this issue of theEuropean Respiratory Journal

TABLE 6 Pulmonary hypertension (PH) due to pulmonary artery obstructions

4.1 Chronic thromboembolic PH4.2 Other pulmonary artery obstructions4.2.1 Sarcoma (high or intermediate grade) or angiosarcoma4.2.2 Other malignant tumoursRenal carcinomaUterine carcinomaGerm cell tumours of the testisOther tumours

4.2.3 Non-malignant tumoursUterine leiomyoma

4.2.4 Arteritis without connective tissue disease4.2.5 Congenital pulmonary artery stenoses4.2.6 ParasitesHydatidosis

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Splenectomy deserves particular discussion. Following the first association of splenectomy and PH [74], itwas not clear whether it represented a risk factor or a particular condition. Since then, splenectomy hasbeen associated with the development of PH in many haematological conditions, as in the aforementionedβ-thalassaemia [69, 70]. Most importantly, it has been strongly associated with the development of chronicthromboembolic PH [75]. Nevertheless, no other particular phenotype or change in clinical behaviour hasbeen associated with the presence of splenectomy, suggesting that it should be better considered as a riskfactor for PH instead of a particular condition deserving a specific classification.

Group 5.2: Systemic and metabolic disordersIt is important to emphasise that the concept supporting the classification of a clinical condition withsystemic manifestations and a clear risk for PH into group 5 is, again, the lack of robust data allowing adefinite recognition of predominant pathophysiological mechanisms, or describing the histopathologicalfindings or yet, describing management strategies. For this reason, several conditions have been classifiedin this group, including sarcoidosis, lymphangioleiomyomatosis (LAM), pulmonary Langerhans cellhistiocytosis, thyroid disorders, Gaucher disease, glycogen storage disease and neurofibromatosis

Regarding LAM, a recent screening study [76], in a significant cohort of more than 100 LAM patients,reinforced that PH in LAM is usually mild, as previously described [77]. From six patients (5.7%) presentingwith pre-capillary PH, none had mPAP >30 mmHg. Moreover, the presence of PH was associated with poorpulmonary function, suggesting that the rise in pulmonary pressure is associated with parenchymalinvolvement, which was further reinforced by a more recent echocardiographic study [78]. Based on thesefindings, PH in LAM seem to be better classified together with other parenchymal lung diseases, in group 3.

Sarcoidosis is a more challenging situation, given the fact that PH might develop as a consequence ofsignificantly different factors, from parenchymal lung disease to extrinsic compression of pulmonaryvessels, direct myocardial involvement or even granulomatous arteriopathy [79]. Significant lungparenchymal disease is a highly prevalent condition in patients with sarcoidosis-associated PH [80, 81],although the presence of left ventricular dysfunction cannot be neglected [80]. It is difficult, however, tosolely consider lung parenchymal involvement to reclassify sarcoidosis, given the multiplicity of otherfactors yet to be clarified, including the different histopathological pattern of the pulmonary vesselscommonly seen in sarcoidosis, with granuloma formation in some cases [79], as opposed to other diseasesin group 3. While these features are better studied, sarcoidosis remains classified into group 5.

There is a strong rationale for the concomitance of thyroid diseases and PH, from autoimmunity to thepresence of high or low CO, left ventricular dysfunction, or even an angioproliferation profile. Theprevalence of thyroid disorders is increased in patients with PAH [82, 83]; furthermore, the level of thyroiddysfunction is also associated with prognosis in this setting [84]. Nevertheless, similarly to splenectomy, thepresence of thyroid dysfunction does not necessarily characterise a specific clinical condition; it behavesmore like a risk factor or a comorbidity that should be specifically controlled during the course of PHmanagement. Until novel data prove otherwise, it was a consensus to withdraw thyroid disorders from theclassification as a specific entity and better discuss their role as risk factors and/or associated comorbidities.

Many different conditions associated with PH still need better designed studies that add to theunderstanding of disease development. We propose that changes be made only after the generation ofrobust data to support such reclassification.

ConclusionsThis Task Force first revisited the definition of PH, suggesting a new pressure level to define an abnormalelevation in the mPAP >20 mmHg and the need for PVR ⩾3 WU to define the presence of pre-capillary PH.Furthermore, the Task Force proposed to simplify the core of the clinical classification of PH (table 2) whichhas been developed in additional tables. The two main changes in group 1 (PAH) include 1) the designationof a subgroup “PAH long-term responders to CCBs” and 2) the inclusion of the subgroup “PAH with overtfeatures of venous/capillaries (PVOD/PCH) involvement”. Group 5 (PH with unclear and/or multifactorialmechanisms) was simplified with 1) the removal of splenectomy and thyroid disorders, and 2) theclassification of LAM-associated PH together with other parenchymal lung diseases in group 3. Importantnew insights for groups 2, 3 and 4 have been addressed by the respective Task Forces in this issue of theEuropean Respiratory Journal [10, 32, 33].

Conflict of interest: G. Simonneau reports grants, personal fees and non-financial support from ActelionPharmaceuticals, Bayer Healthcare, Merck and GSK, outside the submitted work. D. Montani reports grants, personalfees and non-financial support from Actelion Pharmaceuticals, Bayer Healthcare, Merck and GSK, outside thesubmitted work. D.S. Celermajer is an investigator on two clinical trials sponsored by Actelion. C.P. Denton reportsgrants and personal fees from Actelion and Roche, grants from GSK, and personal fees from Bayer and Boehringer

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Ingelheim, during the conduct of the study; grants and personal fees from Inventiva and CSL Behring, and personal feesfrom Leadiant, outside the submitted work. M.A. Gatzoulis reports personal fees for steering committee membershipfrom Actelion Pharmaceuticals, and grants from Actelion Global, Pfizer and GSK, during the conduct of the study.M. Krowka is a steering committee member for PORTICO (Macitentan for Portopulmonary Hypertension Study),which is sponsored by Actelion, outside the submitted work. P.G. Williams received personal fees for advisory boardmeetings from Aspen SA and GSK, outside the submitted work. R. Souza reports lecture and consultancy fees fromActelion, Bayer, GSK and Pfizer, outside the submitted work.

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Diagnosis of pulmonary hypertension

Adaani Frost1, David Badesch2, J. Simon R. Gibbs3, Deepa Gopalan4,Dinesh Khanna5, Alessandra Manes6, Ronald Oudiz7, Toru Satoh8,Fernando Torres9 and Adam Torbicki10

Number 5 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1Dept of Medicine, Institute of Academic Medicine, Houston Methodist Hospital, Houston, TX, USA.2Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Denver,CO, USA. 3National Heart and Lung Institute, Imperial College of London, London, UK. 4Dept of Radiology,Imperial College Healthcare NHS Trust and Imperial College London, Hammersmith Hospital, London, UK.5University of Michigan Scleroderma Program, Ann Arbor, MI, USA. 6Cardio-Thoracic and Vascular Dept,Sant’Orsola University Hospital, Bologna, Italy. 7LA Biomedical Research Institute at Harbor-UCLA MedicalCenter, Torrance, CA, USA. 8Division of Cardiology, Kyorin University Hospital, Tokyo, Japan. 9University ofTexas Southwestern Medical School, Dallas, TX, USA. 10Dept of Pulmonary Circulation and Cardidology,Medical Center for Postgraduate Education, ECZ-Otwock, Otwock, Poland.

Correspondence: Adaani Frost, Dept of Medicine, Institute of Academic Medicine, Houston Methodist Hospital,Suite 1001, 6550 Fannin Street, Houston, TX 77030-2707, USA. E-mail: afrost@houstonmethodist.org

@ERSpublicationsState of the art and research perspectives in the diagnostic procedures of patients with pulmonaryhypertension including a comprehensive diagnostic algorithm http://ow.ly/Ow9730mknM6

Cite this article as: Frost A, Badesch D, Gibbs JSR, et al. Diagnosis of pulmonary hypertension. Eur Respir J2019; 53: 1801904 [https://doi.org/10.1183/13993003.01904-2018].

ABSTRACT A revised diagnostic algorithm provides guidelines for the diagnosis of patients withsuspected pulmonary hypertension, both prior to and following referral to expert centres, and includesrecommendations for expedited referral of high-risk or complicated patients and patients withconfounding comorbidities. New recommendations for screening high-risk groups are given, and currentdiagnostic tools and emerging diagnostic technologies are reviewed.

Received: Oct 05 2018 | Accepted: Oct 09 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

https://doi.org/10.1183/13993003.01904-2018 Eur Respir J 2019; 53: 1801904

| SERIESWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

IntroductionThere has been no meaningful decrease in the time from symptom onset to diagnosis of pulmonaryhypertension (PH) in the past 20 years. Therefore, the diagnostic algorithm and guidelines for screeningat-risk groups have been modified, balancing the benefits of earlier diagnosis and disease recognitionagainst the economic healthcare burden of additional screening and increased referrals to PH centres.

Diagnostic approach in patients with clinical suspicion for PH/pulmonary arterialhypertensionPH due to parenchymal, cardiac, thromboembolic and other diseases (diagnostic groups 2, 3, 4 and 5,respectively) is associated with worse outcomes and limited treatment options, resulting in referral of thesepatients to PH centres. Guidelines for the diagnosis and management for these subgroups are addressedseparately by the relevant 6th World Symposium on Pulmonary Hypertension (WSPH) Task Force articlesin this issue of the European Respiratory Journal [1–3].

Clinical suspicion of PHSymptomsSymptoms of PH are non-specific: exertional dyspnoea, fatigue, weakness, chest pain, light-headedness/syncope and, less frequently, cough. Progressive right-sided heart failure (oedema, ascites, abdominaldistension) occurs in later or more accelerated disease. Rarely, haemoptysis, Ortner’s syndrome/hoarseness(unilateral vocal chord paralysis) and arrhythmias may characterise PH.

Physical findingsPhysical findings include augmented second heart sound (P2 component), right ventricular lift, jugularvenous distension, hepatojugular reflux, ascites, hepatomegaly and/or splenomegaly, oedema, tricuspidregurgitant or pulmonary regurgitant murmurs, and S3 gallop.

Diseases associated with PH can be suggested by history and physical exam.

Established diagnostic toolsElectrocardiographySince the US National Institutes of Health (NIH) registry report on primary PH in 1987 [4], the ECG hasbeen considered a reliable clue to the presence of PH. ECG features in patients with pulmonary arterialhypertension (PAH) have been demonstrated to be associated with worse prognosis [5, 6]. The derivativepopulations for these conclusions were patients with known PAH, predominantly World HealthOrganization Functional Class III and IV. The utility of the ECG as a screening tool in complicatedpatients or those early in the course of their disease is uncertain. A normal ECG does not exclude PH.

Blood tests and immunologyBlood tests are not useful for PH diagnosis, but distinguish some forms of PH and indicate end-organcompromise. Routine biochemistry, haematology and thyroid function tests are required in all patients.Liver function abnormalities may represent congestion, primary liver disease and/or consequences oftherapy. Thyroid disease is common in PAH, may develop during the disease and should be considered incases of abrupt deterioration. Elevations of brain natriuretic peptide (BNP) and N-terminal pro-BNP(NT-proBNP) are associated with right ventricular overload, and are predictors of worse outcome.

Routine screening for connective tissue disease (CTD), hepatitis and HIV is required. Elevated antinuclearantibodies (ANAs) occur frequently, although in low titres (1:80). Recommended serological testing forscleroderma includes ANAs (as ELISA can be associated with false-negative tests, ANAimmunofluorescence is recommended and should be considered positive at ⩾1:160). If there is a highindex of suspicion, consider a panel that consists of anticentromere, antitopoisomerase, anti-RNApolymerase III, double-stranded DNA, anti-Ro, anti-La and U1-RNP antibodies.

Patients with CTD (associated with thombophilic states) and chronic thromboembolic PH (CTEPH)should undergo screening for coagulopathies and thrombophilia, including anticardiolipin antibodies,lupus anticoagulant and anti-β2-glycoprotein antibodies.

Pulmonary function tests and arterial blood gasesPulmonary function tests are addressed in the PH lung disease Task Force article in this issue of theEuropean Respiratory Journal [2], and should include total lung capacity and diffusing capacity of the lungfor carbon monoxide (DLCO). In most patients with PAH there is a mild restrictive component. Markedreduction in DLCO (<60% of predicted) or severe exertional hypoxaemia can indicate pulmonaryveno-occlusive disease/pulmonary capillary haemangiomatosis [7].

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Cardiopulmonary exercise testingCardiopulmonary exercise testing (CPET) for diagnostic purposes can be done non-invasively or withhaemodynamic testing [8]. CPET can quantify the degree of relative hypoperfusion of the lung and thesystemic circulation that occurs during exercise in patients with PH [9], and can grade the severity ofexercise limitation and assess responses to therapy [10].

Abnormalities in effort-independent ratio of minute ventilation to carbon dioxide production (V ̇E/V ̇CO2)and end-tidal carbon dioxide tension (PETCO2) obtained during CPET have been used to estimate thelikelihood of PH (lower peak oxygen uptake (V ̇O2) and/or higher V ̇E/V ̇CO2 signifying an increasinglikelihood of pulmonary vascular disease) [11]. Several investigators have demonstrated the utility of CPETin defining abnormal exercise responses specific to PAH [12–15]. CPET can be particularly useful inhelping identify the predominant underlying cardiopulmonary pathophysiology [13, 16–19]. A detaileddescription of the methodologies used in CPET for PH can be found in SUN et al. [9]. Submaximalexercise testing to evaluate PAH severity using a simplified gas exchange system has also beenproposed [20].

Accurate utilisation of CPET requires performance by a competent facility and interpretation by a clinicianwith expertise in gas exchange in conjunction with the patient’s history, physical and laboratory findings.CPET is useful for determining the nature of the exercise limitation in patients with unexplaineddyspnoea, but should not be used as the sole screening tool for asymptomatic subjects at risk fordeveloping PAH; CPET can help evaluate cardiopulmonary limitations and assess pulmonary vascularinvolvement in these patients; emerging evidence suggests that CPET may be useful for evaluatingsymptomatic patients at high risk for developing PAH [15]. In addition, CPET should be considered afterdiagnosis of PAH to quantify the severity of exercise impairment and to estimate prognosis.

Transthoracic echocardiographyThe transthoracic echocardiogram (TTE) remains the most important non-invasive screening tool andright heart catheterisation (RHC) remains mandatory to establish the diagnosis.

The echocardiographic probability of PH was derived from previously published data in normal adults[21–23], and consolidated by expert opinion using the combination of tricuspid regurgitant velocity, rightventricular size, interventricular septal function, inferior vena cava diameter fluctuations with respiratorycycle, systolic right atrial area, pattern of systolic flow velocity and early diastolic pulmonary regurgitantvelocity, and diameter of the pulmonary artery (tables 1 and 2) [24–27].

Ventilation/perfusion lung scanningVentilation/perfusion (V/Q) lung scanning is addressed in the CTEPH Task Force article in this issue ofthe European Respiratory Journal [3]. A normal V/Q scan remains the preferred diagnostic tool and rulesout CTEPH. Nuclear medicine societies are recommending a transition of V/Q reporting to a binaryinterpretation [28, 29].

Chest computed tomographyChest computed tomography (CT) demonstrating right ventricular dilation, right atrial dilation, enlargedmain pulmonary artery (diameter ⩾29 mm) or a main pulmonary artery/ascending aorta diameter ratio

TABLE 1 Echocardiographic probability of pulmonary hypertension (PH) in symptomatic patientswith a suspicion of PH

Echocardiographicprobability of PH

Presence of other echocardiographic "PH signs"#

Peak tricuspid regurgitation velocity m·s–1

LowNo≤2.8 or not measurable

HighYes2.9–3.4Not required>3.4

IntermediateYes≤2.8 or not measurableNo2.9–3.4

#: see table 2. Reproduced and modified from [24] with permission.

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⩾1 is suggestive of PH [30]. High-resolution non-contrast examination can identify parenchymal lungdisease and discriminate between PH lung disease and PAH (group 3 versus group 1).

Current state-of-the-art diagnostic algorithmThe modified diagnostic algorithm divides the diagnostic approach into 1) that undertaken outside the PHexpert centre, including recommendations for high-risk/accelerated disease requiring expedited triage tothe expert centre (figure 1), and 2) that focusing on the diagnosis of PH once referred to a PH expertcentre (figure 2).

Practice recommendations (including high-risk population screeningrecommendations)Patients with congenital heart disease (CHD), CTD, HIV and portopulmonary hypertension (POPH) areat increased risk for PH. As little or no progress has been made in earlier diagnosis, this Task Forcerecommends more aggressive assessment and screening of some of these high-risk populations.

Scleroderma (systemic sclerosis) and scleroderma spectrumThe 5th WSPH report, the 2015 European Society of Cardiology (ESC)/European Respiratory Society(ERS) PH guidelines and the NIH-supported 2013 CTD-PAH guidelines recommend annual screening inpatients with systemic sclerosis (SSc) [24, 31, 32]. All guidelines recommend the DETECT algorithm(evidence-based detection of PAH in SSc) in patients with SSc spectrum disorders (SSc, mixed CTD orother CTDs with prominent scleroderma features (e.g. sclerodactyly, nail fold capillary abnormalities andSSc-specific autoantibodies)) associated with DLCO <60% of predicted and disease duration >3 years. Thecurrent diagnosis Task Force undertook a systematic review of the published literature for screening toolsavailable for CTD-PAH [33]. The review supports incorporating TTE, DETECT (with preliminary data onits performance with those with DLCO <80% of predicted) or forced vital capacity (FVC)/DLCO ratio >1.6and blood markers (such as NT-proBNP) in SSc spectrum disorders. Based on this data and on thepublished guidelines, this Task Force recommends the incorporation of DETECT, TTE or FVC/DLCO ratiowith elevated NT-proBNP to screen for SSc spectrum disorders. Although the prevalence of PAH is lowerin those with DLCO ⩾80% of predicted, review of two large cohorts in the USA ([33] and Steve Mathai,Johns Hopkins, Baltimore, MD, USA; personal communication) suggested that PAH is present in thesepatients.

Recommendations

• For patients with SSc and SSc spectrum with uncorrected DLCO <80% of predicted, annual screeningshould be considered. The appropriate screening tools include DETECT, the 2015 ESC/ERSrecommendations for TTE or FVC/DLCO ratio >1.6 (assuming none-to-mild interstitial lung disease)and >2-fold upper limit of normal of NT-proBNP. If any of these screening tests are positive, thesepatients should be referred for RHC. For those with uncorrected DLCO ⩾80% of predicted, screeningmay be considered with TTE.

TABLE 2 Echocardiographic signs suggesting pulmonary hypertension (PH) used to assess theprobability of PH in addition to tricuspid regurgitation velocity measurement in table 1

A: The ventricles B: Pulmonary artery C: Inferior vena cava andright atrium

Right ventricle/left ventriclebasal diameter ratio >1.0

Right ventricular outflow Doppleracceleration time <105 ms and/or

mid-systolic notching

Inferior cava diameter >21 mmwith decreased inspiratorycollapse (<50% with a sniff

or <20% with quiet inspiration)

Flattening of the interventricularseptum (left ventriculareccentricity index >1.1 insystole and/or diastole)

Early diastolic pulmonaryregurgitation velocity >2.2 m·s–1

Right atrial area (end-systole)>18 cm2

Pulmonary arterydiameter >25 mm

Echocardiographic signs from at least two different categories (A/B/C) from the list should be present toalter the level of echocardiographic probability of PH. Reproduced and modified from [24] with permission.

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HIVAlthough the incidence of PAH in HIV is low, the large number of HIV-infected individuals worldwidemakes HIV a major contributor to the worldwide incidence of PAH and a significant contributor to HIV-related death. Prior guidelines did not recommend PAH screening in HIV-infected patients, a conclusionderived from contemporary RHC-based studies in Europe [34] and the USA [35].

Preliminary data from an ongoing RHC-based study in Atlanta HIV clinics suggests a higher incidence ofPH than previously reported in the USA (prevalence 2% in this US-based African-American population)(Marshaleen Henriques-Forsythe, Morehouse School of Medicine, Atlanta, GA, USA and HarrisonW. Farber, Pulmonary Center, Boston University School of Medicine, Boston, MA, USA; personalcommunication). Risks for PAH in HIV include sex and i.v. drug use. Males are more frequently infectedwith HIV than females, but HIV-infected females are disproportionately diagnosed with PAH (around2-fold). Intravenous drug use has been associated with HIV-PAH [36] in univariate analysis, although itdropped out in multivariate analysis; however, a biological rationale for this association has beendemonstrated [37]. Data suggest that cocaine acts synergistically with the HIV-1 Tat (transactivator oftranscription) protein [38] by suppressing bone morphogenetic protein receptor expression on pulmonaryartery smooth muscle cells.

Other studies report an association between HIV-PAH and female sex [39], chronic hepatitis C virus infection(multivariate OR 3.01, 95% CI 1.2–8.2; p=0.02 [21, 40]) and origin from high-prevalence country [41].

The following higher-risk features are proposed for PAH screening in HIV to enrich the likelihood ofearlier diagnosis of HIV-PAH in asymptomatic patients: female sex, i.v. drug use/cocaine use, hepatitis Cvirus infection, origin from high-prevalence country, known Nef (negative regulatory factor) or Tat HIVproteins and US African-American patients independent of symptoms.

Recommendations

• Screen for PAH in HIV patients with symptoms or with more than one risk factor for HIV-PAH.

History, symptoms, signs and/or laboratory tests suggestive of PH

Echocardiographic probability of PH#Assess probability of PH

Identify high-risk patients

Diagnose commoncauses of PH

Diagnose rare causes of PHRefer to PH expert

centreƒ

Low

High or intermediate

Consider V/Q scan toscreen for CTEPH+

Consider left heart disease (assess pre-test

probability) and lung disease§

No clinically significant left heart disease or

lung disease

Fast-track referral of selected patients

Consider othercauses and/or

follow-up¶

V/Q scan abnormal

FIGURE 1 Algorithm for the diagnosis of pulmonary hypertension (PH) and its causes: triage of urgent casesand diagnosis of common conditions (for more details, see the accompanying text). V/Q: ventilation/perfusion;CTEPH: chronic thromboembolic PH. #: described in the 2015 European Society of Cardiology/EuropeanRespiratory Society PH guidelines [24]; ¶: these include chronic thromboembolic disease without PH, whichshould be considered in patients with risk factors and/or previous venous thromboembolism; +: single photonemission computed tomography or planar V/Q scan is acceptable (interpretation is binary: normal orabnormal); §: see algorithms for left heart disease and lung disease/hypoxia-related PH [1–3], which providedetails of further management of these patients; ƒ: referral of a patient to be seen in person or for ateleconsultation.

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HeritableRecommendations in the USA for PAH genetic screening are largely ignored, misunderstood or unfunded[42]. In contrast, genetic screening and counselling offered by French PH referral centres have identifiedPAH mutations in 16.9% of presumed sporadic PAH patients, in 89% of patients with a family history[43] and in asymptomatic first-degree relatives of mutation carriers pre-emptively screened. Recentlongevity data indicates a lifelong risk of developing disease in 14% of male and 42% of female carriers,prompting our recommendation for annual echocardiography in asymptomatic carriers [44].

Recommendations

• Genetic counselling of all idiopathic, anorexiant and familial PAH patients and first-generationasymptomatic family members of patients with known genetic mutations.

• Subsequent evaluations for PAH should be offered (e.g. CPET and TTE), in mutation-positiveindividuals.

• National databases for genotyping all PAH patients should be advocated by the WSPH. Biobanking ofsamples and/or genotyping should be mandated in future interventional studies in PAH patients andpossibly in PH patients.

Other heritable PHHereditary haemorrhagic telangiectasiaThe French hereditary haemorrhagic telangiectasia (HHT) registry [45] demonstrated theechocardiographic prevalence of PH in HHT as 4.23%, although this was usually associated withhigh-output left heart failure. However, the review indicated that while PAH was rare, it was associatedwith much poorer survival.

RHC for PH diagnosis and haemodynamic

characterisationConsider other

causes¶

Review by multidisciplinary PH

team+

PH confirmed

PH notconfirmed

CTEPH not confirmed

CTEPH confirmed

PH notconfirmed

Normal perfusionAny mismatchedperfusion defect

Review or perform

V/Q scan#

Multimodality diagnostic

assessment

CTEPH diagnosticalgorithm

Management atPH expert centre

Consider trial oftreatmentƒ

PH classification not certain

Appropriatetreatment

PH classified§

Monitor and reassess

FIGURE 2 Algorithm for the diagnosis of pulmonary hypertension (PH) and its causes: role of the PH expertcentre. CTEPH: chronic thromboembolic PH; V/Q: ventilation/perfusion; RHC: right heart catheterisation.#: single photon emission computed tomography or planar V/Q scan is acceptable; ¶: these include patientswith chronic thromboembolic disease without PH; +: the composition of the multidisciplinary team may differdepending on the type of clinical problem; §: according to clinical classification of PH; ƒ: only in expert centresand only with a reassessment plan in place.

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Recommendations

• In symptomatic patients and those with heart failure or hepatic arteriovenous malformations, withHHT or family history of HHT, genetic testing and an echocardiogram should be undertaken. If TTEpositive (tables 1 and 2) or suggestive of PH, RHC should be undertaken to distinguish the aetiologyof PH.

Portopulmonary hypertensionThe frequency of PH in patients with liver disease varies with disease severity and duration. By time ofliver transplantation 10.3% of patients had RHC-proven mean pulmonary arterial pressure (mPAP)>35 mmHg [46]. A retrospective review of the UK National Registry of all incident treatment-naivepatients with POPH suggested a prevalence of 0.85 cases per million population [47]. The prevalence ofPOPH in the portal hypertensive population has been previously estimated as 2–6%. Estimated mediansurvival time was 3.75 years in this patient population, with 1-, 2-, 3- and 5-year survival of 85%, 73%,60% and 35%, respectively.

Recommendations

• Echocardiographic screening is recommended in all patients with portal hypertension. If a tricuspidregurgitant jet of >3.4 m·s−1 or right atrial or right ventricular enlargement or dysfunction is found,then further evaluation with RHC and referral to PH expert centre is recommended.

Congenital heart diseaseIn CHD, PAH can be identified in four distinct subgroups of patients: 1) Eisenmenger syndrome, 2)persistent systemic-to-pulmonary shunts, 3) those with small, coincidental defects, and 4) patients whohave undergone defect correction. PAH is present by definition in subgroups 1 and 3. Thus, PAHscreening in the CHD population should be undertaken in subgroup 2 and, importantly, subgroup 4.

Recommendations

• Post-operative PAH screening in subgroup 4 should include clinical and echocardiographic and ECGscreening during follow-up visits 3–6 months after correction and then throughout their plannedlong-term cardiological follow-up. Annual screening should be planned for corrected patients whopresented with increased baseline pulmonary vascular resistance or with combinations of otherpredisposing factors.

Novel diagnostic modalitiesInnovative imagingV/Q single photon emission CTV/Q single photon emission CT (SPECT) has higher sensitivity compared with planar imaging and outcomestudies have confirmed a high negative predictive value in excluding pulmonary embolism [48, 49].

Dual-modality techniques with varying combinations of hybrid SPECT/CT pulmonary imaging canimprove the specificity of V/Q SPECT by identifying lung diseases in patients with perfusionabnormalities. The addition of low-dose CT improves the specificity of V/Q SPECT from 88% to 100%while maintaining the same high sensitivity of 97% [50]. V/Q SPECT reduces radiation exposure relative toCT [51–53].

The three-dimensional aspects of V/Q SPECT allow for data objectification and facilitate automatedanalysis. The perfusion redistribution index as measured by V/Q SPECT showed perceptible reduction inthe normal gravity-dependent redistribution of lung perfusion in PAH patients compared with the normalpopulation [54] and hence can be a potential marker of pulmonary vascular disease.

V/Q SPECT and hybrid pulmonary imaging are not universally available.

Dual-energy CT: pulmonary perfusionDual-energy CT (DECT) offers visualisation of morphological and perfusion abnormalities in thepulmonary vasculature. Perfusion alterations were less common but more homogeneous in PAH and weremainly in the form of patchy defects [55]. In CTEPH, perfusion alterations were more frequent andheterogeneous with a high level of concordance with V/Q scintigraphy. The utility of DECT in thediagnosis and prognosis of PH, particularly CTEPH, requires further evaluation.

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Three-dimensional dynamic contrast-enhanced magnetic resonance: lung perfusionDynamic contrast-enhanced magnetic resonance estimates of perfusion are based on quantification oftissue enhancement at serial time-points after injection of gadolinium and the technique has comparablesensitivity to perfusion scintigraphy for diagnosing CTEPH [56, 57]. Although the lack of ionisingradiation makes this an attractive alternative, limited availability and higher costs preclude this techniquefrom superseding V/Q scintigraphy.

Functional magnetic resonance imaging: ventilationThe ready availability and ease of inhaled oxygen as a contrast medium makes pulmonary magneticresonance imaging (MRI) a promising tool for assessing ventilation. In a small study, oxygen-enhancedventilation and contrast-enhanced perfusion MRI was concordant with scintigraphy [58]. Standardisationof analyses and reproducibility of oxygen-enhanced MRI metrics is needed before routine use in clinicalpractice.

Subclinical right ventricular dysfunctionParametric mappingA review of the magnetic resonance literature found 21 magnetic resonance metrics indicative of PH [59].Of these, the ventricular mass index (VMI) was frequently used to assess right ventricular functional andstructural changes compared with RHC. A meta-analysis of VMI revealed a positive likelihood ratio of4.894, indicating a modest ability to differentiate PH patients from healthy controls.

Late gadolinium enhancement (LGE) at the right ventricular insertion points in PH due to delayedclearance of gadolinium correlates inversely with right ventricular performance [60]; however, its utilityhas been called into question in recent studies as a prognostic indicator in PH [61].

T1 mapping is a non-invasive technique for extracellular volume (ECV) quantification and facilitates earlydetection of myocardial involvement that is not detectable by LGE. PH has been shown in a small study tobe independently associated with increased right ventricular ECV even after adjustment for rightventricular dilatation and dysfunction [62].

Larger studies are required to determine if right ventricular ECV reliably predicts adverse clinicaloutcomes, offering the potential for risk stratification, prognostication and therapeutic efficacy assessment.

Right ventricular strainCardiac magnetic resonance-based right ventricular strain imaging evaluates regional myocardial functionby measuring the percentage change in myocardial deformation. Cardiac magnetic resonance featuretracking has shown a significant reduction in right ventricular strain in PH patients with normal rightventricular ejection fraction, predicting subsequent clinical deterioration [63]. Magnetic resonance strainindices are similar to echocardiographic indices, but longitudinal and circumferential strain measurementsare more reliable.

Pulmonary artery four-dimensional flow imagingTime-resolved three-dimensional phase-contrast MRI, also known as four-dimensional flow magneticresonance, visualises and quantifies cardiovascular blood flow. The pulmonary artery flow patterns can bea non-invasive early marker in those at risk for developing PH.

Main pulmonary artery flow vortices are a marker of elevated mPAP. Vortical blood flow in the mainpulmonary artery >14.3% of the cardiac interval corresponds to PH with 97% sensitivity and 96%specificity [64]. The duration of the vortical flow shows a linear increase with mPAP and can be used toestimate PAPs [65]. Early onset of retrograde flow in the dorsal aspect of the main pulmonary artery isanother characteristic of PAH [66].

Wall shear stress is reduced in the proximal pulmonary arteries of PAH patients, and may contribute topulmonary endothelial cell dysfunction and PAH progression [67]. Wall shear stress can be characterisedby four-dimensional flow magnetic resonance with the ability to discriminate PAH patients from normalcontrols [68–70].

These metrics are not available from routine RHC and therefore have potential for non-invasive PHscreening and monitoring. Data extraction is complex and clinical trials are necessary to explore thebenefits of four-dimensional flow magnetic resonance over standard practices.

Intravascular ultrasound and optical coherence tomography in PAHIntravascular ultrasound and optical coherence tomography (OCT) can demonstrate intimal fibrosis, asurrogate marker of pulmonary arterial remodelling that correlates negatively with pulmonary arterial

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compliance and is associated with unfavourable clinical outcomes during mid-term follow-up [71]. OCThas shown development of pulmonary arterial remodelling in patients with borderline PH and theoccurrence of reverse remodelling following effective treatment [72].

Machine learningTechnological advances in cardiac imaging coupled with exceptional computing power and innovativeanalytical modelling offer an unprecedented amount of data that can contribute to the search for novelimaging biomarkers.

A recently published machine learning-based survival model had incremental prognostic power whencompared with conventional parameters to more accurately predict outcomes in PH [73]. Suchcomputational simulations can illuminate pathophysiological mechanisms of right ventricular failure, riskstratify different PH groups and identify imaging end-points following therapeutic interventions.

Future biomarkersNumerous potential biomarkers (e.g. asymmetric dimethylarginine, cystatin C, volatile exhaled gases,exhaled nitric oxide (NO) fraction (FENO) and NOx derivates) [74] have been associated with endothelialcell dysfunction, inflammation, epigenetics, cardiac function, oxidative stress, metabolism, extracellularmatrix and exhaled breath condensate [75, 76]; while novel, these have not yet demonstrated sensitivityand specificity for diagnosis, risk assessment or management of PH.

The future of laboratory biomarkers may hinge on the ability to use “deep phenotyping”, i.e. characteristicpatterns in the genome, transcriptome, proteome and/or metabolome of the patient [77–81]. Currentlymetabolomics emerges as a potentially informative area of systems biology. In the future, a metabolomicsfingerprint may inform treatment decisions, while changes may be considered “deep monitoring” oftreatment results. Currently, however, abnormal responses versus normal responses to abnormal stimuli areindistinguishable and metabolic signatures have only been evaluated in well-defined, homogenous studypopulations. New research paradigms are necessary to prove their value for early detection and differentialdiagnosis of PAH in real life.

Conflict of interest: A. Frost reports personal fees and non-financial support (travel and lodging for attendance andparticipation in the 6th WSPH) from Actelion, Gilead, United Therapeutics and Bayer, honoraria for presentations fromGilead, and honoraria for participation in an end-point adjudication committee for an FDA-approved study fromUnited Therapeutics, during the conduct of the study; and personal fees (honoraria and travel and lodging forpresentations at meetings) from Actelion Pharmaceuticals, outside the submitted work. D. Badesch reports grants andpersonal fees (as steering committee member and site investigator) from Acceleron, Complexa, Bellerophon andLiquidia, grants, personal fees and advisory board work from Actelion, is a long-term stock holder of Johnson andJohnson, grants and personal fees (as advisory board member and site investigator) from Arena, Gilead and UnitedTherapeutics/Lung LLC, personal fees for consultancy from Respira, grants and personal fees (as site investigator,advisory board member and consultant) from Bayer, outside the submitted work. J.S.R. Gibbs reports grants andpersonal fees from Actelion, GSK, MSD and Pfizer, personal fees from Arena, Bayer, Bellerophon, Complexa andAcceleron, and grants from United Therapeutics, during the conduct of the study. D. Gopalan has nothing to disclose.D. Khanna reports personal fees from Actelion, Bayer, Boehringer Ingelheim, Chemomab, Corbus, Covis, Cytori, EMDSereno, Genentech/Roche, Gilead, GSK, Sanofi-Aventis and UCB Pharma; grants from Bayer, Boehringer Ingelheim,Genentech/Roche, Pfizer and Sanofi-Aventis; and has stock options with Eicos Sciences, Inc. He was also supported bythe NIH/NIAMS (K24 AR063120). A. Manes reports grants and personal fees from Actelion, and grants from Bayer andPfizer, outside the submitted work. R. Oudiz reports grants and consulting and speaker fees from Actelion, Gilead andUnited Therapeutics, grants from Aadi and GSK, consulting fees from Complexa, Acceleron and Medtronic, and grantsand consulting fees from Arena and Reata, outside the submitted work. T. Satoh has nothing to disclose. F. Torresreports personal fees from Actelion, Bayer, Reata and Arena, and grants from Gilead, United Therapeutics, Medtronic,Eiger and Bellerophon, during the conduct of the study. A. Torbicki reports personal fees from Actelion, AOP OrphanPharmaceutics, Bayer and MSD, and non-financial support from Pfizer, outside the submitted work; and is also achairperson of the Foundation for Pulmonary Hypertension, which receives donations from outside parties to supportits activities. The chair receives no financial compensation for this function.

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54 Lau EM, Bailey DL, Bailey EA, et al. Pulmonary hypertension leads to a loss of gravity dependent redistribution ofregional lung perfusion: a SPECT/CT study. Heart 2014; 100: 47–53.

55 Giordano J, Khung S, Duhamel A, et al. Lung perfusion characteristics in pulmonary arterial hypertension (PAH)and peripheral forms of chronic thromboembolic pulmonary hypertension (pCTEPH): dual-energy CT experiencein 31 patients. Eur Radiol 2017; 27: 1631–1639.

56 Rajaram S, Swift AJ, Telfer A, et al. 3D contrast-enhanced lung perfusion MRI is an effective screening tool forchronic thromboembolic pulmonary hypertension: results from the ASPIRE Registry. Thorax 2013; 68: 677–678.

57 Johns CS, Swift AJ, Rajaram S, et al. Lung perfusion: MRI vs. SPECT for screening in suspected chronicthromboembolic pulmonary hypertension. J Magn Reson Imaging 2017; 46: 1693–1697.

58 Nakagawa T, Sakuma H, Murashima S, et al. Pulmonary ventilation-perfusion MR imaging in clinical patients.J Magn Reson Imaging 2001; 14: 419–424.

59 Wang N, Hu X, Liu C, et al. A systematic review of the diagnostic accuracy of cardiovascular magnetic resonancefor pulmonary hypertension. Can J Cardiol 2014; 30: 455–463.

60 Freed BH, Gomberg-Maitland M, Chandra S, et al. Late gadolinium enhancement cardiovascular magneticresonance predicts clinical worsening in patients with pulmonary hypertension. J Cardiovasc Magn Reson 2012;14: 11.

61 El Abouelnour A, Doyle M, Thompson DV, et al. Does late gadolinium enhancement still have value? Rightventricular internal mechanical work, Ea/Emax and late gadolinium enhancement as prognostic markers in patientswith advanced pulmonary hypertension via cardiac MRI. Cardiol Res Cardiovasc Med 2017; 2017: CRCM-111.

62 Mehta BB, Auger DA, Gonzalez JA, et al. Detection of elevated right ventricular extracellular volume inpulmonary hypertension using Accelerated and Navigator-Gated Look-Locker Imaging for Cardiac T1 Estimation(ANGIE) cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2015; 17: 110.

63 De Siqueira ME, Pozo E, Fernandes VR, et al. Characterization and clinical significance of right ventricularmechanics in pulmonary hypertension evaluated with cardiovascular magnetic resonance feature tracking.J Cardiovasc Magn Reson 2016; 18: 39.

64 Reiter G, Reiter U, Kovacs G, et al. Magnetic resonance-derived 3-dimensional blood flow patterns in the mainpulmonary artery as a marker of pulmonary hypertension and a measure of elevated mean pulmonary arterialpressure. Circ Cardiovasc Imaging 2008; 1: 23–30.

65 Reiter G, Reiter U, Kovacs G, et al. Blood flow vortices along the main pulmonary artery measured with MRimaging for diagnosis of pulmonary hypertension. Radiology 2015; 275: 71–79.

66 Helderman F, Mauritz GJ, Andringa KE, et al. Early onset of retrograde flow in the main pulmonary artery is acharacteristic of pulmonary arterial hypertension. J Magn Reson Imaging 2011; 33: 1362–1368.

67 Tang BT, Pickard SS, Chan FP, et al. Wall shear stress is decreased in the pulmonary arteries of patients withpulmonary arterial hypertension: an image based, computational fluid dynamics study. Pulm Circ 2012; 2:470–476.

68 Odagiri K, Inui N, Miyakawa S, et al. Abnormal hemodynamics in the pulmonary artery seen on time-resolved3-dimensional phase-contrast magnetic resonance imaging (4D-flow) in a young patient with idiopathicpulmonary arterial hypertension. Circ J 2014; 78: 1770–1772.

69 Odagiri K, Inui N, Hakamata A, et al. Non-invasive evaluation of pulmonary arterial blood flow and wall shearstress in pulmonary arterial hypertension with 3D phase contrast magnetic resonance imaging. Springerplus 2016;5: 1071.

70 Barker AJ, Roldan-Alzate A, Entezari P, et al. Four-dimensional flow assessment of pulmonary artery flow andwall shear stress in adult pulmonary arterial hypertension: results from two institutions. Magn Reson Med 2015;73: 1904–1913.

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71 Domingo E, Grignola JC, Aguilar R, et al. In vivo assessment of pulmonary arterial wall fibrosis by intravascularoptical coherence tomography in pulmonary arterial hypertension: a new prognostic marker of adverse clinicalfollow-up. Open Respir Med J 2013; 7: 26–23.

72 Dai Z, Fukumoto Y, Tatebe S, et al. OCT imaging for the management of pulmonary hypertension. JACCCardiovasc Imaging 2014; 7: 843–845.

73 Dawes TJW, de Marvao A, Shi W, et al. Machine learning of three-dimensional right ventricular motion enablesoutcome prediction in pulmonary hypertension: a cardiac MR imaging study. Radiology 2017; 283: 381–390.

74 McMahon TJ, Bryan NS. Biomarkers in pulmonary vascular disease: gauging response to therapy. Am J Cardiol2017; 120: S89–S95.

75 Rameh V, Kossaify A. Role of biomarkers in the diagnosis, risk assessment, and management of pulmonaryhypertension. Biomark Insights 2016; 11: 85–89.

76 Anwar A, Ruffenach G, Mahajan A, et al. Novel biomarkers for pulmonary arterial hypertension. Respir Res 2016;17: 88.

77 Austin ED, West J, Loyd JE, et al. Translational advances in the field of pulmonary hypertension molecularmedicine of pulmonary arterial hypertension. From population genetics to precision medicine and gene editing.Am J Respir Crit Care Med 2017; 195: 23–31.

78 Elinoff JM, Agarwal R, Barnett CF, et al. Challenges in pulmonary hypertension: controversies in treating the tipof the iceberg. Am J Respir Crit Care Med 2018; 198: 166–174.

79 Maron BA, Abman SH. Translational advances in the field of pulmonary hypertension. focusing on developmentalorigins and disease inception for the prevention of pulmonary hypertension. Am J Respir Crit Care Med 2017;195: 292–301.

80 Nakhleh MK, Haick H, Humbert M, et al. Volatolomics of breath as an emerging frontier in pulmonary arterialhypertension. Eur Respir J 2017; 49: 1601897.

81 Newman JH, Rich S, Abman SH, et al. Enhancing insights into pulmonary vascular disease through a precisionmedicine approach. A joint NHLBI–Cardiovascular Medical Research and Education Fund Workshop Report. AmJ Respir Crit Care Med 2017; 195: 1661–1670.

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Risk stratification and medical therapy ofpulmonary arterial hypertension

Nazzareno Galiè1, Richard N. Channick2, Robert P. Frantz3, Ekkehard Grünig4,Zhi Cheng Jing5, Olga Moiseeva6, Ioana R. Preston7, Tomas Pulido8,Zeenat Safdar9, Yuichi Tamura10 and Vallerie V. McLaughlin11

Number 6 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1Dept of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum,University of Bologna, Bologna, Italy. 2Pulmonary and Critical Care Division, Massachusetts General Hospital,Harvard Medical School, Boston, MA, USA. 3Dept of Cardiovascular Diseases, Mayo Clinic, Rochester, MN,USA. 4Pulmonary Hypertension Center, Thoraxklinic at Heidelberg University Hospital, Heidelberg, Germany.5State Key Lab of Cardiovascular Disease, FuWai Hospital and Key Lab of Pulmonary Vascular Medicine,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 6Non-CoronaryHeart Disease Dept, Almazov National Medical Research Centre, St Petersburg, Russian Federation. 7TuftsUniversity School of Medicine, Pulmonary, Critical Care and Sleep Division, Tufts Medical Center, Boston, MA,USA. 8Cardiopulmonary Dept, National Heart Institute, La Salle University, Mexico City, Mexico. 9Pulmonary,Critical Care Division, Houston Methodist Hospital, Weill Cornell College of Medicine, Houston, TX, USA.10Dept of Cardiology, International University of Health and Welfare School of Medicine, Tokyo, Japan.11Cardiovascular Medicine, The University of Michigan, Ann Arbor, MI, USA.

Correspondence: Nazzareno Galiè, Dept of Experimental, Diagnostic and Specialty Medicine (DIMES), AlmaMater Studiorum, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. E-mail: nazzareno.galie@unibo.it

@ERSpublicationsState of the art and research perspectives on medical therapy of pulmonary arterial hypertension,including treatment algorithm http://ow.ly/4UkJ30md5GS

Cite this article as: Galiè N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy ofpulmonary arterial hypertension. Eur Respir J 2019; 53 1801889 [https://doi.org/10.1183/13993003.01889-2018].

ABSTRACT Pulmonary arterial hypertension (PAH) remains a severe clinical condition despite theavailability over the past 15 years of multiple drugs interfering with the endothelin, nitric oxide andprostacyclin pathways. The recent progress observed in medical therapy of PAH is not, therefore, related tothe discovery of new pathways, but to the development of new strategies for combination therapy and onescalation of treatments based on systematic assessment of clinical response. The current treatmentstrategy is based on the severity of the newly diagnosed PAH patient as assessed by a multiparametric riskstratification approach. Clinical, exercise, right ventricular function and haemodynamic parameters arecombined to define a low-, intermediate- or high-risk status according to the expected 1-year mortality.The current treatment algorithm provides the most appropriate initial strategy, including monotherapy, ordouble or triple combination therapy. Further treatment escalation is required in case low-risk status is notachieved in planned follow-up assessments. Lung transplantation may be required in most advanced caseson maximal medical therapy.

Received: Oct 04 2018 | Accepted: Oct 07 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

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| SERIESWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

IntroductionPulmonary arterial hypertension (PAH) remains a severe clinical condition despite the publication of 41randomised clinical trials (RCTs) in the past 25 years and the regulatory approval of multiple drugs activeby four routes of administration (i.v., s.c., oral and inhaled) [1, 2]. Currently approved therapies targetthree main pathways important in endothelial function: the prostacyclin and nitric oxide (NO) pathways,which are underexpressed in PAH patients, and the endothelin pathway, which is overexpressed in PAHpatients (see the Task Force article by HUMBERT et al. [3] in this issue of the European Respiratory Journal).This imbalance in vasoactive mediators plays a critical role in the development and progression of theobstructive proliferative pathological changes of the distal pulmonary arteries [3], which, when untreated,will lead to heart failure and premature death (see the Task Force article by VONK NOORDEGRAAF et al. [4]in this issue of the European Respiratory Journal). Prostacyclin analogues (PCAs) and prostacyclin receptoragonists, phosphodiesterase type 5 inhibitors (PDE5is) and guanylate cyclase stimulators, and endothelinreceptor antagonists (ERAs) are intended to correct the dysfunction of the prostacyclin, NO andendothelin pathways, respectively. Interestingly, drugs targeting the three pathways were already approvedand included in the treatment algorithm for PAH patients proposed in 2003 at the 3rd World Symposiumon Pulmonary Hypertension (WSPH) held in Venice, Italy [5]. The progress observed in medical therapyof PAH patients over the past 15 years is not, therefore, related to the discovery of new pathways, but tothe evolution and testing of new drugs and strategies for combination therapy, and on escalation oftreatments based on systematic assessment of clinical response [1, 2]. In fact, in the 2015 European Societyof Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension (PH) guidelines thetreatment strategy was intimately linked to the baseline severity of the newly diagnosed PAH patient andrecommendations for subsequent treatment escalation were founded on the patient’s conditions after apre-specified period of therapy [1, 2]. Both the baseline assessment and the treatment response were basedon a multiparametric approach to stratify the patients in low-, intermediate- or high-risk groups for 1-yearmortality. The “risk” table included clinical, functional, exercise, right ventricular function andhaemodynamic parameters.

This central connection between methodical risk assessment and treatment strategy in PAH patientshas been recently validated by retrospective analyses of three independent registries, showing a clearprediction of survival or event-free survival based on this multiparametric approach at baseline and atfollow-up [6–9].

This article will provide an updated analysis of risk stratification and its relationship with differenttreatment strategies available for PAH patients, including general measures, supportive therapies,monotherapy, initial and sequential combination therapy, and interventional therapies.

Risk stratificationThe assessment of the prognosis of patients with PAH has been considered an important part of caresince the publication of the first US National Institutes of Health idiopathic PAH (IPAH) registry nearlythree decades ago [10]. Over time, different baseline and follow-up parameters, including clinical,functional, exercise, non-invasive and invasive variables, have been utilised individually or combined informulas or calculators to predict outcome: the French Pulmonary Hypertension Network (FPHN) registryrisk equation [11, 12], the PH connection equation [13, 14], the Scottish composite score [15], the USRegistry to Evaluate Early and Long-term PAH Disease Management (REVEAL) risk equation [16] andrisk score [17, 18], and the 2015 ESC/ERS PH guidelines risk table [1, 2]. Table 1 shows the characteristicsof four registries testing the PAH risk stratification strategy of the REVEAL score and of the 2015ESC/ERS PH guidelines risk table [6–9, 17–19].

The REVEAL equation [16] and the subsequent score [17, 18], derived from a cohort of 2716 PAH patientsand using 12 modifiable and non-modifiable parameters measured at baseline, provided the 12-monthlikelihood of survival (five strata) in incident and prevalent IPAH and associated PAH patients. If utilisedat follow-up, the equation can predict outcome at 1 additional year [18]. The risk score calculator wasvalidated internally in 504 newly diagnosed PAH patients, externally in registries and in clinical trialsdatasets [20, 21]. Survival up to 5 years has been reported according to baseline REVEAL score data, butnot at follow-up reassessment [22]. REVEAL survival up to 5 years has also been provided for a subgroupof 1426 patients and based only on repeated high versus low brain natriuretic peptide (BNP) plasma levelassessments [23]. The REVEAL registry also demonstrated the prognostic value of renal dysfunction atbaseline and follow-up measurements of estimated glomerular filtration rate (eGFR) [24].

The REVEAL 2.0 risk score calculator is a refinement of the original REVEAL risk score calculator; itincludes all-cause hospitalisations within the previous 6 months and eGFR, both of which have beenshown to impact mortality [24, 25].

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The REVEAL 2.0 risk score calculator (14 variables) has been compared [19] with the strategies utilised inthe FPHN registry [8] and in the Prospective Registry of Newly Initiated Therapies for PulmonaryHypertension (COMPERA) registry [7]. In this experience the data showed that, based on the 12-monthmortality, the correspondences between the low-, intermediate- and high-risk groups as defined by the2015 ESC/ERS PH guidelines and the REVEAL 2.0 calculator (14 variables) were as follows: lowrisk=REVEAL score ⩽6, intermediate risk=REVEAL score 7 and 8, and high risk=REVEAL score ⩾9. Theauthors propose a more discriminating risk stratification provided by the REVEAL score, although it is notclear how this translates to the approach to treatment [7].

The limitations of the REVEAL score include the relatively short prediction period (1 year) when assessedat follow-up and the large number of variables required (from 12 to 14 variables). Simplified versions ofthe REVEAL score utilising high-yield variables seem to have a similar predictive value as the originalversion [26].

The 2015 ESC/ERS PH guidelines have recommended a flexible approach to PAH patient risk assessment:using a multidimensional stratification according only to modifiable clinical, functional, exercise,biochemical, echocardiographic and haemodynamic variables with known prognostic significance(ESC/ERS PH guidelines Table 13 Risk assessment in PAH). Patients were categorised as low, intermediateor high risk based on expected 1-year mortality [1, 2]. Recently, a retrospective analysis of three majorregistries (total of 3135 patients) provided an independent validation of this approach and showed a cleardifference in 5-year survival or transplantation-free survival, depending on risk stratification category atboth baseline and first follow-up [6–8]. In addition, post hoc analysis of the SERAPHIN haemodynamicsubstudy has shown a reduction in the morbidity and mortality end-point if low-risk haemodynamicsthresholds included in the 2015 ESC/ERS PH guidelines were reached after 6 months of treatment withmacitentan [27].

Interestingly, the risk stratification strategies have varied significantly among the registry studies: in theSwedish PAH Registry (SPAHR) [6] and COMPERA [7] studies (both including IPAH and associatedPAH patients), individual risk was calculated at baseline and at the first follow-up by assigning a score of1, 2 or 3 to each criterion (1=low risk, 2=intermediate risk and 3=high risk according with the 2015ESC/ERS PH guidelines) and rounding to the mean of the available variables. In the FPHN registry [8],risk assessment was performed in incident IPAH patients according to the presence of four low-riskcriteria: World Health Organization (WHO)/New York Heart Association Functional Class (FC) I or II, 2)6-min walk distance (6MWD) >440 m, 3) right atrial pressure (RAP) <8 mmHg and 4) cardiac index⩾2.5 L·min−1·m−2. Patients were classified according to the number of low-risk criteria present at baseline(i.e. at the time of PAH diagnosis) or at the time of re-evaluation. As exploratory analyses, the additivevalue of BNP <50 ng·L−1 or N-terminal pro-BNP (NT-proBNP) <300 ng·L−1 plasma levels or mixedvenous oxygen saturation (SvO2) >65% as low-risk criteria was assessed in the subsets of patients for whomthese data were available.

Recently, the FPHN non-invasive risk assessment strategy using three dichotomised low-risk criteria(FC, 6MWD and NT-proBNP or BNP plasma levels) has been applied to the COMPERA cohort atbaseline and at the first follow-up: the authors conclude that the FPHN risk assessment strategy provides amore accurate identification of patients with an excellent long-term survival than the approach ofaveraging risk scores [9].

Interestingly, the variables with the highest yield in the registriy analyses are similar, i.e. FC, 6MWD,NT-proBNP or BNP plasma levels, cardiac index, RAP and SvO2 [6–8]. These variables are appropriate at

TABLE 1 Summary of four registries assessing risk scores

REVEAL [17–19] Swedish PAH Register [6] COMPERA [7] French PulmonaryHypertension Network [8]#

Required variables n 12–14 8 8 4Patients at baseline n 2716 530 1588 1017Patients at follow-up n 2529 383 1094 1017Associated PAH included Yes Yes Yes NoDefinition of low risk ⩽6 REVEAL score <1.5 average score <1.5 average score 3–4 out of 4 low-risk criteria1-year mortality by risk group(low/intermediate/high) %

⩽2.6/7.0/⩾10.7 1.0/7.0/26.0 2.8/9.9/21.2 1.0/NA/13.0–30.0

PAH: pulmonary arterial hypertension; NA: not available. #: incident patients only.

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both baseline and first follow-up, and the fulfilment of low-risk criteria in three or four parametersrepresents a clinical response to the treatment that portends a good prognosis [8, 9]. A new riskstratification strategy based on four criteria and using these six variables has recently been proposed [28].

The limitations of the 2015 ESC/ERS PH guidelines risk table are related to the presence of “overlappatients” with prognostic parameters belonging to more than one risk designation [1, 2]. This problem hasbeen addressed in the registry analyses with both the “score and average” method of the SPAHR andCOMPERA registries and the “low-risk focused” method of the FPHN study. These methods may prove tobe difficult to utilise in clinical practice, particularly for the exact distinction between intermediate- andhigh-risk status in individual patients. In addition, the simplified approach does not includenon-modifiable or partially modifiable prognostic parameters such as age, sex, PAH type andcomorbidities (renal insufficiency, diabetes mellitus, coronary artery diseases, etc.).

There are several limitations present in all risk assessment methods, including the retrospective nature ofthe validating analyses even when applied to prospective observational registries. In addition, datacollection was not standardised in all published registries, and significant missing data and numbers ofpatients lost to follow-up were reported. Other important prognostic variables such as echocardiographic,cardiac magnetic resonance imaging and cardiopulmonary exercise test data were not collectedsystematically or analysed. Life-threatening complications such as haemoptysis, pulmonary arteryaneurismal dilatation with chest organ compression, arrhythmias, etc., are not included in the current riskstratification tools. The exact influence of these parameters on the risk level designation and on theconsequent treatment decisions need to be clarified in future and prospective studies. These data should beconsidered as part of a comprehensive risk assessment strategy which, of course, should also includeclinical judgement [29].

Clinical trials in PAHFigure 1 shows the time-course of the 41 RCTs performed in 9061 PAH patients and published so far[30–70]. 21 RCTs tested monotherapy versus placebo, 18 RCTs included patients already treated and testedsequential combination therapy versus background therapy plus placebo, and finally two RCTs enrolledtreatment-naive patients and tested initial monotherapy versus initial double combination therapy. Thedifferent treatment strategies adopted and compared, and the diverse background therapies of enrolledPAH patients, has allowed evidence to be collected on efficacy and safety for the multiplicity of conditionsencountered in clinical practice.

An important evolution in PAH RCT design is the shifting of the primary end-point from a short-termcorrelate such as 6MWD to a long-term true clinical efficacy measure such as clinical worsening [60, 68,69] or clinical failure [67]. Interestingly, this change in strategy was recommended by the Task Force onClinical Trials Design at the 4th WSPH held in Dana Point, CA, USA, in 2008 [71]. This shift hassupported an increase in the level of evidence of the efficacy of the tested PAH drugs according with thescale adopted by experts [72, 73].

Epoprostenol IPAH

1990 1996 2000 2001 2002 2003 2004 2005 2006 2009 2010 2011 2012 2013 2014 2015

Epoprostenol IPAH

Epoprostenol SSc

Bosentan Beraprost-US VARDENAFIL

Year

RCTs on monotherapy versus placebo or versus monotherapy (n=21)RCTs on monotherapy and/or sequential combination versus placebo (n=18)RCTs on initial combination versus monotherapy (n=2)

SELEXIPAGFREEDOM-C1

AMBITIONGRIPHON

COMPASS-2

FREEDOM-MFREEDOM-C2

PATENTIMPRES

PATENT PLUSZhuang

TerbogrelTreprostinil

AIRBREATHE-1ALPHABET

SastryBREATHE-2STRIDE-1

STEPSingh

STRIDE-2TRIUMPHIMATINIBIversenCOMBI

BREATHE-5

PHIRST SERAPHIN

ARIES-1/2EARLYPACES

SUPERSERAPH

FIGURE 1 Time-course of completed randomised controlled trials (RCTs) in pulmonary arterial hypertension (PAH) (n=41) according to treatmentstrategy. SSc: systemic sclerosis; IPAH: idiopathic PAH. Reproduced and modified from [70] with permission.

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The effect of PAH drugs on mortality was explored in a meta-analysis of 3839 patients enrolled in 25RCTs testing monotherapy versus placebo in treatment-naive patients and reporting a risk reduction of44% (p=0.016) in the 14 weeks of the average treatment comparison time [70, 74]. An additionalmeta-analysis was performed in 4095 patients enrolled in 17 RCTs that compared sequential combinationtherapy with monotherapy [75]: in this analysis, sequential therapy was associated with a significant riskreduction for clinical worsening (−35%; p<0.0001), but not mortality (−14%; p=0.09). The potentialreasons for the lack of apparent mortality benefit include reduced statistical power of this meta-analysis formortality as well as an overall reduced number of fatal events linked also to a short duration of thetreatment comparison period [75].

In summary, based on global experience collected in the RCTs on PAH patients, the following commentscan be proposed:

• In treatment-naive PAH patients, initial monotherapy is able to improve exercise capacity,haemodynamics and outcome compared with untreated patients [70, 74].

• In treatment-naive and newly diagnosed (incident) PAH patients, initial combination therapy is able toimprove symptoms, exercise capacity and outcome compared with initial monotherapy [67, 76].

• In already treated (prevalent) PAH patients, sequential combination therapy is able to improve exercisecapacity, haemodynamics and outcome compared with patients continuing with their backgroundtherapy [60, 69, 75].

General measures and supportive therapyNo major advances have been reported on general measures and supportive therapy since the publicationof the 2015 ESC/ERS PH guidelines, and the recommendations included in the 2015 ESC/ERS PHguidelines Table 16 Recommendations for general measures and Table 17 Recommendations for supportivetherapy can be referred to [1, 2]. In particular, oral anticoagulant therapy is not recommended inassociated forms of PAH, while in IPAH, heritable PAH (HPAH) and drug-induced PAH the data onefficacy is more conflicting. Therefore, in this subgroup, the decision about anticoagulation has to be madeon a case-by-case basis after an individual risk–benefit analysis. The 2015 ESC/ERS PH guidelines suggestthat PAH patients should be advised to be active within symptom limits, but to avoid excessive physicalexertion if this causes symptoms. Physically deconditioned patients who are stable on targeted medicationare also advised to undertake supervised exercise training. Recently, two further RCTs and meta-analyseshave been published in this regard, confirming the positive effect of training in PAH [77, 78].

Treatment algorithmThe recommended treatment algorithm for PAH patients is shown in figure 2.

The PAH treatment algorithm does not apply to patients in other clinical groups, and in particular it doesnot apply to patients with PH associated with group 2 (left heart disease) or group 3 (lung diseases). Inaddition, the different treatments have been evaluated by RCTs mainly in IPAH, HPAH, PAH due todrugs and in PAH associated with connective tissue disease, with Eisenmenger syndrome or with correctedcongenital heart disease. The haemodynamic inclusion criteria in the majority of the RCTs were asfollows: pulmonary arterial wedge pressure ⩽15 mmHg, mean pulmonary arterial pressure ⩾25 mmHgand pulmonary vascular resistance >3 Wood Units (>5 Wood Units in some RCTs). It is not clear if theefficacy/safety ratio of the PAH drugs is favourable when used in patients not fulfilling the above criteria.There is insufficient evidence to make recommendations in group 5 patients.

Since the release of the 2015 ESC/ERS PH guidelines no new RCTs leading to the approval of new PAHtreatments have been published; we refer to the tables of these guidelines for the classes ofrecommendations and the level of evidence of the approved PAH treatments [1, 2]. In particular, theguidelines tables of interest are: Table 1 Classes of recommendations, Table 2 Level of evidence, Table 19Recommendations for efficacy of drug monotherapy, Table 20 Recommendations for efficacy of initial drugcombination therapy, Table 21 Recommendations for efficacy of sequential drug combination therapy, andTable 22 recommendations for efficacy of intensive care unit management, balloon atrial septostomy andlung transplantation. Amendments to these tables are required only for approvals granted by regulatoryagencies after the 2015 ESC/ERS PH guidelines as follows: selexipag has been approved by the EuropeanMedicines Agency in patients with WHO FC II either as double or triple combination with an ERA and/or a PDE5i, or as monotherapy in patients who are not candidates for these therapies.

The 2015 ESC/ERS PH guidelines tables provide the necessary evidence for alternative evidence-basedtherapeutic strategies recognising that the therapeutic approach to PAH may vary depending on localavailability (and expertise) of therapeutic options in various hospitals and clinical settings. In these tables,only the compounds officially approved for PAH or under regulatory approval process in at least one

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country are included. A four-level hierarchy for end-points in RCT has been proposed by experts based onlevel of evidence regarding efficacy [72, 73]. According to this hierarchy, drugs or combination of drugswith outcome as the primary end-point in RCTs or drugs with demonstrated reduction in all-causemortality (prospectively defined) have been highlighted with a footnote in the 2015 ESC/ERS PHguidelines Tables 19–21.

Treatment algorithm descriptionSee the treatment algorithm in figure 2.

Initial approach

• After confirmation of the diagnosis of the treatment-naive PAH patient in an expert centre, thesuggested initial approach is the adoption of general measures and the initiation of supportive therapy(2015 ESC/ERS PH guidelines Tables 16 and 17).

• Acute vasoreactivity testing should be performed to predict response to calcium channel blocker(CCBs) only in patients with IPAH, HPAH, and PAH associated with drugs and toxin use.Vasoreactive patients (see the Task Force article by SIMONNEAU et al. [79] in this issue of the EuropeanRespiratory Journal) should be treated with high doses (progressively titrated) of CCBs; adequateresponse should be confirmed after 3–6 months of treatment (2015 ESC/ERS PH guidelines Table 18).Adequate treatment response to high doses of CCBs is considered WHO FC I/II with sustainedhaemodynamic improvement (same or better than achieved in the acute test) after at least 1 year onCCBs only. Vasoreactive patients without an adequate treatment response to high doses of CCBs

Acute vasoreactivity test(IPAH/HPAH/DPAH only)

Low riskd

Structured follow-upg

Initial oralcombinationf

Residual role for initial monotherapy (table 2)e

Initial combinationincluding i.v. PCAf

Triple sequentialcombinationh

Consider referralfor lung

transplantation

Non-vasoreactive

After 3–6 months of treatment

After 3–6 months of treatment

Low or intermediate riskd

Intermediate or high riskd

Intermediate or high riskd

High riskd

CCB therapyc

Vasoreactive

General measuresa

Supportive therapybPAH confirmed by

expert centreTreatment-naive

patient

Patient already on treatment

Maximal medical therapyi

and listing for lung transplantationj

FIGURE 2 Treatment algorithm. PAH: pulmonary arterial hypertension; IPAH: idiopathic PAH; HPAH: heritablePAH; DPAH: drug-induced PAH; CCB: calcium channel blocker; PCA: prostacyclin analogue; PH: pulmonaryhypertension. a: 2015 ESC/ERS PH guidelines Table 16; b: 2015 ESC/ERS PH guidelines Table 17; c: 2015 ESC/ERS PH guidelines Table 18; d: 2015 ESC/ERS PH guidelines Table 13; e: 2015 ESC/ERS PH guidelines Table19; f: 2015 ESC/ERS PH guidelines Table 20; g: 2015 ESC/ERS PH guidelines Table 14; h: 2015 ESC/ERS PHguidelines Table 21; i: maximal medical therapy is considered triple combination therapy including a s.c. or ani.v. PCA (i.v. preferred in high-risk status); j: 2015 ESC/ERS PH guidelines Table 22.

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should be treated with approved PAH medications according to the non-vasoreactive patients’treatment strategy.

• Non-responders to acute vasoreactivity testing who are at low or intermediate risk should be treatedwith initial oral combination therapy with an ERA and a PDE5i (2015 ESC/ERS PH guidelinesTable 20) [76, 80, 81].

• Some specific PAH subsets in which the efficacy/safety ratio of initial combination therapy is notestablished (table 2) should be treated with initial monotherapy.

Recommendations for initial monotherapy are reported in the 2015 ESC/ERS PH guidelines Table 19.

• If initial monotherapy is chosen, as head-to-head comparisons among different compounds are notavailable, no evidence-based first-line monotherapy can be proposed. The choice of drug may dependon a variety of factors, including approval status, labelling, route of administration, side-effect profile,potential interaction with background therapies, patient preferences, comorbidities, physicianexperience and cost.

• In non-vasoreactive and treatment-naive patients at high risk, initial combination therapy including i.v.PCAs is recommended (2015 ESC/ERS PH guidelines Table 20). Intravenous epoprostenol receives thestrongest recommendation as it has reduced the 3-month rate of mortality in high-risk PAH patientsalso as monotherapy (2015 ESC/ERS PH guidelines Table 19) [82]. Alternative types of initialcombination therapy may be considered (2015 ESC/ERS PH guidelines Table 20). Referral for lungtransplantation should also be considered.

Follow-up therapy

• When the initial treatment approach results in a low-risk status within 3–6 months, the therapy shouldbe continued and structured follow-up established (2015 ESC/ERS PH guidelines Table 14).

• When the initial treatment approach results in an intermediate-risk status, escalation to triplecombination therapy is recommended according to the 2015 ESC/ERS PH guidelines Table 21 or todouble combination in case monotherapy has been chosen. The combinations of macitentan andsildenafil [60], riociguat and bosentan [61], and selexipag and ERA and/or PDE5i [69] have thehighest recommendation and evidence. PCAs should also be considered. The combination of riociguatand PDE5i is contraindicated [62]. Referral for lung transplantation should also be considered.

• When the initial treatment approach results in a high-risk status, maximal medical therapy includingi.v. PCAs is recommended (2015 ESC/ERS PH guidelines Table 20). Referral for lung transplantationshould also be considered.

• When the second treatment step results in the low-risk status within 3–6 months, the therapy should becontinued and structured follow-up continued (2015 ESC/ERS PH guidelines Table 14). Referral forlung transplantation should also be considered according to local rules for organ allocation andaverage waiting time in the list.

• When the second treatment step results in an intermediate- or high-risk status, escalation to maximalmedical therapy is recommended according to the 2015 ESC/ERS PH guidelines Table 21. Maximalmedical therapy is considered to be triple combination therapy including a s.c. or an i.v. PCA (i.v.preferred in high-risk status). For patients on intermediate-risk status on double combination therapywith an ERA and a PDE5i or riociguat, the addition of selexipag should be considered [69]. For

TABLE 2 Potential role for initial monotherapy in specific pulmonary arterial hypertension (PAH) subsets

IPAH, HPAH and drug-induced PAH patient responders to acute vasoreactivity tests and with WHO FC I/II and sustained haemodynamicimprovement (same or better than achieved in the acute test) after at least 1 year on CCBs only

Long-term-treated historical PAH patients with monotherapy (>5–10 years) stable with low-risk profileIPAH patients >75 years old with multiple risk factors for heart failure with preserved LVEF (high blood pressure, diabetes mellitus, coronaryartery disease, atrial fibrillation, obesity)

PAH patients with suspicion or high probability of pulmonary veno-occlusive disease or pulmonary capillary haemangiomatosisPatients with PAH associated with HIV infection or portal hypertension or uncorrected congenital heart disease, as they were not included inRCTs of initial combination therapy

PAH patients with very mild disease (e.g. WHO FC I, PVR 3–4 WU, mPAP <30 mmHg, normal right ventricle at echocardiography)Combination therapy unavailable or contraindicated (e.g. severe liver disease)

IPAH: idiopathic PAH; HPAH: heritable PAH; CCB: calcium channel blocker; PAP: pulmonary arterial pressure; PVR: pulmonary vascularresistance; LVEF: left ventricular ejection fraction; RCT: randomised controlled trial; WHO: World Health Organization; FC: Functional Class;WU: Wood Units; mPAP: mean PAP.

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patients on triple combination therapy including selexipag who remain in the intermediate-risk groupor progress to high risk, the substitution with s.c. or i.v. PCAs should be considered. Referral for lungtransplantation should also be considered.

• Patients on follow-up with low-risk status who deteriorate to the intermediate- or high-risk groupshould be treated with double, triple or maximal combination therapy depending on the initialbackground treatment.

• We recommend consideration of lung transplantation in all patients on maximal triple combinationtherapy, with priority for those in intermediate- and high-risk groups, in accordance with local rulesfor organ allocation and average waiting time in the list (2015 ESC/ERS PH guidelines Table 22) (seethe Task Force article by HOEPER et al. [83] in this issue of the European Respiratory Journal).

• Advanced treatments for patients in severe right ventricular failure who are admitted to intensive careunits are reported by HOEPER et al. [83].

• Balloon atrial septostomy should be regarded as a palliative or bridging procedure in patientsdeteriorating despite maximal medical therapy.

Transitions of PAH therapiesClinicians might consider transitioning from one PAH-specific therapy to another for a number ofreasons, including improvement of the side-effect profile and convenience or compliance with therapy. Inpatients who are not meeting treatment goals, transitions are considered to escalate therapy and improvepatient status. Occasionally, patients have an extraordinary response to therapy and transition to a lessinvasive therapy is considered. As much of the literature on this topic is retrospective, prospective butobservational or prospective randomised but open label, we do not recommend this approach except inrare circumstances and under close expert care. One study showed that, in carefully selected patients, thetransition from i.v. epoprostenol to i.v. treprostinil was achievable around 80% of the time [84]. Transitionfrom parenteral epoprostenol to the thermostable form was generally achievable [84].

There have been conflicting outcomes in the transition from parenteral prostacyclins to inhaled or oralprostacyclins [84]. When discontinuation of bosentan is necessary due to liver function test elevations,transitioning to ambrisentan [85] or macitentan is safe.

In case of lack of efficacy, transition from selexipag or non-parenteral PCAs to s.c. or i.v. PCAs isrecommended.

There is insufficient evidence to recommend transition from sildenafil or tadalafil to riociguat forimproving efficacy [86]. An additional open-label, randomised study is currently ongoing on this issue(ClinicalTrials.gov identifier NCT02891850).

PAH complicationsPAH-related hospitalisations which usually are associated with different types of complications arepredictive of mortality in post hoc analyses of the SERAPHIN and GRIPHON studies [87].Recommendations for the diagnosis and treatment of arrhythmias, haemoptysis and mechanicalcomplications related to the dilatation of the pulmonary artery are already reported in the 2015 ESC/ERSPH guidelines [1, 2]. Recently, a study has reported a large series of PAH patients with angina orangina-like symptoms who underwent percutaneous coronary interventions with stenting due to severe leftmain coronary artery stenosis by extrinsic compression from a dilated pulmonary artery [88]. Thefavourable acute and long-term results of this procedure suggest increased awareness for this importantand potentially catastrophic complication.

ConclusionsAssessment of the severity of the newly diagnosed PAH patient by a multiparametric risk stratificationapproach is utilised for defining a low-, intermediate- or high-risk status. According to the risk status, themultiple drugs approved for PAH, interfering with the endothelin, NO and prostacyclin pathways, can beutilised with different strategies including monotherapy or combination therapies. Further treatmentescalation is required in case low-risk status is not achieved in planned follow-up assessments. Low-riskpatients should continue with the chosen therapy and be assessed accurately in a structured follow-up totimely identify possible deteriorations. Triple combination therapy and lung transplantation may berequired in most advanced cases.

Conflict of interest: N. Galiè reports grants and personal fees from Actelion, Bayer, GSK and Pfizer, and personal feesfrom MSD, outside the submitted work. R.N. Channick reports grants and personal fees from Actelion and Bayer, andpersonal fees from Arena, outside the submitted work. R.P. Frantz reports steering committee membership and researchfunding from Actelion, data and safety monitoring board and adjudication committee membership for United

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Therapeutics, and advisory board work for Abbott and Arena, outside the submitted work. E. Grünig reports grants andpersonal fees from Actelion and Bayer/MSD, grants from GSK, and personal fees from Bial, OrPhaSwiss GmbH andMedscape, outside the submitted work. Z.C. Jing reports grants from the Chinese Academy of Medical Sciences, BeijingNatural Science Foundation and National Natural Science Foundation of China, during the conduct of the study; andpersonal fees from Actelion Pharmaceuticals, Bayer Healthcare Pharmaceuticals, GSK, Pfizer and United Therapeutics,outside the submitted work. O. Moiseeva has nothing to disclose. I.R. Preston reports grants and personal fees forconsultancy from Actelion, Gilead and United Therapeutics, grants from Bayer, and personal fees for adjudicationcommittee membership from Pfizer, during the conduct of the study; and grants and personal fees for consultancy fromAcceleron, Liquidia and Arena, outside the submitted work. T. Pulido reports research grants from Actelion, Lilly, ReataPharmaceuticals and Bayer, personal fees for advisory board membership, speaking and lectures from Actelion, personalfees for lectures from Bayer, personal fees for advisory board membership from GSK, personal fees for advisory boardmembership and lectures from Pfizer, outside the submitted work. Z. Safdar reports speaker bureau, consultation andinstitutional grants for clinical trials from Actelion Pharmaceutical, United Therapeutics Gilead Pharmaceuticals,Genetech, Boehringer Ingelheim and Bayer Pharmaceuticals, outside the submitted work. Y. Tamura reports grants fromNippon Shinyaku Co., Ltd, and grants and personal fees from Actelion Pharmaceuticals Japan Ltd, during the conductof the study. V.V. McLaughlin reports grants and personal fees from Actelion, Acceleron, Arena and Bayer, grants fromGilead and Sonovie, and personal fees from Caremark and United Therapeutics, during the conduct of the study.

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Intensive care, right ventricular supportand lung transplantation in patients withpulmonary hypertension

Marius M. Hoeper1, Raymond L. Benza2, Paul Corris3, Marc de Perrot4,Elie Fadel5, Anne M. Keogh6,7, Christian Kühn8, Laurent Savale 9,10,11 andWalter Klepetko12

Number 7 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1Dept of Respiratory Medicine, Hannover Medical School and Member of the German Center forLung Research (DZL), Hannover, Germany. 2The Cardiovascular Institute, Allegheny General Hospital,Pittsburgh, PA, USA. 3Institute of Cellular Medicine, Newcastle University and Newcastle Hospitals NHSFoundation Trust, Newcastle upon Tyne, UK. 4Division of Thoracic Surgery, Toronto General Hospital,University of Toronto, Toronto, ON, Canada. 5Dept of Thoracic and Vascular Surgery and Heart-LungTransplantation, Hôpital Marie Lannelongue and Université Paris-Sud, Paris, France. 6Heart Transplant Unit,St Vincent’s Public Hospital, Darlinghurst, Australia. 7University of New South Wales, Sydney, Australia. 8Deptof Cardiothoracic, Vascular and Transplantation Surgery, Hannover Medical School and Member of theGerman Center for Lung Research (DZL), Hannover, Germany. 9Université Paris-Sud, Faculté de Médecine,Université Paris-Saclay, Le Kremlin-Bicêtre, France. 10AP-HP, Service de Pneumologie, DépartementHospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Hôpital Bicêtre, Le Kremlin-Bicêtre, France.11INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France. 12Dept of Thoracic Surgery,Medical University of Vienna, Vienna, Austria.

Correspondence: Marius M. Hoeper, Dept of Respiratory Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail: hoeper.marius@mh-hannover.de

@ERSpublicationsState of the art and research perspectives on the ICU management of patients with pulmonaryhypertension and right heart failure, the timing of transplant referral, and the use of extracorporeallife support http://ow.ly/pISA30mfQk4

Cite this article as: Hoeper MM, Benza RL, Corris P, et al. Intensive care, right ventricular support andlung transplantation in patients with pulmonary hypertension. Eur Respir J 2019; 53: 1801906 [https://doi.org/10.1183/13993003.01906-2018].

ABSTRACT Intensive care of patients with pulmonary hypertension (PH) and right-sided heart failureincludes treatment of factors causing or contributing to heart failure, careful fluid management, andstrategies to reduce ventricular afterload and improve cardiac function. Extracorporeal membraneoxygenation (ECMO) should be considered in distinct situations, especially in candidates for lungtransplantation (bridge to transplant) or, occasionally, in patients with a reversible cause of right-sidedheart failure (bridge to recovery). ECMO should not be used in patients with end-stage disease without arealistic chance for recovery or for transplantation. For patients with refractory disease, lungtransplantation remains an important treatment option. Patients should be referred to a transplant centrewhen they remain in an intermediate- or high-risk category despite receiving optimised pulmonary arterialhypertension therapy. Meticulous peri-operative management including the intra-operative and post-operative use of ECMO effectively prevents graft failure. In experienced centres, the 1-year survival ratesafter lung transplantation for PH now exceed 90%.

Received: Oct 05 2018 | Accepted: Oct 09 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

https://doi.org/10.1183/13993003.01906-2018 Eur Respir J 2019; 53: 1801906

| SERIESWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

IntroductionThe present article addresses the management of patients with advanced pulmonary hypertension (PH) orpulmonary arterial hypertension (PAH) and right-sided heart failure, focusing on intensive care, use ofextracorporeal life support (ECLS) and lung transplantation. Other causes of right-sided heart failure asseen for instance in patients with acute pulmonary embolism, right ventricular infarction or right-sidedheart failure secondary to left-sided heart failure will not be discussed here.

The following definitions of right-sided heart failure will be used:

1) Right-sided heart failure is characterised by low cardiac output and/or elevated right-sided fillingpressures due to systolic and/or diastolic right ventricular dysfunction.

2) Right-sided heart failure is severe if it leads to secondary dysfunction of other organs and tissues, inparticular liver, kidneys and gut.

This article addresses topics where robust data from large clinical trials are not available. Hence, most ofthe statements and recommendations are based on clinical experience and expert consensus rather thanscientific evidence.

Pathophysiology of right-sided heart failureThe pathophysiology of right-sided heart failure has been described in depth elsewhere [1–3]. Here, only acouple of points will be highlighted that are considered of importance for treatment considerations.

Like left-sided heart failure, right-sided heart failure may present as isolated systolic heart failure orisolated diastolic heart failure; however, combined forms are frequently encountered in patients requiringtreatment on the intensive care unit (ICU). Systolic right-sided heart failure results in left ventricularunderfilling and low cardiac output, which impairs tissue perfusion and oxygenation. Diastolic right-sidedheart failure results in elevated systemic venous pressure with detrimental consequences for tissueperfusion and oxygenation as well.

With increasing afterload, the right ventricle remodels, i.e. hypertrophies and eventually dilates, developinga spherical shape accompanied by increased right ventricular wall stress, impaired myocardial contractilityand progressive tricuspid regurgitation, which further reduces effective cardiac output. Ventricularinterdependence results in impaired left ventricular filling and function.

Severe right-sided heart failure affects all organ systems; in the ICU setting, the consequences for the liver,kidneys and gut are often most relevant. Several lines of evidence suggest that elevated venous pressureswith chronic congestion are particularly damaging to these organs [4–9]. Malperfusion and congestionalter bowel wall permeability, and may cause translocation of bacteria and endotoxins from the bowel intothe circulation resulting in a systemic inflammatory response or sepsis [4, 10, 11], which are commoncontributors to death in patients with right-sided heart failure [12].

Symptoms and signs of right-sided heart failureSymptoms and signs of low cardiac output failure can be subtle. Tachycardia is often present, whilesystemic hypotension usually develops only at advanced stages. The skin may have a pale appearance;cyanosis may be present but is not obligate. Patients frequently complain about fatigue and appear tired.Agitation may be present as well and may signal imminent death. The clinical signs of right-sidedbackward failure such as prominent and pulsating jugular veins, ascites, and oedema are usually obvious.

Principles of ICU monitoring of patients with right-sided heart failureICU monitoring of patients with PH/PAH and right-sided heart failure should focus on cardiac functionand the function of other organs (table 1).

In patients requiring ICU treatment, monitoring of cardiac function is essential. Right heartcatheterisation, preferably with continuous cardiac output measurement, is not always necessary, butshould be considered in severe and complex cases. Other tools to measure cardiac output should beconsidered as well.

Insertion of a central venous line is considered mandatory in patients requiring ICU treatment forright-sided heart failure. Central venous pressure measurement, which has been abandoned in most ICUpatients due to poor correlation with fluid status, is pivotal in patients with right ventricular failure todetermine right-sided filling pressures, keeping in mind the detrimental effects of elevated filling pressures(see earlier). In addition, central venous oxygen saturation (ScvO2) measurements are important todetermine tissue oxygenation as ScvO2 correlates with cardiac output [13].

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Recommendations for ICU monitoring of patients with PH and severe right-sided heart failure• ICU monitoring of patients with severe right-sided heart failure should include regular measurements

of central venous pressure and ScvO2.• Key warning signs of imminent death in patients with right-sided heart failure are a decline in ScvO2

accompanied by an increase in lactate and a decline in urine output.• The use of right heart catheterisation or other devices to monitor haemodynamics and cardiac output

should be considered in patients with severe right-sided heart failure and in complex situations.

ICU treatment of severe right-sided heart failurePatients with severe right-sided heart failure require comprehensive care including treatment offactors causing or contributing to heart failure, fluid management and strategies to improve cardiacfunction (figure 1). If possible, such patients should be treated at expert centres capable of providing alltreatment options, i.e. medical therapy, ECLS and lung transplantation. Interhospital transfer must beconsidered on an individual basis. Some centres provide mobile units facilitating interhospital transferwith ECLS [14].

Treatable precipitants of right-sided heart failure include infection, anaemia, thyroid dysfunction,pulmonary embolism, arrhythmia or non-adherence to prescribed medications. Supraventriculartachyarrhythmias, especially atrial flutter and atrial fibrillation, are common causes of right-sided heartfailure in patients with severe PH [15] and rapid restoration of sinus rhythm should be attempted in suchcases. Infection is another important contributor to death in patients with right-sided heart failure. If thesource of infection is not obvious, broad-spectrum antibiotics should be considered bearing in mind thattranslocation from the bowel is a frequent cause of systemic inflammation and sepsis in patients withright-sided heart failure [10, 11].

Supplementary oxygen should be administered as needed to maintain peripheral oxygen saturations >90%.Hypercapnic patients may benefit from non-invasive ventilation [16], although caution is necessary aseven non-invasive ventilation may further impair right ventricular function [17]. Whenever possible,intubation and invasive mechanical ventilation should be avoided in patients with severe right heartfailure, as the induction of general anaesthesia together with a further increase in right ventricularafterload carries a high risk of death in these patients. If intubation is unavoidable, maintaining a stableblood pressure is of key importance.

Fluid management is often critical in patients with right-sided heart failure. It is a common reflex amongintensivists to administer fluids to patients with hypotension or shock. Only rarely are patients withright-sided heart failure fluid-depleted as well. Most of these patients have markedly elevated right-sidedfilling pressures and a low cardiac output. In these patients, fluid administration may further increaseright-sided filling pressures and chamber dimensions, thereby aggravating the shift of the interventricularseptum to the left and increasing tricuspid regurgitation [18], all resulting in further deterioration of left

TABLE 1 Intensive care unit (ICU) monitoring of patients with right-sided heart failure

Tools Information provided

Basic ICU monitoring Heart rate and rhythmBlood pressure (non-invasive or invasive)Body temperaturePeripheral oxygen saturation or arterial blood gasesUrine output, changes in body weight

Central venous catheter Central venous pressureCentral venous oxygen saturation

Laboratory values Cardiac biomarkers (N-terminal pro-brain natriuretic peptide/brain natriuretic peptide, troponin)Electrolytes and renal function (estimated glomerular filtration rate, blood urea nitrogen, uric acid)Liver function (aminotransferases, bilirubin)Inflammation/infection (C-reactive protein, procalcitonin)Tissue damage or hypoxia (blood gases, lactate)

Echocardiography Right and left ventricle function, valve function, pericardial effusionRule out other conditions mimicking right ventricular failure, such as pericardial tamponade

Right heart catheterisation(facultative)

Comprehensive haemodynamic assessmentTo be considered in severe or complex situations

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ventricular filling and function, as illustrated in figure 2. In such patients, a negative fluid balance shouldbe sought by using i.v. loop diuretics or even haemofiltration [19].

To reduce right ventricular afterload, all drugs approved for PAH may be considered in patients presentingwith severe right-sided heart failure. Intravenous prostacyclin analogues (PCAs) are usually preferred becauseof their efficacy and a rapid onset of action. Initial triple combination therapy consisting of i.v. epoprostenol,oral phosphodiesterase type 5 inhibitors and endothelin receptor antagonists in patients with newly diagnosedPAH and right-sided heart failure has been reported with excellent short-term and mid-term results [20].

Patients with low cardiac output may initially require the use of inotropes, with dobutamine andmilrinone being the most widely used agents in this setting. In animal models of right-sided heart failure,levosimendan appears more effective than dobutamine [21, 22], but reliable clinical data are lacking.Patients with a low systemic vascular resistance may need additional vasopressor treatment.Norepinephrine and vasopressin are the preferred agents. Vasopressin may be advantageous as it haspulmonary vasodilator effects [23, 24], but the clinical relevance of this property is unknown (table 2).

Recommendations for ICU treatment of patients with severe right-sided heart failure• Patients with PAH or other forms of severe PH with right-sided heart failure requiring ICU therapy

should be treated at expert centres capable of providing all treatment options, i.e. medical therapy,ECLS and advanced treatment including lung transplantation, if possible.

Detect right heart failure, ensure appropriate monitoring, avoid intubation, contact expert centre

Treat triggering factors such as

infection, arrhythmias, pulmonary embolism,

etc., and administer supportive therapy

Optimise fluidstatus, removeexcess fluids

by using diuretics or haemofiltration

Reduce RVafterload

(i.v. prostacyclin,other PAH drugs,

inhaled NO)

Optimise cardiacoutput (inotropes

such as dobutamine,milrinone)

Optimise bloodpressure

(vasopressors such as norepinephrine,

vasopressin)

Insufficient response or further clinicaldeteriorationRealistic perspective of recovery

or lung transplantationNo realistic perspective of recovery

or lung transplantation

Awake ECMO or other ECLS devices as bridge to transplant or until recovery Best supportive care

FIGURE 1 Therapeutic approach to patients with severe right-sided heart failure. RV: right ventricular; PAH: pulmonary arterial hypertension; NO:nitric oxide; ECMO: extracorporeal membrane oxygenation; ECLS: extracorporeal lung support. Reproduced and modified from [80] with permission.

RVEDPTRSeptum shiftLV fillingCO

RV LV

RV LV

RV LV

RVEDPTRSeptum shiftLV fillingCO

RV LV

Fluid –

Fluid +

FIGURE 2 Effects on volume changes on cardiac function in right-sided heart failure. RV: right ventricle; LV: leftventricle; RVEDP: right ventricular end-diastolic pressure; TR: tricuspid regurgitation; CO: cardiac output.Reproduced and modified from [80] with permission.

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• Interhospital transfer should be considered on an individual basis. Some centres provide mobile unitsfacilitating interhospital transfer with ECLS.

• ICU treatment of patients with right-sided heart failure should include treatment of underlying causesand comorbidities, supportive measures, meticulous fluid management, reduction of right ventricularafterload with drugs approved for PAH, and an individualised use of inotropes and vasopressors.

Mechanical support of the right heartIn patients with right-sided heart failure refractory to treatment, mechanical support should be consideredin certain situations, i.e. in candidates for lung transplantation (bridge to transplant) and, occasionally, inpatients with a treatable cause of right-sided heart failure or in hitherto treatment-naive patients (bridge torecovery).

Technical principles and features of mechanical right ventricular supportThere are various devices and device configurations to support the right ventricle, and the list is constantlygrowing [25, 26]. At present, the most widely used techniques are peripheral veno-arterial extracorporealmembrane oxygenation (ECMO) and pumpless membrane oxygenators inserted between the pulmonaryartery and the pulmonary veins or left atrium (PA-LA).

Peripheral ECMO support is usually established via the femoral vessels but upper body approaches havebeen used as well, the latter mostly to enable ambulation, which is not possible with lower bodycannulation. The veno-arterial configuration ensures rapid and effective unloading of the right ventricle[27]. With residual pulmonary blood flow, an ECMO blood flow of 2.5–4 L·min−1 is usually adequate tomaintain sufficient perfusion of the entire organism, while effectively unloading the right ventricle andavoiding an unnecessary increase in left ventricular afterload. Still, this configuration is characterised byopposing blood flows in the aorta, one coming from the left ventricle, the other from the ECMO system.The area where these two blood flows meet is called the ECMO watershed, which is clinically relevantmostly for differential oxygenation [28]. In patients with femoral veno-arterial ECMO support, the lowerbody is supplied by blood originating from the ECMO and the upper body by blood coming from theheart. The location of the watershed is variable, and depends on the respective pressures and flows in thetwo circuits. While lower body oxygenation is safely maintained by ECMO, upper body oxygenation canbe impaired when the blood coming from the left heart carries a low oxygen content. This affectspredominantly the brain and the heart itself. While brain oxygenation can be indirectly monitored by rightforearm oxygenation, it is usually not possible to measure the oxygen content in the aortic bulb and thecoronary arteries. Hence, monitoring of cardiac function by regular troponin measurements andechocardiography is mandatory.

With the PA-LA approach, a membrane oxygenator is placed between the pulmonary artery and the leftatrium. In patients with PH, a pump is usually not required, at least when low-resistance membranes arebeing used [29, 30]. PA-LA insertion is more complex than ECMO support as it requires surgery via

TABLE 2 Inotropes and vasopressors in clinical use to treat advanced right heart failure

Drug Cardiacoutput

PVR SVR Tachycardia/arrhythmia

Pre-clinicalstudies

Clinical studies/experience

InotropesDobutamine<5 µg·kg−1·min−1 ↑ ↘ → or ↘ ++ ++++ Large clinical experience,

haemodynamic studies5–15 µg·kg−1·min−1 ↑↑ → ↘ +++Dopamine2.5–5 µg·kg−1·min−1 ↑ ? ↑↑ +/− ↑ Renal blood flow>5 µg·kg−1·min−1 ↑ ↑ +++

Milrinone ↑↑ ↘ ↘↘ +++ ++ Group 2 PH case reports in PAHLevosimendan ↑↑ ↘ ↘↘ + ++ Group 2 PH case reports in PAHEpinephrine ↑↑ ↘ ↑↑ +++ Effective, but risk of myocardial

necrosis and lactic acidosisVasopressorsNorepinephrine ↑ → or ↑ ↑↑ ++ ++ Large clinical experienceVasopressin (low doses) → or ↑ ↘ ↑↑ +++ ++ Limited clinical data in PAH

PVR: pulmonary vascular resistance; SVR: systemic vascular resistance; PH: pulmonary hypertension; PAH: pulmonary arterial hypertension.

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sternotomy or antero-lateral thoracotomy. In addition, patients with advanced right-sided heart failureoften need temporary ECMO support prior to anaesthesia. The main advantages of the PA-LA approachare that 1) ambulation is feasible, 2) oxygen-enriched blood enters the left ventricle and thereby the entiresystemic circulation, and 3) the pre-load of the left ventricle is increased, which helps “priming” for thehaemodynamic situation after transplantation (see later).

Right ventricular assist devicesThere are sporadic reports on isolated right ventricular assist device (RVAD) support in PAH [31].However, successful long-term use of RVADs in patients with PAH has not yet been reported. The role ofthis intervention is limited given the pathophysiology of PAH, which may include aggravation ofpulmonary vascular remodelling, risk of pulmonary bleeding and induction of pulmonary oedema inpatients with left ventricular diastolic dysfunction [32–34]. For these reasons, isolated RVAD supportshould be used with utmost care or not at all in these patients. Smaller-sized devices with good ability tocontrol the pump flow in the pulmonary circulation may open new options in the future [35].

Indications for mechanical support of the right ventricleThe only established option for the use of ECLS in patients with PH and right-sided heart failure is bridgeto transplantation (table 3) [36, 37]. Hence, ECLS should be considered 1) if conventional treatmentstrategies fail in patients who 2) have already been fully evaluated for lung transplantation, who 3) have arealistic chance of receiving a donor organ in a reasonable time frame and who 4) can still be expected tohave a good outcome after transplantation [26]. If possible, ECMO should preferably be used in awake,non-intubated and spontaneously breathing patients, not only to avoid the risks and complicationsassociated with general anaesthesia and intubation in patients with right-sided heart failure, but also toprevent the negative consequences of mechanical ventilation, such as ventilator-associated pneumonia,muscular deconditioning and critical care illness. The awake ECMO strategy has proven feasible, even withbridging times of several weeks [38], and has been associated with better outcomes than historical bridgingstrategies that included intubation and mechanical ventilation [14, 39, 40].

The use of ECLS in patients who have not been evaluated for transplantation should be avoided unlessthere is a reasonable perspective for recovery. This may be the case in previously stable patients with areversible cause of right-sided heart failure (e.g. arrhythmia or infection) or in hitherto untreated orundertreated patients with newly diagnosed PAH. Case reports demonstrating success of this approach are,however, rare [14, 41].

TABLE 3 Summary of published data on outcomes of patients with pulmonary arterialhypertension bridged to lung transplant with the use of extracorporeal life support devices

First author [ref.] Patients who receivedECMO support

Patients bridgedto transplant

Patients dischargedfrom hospital

DE PERROT [30] 6 (4 PA-LA, 2 VA ECMO) 6/6 (100%) 4/6 (66%)FUEHNER [39] 7 (all VA ECMO) 6/7 (86%) 5/6 (71%)HOOPES [73] 5 (all VA ECMO) 5/5 (100%) 5/5 (100%)LANG [74] 4 (all VA ECMO) 4/4 (100%) 4/4 (100%)ROSENZWEIG [41] 6 (all VA ECMO) 2/2 (100%); 4 received

ECMO as bridge torecovery

2/2 (100%); 1/4 (25%)bridge to recovery patientssurvived for >2 months

SHAFII [75] 3 (all VA ECMO) 2/3 (66%) 2/2 (100%)CROTTI [76] 4 (3 VA ECMO, 1 VV ECMO) 4/4 (100%) 3/4 (75%)HOETZENECKER [77] 13 (9 PA-LA, 4 VA ECMO) 11/13 (85%) 7/11 (63%) survived at

1 yearSAVALE [56] 13 (all VA ECMO) 13/13 (100%) 8/13 (62%)DELLGREN [78] 2 (both VA ECMO) 2/2 (100%) 1/2 (50%)GLORION [79] 18 (13 VA ECMO, 3 VV

ECMO, 2 PA-LA)17/18 (94%) 15/17 (88%)

Total 81 (66 ECMO, 15 PA-LA);77 as bridge to transplant

72/77 (94%) 56/72 (78%)

ECMO: extracorporeal membrane oxygenation; PA-LA: pulmonary artery to left atrium device; VA:veno-arterial; VV: veno-venous.

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Recommendations for the use of ECLS in patients with PH and right-sided heart failureIndications and contraindications

• Established indication: bridge to transplant in patients who have been fully evaluated and accepted forthis procedure.

• Potential indications in highly selected cases:– bridge to transplant decision in potentially eligible patients who have not yet been fully evaluated;– bridge to recovery in patients with untreated or undertreated PAH, or in patients with a reversiblecause of right ventricular failure.

• Contraindication: end-stage disease without a realistic chance for recovery or successful transplantation(futility).

Choice of ECLS

• Veno-arterial ECMO and the PA-LA approach are currently the only established right ventricularsupport strategies, but there is rapid evolution in device technologies.

• At present, veno-arterial ECMO is the most widely used ECLS strategy.• The PA-LA approach should be considered if the expected ECLS time is of longer duration or in

children with small femoral arteries.• The choice of ECLS depends largely on centre experience.

Timing of ECLS

• All forms of ECLS are associated with potentially life-threatening complications; hence, ECLS shouldbe used only when less invasive treatment options have been exhausted.

• ECLS should be initiated when the clinical course suggests that terminal right heart failure and/orsecondary organ failure is imminent despite optimised medical therapy.

• ECLS initiated in patients with advanced PH/PAH undergoing cardiopulmonary resuscitation forright-sided heart failure will rarely result in good outcomes.

ECLS and lung transplantation

• ECLS is now an established strategy to bridge patients with right heart failure to lung transplantation.• Centres performing lung transplantation in patients with PAH should have an established ECLS

programme.

Lung transplantationThe modern era of successful lung and heart–lung transplantation started in the early 1980s with patientssuffering from PH [42]. Today, due to the introduction of effective therapies for PAH and chronicthromboembolic PH, lung transplantation is performed less frequently in patients with severe PH, butremains an important treatment option for patients with refractory disease.

When to refer and when to list patients for lung transplantationReferral to a transplant centreGeneral recommendations for the selection of lung transplant candidates have been published elsewhere[37]. In patients with PAH, referral to a lung transplant centre should be considered early, i.e. wheneverpatients display an inadequate response to treatment and are not at low risk of death despite receiving oralcombination therapy (table 4). Early transplant referral is also recommended in patients who are suspectedto suffer from disease variants responding poorly to medical therapy, such as pulmonary veno-occlusivedisease. An early referral strategy ensures that patients have time to consider lung transplantation with allits consequences, and that centres can fully evaluate potential candidates and optimise their pre-transplantcondition. In reality, patients with PAH are often referred in an advanced disease state or when they arerapidly deteriorating, which may prohibit a careful evaluation, thereby exposing them to unnecessary risksand sometimes effectively depriving them of a chance of receiving a donor organ. Early referral fortransplant evaluation does not mean that patients are necessarily listed right away; a completed evaluationjust allows optimal timing and rapid listing in case of clinical deterioration.

Listing patients for lung transplantationPatients suffering from PAH should be listed for lung transplantation when they present with a high riskof death despite optimised medical therapy, which usually consists of combination therapy including s.c.

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or i.v. PCAs (table 4). According to the 2015 European Society of Cardiology (ESC)/European RespiratorySociety (ERS) PH guidelines [43, 44], patients are classified as high risk when the estimated 1-yearmortality exceeds 10%. Registry data suggest that the 1-year mortality rate of these patients is in fact >20%[45, 46]. Thus, utilising risk stratification tools or scores (i.e. REVEAL (Registry to Evaluate Early andLong-term Pulmonary Arterial Hypertension Disease Management) score ⩾10) [47]) that denote high-riskindividuals may be particularly useful in deciding when to refer a patient for evaluation. Since the 1-yearmortality after lung transplantation for severe PH in experienced centres is currently around 10% [48, 49],a survival benefit can be expected for such patients.

Patients listed for lung transplantation benefit from pre-transplant rehabilitation programmes [50].

With the introduction of the lung allocation score (LAS), waiting list mortality has decreased and the oddsof receiving a donor organ have increased for most major lung diseases, including PAH [51, 52]. Still, theLAS does not always adequately reflect disease severity in patients suffering from PAH [53]. In amultivariable analysis comparing mortality predicted by the LAS system to actual mortality in REVEAL,two additional variables were independently associated with increased mortality compared with the LAS:mean right atrial pressure ⩾14 mmHg and 6-min walk distance ⩽300 m [54]. These two factors, inaddition to total bilirubin and cardiac index, were added to a modified LAS, released in February 2015[55], which also reweighted weight, list urgency and post-transplant outcomes in favour of PAH. Theeffect of these changes on outcome should be forthcoming in the next several years.

In some countries, an “exceptional LAS” can be obtained for patients with severe PH [56]. Some othercountries not using the LAS have successfully implemented high-priority programmes for these patients [57].

Transplant procedure, post-transplant care and outcomesMajor progress has been made over the past years in lung transplantation for PAH. One of the mostimportant innovations was the use of ECMO support during and after transplantation [58]. Meanwhile,the intra-operative use of ECMO has almost completely replaced the use of conventional cardiopulmonarybypass as it has been associated with a reduction of peri-operative complications including renal failure, areduced need for transfusions of blood products and (in some, but not all, series) with better survival [49,59–63]. In patients with PH and right-sided heart failure undergoing transplantation, veno-arterial ECMOis occasionally established prior to general anaesthesia to avoid haemodynamic instability.

A better understanding of the pathophysiological changes after transplantation for PH with adaptation oftherapeutic strategies (e.g. achieving a negative fluid balance including use of haemofiltration whennecessary and extended ECMO support) has substantially reduced the occurrence of early graftdysfunction, which was the major obstacle of post-transplant survival in these patients and the mainreason why the early post-operative mortality was historically higher in patients undergoing lungtransplantation for PAH than for most other end-stage lung diseases [64].

TABLE 4 Specific criteria for lung transplant referral and listing in patients with pulmonaryarterial hypertension (PAH)

Referral Potentially eligible patients for whom lung transplantation might be an option in case oftreatment failure

ESC/ERS intermediate or high risk or REVEAL risk score >7 on appropriate PAH medicationProgressive disease or recent hospitalisation for worsening of PAHNeed for i.v. or s.c. prostacyclin therapyKnown or suspected high-risk variants such as PVOD or PCH, scleroderma, large andprogressive pulmonary artery aneurysms

Signs of secondary liver or kidney dysfunction due to PAH or other potentially life-threateningcomplications such as recurrent haemoptysis

Listing Patient has been fully evaluated and prepared for transplantationESC/ERS high risk or REVEAL risk score >10 on appropriate PAH medication, usually includingi.v. or s.c. prostacyclin analogues

Progressive hypoxaemia, especially in patients with PVOD or PCHProgressive, but not end-stage, liver or kidney dysfunction due to PAH or life-threateninghaemoptysis

ESC: European Society of Cardiology; ERS: European Respiratory Society; REVEAL: Registry to EvaluateEarly and Long-term Pulmonary Arterial Hypertension Disease Management; PVOD: pulmonary veno-occlusive disease; PCH: pulmonary capillary haemangiomatosis.

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As already reported in 1999 [65], the main cause of primary graft dysfunction in these patients was notresidual PH, but left ventricular failure [33]. However, the notion that the small and “unconditioned” leftventricles of patients with severe PH are prone to developing diastolic dysfunction when exposed to a normalor high pre-load after transplantation only recently came into a wider focus of interest [32, 33, 48]. Leftventricular dysfunction results in elevated left-sided filling pressures and pulmonary oedema, which tends toworsen whenever patients are awake and agitated. In the past, this has frequently led to a vicious cyclemaking it difficult, and sometimes impossible, to wean patients from the ventilator, thereby exposing themto the risks associated with prolonged mechanical ventilation and intensive care. To overcome this problem,several centres over many years have used combined heart and lung transplantation for patients with severePH [66, 67]. Today, however, the post-operative prolongation of veno-arterial ECMO after transplantationeffectively prevents primary graft dysfunction [48, 68]. Two different approaches have been described:1) prolongation of ECMO with extubation first and continuation of ECMO support for 3–7 days [48] or2) brief post-operative prolongation of ECMO in intubated patients until stabilisation of haemodynamicsand normalisation of fluid balance followed by a few days of ventilation [49]. For both strategies, 1-yearsurvival rates >90% have been reported [48, 49]. There is now consensus among experts that bilateral lungtransplantation is the procedure of choice for most patients with PAH. Of note, almost any right ventriclerecovers within a few weeks after transplantation, regardless of the degree of pre-transplant dilatation anddysfunction, and regardless of the severity of pre-operative tricuspid regurgitation [69–71].

Recommendations for lung transplantation in patients with PH/PAH

• Repeated risk assessment is pivotal to identify the appropriate time for initiating transplant evaluation.• Established and validated risk prediction tools such as the REVEAL risk score or the ESC/ERS risk

prediction strategy should be applied in patients with PAH to determine timing for referral to atransplant centre.

• Potentially eligible candidates should be referred for lung transplantation evaluation early, i.e. whenthey have an inadequate response to oral combination therapy, indicated by an intermediate or highrisk according to the ESC/ERS risk stratification strategy or by a REVEAL risk score >7.

• Listing for lung transplantation should be considered in patients who present with a high risk of deathaccording to the ESC/ERS risk stratification strategy or by a REVEAL risk score ⩾10 despite receivingoptimised medical therapy including s.c. or i.v. PCAs, as the expected mortality on medical therapyexceeds the expected mortality after bilateral lung transplantation. Depending on local circumstances,listing of patients at intermediate risk might be appropriate in some countries.

• Timing of listing must depend on expected local waiting time.• Bilateral lung transplantation is the method of choice in patients with PH.• There is no degree of right ventricular dysfunction that precludes bilateral lung transplantation in

patients with PAH.• Despite advances in ICU management and ECLS, the ideal recipient is an ambulant outpatient.• Extended use of ECMO support should be considered after lung transplantation in patients with PH

to prevent early graft dysfunction.• Given the low number and high risk of lung transplants performed for PAH worldwide, this procedure

should be concentrated in specialised centres.

Ethical considerationsDespite therapeutic progress, PAH remains a chronic, incurable and often fatal disease. Advanced ICUtreatment including the use of ECLS is warranted whenever there is a clear treatment objective, be itrecovery or transplantation. However, if these treatment goals are not realistically achievable, advancedintensive care will be futile and should be replaced by best supportive care, as should be the case in allpatients who have reached the end of their life. It is important to consider the patient’s preferenceswhenever possible and to proactively discuss end-of-life matters early on. Still, patients may change theirperspectives once they are no longer in a stable situation but face imminent death.

Future perspectivesIn the foreseeable future, PAH will remain an incurable, chronic and progressive disease. Reverseremodelling of the pulmonary vasculopathy is a main target of ongoing research, but success in humandisease has been limited so far [72]. Hence, future studies should aim at developing new drugs to affect thedisease itself, but also at developing new means to support the failing right ventricle. The development of(awake) ECMO as a bridge to transplantation has been a first step. Future devices will allow an extendeduse of extracorporeal or intracorporeal support systems, even in outpatients, like the use of left ventricularassist devices in patients with left-sided heart failure. It is impossible to foresee if or when such devices

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may obviate the need for lung transplantation. For the time being, lung transplantation remains animportant treatment option for patients with otherwise refractory PAH.

Conflict of interest: M.M. Hoeper reports personal fees for speaking/consulting from Actelion, Bayer, GSK and Merck.R.L. Benza has nothing to disclose. P. Corris reports grants and personal fees for lectures and consultations fromActelion and Bayer, and personal fees for lectures and consultations from MSD, during the conduct of the study. M. dePerrot reports grants and personal fees for lectures and consultations from Bayer, Merck and Actelion, during theconduct of the study. E. Fadel has nothing to disclose. A.M. Keogh reports personal fees for lectures and consultationsfrom Bayer, Actelion, GSK and Pfizer, during the conduct of the study. C. Kühn reports personal fees for lecturing fromMaquet and Zoll, during the conduct of the study. L. Savale reports grants and personal fees for lectures andconsultations from Bayer and Actelion, and personal fees for lectures and consultations from GSK and MSD, during theconduct of the study. W. Klepetko has nothing to disclose.

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Clinical trial design and new therapiesfor pulmonary arterial hypertension

Olivier Sitbon 1, Mardi Gomberg-Maitland2, John Granton3, Michael I. Lewis4,Stephen C. Mathai5, Maurizio Rainisio6, Norman L. Stockbridge7,Martin R. Wilkins8, Roham T. Zamanian9 and Lewis J. Rubin10

Number 8 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1Université Paris-Sud, Hôpital Bicêtre, INSERM UMR_S999, Le Kremlin-Bicêtre, France. 2GeorgeWashington University, Dept of Medicine, Washington, DC, USA. 3University Health Network-General Division,University of Toronto, Toronto, ON, Canada. 4Pulmonary/Critical Care Division and Smidt Heart Institute,Cedars Sinai Medical Center, UCLA, Los Angeles, CA, USA. 5Division of Pulmonary and Critical Care, Dept ofMedicine, Johns Hopkins University, Baltimore, MD, USA. 6AbaNovus srl, Sanremo, Italy. 7Food and DrugAdministration, Silver Spring, MD, USA. 8Dept of Medicine, Faculty of Medicine, Imperial College London,London, UK. 9Dept of Medicine, Stanford University Medical Center, Stanford, CA, USA. 10San Diego School ofMedicine, University of California, La Jolla, CA, USA.

Correspondence: Olivier Sitbon, Service de Pneumologie, Hôpital Bicêtre, 78 rue du Général Leclerc, 94275Le Kremlin-Bicêtre, France. E-mail: olivier.sitbon@aphp.fr

@ERSpublicationsState of the art and research perspectives in clinical trial design and new therapies for pulmonaryarterial hypertension http://ow.ly/VHQ030mfRxc

Cite this article as: Sitbon O, Gomberg-Maitland M, Granton J, et al. Clinical trial design and newtherapies for pulmonary arterial hypertension. Eur Respir J 2019; 53: 1801908 [https://doi.org/10.1183/13993003.01908-2018].

ABSTRACT Until 20 years ago the treatment of pulmonary arterial hypertension (PAH) was based oncase reports and small series, and was largely ineffectual. As a deeper understanding of the pathogenesisand pathophysiology of PAH evolved over the subsequent two decades, coupled with epidemiologicalstudies defining the clinical and demographic characteristics of the condition, a renewed interest intreatment development emerged through collaborations between international experts, industry andregulatory agencies. These efforts led to the performance of robust, high-quality clinical trials of noveltherapies that targeted putative pathogenic pathways, leading to the approval of more than 10 noveltherapies that have beneficially impacted both the quality and duration of life. However, our understandingof PAH remains incomplete and there is no cure. Accordingly, efforts are now focused on identifyingnovel pathogenic pathways that may be targeted, and applying more rigorous clinical trial designs to betterdefine the efficacy of these new potential treatments and their role in the management scheme. Thisarticle, prepared by a Task Force comprised of expert clinicians, trialists and regulators, summarises thecurrent state of the art, and provides insight into the opportunities and challenges for identifying andassessing the efficacy and safety of new treatments for this challenging condition.

Received: Oct 05 2018 | Accepted: Oct 09 2018

The content of this work is copyright of the authors or their employers. Design and branding are copyright ©ERS 2019.This article is open access and distributed under the terms of the Creative Commons Attribution Non-CommercialLicence 4.0.

https://doi.org/10.1183/13993003.01908-2018 Eur Respir J 2019; 53: 1801908

| SERIESWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

Current state of clinical trial design and therapeutics in pulmonary arterialhypertensionWith advances in our understanding of the pathobiology of pulmonary hypertension (PH) over the past20 years, more than 10 drugs have been developed and approved for the treatment of pulmonary arterialhypertension (PAH) and one for chronic thromboembolic PH (CTEPH). Initial clinical trials performed innewly diagnosed PAH and CTEPH were single agent, placebo controlled, of short duration, focused onchanges in measures of exercise capacity and comprised of relatively small populations of patients.However, over the past 5 years, clinical trial designs testing novel therapies for PAH have evolved intomuch larger, placebo controlled, on background therapy and upfront combination therapy trials. Inaddition, event-driven studies examining the effect of sequential combination therapy on clinicalworsening have forced the community to search for more clinically relevant, novel efficacy end-points andtrial design. Here, we review the evolution of clinical trial end-points, report on new therapeutic targets,evaluate clinical trial design and propose goals for clinical investigation.

Evolution of end-points in clinical trials of PH6-min walk testThe 6-min walk test (6MWT), a submaximal exercise test, has been the most commonly employedprimary end-point in clinical trials of PH therapies, beginning with the first randomised controlled trial(RCT) for drug registration of epoprostenol in 1990 [1]. Since that initial study, most of the registrationstudies for novel PAH or CTEPH therapies employed short-term change in distance achieved on the6MWT (Δ6MWD) as the primary outcome (figure 1) [2–13]. These studies identified statisticallysignificant differences in Δ6MWD that resulted in regulatory approval for use in PH, but the clinicalrelevance of these changes remained less well defined. Multiple studies examining the relationship betweenΔ6MWD and short- and long-term outcomes, such as need for hospitalisation, lung transplantation,initiation of rescue therapy or death, failed to consistently demonstrate significant associations [14–18].Subsequent studies defined clinically relevant changes in 6MWD pertaining to patient-importantoutcomes, such as health-related quality of life and prediction of clinical deterioration [17, 19–21].However, the utility of Δ6MWD as a primary outcome measure in clinical trials is limited, particularly in

0Duration weeks

20 40 60 80 100

Ambrisentan+tadalafil (AMBITION)

Selexipag (GRIPHON)

Macitentan (SERAPHIN)

Oral treprostinil (FREEDOM-M)

Oral treprostinil (FREEDOM-C)

Oral treprostinil (FREEDOM-C2)

Inhaled treprostinil (TRIUMPH)

Treprostinil s.c.Iloprost (STEP)

Iloprost (AIR)

Riociguat (PATENT)

Tadalafil (PHIRST)

Sildenafil (PACES)

Sildenafil (SUPER-1)

Ambrisentan (ARIES-2)

Ambrisentan (ARIES-1)

Bosentan (EARLY)

Bosentan (BREATHE-1)

Bosentan (351) n=32

n=213

n=185

n=202

n=192

n=277

n=267

n=405

n=443

n=203

n=67

n=470

n=235

n=349

n=350

n=310

n=742

n=1156

n=500

FIGURE 1 Duration of main registration studies (randomised controlled trials (RCTs)) for currently approvedpulmonary arterial hypertension therapies. Blue bars: RCTs with change in 6-min walk distance as primaryoutcome measure; red bars: RCTs with morbidity and mortality composite primary outcome measure.

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more contemporary trials involving sequential, add-on therapy. The change is less than the clinicallyrelevant thresholds described, despite the significance achieved by other clinical outcomes [7–10, 22, 23].

Patient-reported outcomesAlternate outcome measures that are clinically meaningful end-points, measuring how a patient “feels,functions or survives”, are sought by regulatory agencies. In PH, patient-reported outcomes (PROs) nowexist, but have been less responsive to therapeutic impact [24–26]. Disease-specific measures needvalidation in varied languages and need to be included in future clinical trials at all stages of development.The CAMPHOR (Cambridge Pulmonary Hypertension Outcome Review) questionnaire, the first PAH/CTEPH-specific questionnaire, is quite lengthy and does not track with other clinical measures over time[27]. The 10-question survey proposed by the Pulmonary Hypertension Association UK (emPHasis-10) ismore efficient, but needs further study [28], and the recently reported SYMPACT study appears to be themore efficient and inclusive, but also needs additional validation [29].

Other surrogate end-pointsPH is a disease that lacks strong surrogate end-points [30]. By definition, a surrogate end-point should be:1) part of the causative pathway from therapy to clinical outcome, 2) its baseline value should be related toclinical outcome, 3) a change in its value should reflect a change in outcome both in direction andmagnitude of change, and 4) the estimate of its clinical benefit should be independent of the nature oftreatment (e.g. the relationship of change in the surrogate with the outcome should be the same regardlessof the intervention that led to the change) [31]. A recent systematic review of surrogate end-pointsemployed in clinical trials of PAH therapy between 1985 and 2013 found that inclusion of invasivemeasures, such as haemodynamics, as either primary or secondary end-points, significantly decreased overtime, while measures of functional capacity, functional status and PROs increased significantly [32].

Evolution to composite outcome end-pointsTo address some of the limitations of the 6MWT as a primary outcome measure in clinical trials and toexplore novel end-points, registration studies in the mid-2000s incorporated composite end-points reflectingtime to clinical worsening (TTCW) [6, 7]. Reductions in risk of clinical deterioration noted in these studiesmotivated the decision to use this composite end-point of morbidity and mortality as the primary outcome ina large registration study of macitentan [22]. The significant reduction in the risk of clinical worsening notedbetween treatment arms was not reflected by the Δ6MWD. This suggested a distinct effect on the risk ofclinical events versus improvement of functional capacity. Similar associations between treatment assignment,TTCW and Δ6MWD were noted in the RCT of selexipag [23]. Combined with data from an RCT of initialcombination of ambrisentan and tadalafil versus either one alone demonstrating responsiveness of themeasure in a treatment-naive cohort, TTCW is now an approved end-point for PAH therapeutic registrationtrials (ClinicalTrials.gov identifiers NCT01908699, NCT02932410 and NCT01824290) (table 1).

Limitations to outcome end-pointsFuture clinical trials need to be more efficient. While TTCW as the primary end-point has been widelyaccepted, it is not the solution. First, there is no standard definition across trials for TTCW, limiting theability to compare treatment effects between studies (table 1). Second, each component of a compositeend-point should be weighted with respect to clinical importance and frequency of occurrence; the currentcomponents of TTCW in PH are not (e.g. death is infrequent and clinical worsening is frequent) [33].Third, the relationship between clinical worsening and subsequent survival is not well defined and notalways adjudicated by an events committee with expertise in PH (table 1) [34]. A more recent analysisutilising data from the SERAPHIN [22] and GRIPHON [23] TTCW trials found a strong associationbetween both symptomatic progression and hospitalisation and mortality at 3, 6 and 12 months [35].Rigorous studies of the association between TTCW and subsequent events, such as survival, are stillneeded to fully establish TTCW as a validated surrogate for mortality.

New drug targets for PAHThe currently licensed drugs are directed at correcting the imbalance of vasoactive factors in PAH. Thereis widespread acceptance that new drugs need to address other pathological mechanisms that drivevascular remodelling. There is no shortage of novel drug targets of potential therapeutic interest; thecurrent challenge is prioritising candidates according to likelihood of success in clinical trials, side-effects,quality of life and cost-effectiveness.

Genetically determined targetsGenetics is a powerful mechanism for identifying and prioritising new drug targets with confidence.Mutations in BMPR2 (bone morphogenetic protein receptor type 2), the most common susceptibility gene

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for PAH, have focused attention on the transforming growth factor-β (TGF-β)/BMP signalling pathway[36]. To date, the only treatment that has been used to target BMPR2 signalling in clinical trials is FK506(tacrolimus) [37], which is currently in phase 2 (ClinicalTrials.gov identifier NCT01647945). FK506 bindsits pharmacological target FKBP12 (12-kDa FK506-binding protein) and removes it from all three BMPRtype 1 receptors (ALK1, ALK2 and ALK3), including those preferred by BMPR2 (ALK1 and ALK3). It isable to activate BMPR2-mediated signalling even in the absence of exogenous ligand and BMPR2.

Strategies proposed for correcting impaired BMPR2 signalling, beyond the aspiration of gene therapy,include pharmacological approaches such as chloroquine (which prevents lysosomal degradation of theBMPR2), ataluren (with the aim of reading through missense mutations) and increasing BMP9 levels [38].An alternative to increasing BMP signalling is to inhibit TGF-β activity using a novel activin–receptorfusion protein (sotatercept) that competitively binds and neutralises TGF-β superfamily ligands [39].Potential targets will emerge as we better understand the genetic architecture of PAH, including ionchannels (KCNK3 (potassium channel subfamily K, member 3)), aquaporin and SOX17 (SRY-box 17) [36,40]. Further pre-clinical studies will be needed to realise how these, or their signalling pathways, might bemanipulated for therapeutic benefit.

Epigenetic modificationLittle is known of the epigenetics of PAH, but studies of histone deacetylase (HDAC) inhibitors inpre-clinical cell and animal models have reported beneficial effects, although cardiotoxicity is a concern[41]. Translating the therapeutic potential of HDAC inhibition in PAH will require a clearer insight intothe HDAC subtypes involved in the vascular pathology. Likewise, a better understanding of the role ofmicroRNAs in PAH is needed to inform how best to manipulate pharmacologically to have an impact onpulmonary vascular disease [42].

DNA damageInhibition of poly(ADP-ribose) polymerase (PARP) reverses PAH in several animal models [43]. Anopen-label early phase 1 study of olaparib, an orally available PARP1 inhibitor approved for the treatment ofBRCA (breast cancer gene)-related breast cancer, has been proposed in PAH patients in World HealthOrganization Functional Class II–III on stable vasoactive therapy (ClinicalTrials.gov identifier NCT03251872).

TABLE 1 Definitions of time to clinical worsening (TTCW) when used as primary outcome measure in pulmonary arterialhypertension (PAH) clinical trials

Macitentan versus placebo (SERAPHIN) [22] Selexipag versus placebo (GRIPHON) [23] Ambrisentan+tadalafil versus either alone(AMBITION) [102]

Worsening PH: Disease progression: Disease progression:⩾15% decrease in 6MWD from baseline ⩾15% decrease in 6MWD from baseline ⩾15% decrease in 6MWD from baseline

+ + +Worsening symptoms (WHO FC or signs of

right heart failure)Worsening WHO FC or need for additional

PAH therapyWHO FC III or IV

+Need for additional PAH therapy

Hospitalisation for worsening PAH Hospitalisation for worsening PAH

Start of i.v./s.c. prostanoids therapy Start of i.v./s.c. prostanoids therapy orLTOT

Start of i.v./s.c. prostanoids therapy

Lung transplantation or atrial septostomy Lung transplantation or atrial septostomy Lung transplantation or atrial septostomy

Unsatisfactory long-term clinical response:Any decrease in baseline 6MWD at two

consecutive visits+

WHO FC III at two visits separated by at least6 months

All-cause death All-cause death All-cause death

PH: pulmonary hypertension; 6MWD: 6-min walk distance; WHO: World Health Organization; FC: functional class; LTOT: long-term oxygen therapy.

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Growth factorsThe tyrosine kinase receptor imatinib was the first significant compound used in a large-scale trial todirectly target vascular remodelling in PAH. Imatinib inhibits platelet-derived growth factor (PDGF)receptor-α and -β [44]. PDGF is a trophic factor in vascular cells and lung tissue from PAH patientsshows increased expression of PDGF receptors. The phase 3 PAH trial reported a 32 m increase in meanplacebo-corrected 6MWD and a reduction in pulmonary vascular resistance (PVR) without improvementin TTCW. Unfortunately subdural haematoma occurred in eight patients receiving both imatinib andanticoagulation with vitamin K antagonists [45]. However, there remains considerable interest in tyrosinekinase inhibitors, and imatinib in particular, as some patients have stabilised and even improved onimatinib treatment in anecdotal reports. Identifying the clinical and molecular characteristics of patientslikely to respond is key to the success of this programme.

Clinical experience with other tyrosine kinase inhibitors urges caution. Indeed, exposure to dasatinib isassociated with the development of PAH [46, 47]. In a 16-week, single-centre, open-label trial in 12patients with PAH, the multikinase/angiogenesis inhibitor sorafenib worsened pulmonary haemodynamicsand was associated with adverse events, such as moderate skin reactions on the hands and feet andalopecia [48].

MetabolismInsulin resistance contributes to the morbidity and mortality of PAH [49]. This has led to interest in theuse of agents such as rosiglitazone, metformin and glucagon-like peptide 1 agonists (table 2) [50, 51]. Asmall clinical trial with metformin is underway, with detailed study of the impact on the right ventricleand pulmonary haemodynamics. Whereas normal myocardium uses fatty acid oxidation as an energysource, the maladapted myocardium relies on glycolysis, which is much less efficient [52]. Glutaminolysisis also induced. Inhibition of fatty acid oxidation increases glucose oxidation, leading to the possibility thattrimetazidine (an inhibitor of 3-ketoacyl coenzyme A thiolase), approved for angina, may have utility inPAH [53]. Ranolazine, another antianginal agent, is also an option [54].

In PAH, proliferating cells switch their metabolism from oxidative phosphorylation to glycolysis for ATPproduction. Dichloroacetate (DCA), which inhibits pyruvate dehydrogenase kinase, is a potential treatmentfor PAH [55]. Gene variants that reduce the function of SIRT (sirtuin 33) or UCP2 (uncoupling protein 2)impair the clinical response to DCA. A small clinical study with DCA has shown haemodynamicimprovement in genetically susceptible patients [56].

Inflammation and immune modulationHistological studies of the lung, the presence of circulating autoantibodies and high plasma levels ofcytokines in PAH all point to inflammation as a driver of its pathology [57]. Direct investigation of thiscurrently lies with a clinical trial of the anti-CD20 monoclonal antibody, rituximab, in PAH associatedwith connective tissue disease (ClinicalTrials.gov identifier NCT01086540), and a trial of tocilizumab, aninterleukin-6 receptor antagonist in PAH (ClinicalTrials.gov identifier NCT02676947) (table 3). Elafin, anendogenously produced elastase inhibitor, has now progressed to clinical trials [58]. Elafin is pro-apoptoticand decreases neointimal lesions in lung organ culture [59].

Oestrogen signallingAromatase converts androgens to oestrogen and is evident in the pulmonary vasculature of PAH lungs.A small trial of anastrozole, an aromatase inhibitor, in PAH has reported an increase in 6MWD [60] anda further study is underway (table 4).

Oxidative and hypoxic stressOxidative stress is another mechanism that has been targeted in PAH. In contrast to animal studies [61], aphase 2 study of an inhibitor of apoptosis signal-regulating kinase 1 (ASK1) failed to show overallimprovement [62]. A phase 3 study with bardoxolone methyl in scleroderma has been completed,following some signals of efficacy in phase 2 (ClinicalTrials.gov identifier NCT02036970). This druginduces the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulatesantioxidant proteins, and suppresses activation of the pro-inflammatory factor NF-κB.

Increased expression of hypoxia-inducible factor (HIF), specifically HIF1α and HIF2α, in the PAH lung,genetic manipulation in animals [63] and naturally occurring mutations in humans (e.g. Chuvashpolycythaemia [64]) highlight the potential importance of hypoxic stress in PAH. Several groups haveshown that iron deficiency in the absence of anaemia is common in PAH and is associated with reducedsurvival in PAH [65]. Open-label studies of i.v. iron replacement in PAH suggest an improvement inexercise capacity [66] and a double-blind study is near completion.

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TABLE 2 Clinical trials with drugs targeting metabolic dysfunction in pulmonary arterial hypertension (PAH)

Drug tested ClinicalTrials.govidentifier

Study design Studyduration

Main inclusion criteria Primary outcome measure Secondary outcome measures

Fatty acid oxidation: ranolazine and trimetazidineRanolazine NCT02829034 Multicentre RCT

versus placebo26 weeks PH on stable specific therapies

but with RV dysfunction (RVEF<45%)

Percentage change in RVEF(assessed by MRI)

Ranolazine NCT01839110 Multicentre RCTversus placebo

26 weeks PH on stable specific therapiesbut with RV dysfunction (RVEF

<45%)

Number and percentage ofsubjects with high-risk profile at

end of the study

Baseline comparison of the metabolicprofiling, microRNA and iPSCs of subjects

with and without RV dysfunction

Ranolazine NCT02133352 Single-centreopen-label phase 4

26 weeks PH with LV diastolic dysfunction Percentage change in mPAP,PAOP and PVR (RHC)

Other haemodynamic variables, 6MWD, MRI,echocardiography and NT-proBNP

Ranolazine NCT01757808 Phase 1 12 weeks PAH on one or more backgroundspecific therapies (including i.v./

s.c. prostacyclins)

Change in PVR (RHC) Change in CPET, RV echocardiographyparameters and 6MWD

Trimetazidine NCT03273387 Single-centre phase2 and 3

12 weeks PAH Changes in RV function (MRI) Changes in cardiac fibrosis level (MRI), NYHAFC and LDH level

Glycolysis: dichloroacetateDichloroacetate NCT01083524 Two-centre

open-label phase 116 weeks PAH on one or more background

oral specific therapiesSafety and tolerability Change in PVR, 6MWD, RV size and function

(MRI), NT-proBNP and lung/RV metabolism(FDG-PET)

Modulation of Nrf2 pathway/NF-κB pathway: bardoxolone methylBardoxolone methyl NCT02036970

(LARIAT)Multicentre phase 2RCT versus placebo

16 weeks PAH, PH-ILD, subset of patientswith group 3 or 5 PH

Change in 6MWD Determine recommended dose range

Bardoxolone methyl NCT02657356(CATALYST)

Multicentre phase 3RCT versus placebo

24 weeks PAH-CTD Change in 6MWD

Bardoxolone methyl NCT03068130(RANGER)

Multicentre phase 3open-label extension

Up to5 years

Patients with PH who previouslyparticipated in RCTs with

bardoxolone

Long-term safety

Metabolic syndrome: AMPK signalling and metforminHormonal, metabolicand signallinginteractions in PAH

NCT01884051 Observational 5 years PAH and healthy subjects Safety and biomarkers of mechanism

Metformin NCT03349775 Early phase 1 12 weeks PH and obesity Pulmonary vascularhaemodynamics at rest and on

exercise

Effect on PA endothelial cell phenotypes

RCT: randomised controlled trial; PH: pulmonary hypertension; RV: right ventricle; RVEF: right ventricular ejection fraction; MRI: magnetic resonance imaging; iPSC: induced pluripotentstem cell; LV: left ventricle; mPAP: mean pulmonary arterial pressure; PAOP: pulmonary artery occlusion pressure; PVR: pulmonary vascular resistance; RHC: right heartcatheterisation; 6MWD: 6-min walk distance; NT-proBNP: N-terminal pro-brain natriuretic peptide; CPET: cardiopulmonary exercise testing; NYHA: New York Heart Association; FC:functional class; LDH: lactate dehydrogenase; FDG: 18F-2-fluoro-2-deoxy-D-glucose; PET: positron emission tomography; Nrf2: nuclear factor erythroid 2-related factor 2; ILD: interstitiallung disease; AMPK: AMP-activated protein kinase; PA: pulmonary artery.

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TABLE 3 Clinical trials with drugs targeting inflammation in pulmonary arterial hypertension (PAH)

Drug tested ClinicalTrials.govidentifier

Study design Studyduration

Main inclusion criteria Primary outcomemeasures

Secondary outcome measures

Modulation of cytokines pathway: anakinra and tocilizumabAnakinra NCT01479010 Single-centre open-label pilot

study: phase 1 and 24 weeks PAH (excluding PAH-CTD, ILD,

POPH) in FC III despite optimalPAH therapy

Change in peak V′O2 and inV′E/V′CO2 slope (CPET)

Change in biomarkers; correlation betweenchanges in biomarkers and CPET measures

Anakinra NCT03057028 Single-centre open-label pilotstudy: phase 1

14 days PAH (excluding PAH-CTD) in FCII or III despite optimal PAH

therapy

Change in peak V′O2 andventilatory efficiency

(CPET)

Change in hs-CRP, NT-proBNP, IL-6 andsymptoms of heart failure (MLHFQ); correlationbetween biomarkers and measures of exercise

capacity

Tocilizumab NCT02676947 Open-label: phase 2(TRANSFORM-UK)

24 weeks PAH (excluding PAH-CTD due toSLE, RA and MCTD)

Safety (incidence andseverity of adverse events);

change in PVR (RHC)

Change in 6MWD, NT-proBNP, WHO FC and QoL

Inflammation: ubenimexUbenimex NCT02736149 Multicentre open-label

extension study: phase 2(LIBERTY-2)

Variable(average1 year)

PAH on ⩾1 PAH-specifictherapies, in FC II or III, whocompleted the phase 2 study

Safety (adverse events) Change in PVR, 6MWD, WHO FC andBNP/NT-proBNP

Ubenimex NCT02664558 Multicentre double-blind RCTversus placebo: phase 2

(LIBERTY)

24 weeks PAH on ⩾1 PAH-specifictherapies in WHO FC II or III

Change in PVR Change in 6MWD, WHO FC, TTCW, QoLand NT-proBNP

CTD: connective tissue disease; ILD: interstitial lung disease; POPH: portopulmonary hypertension; FC: functional class; V′O2: oxygen uptake; V′E/V′CO2: ventilatory response (minuteventilation/carbon dioxide production); CPET: cardiopulmonary exercise testing; hs-CRP: high-sensitivity C-reactive protein; NT-proBNP: N-terminal pro-brain natriuretic peptide; IL-6:interleukin-6; MLHFQ: Minnesota Living with Heart Failure Questionnaire; SLE: systemic lupus erythematosus; RA: rheumatoid arthritis; MCTD: mixed connective tissue disease; PVR:pulmonary vascular resistance; RHC: right heart catheterisation; 6MWD: 6-min walk distance; WHO: World Health Organization; QoL: quality of life; RCT: randomised controlled trial;TTCW: time to clinical worsening.

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TABLE 4 Clinical trials with drugs targeting other signalling pathways

Drug tested ClinicalTrials.govidentifier

Study design Studyduration

Main inclusion criteria Primary outcomemeasures

Secondary outcome measures

Modulation of the oestrogen pathway: anastrozole and fulvestrantAnastrozole NCT03229499 RCT versus placebo: phase

2 (PHANTOM)24 weeks PAH in WHO FC I–III; stable

PAH-specific therapy allowedChange in 6MWD Change in 6MWD (3 and 12 months), RVEF, NT-proBNP,

biomarkers, SF-36, emPHasis-10, physical activity(actigraphy), TTCW and bone mineral density

Anastrozole NCT01545336 Double-blind RCT versusplacebo: phase 2

12 weeks PAH in WHO FC I–III on stablePAH-specific therapy

Change in plasmaoestradiol and in

TAPSE

Change in 6MWD

Fulvestrant NCT02911844 Open-label: phase 2 9 weeks Post-menopausal female patientswith PAH in WHO FC I–III on stable

PAH-specific therapy

Change in plasmaoestradiol, TAPSE,

6MWD andNT-proBNP

Improvement of oxygenation: acetazolamideAcetazolamide NCT02755298 Double-blind crossover

RCT versus placebo: phase2 and 3

5 weeks Stable patients with pre-capillaryPH who are undergoing RHC for a

clinical indication

Change in 6MWD Change in QoL (MLHFQ), maximal ramp CPET, cerebraland muscle tissue oxygenation, daily activity (actigraphy),

echocardiography parameters, FC, PRO (SF-36,CAMPHOR), NT-proBNP, etc.

RCT: randomised controlled trial; PAH: pulmonary arterial hypertension; WHO: World Health Organization; FC: functional class; 6MWD: 6-min walk distance; RVEF: right ventricularejection fraction; NT-proBNP: N-terminal pro-brain natriuretic peptide; SF-36: Short Form-36; emPHasis-10: 10-question survey proposed by the Pulmonary Hypertension AssociationUK; TTCW: time to clinical worsening; TAPSE: tricuspid annular plane systolic excursion; PH: pulmonary hypertension; RHC: right heart catheterisation; QoL: quality of life; MLHFQ:Minnesota Living with Heart Failure Questionnaire; CPET: cardiopulmonary exercise testing; PRO: patient-reported outcome; CAMPHOR: Cambridge Pulmonary Hypertension Outcome Review.

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Serotonin and humoral modulationSerotonin (5-HT) is a potent vasoconstrictor and pro-proliferative factor in pulmonary vascular cells [67].Terguride, a 5-HT2A/2B receptor antagonist, showed no clinical benefit in a phase 2 study in PAH [68].This may be explained, in part, because the 5-HT1B receptor is the most highly expressed 5-HT receptor inthe pulmonary arteries in PAH lungs. Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzymein 5-HT biosynthesis and studies with a selective inhibitor of TPH1 are planned.

There is interest in further examination of the role of augmenting vasoactive intestinal polypeptide activity,despite previous disappointment with inhaled administration [69].

Careful use of β-blockers in stable PAH is safe, but which patients might benefit remains an open question[70]. While angiotensin-converting enzyme (ACE) inhibitors are importantly renoprotective inscleroderma, they have not been shown to be of benefit in PAH. The homologue of ACE, known as ACE2,converts angiotensin I and angiotensin II to angiotensin-(1–7), angiotensin-(1–9) and angiotensin-(1–5),and is of interest. Decreased ACE2 levels and ACE2 autoantibodies have been reported in PAH [71] andACE2 replacement using a purified i.v. formulation of soluble recombinant human ACE2 is underway. Twoprospective studies examining the effect of the aldosterone antagonist, spironolactone, are also underway.

Pulmonary artery denervationPulmonary artery denervation is an interventional therapy aimed at abolishing the sympathetic nervesupply to the pulmonary circulation. In a single-centre study, 13 patients underwent the procedure using aradiofrequency ablation catheter, and significant reductions of mean pulmonary arterial pressure andimprovement in 6MWD were reported [72]. Several trials are ongoing to determine efficacy and safety ofthe procedure in PAH (table 5).

Stem cellsThere are a few clinical reports of cell therapy in patients with PAH. In a 12-week open-label controlledstudy, infusion of autologous endothelial progenitor cells (EPCs) improved 6MWD and haemodynamicvariables in adult patients with severe PAH [73]. Similar results were observed in children with idiopathicPAH [74]. In the phase 1 PHACeT trial, EPCs transduced with endothelial nitric oxide synthase wereadministered to patients with PAH [75]. The 6MWD improved significantly at 1, 3 and 6 monthspost-infusion, by 65, 48 and 47 m, respectively. During the 3-day infusion protocol, no adversehaemodynamic or gas exchange parameters were observed [75].

There are several reasons to believe that therapy with cardiac stem cells such as cardiosphere-derived cells(CDCs) would benefit PAH patients with or without right ventricular dysfunction. CDCs have beendemonstrated in pre-clinical models to ameliorate most of the major aberrations that underlie thepathobiology/pathophysiology of both the maladapted right ventricle muscle and the remodelledpulmonary vessels [76]. They are potently angiogenic, antifibrotic and antiapoptotic; they have significantanti-inflammatory effects; they attenuate both oxidative and nitrosative stress; and they attract endogenousstem cells to sites of vascular injury. Recently, the phase 1 trial ALPHA of allogeneic CDCs for PAHwas initiated, with the primary objective to determine the maximum feasible dose and safety profile ofCDCs administered by central infusion into the right ventricle outflow tract of patients with idiopathicPAH (table 6).

Clinical trial failuresThe introduction of several new drugs for the treatment of PAH speaks to the success of drugdevelopment in this therapeutic area over the past two decades, but a growing number of clinical trialshave not met their primary end-point or have reported major safety concerns (table 7). Limited data arepublically available on these studies, but a deeper understanding is important to reduce risk and improvesuccess going forward.

There is a high attrition rate as drug development progresses through its phases from first-in-humanstudies to pivotal registration studies. Of a total of 9985 clinical trials from 7455 development programmesbetween 2006 and 2015, only one in 10 progressed from phase 1 to approval [77]. For cardiopulmonarydisease therapeutics the range was 6.6–12.8%. Phase transition success rate ranges for cardiopulmonarydiseases are estimated at 58.9–65.3% for phase 1 to 2, 24.1–29.1% for phase 2 to 3 and 55.5–71.1% forphase 3 to new drug application. Despite this poor overall probability of success, drug development for raredisease indications remains one of the more successful programmes across all phases of development [77].

The main reason for terminating the development of a drug is lack of efficacy. 52% of programmes arestopped because of lack of efficacy compared with 21% due to safety concerns [78, 79]. Our limitedunderstanding of the pathological drivers of PH contributes to this trial failure rate. Overemphasis on a

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TABLE 5 Clinical trials investigating pulmonary artery denervation

Intervention ClinicalTrials.govidentifier

Study design Studyduration

Main inclusion criteria Primary outcome measures Secondary outcome measures

Therapeutic Intra-VascularUltraSound (TIVUS) system

NCT02516722 Multicentre open-labelstudy (TROPHY)

12 months PAH in WHO FC III onstable double combination

therapy other thanparenteral PGI2

Safety (procedure-related AE:1 month); safety (PAH-related AEsand all-cause death: 12 months)

Change in mPAP, PVR, 6MWD andQoL at 4 months

Therapeutic Intra-VascularUltraSound (TIVUS) system

NCT02835950 Multicentre open-labelstudy (TROPHY-US)

12 months PAH in WHO FC III onstable double combination

therapy other thanparenteral PGI2

Safety (procedure-related AE:1 month); safety (AEs, PAH-related

AEs and all-cause death:12 months)

Change in mPAP, PVR, 6MWD, QoL,NT-proBNP and RV function (MRI and

echocardiography) at 6 months

Pulmonary artery denervation NCT02525926 Multicentresingle-blinded RCTversus placebo(DENERV’AP)

24 weeks PAH patients in WHO FCIII–IV despite dual therapyincluding a PGI2 or dualoral therapy in patientsunable to receive PGI2

therapy

Change in mPAP (RHC) Change in mPAP (3 months), PVR and otherhaemodynamic variables (6 months), FC,

6MWD, oxygen dependence, supraventriculararrhythmia, BNP, cardiac troponin, and RV

function (echocardiography)

PA denervation (+sildenafil) NCT03282266 Multicentresingle-blinded RCTversus placebo(PADN-CFDA)

24 weeks PAH Change in 6MWD Change in haemodynamic variables (RHC), RVfunction (echocardiography) and PAH-related

events

PAH: pulmonary arterial hypertension; WHO: World Health Organization; FC: functional class; PGI2: prostacyclin I2; AE: adverse event; mPAP: mean pulmonary arterial pressure; PVR:pulmonary vascular resistance; 6MWD: 6-min walk distance; QoL: quality of life; NT-proBNP: N-terminal pro-brain natriuretic peptide; RV: right ventricle; MRI: magnetic resonanceimaging; RCT: randomised controlled trial; RHC: right heart catheterisation.

TABLE 6 Clinical trials investigating cell therapy

Cells ClinicalTrials.govidentifier

Study design Studyduration

Main inclusion criteria Primary outcome measures Secondary outcome measures

Autologous EPCstransfected with human eNOS

NCT03001414 Multicentredouble-blind crossoverRCT versus placebo:phase 2 (SAPPHIRE)

24 weeks PAH in WHO FC II–IV onstable PAH-specific

therapy

Change in 6MWD Change in 6MWD (3, 9 and 12 months) andPVR; number of deaths or clinical worsening

of PAH; change in RV function(echocardiography and MRI) and QoL (SF-36)

Allogeneic humancardiosphere-derivedstem cells

NCT03145298 Phase 1a: open-label;phase 1 (ALPHA)

1 year PAH in WHO FC II–III onstable PAH-specific

therapy

Safety (gas exchange,haemodynamics); arrhythmia;sudden death; mortality and

morbidity

Long-term safety end-points; TTCW(including death)

Phase 1b: double-blindRCT versus placebo:phase 1 (ALPHA)

1 year

EPC: endothelial progenitor cell; eNOS: endothelial nitric oxide synthase; RCT: randomised controlled trial; PAH: pulmonary arterial hypertension; WHO: World Health Organization; FC:functional class; 6MWD: 6-min walk distance; PVR: pulmonary vascular resistance; RV: right ventricle; MRI: magnetic resonance imaging; QoL: quality of life; SF-36: Short Form-36;TTCW: time to clinical worsening.

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single mechanism and the limitations of model systems also constrain drug development [78, 80].Pre-clinical animal models do not completely reflect true human disease. When tested in the best models,novel therapies have not been evaluated in animals on background PAH therapies. Moreover, pre-clinicalstudies do not employ rigours such as sample size determination and randomisation, and they have nottraditionally evaluated end-points used in human trials. Finally, it is possible that therapeutic responsesresult from off-target effects (i.e. enhanced blood flow to skeletal muscle), which are usually not evaluatedin animal models [78, 80]. Overcoming these potential pre-clinical factors will require a more completeunderstanding of relevant mechanisms in modern day phenotypes through initiatives such as PVDOMICS(ClinicalTrials.gov identifier NCT02980887), and advancement of technologies to improve applicability ofex vivo and in vitro assays. Establishing rigorous standards guiding pre-clinical animal model testing [80]will also likely result in improved selection of therapeutic candidates and minimise the impact of bias andfalse-positive results when tested in the human clinical trial environment.

Given that clinical trials are more likely to “fail” than succeed, it is important to build in plans to learnfrom “failure” [81]. The goals and objectives of early-phase clinical trials should be focused on safety,informative biomarkers and identification of responsive subpopulations. While bound by statistical norms,decisions in early-phase trials should not be made based on single p-value thresholds. Basing scientific,business or policy decisions in early development on a “mechanical bright-line rule” such as p-value <0.05as a threshold of scientific claim justification can lead to incorrect conclusions [82]. Later-phase studiesneed to be informed by adequate data on dose–response relationships and the characteristics of patientsthat show an efficacy signal. However, data are generated all along the drug development pathway and it isimperative that these data are available for careful evaluation. This will inform critical analysis of studypower, end-points and population selection.

Although commonly used, the term “failure” in the context of clinical trials does not distinguish betweenwell-designed negative studies versus studies that are simply inconclusive due to flawed design or conduct.Moreover, the perception of clinical trial “failure” is complex and depends on perspective. While clinicaltrialists and scientists may consider interventions that do not meet relevant primary or secondaryend-points as “failed”, patients may think of therapies that do not provide symptomatic improvement asunhelpful. Beyond issues of definition and perspective, data from these clinical trials are often notpublically disclosed due to a multifaceted set of issues ranging from business agendas and academicdisinterest to publication bias. Unsuccessful trials can be as, or even more, informative as “positive” trials.Data from the IMPRES trial serve as a good example [45]. Despite demonstrable improvement in exercisecapacity and haemodynamics, the higher rate of serious adverse events and study drug discontinuationultimately led to the decision to halt development of imatinib mesylate as add-on therapy for PAH.However, the publication and ensuing academic dialogue has empowered discussion around themethodology, dosing and approach to repurposing of therapeutics in PAH. More importantly, the data hasaugmented discussion of the utility of an integral biomarker as an enrichment strategy for optimumclinical trial candidate selection. The use of selected biomarkers appears to be linked with 13–21% relativeincrease in probability of successful transition between phases of clinical trial development [77].

Publication of all studies, irrespective of outcome, has the potential for cost reduction, improvement infuture trial design, reduction in attrition rates and, most importantly, reduction in the number of clinicaltrial subjects exposed to ineffective drugs or enrolled in flawed clinical trial designs [83]. In fact, initiativessuch as Medical Publishing Insights and Practices (www.mpip-initiative.org) and others supported by

TABLE 7 Main recent clinical trials in pulmonary arterial hypertension with either negative result or tolerability/safety issues

Study/compound(s) Phase End-point: result Formal presentation [ref.] Published [ref.]

ASA-STAT: aspirin and simvastatin 2 6MWD: lack of efficacy Yes Yes [103]ARROW: selonsertib (ASK-1 inhibitor) 2 6MWD: lack of efficacy Yes [62] NoCicletanine (antihypertensive withvasorelaxant and diuretic properties)

2 PVR: lack of efficacy Yes [104] No

Aviptadil (vasoactive intestinal peptide) 2 PVR: lack of efficacy Yes [105] NoIMPRES: imatinib (tyrosine kinase inhibitor) 3 6MWD: positive tolerability and

safety issuesYes Yes [45]

Terguride (partial dopamine agonist andserotonin receptor antagonist)

2 6MWD: lack of efficacy Yes [68] No

LIBERTY: ubenimex (leukotriene B4 inhibitor) 2 PVR: lack of efficacy No No

6MWD: 6-min walk distance; ASK1: apoptosis signal-regulating kinase 1; PVR: pulmonary vascular resistance.

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pharmaceutical partners, the World Health Organization, and the Pharmaceutical Research andManufacturers of America have called for transparency in publication of clinical trials protocols andresults [83]. We in the PAH scientific community must recognise our ethical obligation to clinical trialsubjects who allow us to expose them to investigational interventions with the hope that incrementalknowledge will be gained. We are bound by this moral obligation to learn and disseminate knowledgeproduced by participation of each and every clinical trial subject. A transparent process for reporting andexamining negative clinical trials, with the commitment to evaluation of full data sets (not only thetop-line data) is essential. The process should exceed current data-sharing policies of individualinstitutions or medical journals and be funded to allow independently conducted analyses by scientificcommittees (i.e. data safety monitoring boards) with the necessary expertise (i.e. clinical trialist, ethicistand statistician). The obligation for such reporting processes should be balanced with (but not hinderedby) the need for data confidentiality when analysing early-phase proof-of-concept studies.

Challenges for future trial designThe successful development of drugs for PAH has provided significant impact on patient outcomes, buthas not yet produced a cure. The surge of novel potential options has created new challenges in clinicalcare and future drug development programmes. Of course, this is a “good” stress to need to overcome, butit requires thoughtful consideration of novel trial end-points and design. It also means thatpharmacological interactions, pharmacodynamics and individual pharmacokinetics will become moreimportant to incorporate into future studies. Novel biomarkers and genetic association discovery will berequired to truly develop and personalise therapies. There are still considerable unknowns regarding themechanisms of action of our current drugs, their in vivo pharmacology and their optimal usage.Additionally, larger trials will, by necessity, need to be more collaborative in order to study potentialmeaningfulness of disease state biomarkers. Trials in PAH starting from the pre-clinical phase throughphases 1 and 2 should focus on “learning” to improve efficiency of the entire enterprise. In addition, thenumber of patients with an orphan disease who are available to participate in clinical trials is limited. It isimperative to gain the most knowledge with the fewest patients placed at risk.

Future therapies can no longer be studied as de novo treatments with placebo-treated comparator groups.One solution to this dilemma is to implement creative adaptive designs. Informatics technology can allowreal-time “adaptation” based on clinical data received, with adjustment of enrolment stratification andoutcome targets, and determination of futility [84]. In addition, this technology can allow for testingmultiple therapeutic choices if all stakeholders are willing to work together to find the best therapeuticeffect. The 2018 US Food and Drug Administration guidance on adaptive designs for clinical trials definedthese trials as “a study design that allows for prospectively planned modifications to one or more aspectsof the design based on accumulating data from subjects in the trial” [85]. It is important to recognise thatonce interim monitoring occurs there is little statistical cost in having frequent monitoring from that pointforward [86]. These Bayesian models allow statistical inferences to take into account the data-drivenadaptations and thus allow trial flexibility [87].

The easiest trial to implement is a phase 2/3 trial that allows an interim “look” to assess whether theexperimental arm is effective and therefore worth continuing on to its phase 3 stage [88]. This is a faster,more efficient way to proceed but is limited to trials utilising end-points in phase 2 that occur prior toreaching the definitive end-point needed for phase 3. Issues to address in advance include setting theresponse rate needed to proceed to phase 3, selecting the end-points and determining if there will be atime lag to allow for data to mature prior to analysis [89]. In contrast, a less traditional approach to beconsidered might be a multiarm trial with multiple experimental therapies tested against a single controlarm [84]. This can be done with efficacy and futility stopping rules for each therapy, and potentially onlydropping some of the arms while continuing the study with others [90].

Biomarker-driven trials typically consist of randomised block, marker-enriched and marker-directeddesigns [87]. Block design uses the biomarker as one of many factors used for randomisation, whereas thebiomarker is central to the treatment assignment in marker-directed designs. Marker-enriched designsselect a prognostic marker for treatment response or a determinant of higher risk to enhance success [87].The main adaptive platform combining these concepts is the master protocol approach. The approach or“platform” allows adding new treatment arms in the existing cohort or in new subgroups to an ongoingtrial in which several treatments are being tested at once [84]. The downside is that the later added armscan only be compared with the control patients randomised from the identical time-point of enrolment.This is not an easy task to organise as multiple industry partners need to collaborate in the trial design,control and privacy of data, funding, and regulatory requirements [91].

Use of biomarkers in adaptive design can strengthen trial efficiency [92]. Umbrella or basket trials describemaster protocols designed to integrate proven molecular, genetic or serological biomarkers that are

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associated with treatment response. This is now possible in oncology drug development and could be apotential design for PH trials. One example could be the use of a risk assessment tool as a biomarker atenrolment or during the study to stratify subjects. Eventually, the risk tools could then be modified toyield prognosis over time with these new markers. Biomarker-defined subgroups may be small proportionsof the total cohort studied with this approach. In addition, the ability to discontinue the study ofineffective therapies and add an arm if the therapy is proven beneficial increases trial efficiency.Depending on the stage of the trial, the evidence required to meet a proven threshold will vary and willneed consensus prior to trial initiation [84].

Proposals for future clinical trial design in PAHCollaboration and utilisation of existing resources are the keys to successful clinical development in PAHtherapeutics. The ability to examine data upon completion in both successful and unsuccessful studiesshould be the rule, not the exception. Results of recent phase 1–2 studies with drugs targeting novelmechanisms of action have not yielded success, due to the heterogeneity of subjects studied, the use ofmyriad background therapies, the inclusion of patients with mild disease and perhaps selection of thewrong end-points. Rather than using traditional PAH clinical and haemodynamic trial end-points fortargeted agents (e.g. 6MWT and PVR), the end-points should be tailored to the disease biology andanticipated mechanistic effects. This approach will allow for potential regulatory consideration of novelbiomarkers.

Phase 1–2 goals1) Pharmacokinetic and pharmacodynamics studies should be evaluated, particularly since we know

little of the myriad combinations of therapies.2) These trials should encompass biological and mechanistic markers of disease to better assess

responses to therapy.3) To improve generalisability and interpretation of the changes seen in functional capacity, early drug

trials should include more homogenous subject groups.4) Trials should use risk tools as an enrichment strategy to better phenotype a heterogeneous group.5) Novel efficacy markers in phase 2 (e.g. magnetic resonance imaging and PROs) should be

incorporated and then utilised in phase 3.

It is clear that performing long-term composite event-driven trials will be challenging and may halt thesurge of new development by committing study participants for many years [93]. Morbidity and mortalityevent trials require large numbers of subjects upfront to demonstrate effects even at 1 year [35, 94]. Futureclinical trials in PAH will need clinically meaningful end-points that reflect morbidity and mortality aswell as how patients feel and function [95]. It is known that a “low-risk” patient profile after initialtreatment of PAH is associated with better survival [96–99]: a potential exploratory end-point could be theability to reach or maintain a “low-risk” status according to the REVEAL (Registry to Evaluate Early andLong-Term Pulmonary Arterial Hypertension Disease Management) score [96] or the number of low-riskcriteria as defined by the European Society of Cardiology/European Respiratory Society PH guidelines [94,98, 100, 101].

Phase 2–3 goalsThe overarching goal should be to improve patients’ ability to live more functional and fulfilled lives.

1) Examine time to clinical improvement instead of TTCW. This will entail defining clinically significantdifferences in existing end-points and allowing for derivation of these differences post-trial with novelmarkers.

2) Utilise change in risk as a marker of efficacy as an exploratory end-point now to examine itspredictability as a clinical end-point in the future.

3) Utilise novel biomarkers (serum, plasma, genomics, metabolics and PROs) as an exploratoryend-point now to examine its predictability as a clinical end-point in the future.

4) Limit unnecessary post-marketing and small investigator-initiated studies that are unlikely to enhanceour scientific knowledge base or improve patient care.

Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from MSD, ActelionPharmaceuticals and GSK, personal fees from GossamerBio, Arena Pharmaceuticals and Acceleron Pharmaceuticals,and grants and personal fees from Bayer HealthCare, outside the submitted work. M. Gomberg-Maitland is aconsultant/data and safety monitoring board member/scientific advisory board member for Actelion, Acceleron,Complexa, Merck, Reata and United Therapeutics. Inova receives research support for her to do research from Actelion,AADi and United Therapeutics. J. Granton has received support from Actelion, Bayer and Pfizer to supportinvestigator-initiated research. He is a member of a steering committee for Bellerophon clinical trial in PAH and anadjudication committee member for a clinical trial sponsored by United Therapeutics. M.I. Lewis reports that the

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ALPHA study cited is funded by a grant from the California Institute for Regenerative Medicine (grant CLIN2-09444).S.C. Mathai reports personal fees for consultancy and data and safety monitoring board membership from Actelion,personal fees for consultancy from United Therapeutics, and grants from Scleroderma Foundation, outside thesubmitted work; and is a member of the Scientific Leadership Council, Pulmonary Hypertension Association and of theRare Disease Advisory Panel of the Patient Centered Outcomes Research Institute. M. Rainisio has nothing to disclose.N.L. Stockbridge has nothing to disclose. M.R. Wilkins reports personal fees from Actelion Pharmaceuticals, BayerHealthCare, GossamerBio and Morphogen-IX, outside the submitted work. R.T. Zamanian is a consultant for ActelionPharmaceuticals, Merck, Vivus and GossamerBio, and has received grants from Actelion Pharmaceuticals; and has apatent FK506, for the treatment of PAH, issued. L.J. Rubin reports personal fees from Actelion, Arena, Bellerophon,SoniVie and Roivant, during the conduct of the study.

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Pulmonary hypertension due to leftheart disease

Jean-Luc Vachiéry1, Ryan J. Tedford2, Stephan Rosenkranz3,Massimiliano Palazzini4, Irene Lang5, Marco Guazzi6, Gerry Coghlan7,Irina Chazova8 and Teresa De Marco9

Number 9 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1Dept of Cardiology, Cliniques Universitaires de Bruxelles – Hôpital Erasme, Brussels, Belgium.2Division of Cardiology, Dept of Medicine, Medical University of South Carolina (MUSC), Charleston, SC, USA.3Clinic III for Internal Medicine, Dept of Cardiology, Heart Center at the University of Cologne and CologneCardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany. 4Dept of Investigational,Diagnostic and Specialty Medicine, Bologna, Italy. 5Dept of Cardiology, AKH-Vienna, Medical University ofVienna, Vienna, Austria. 6Dept of Biomedical Sciences for Health, University of Milan and Dept of CardiologyUniversity, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy. 7Dept of Cardiology, Royal FreeHospital, London, UK. 8Russian Cardiology Research Complex, Moscow, Russia. 9University of California,San Francisco, CA, USA.

Correspondence: Jean-Luc Vachiéry, Dept of Cardiology, Cliniques Universitaires de Bruxelles – HôpitalErasme, 808 Route de Lennik, 1070 Brussels, Belgium. E-mail: jeanluc.vachiery@erasme.ulb.ac.be

@ERSpublicationsState of the art and research perspectives in pulmonary hypertension due to left heart diseaseincluding diagnostic and treatment insights http://ow.ly/vr0I30md6KC

Cite this article as: Vachiéry J-L, Tedford RJ, Rosenkranz S, et al. Pulmonary hypertension due to leftheart disease. Eur Respir J 2019; 53: 1801897 [https://doi.org/10.1183/13993003.01897-2018].

ABSTRACT Pulmonary hypertension (PH) is frequent in left heart disease (LHD), as a consequence ofthe underlying condition. Significant advances have occurred over the past 5 years since the 5th WorldSymposium on Pulmonary Hypertension in 2013, leading to a better understanding of PH-LHD,challenges and gaps in evidence. PH in heart failure with preserved ejection fraction represents the mostcomplex situation, as it may be misdiagnosed with group 1 PH. Based on the latest evidence, we propose anew haemodynamic definition for PH due to LHD and a three-step pragmatic approach to differentialdiagnosis. This includes the identification of a specific “left heart” phenotype and a non-invasiveprobability of PH-LHD. Invasive confirmation of PH-LHD is based on the accurate measurement ofpulmonary arterial wedge pressure and, in patients with high probability, provocative testing to clarify thediagnosis. Finally, recent clinical trials did not demonstrate a benefit in treating PH due to LHD withpulmonary arterial hypertension-approved therapies.

Received: Oct 04 2018 | Accepted: Oct 07 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

https://doi.org/10.1183/13993003.01897-2018 Eur Respir J 2019; 53:1801897

| SERIESWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

IntroductionPulmonary hypertension (PH) is a common complication of left heart disease (LHD), in response to apassive increase in left-sided filling pressures, more specifically left atrial pressure [1]. It is currentlydefined as post-capillary PH, by an increase in mean pulmonary arterial pressure (mPAP) ⩾25 mmHg anda pulmonary arterial wedge pressure (PAWP) >15 mmHg [2]. In most cases, PH-LHD (group 2 PH) is aconsequence or an abnormal biomarker of the underlying cardiac disorder. However, the structure andfunction of the pulmonary circulation may be further affected by several mechanisms potentially leadingto pulmonary arterial and venous remodelling. In heart failure, recent data even suggest that the severity ofPH correlates most strongly with venous and small arteriolar intimal thickening [1–3]. In addition, thefunction of the right ventricle is often affected independently from the afterload increase [4–7], leading touncoupling of the right ventricle/pulmonary artery unit [8–10] with further exercise limitation and adverseoutcome. This is especially true in heart failure with preserved ejection fraction (HFpEF) [4–11]. Over thepast 5 years since the 5th World Symposium on Pulmonary Hypertension (WSPH) in 2013, significantadvances have improved our understanding of PH-LHD. This article summarises these findings, keychallenges and proposals for the approach to this condition, with a specific focus on PH due to HFpEF.

Definition and classification of PH-LHDAt the 5th WSPH in 2013, a new terminology was adopted to distinguish isolated post-capillary PH(IpcPH) from combined post-capillary and pre-capillary PH (CpcPH), based on the diastolic pressuredifference/gradient (DPG) between the diastolic PAP (dPAP) and PAWP [1]. However, this definition wasfound to be too restrictive and exposed to interpretation, leading to controversies about whether the DPGwould [12–15] or would not [16–21] predict outcome in patients with group 2 PH. Pulmonary vascularresistance (PVR) was subsequently reintroduced to better reflect the impact of the right ventricle onoutcome [2]. To date, the haemodynamic definition of PH-LHD stands as: 1) post-capillary PH whenmPAP ⩾25 mmHg and PAWP >15 mmHg; 2) IpcPH, when DPG <7 mmHg and/or PVR ⩽3 Wood Units(WU); and 3) CpcPH when DPG ⩾7 mmHg and/or PVR >3 WU. These two distinct haemodynamicphenotypes may be further defined by several variables obtained during diagnostic right heartcatheterisation (RHC), none being totally independent from potential limitations [22]. The combination ofrecent analyses and basic physiology reveals that the haemodynamic definition of PH-LHD relies heavilyon the accurate measurement of PAWP.

What is a normal PAWP and how to measure it?In normal individuals, PAWP is close to dPAP, with a mean±SD value of 8.0±2.9 mmHg [23] for a normalDPG between 0 and 2 mmHg [1, 2, 22]. Therefore, taking into account 2 standard deviations, a value⩾14 mmHg should be considered abnormal. Accordingly, clinical trials in pulmonary arterial hypertension(PAH) have historically included patients with PAWP ⩽15 mmHg (in agreement with the 2016recommendations on heart failure from the European Society of Cardiology [24]) and PVR >3 WU. Toavoid inconsistencies, a common approach to the interpretation of the measurement is necessary. Thisincludes timing of the measurement with respect to the cardiac and respiratory cycle, relationship with leftventricular end-diastolic pressure (LVEDP), and other confounding factors, such as the presence of largev-waves and atrial fibrillation [25]. In the absence of mitral stenosis, PAWP measured at end-diastole(i.e. typically as the mean of the a-wave or, alternatively, a QRS-gated approach) more closelyapproximates LVEDP [25–27]. By contrast, the mean PAWP (averaged throughout the cardiac cycle) inthe presence of large v-waves (mitral regurgitation or non-compliant left atrium) will be higher thanend-diastolic PAWP and will overestimate LVEDP. This contributes to negative DPG values reported inmany studies and may also be observed in atrial fibrillation, when no a-wave is present [28–31]. Since thev-wave contribution may augment the systolic PAP (sPAP), using the end-diastolic PAWP rather thanmean PAWP may lead to a slight overestimation of PVR in the aforementioned scenarios.

Recommendations for measurement of PAWP/LVEDP in the differential diagnosis of PH

• A value of PAWP >15 mmHg, measured at end-expiration at rest, is considered consistent withPH-LHD. There is insufficient new data since the 5th WSPH in 2013 to recommend a change in thiscut-off value.

• PAWP should be measured at end-diastole to determine the pre-capillary component of PH-LHD andthe calculation of PVR. In sinus rhythm, this corresponds to the mean of the a-wave. In atrial fibrillation,it is appropriate to measure PAWP 130–160 ms after the onset of QRS and before the v-wave.

• There are no new data to suggest a change in standards for the measurement of PAWP. Therefore,we continue to recommend the assessment of PAWP at end-expiration, as averaging over of therespiratory cycle would reclassify many post-capillary PH patients to pre-capillary disease withthe current PAWP cut-off value.

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• Best practice suggests that RHC should be performed in stable, non-acute clinical conditions for thedifferential diagnosis of PH. Proper levelling at the mid-chest and “zero”ing the transducer toatmospheric pressure are critical. Patients should be positioned supine with legs flat and pressuresrecorded during spontaneous breathing (no breath-hold). Measurements should be repeated intriplicate to obtain values within a 10% agreement.

• If PAWP is elevated and the accuracy of PAWP is in question, blood oxygen saturation should bedetermined in the wedge position. If the PAWP oxygen saturation is <90%, direct LVEDPmeasurement should be obtained.

• The presence of significant, large v-waves should be noted as this strongly suggests LHD regardless ofresting PAWP.

How to define CpcPH?Evidence in PH-LHD has been generated since the 5th WSPH in 2013 to 1) characterise the clinicalprofile, 2) describe the haemodynamic features and 3) identify outcome predictors. Indeed, the presenceand the identification of a pre-capillary component in post-capillary PH are critical as it may have animpact on prognosis, can modify management and serves as the basis for clinical trial design [32]. Inaddition, CpcPH is associated with a reduced exercise capacity and a phenotype similar to PAH [21, 33].Finally, it has been recently suggested that CpcPH may present a genetic profile that could be differentfrom IpcPH [16].

Nevertheless, the populations studied in these retrospective registries are heterogeneous, from pure heartfailure with reduced ejection fraction (HFrEF) cohorts [16–18], all causes of LHD [12, 15, 20, 21, 28, 34], topure valvular heart disease (VHD) registries [13, 14]. The typical profile of PH-LHD combines an elevatedPAWP (>20 mmHg), a mildly elevated mPAP (25–40 mmHg), a low cardiac index (⩽2.5 L·min−1·m−2), anelevated transpulmonary pressure gradient (TPG) (>12 mmHg), a normal DPG (<3 mmHg) and PVRranging from 3 to 4.9 WU. In addition, right atrial pressure is consistently elevated (>10 mmHg), whichmay, together with elevated PAWP, suggest fluid overload or pericardial constraint. Finally, most studiesreported a significant proportion (roughly one-third) of negative DPG that may be explained by theaforementioned limitations [27]. This is in keeping with a high rate of atrial fibrillation, affecting around40% of patients.

The search for an ideal predictor of outcome in PH-LHD has led to conflicting results. On multivariateanalysis, several predictors were found: a combination of mPAP and PVR [13, 16], pulmonary arterialcompliance (PAC) either alone [19, 20] or in combination with mPAP and PAWP [16], or a combinationof mPAP and DPG [12]. A meta-analysis identified 10 retrospective analyses using PVR, DPG and/or PACto predict survival in PH-LHD [35]. For the purpose of consistency, and to better individuate the riskassociated with each variable, independently of arbitrary cut-offs, only studies reporting the prognosticpower of continuous variables were included. The analysis was done on a total of 2513 patients, followedfor up to 15 years. The haemodynamic profile revealed average values of mPAP, PVR, DPG and PAC of35 mmHg, 3.0 WU, 1.2 mmHg and 2.5 mL·mmHg−1, respectively. In this analysis, DPG, PVR and PACappeared to be associated with survival. However, both PVR and PAC were stronger predictors of outcomewhen compared with DPG [35]. It was suggested that a combination of variables might be better than anisolated value for prognosis purposes [35]. Interestingly, a recent analysis of three large US cohorts showedthat higher pulmonary artery elastance and lower PAC are associated with increased mortality and rightventricular dysfunction, across the spectrum of heart failure and even when resistive load was normal [36].This strongly suggests that, in CpcPH due to heart failure, the total right ventricular load is closely linkedto outcome. Finally, a recent large retrospective analysis of 2587 patients with PH-HFpEF showed thatTPG ⩾12 mmHg, PVR ⩾3 WU and DPG ⩾12 mmHg were predictors of mortality and heart failurehospitalisations [37].

Therefore, the best way to describe the pre-capillary component of post-capillary PH remainscontroversial; none of the haemodynamic variables proposed to describe PH-LHD [22] are free fromlimitations.

Recommendations

• After careful consideration of the changes in the general definition of PH [36], the proposedhaemodynamic definition of PH in LHD is: 1) IpcPH: PAWP >15 mmHg and mPAP >20 mmHg andPVR<3 WU; and 2) CpcPH: PAWP >15 mmHg and mPAP >20 mmHg and PVR ⩾3 WU.

• Beyond a strict haemodynamic definition, other markers of disease may be taken in consideration tobetter determine a patient’s prognosis. These could include an additional haemodynamic marker (e.g.DPG or PAC), cardiopulmonary exercise testing (CPET) profile (level of V′E/V′CO2 (minuteventilation/oxygen uptake) slope, exercise oscillatory ventilation, end-tidal carbon dioxide tension

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(PETCO2)), indices of right ventricular function and right ventricle/pulmonary artery coupling(compliance and elastance) and biomarkers. In the context of PH due to HFpEF, ST2, a member ofthe interleukin-1 superfamily, may be complementary to N-terminal pro-brain natriuretic peptide(NT-proBNP) [24].

• Given the limitations of pure haemodynamic definitions, future studies should be aimed at developingbiomarkers and other non-haemodynamic diagnostics to discriminate IpcPH and CpcPH.

Diagnostic approach and differential diagnosis of PH-LHDAlthough RHC is the gold standard for the diagnosis of PH, it is not sufficient to make a clear distinctionbetween idiopathic PAH (IPAH) and PH-LHD, especially when risk factors or documented history ofcardiovascular disease (CVD) coexist [1, 2, 32, 34, 38]. Therefore, we propose a three-step approach tothe differential diagnosis: 1) identification of a clinical phenotype to establish the characteristics ofgroup 2 PH, 2) determination of a pre-test probability to identify which patients should move to aninvasive evaluation and 3) haemodynamic characterisation, which could include provocative testing inselected cases.

Clinical phenotype of PH due to LHDThe revised clinical classification distinguishes three main entities in group 2 PH [38]: 1) PH due toHFpEF, 2) PH due to HFrEF and 3) PH due to VHD. In contrast to the other aetiologies, the distinctionbetween PH due to HFpEF, PAH and chronic thromboembolic PH (CTEPH) may be challenging. Indeed,traditional cardiovascular risk factors may be present in patients with PAH [32, 34, 39]. Patients withsystemic sclerosis may present with left ventricular involvement, independent from the presence of PH andpulmonary vascular disease (PVD) [40]. In patients with CTEPH, PAWP may be difficult to measure dueto pulmonary artery obstruction and LVEDP may be elevated as patients may have concomitant cardiacinvolvement [41]. Finally, patients with HFpEF [32] and PH due to HFpEF [42] may present with a lowdiffusing capacity of the lung for oxygen (DLCO), an independent predictor of outcome [43]. All thesepotential confounding factors may lead to misclassification of PH.

The latter may be avoided by combining factors that are typically associated with group 2 PH, which includeclinical features, echocardiographic abnormalities and other tests (e.g. magnetic resonance imaging andCPET) [1, 2, 39]. Interestingly, the prevalence of such risk factors in the COMPERA registry is high,particularly in an older subgroup of patients with cardiovascular comorbidities (referred to as “atypicalPAH”) and in patients with PH due to HFpEF [34]. Importantly, a high rate of atrial fibrillation was reportedat the time of diagnosis in IPAH, “atypical PAH” and PH due to HFpEF, in 10%, 42% and 54%, respectively.

Pre-test probability of PH due to LHDAs a single variable will unlikely be sufficient for accurate differential diagnosis, a combination of theprevious features may help to determine a pre-test probability of group 2 PH. Composite scores integratingclinical and non-clinical features were derived from retrospective single-centre analyses [44–48], lackingexternal validation. A proposal to integrate these features is shown in table 1, some being markers of highprobability of PH-LHD (previous cardiac interventions, presence of atrial fibrillation at diagnosis, evidencefor structural LHD and CPET abnormalities). This approach is in line with the current strategy for thegeneral diagnosis of PH [2, 49] and has also recently been suggested in the assessment of HFpEF [50].

Haemodynamic evaluation of PH-LHDAs a general rule, the decision for invasive confirmation of PH-LHD assumes the presence of anintermediate to high probability of PH based on symptoms and echocardiographic features, following therevised diagnostic algorithm [51]. In patients with a high probability of LHD as a cause of PH, the generalmanagement should be guided according to the recommendation for the underlying condition. In patientswith an intermediate probability, invasive characterisation may be performed in patients with risk factorsfor PAH (e.g. systemic sclerosis), CTEPH or in cases of unexplained dyspnoea. The presence of rightventricular abnormalities also requires invasive assessment as it may have an influence on management(figure 1a). Due to the presence of multiple confounding factors and the complexity of the interpretationof invasive measurements, RHC should be performed in expert centres [2]. Provocative testing duringRHC may be useful in the distinction between healthy subjects and HFpEF [51–54] or to uncoverPH-LHD in patients with PAWP at the upper limit of normal (ULN) (i.e. 13–15 mmHg) [55–58]. For thispurpose, both exercise testing and fluid loading are used in clinical practice (table 2).

The ULN of mPAP during an incremental dynamic exercise challenge has been suggested at >30 mmHgwith a cardiac output (CO) <10 L·min−1, which corresponds to a total pulmonary vascular resistance(TPR=mPAP/CO) of 3 WU [59, 60]. The ULN of PAWP during exercise is thought to be between 15 and

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25 mmHg, but higher values can be recorded in elderly subjects [59, 60]. In addition, other factors mayinfluence the interpretation of PAWP during exercise, including body position (supine versus upright, withsupine values being 5 mmHg higher than upright on average), age, sex, duration of exercise and timingover the respiratory cycle [60, 61–64]. Many of these issues are discussed in a recent position paper [60].Recent data suggest that initial increases in PAWP and mPAP in middle-aged healthy individuals do notnecessarily reflect abnormal cardiopulmonary physiology, as pressures may normalise within minutes [61].The ULN to detect an abnormal response of PAWP to exercise is therefore unknown. Some authorssuggest a cut-off value of 25 mmHg for the diagnosis of heart failure [51–54], although PAWP >25 mmHghas been found in elderly individuals free of apparent CVD [61]. Finally, different cut-offs may be usedaccording to age and sex [55, 62, 63]. Therefore, a flow-adjusted measure of PAWP may be moreappropriate than PAWP alone [59, 60], with recent work suggesting a PAWP/CO slope>2 mmHg·L−1·min−1 is associated with reduced functional capacity, higher NT-proBNP and reduced heartfailure-free survival [61].

As measurements of pressures during exercise are technically difficult and require specialised equipment, afluid challenge may be easier to standardise and more readily available. Any condition associated withreduced left ventricular diastolic compliance or VHD will be associated with a rapid increase in PAWPwhen challenged with an increased systemic venous return [53, 54]. Although not as profound, fluidloading also increases PAWP in healthy volunteers as a function of age, sex, amount infused and infusionrate [52]. Thus, the standardisation of the test cut-off values for PAWP has raised controversies [53–55,65, 66]. It has been shown that up to 20% of patients with pre-capillary PH may present an increase inPAWP >15 mmHg after fluid loading [56, 57, 65]. However, current evidence suggests a PAWP of18–20 mmHg after infusion might represent the ULN (table 2) [53, 66]. The advantages and limitations ofexercise testing and fluid loading are presented in table 3.

Recommendations

• The nomenclature of “PAH with cardiovascular risk factors” should be preferred over any other, toaccount for their coexistence without suggesting that risk factors may be influencing the cause of thePVD. The role of comorbidities in the disease process of PAH is not demonstrated and remains unclear.

• A three-step approach should be followed to perform the differential diagnosis between group 2 PH(mainly HFpEF) and PAH: 1) identification of a clinical phenotype suggesting PH-LHD, 2)determination of a pre-test probability for PH-LHD and 3) haemodynamic characterisation.

• Invasive assessment should be performed in patients with intermediate probability of PH-LHD,presence of right ventricular abnormality and when risk factors for PAH/CTEPH coexist (figure 1b).

• In patients with a PAWP 13–15 mmHg and high/intermediate probability of PH-HFpEF, provocativetesting should be considered to uncover PH due to HFpEF. For technical reasons and reliability ofpressure recording, a fluid challenge is preferred over exercise in the approach to differential diagnosis.

• PAWP >18 mmHg immediately after administration of 500 mL of saline over 5 min is consideredabnormal.

TABLE 1 Pre-test probability of left heart disease (LHD) phenotype

Feature High probability Intermediate probability Low probability

Age >70 years 60–70 years <60 yearsObesity, systemic hypertension,dyslipidaemia, glucoseintolerance/diabetes

>2 factors 1–2 factors None

Previous cardiac intervention# Yes No NoAtrial fibrillation Current Paroxysmal NoStructural LHD Present No NoECG LBBB or LVH Mild LVH Normal or signs of RV strainEchocardiography LA dilation; grade >2 mitral flow No LA dilation; grade <2 mitral flow No LA dilation; E/e′ <13CPET Mildly elevated V′E/V′CO2 slope; EOV Elevated V′E/V′CO2 slope or EOV High V′E/V′CO2 slope; no EOVCardiac MRI LA strain or LA/RA >1 No left heart abnormalities

LBBB: left bundle branch block; LVH: left ventricular hypertrophy; RV: right ventricular; LA: left atrial; E/e′: early mitral inflow velocity/mitralannular early diastolic velocity ratio; CPET: cardiopulmonary exercise testing; V′E: minute ventilation; V′CO2: carbon dioxide production; EOV:exercise oscillatory ventilation; MRI: magnetic resonance imaging; RA: right atrial. #: coronary artery and/or valvular surgical and/ornon-surgical procedures, including percutaneous interventions.

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• However, how this should impact management is unknown. If PAH-specific therapies are initiated inpatients with an “abnormal” response, caution should be exercised, including close monitoring ofresponse and side-effects.

Clinical trials and therapy for PH due to LHDPathways involved in the development of PAH may contribute to the pathogenesis of heart failure and PHdue to LHD, providing a rationale for investigating the role of their modulation in this setting [1, 2, 32, 39].Until recently, most studies were performed in HFrEF patients, leading to disappointing results [1, 2, 32, 39].The results of the ENABLE trials with bosentan were recently published, confirming that blockingendothelin-1 has no effect on outcome in patients with HFrEF [67]. The SOCRATES programme assessedthe role of vericiguat, a guanylate cyclase stimulator, in HFrEF [68] and HFpEF [69]. In SOCRATES-Reduced, vericiguat did not change the NT-proBNP level at 12 weeks compared with placebo [68]. Similarresults were observed in SOCRATES-Preserved, with no effect on left atrial volume index, the coprimaryend-point [69]. Inhaled sodium nitrite has been shown to acutely decrease left-sided filling pressures andPAP at rest [70] and exercise [71]. However, the multicentre INDIE-HFpEF trial (ClinicalTrials.gov identifierNCT02742129) did not show a benefit of the compound on exercise capacity in HFpEF after 12 weeks [72].

Since 2013, several randomised controlled trials have been completed in patients with PH-LHD (table 4).The effects of 60 mg sildenafil 3 times a day were compared with placebo in 52 patients with PH due toHFpEF at 12 weeks [73]. No effect was observed on the primary end-point of mPAP, while a decrease inPVR and an improvement in exercise capacity were previously shown in a single-centre trial [74]. Riociguat,a guanylate cyclase stimulator, did not improve mPAP after 12 weeks in patients with PH due to HFrEF [75].

Consider RHCin selected cases#

Management of LHD

No RV abnormality

Intermediate

Pre-test probability of PH-HFpEFa)

RHC recommended

RV abnormality(imaging, ECG)

High

PAWP 13–15 mmHg

Pre-capillary PH

Low probability

b)

PH-HFpEFnot excluded

1) Consider provocative testing2) Consider other cardiac testing+

Consider LVEDPvalidation+

Intermediate orhigh probability

PAWP >15 mmHg

PH-HFpEF likely

Low probability

RHC at expert centres¶

PH-HFpEF confirmed

Intermediate orhigh probability

FIGURE 1 Haemodynamic assessment of pulmonary hypertension (PH) due to heart failure with preservedejection fraction (HFpEF). RV: right ventricular; RHC: right heart catheterisation; LHD: left heart disease;PAWP: pulmonary arterial wedge pressure; LVEDP: left ventricular end-diastolic pressure; CTEPH: chronicthromboembolic PH. a) Pre-test probability of PH-LHD is based on the features presented in table 1. RHC isrecommended in intermediate probability when risk factors of pulmonary arterial hypertension/CTEPH arepresent and/or if there is evidence of right ventricle abnormality. If the probability is high, patients should bemanaged according to recommendations for LHD. b) For the assessment of PH, RHC should be performed atexpert centres. In patients with intermediate/high probability (table 1) and PAWP between 13 and 15 mmHg,PH-HFpEF is not excluded; provocative testing (tables 2 and 3) should be considered. #: for patients withsystemic sclerosis, risk factors for CTEPH and/or unexplained dyspnea; ¶: after [2]; +: if PAWP >15 mmHg,LVEDP validation should be considered.

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The MELODY-1 study was the only study specifically including patients with CpcPH [76]. Patients wererandomised to placebo or macitentan 10 mg. The main end-point assessed a composite of significant fluidretention (weight gain ⩾5% or ⩾5 kg because of fluid overload or parenteral diuretic administration) orworsening in New York Heart Association Functional Class (NYHA FC) from baseline to end oftreatment. Exploratory end-points included changes in NT-proBNP and haemodynamics at week 12.Treatment with macitentan was associated with a 10.1% increased risk of fluid retention versus placebo,mostly within the first month. At week 12, the macitentan group showed no change in PVR, mean rightatrial pressure or PAWP with respect to placebo.

Finally, the SIOVAC trial aimed to determine whether treatment with sildenafil improves outcomes ofpatients with persistent PH after correction of VHD [77]. Patients who had undergone a successful valvereplacement or repair procedure at least 1 year before inclusion were randomised to 40 mg sildenafil 3times daily (n=104) versus placebo (n=96) for 6 months. The primary end-point was a composite clinicalscore combining death, hospital admission for heart failure, change in NYHA FC and patient globalself-assessment. Improvement in the clinical score was significantly more frequent in the placebo group(44 versus 27 patients receiving sildenafil). In contrast, worsening was more common in the sildenafilgroup (33 versus 14 patients in the placebo group). The Kaplan–Meier estimates for survival withoutadmission due to heart failure were 0.76 and 0.86 in the sildenafil and placebo group, respectively,although this did not reach statistical significance.

The typical profile of patients included in the trials modulating the nitric oxide/cGMP pathway shows anelderly (70 years) female predominance, with a high rate of atrial fibrillation at baseline (44–77%) and

TABLE 2 Pulmonary arterial wedge pressure (PAWP) response to exercise in normal and heart failure with preserved ejectionfraction (HFpEF), and response to fluid loading in normal, HFpEF and pulmonary hypertension (PH)

First author[ref.]

Subjects n Age (sex) Protocol Average PAWP: restto peak mmHg

Comment

ExerciseWRIGHT [62] 28 healthy 55 years (12 female) Semi-upright 11±3–22±5 early to 17

±6 lateTime-variant changes, earlyincrease and late decrease

WOLSK [63] 62 healthy 20–80 years(50% female)

Supine 8–10 rest;16 leg raising;

19 at 25% peak V′O2;23 at 75% peak V′O2

35% elderly had PAWP>25 mmHg

ANDERSEN [52] 26 (14HFpEF, 12controls)

70 years HFpEF (57%female); 63 years

controls (58% female)

Supine exerciseversus fluid loading

Control: 7±3–13±5;HFpEF: 14±3–32±6

Similar increase in healthysubjects; 2-fold increase in allfilling pressures during exerciseversus fluid loading in HFpEF

Fluid loadingFUJIMOTO [53] 60 healthy;

11 HFpEFYoung: <50 years;older: ⩾50 years

100–200 mL·min−1 Young: 10±2–16±2;older: 9±2–17±2;HFpEF: 14±4–20±4

Normals reach PAWP 18–19mmHg

ANDERSEN [52] 26 (14HFpEF, 12controls)

70 years HFpEF(57% female); 63 yearscontrols (58% female)

10 mL·kg−1·min−1

saline (150 mL·min−1)Control: 7±3–13±5;HFpEF: 14±3–21±4

Similar increase of PAWP inhealthy subjects

FOX [55] 107 SSc withPH suspicion

59 years PAH(94% female); 66 yearsOPVH (64% female)

500 mL saline(5–10 min)

PAH: 8±3–12±2(LVEPD 9–12);

OPVH: 12±3–17±5(LVEDP 15–21)

Retrospective analysis; OPVHdefined by increase in PAWP

>15 mmHg

ROBBINS [57] 207 PAH 51 years PAH(82% female); 57 yearsOPVH (74% female)

500 mL saline(5–10 min)

PAH: 9±3–11±4;OPVH: 12±2–19±3

Retrospective analysis; 30% hadincrease in PAWP >15 mmHg,

predominantly female, mostly innormal range

D’ALTO [65] 212 PHevaluation

58 years pre-capillary(68% female);

65 years post-capillary

7 mL·kg−1 rapidinfusion

PAH: 9±2–12±2;HPH: 11±2–22±3

Overlap between groups; cut-offfor PAWP abnormal response at

18 mmHg

V′O2: oxygen uptake; SSc: systemic sclerosis; PAH: pulmonary arterial hypertension; LVEDP: left ventricular end-diastolic pressure; OPVH: occultpulmonary venous hypertension (defined as PAWP >15 mmHg after fluid loading); HPH: hidden pulmonary hypertension due to left heart disease.

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preserved ejection fraction in more than half of the cases. With the exception of the MELODY trial,patients had IpcPH, as shown by a combination of DPG around 2 mmHg and PVR below or slightlyabove 3 WU [73, 75, 77]. In contrast, the patients recruited in the MELODY trial had a typical CpcPHprofile, which was associated with higher baseline NT-proBNP, reflecting worse right ventricular function[76]. Several studies using PAH therapies/pathways in PH-LHD are underway (table 5).

PH and vasoreactivity testing in end-stage heart failureIn the context of heart transplantation, PH is associated with an increased 30-day mortality in patientswith TPG >15 mmHg and PVR >5 WU [78]. A continuous risk of morbidity and mortality increases withprogressive elevation in mPAP, TPG and PVR [79]. Finally, PH reverses soon after heart transplantation,the most pronounced reduction in PVR occurring within 1 month post-transplant [80]. Implantation of aleft ventricular assist device (LVAD) rapidly reduces “fixed” PH in heart transplant candidates, withsurvival outcomes comparable to patients without [81]. In addition, right ventricular afterload almostalways declines with LVAD insertion and does so rapidly [82]. It is therefore recommended to performRHC in all candidates before listing and at 3–6-month intervals in listed patients, especially in thepresence of reversible PH or worsening heart failure [83]. LVAD recipients with at least one post-implantRHC without PH likely require less frequent assessments [84]. The current recommendations for hearttransplantation suggest that an acute vasodilator challenge should be performed if sPAP >50 mmHg, andeither TPG ⩾15 mmHg or PVR >3 WU and systemic systolic arterial pressure >85 mmHg [83]. However,

TABLE 3 Limitations and advantages of exercise testing and fluid loading in the assessment of pulmonary hypertension

Exercise testing Fluid loading

Clinical relevance forsymptom assessment

+++ +

Clinical relevance fordifferential diagnosis

+ +++

Main advantages Respects the pathophysiology; comprehensive test,allowing for additional insights in pulmonary vasculardisease (dynamic pulmonary vascular resistance);

complementary with cardiopulmonary exercise testing

Easy to perform, no specific setting; minimal risk ofmisinterpretation of pressures reading; better

established cut-off defining abnormal increase inpulmonary arterial wedge pressure

Main limitations Requires a specific complex setting; expertise inconducting the test; pressure reading during exercise;

range of normal response uncertain

Unknown response in disease state; age dependency ofresponse

Standardised protocol +/− ++

TABLE 4 Recently completed randomised controlled trials targeting the phosphodiesterase type 5 inhibitor/nitric oxide andendothelin pathways in pulmonary hypertension due to left heart disease

First author orstudy [ref.]

Studydrug

Dose Subjectsn

Duration Population Primary outcome Result

GUAZZI [74] Sildenafil 50 mg3 times a day

44 12 months HFpEF PVR,RV performance,

CPET

Improvement

LEPHT [75] Riociguat 0.5, 1 or 2 mg3 times a day

201 16 weeks HFrEF mPAP versusplacebo

No change

HOENDERMIS [73] Sildenafil 60 mg3 times a day

52 12 weeks HFpEF mPAP versusplacebo

No change

SIOVAC [77] Sildenafil 40 mg3 times a day

231 24 weeks VHD Composite clinicalscore#

Worsening in activegroup

MELODY-1 [76] Macitentan 10 mgonce daily

48 12 weeks HF (EF >30%);75% HFpEF

Safety andtolerability

+10% fluid retentionin active group

HF: heart failure; pEF: preserved ejection fraction; PVR: pulmonary vascular resistance; RV: right ventricular; CPET: cardiopulmonary exercisetesting; rEF: reduced ejection fraction; mPAP: mean pulmonary arterial pressure; VHD: valvular hear disease. #: combination of death,hospitalisation for HF, change in New York Heart Association Functional Class and patient global self-assessment.

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there is no specific recommendation on the agent to be used. Outside of this setting, the role ofvasoreactivity testing does not clearly predict outcome in PH-LHD [1, 2, 20]. Finally, there is a paucityof evidence supporting the use of PAH-approved therapies in patients awaiting heart transplantationand/or LVAD.

Recommendations

• There is still no multicentre trial that suggests targeting PH-LHD with PAH-specific drugs isbeneficial. Therefore, we maintain a strong recommendation against the use of PAH therapies in group2 PH.

• In addition, a safety signal should be acknowledged: 1) the use of sildenafil in the context of PHpost-VHD intervention is associated with an increased risk of clinical deterioration and death, and 2)the use of macitentan in CpcPH due to heart failure is associated with an increased risk of fluidretention.

• Following the MELODY-1 trial, new standards have been proposed to explore the role ofPAH-approved therapies in the context of group 2 PH. If pursued, such trials should be limited to PHdue to HFpEF with CpcPH. The agent of choice should ideally be a HFpEF disease-modifying drug.Finally, a proof-of-concept study should be performed first, with safety and tolerability, haemodynamicand/or CPET efficacy end-points.

• Vasoreactivity testing is not recommended in patients with PH-LHD, outside of the context ofassessment for heart transplantation.

ConclusionsPH is common in LHD; it is not a disease, although a subset of patients present with significantpulmonary vascular changes. Clinical research and prospective long-term multicentre analysis ofPH-HFpEF cohorts may help to better identify risk factors for CpcPH and provide insights on outcomepredictors. A pre-test probability assessment of LHD should be part of the diagnostic approach of PH.Further studies are needed to develop a multidimensional prediction score. Invasive confirmation on RHCrequires attention to accurate resting PAWP measurement, at end-diastole and end-expiration. An increaseof PAWP >18 mmHg after fluid loading, in patients with resting values between 13 and 15 mmHg and

TABLE 5 Planned and ongoing trials in pulmonary hypertension (PH) due to left heart disease

Study# Study drug Dose Subjectsn

Duration Population Primary outcome

SERENADE(NCT03153111)

Macitentan 10 mgonce daily

300 52 weeks LVEF ⩾40% and ESC-definedHFpEF; HF hospitalisation within

12 months and/or PAWP orLVEDP >15 mmHg within

6 months; elevated NT-proBNP;PVD or RVD

% change from baseline inNT-proBNP at week 24

SOPRANO(NCT02554903)

Macitentan 10 mgonce daily

78 12 weeks LVAD within 45 days; PH by RHCwith PAWP ⩽18 mmHg and

PVR >3 WU

PVR ratio of week 12to baseline

DYNAMIC(NCT02744339)

Oral riociguat 1.5 mg3 times a day

114 26 weeks HFpEF; mPAP >25 mmHg andPAWP >15 mmHg

Change in CO

Oral treprostinil(NCT03037580)

Oraltreprostinil

310 24 weeks LVEF ⩾50%; RHC within 90 daysof randomisation; 6MWD >200 m

Change in 6MWD frombaseline to week 24

PASSION (notregistered)

Oral tadalafil 40 mgonce daily

320 NA HFpEF; PH with PAWP>15 mmHg and mPAP >25 mmHg

and PVR >3 WU

Time to first event defined asHF-associated hospitalisation(independently adjudicated)or death from any cause

#: ClinicalTrials.gov identifier numbers are provided where possible. LVEF: left ventricular ejection fraction; ESC: European Society ofCardiology; HF: heart failure; pEF: preserved ejection fraction; PAWP: pulmonary arterial wedge pressure; LVEDP: left ventricular end-diastolicpressure; NT-proBNP: N-terminal pro-brain natriuretic peptide; PVD: pulmonary vascular disease; RVD: right ventricular dysfunction; LVAD:left ventricular assist device; RHC: right heart catheterisation; PVR: pulmonary vascular resistance; mPAP: mean pulmonary arterial pressure;CO: cardiac output; 6MWD: 6-min walk distance; NA: not available.

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intermediate/high probability of HFpEF, may be considered abnormal. However, we strongly encouragefurther study of this population as well as non-haemodynamic, alternative strategies to differentiate IpcPHand CpcPH. The CpcPH haemodynamic presentation is now defined by PVR >3 WU on top of apost-capillary PH phenotype. Finally, multicentre randomised trials using PAH therapies in PH-LHD havenot demonstrated benefit and have raised safety concerns. Their use is still not recommended in PH-LHD.

Conflict of interest: J-L. Vachiéry reports consultancy and speaker fees paid to institution, and is an investigator inclinical trials for Actelion Pharmaceuticals and Bayer, consultancy fees paid to institution from Novartis, andconsultancy fees paid to institution, and is an investigator in clinical trials for Sonivie and Pfizer, during the conduct ofthe study; consultancy fees paid to institution, and is an investigator in clinical trials for Arena Pharmaceuticals, BialPortela and Sonivie, consultancy and speaker fees paid to institution, and is an investigator in clinical trials for GSK andPfizer, consultancy fees and travel grants paid to institution from MSD, and is an investigator in clinical trials for Reata,outside the submitted work. R.J. Tedford reports personal fees (Hemodynamic Core Lab) from Actelion, J&J and Merck,and personal fees for steering committee membership from Abbott, outside the submitted work. S. Rosenkranz reportspersonal fees for lectures and/or consultancy from Abbott, Actelion, Arena, Bayer, BMS, MSD, Novartis, Pfizer andUnited Therapeutics, and institutional research grants from Actelion, Bayer, Novartis, Pfizer and United Therapeutics,outside the submitted work; and serves as chair of the Working Group “Pulmonary circulation and right ventricularfunction” of the European Society of Cardiology. M. Palazzini has nothing to disclose. I. Lang reports grants andpersonal fees from Actelion and AOP Orphan Pharma, and personal fees from Sanofi and Novartis, outside thesubmitted work. M. Guazzi has nothing to disclose. G. Coghlan has nothing to disclose. I. Chazova has nothing todisclose. T. De Marco reports grants from Actelion Pharmaceuticals, Pfizer, United Therapeutics, Gilead, BostonScientific, Bellerophon, Respirex, Arena Pharmaceutical and Novartis, outside the submitted work.

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Pulmonary hypertension in chronic lungdisease and hypoxia

Steven D. Nathan1, Joan A. Barbera2,3, Sean P. Gaine4, Sergio Harari5,Fernando J. Martinez6, Horst Olschewski7, Karen M. Olsson8,Andrew J. Peacock9, Joanna Pepke-Zaba10, Steeve Provencher11,Norbert Weissmann12 and Werner Seeger12

Number 10 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1Inova Fairfax Hospital, Falls Church, VA, USA. 2Dept of Pulmonary Medicine, Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain. 3Biomedical Research Networking Center on RespiratoryDiseases, Madrid, Spain. 4Respiratory Medicine, Mater Misericordiae University Hospital, Dublin, Ireland. 5U.O.di Pneumologia e Terapia Semi-Intensiva Respiratoria, Servizio di Fisiopatologia Respiratoria ed EmodinamicaPolmonare, Ospedale San Giuseppe, MultiMedica IRCCS, Milan, Italy. 6Weill Cornell Medicine, New York, NY,USA. 7Division of Pulmonology, Medizinische Universitat Graz, Graz, Austria. 8Dept of Respiratory Medicine,Hannover Medical School and Member of the German Center for Lung Research (DZL), Hannover, Germany.9Scottish Pulmonary Vascular Unit, Regional Lung and Heart Centre, Glasgow, UK. 10Pulmonary HypertensionUnit, Papworth Hospital, Cambridge, UK. 11Institut Universitaire de Cardiologie et de Pneumologie de QuébecResearch Center, Laval University, Quebec City, QC, Canada. 12University of Giessen and Marburg Lung Center(UGMLC), Justus-Liebig University Giessen and Member of the German Center for Lung Research (DZL),Giessen, Germany.

Correspondence: Steven D. Nathan, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042, USA.E-mail: steven.nathan@inova.org

Correspondence: Werner Seeger, University of Giessen and Marburg Lung Center, Klinikstrasse 33, 35392Giessen, Germany. E-mail: Werner.Seeger@UGMLC.de

@ERSpublicationsState of the art and research perspectives in pulmonary hypertension in chronic lung disease andhypoxia http://ow.ly/XcW730meWxy

Cite this article as: Nathan SD, Barbera JA, Gaine SP, et al. Pulmonary hypertension in chronic lungdisease and hypoxia. Eur Respir J 2019; 53: 1801914 [https://doi.org/10.1183/13993003.01914-2018].

ABSTRACT Pulmonary hypertension (PH) frequently complicates the course of patients with variousforms of chronic lung disease (CLD). CLD-associated PH (CLD-PH) is invariably associated with reducedfunctional ability, impaired quality of life, greater oxygen requirements and an increased risk of mortality.The aetiology of CLD-PH is complex and multifactorial, with differences in the pathogenic sequelaebetween the diverse forms of CLD. Haemodynamic evaluation of PH severity should be contextualisedwithin the extent of the underlying lung disease, which is best gauged through a combination ofphysiological and imaging assessment. Who, when, if and how to screen for PH will be addressed in thisarticle, as will the current state of knowledge with regard to the role of treatment with pulmonaryvasoactive agents. Although such therapy cannot be endorsed given the current state of findings, futurestudies in this area are strongly encouraged.

Received: Oct 06 2018 | Accepted: Oct 09 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

https://doi.org/10.1183/13993003.01914-2018 Eur Respir J 2019; 53: 1801914

| SERIESWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

IntroductionThis article provides an update on pulmonary hypertension (PH) associated with chronic lung disease(CLD), with the main focus being on chronic obstructive pulmonary disease (COPD) and interstitial lungdisease (ILD) [1]. There is evidence that PH is associated with other CLDs such as cystic fibrosis andbronchopulmonary dysplasia [2, 3]. CLD-associated PH (CLD-PH) is clearly linked with reducedfunctional status and worse outcomes [4, 5]. Even in patients who fulfil diagnostic criteria for group 1pulmonary arterial hypertension (PAH), the presence of minor lung disease affects survival [6]. Moreover,there is data suggesting that mean pulmonary arterial pressure (mPAP) ⩽25 mmHg is associated withworse outcome in CLD-PH [7, 8]. Whether the presence of PH is causative or a surrogate of other factorsaffecting outcomes remains largely uncertain.

PH in the context of acute exacerbations of the various CLDs will not be discussed. However, it isimportant that defining PH should not be undertaken during an acute exacerbation, but under stableconditions. For purposes of consistent nomenclature, the lung condition will be mentioned first, followedby “-PH” since mostly it is the lung condition which initially manifests clinically.

Epidemiology and clinical relevance of PH in lung diseaseChronic obstructive lung diseaseThe prevalence of PH in COPD (COPD-PH) is in general dependent on the severity of the disease, butalso on the definition of PH and the method of diagnostic assessment. Specific genetic signatures are alsolinked with the development of PH in COPD [9]. Several studies in patients with spirometric GlobalInitiative for Chronic Obstructive Lung Disease stage IV showed that up to 90% have mPAP >20 mmHg,with most ranging between 20 and 35 mmHg. Approximately 1–5% of COPD patients have mPAP >35–40 mmHg at rest [10]. Even under moderate exercise conditions, COPD patients may show a rapid rise inmPAP, indicating loss of lung vasculature, vascular distensibility and/or vessel recruitment capability. Inaddition, exercise PH in COPD may be due to comorbid left heart disease. There is a cluster of patientsrepresenting a “pulmonary vascular COPD phenotype”, characterised by less severe airflow limitation,hypoxaemia, very low diffusing capacity of the lung for carbon monoxide (DLCO), normo- or hypocapniaand a cardiovascular exercise limitation profile [11]. Interestingly, the vascular lesions in COPD-PHpatients are morphologically similar to those in idiopathic PAH (IPAH). It has previously been establishedthat the presence of PH has a stronger association with mortality in COPD than forced expiratory volumein 1 s (FEV1) or gas exchange variables [1]. In addition, an enlarged pulmonary artery diameter, asdetected by computed tomography (CT) scan, predicts hospitalisation due to acute COPDexacerbation [4, 12].

Idiopathic pulmonary fibrosis and other idiopathic interstitial pneumoniasMost of the data on the prevalence and impact of PH complicating fibrotic lung disorders emanates fromthe idiopathic pulmonary fibrosis (IPF) literature. In IPF, mPAP ⩾25 mmHg has been reported in 8–15%of patients upon initial work-up, with greater prevalence in advanced (30–50%) and end-stage (>60%)disease [13–15]. Additionally, echocardiography studies have suggested a high prevalence of PH [16].However, echocardiography and other non-invasive measures, including an enlarged main pulmonaryartery on CT scan, are limited in their accuracy to detect PH in lung diseases, thus serving as screeningtools only [16, 17]. Nonetheless, both of these modalities have been shown to provide independentprognostic information in patients with fibrotic lung disease. In most patients, PH is mild to moderate, butmay also be severe [14]. One longitudinal study suggested that mPAP increases by around 1.8 mmHgper year, but rapid progression of PH has also been reported in late-stage IPF patients [18]. Intriguingly,there is limited correlation between PH severity and lung function impairment or high-resolution CTfibrosis score [14–16, 19, 20], whereas distinct gene signatures have been observed in IPF-PH lungs [21].PH may also be associated with an increased risk for acute exacerbation in advanced IPF [22]. Adverseoutcomes with mPAP thresholds ⩾25 mmHg have been reported in IPF. Indeed, the prognosis of fibroticidiopathic interstitial pneumonia (IIP) with PH is worse than IPAH [23].

Combined pulmonary fibrosis and emphysema, and other lung diseasesCombined pulmonary fibrosis and emphysema (CPFE) is currently defined by the simultaneous presenceof emphysema in the upper lobes and fibrosis in the lower lobes on chest CT. Patients with CPFE areparticularly prone to develop PH, with estimates suggesting a prevalence of 30–50% [24]. Typically,normal or mildly abnormal lung volumes and the absence of airflow obstruction are accompanied by amarkedly impaired diffusion capacity, significant hypoxaemia and PH. The PH appears to contribute tothe functional limitation in CPFE and is associated with poor survival [24, 25].

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SarcoidosisThe prevalence of PH in sarcoidosis ranges from 5.7% to 74% [26]. Sarcoidosis-PH has a reported 5-yearsurvival of 50–60% [27, 28]. While the vast majority of patients with sarcoidosis-PH have extensiveparenchymal disease, it may also occur in patients without pulmonary fibrosis [27–29]. The mechanismsunderlying PH in sarcoidosis are complex, and include fibrosis-associated remodelling and obliteration ofpulmonary vessels, extrinsic compression of central pulmonary vessels by lymphadenopathy or mediastinalfibrosis, pulmonary veno-occlusive-like lesions, granulomatous involvement of pulmonary vessels, leftventricular dysfunction, and portopulmonary hypertension [27].

Other CLDsThe prevalence of PH in patients with pulmonary Langerhans cell histiocytosis is high, with haemodynamicfeatures frequently resembling PAH, while PH complicating lymphangioleiomyomatosis tends to be mildto moderate and mostly related to the extent of parenchymal involvement [30, 31]. PH may complicatethe course of adults with a history of bronchopulmonary dysplasia and cystic fibrosis [2, 3]. PH may alsodevelop in patients with chronic hypersensitivity pneumonitis and, possibly, lung cancer [32, 33].

Detection of PH in CLDNon-invasive modalities that might raise suspicion for the presence of PH in CLD include circulatingbiomarkers, pulmonary function testing, echocardiography and imaging (figure 1). Plasma levels of brain

Suspect

Support

Confirm

Stratify

Obstructive LD: FEV1 >60%Restrictive LD: FVC >70%

Minimal parenchymalCT changes

Morphological severity

Physiological severity

Limited CLD

Obstructive LD: FEV1 <60%Restrictive LD: FVC <70%

Extensive parenchymalCT changes

Severe CLD

Individualised careNo PAH therapy

Severe PHMild-to-moderate PH

Registries and RCTs requiredConsider exercise training

Clinical, functional or imaging results suggestive of concomitant PH#

Echocardiogram¶

Right heart catheterisation+

Group 1 versus group 3 PH

Refer to expert PH and LD centre§Treatment algorithm for PAH

Group 3 PHGroup 1 (PAH)/classification unclear

FIGURE 1 Evaluation of pulmonary hypertension (PH) in chronic lung disease (CLD). FEV1: forced expiratoryvolume in 1 s; FVC: forced vital capacity; CT: computed tomography; PAH: pulmonary arterial hypertension;RCT: randomised controlled trial; DLCO: diffusing capacity of the lung for carbon monoxide; KCO: transfercoefficient of the lung for carbon monoxide. #: suggestive findings include: 1) symptoms and signs (dyspnoeaout of proportion, loud P2, signs of right heart failure, right axis deviation on ECG, elevated natriuretic peptidelevels); 2) pulmonary function test abnormalities (low DLCO (e.g. <40% of predicted), elevated %FVC/%DLCO

ratio (low KCO)); 3) exercise test findings (including decreased distance, decreased arterial oxygen saturationor increased Borg rating on 6-min walk test and decreased circulatory reserve, preserved ventilatory reserveon cardiopulmonary exercise testing); and 4) imaging findings (extent of LD, enlarged pulmonary arterysegments, increased pulmonary artery/aorta diameter ratio >1 on CT). ¶: signs supporting the diagnosis of PHinclude elevated systolic pulmonary arterial pressure and signs of right ventricular dysfunction. However,echocardiography measures are only suggestive and have limited accuracy in patients with CLD. +: stronglyconsider referring the patient to a PH expert centre. §: expert centres should comprise multidisciplinaryteams. Any decision for individualised treatment should follow a goal-orientated approach with predefinedtreatment targets, to be stopped if these targets are not met after a predefined time period.

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natriuretic peptide (BNP) or N-terminal pro-BNP are elevated in severe CLD-PH, but have less sensitivityand specificity for moderate PH and may be confounded by left heart abnormalities [34, 35]. In both ILDand COPD, PH is generally associated with a lower DLCO, diminished exercise capacity and more impairedgas exchange at rest or during exercise than expected based on ventilatory impairments [14, 16, 19, 36, 37].

Echocardiography is considered the best non-invasive modality to screen for CLD-PH. However, theability to determine peak tricuspid regurgitation velocity to estimate the right ventricular systolic pressureis limited in these patients [38]. Alternate echocardiographic measures including right ventricular outflowtract diameter, tricuspid annular plane systolic excursion, and qualitative assessment of right chamberstructure and function have been advocated in IPF and COPD [39, 40].

The ratio of the main pulmonary artery to ascending aorta diameter on imaging may predict PH in bothCOPD and IPF, with a ratio >1 (range 0.9–1.1) suggested as a threshold [12, 41, 42]. Combining thepulmonary artery/aorta diameter ratio and other non-invasive measures (including echocardiographic andphysiological variables) improves the accuracy of predicting PH [36, 41].

Right heart catheterisation (RHC) remains the gold standard for the diagnosis of CLD-PH. However,suspicion for underlying PH does not always mandate performance of RHC in patients with establishedlung disease if there is no therapeutic or management consequence.

RecommendationsWhen to perform RHCRHC should be performed in patients with CLD when significant PH is suspected and the patient’smanagement will likely be influenced by RHC results, including referral for transplantation, inclusion inclinical trials or registries, treatment of unmasked left heart dysfunction, or compassionate use of therapy.

RHC may be considered when:

1) Clinical worsening, progressive exercise limitation and/or gas exchange abnormalities are not deemedattributable to ventilatory impairment.

2) An accurate prognostic assessment is deemed sufficiently important.

Pressure measurements during RHCAs a result of exaggerated changes in intrathoracic pressures during the breathing cycle in patients withlung disease, a floating average over several breaths (without a breath hold) is suggested for measurementof mean pressures, including the pulmonary capillary wedge pressure.

We suggest adapting the definition for PH in the context of CLD-PH:

1) CLD without PH (mPAP <21 mmHg, or mPAP 21–24 mmHg with pulmonary vascular resistance(PVR) <3 Wood Units (WU)).

2) CLD with PH (mPAP 21–24 mmHg with PVR ⩾3 WU, or mPAP 25–34 mmHg) (CLD-PH).3) CLD with severe PH (mPAP ⩾35 mmHg, or mPAP ⩾25 mmHg with low cardiac index

(<2.0 L·min−1·m−2)) (CLD-severe PH).

The rationale for the choice of mPAP ⩾35 mmHg as a cut-off for severe PH follows previously presentedevidence [1]. There are currently no valid data to support the routine use of acute vasodilator testing in CLD-PH.

The randomised controlled trials (RCTs) in group 1 for PAH therapies set exclusion criteria usingpulmonary function testing in the following ranges: total lung capacity <60–70% of predicted, FEV1 <55–80% of predicted or FEV1/forced vital capacity (FVC) ratio <50–70%. PAH studies have not previouslyutilised chest imaging to exclude patients with lung disease; indeed, it is possible that a number of patientswith lung volumes above these inclusion thresholds might have an underappreciated burden ofparenchymal lung disease. However, lung diseases (especially COPD) are common conditions and PAHdeveloping in such patients may not be attributable to these diseases, but may be coincidental. Criteria fordiscrimination between group 1 and group 3 PH are summarised in table 1. The spectrum of severity ofboth the pulmonary vascular and parenchymal lung disease is likely a continuum, which often makes thedistinction between group 1 and group 3 PH very difficult. When there is uncertainty whether to classify apatient with lung disease and PH into group 1 or group 3, then the patient should be referred to centreswith expertise in both PH and CLD.

Treatment of PH due in CLD: evidence for appropriate risk–benefit balance ofPAH-targeted therapyThe underlying lung disease should be optimally treated according to current guidelines. Long-termoxygen treatment (LTOT) makes intuitive sense in patients with lung disease who are hypoxaemic.

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However, it has only been prospectively evaluated in COPD. In stabilised hypoxaemic COPD patients,LTOT for 15 h per day prevented the progressive increase of mPAP and when used for >18 h per dayproduced a slight decrease of mPAP [43, 44]. However, in COPD patients with moderate resting oxygendesaturation (SpO2 89–93%) or exercise-induced oxygen desaturation (SpO2 <90% for ⩾10 s), LTOT doesnot provide benefit in terms of survival or hospitalisations [45]. Evidence for the beneficial effect of LTOTin ILD is less clear than in COPD and there are no studies addressing the impact of LTOT on PHassociated with this group of diseases [46].

Safety and efficacy of PAH-targeted therapy in CLD-PH has been evaluated in recent years; however, therehave only been a few RCTs in ILD, COPD and sarcoidosis. Pertinent studies which included more than 20participants are shown in table 2.

COPDEffect on pulmonary haemodynamicsLong-term use of PAH-targeted therapy improves pulmonary haemodynamics in COPD patients with PH,as shown in two different meta-analyses [47, 48]. Beneficial haemodynamic effects with long-term PAHtherapy, assessed by RHC, have been demonstrated with both sildenafil and bosentan [49, 50].

Effect on exercise tolerance, symptoms and quality of lifeThe effect of PAH-targeted therapy on exercise capacity in patients with COPD-PH is less apparent. Twometa-analyses failed to show significant improvement in 6-min walk distance (6MWD), whereas a thirdreported an improvement in 6MWD in COPD patients with demonstrated PH [47, 48, 51].

TABLE 1 Criteria favouring group 1 versus group 3 pulmonary hypertension (PH)#

Criteria favouring group 1(PAH)

Testing Criteria favouring group 3(PH due to lung disease)

Normal or mildly impaired:• FEV1 >60% pred (COPD)• FVC >70% pred (IPF)• Low diffusion capacity in relation

to obstructive/restrictive changes

Pulmonary function testing Moderate to very severely impaired:• FEV1 <60% pred (COPD)• FVC <70% pred (IPF)• Diffusion capacity “corresponds”

to obstructive/restrictive changes

Absence of or only modest airway or parenchymal abnormalities

High-resolution CT scan¶ Characteristic airway and/or parenchymal abnormalities

Extent of lung disease

Haemodynamic profile

Ancillary testing

Moderate-to-severe PH Right heart catheterisation Echocardiogram

Mild-to-moderate PH

Present Further PAH risk factors(e.g. HIV, connective tissue disease,

BMPR2 mutations, etc.)

Absent

Features of exhausted circulatory reserve:

• Preserved breathing reserve• Reduced oxygen pulse• Low CO/V’O2 slope• Mixed venous oxygen saturation at

lower limit• No change or decrease in PaCO2

during exercise

Cardiopulmonary exercise test+

(PaCO2 particularly relevant in COPD)

Predominant obstructive/restrictive profile

Features of exhausted ventilatory reserve:

• Reduced breathing reserve• Normal oxygen pulse• Normal CO/V’O2 slope• Mixed venous oxygen saturation

above lower limit• Increase in PaCO2 during exercise

Predominant haemodynamic profile

PAH: pulmonary arterial hypertension; FEV1: forced expiratory volume in 1 s; COPD: chronic obstructivepulmonary disease; FVC: forced vital capacity; IPF: idiopathic pulmonary fibrosis; CT: computedtomography; BMPR2: bone morphogenetic protein receptor type 2; CO: cardiac output; V′O2: oxygen uptake;PaCO2: arterial carbon dioxide tension. #: group 2 and 4 patients are excluded based on the diagnosticcriteria of these groups; ¶: parenchymal changes linked to pulmonary veno-occlusive disease may bediscriminated from those associated with diffuse parenchymal lung diseases; +: features of a limitedcirculatory reserve may be noted in severe COPD-PH and severe IPF-PH.

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TABLE 2 Randomised controlled trials (RCTs) with pulmonary arterial hypertension (PAH)-targeted therapy in lung disease

First author(year)[ref.]

Subjectsn

Inclusion criteria Study design Diagnosis of PH Baselinehaemodynamics#

Baseline PFTs# Therapy Duration Primaryend-point result

Other outcomes

COPDVONBANK

(2003)[86]

40 COPD onsupplemental oxygen

with PH by RHC

RCT (openlabel)

RHC: mPAP⩾25 mmHg

mPAP 27.6±4.4 mmHg,CI 2.7±0.6 L·min−1·m−2

FEV1 1.09±0.4 L,FEV1/FVC 44.5%

“Pulsed” nitricoxide with oxygen

vs oxygen

3 months PVRI, improved Improved mPAP, CO andPVR; no worsened

hypoxaemia

STOLZ

(2008)[53]

30 GOLD III–IV; nohaemodynamicrequirement

RCT (2:1) Echo sPAP 32 (29–38) mmHg Not reported Bosentan 125 mg2 times daily

12 weeks 6MWD, nochange

Worsened hypoxaemiaand health-related QoL

VALERIO(2009)[50]

32 COPD with PH byRHC

RCT (openlabel)

RHC mPAP 37±5 mmHg FEV1 37±18% Bosentan 125 mg2 times daily

18 months No definedprimary

mPAP, PVR, BODE indexand 6MWD improved

RAO

(2011)[87]

33 GOLD III–IV RCT Echo: sPAP>40 mmHg

sPAP 52.7±11.9 mmHg FEV1 32.5±11.1% Sildenafil 20 mg3 times daily

12 weeks 6MWD,increased 190 m

Decrease in sPAP

BLANCO

(2013)[88]

60 COPD with PH byRHC or echo

RCT RHC: mPAP⩾25 mmHg; echo:sPAP ⩾35 mmHg

sPAP 42±10 mmHg,mPAP 31±5 mmHg

FEV1 32±11% Sildenafil 20 mgor placebo 3

times daily andPR

3 months Exerciseendurance time,

no change

No change in 6MWD,peak V′O2, QoL or

oxygenation

GOUDIE

(2014)[89]

120 COPD with PH byecho

RCT Echo: pulmonaryacceleration time<120 ms or sPAP

>30 mmHg

Echo: sPAP 42±10 mmHg FEV1 41±16% Tadalafil 10 mgdaily

12 weeks 6MWD, nochange

Decreased sPAPcompared with placebo;no difference in QoL,

BNP or SaO2

VITULO(2016)[49]

28 COPD with PH byRHC

RCT (2:1) RHC: mPAP>35 mmHg (ifFEV1 <30%),

mPAP ⩾30 mmHg(if FEV1 ⩾30%)

mPAP 39±8 mmHg,CI 2.4±0.5 L·min−1·m−2,

PVR 7±2.6 WU

FEV1 54±22%,DLCO 33±12%

Sildenafil 20 mg3 times daily

16 weeks PVR, decreased1.4 WU

Improved CI, BODEscores and QoL; no

effect on gas exchange

ILDHAN

(2013)[90]

119 IPF with echoavailable (66% of the

whole cohort)

RCT Echo: RVSD Not available FVC 57%,DLCO 26%

Sildenafil 20 mg3 times daily

12 weeks 6MWD, lessdecline in

patients withRVSD onsildenafil

Improvement in QoL inpatients with RVSD

CORTE

(2014)[60]

60 IPF or idiopathicfibrotic NSIP

RCT (2:1) RHC: mPAP⩾25 mmHg

mPAP 37±9.9 mmHg,CI 2.2±0.5 L·min−1·m−2

FVC 55.7±20%,KCO 45±22%

Bosentan 16 weeks PVRI decrease of20%, negative

Secondary end-points allnegative; no change infunctional capacity or

symptoms

RAGHU

(2015)[14]¶

68 IPF with group 2 PH(14% of whole

cohort)

RCT (2:1) RHC mPAP 30±8 mmHg FVC 67±12%,DLCO 39±15%

Ambrisentan10 mg·day−1

Event-drivenstudy

terminatedearly

Diseaseprogression,unfavourable

trend

More hospitalisedambrisentan arm

NATHAN

(2017)[57]

147 IIP, FVC >45%, mPAP>25 mmHg

RCT RHC mPAP 33.2±8.2 mmHg,CI 2.6±0.7 L·min−1·m−2

FVC 76.3±19%,DLCO 32±12%

Riociguat 2.5 mg3 times daily

26 weeks 6MWD, nodifference atstudy halt

Study stopped early forincreased harm to

riociguat arm (death andhospitalisation)

Continued

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TABLE 2 Continued

First author(year)[ref.]

Subjectsn

Inclusion criteria Study design Diagnosis of PH Baselinehaemodynamics#

Baseline PFTs# Therapy Duration Primaryend-point result

Other outcomes

SarcoidosisBARNETT

(2009)[65]

22 Any SAPH andtreatment with PAH

therapy

Retrospectivecase series

RHC mPAP 46.1±2.7 mmHg,CO 4.2±0.4 L·min−1

FVC 53.6±3.3%,FEV1 51.2±3.7%

Bosentan,sildenafil

Median (range)11 (5.2–46.6)

months

6MWD improvedby 59 m

NYHA FC improvementin nine patients

BAUGHMAN

(2009)[66]

22 Any SAPH Prospectiveopen label

RHC mPAP 33 (20–62) mmHg,CO 5.9 (3.1–9.5) L·min−1,PVR 5.1 (1.96–16.3) WU

FVC 50% (41–101%),FEV1/FVC 73%

(53–91%)

Inhaled iloprost 4 months 6MWDunchanged0.6±40 m

7 patients withdrew; 6patients with ⩾20%

decrease in PVR and 3patients with ⩾30 mincrease in 6MWD

JUDSON(2011)[91]

25 mPAP >25 mmHg,PVR >3 WU, FVC

>40%, WHO FC II orIII, 6MWD 150–450 m

Prospectiveopen label

RHC mPAP 32.7±7 mmHg,CO 4.45±0.94 L·min−1·m−2,

PVR 5.86±2.3 WU

FEV1 59±21%,FVC 61.5±16.5%

Ambrisentan10 mg daily

24 weeks No change in6MWD 9.8±55 m

11 patients discontinueddrug at 12 weeks; 10 out

of 21 patients whocompleted had

improvements in WHOFC and QoL

BAUGHMAN

(2014)[67]

39 mPAP ⩾25 mmHg,NYHA FC II or III

RCT (2:1) RHC mPAP 36±7 mmHg,CI 2.6±0.7 L·min−1·m−2

FVC 60±16.6% Bosentan 16 weeks Decrease inmPAP (to32 mmHg)

No change in 6MWD;PVR decreased from 6.1

to 4.4 WU

KEIR

(2014)[92]

33 Any SAPH Retrospectivecase series

RHC mPAP 44±8.6 mmHg,PVR 10±5.1 WU,

CI 2.1±0.6 L·min−1·m−2,TAPSE 17.5 (8–27) mm

FEV1 51.8±18.3%,FVC 64.8±22.3%

Sildenafil n=29,bosentan n=4

6 months None identified 6MWD improved 14 m;BNP and TAPSE

improved

BONHAM

(2015)[93]

26 Any treated SAPH, noleft-sided disease

Retrospectivecase series

RHC mPAP 46 (38–56) mmHg,CI 2.1 (1.8–2.6)L·min−1·m−2,

PVR 8.3 (5.7–11.1) WU

FEV1 48% (38–59%),FVC 48% (44–64%),DLCO 29% (25–44%)

Epoprostenoln=7, treprostiniln=6, ERA n=12,PDE5i n=20

Variable None identified Increased CI/CO,decreased PVR (median

12.7 months in 10prostacyclin patients)

and improvedN-terminal pro-BNP

PH: pulmonary hypertension; PFT: pulmonary function test; COPD: chronic obstructive pulmonary disease; RHC: right heart catheterisation; mPAP: mean pulmonary arterial pressure;CI: cardiac index; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; PVR(I): pulmonary vascular resistance (index); CO: cardiac output; GOLD: Global Initiative for ChronicObstructive Lung Disease; sPAP: systolic PAP; 6MWD: 6-min walk distance; QoL: quality of life; BODE: body mass, airflow obstruction, dyspnoea, exercise capacity; echo:echocardiography; PR: pulmonary rehabilitation; V′O2: oxygen uptake; BNP: brain natriuretic peptide; SaO2: arterial oxygen saturation; WU: Wood Units; DLCO: diffusing capacity of the lungfor carbon monoxide; ILD: interstitial lung disease; IPF: idiopathic pulmonary fibrosis; RVSD: right ventricular systolic dysfunction; NSIP: non-specific interstitial pneumonia; KCO: transfercoefficient of the lung for carbon monoxide; IIP: idiopathic interstitial pneumonia; SAPH: sarcoidosis-associated PH; NYHA: New York Heart Association; FC: Functional Class; WHO:World Health Organization; TAPSE: tricuspid annular plane systolic excursion; ERA: endothelin receptor antagonist; PDE5i: phosphodiesterase type 5 inhibitor. #: for RCTs, the data forthe treatment arm are reported as mean±SD or median (interquartile range); ¶: subgroup analysis of the ARTEMIS-IPF trial (study performed to evaluate the antifibrotic effects of thestudy medication, not all patients had PH).

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The effect of PAH-targeted therapy on dyspnoea or quality of life measures in COPD-PH is also generallydisappointing when evaluated in RCTs [47, 48]. However, one recent study conducted in COPD patientswith severe PH showed that sildenafil significantly improved the BODE (body mass, airflow obstruction,dyspnoea, exercise capacity) index, the modified Medical Research Council scale and the Short Form-36general health domain [49]. Taken together, the available studies do not provide clear evidence that theeffect of PAH-targeted therapy on pulmonary haemodynamics in COPD-PH translates into animprovement in exercise tolerance and symptoms.

Effect on oxygenationVasodilator treatment may worsen gas exchange due to the inhibition of hypoxic pulmonaryvasoconstriction, thereby increasing ventilation/perfusion mismatching in COPD [52]. Evidence for along-term benefit of PH therapy in COPD-PH is heterogeneous [47]. While deterioration of gas exchangewas shown in some studies with the long-term use of bosentan or sildenafil, no change was observed inothers using sildenafil or tadalafil [49, 53, 54] and rarely resulted in treatment withdrawal [55]. It isimportant to note that any reduction in oxygenation related to pulmonary vasodilation might becompensated for by an increased cardiac output that may maintain or even improve tissue oxygen delivery,especially with exercise.

ConclusionAlthough preliminary evidence suggests that currently available vasoactive medications may have a benefitin COPD-PH patients with mPAP ⩾35 mmHg, further studies are required before PAH therapies can berecommended. Therefore, these patients should be a target population for larger prospective studies. Thisdoes not preclude COPD patients with lower mPAP being enrolled in future studies, especially if thecardiac index is low or PVR is significantly elevated.

Idiopathic interstitial pneumoniasSafetyTreatment with PAH-targeted therapies in patients with IIP has yielded important safety signals in someRCTs. The ARTEMIS study was terminated prematurely because an interim analysis indicated thatambrisentan-treated patients with IPF were more likely to have disease progression, particularlyhospitalisations due to respiratory events [56]. Thus, ambrisentan is contraindicated in patients with IPF.

The RISE-IIP trial evaluated the effect of riociguat on 6MWD in patients with IIP. The study wasterminated early on the basis of interim results showing increased mortality and risk of serious adverseevents in the riociguat group [57]. Accordingly, riociguat is contraindicated in patients with IIP-PH.

Effect on pulmonary haemodynamicsUncontrolled studies have shown improvement in pulmonary haemodynamics in patients with IIP-PHusing riociguat and treprostinil [58, 59]. However, RCTs have failed to substantiate such an improvementin this population. The BPHIT study did not show significant changes in pulmonary haemodynamics inpatients with IIP-PH treated with bosentan during 16 weeks [60]. The ARTEMIS-IPF trial also failed toshow any significant effect of ambrisentan on pulmonary haemodynamics in the subgroup of patients whounderwent a second assessment with RHC [14].

Effect on exercise toleranceA recent meta-analysis did not show improvement in 6MWD in patients with ILD-PH treated withPAH-targeted therapy [48]. The STEP-IPF study, which was enriched for underlying IPF-PH by theinclusion of patients with DLCO <35% of predicted, failed to meet its primary end-point of a 20% increasein the 6MWT distance [61]. In contrast, open-label studies with sildenafil, riociguat and treprostinil didshow significant improvements in 6MWD, with an average increase of 46 m over baseline [48]. The largestobservational study to date of severe IIP-PH patients (n=151) found that the improvement in 6MWD at6 months in response to PAH therapy was equivalent to that seen in IPAH patients [23].

Effect on symptoms and quality of lifeThe effect of PAH-targeted therapy on symptomatic burden in patients with PH-ILD has been assessed intwo RCTs and three open-label studies [48]. The STEP-IPF study also demonstrated a positive effect ofsildenafil on quality of life compared with the placebo arm, while one study showed significantimprovement in shortness of breath using treprostinil [59, 61]. The remaining studies failed to showsignificant change in quality of life questionnaires or dyspnoea scales [48].

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Effect on oxygenationIn ILD, the acute administration of aerosolised iloprost, inhaled nitric oxide or sildenafil does not worsenventilation/perfusion relationships. In contrast, acute administration of i.v. epoprostenol causesdeterioration of gas exchange due to increased perfusion in non-ventilated alveolar units [62–64]. Inlonger-term studies, treatment with PAH-targeted therapy did not result in worsening of gas exchange inpatients with ILD [48].

ConclusionRiociguat and ambrisentan are both contraindicated in IIP-PH. There is no evidence of benefit for otherendothelin receptor antagonists in IIP-PH. Data on the use of sildenafil in IIP-PH is conflicting, whileevidence for prostanoid therapy is too limited for any current recommendations. Further RCTs areencouraged.

Combined pulmonary fibrosis and emphysemaTreatment options remain limited with currently little evidence to support PAH therapies in this disease.

SarcoidosisThere is still a lack of data on the safety and efficacy of drugs approved for PAH in sarcoidosis-PHpatients. Case series have suggested beneficial effects of various compounds (table 2) [28, 65, 66].However, only a single RCT has been performed in this group of patients and the results wereinconclusive [67]. At present, no PAH-targeted therapy can routinely be recommended for patients withsarcoidosis-PH.

Other CLDsClinical experience and case series suggest beneficial effects of drugs approved for PAH in some patientswith pulmonary Langerhans cell histiocytosis and lymphangioleiomyomatosis, but the lack of robust dataprecludes firm recommendations for any of these other conditions [31, 68].

Retrospective survival analysis in group 3 PHThe impact of PAH-targeted therapy on survival in group 3 PH has been assessed in retrospective studies,which included patients with different CLDs and usually with severe PH. One study found a survivalbenefit in severe PH-COPD patients with a favourable haemodynamic and functional response after3 months of therapy, while two studies showed longer survival in patients treated with PAH-targetedtherapy (mostly phosphodiesterase type 5 inhibitors) compared with patients who did not receivePAH-targeted treatment [69–71]. In one of these studies, the survival benefit was apparent in patients withsevere PH, but not mild-to-moderate PH [70]. These studies need to be interpreted with caution given thenature of their study design with no RCTs as yet attesting to a survival benefit.

Recommendations for treatment of different patient groups with CLD and PHFurther long-term RCTs focusing on, but not limited to, patients with CLD-severe PH and COPD or ILDsare needed. Due to the major differences in underlying pathophysiology, obstructive and restrictive lungdiseases should be investigated separately. Combining different groups with lung fibrosis is one potentialclinical trial approach, with the advantage of increased patient numbers and abrogation of the diagnosticdilemma that often accompanies fibrotic lung disorders. This might be disadvantageous in view of thediffering aetiologies, but there are precedents for this approach in PAH where IPAH has typically beencombined with other group 1 subgroups in RCTs. This problem may be addressed by detailedphenotyping of the patients and predefined subgroups to be analysed separately in addition to the overallanalysis. Based on physiological testing (lung function, haemodynamics and exercise) as well as CTmorphology, the following groups of PH patients may be distinguished with respect to classification andmanagement recommendations (summarised in table 1 and figure 1):

1) Patients with mild obstructive or restrictive lung disease, in whom CT analysis shows no gross parenchymalor airway abnormalities and who present with clinically relevant PH. Whether such patients have PAH(group 1) with concomitant lung disease or PH due to lung disease (group 3) remains a diagnosticdilemma (see earlier). Therefore, these patients should be referred to an expert centre.

2) Patients with more severe obstructive and/or restrictive lung disease (IPF with FVC <70% of predicted,COPD with FEV1 <60% of predicted) and accompanying less severe PH (mPAP 20–24 mmHg withPVR ⩾3 WU, or mPAP 25–34 mmHg). These groups represent the majority of patients presentingwith CLD-PH. Current data do not support therapy with PAH-approved drugs in these patients.Moreover, as the limitation in exercise capacity in these patients is largely due to ventilatory and notcirculatory impairment, any functional benefit from PAH treatment is questionable. Vascular changes

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may, however, contribute to disease progression and future studies addressing this aspect of thedisease may be a worthy endeavour.

3) Patients with more severe obstructive and/or restrictive lung disease and severe PH as defined earlier(mPAP ⩾35 mmHg; severe COPD-PH, severe ILD-PH, severe CPFE-PH). These patients have a poorprognosis and should be referred to a centre with expertise in both PH and CLD for individualisedpatient care. These patients should preferably be included in RCTs if available.

4) Patients with “end-stage” obstructive and/or restrictive lung diseases and associated PH. In theseadvanced cases, life-preserving measures, such as mechanical ventilatory or extracorporeal membraneoxygenation support, should only be considered as a bridge to transplantation. Patients in any ofthese groups may be candidates for lung transplantation, an option that should be part of themanagement algorithm if all else fails and they are otherwise appropriate candidates. RCTs shouldaddress whether PAH-approved drugs may improve functional ability, quality of life, prolong time toclinical worsening, improve survival or provide a bridge to transplantation. In the absence of suchtrials, decisions on individualised patient care should be made in the context of expert centres.

Specific aspects of PH in systemic sclerosisPH in patients with systemic sclerosis (SSc) can be multifactorial. These patients are at high risk ofdeveloping isolated PAH, but they may also develop significant parenchymal lung disease and/or acomponent of left heart disease. There is often difficulty in discriminating group 1 PAH from group 3 PHin SSc patients, since quite commonly these patients have evidence of parenchymal lung disease onhigh-resolution CT, which may or may not be accompanied by restrictive physiology. SSc patients withcombined pulmonary fibrosis and PH have a particularly high mortality risk [72]. Both PH severity andthe extent of pulmonary fibrosis can vary widely. Patients with pre-capillary PH and mild fibrosis areusually classified as having PAH, and have been included in most of the RCTs of PAH medications.However, assessment of the degree of fibrosis was usually based on pulmonary function testing and notscrutiny of the extent of fibrosis on high-resolution CT. Patients with preserved lung volumes can be safelytreated with PAH drugs, but there is no evidence for treatment of PH-SSc with more advanced ILD.

RecommendationsWhile there are clearly SSc patients who are “pure” group 1, there are others who are group 2 or 3. Thereis likely a significant grey zone of these patients with features of more than one group. To best evaluate theextent of lung disease in relation to the patient’s haemodynamic profile requires lung imaging rather thanreliance on pulmonary function test criteria only. In the absence of RCTs, SSc patients with PH and morethan minimal fibrosis on high-resolution CT should be referred to expert centres for individualisedtreatment.

Hypoventilation and hypoxia-associated PHChronic PH in obstructive sleep apnoea is rare and most commonly mild. In marked contrast, asignificant proportion of patients with obesity–hypoventilation syndrome (OHS) or overlap syndrome(combination of obstructive sleep apnoea and COPD) present with PH [73, 74]. This represents animportant group of patients given that current estimates suggest that around 0.4% of the US populationsuffers from OHS, reaching up to 31% among hospitalised patients with a body mass index >35 kg·m−2

[75]. Although variable, PH is frequently severe in these patients, being commonly associated with rightventricular failure and poor outcomes [76]. In addition to the improvements in gas exchange andsleepiness, one RCT and two series documented near normalisation of pulmonary haemodynamics, rightventricular function and exercise capacity after 3–6 months of non-invasive ventilation [73, 74, 76]. Similarfindings were reported in a series of patients with PH associated with restrictive thoracic diseases treatedwith non-invasive ventilation [77].

RecommendationsThe mainstay treatment of OHS is non-invasive ventilation, which does not, however, always correctthe PH.

PH at high altitudeHigh altitude is defined as an elevation of >2500 m above sea level. 140 million people permanently resideat high altitudes and >40 million visitors reach high-altitude levels yearly [78]. Data on prevalence ofhigh-altitude PH, defined as mPAP ⩾30 mmHg by the International Society for Mountain Medicine [79],are rare and figures range from 5% to 23%, dependent on the geographic region and sex. Thus,hypoxia-induced PH is a major health problem at high-altitude regions of the world [78, 79]. Low ambientoxygen induces hypoxic pulmonary vasoconstriction, which increases PVR. In addition, pulmonary

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arterial remodelling occurs during long-term hypoxia. Both hypoxic pulmonary vasoconstriction andvascular remodelling act in concert with erythrocytosis, leading to PH at high altitude [80]. Importantly,high-altitude PH is reversible upon re-exposure to normal inspired oxygen tension (PIO2). Acute treatmentstudies with sildenafil and the ROCK (RhoA/Rho kinase) inhibitor fasudil reduced PAP and/or increasedexercise capacity [81–83]. Only sildenafil and captopril have been investigated in long-term studies over aperiod of 3 months, with lowered PAP levels being noted [84, 85].

RecommendationsRe-exposure to normal PIO2 is the primary treatment of high-altitude PH. Long-term treatment studieswith vasodilators are largely missing.

General conclusionsThe association between PH and CLD with impaired functional status and worse outcomes is wellestablished. Whether PH is the driver of outcomes or a surrogate for the severity of the underlying CLDremains uncertain. However, given the worldwide prevalence of CLD, and the associated morbidity and

TABLE 3 Recommendations and questions for the future direction of research in chronic lung disease (CLD)-associatedpulmonary hypertension (PH)

Development of better animal models of PH in both COPD and ILD encouraged– Differential molecular mechanisms (parenchymal versus vascular)– Identification of novel molecular targets

Novel techniques employing ex vivo cultured human lung tissue to identify the key cellular and molecular drivers of pathological lung andvascular remodelling and for individualised drug testing– (Co-)cultured human pulmonary vascular cells, viable human lung slices, ex vivo grown or iPSC-derived human lung organoids

Research into biomarkers for group 3 PH encouraged– Classical circulating peptides, circulating RNA subsets, monocyte/leukocyteomics, volatile exhaled compounds, exhaled “genomic

fingerprint”– Shared access to existing biobanks/biosamples from disparate registries, trials including industry-sponsored studies, regulatory agency

involvement– Patients enrolled into future clinical trials should be consented to enable sharing of their biospecimens

Clinical variables for enrolment in group 3 clinical trials require more sophisticated “deep phenotyping”– Image phenotyping of parenchymal and vascular changes, novel imaging techniques including CT “vascular morphometry”, SPECT/CT,

PET “metabolomics”, four-dimensional MRI, artificial intelligence machine learning (“radiomics”)– Nature, extent and spatial distribution of the parenchymal and vascular abnormalities

Optimal patient phenotype for trials of therapy– Best haemodynamic variable(s) and threshold to define the patient phenotype; evaluation of right ventricular dysfunction for enrolment;

extent of permissible parenchymal lung disease?– Combination of pulmonary function testing, haemodynamic profile and imaging required

Clinical trial end-points in PH with underlying lung disease– Phase 2 studies: physiological variables (e.g. right ventricular function, haemodynamics, 6MWT) and biomarkers (e.g. BNP) acceptable– Phase 3 studies: comprehensive patient centric clinical outcomes preferable: composite end-point, time to clinically meaningful change

(clinical worsening and/or improvement)– Clinical worsening events may include: mortality, hospitalisation (cardiopulmonary), categorical changes in a functional test (e.g. 6MWT),

QoL measures, NYHA Functional Class change, need for supplemental oxygen, disease exacerbation, lung transplantation6MWT: improve its group 3 informative value (“integrate” distance, deoxygenation, Borg dyspnoea score, heart rate recovery?)Encourage cardiopulmonary exercise testing for more elaborate distinction between respiratory versus circulatory limitation (problem:

supplemental oxygen dependency)Haemodynamic assessment while exercising is encouraged and is to be standardisedInclusion spectrum in group 3 in view of different aetiology, molecular pathology and clinical course: “narrow versus broad”?IIP can be studied together with chronic hypersensitivity pneumonitis and occupational lung diseaseSarcoidosis-PH sufficiently different and should be studied independentlyCOPD-PH should be studied independentlyCPFE-PH included in ILD-PH studies; permissible provided the extent of their emphysema is not too great; or risk for confounding signal?Studies employing inhaled PH therapies are an attractive option as this may enable better ventilation/perfusion matching and limit systemic

side-effectsFuture studies should focus on the prevention/inhibition/reversal of vascular remodelling in addition to vasodilation CLD-PHFuture studies should also target role of the vascular compartment in driving parenchymal abnormalities (“vascular therapy beyond PH”)Further studies of the role of pulmonary rehabilitation (exercise training) in lung disease complicated by PH are encouraged

COPD: chronic obstructive pulmonary disease; ILD: interstitial lung disease; iPSC: induced pluripotent stem cell; CT: computed tomography;SPECT: single photon emission CT; MRI: magnetic resonance imaging; 6MWT: 6-min walk test; BNP: brain natriuretic peptide; NYHA:New York Heart Association; QoL: quality of life; IIP: idiopathic interstitial pneumonia; CPFE: combined pulmonary fibrosis and emphysema.

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mortality of CLD-PH, this area is one of great unmet medical need where future research should bestrongly encouraged and supported (table 3).

Conflict of interest: S.D. Nathan is a consultant for and has received research funding from Bellerophon, UnitedTherapeutics and Bayer Pharmaceuticals; is a consultant for Third Pole and Actelion, and is a consultant for, hasreceived research funding from and is on the speakers’ bureau of Roche-Genentech and Boehringer Ingelheim. J.A.Barbera reports grants and personal fees from Actelion and MSD, personal fees from Arena, and grants from Bayer andGSK, outside the submitted work. S.P. Gaine reports personal fees from Actelion, United Therapeutics, MSD and GSK,outside the submitted work. S. Harari has received grants for research and speakers fees from Actelion, BoehringerIngelheim and Roche. F.J. Martinez has received grants from the NIH (IPF UO1, COPD UO1/RO1); personal fees,honoraria and non-personal travel support from the American College of Chest Physicians, Continuing Education,ConCert, Inova Fairfax Health System, MD Magazine, Miller Communications, National Association for ContinuingEducation, Novartis, Pearl Pharmaceuticals, PeerView Communications, Prime Communications, Puerto RicanRespiratory Society, Roche, Sunovion, Theravance, Potomac, University of Alabama Birmingham and Zambon; personalfees and non-personal or non-financial travel support from AstraZeneca; personal fees, non-personal travel support, andnon-financial support for data and safety monitoring board work from Boehringer Ingelheim; personal fees, honoraria,non-personal travel support, and non-financial support for data and safety monitoring board work from Genentech andGlaxoSmithKline; personal fees and honoraria from Columbia University, Integritas, Methodist Hospital Brooklyn,New York University, Unity, UpToDate, WebMD/MedScape, Western Connecticut Health Network, Academic CME,Patara, PlatformIQ, American Thoracic Society, Rockpointe and Rare Disease Healthcare Communications;non-personal travel support from Nitto; personal fees, honoraria, travel support and non-personal travel support fromChiesi; personal fees, honoraria and travel support from Physicians Education Resource and Teva; honoraria and travelsupport from Canadian Respiratory Network; personal fees from France Foundation; and has participated on scientificadvisory boards (no direct financial compensation) for ProterrixBio and Bridge Biotherapeutics; participated on IPFstudy steering committees (no direct financial compensation) for Afferent/Merck, Gilead, Veracyte, Prometic, Bayer andProMedior; and participated on an IPF study steering committee and data safety monitoring board (no direct financialcompensation) for Biogen. H. Olschewski reports personal fees and non-financial support from Bayer, MSD, Pfizer andNovartis, grants, personal fees and non-financial support from Actelion, grants from Inventiva, and personal fees fromBellerophon, outside the submitted work; and is part-time employee of the Ludwig Boltzmann Institute for LungVascular Research. K.M. Olsson received fees for talks and consulting work from Actelion, Bayer, GSK, Pfizer andUnited Therapeutics. A.J. Peacock has received research grants and personal fees from Actelion Pharmaceuticals, Bayer,GSK, MSD, Pfizer and United Therapeutics, outside the submitted work. J. Pepke-Zaba is a member of the advisoryboards for Actelion, Merck, Bayer and GSK, has received grants, personal fees and non-financial support from Actelion,Merck and Bayer, and personal fees from GSK. S. Provencher has received research grants from ActelionPharmaceuticals and Boehringer Ingelheim, and has received speaker fees from Actelion Pharmaceuticals.N. Weissmann has nothing to disclose. W. Seeger has received consultancy fees from Bayer AG, United Therapeutics,Liquidia, Vectura and Novartis.

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Chronic thromboembolic pulmonaryhypertension

Nick H. Kim1, Marion Delcroix 2, Xavier Jais3, Michael M. Madani4,Hiromi Matsubara5, Eckhard Mayer6, Takeshi Ogo7, Victor F. Tapson8,Hossein-Ardeschir Ghofrani 6,9,10,12 and David P. Jenkins11,12

Number 11 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1Dept of Medicine, University of California San Diego, La Jolla, CA, USA. 2Dept of RespiratoryDiseases, University Hospitals of Leuven and Respiratory Division, Dept CHROMETA, KU Leuven – University ofLeuven, Leuven, Belgium. 3Université Paris-Sud, AP-HP, Centre de Référence de l’Hypertension Pulmonaire,Service de Pneumologie, Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), HôpitalBicêtre, Le Kremlin-Bicêtre, France. 4Cardiovascular and Thoracic Surgery, University of California San Diego,La Jolla, CA, USA. 5National Hospital Organization Okayama Medical Center, Okayama, Japan. 6KerckhoffClinic Bad Nauheim, University of Giessen, Bad Nauheim, Germany. 7Division of Advanced Medical Researchin Pulmonary Hypertension, Dept of Pulmonary Circulation, National Cerebral and Cardiovascular Center,Osaka, Japan. 8Dept of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 9University of Giessenand Marburg Lung Centre (UGMLC), Justus-Liebig University Giessen and Member of the German Center forLung Research (DZL), Giessen, Germany. 10Dept of Medicine, Imperial College London, London, UK. 11RoyalPapworth Hospital, Cambridge, UK. 12These two authors contributed equally to this work.

Correspondence: Nick H. Kim, Dept of Medicine, University of California San Diego, 9300 Campus Point Drive,MC 7381, La Jolla, CA 92037, USA. E-mail: h33kim@ucsd.edu

@ERSpublicationsState of the art and research perspectives in chronic thromboembolic pulmonary hypertension,including treatment algorithm http://ow.ly/C3Iy30mfUly

Cite this article as: Kim NH, Delcroix M, Jais X, et al. Chronic thromboembolic pulmonary hypertension.Eur Respir J 2019; 53: 1801915 [https://doi.org/10.1183/13993003.01915-2018].

ABSTRACT Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication ofpulmonary embolism and a major cause of chronic PH leading to right heart failure and death. Lungventilation/perfusion scintigraphy is the screening test of choice; a normal scan rules out CTEPH. In thecase of an abnormal perfusion scan, a high-quality pulmonary angiogram is necessary to confirm anddefine the pulmonary vascular involvement and prior to making a treatment decision. PH is confirmedwith right heart catheterisation, which is also necessary for treatment determination. In addition tochronic anticoagulation therapy, each patient with CTEPH should receive treatment assessment startingwith evaluation for pulmonary endarterectomy, which is the guideline recommended treatment. Fortechnically inoperable cases, PH-targeted medical therapy is recommended (currently riociguat based onthe CHEST studies), and balloon pulmonary angioplasty should be considered at a centre experienced withthis challenging but potentially effective and complementary intervention.

Received: Oct 06 2018 | Accepted: Oct 09 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

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| SERIESWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

IntroductionSince the 5th World Symposium on Pulmonary Hypertension (WSPH) in 2013, major progress has occurredin the understanding and management of chronic thromboembolic pulmonary hypertension (CTEPH). First,the link between CTEPH and acute pulmonary embolism, and some of the challenges associated withmaking the connection, will be reviewed. Key diagnostic steps in establishing early and accurate diagnosiswill be emphasised. Each component of the current CTEPH treatment approach will be overviewed.Finally, an updated treatment algorithm is proposed taking into account the advances since 2013.

CTEPH and pulmonary embolismCTEPH is classified within group 4 PH [1], and is characterised pathologically by organisedthromboembolic material and by altered vascular remodelling initiated or potentiated by a combination ofdefective angiogenesis, impaired fibrinolysis and endothelial dysfunction [2–4]. These changes lead to PHand ultimately right ventricular failure [5, 6]. The precise pathogenesis of CTEPH remains unclear, butappears to be incited by acute pulmonary embolism [7].

However, classic risk factors for venous thromboembolism do not appear to increase the risk of CTEPH[8] and there are clear geographic differences in CTEPH epidemiology. An international CTEPH registry(Europe and Canada) indicated that 75% of patients with CTEPH had a documented antecedent history ofacute pulmonary embolism [9], while in Japan, the rates of acute pulmonary embolism preceding CTEPHrange from only 15% to 33% [10, 11]. There is an 80% female preponderance of CTEPH in Japan; thesestatistics differ significantly from the USA and Europe [9]. A number of abnormal autoimmune,inflammatory and thrombophilia markers have been found in CTEPH patients [2]; it is feasible thatvariability in this underlying pathological milieu contributes to the variability in the worldwide CTEPHepidemiology. Furthermore, variable gene expression has been demonstrated in pulmonary arteryendothelial cells from patients with CTEPH compared with normal controls [12].

In published prospective studies with the diagnosis confirmed by right heart catheterisation (RHC) theincidence of CTEPH after symptomatic acute pulmonary embolism is reported to range from 0.4% to 6.2%[13–25], giving a pooled incidence of 3.4% (95% CI 2.1−4.4%) [7]. Since that analysis, a new report fromSwitzerland screened 508 patients after acute pulmonary embolism over 2 years and found a cumulativeincidence of CTEPH confirmed with RHC of just 0.79% [26].

Determining the precise CTEPH incidence is complex. CTEPH is likely both underdiagnosed and theincidence of CTEPH after acute pulmonary embolism prone to overestimation, making the actualincidence difficult to quantify. Non-specific symptoms, variable rates of antecedent acute pulmonaryembolism and the expertise required to read computed tomography pulmonary angiography (CTPA)contribute to underdiagnosis [27, 28]. Underdiagnosis is further compounded by the infrequent use oflung ventilation/perfusion scintigraphy (V/Q scan) despite guideline recommendations [29, 30].Approximately 30000 acute pulmonary embolism cases are diagnosed annually in France, with theCTEPH incidence estimated at 3.4% [31]. GUÉRIN et al. [22] suggested a CTEPH incidence of 4.8%.Neither of these estimates is consistent with the current frequency of newly diagnosed CTEPH. Alimitation of the numerous CTEPH incidence reports after acute pulmonary embolism may be attributedto an unrecognised amalgam of incident and prevalent cases [22].

In terms of reducing the risk of CTEPH following acute pulmonary embolism, no prospective randomisedacute pulmonary embolism trials have examined systemic or catheter-based thrombolysis or clot extractionwith RHC as an outcome measure in patients with persistent symptoms. Claims have been made that theincidence of CTEPH in patients receiving thrombolytic therapy is reduced, but end-points such as anechocardiogram-derived systolic pulmonary arterial pressure (sPAP) of 40 mmHg do not define PH orCTEPH [32]. Systemic thrombolysis failed to reduce the risk of CTEPH in intermediate/high-risk(submassive) pulmonary embolism patients in the 3-year follow-up of the PEITHO trial (average sPAP atfollow-up was around 31 mmHg in each group) [33]. To date, there is no proof that aggressive treatmentof acute pulmonary embolism can prevent CTEPH.

Chronic thromboembolic diseaseChronic thromboembolic disease (CTED) is characterised by similar symptoms and perfusion defects, butwithout PH at rest. Currently a new threshold for PH (mean PAP (mPAP) >20 mmHg) and pre-capillaryPH (combination of mPAP >20 mmHg, pulmonary arterial wedge pressure ⩽15 mmHg and pulmonaryvascular resistance (PVR) ⩾3 Wood Units) has been proposed by the 6th WSPH Task Force on PHdiagnosis and classification [1]. While there is good evidence to suggest these new thresholds, theconsequences for CTEPH and CTED, respectively, are not yet established. In the future, however, these newthresholds might also be applied to group 4 PH. Exercise limitation in CTED has been attributed either toexercise-induced PH, with an increased slope of the pulmonary arterial pressure–flow relationship, or to

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dead-space ventilation, with increased ventilatory equivalents for carbon dioxide [34, 35]. Both new andworsened dyspnoea and persistent perfusion defects are often encountered after acute pulmonary embolism,in, respectively, 30% and 30–50% of patients, which makes the recognition of CTED challenging [18, 36, 37].Cardiopulmonary exercise tests and echocardiographic evaluations are recommended to exclude patients inwhom symptoms are related to lung disease, left heart disease, obesity or deconditioning. A tentative,comprehensive definition of CTED is proposed in table 1. Selected patients with CTED may benefit frompulmonary endarterectomy (PEA) as shown in a series of 42 patients out of 1019 who underwent surgery inthe UK reference centre [38]. Post-operative improvement in symptoms, functional class and quality of lifewere reported. However, while there was no in-hospital mortality, major complications occurred in 40% ofthe cohort (small subdural haematomas, tracheostomy). Although endarterectomy is aimed to preventsubsequent disease, the natural history of CTED is unknown and there is no evidence that CTED evolves toCTEPH. At present, patients with CTED represent a group in need of both symptom relief and betterunderstanding of their disorder. CTEPH treatment guidelines should not be applied to CTED.

Diagnosis of CTEPHA normal V/Q scan effectively excludes CTEPH with a sensitivity of 90–100% and a specificity of 94–100% [39, 40]. In a study of confirmed cases of CTEPH, V/Q scan was found to be superior to CTPA witha sensitivity of 97.4% versus 51% [39]. This difference has narrowed as CT technology and interpretationhave advanced. Indeed, a more recent study has shown that both V/Q scan and CTPA are accuratemethods for the detection of CTEPH with excellent diagnostic efficacy (100% sensitivity, 93.7% specificityand 96.5% accuracy for V/Q scan; 96.1% sensitivity, 95.2% specificity and 95.6% accuracy for CTPA) [40].However encouraging, V/Q scan remains the preferred initial imaging test for CTEPH screening [5, 29].Recent retrospective studies have also assessed the diagnostic accuracy of three-dimensional dynamiccontrast-enhanced lung perfusion magnetic resonance imaging (MRI) against planar V/Q scan or SPECT(single photon emission CT) scan as a screening tool for CTEPH [41, 42]. These studies demonstratedthat dynamic contrast-enhanced lung perfusion MRI has a similar sensitivity (97%) for diagnosingCTEPH when compared with planar V/Q scan and a higher sensitivity (100% versus 97%) when comparedwith SPECT scan. Prospective studies examining the value of lung perfusion MRI and SPECT scan as ascreening test for CTEPH are required to address the clinical utility (including their costs) and diagnosticperformance of these modalities.

Digital subtraction angiography (DSA) had been considered the gold standard for characterising vesselmorphology in CTEPH, but is being challenged by advances in non-invasive modalities. CTPA is currentlywidely used for assessment of operability. CTPA in more recent reports has a high sensitivity andspecificity in detecting chronic thromboembolic lesions at the main/lobar (89–100% and 95–100%,respectively) and segmental (84–100% and 92–99%, respectively) levels [43–45]. CTPA can also bevaluable by revealing bronchial artery collaterals, which can correlate with more central disease [46], andby evaluating the lung parenchyma and mediastinum. Advanced CT technologies, including dual-energyCT (DECT), ECG-gated area detector CT (ADCT), cone-beam CT (CBCT) and contrast-enhancedmagnetic resonance pulmonary angiography, are emerging as valuable modalities for detailing thepulmonary vasculature. With advances with distal endarterectomy and the advent of balloon pulmonaryangioplasty (BPA), and general focus on more distal vascular assessment, conventional DSA may notalways be suitable for providing fine details. More selective segmental angiography, CBCT and ADCT maybe better for pre-BPA planning by providing greater resolution than conventional DSA, particularly in themore distal vessels [47]. These imaging techniques are not widely available and require expertise.

TABLE 1 Chronic thromboembolic disease (CTED) compared with chronic thromboembolic pulmonary hypertension (CTEPH)

Diagnostic criteria CTEPH CTED

Symptoms Exercise dyspnoea Exercise dyspnoeaPH Present at rest Absent at restRHC at exercise mPAP/CO slope >3 mmHg·L−1·min−1

V/Q scan Any mismatched perfusion defect Any mismatched perfusion defectAngiography (CTPA or DSA) Typical findings of CTEPH Typical findings of CTEPHCPET Excluding ventilatory limitation, deconditioningTTE Excluding left ventricular myocardial or valvular diseaseAnticoagulation At least 3 months At least 3 months

RHC: right heart catheterisation; V/Q: ventilation/perfusion; CTPA: computed tomography pulmonary angiogram; DSA: digital subtraction angiogram;CPET: cardiopulmonary exercise test; TTE: transthoracic echocardiogram; mPAP: mean pulmonary arterial pressure; CO: cardiac output.

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Pulmonary endarterectomyPEA should be offered to all eligible patients with CTEPH. The international registry of incident cases ofCTEPH reported 3-year survival of 90% in those operated and 70% in those not having surgery [48].Long-term follow-up of a large cohort reported 10-year survival of 72% (average age 58 years) [49]. Deathwas attributed to unrelated causes in 49% of patients; residual PH with PVR ⩾425 dyn·s·cm−5 correlatedwith worse survival [49]. Strict objective definitions of operability remain elusive, but certain features aremore likely to predict a good surgical outcome (table 2). While select patients may be technically operable,they may not benefit from endarterectomy due to significant comorbidities; the best treatment for suchcases remains uncertain. The traditional routine of inserting an inferior vena cava filter (IVC) device priorto endarterectomy has not been formally studied and has been abandoned at the leading surgical centres.In the international registry, IVC filter prior to surgery did not influence long-term survival [48].

The most important surgical advance has been in redefining the distal limits of endarterectomy [50, 51].In expert centres, surgery can be performed successfully in patients with distal chronic thromboembolism[51]. The advances in diagnostics and growing surgical experience have contributed to this success. As aresult, the previously published intra-operative classification [52] has been refined to better reflect thecurrent surgical approach and level of revascularisation (table 3) [50]. This also means not all surgicalcentres will view operability in the same manner [53]. A three-step stratified definition of expert surgicalcentre has been proposed which factors the following important goals: surgical mortality (<5%), surgicalvolume (more than 50 PEAs per year) and ability to perform segmental endarterectomy [53].Furthermore, in this era of a comprehensive approach to CTEPH, an expert centre should be capable ofevaluating and offering any/all established treatment modalities according to individual need.

The place of PH-targeted medical therapy and BPA relative to surgery is dependent on the anatomicaldistribution of disease and is not fully defined. Combining endarterectomy with BPA either as a hybrid orstepwise approach is being evaluated at select expert programmes [54]. In the CHEST-1 study, riociguatwas beneficial for patients with residual PH after endarterectomy [55]. A trial is needed to clarify ifPH-targeted medical therapy prior to endarterectomy in operable patients confers harm or benefit(ClinicalTrials.gov identifier NCT0327357).

Balloon pulmonary angioplastyBPA has evolved into an important component of the CTEPH treatment algorithm since the 2012 reportsfrom Japan [56–58]. BPA has been reported to improve haemodynamics, symptoms, exercise capacity andright ventricular function, with significantly lower rates of major complications than compared with thereport from 2001 [59–62]. In retrospective analyses, the benefits of BPA also appear to be maintained inthe medium term [10, 63]. Subsequent publications from Europe report similar results [64–66]. The recentBPA series from Germany is unique as these centres started BPA alongside a well-established PEAprogramme [67]. Although their complication rates were similar to those from Japan, the magnitude ofefficacy (e.g. PVR reduction) was less in comparison with the reports from Japan. The potentialexplanations offered included the possibility of differences in operability threshold and the variability inthe types of patients treated with BPA between centres.

Although these results of BPA are encouraging, the reports are from expert centres and may not begeneralisable. Even with the technical refinements, there remains a steep learning curve in order to safely,effectively and consistently perform BPA [68]. A successful BPA requires extensive training and caseexperience. BPA should be reserved for expert centres, where it should be considered for symptomatic

TABLE 2 Favourable risk–benefit assessment for pulmonary endarterectomy

Characteristics Lower risk with predictable good long-term outcome Higher risk with less predictable long-term outcome(not contraindications)

History History of DVT/PE No history of DVT/PEExamination No signs of right heart failure Signs of right heart failureComorbidity None Significant concomitant lung or left heart diseaseFunctional limitation Functional class II or III Functional class IVImaging Clear disease concordant on all images Inconsistency on imaging modalitiesType of disease Bilateral lower lobe disease No disease appreciable in lower lobesHaemodynamics PVR <1000 dyn·s·cm−5, in proportion to site and number

of obstructions on imaging; higher PA pulse pressurePVR >1200 dyn·s·cm−5, out of proportion to site and numberof obstructions on imaging; higher PA diastolic pressure

DVT: deep vein thrombosis; PE: pulmonary embolism; PVR: pulmonary vascular resistance; PA: pulmonary artery.

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CTEPH patients ineligible for PEA due to distal chronic thromboembolism or persistent/recurrent PHafter surgery. The role of BPA for those with technically operable disease, but who are unsuitable forsurgery due to subjective determination or patient refusal, has not been established.

BPA patient selection at an expert centre starts with a multidisciplinary review of all available andpertinent data. Anatomical and functional assessment of pulmonary arteries and lung perfusion are criticalto identify the target vessels [69]. A selective pulmonary angiogram of the target vessels will show moredetails and serves as confirmation prior to intervention during BPA. A selective angiogram may notcapture all the distal lesions potentially amenable to BPA, necessitating multiple complementary imagingmodalities such as intravascular imaging and pressure gradient analysis to aid in lesion assessment andballoon sizing [70].

BPA complications should be defined and uniformly reported. Unlike reperfusion lung injury after PEAwhich can be delayed for days before onset [71], the injury associated with BPA appears to be morevascular injury related to the intervention than the capillary leak syndrome described post-PEA [72].Table 4 is proposed as a guide for BPA centres for classification of complications. Injury caused by wireperforation or interruption of the diseased vessel is the most common [69]. Lung injury by wireperforation or balloon overdilatation in the setting of severe PH risks potentially fatal massive infiltrationand/or haemorrhage which may require mechanical ventilation or extracorporeal support. Classicreperfusion lung injury is rare with BPA. Published low BPA complications reflect limited experienceconfined to experienced BPA centres. In experienced hands, BPA has emerged as a promising andestablished treatment for inoperable CTEPH.

PH-targeted medical therapyWhile PEA remains the treatment of choice for most patients with CTEPH, around 40% of the patients inthe international CTEPH registry were considered inoperable due to concern for inaccessible vascularobstruction, PAP out of proportion to morphological lesions and significant prohibitive comorbidities [9].A large number of small studies and three large randomised controlled trials (table 5) have demonstratedvarying improvements with targeted medical therapy in technically inoperable patients [55, 73, 74].

TABLE 3 University of California San Diego chronic thromboembolism (CTE) surgicalclassification

Surgical levels Location of CTE

Level 0 No evidence of thromboembolic disease in either lungLevel I CTE starting in the main pulmonary arteries(Level IC) (Complete occlusion of one main pulmonary artery with CTE)

Level II CTE starting at the level of lobar arteries or in the main descending pulmonary arteriesLevel III CTE starting at the level of the segmental arteriesLevel IV CTE starting at the level of the subsegmental arteries

Information from [50].

TABLE 4 Balloon pulmonary angioplasty complications

During the procedureVascular injury# with/without haemoptysisWire perforationBalloon overdilatationHigh-pressure contrast injection

Vascular dissectionAllergic reaction to contrastAdverse reaction to conscious sedation/local anaesthesia

After the procedureLung injury¶ (radiographic opacity with/without haemoptysis, with/without hypoxaemia)Renal dysfunctionAccess site problems

#: signs of vascular injury: extravasation of contrast, hypoxaemia, cough, tachycardia, increased pulmonaryarterial pressure; ¶: causes of lung injury: vascular injury much greater than reperfusion lung injury.

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However, data are lacking for patients with medical contraindications or those refusing surgery. Riociguatis the currently approved medical therapy in many countries for inoperable CTEPH based on the CHESTtrials [55, 75]. Recently, the MERIT-1 trial of macitentan in the treatment of inoperable CTEPH showedimprovements of the primary end-point (PVR (p=0.041)) and of other end-points (e.g. 6-min walkdistance (p=0.033) and N-terminal pro-brain natriuretic peptide (p=0.040)) [74]. This last study providedthe first evidence on combination drug therapy in CTEPH. 61% of the included patients were alreadytreated with phosphodiesterase type 5 inhibitors and/or oral/inhaled prostanoids at inclusion, and additionof macitentan showed similar efficacy compared with the drug-naive patients. Accordingly, macitentan isbeing considered for potential CTEPH registration. Event-driven morbidity/mortality studies have notbeen performed in CTEPH.

Patients with persistent/residual post-operative PH were also included in BENEFIT and CHEST-1,representing around 30% of the study population [55, 73]. Both studies included patients with mPAP⩾25 mmHg and PVR ⩾300 dyn·s·cm−5 at >6 months after endarterectomy. This can be put in perspectivewith real-life data from the large UK national cohort, in which 3–6 months after PEA: 1) 51% of thepatients had mPAP ⩾25 mmHg, 2) mPAP ⩾30 mmHg predicted initiation of PH-targeted medical therapy,and 3) mPAP ⩾38 mmHg and PVR ⩾425 dyn·s·cm−5 correlated with worse long-term survival [49].

Using medical therapy as a “bridge to PEA” is more controversial, and is felt to delay timely surgicalreferral and, therefore, definitive treatment. In the international registry and in a University of CaliforniaSan Diego cohort, 28% and up to 37%, respectively, of the patients were on some form of PH-targeteddrug(s) at the time of surgical referral [9, 76]. In both cohorts, the delay between diagnosis and surgerywas doubled in the pre-treated patients, without demonstrable clinical benefit. In the international registry,pre-treatment even independently predicted worse outcome (hazard ratio 2.62; p=0.0072) [48]. Keylimitations of these reports are with inherent referral bias and the possibility of medical therapy potentiallystabilising otherwise deteriorating cases (unknown and not tested). In order to provide the missingevidence, a phase 2 study will soon commence to include CTEPH patients with high PVR forpre-operative treatment with riociguat versus placebo (ClinicalTrials.gov identifier NCT0327357). Usingmedical therapy as a “bridge to BPA”, although not studied, has become common practice and in keepingwith the indication for riociguat for technically inoperable disease. A study is currently ongoing whichcompares riociguat versus BPA for technically inoperable CTEPH, followed by an opportunity to crossoverafter 6 months (ClinicalTrials.gov identifier NCT02634203).

CTEPH treatment algorithmThe newly proposed CTEPH treatment algorithm is provided in figure 1 and starts with lifelonganticoagulation. Antiplatelet therapy is not an alternative to anticoagulation in patients with CTEPH. Datadifferentiating the best form of anticoagulation therapy is lacking in CTEPH. Traditional anticoagulationhas been with oral vitamin K antagonists. Whether the newer oral anticoagulants or chronic injectableanticoagulants are adequate in CTEPH is unknown. The algorithm emphasises the need for amultidisciplinary assessment, including a surgeon experienced with PEA, PH specialist, BPAinterventionist and CTEPH-trained radiologist. A PH referral centre was previously defined andrecommended as a minimum volume of 50 pulmonary arterial hypertension or CTEPH patients managedper year [77]. However, given the highly specialised nature of CTEPH treatment, additional factors shouldbe considered when gauging clinical expertise.

In the CHEST-1 trial, central adjudication exemption and local operability assessment were allowedprovided a participating centre performed more than 20 PEA operations per year [78]. However, themajority of the operability adjudication occurred with the central committee whose members each

TABLE 5 Pulmonary hypertension-targeted medical therapy randomised controlled trials in chronic thromboembolicpulmonary hypertension

Trial [ref.] Study drug Duration weeks Subjects n NYHA FC 6MWD m 6MWD effect m PVR baseline dyn·s·cm−5 PVR effect %

BENEFIT [73] Bosentan 16 157 II–IV 342±84 +2NS 783 (95% CI 703–861) −24CHEST-1 [55] Riociguat 16 261 II–IV 347±80 +46 787±422 −31MERIT-1 [74] Macitentan 16 (24#) 80 II–IV 352±81 +34 957±435 −16

Data are presented as n or mean±SD, unless otherwise stated. NYHA FC: New York Heart Association Functional Class; 6MWD: 6-min walkdistance; PVR: pulmonary vascular resistance; NS: non-significant. All three trials had an adjudication process for operability. #: 6MWDmeasured at 24 weeks.

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performed well in excess of 50 operations per year. In addition, the central adjudication committee haddouble the rate of operability determination than the local adjudication committee (15% operable versus7% operable, respectively). From the international CTEPH registry, a trend with the best in-hospital and1-year post-operative mortality was observed from centres performing higher volumes of PEA, with thebest results observed from centres performing more than 50 operations per year [79]. This observationlikely does not take into account the relative differences in case complexity, with potentially morechallenging cases referred to higher-volume programmes. Additional emphasis on the importance ofsurgical centre experience was reported in the UK national registry of patients undergoing PEA [49]. Inthis report, significantly lower in-hospital mortality was observed in the second group of consecutive 500operated cases compared with the initial group of 500 operated cases. In addition, the ability forhigh-volume centres to perform more distal endarterectomy necessitates stratification of surgical centreexpertise [53]. A similar observation applies to BPA success; the safety and efficacy reports of the refinedBPA techniques from Japan are from centres performing the highest volume of procedures (typically morethan 100 per year) [58, 59]. In summary, an expert CTEPH centre should be able to assess and deliver allestablished treatment modalities with outcomes similar to or exceeding those published.

Patients with operable CTEPH should receive PEA as the treatment of choice. For those deemedinoperable, the best level of evidence supports initiating medical therapy and consideration of BPA.Patients with persistent/recurrent symptomatic PH following PEA should receive medical therapy and beconsidered for BPA or re-do endarterectomy in cases of significant re-occlusion [80]. Lastly, given thesubjectivity of operability assessment, it is possible for a patient initially deemed to be inoperable to receivePEA with or without treatments for inoperable CTEPH. The new algorithm therefore allows for fluiditybetween these treatment modalities as information and expertise is gained.

ConclusionsPEA remains the treatment of choice for patients with operable CTEPH. Two additional recognisedtreatments are now available (i.e. targeted medical therapy and BPA). A multimodal, individualisedapproach to treatment at expert centres integrating surgical, interventional, imaging and medical PHexpertise with the development of clear outcomes analyses is mandatory going forward.

Conflict of interest: N.H. Kim reports personal fees for consultancy, steering committee work and speaker bureaumembership from Actelion and Bayer; personal fees for consultancy from Merck; and is a board member of theInternational CTEPH Association, CTEPH.com. M. Delcroix is an investigator, speaker, consultant or steeringcommittee member for Actelion, Bayer AG, Bellerophon, Eli Lilly, GSK, MSD, Pfizer and Reata; and has received aninstitutional research grant from Actelion. X. Jais received grants and personal fees from Actelion, GSK, Bayer andMSD. M.M. Madani has received consultancy fees from MSD/Bayer, Wexler Surgical and Actelion, and is an executiveboard member of the International CTEPH Association, CTEPH.com. H. Matsubara has received lecture fees from

CTEPH diagnosisContinue lifelong anticoagulation

Treatment assessment by anexpert CTEPH team#,¶

Persistent/recurrent symptomatic pulmonary hypertension

Operable Non-operable

Pulmonary endarterectomy(treatment of choice)

Targeted medical therapywith or without BPA¶,+

FIGURE 1 Chronic thromboembolic pulmonary hypertension (CTEPH): revised treatment algorithm. BPA:balloon pulmonary angioplasty. #: multidisciplinary: pulmonary endarterectomy surgeon, PH expert, BPAinterventionist and radiologist; ¶: treatment assessment may differ depending on the level of expertise;+: BPA without medical therapy can be considered in selected cases.

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Actelion Pharmaceuticals Japan, Ltd, AOP orphan Pharmaceuticals AG, Bayer Yakuhin, Ltd, Pfizer Japan, Inc, NipponShinyaku, Co, Ltd and Kaneka Medix Corporation, outside the submitted work. E. Mayer has received consultancy feesfrom Actelion, Bayer and MSD; and is on the speaker bureau for Actelion, Bayer, MSD and Pfizer. T. Ogo is a memberof the speaker bureau for Actelion and Bayer. V.F. Tapson received research support from Actelion, Arena, Bayer, BiO2,Edwards Scientific, Ekos/BTG, Janssen, Inari, Portola, Reata, United Therapeutics, Daiichi and Penumbra; consultancyfees from Actelion, Bayer, BiO2, Ekos/BTG, Inari, Janssen, Portola, United Therapeutics, VWave, Daiichi andPenumbra; speaker bureau for Actelion, Bayer and Janssen. H-A. Ghofrani reports personal fees for advisory boardwork payment for lectures including service on speaker bureaus from Actelion, Bayer, GSK, Novartis and Pfizer;consultancy fees from Actelion, Bayer, Bellerophon Pulse Technologies, GSK, MSD, Novartis and Pfizer; and grantsfrom Deutsche Forschungsgemeinschaft (DFG), outside the submitted work. D.P. Jenkins worked as adjudicator forActelion and Bayer for MERIT and CHEST-1 studies; received honoraria for speaking from Actelion and Bayer; and is aboard member of the International CTEPH Association, CTEPH.com.

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54 Wiedenroth CB, Liebetrau C, Breithecker A, et al. Combined pulmonary endarterectomy and balloon pulmonaryangioplasty in patients with chronic thromboembolic pulmonary hypertension. J Heart Lung Transplant 2016; 35:591–596.

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56 Mizoguchi H, Ogawa A, Munemasa M, et al. Refined balloon pulmonary angioplasty for inoperable patients withchronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2012; 5: 748–755.

57 Kataoka M, Inami T, Hayashida K, et al. Percutaneous transluminal pulmonary angioplasty for the treatment ofchronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2012; 5: 756–762.

58 Sugimura K, Fukumoto Y, Satoh K, et al. Percutaneous transluminal pulmonary angioplasty markedly improvespulmonary hemodynamics and long-term prognosis in patients with chronic thromboembolic pulmonaryhypertension. Circ J 2012; 76: 485–488.

59 Ogo T. Balloon pulmonary angioplasty for inoperable chronic thromboembolic pulmonary hypertension. CurrOpin Pulm Med 2015; 21: 425–431.

60 Fukui S, Ogo T, Goto Y, et al. Exercise intolerance and ventilatory inefficiency improve early after balloonpulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension. Int JCardiol 2015; 180: 66–68.

61 Fukui S, Ogo T, Morita Y, et al. Right ventricular reverse remodelling after balloon pulmonary angioplasty. EurRespir J 2014; 43: 1394–1402.

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62 Feinstein JA, Goldhaber SZ, Lock JE, et al. Balloon pulmonary angioplasty for treatment of chronicthromboembolic pulmonary hypertension. Circulation 2001; 103: 10–13.

63 Inami T, Kataoka M, Yanagisawa R, et al. Long-term outcomes after percutaneous transluminal pulmonaryangioplasty for chronic thromboembolic pulmonary hypertension. Circulation 2016; 134: 2030–2032.

64 Andreassen AK, Ragnarsson A, Gude E, et al. Balloon pulmonary angioplasty in patients with inoperable chronicthromboembolic pulmonary hypertension. Heart 2013; 99: 1415–1420.

65 Bouvaist H, Thony F, Jondot M, et al. Balloon pulmonary angioplasty in a patient with chronic thromboembolicpulmonary hypertension. Eur Respir Rev 2014; 23: 393–395.

66 Roik M, Wretowski D, Rowinski O, et al. Refined balloon pulmonary angioplasty in inoperable chronicthromboembolic pulmonary hypertension – a multi-modality approach to the treated lesion. Int J Cardiol 2014;177: e139–e141.

67 Olsson KM, Wiedenroth CB, Kamp J-C, et al. Balloon pulmonary angioplasty for inoperable patients with chronicthromboembolic pulmonary hypertension: the initial German experience. Eur Respir J 2017; 49: 1602409.

68 Ogawa A, Matsubara H. Balloon pulmonary angioplasty: a treatment option for inoperable patients with chronicthromboembolic pulmonary hypertension. Front Cardiovasc Med 2015; 2: 4.

69 Kawakami T, Ogawa A, Miyaji K, et al. Novel angiographic classification of each vascular lesion in chronicthromboembolic pulmonary hypertension based on selective angiogram and results of balloon pulmonaryangioplasty. Circ Cardiovasc Interv 2016; 9: e003318.

70 Roik M, Wretowski D, Labyk A, et al. Refined balloon pulmonary angioplasty driven by combined assessment ofintra-arterial anatomy and physiology – multimodal approach to treated lesions in patients with non-operabledistal chronic thromboembolic pulmonary hypertension – technique, safety and efficacy of 50 consecutiveangioplasties. Int J Cardiol 2016; 15: 228–235.

71 Kerr KM, Auger WR, Marsh JJ, et al. The use of cylexin (CY-1503) in prevention of reperfusion lung injury inpatients undergoing pulmonary thromboendarterectomy. Am J Respir Crit Care Med 2000; 162: 14–20.

72 Lang I, Meyer BC, Ogo T, et al. Balloon pulmonary angioplasty in chronic thromboembolic pulmonaryhypertension. Eur Respir Rev 2017; 26: 160119.

73 Jais X, D’Armini AM, Jansa P, et al. Bosentan for treatment of inoperable chronic thromboembolic pulmonaryhypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonaryhypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol 2008; 52: 2127–2134.

74 Ghofrani HA, Simonneau G, D’Armini AM, et al. Macitentan for the treatment of inoperable chronicthromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised,double-blind, placebo-controlled study. Lancet Respir Med 2017; 5: 785–794.

75 Simonneau G, D’Armini AM, Ghofrani HA, et al. Predictors of long-term outcomes in patients treated withriociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised,long-term extension trial. Lancet Respir Med 2016; 4: 372–380.

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78 Jenkins DP, Biederman A, D’Armini AM, et al. Operability assessment in CTEPH: lessons from the CHEST-1study. J Thorac Cardiovasc Surg 2016; 152: 669–674.

79 Mayer E, Jenkins D, Lindner J, et al. Surgical management and outcome of patients with chronic thromboembolicpulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg 2011; 141:702–710.

80 Mo M, Kapelanski DP, Mitruka SN, et al. Reoperative pulmonary thromboendarterectomy. Ann Thorac Surg 1999;68: 1770–1777.

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Paediatric pulmonary arterialhypertension: updates on definition,classification, diagnostics and management

Erika B. Rosenzweig1, Steven H. Abman2, Ian Adatia3, Maurice Beghetti4,Damien Bonnet5, Sheila Haworth6, D. Dunbar Ivy2 and Rolf M.F. Berger7

Number 12 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, USA.2University of Colorado, Children’s Hospital Colorado, Denver, CO, USA. 3Glenwood Children’s Heart Clinic,Edmonton, AB, Canada. 4Pediatric Cardiology Unit and Centre Universitaire de Cardiologie et ChirurgieCardiaque Pédiatrique, University Hospitals of Geneva and Lausanne, Lausanne, Switzerland. 5Hôpital NeckerEnfants Malades, AP-HP, Université Paris Descartes, Paris, France. 6University College London, London, UK.7Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children’s Hospital, University MedicalCenter Groningen, University of Groningen, Groningen, The Netherlands.

Correspondence: Erika B. Rosenzweig, Pulmonary Hypertension Comprehensive Care Center, ColumbiaUniversity Medical Center, New York Presbyterian Hospital, 3959 Broadway, New York, NY 10032, USA.E-mail: esb14@cumc.columbia.edu

@ERSpublicationsState of the art and future perspectives in paediatric pulmonary hypertension with special emphasison classification, diagnosis and treatment http://ow.ly/uVPo30mksOj

Cite this article as: Rosenzweig EB, Abman SH, Adatia I, et al. Paediatric pulmonary arterial hypertension:updates on definition, classification, diagnostics and management. Eur Respir J 2019; 53: 1801916 [https://doi.org/10.1183/13993003.01916-2018].

ABSTRACT Paediatric pulmonary arterial hypertension (PAH) shares common features of adult disease,but is associated with several additional disorders and challenges that require unique approaches. Thisarticle discusses recent advances, ongoing challenges and distinct approaches for the care of children withPAH, as presented by the Paediatric Task Force of the 6th World Symposium on PulmonaryHypertension. We provide updates of the current definition, epidemiology, classification, diagnostics andtreatment of paediatric PAH, and identify critical knowledge gaps. Several features of paediatric PAHincluding the prominence of neonatal PAH, especially in pre-term infants with developmental lungdiseases, and novel genetic causes of paediatric PAH are highlighted. The use of cardiac catheterisation asa diagnostic modality and haemodynamic definitions of PAH, including acute vasoreactivity, areaddressed. Updates are provided on issues related to utility of the previous classification system to reflectpaediatric-specific aetiologies and approaches to medical and interventional management of PAH,including the Potts shunt. Although a lack of clinical trial data for the use of PAH-targeted therapypersists, emerging data are improving the identification of appropriate targets for goal-oriented therapy inchildren. Such data will likely improve future clinical trial design to enhance outcomes in paediatric PAH.

Received: Oct 06 2018 | Accepted: Oct 09 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

https://doi.org/10.1183/13993003.01916-2018 Eur Respir J 2019; 53: 1801916

| SERIESWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

IntroductionPulmonary hypertension (PH) in children is associated with diverse diseases with onset at any age. Thedistribution of aetiologies in paediatric PH is quite different to that of adults, with children having agreater predominance of idiopathic pulmonary arterial hypertension (IPAH), pulmonary arterialhypertension (PAH) associated with congenital heart disease (PAH-CHD) and developmental lungdiseases. Differences in aetiology, presentation and outcomes require a unique approach in children. Themanagement of children remains challenging because treatments have long depended on evidence-basedadult studies and the clinical experience of paediatric experts. Although there is still a lack of data oneffectiveness, formulation, pharmacokinetics, optimal dosing and treatment strategies, data are emergingthat allow for the definition of appropriate treatment targets and goal-oriented therapy in children.Nevertheless, children with PAH are currently treated with targeted PAH drugs with benefit. We providean overview of recent updates in the current definition, epidemiology, classification, diagnostics andtreatment of PAH in children, and identify current needs based on discussions and recommendationsfrom the Paediatric Task Force of the 6th World Symposium on Pulmonary Hypertension (WSPH) inNice, France (2018).

DefinitionsHistorically, the definition of PH in children has been the same as in adults, i.e. mean pulmonary arterialpressure (mPAP) ⩾25 mmHg. In the normal fetal circulation, PAP is similar to systemic pressure andrapidly falls after birth, achieving levels that are similar to the adult by 2–3 months of age. Due tovariability in pulmonary haemodynamics during post-natal transition, paediatric PH has been defined asmPAP ⩾25 mmHg after 3 months of age. In paediatric PH, especially in association with CHD, it isrecommended to use pulmonary vascular resistance (PVR) as indexed to body surface area (PVRI) inorder to assess the presence of pulmonary vascular disease (PVD), as defined by PVRI ⩾3 WU·m2.

The 6th WSPH proposed to modify the definition for PH in adults as mPAP >20 mmHg and to includePVR ⩾3 WU to identify pre-capillary PH. Whether or not the same findings of high normal or “borderlinePH” with mPAP of 21–24 mmHg in subgroups of adult PH such as scleroderma, chronic obstructivepulmonary disease and interstitial lung disease is a risk factor for developing PAH and related morbiditiesin children as in adults will require further study [1]. However, in order to speak a universal language andfacilitate transition from paediatric to adult PH care, the Paediatric Task Force chose to follow the newlyproposed adult definition of PH and encourages further study of these patients. The proposed use of PVRto assess PVD at the 6th WSPH had already been included previously in the haemodynamic assessment ofPH in children. The Paediatric Task Force further reinforced the need for indexing of PVR in children.

VasoreactivityIn IPAH/heritable PAH (HPAH), acute vasodilator testing (AVT) is recommended to identify patientswho are likely to have a good long-term prognosis when treated with long-term calcium channel blocker(CCB) therapy. In the recent past, positive vasoreactivity was believed to be more common in childrenwith IPAH when compared with adults and that specific response criteria were indicated for children.However, using the same criteria for adult and paediatric subjects with IPAH/HPAH showed that theproportion of AVT responders was similar in both age groups [2]. A recent large study including 382patients showed a substantial discrepancy in how AVT is performed and interpreted in children, and thatstandardisation is required [2]. As in adults, inhaled nitric oxide at 10–80 ppm is the preferred agent, buti.v. epoprostenol, i.v. adenosine or inhaled iloprost may be used as alternatives. However, optimal dosingin small children is not well defined for the latter drugs. As recently reported, the Sitbon criteria forpositive AVT, as defined by a decrease in mPAP by at least 10 mmHg to a value of <40 mmHg withsustained cardiac output that is commonly used in adult IPAH/HPAH, have been shown to identify childrenwho will show sustained benefit from CCB therapy [2, 3]. Positive AVT in subjects with mPAP <40 mmHgat baseline is defined by a drop of at least 10 mmHg without a fall in cardiac output. Based on these data itis advised to use the Sitbon criteria for AVT in children. Since it has been shown that only half of theadult responders have a long-term haemodynamic and clinical improvement on CCB therapy, closelong-term follow-up is required.

Can AVT predict operability if resting PAP and PVR are elevated in children with CHD and opensystemic-to-pulmonary shunts?In CHD-associated PH, AVT is often performed for other reasons than determining the potential use ofCCB therapy and predictor of outcome, as shown in IPAH/HPAH. AVT is also used to distinguishbetween reversible and progressive PAH in patients with PAH-CHD, and thus potential operability [4].However, specific criteria for defining a positive AVT response or specific haemodynamic targets thatpredict reversal of PAH and good long-term prognosis following surgical correction remain lacking.

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In fact, other factors beyond the haemodynamic response to AVT have been shown to be associated withPAH reversal after surgical repair, including age, type of cardiac lesion, comorbidities, resting and exercisesaturation, and clinical history. In the absence of robust data on haemodynamic predictors, currentguidelines suggest criteria for operability of CHD in the presence of PAH that are based on expertopinion. The Paediatric Task Force agreed on general guidance for assessing operability in CHD-PAH, butemphasises that the long-term impact of defect closure in the presence of PAH with increased PVR isunknown (table 1).

Updates in paediatric PH epidemiology and classificationCurrent epidemiological data on paediatric PH are mainly derived from registry cohorts; as a result theyare affected by study design, logistics and the scope of clinical practice underlying patient selection forthese registries. Geographic coverage, referral patterns, inclusion criteria and disease definitions may differbetween registries, leading to potential selection bias that can affect reported incidence and prevalencerates. The estimated incidence of sustained PH in all categories was reported at 4–10 cases per millionchildren per year with a prevalence of 20–40 cases per million in Europe (Spain, the Netherlands) and 5–8cases per million children per year and 26–33 per million children in the USA [5–7]. A Dutch nationwideepidemiological study, that minimised potential bias by including all hospitals in the country bycombining hospital registries with local paediatric cardiology databases over a 15-year period, reported anannual incident rate of PH in children of 63.7 per million children [6]. The majority of children (2845 outof 3262) had “transient” PAH and were infants with either persistent PH of the newborn (PPHN) orrepairable cardiac shunt defects. Of the remaining children, 27% had other forms of PAH (IPAH,PAH-CHD, PAH associated with connective tissue disease (CTD) and pulmonary veno-occlusive disease(PVOD)), while a significant proportion (34%) had PH associated with developmental lung disease,including bronchopulmonary dysplasia (BPD), congenital diaphragmatic hernia (CDH) and congenitalpulmonary vascular abnormalities [6].

Group 1: PAHGroup 1.1: IPAHEstimated incidence rates for IPAH vary from 0.47 to 1–2 cases per million children, with estimatedprevalence rates from 2.1 to 4.4 cases per million children [5–9].

Group 1.2: HPAHAs in adult PAH, gene mutations that have been implicated in the pathogenesis of HPAH have beenidentified in 20–30% of paediatric sporadic PAH cases and 70–80% of familial PAH cases. These includeknown mutations such as those in BMPR2 (bone morphogenetic protein receptor type 2) and ACVRL1(activin receptor-like kinase 1). However, compared with adult PAH, the genetic architecture of paediatricPAH differs and seems enriched in TBX4 and ACVRL1 mutations [10–13]. Whether mutation carriers inpaediatric PAH have a different phenotype or clinical course than non-carriers remains to bedemonstrated [11]. Furthermore, paediatric PAH is frequently associated with chromosome and syndromicanomalies, in which the mechanistic basis for PAH is generally uncertain. A recent exome sequencingstudy in paediatric PAH suggests that de novo variants in novel genes may explain approximately 19% ofpaediatric-onset IPAH cases. The prevalence of known PAH gene mutations in PAH-CHD is controversialas several studies have not detected PAH mutations in these patients, whereas other groups have identifiedBMPR2 mutations in patients presenting with PAH after correction of a defect [11, 14], and a recent studyshows variants in SOX17 associated with PAH-CHD [15]. Genetic testing is still not performed routinelyin all paediatric PH as it may lead to significant psychological impacts, particularly in asymptomatic

TABLE 1 Guidance for assessing operability in pulmonary arterial hypertension associated withcongenital heart disease

Pulmonary vascular resistanceindex WU·m2

Pulmonary vascularresistance WU

Correctability/favourable long-termoutcome

<4 <2.3 Yes4–8 2.3–4.6 Individual patient evaluation in

tertiary centres>8 >4.6 No

WU: Wood Units. Special considerations include: age of patient, type of defect, comorbidities, resting orexercise-induced desaturation is a concern and PAH therapy (treat with intent-to-repair approach has notbeen proven).

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individuals, especially in the setting of incomplete penetrance. Genetic testing should be combined withgenetic counselling by experts in this field so that families have all information before and after testing.

The genetics of PH and genetic testing specifically in paediatrics requires further work and should beperformed in expert centres with a genetic counselling group.

Group 1.3: Drug- and toxin-induced PAHSeveral cases of transient PAH that resolved after discontinuation of diazoxide have been described in theliterature, suggesting that hyperinsulinaemic and hypoglycaemic neonates treated with diazoxide requireechocardiographic surveillance [16]. The US Food and Drug Administration (FDA) issued a warningabout diazoxide and PAH in neonates in 2015 [17].

Group 1.4: Associated PAHGroup 1.4.1: PAH associated with CTDPAH-CTD in children is uncommon, but deterioration is usually rapid when associated with PAH.PAH-CTD occurs in 0–4% of patients in PH clinics [5–7, 18–21]. In a multinational cohort of 389children with systemic juvenile arthritis from the CARRA registry, 16 (4%) were diagnosed with PAH [18].A recent study suggests that PAH was diagnosed by echocardiography in 2% of a cohort of 850 childrenwith systemic lupus erythematosus within the first 2 years of diagnosis, These patients with PH weremostly asymptomatic and, in some cases, the PAH resolved or improved [19].

Group 1.4.2: PAH associated with HIV infectionPAH-HIV in children appears to be rare outside of endemic areas, with one case in each of the Spanish,Dutch and UK registries [5, 6, 22].

Group 1.4.3: PAH associated with portal hypertensionPatients with liver disease suffer from two distinct pulmonary vascular complications: hepatopulmonarysyndrome (HPS) and portopulmonary hypertension (POPH). Whereas HPS is characterised by increasedpulmonary blood flow, low PVR and hypoxaemia, POPH has striking pulmonary vascular remodellingthat adversely affects the outcome of orthotopic liver transplantation [23]. POPH appears to be rare inchildren, with 0–2% of cases reported in PH registries [5, 6, 22, 24].

Group 1.4.4: Congenital heart diseaseGroup 1.4.4 PAH includes patients with simple operable and inoperable CHD, subgrouped as those withEisenmenger physiology, those with PAH and left-to-right shunts, those with PAH thought to beincidental to their CHD and those with postoperative/closed defects. This classification for PAH associatedwith cardiac or arterial shunt has not changed since the previous WSPH 2013 classification [25]. TransientPH following repair of congenital heart disease occurs in 21.9 cases per million and is one of thecommonest forms of PAH in children, second only to persistent pulmonary hypertension of the newborn[6]. Complex heart diseases have been assigned to group 5.4.

Group 1.4.5: SchistosomiasisSchistosomiasis is uncommon in developed countries and lacks studies of targeted PH therapy in children.

Group 1.5: PAH long-term responders to CCBsAs in adults, a subgroup of children with IPAH can be identified who are positive AVT responders andwould now be classified as “PAH long-term responders to CCBs” [25]. Based on the Sitbon criteria, thissubgroup is estimated to include roughly 8–15% of the children with IPAH.

Group 1.6: PAH with overt features of venous/capillaries (PVOD/PCH) involvementPAH with overt features of venous/capillaries (PVOD/pulmonary capillary haemangiomatosis (PCH))involvement in children appears to be rare. PVOD and/or PCH was diagnosed in 0.7–2% cases of PAH inthe Spanish, Dutch and TOPP registries [5, 6, 26]. The EIF2AK4 (eukaryotic translation initiation factor2α kinase 4) mutation was present in two-thirds of children diagnosed with PVOD in France [11].

Group 1.7: Persistent PH of the newborn syndromePPHN is the most common cause of transient PAH (30.1 cases per million children per year) and may beincreasing in frequency [7]. In the era before inhaled nitric oxide therapy, PPHN occurred inapproximately 2 per 1000 live births [27]. In contrast, between 2003 and 2012, the prevalence of PPHNamong 12954 extremely pre-term infants enrolled was 8.1% (95% CI 7.7–8.6%), with the trend increasingannually, in part due to increased survival of extremely low-birthweight infants and growing awareness of

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PPHN in pre-terms. The proportion of newborns with PPHN is inversely related to gestational age, withan incidence of 18.5% (range 15.2–22.4%) for infants born at 22–24 weeks compared with 4.4% (range3.8–5.2%) for those born at 27 weeks [28]. The current WSPH Paediatric Task Force emphasised thatPPHN is a syndrome with multiple associated conditions (table 2). Although multifactorial in origin,recent epidemiological studies show that PPHN is associated with ante-natal events, includingpre-eclampsia, chorioamnionitis and other peri-natal events, leading to abnormal pulmonary vasculargrowth and function, and perhaps increasing the risk for PAH later in life [26].

Group 2: PH due to left heart diseaseVery little epidemiological data are available on this condition in children; however, left ventriculardiastolic dysfunction and impaired myocardial performance can contribute to PH severity in diversesettings, including PPHN, BPD and CDH. Congenital left heart inflow/outflow obstructions are commonin children with CHD, and outcome is dependent on aetiology and the stage in pulmonary vasculardevelopment that the obstruction occurs. Pulmonary vein stenosis, which has a very poor prognosis, cancomplicate the course and is emerging as an important cause of sustained PH, especially in the setting ofex-premature infants with BPD [29–32]. Table 3 shows congenital post-capillary obstructive lesions mostfrequent in childhood now classified as group 2.4 PH

Group 3: PH due to lung diseases and/or hypoxiaGroup 3.5: Developmental lung disordersThis category comprises an important and increasingly recognised proportion of children with PH. BPD isa common developmental disorder of prematurity that is characterised by impaired alveolar and vasculargrowth and maturation. Past registry data report that 10–12% of children with PH have associated lungdisease, with BPD being the most common disorder [26, 33]. This might likely be an underrepresentationof its frequency due to bias in registry enrolment, as previously mentioned. The Netherlandsepidemiological study revealed that 34% of patients with sustained PH have developmental lung disease.The incidence and prevalence of severe BPD and PH increase with increasing survival of 23–26-weekpre-terms. In a prospective study, PH at 7 days of age was present in 42% of premature babies (birthweight500–1250 g) and was associated with late PH (at 36 weeks corrected age) in 14%, worse severity of BPD,longer need for mechanical ventilation and neonatal intensive care unit hospitalisation, and highermortality [34, 35]. In children with BPD, PH can resolve with respiratory and PH-targeted drug therapyover time; however, even in the surfactant era the morbidity and mortality of PH in BPD infants remainshigh. Recent meta-analyses found that the presence of PH in premature born infants was stronglyassociated with mortality (risk ratio 4.7) with an accumulative estimated mortality rate of 16% prior todischarge and of 40% during the first 2 years of life. However, the same meta-analyses identified that mostreports have studied selected patient populations, and accurate estimates of incidence and prevalence rateslater in life are lacking [36]. No trials have yet been conducted to formally assess the effect of PH-specifictherapies on children with BPD.

TABLE 3 Congenital post-capillary obstructive lesions (group 2.4)

Pulmonary vein stenosisIsolatedAssociated (bronchopulmonary dysplasia, prematurity)

Cor triatriatumObstructed total anomalous pulmonary venous returnMitral/aortic stenosis (including supra/subvalvular)Coarctation of the aorta

TABLE 2 Persistent pulmonary hypertension of the newborn (PPHN) and associated disorders

Idiopathic PPHN Myocardial dysfunction (asphyxia, infection)Down syndrome Structural cardiac diseasesMeconium aspiration syndrome Hepatic and cerebral arteriovenous malformationsRespiratory distress syndromeTransient tachypnoea of the newborn Associations with other diseases:Pneumonia/sepsis Placental dysfunction (pre-eclampsia, chorioamnionitis, maternal hypertension)Developmental lung disease Metabolic diseasePeri-natal stress Maternal drug use or smoking

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Table 4 provides a summary of developmental lung disorders that share the common feature ofdevelopmental vascular disturbances.

Group 4: PH due to pulmonary artery obstructionsChronic thromboembolic PH remains uncommon as a cause of PAH in children, at around 0–1.4% ofcases [22, 26]. In contrast, pulmonary artery obstructions occur in a number of CHDs, either congenitallyor acquired after corrective surgery [25].

Group 5: PH with unclear and/or multifactorial mechanismsGroup 5.4: Complex CHDThis group includes haematological disorders, systemic and metabolic disorders, others, and complexCHD. Of specific interest for the paediatric age group are complex heart diseases that are associated withcongenital anomalies of the pulmonary vasculature such as segmental disorders, single ventricle physiologyand the scimitar syndrome (table 5). PH in these settings is extremely difficult to define or classify [37].After extensive discussion at the 5th WSPH in 2013, the Paediatric Task Force agreed to classify severalanomalies with differential pulmonary blood flow under the category of “segmental PH”, indicating thedistinct nature of these entities when compared with other forms of PH [38, 39].

During the current 6th WSPH, the Paediatric Task Force also considered including patients with singleventricle physiology as representing yet another difficult group to define; this group continues to increaseand represents a significant proportion of subjects with PVD at major medical centres. At various stagesthese patients may have increased or decreased pulmonary blood flow, and as they reach an age suitablefor the Fontan procedure or total cavo-pulmonary connection these subjects have variable degrees of PVDand bronchopulmonary collaterals. Subsequently, the chronic non-pulsatile pulmonary circulationassociated with a Fontan circulation likely induces a very specific form of PVD that is dissimilar to PVDin other diseases associated with PH [40]. Patients with Fontan circulation do not usually fulfil thedefinition of PH with mPAP >20–25 mmHg and, accordingly, these patients were previously excludedfrom the official WSPH classification. Nevertheless, these patients develop PVD that markedly impactssurvival and, according to the Paediatric Task Force, PVD in the setting of single ventricle physiologydeserves inclusion and has been classified with other forms of group 5 PH. The nature and mechanismsunderlying the pathobiology of PVD in this setting urgently require further investigation.

TABLE 4 Developmental lung disorders associated with pulmonary hypertension

Bronchopulmonary dysplasiaCongenital diaphragmatic herniaDown syndromeAlveolar capillary dysplasia with “misalignment of veins” (FOXF1)Lung hypoplasia, acinar dysplasiaSurfactant protein abnormalitiesSurfactant protein B deficiencySurfactant protein C deficiencyABCA3

TTF1/NKX2-1TBX4Pulmonary interstitial glycogenesisPulmonary alveolar proteinosisPulmonary lymphangiectasia

TABLE 5 Complex congenital heart disease (group 5.4)

Segmental pulmonary hypertensionIsolated pulmonary artery of ductal originAbsent pulmonary arteryPulmonary atresia with ventricular septal defect and major aorto-pulmonary collateral arteriesHemitruncusOther

Single ventricleUnoperatedOperated

Scimitar syndrome

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In these complex CHD categories (group 5.4), the general definition of PH does not suffice and should becustomised. At present, there is insufficient data showing that targeted therapies are safe and efficient in thispopulation, and further studies are required [41, 42].

Additional special considerations for paediatric clinical classificationThe WSPH classification for PH was originally designed for adults with PH. The rationale for a clinicalclassification includes the ability to strengthen clinical practice, including enhanced diagnostic andmanagement strategies, and to help provide guidance for prioritising laboratory, translational andepidemiological research questions. In addition, goals for improving classification systems include the needfor clarification of disease phenotype, encouraging new thinking on causation and disease pathobiology,enhancement of diagnostic evaluations, improvements in correlations of phenotype and therapeuticresponsiveness, and enhancement of clinical trial design.

While the major categories of PH as classified by the WSPH have been shown to be helpful also inneonates and children, there are persistent and important gaps that should be considered to improve theirutility in these specific age groups.

In 2013, the first WSPH Paediatric Task Force reasoned that a common classification for both adults andchildren is preferred, since children with PH who were diagnosed in the neonatal through adolescent ageranges are now surviving into adulthood and such classification will facilitate transition from paediatric toadult services. They then proposed several modifications in order to highlight aspects of paediatricdisorders and better address specific features of paediatric PH within the core of the existing classification.These modifications included the designation of PPHN as a subclass within group 1 disorders, moredetailed categorisation of PAH in CHD, the addition of congenital left heart inflow and outflow tract togroup 2, and the introduction of the category of “developmental lung disease” to group 3 and of“segmental PH” to group 5.

In 2018, the WSPH Paediatric Task Force aimed to further capture specific paediatric features in the WSPHclinical classification, while preserving the main core of the classification as given in table 2 of the Task Forcearticle by SIMONNEAU et al. [25] in this issue of the European Respiratory Journal. They proposed additionalfurther refinements of these groups as discussed in the previous subsections, including a separate designationfor congenital/acquired cardiovascular conditions leading to post-capillary PH (group 2.4), developmentallung disorders (group 3.5), other pulmonary artery obstructions (group 4.2) and complex CHD (group 5.4)

Recent observational paediatric data reveal that PAH in “older” children, despite specific differences,shares many common features with adult PAH. However, PH presenting in neonates is often associatedwith developmental vascular abnormalities and responses, and in the current classification is assigned togroup 3 PH associated with lung disease and/or hypoxia. These PVDs are much less comparable to adultPH, since the impact of PH on the immature, developing lung is recognised as a major factor integral tothe presentation, diagnosis, response to therapy and outcome, both immediate and long term. It is clearthat although paediatric and adult PH share common features, the aetiology, epidemiology andpresentation of neonatal and paediatric PVD differ significantly from those in adults. One of thedistinguishing features of PH in children is the injury of the developing fetal, neonatal and paediatric lungcirculation [43]. Another distinguishing feature is the frequent association with chromosome, genetic andsyndromic anomalies (11–52%), and the phenotypic associations that may result in multifactorial causes ofPH in up to 33% of cases [5, 44].

The current WSPH Paediatric Task Force therefore proposed to designate the developmental (vascular) lungdisorders as a special subcategory within group 3 PH (group 3.5). In addition to the recognised frequencyand importance of PVD and PH in disorders such as BPD and CDH, this category includes a rapidlyexpanding list of newly recognised genetic developmental lung disorders, including surfactant abnormalities,pulmonary interstitial glycogenesis, alveolar capillary dysplasia, TBX4 mutations and others (table 4).

Paediatric PVDs are often associated with multiple comorbidities that may contribute to PH severity anddictate overall outcomes. As discussed, the genetic background of paediatric PH appears to differ from thatof adult PH, and accompanying genetic disorders, syndromes and growth abnormalities are frequent inchildren with PH. Whether these latter should be regarded as causally related, disease modifiers orinnocent bystanders is often not clear. Therefore, accurate phenotyping of children with PH andassessment of the effect on outcome of comorbidities remains of crucial importance in any classification.

Down syndromeAn illustrative example of the complex role of comorbidities in paediatric PH warranting further attentionis Down syndrome. This Paediatric Task Force discussed the unique clinical phenotype of neonates, infantsand children with Down syndrome, and the potential role for PH screening in this group.

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Down syndrome, or trisomy 21, is associated with significant cardiovascular and pulmonary morbidityand mortality in children, including PH, chronic hypoxaemia and recurrent respiratory illnesses. Newborninfants with Down syndrome are at high risk of developing severe PPHN at birth and often have moreaggressive PVD secondary to CHD or airways obstruction than do subjects without Down syndrome.Mechanisms that increase the susceptibility of infants and children with Down syndrome to develop worsePH and cardiorespiratory disease are incompletely understood. Past studies have shown that infants dyingwith Down syndrome can have evidence of lung hypoplasia as demonstrated by decreased alveolarisation,peripheral lung cysts and persistence of the double-capillary network [45]. These early abnormalities ofarrested lung development may contribute to increased susceptibility for more aggressive cardiovascularand respiratory diseases in Down syndrome. Although mechanisms for abnormal lung and lung vasculardevelopment are uncertain, recent work has shown that three antiangiogenic (anti-vascular endothelialgrowth factor) genes are present on chromosome 21, and are each overexpressed in human fetal and infantlung tissue, including endostatin, RCAN-1 (regulator of calcineurin-1) and β-amyloid peptide.Experimentally, early disruption of angiogenic signalling decreases vascular growth and increases the riskfor PH, and also impairs distal airspace (alveolar) growth [46, 47]. Overall, these laboratory and clinicalfindings suggest that subjects with Down syndrome are highly susceptible to decreased lung vascular andalveolar growth, which may increase the risk for PH and lung hypoplasia. Impaired lung vascular growthmay increase the risk for environmental stimuli, such as haemodynamic stress, especially with associatedCHD, intermittent or sustained hypoxia with obstructive apnoea or lung disease, viral infection, aspirationand other factors, to induce more accelerated PH in subjects with Down syndrome than others. Thus, thegenetic consequences of Down syndrome may be linked with disruption of lung vascular and alveolargrowth, suggesting that Down syndrome represents a “developmental lung disease”. The current WSPHPaediatric Task Force agreed that the phenotype of Down syndrome-related PH is variable and does notuniversally fit into a single classification group, but that children with Down syndrome will be classified asgroup 3 in the absence of CHD (group 1 or 2).

Diagnosis of paediatric PHSince the aetiology of PH is very diverse, a methodical and comprehensive diagnostic approach is crucialto reach an accurate diagnosis and treatment plan. Moreover, IPAH is a diagnosis “per exclusion” and canbe made only by excluding known causes of PH. Despite this, recent registries have shown that mostchildren do not undergo a complete evaluation [48]. An updated comprehensive paediatric diagnosticalgorithm is shown in figure 1. Special situations may predispose to the development of PAH and shouldbe considered.

Right heart catheterisationThe Paediatric Task Force addressed several questions regarding the risks and benefits of right heartcatheterisation (RHC) in confirming the diagnosis of PH or PAH in children, and which children may be athighest risk for adverse events during RHC.

RHC remains the gold standard for the definitive diagnosis and nature of PAH, performing AVT, andproviding useful data for risk stratification. This necessity should be balanced with associated risks. Majorcomplications associated with RHC in children with PH have been reported to be 1–3%, and are generallyassociated with clinical condition and young age (newborns and young infants) [49–52]. As a result,cardiac catheterisation in paediatric PAH is strongly recommended to be performed in experiencedpaediatric PH centres using strategies to prevent these potential complications and having the ability tomanage complications including PH crisis with aggressive interventions such as extracorporeal life support(ECLS). In rare instances, a child may be too sick to undergo cardiac catheterisation safely (e.g. WorldHealth Organization Functional Class (WHO FC) IV). In these cases, when the suspicion of PAH is highand the non-invasive imaging is highly supportive, one should stabilise first and cautiously initiateappropriate PH therapy under careful observation, most often in the intensive care unit setting. RHC canthen be performed more safely when the patient is sufficiently stabilised. Every attempt should be madefor children with IPAH/HPAH to undergo RHC and AVT safely so one can determine whether they areacutely responsive to vasoreactivity testing and could benefit from CCB treatment. For those robustlyresponsive, but with poor cardiac function, a CCB would not be utilised unless the function improved.

Indications for repeat cardiac catheterisation in children with PH are not well defined, but includeassessment of treatment effect, clinical deterioration, detection of early disease progression, listing for lungtransplantation and prediction of prognosis. It has, however, not been shown whether changes inhaemodynamic parameters are associated with change in clinical outcome and therefore these parameters donot meet the requirements to serve as established treatment goals.

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Treatment strategies and clinical end-pointsCurrently, a goal-oriented treatment strategy is suggested for the treatment of paediatric PAH. Despite theabsence of validated treatment goals in paediatric PAH, various treatment guidelines were proposed forchildren with PAH, predominantly based on expert opinion [53–56]. An apparent lack of consensus inthese opinions resulted in important differences in reported paediatric treatment recommendations,stressing the need for evidence.

In 2013, the Paediatric Task Force of the 5th WSPH summarised determinants of higher risk in children,which included clinical evidence of right ventricular failure, progression of symptoms, syncope, failure tothrive, WHO FC III or IV, significantly elevated or rising brain natriuretic peptide (BNP) levels,echocardiographic signs of severe right ventricular enlargement or dysfunction, pericardial effusion, andhaemodynamic parameters such as mPAP/mean systemic arterial pressure (mSAP) ratio >0.75, mean rightatrial pressure (mRAP) >10 mmHg and PVRI >20 WU·m2 [54]. A recent systematic review andmeta-analyses concluded that WHO FC, N-terminal pro-BNP (NT-proBNP)/BNP, mRAP, PVRI, cardiacindex and acute vasodilator response are consistently reported as useful prognostic factors for assessinglong-term outcomes in paediatric PAH, and thus could be used for initial risk stratification and as suchincorporated in recommendations and guidelines [57, 58].

However, parameters with prognostic capabilities are not automatically suitable to serve as a treatmentgoal. Treatment goals are either clinically meaningful parameters that reflect how a patient feels orfunctions and can thus be a target for treatment, or should be surrogates for survival. Surrogates for

Symptoms, clinical signs, genetic syndromes,

personal or family history suggestive of PH

Yes

Yes Yes

Yes

No

No

NoYes

Yes Perform V/Q scan to rule out CTEPH

Are mismatched defects present?

Echocardiogram, ECG, chest radiograph compatible

with PH

Consider most common causes of PH in children

(i.e. CHD, chronic lung disease)

PH unlikely

Review history, signs, risk factors, PFTs including DLCO,

"polysomnography", chest CT

Consider other causes of symptoms

or re-check

CTEPH suspect: CTA and selective PA angiograms with

referral to PEA expertCardiac catheterisation at paediatric centre with AVT:

mPAP >20 mmHg, PAWP ≤15 mmHg and PVRI ≥3 WU·m2;

include full shunt evaluation to rule out CHD

Diagnosis of lung disease confirmed?

No signs of severe PH or RV dysfunction Signs of moderate–severe PH or RV dysfunction

Treat underlying lung disease Refer to paediatric PH expert

Consider other causes

CTD, HIV, CHD, portopulmonary, drugs/toxins, PVOD/PCH

IPAH/FPAH genetic testing

(counselling)

Additional diagnostic testing:

Serological markers

Laboratory testing

Liver ultrasound

6MWT/CPET

Cardiac MRI

Genetic testing?

No

FIGURE 1 Diagnostic algorithm for pulmonary hypertension (PH) in children. CHD: congenital heart disease; PFT: pulmonary function test; DLCO:diffusing capacity of the lung for carbon monoxide; CT: computed tomography; RV: right ventricular; V/Q: ventilation/perfusion; CTEPH: chronicthromboembolic PH; CTA: CT angiography; PA: pulmonary artery; PEA: pulmonary endarterectomy; AVT: acute vasodilator testing; mPAP: meanpulmonary arterial pressure; PAWP: pulmonary arterial wedge pressure; PVRI: pulmonary vascular resistance index; WU: Wood Units; 6MWT:6-min walk test; CPET: cardiopulmonary exercise test; MRI: magnetic resonance imaging; CTD: connective tissue disease; PVOD: pulmonaryveno-occlusive disease; PCH: pulmonary capillary haemangiomatosis; IPAH/FPAH: idiopathic/familial pulmonary arterial hypertension.

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survival by definition are parameters with a strong correlation with survival, which can be changed bytreatment, while such change should indicate disease worsening or improvement and should be predictiveof long-term outcome.

WHO FC, used in children with PAH and indicating how the child feels and function, has beendemonstrated to be also a strong predictor of transplant-free survival. Moreover, WHO FC has beenshown recently in paediatric PAH to be also a surrogate for survival and as such WHO FC qualifies as atreatment goal, despite its disadvantage of being a potentially subjective assessment [53]. A functional classdesigned specifically for children was proposed in 2011, but is still being considered because of itscomplexity and influence by comorbidities, and therefore has not yet reached broad use [59, 60].

In adults with PAH the 6-min walk test (6MWT) has been used to demonstrate drug efficacy. Althoughits ability to serve as a surrogate end-point for late outcomes is debatable, the 6MWT may be useful as atreatment goal in paediatric patients developmentally able to perform the test (children >6 years of age) [61,62]. Unfortunately, younger children cannot reliably perform the test, making this a suboptimal primaryend-point in a study of the full age range of children. Cardiopulmonary exercise testing (CPET) is evenmore demanding with respect to developmental skills and paediatric reference values for CPET inassociation with outcome are lacking [63].

Echocardiography seems an obvious tool to monitor treatment effect in children with PH. It providesfunctional and structural assessment of the heart and estimates of pulmonary haemodynamics, and iswidely available, non-invasive and well tolerated by children. Unfortunately, echocardiography is alsosubject to significant operator and interpretation variability [64]. Where several echocardiographic variableshave been suggested as predictors of outcome in paediatric PAH, today only tricuspid annular plane systolicexcursion (TAPSE) has been shown as strongly associated with improved survival during treatment,indicating its potential utility as a treatment goal [53]. New echocardiographic modalities for evaluatingright ventricular function (three-dimensional echocardiography, strain and strain rate, and rightventricular stroke work) as well as magnetic resonance imaging (MRI) assessment of right ventricularvolume and function both hold promise here, but more data in the paediatric population are needed todetermine the value of these techniques regarding establishment of predictive value or surrogacy forclinical outcomes [65, 66].

In addition to right ventricular function, right ventricular pulmonary vascular coupling reflects rightventricular afterload, and is regarded to be an important measure for the cardiovascular state and thusprognosis in patients with PH. MRI and echocardiography are potential candidates for non-invasivemonitoring of this coupling state.

At the pulmonary arterial side of ventricular–arterial coupling, pulmonary arterial stiffness parameters aregaining interest as prognostic indicators in PAH. Recently, pulmonary vascular stiffness indices have beenshown to predict the development of advanced PAH and mortality in paediatric PVD [67–71].

Serum biomarkers have the advantage of being relatively easy to obtain in peripheral blood and severalbiomarkers have been studied in paediatric PAH. Two serum biomarkers have been repeatedly shown tohave prognostic capabilities in paediatric PAH: NT-proBNP and uric acid. A recent meta-analysisconfirmed that NT-proBNP correlated strongly and consistently with survival in children with PAH, andthus can be used for risk stratification in this population. However, to be used as a treatment target orclinical end-point, biomarkers should be representative of the disease process and its evolution, which isoften difficult to demonstrate. Nevertheless, changes in NT-proBNP levels following treatment initiationwere recently shown to be predictive for survival in paediatric PAH, indicating that NT-proBNP qualifiesas a treatment goal [72, 73]. Baseline uric acid levels had previously been shown to correlate with survivalin paediatric PAH [74]. More recently, it was shown that the development of uric acid levels over timecorrelates with outcome in paediatric PAH [75]. These findings show that uric acid is capable ofpredicting outcome not only at baseline, but also during the disease course of PAH, and therefore mayalso qualify to be a treatment goal.

Recently, clinical worsening has been introduced as a composite end-point for large randomised controlledtrials (RCTs) in adults with PAH. Components of clinical worsening included unambiguous events such asdeath or lung transplantation, which are combined with softer events, including hospitalisations, need foradditional therapy and worsening of function. The use of clinical worsening as an end-point has beenvalidated in adults with PAH and the soft clinical worsening end-point components were shown to behighly predictive for subsequent mortality. These results have now been reproduced in the paediatric PAHpopulation using clinical worsening components: death, lung transplantation, non-elective PAH-relatedhospitalisations, including hospitalisations for atrial septostomies, initiation of i.v. prostanoids andfunctional deterioration (worsening of WHO FC, ⩾15% decrease in 6MWD or both) [76]. Moreover, this

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study showed that clinical worsening occurred with a high event rate in paediatric PAH, indicating thatclinical worsening may serve as a suitable end-point in future paediatric trials.

Monitoring daily physical activity has also been suggested as an alternative tool to assess functionalcapacity in children. A recent pilot study using three-axis accelerometry in 29 children with PAH and 60controls showed that physical activity was markedly decreased in children with PAH, and thataccelerometer output correlated with clinical disease severity markers and predicted outcome [77]. Largerstudies are in progress to validate the use of accelerometry output as a clinically meaningful end-point forclinical trials in paediatric PAH.

In summary, the emerging paediatric data provide increasing evidence and support for the riskstratification model proposed by the WSPH Paediatric Task Force in 2013, with some minor modificationsin 2018. For example, the prognostic significance of syncope could not be demonstrated and is thereforequestioned as a high-risk factor for poor outcomes. Importantly, upcoming evidence suggests that inpaediatric PAH striving for a low-risk profile using this WSPH paediatric risk assessment tool might alsobe used as treatment target, as has recently been suggested in adults [78–80].

Updates to the paediatric treatment algorithmThe prognosis of children with PAH has improved in the past decade owing to new therapeutic agentsand aggressive treatment strategies. However, the use of targeted pulmonary PAH therapies in children isalmost exclusively based on experience and data from adult studies, rather than evidence from clinicaltrials in paediatric patients. Due to the complex aetiology and relative lack of data in children with PAH,selection of appropriate therapies remains difficult. We propose a pragmatic treatment algorithm based onthe strength of expert opinion that is most applicable to children with IPAH (figure 2). The ultimate goalof treatment should be improved survival and to facilitate normal activities of childhood withoutself-limitation.

Background therapy with diuretics, oxygen, anticoagulation and digoxin should be considered on anindividual basis. Care should be taken to not overly decrease intravascular volume due to the pre-loaddependence of the right ventricle. Following the complete evaluation for all causes of PH, AVT isrecommended to help determine therapy.

In children with a positive AVT response, oral CCBs may be initiated [2–4]. In the child with a sustainedand improved response, CCBs may be continued, but patients may deteriorate, requiring repeat evaluationand additional therapy [81]. Clinical experience suggests that these children remain on CCBs in additionto targeted PAH therapy. For children with a negative AVT response or in the child with a failed or

Positive

No

Yes

Negative

Expert referral

General: consider diuretics,

oxygen, anticoagulation, digoxin Acute vasoreactivity testing

ERA or PDE5i (oral)

Oral/inhaled prostacyclin/prostacyclin agonist

Consider combination therapy

(sequential or upfront)

Lower risk

Serial reassessment#

Epoprostenol or

treprostinil (i.v./s.c.)Consider early combination

Higher risk

Atrial

septostomy

Lung

transplant

Oral CCB

Continue

CCB

Improved and

sustained

reactivity

Potts shunt

FIGURE 2 Paediatric idiopathic/familial pulmonary arterial hypertension treatment algorithm. CCB: calcium channel blocker; ERA: endothelinreceptor agonist; PDE5i: phosphodiesterase type 5 inhibitor. #: deterioration or not meeting treatment goals.

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non-sustained response to CCBs, risk stratification should determine additional therapy (table 6).Although the specific number of lower- or higher-risk criteria to drive therapeutic choices is not yetknown, a greater proportion of either should be considered as justification for therapy. As in adultpatients, determinants of higher risk in children include clinical evidence of right ventricular failure,progression of symptoms, WHO FC III or IV, significantly elevated or rising BNP/NT-proBNP levels,severe right ventricular enlargement or dysfunction and pericardial effusion. Additional haemodynamicparameters that predict higher risk include mPAP/mSAP ratio >0.75 [82], mRAP >10 mmHg and PVRI>20 WU·m2 [83]. Additional high-risk parameters include failure to thrive. In the child with a negativeacute vasoreactivity response and lower risk, initiation of oral monotherapy is recommended. Treatment ofchoice is an endothelin receptor antagonist (bosentan [83–90], ambrisentan [91, 92]) or phosphodiesterasetype 5 (PDE5) inhibitor (sildenafil [93–100], tadalafil [101, 102]).

Children who deteriorate on either endothelin receptor antagonists or PDE5 inhibitors may benefit fromconsideration of early combination therapy (add-on or up-front). If the child remains in a low-riskcategory, addition of inhaled prostacyclin (iloprost [103–106], treprostinil [107]) to background therapymay be beneficial. It is crucial to emphasise the importance of continuous repeat evaluation forprogression of disease in children on any of these therapies. In children who are at higher risk, initiationof i.v. epoprostenol [108, 109] or treprostinil [110] should be strongly considered. Experience using s.c.treprostinil in children is increasing as well [111–113]. In the child deteriorating with high-risk features,early consideration of lung transplantation and interventional palliative bridges are important.

Interventional palliative bridgesAtrial septostomyAtrial septostomy in children with IPAH has been performed to treat syncope, and improve cardiacoutput and systemic oxygen carrying capacity, especially in countries without easy access to targeted PHdrugs or in IPAH refractory to medical therapy, or as a bridge to lung transplantation [114]. Atrialseptostomy improves symptoms and quality of life in paediatric PAH, and may serve as a bridge to lungtransplantation [56]. It appears to be safe in centres with experience, and one study reported lungtransplantation-free and repeat-balloon atrial septostomy (BAS)-free survival at 30 days, 1 year and 5 yearswas 87%, 61% and 32%, respectively [115].

However, in most cases BNP levels do not change after BAS and it seems likely that the creation of thePotts shunt (see following subsection) may ultimately be the preferred procedure as in contrast to BAS itunloads the pulmonary vascular bed, as well as the right ventricle with preserved oxygenation to the upper

TABLE 6 Determinants of paediatric idiopathic/heritable pulmonary arterial hypertension risk

Lower risk Determinants of risk Higher risk

No Clinical evidence of RV failure YesNo Progression of symptoms Yes>350 6MWT (>6 years old) m <350

Normal Growth Failure to thriveI, II WHO FC III, IV

Minimally elevated Serum BNP/NT-proBNP Significantly elevatedRising level

Echocardiography RA/RV enlargementReduced LV size

Increased RV/LV ratioReduced TAPSELow RV FAC

Pericardial effusion

Systemic CI >3.0 L·min−1·m−2 Haemodynamics Systemic CI <2.5 L·min−1·m−2

Systemic venous saturation >65% mRAP >10 mmHgAcute vasoreactivity PVRI >20 WU·m2

Systemic venous saturation <60%PACI <0.85 mL·mmHg−1·m−2

RV: right ventricle; 6MWT: 6-min walk test; WHO: World Health Organization; FC: Functional Class; BNP:brain natriuretic peptide; NT-proBNP: N-terminal pro-BNP; RA: right atrium; LV: left ventricle; FAC:fractional area change; TAPSE: tricuspid annular plane systolic excursion; CI: cardiac index; mRAP: meanright atrial pressure; PVRI: pulmonary vascular resistance index; WU: Wood Units; PACI: pulmonaryarterial compliance index.

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body including coronary and cerebral vessels. Relative contraindications for atrial septostomy include1) mRAP >20 mmHg, 2) resting arterial oxygen saturation <90%, 3) severe right ventricular failure and4) patients with impending death.

Atrial septostomy may be considered in the child with worsening PAH despite optimal medical therapy,but should be considered before the later stages with increased risk. Atrial septostomy can be consideredin patients with WHO FC III and IV symptoms and recurrent syncope on combined medical therapy, aspalliative bridge to transplant, increasing the chance for survival while waiting for a donor organ.

Reversed Potts shuntThe Paediatric Task Force also discussed whether the reversed Potts shunt should be offered to children withsevere IPAH/HPAH who are refractory to medical therapy.

Surgical creation of a palliative reversed Potts shunt (left pulmonary artery to descending aorta) has beendescribed as a new option for severely ill children with suprasystemic IPAH [56, 116]. This surgicalprocedure implies the creation of a connection between the left pulmonary artery and the descendingaorta, which allows right-to-left shunting, similar to a patient with patent ductus arteriosus-relatedEisenmenger syndrome. The use of a reversed Potts shunt in suprasystemic PH is considered advantageouscompared with atrial septostomy as it provides high oxygen saturated blood to the coronary arteries andthe central nervous system, and only causes desaturation of the lower body. Another benefit arises from itseffect on haemodynamics by the relief of right ventricular pressure overload in systole and, in part, also indiastole, with a subsequent reduction in shifting of the interventricular septum towards the left ventriclewith an improvement in systolic and diastolic left ventricular performance. A run-off through the Pottsshunt, if too big, with decreased pulmonary perfusion and extreme desaturation of the lower body, withsubsequent undersupply of the myocardium and the brain, should be avoided. The procedure may beconsidered in patients with suprasystemic PH refractory to any medical treatment, including combinedtherapy presenting with WHO FC IV symptoms.

The largest series published consisted of 24 children with drug-refractory PAH in which a permanentPotts shunt was created (19 surgical left pulmonary artery–descending aorta, six via stenting of a persistentductus arteriosus) [117]. Six patients experienced severe post-operative complications and there were threeearly deaths related to low cardiac output. After a median follow-up of 2.1 years, the 21 survivors showedpersistent improvement in functional capacities and none of the patients had syncope or overt rightventricular failure [76]. These favourable long-term results suggest that creation of a Potts shunt can be avaluable alternative, or bridge to bilateral lung transplantation, at least in selected cases.

Recently, several case series demonstrated the feasibility of the pure catheter-based interventionalimplementation of the connection between the left pulmonary artery and the descending aorta [118]. Themost elegant method is obviously the implantation of a stent in a still patent persistent ductus arteriosus,which is not infrequently present in infants and young children. This procedure is an established methodin CHD with duct-dependent circulation and can be established with considerable low peri-procedural riskin experienced centres. The interventional de novo creation of a left pulmonary artery–descending aortaconnection with a covered stent from the left pulmonary artery or descending aorta side [119] has beenshown to be feasible, but currently must be considered a high-risk procedure in patients with end-stagePAH who are too sick to undergo surgery and only in a programme with expertise in performing thisprocedure. SALNA et al. [120] described a novel successful approach to the Potts shunt in a young adultwith IPAH using a unidirectional valved shunt from the main pulmonary artery to the descending aorta,which has the advantage of preventing any back flow from the aorta when the PAP is subsystemic andduring diastole. Whether this will prove to be a preferred approach remains to be seen. The currentWSPH Paediatric Task Force decided to include the Potts shunt in the treatment algorithm, but cautionsthat it should only be done in selected patients in a centre with the expertise to perform the procedure,including ECLS back-up (figure 2). Whether this is preferred over an atrial septostomy will require furtherexperience and study.

Clinical trial designThe Paediatric Task Force further discussed whether we can develop new paediatric-specific clinicalend-points in clinical trial design.

Our understanding of the pathobiology and treatment of children with PH has improved considerablyduring the past 20 years, but treatment is still based on clinical trial evidence of efficacy from clinical trialdata in adults, individual clinical experience, registry data, short-term trials and open-label studies. RCTshave not been conducted. Clinical trials in adults are most helpful when conducted on the mosthomogeneous, “purest” form of the disease, i.e. IPAH, but this is rare in children. Growth and

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development entail constant hormonal and metabolic change necessitating age-related study,understanding the effect on long-term outcome is crucial and choice of end-points is difficult [121]. TheEuropean Medicines Agency (EMA) and US FDA both require RCTs, but the EMA emphasises the needfor pharmacokinetic and safety studies, which have been done in some instances, while the US FDA seeksto include a clinical end-point for evidence of efficacy. Relevant clinical end-points include death,transplantation and hospitalisation, and determining how the child feels. The traditional means ofevaluation in adults, such as the 6MWT, are obviously not applicable to young children. Potentialsurrogate end-points in children include weight, echocardiography, biomarkers (primarily NT-proBNP),MRI and exercise testing. None of these possibilities have been fully validated. Haemodynamic evaluationdoes not seem to be an appropriate end-point since there are ethical considerations and sequential studiesare not known to relate to long-term outcome. Recruitment, retention and evaluation of a continuallymaturing small population of children is a considerable challenge.

However, since the 5th WSPH, paediatric-specific biomarkers, such as functional classification, TAPSE andNT-proBNP, growth and composite clinical end-points have been evaluated. TAPSE, NT-proBNP andWHO FC identified transplant-free survival in 70 children with PAH [53]. Height for weight was alsoidentified as a clinical end-point [122]. The Panama “Paediatric Functional Class” correlated well withoutcome [60]. A composite end-point of clinical worsening composed of death, lung transplantation andinitiation of parenteral prostanoid therapy was identified [53, 76]. A novel approach to clinical evaluationof treatment efficacy or disease progression may be the use of home accelerometers and a pilot studysuggested that there is a difference in spontaneous physical activity in children with PAH compared withcontrols [77]. Thus, paediatric-specific clinical end-points and trial design are evolving.

ConclusionsDespite many unique characteristics, children with PH are often assessed and managed based on adult PHguidelines. This current WSPH Paediatric Task Force had an opportunity to further highlight some of theinherent differences between children and adults with PH, novel findings in paediatric PH since the 5thWSPH meeting in 2013, and develop additional current paediatric-specific recommendations. The current2018 6th WSPH classification incorporates the growing population of children with developmental lungdiseases, such as BPD and CDH, complex CHD, and novel mutations. The Paediatric Task Forceaddressed a new definition for PAH and AVT in children, a novel palliative bridge approach with thereversed Potts shunt, and clinical trial design. The field of paediatric PH still requires futurepaediatric-specific clinical trials in order to develop specific treatment strategies and clinical end-points forchildren with PH.

Conflict of interest: E.B. Rosenzweig reports institutional grants from Actelion, GSK, Gilead, Bayer and UnitedTherapeutics/Lung Biotech, outside the submitted work. S.H. Abman reports grants from Shire and UnitedTherapeutics, outside the submitted work. I. Adatia reports personal fees (for data and safety monitoring board workfor selexipag trial in children, and for clinical oversight committee work for macitentan trial in children) from Actelion,personal fees (for data and safety monitoring board work for citruline trial in children) from Asklepion, and personalfees (for clinical oversight committee work for tadalafil trial in children) from Eli Lilly, outside the submitted work.M. Beghetti reports grants and personal fees from Actelion, grants, personal fees and non-financial support from BayerHealthcare, and personal fees from GSK, Eli Lilly, MSD and Pfizer, during the conduct of the study. D. Bonnet reportspersonal fees from Actelion Pharmaceuticals Novartis, Bayer Healthcare and Eli Lilly, outside the submitted work.S. Haworth has nothing to disclose. D.D. Ivy: the University of Colorado School of medicine contracts with Actelion,Bayer, Lilly and United Therapeutics for D.D. Ivy to be a consultant and perform research studies. R.M.F. Berger:University Medical Center Groningen contracts with Actelion and Lilly for consultancy and advisory board activities ofR.M.F. Berger.

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92 Zuckerman WA, Leaderer D, Rowan CA, et al. Ambrisentan for pulmonary arterial hypertension due tocongenital heart disease. Am J Cardiol 2011; 107: 1381–1385.

93 Unegbu C, Noje C, Coulson JD, et al. Pulmonary hypertension therapy and a systematic review of efficacy andsafety of PDE-5 inhibitors. Pediatrics 2017; 139: e20161450.

94 Abman SH, Kinsella JP, Rosenzweig EB, et al. Implications of the U.S. Food and Drug Administration warningagainst the use of sildenafil for the treatment of pediatric pulmonary hypertension. Am J Respir Crit Care Med2013; 187: 572–575.

95 Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primarypulmonary hypertension. Heart 2000; 84: E4.

96 Apitz C, Reyes JT, Holtby H, et al. Pharmacokinetic and hemodynamic responses to oral sildenafil duringinvasive testing in children with pulmonary hypertension. J Am Coll Cardiol 2010; 55: 1456–1462.

97 Barst RJ, Layton GR, Konourina I, et al. STARTS-2: long-term survival with oral sildenafil monotherapy intreatment-naive patients with pediatric pulmonary arterial hypertension. Eur Heart J 2012; 33: Suppl. 1, 979.

98 Barst RJ, Ivy DD, Gaitan G, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oralsildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation 2012; 125:324–334.

99 Humpl T, Reyes JT, Erickson S, et al. Sildenafil therapy for neonatal and childhood pulmonary hypertensivevascular disease. Cardiol Young 2011; 21: 187–193.

100 Humpl T, Reyes JT, Holtby H, et al. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterialhypertension: twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation 2005; 111:3274–3280.

101 Rosenzweig EB. Tadalafil for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother 2010;11: 127–132.

102 Takatsuki S, Calderbank M, Ivy DD. Initial experience with tadalafil in pediatric pulmonary arterialhypertension. Pediatr Cardiol 2012; 33: 683–688.

103 Limsuwan A, Wanitkul S, Khosithset A, et al. Aerosolized iloprost for postoperative pulmonary hypertensivecrisis in children with congenital heart disease. Int J Cardiol 2008; 129: 333–338.

104 Ivy DD, Doran AK, Smith KJ, et al. Short- and long-term effects of inhaled iloprost therapy in children withpulmonary arterial hypertension. J Am Coll Cardiol 2008; 51: 161–169.

105 Melnick L, Barst RJ, Rowan CA, et al. Effectiveness of transition from intravenous epoprostenol to oral/ inhaledtargeted pulmonary arterial hypertension therapy in pediatric idiopathic and familial pulmonary arterialhypertension. Am J Cardiol 2010; 105: 1485–1489.

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106 Tissot C, Beghetti M. Review of inhaled iloprost for the control of pulmonary artery hypertension in children.Vasc Health Risk Manag 2009; 5: 325–331.

107 Krishnan U, Takatsuki S, Ivy DD, et al. Effectiveness and safety of inhaled treprostinil for the treatment ofpulmonary arterial hypertension in children. Am J Cardiol 2012; 110: 1704–1709.

108 Lammers AE, Hislop AA, Flynn Y, et al. Epoprostenol treatment in children with severe pulmonaryhypertension. Heart 2007; 93: 739–743.

109 Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associatedcongenital heart defects. Circulation 1999; 99: 1858–1865.

110 Siehr SL, Ivy DD, Miller-Reed K, et al. Children with pulmonary arterial hypertension and prostanoid therapy:long-term hemodynamics. J Heart Lung Transplant 2013; 32: 546–552.

111 Levy M, Del Cerro MJ, Nadaud S, et al. Safety, efficacy and management of subcutaneous treprostinil infusionsin the treatment of severe pediatric pulmonary hypertension. Int J Cardiol 2018; 264: 153–157.

112 Levy M, Celermajer DS, Bourges-Petit E, et al. Add-on therapy with subcutaneous treprostinil for refractorypediatric pulmonary hypertension. J Pediatr 2011; 158: 584–588.

113 Ferdman DJ, Rosenzweig EB, Zuckerman WA, et al. Subcutaneous treprostinil for pulmonary hypertension inchronic lung disease of infancy. Pediatrics 2014; 134: e274–e278.

114 Chiu JS, Zuckerman WA, Turner ME, et al. Balloon atrial septostomy in pulmonary arterial hypertension: effecton survival and associated outcomes. J Heart Lung Transplant 2015; 34: 376–380.

115 Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe primary pulmonaryhypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment. J Am Coll Cardiol1998; 32: 297–304.

116 Baruteau AE, Serraf A, Levy M, et al. Potts shunt in children with idiopathic pulmonary arterial hypertension:long-term results. Ann Thorac Surg 2012; 94: 817–824.

117 Baruteau AE, Belli E, Boudjemline Y, et al. Palliative Potts shunt for the treatment of children withdrug-refractory pulmonary arterial hypertension: updated data from the first 24 patients. Eur J Cardiothorac Surg2015; 47: e105–e110.

118 Schubert S, Peters B, Berger F. Interventional re-opening of a PDA for reverse Potts shunt circulation after ADOI implantation in a child. Catheter Cardiovasc Interv 2017; 89: E133–E136.

119 Esch JJ, Shah PB, Cockrill BA, et al. Transcatheter Potts shunt creation in patients with severe pulmonary arterialhypertension: initial clinical experience. J Heart Lung Transplant 2013; 32: 381–387.

120 Salna M, VanBoxtel B, Rosenzweig EB, et al. Modified Potts shunt in an adult with idiopathic pulmonary arterialhypertension. Ann Am Thorac Soc 2017; 14: 607–609.

121 Adatia I, Haworth SG, Wegner M, et al. Clinical trials in neonates and children: report of the pulmonaryhypertension academic research consortium pediatric advisory committee. Pulm Circ 2013; 3: 252–266.

122 Ploegstra MJ, Ivy DD, Wheeler JG, et al. Growth in children with pulmonary arterial hypertension: alongitudinal retrospective multiregistry study. Lancet Respir Med 2016; 4: 281–290.

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The importance of patient perspectives inpulmonary hypertension

Michael D. McGoon1, Pisana Ferrari2, Iain Armstrong3, Migdalia Denis4,Luke S. Howard5, Gabi Lowe6, Sanjay Mehta7, Noriko Murakami8 andBrad A. Wong9

Number 13 in the series“Proceedings of the 6th World Symposium on Pulmonary Hypertension”Edited by N. Galiè, V.V. McLaughlin, L.J. Rubin and G. Simonneau

Affiliations: 1Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, MN, USA. 2PulmonaryHypertension Association Europe, Vienna, Austria. 3Pulmonary Hypertension Association UK, Sheffield, UK.4Sociedad Latina de Hipertensión Pulmonar, Venezuela. 5National Pulmonary Hypertension Service,Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK. 6Jenna Lowe Trust, Republic ofSouth Africa. 7London Health Sciences Centre, Division of Respirology, Dept of Medicine, Schulich School ofMedicine, Western University and Pulmonary Hypertension Association Canada, London, ON, Canada.8Pulmonary Hypertension Association Japan, Tokyo, Japan. 9Pulmonary Hypertension Association, SilverSpring, MD, USA.

Correspondence: Michael D. McGoon, Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 1stStreet SW, Rochester, MN 55905, USA. E-mail: mdmcgoon@gmail.com

@ERSpublicationsAnalysis and discussion on the importance of patients’ perspectives in pulmonary hypertensionhttp://ow.ly/edOt30mgYoI

Cite this article as: McGoon MD, Ferrari P, Armstrong I, et al. The importance of patient perspectives inpulmonary hypertension. Eur Respir J 2019; 53: 1801919 [https://doi.org/10.1183/13993003.01919-2018].

ABSTRACT The assessment of objective measurement of cardiopulmonary status has helped us achievebetter clinical outcomes for patients and develop new therapies through to the point of market access;however, patient surveys indicate that more can be done to improve holistic care and patient engagement.In this multidisciplinary review, we examine how clinical teams can acknowledge and embrace theindividual patient’s perspective, and thus improve the care for individual patients suffering frompulmonary hypertension by cultivating the importance and relevance of health-related quality of life indirect clinical care. At the individual level, patients should be provided with access to accredited specialistcentres which provide a multidisciplinary approach where there is a culture focused on narrative medicine,quality of life, shared decision making and timely access to palliative care, and where there is participationin education. On a larger scale, we call for the development, expansion and promotion of patientassociations to support patients and carers, lobby for access to best care and treatments, and provide inputinto the development of clinical trials and registries, focusing on the patients’ perspective.

Received: Oct 07 2018 | Accepted: Oct 09 2018

Copyright ©ERS 2019. This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.

https://doi.org/10.1183/13993003.01919-2018 Eur Respir J 2019; 53: 1801919

| SERIESWORLD SYMPOSIUM ON PULMONARY HYPERTENSION

IntroductionThis article provides an overview of the role of the patient’s perspective in understanding and managingpulmonary hypertension (PH). “Patient perspective” is the patient’s experience of PH and its impact onhim/her and caregivers, including symptomatic, intellectual, psychosocial, spiritual and goal-orienteddimensions of the disease and its treatment. Implicit in the concept of perspective is how it can beeffectively communicated, understood and acted upon by others involved with the patient, includingprimary and subspecialty healthcare providers (HCPs), adjunctive professional providers (e.g. mentalhealth and spiritual counsellors), family and social network, and health-related influencers (e.g.government, insurers and medical industry).

Assessing the patient perspectiveSurveysSurveys of pulmonary arterial hypertension (PAH) patients provide insights into patients’ perceptions ofimpactful aspects of their disease [1–5]. A general conclusion among surveys is that although the clinicaldefinition of the severity of disease appropriately includes symptomatology, exercise capacity, biomarkers,invasive and non-invasive haemodynamic measurements, and survival, these parameters do not capturethe extensive realm of physical, emotional and psychosocial issues which affect patients and theircaregivers (figure 1).

Health-related quality of life measuresGeneric and disease-specific measures of “health-related quality of life” (HRQoL) have been evaluated inPH patients (table 1) [6–18]; physical/functional, emotional and social aspects of HRQoL are negativelyimpacted by PH [19–21]. PH therapies produce a variable benefit in HRQoL (table 2) [22–42]. Somemeasures of HRQoL may also correlate with survival prognosis [43]. Importantly, medications directedtowards concomitant health issues (e.g. depression, anxiety and sleep disorders) [44] or non-pharmacological therapies (e.g. exercise programmes, psychosocial counselling, health coaching and accessto nurse specialists or palliative care strategies) [45–51] may improve HRQoL.

SymptomsExercise capacity

BiomarkersHaemodynamics

Survival

Delay in diagnosisMultiple physicians and institutions

before correct diagnosisAnxiety, fearSelf doubt

Apprehension of invasive procedures(right heart catheterisation)

Overall quality of lifeEmployment, education and social life

Loss of intimacyIsolation, loneliness, exclusion, lack of understanding by others

Frustration, worry, depressionSensitivity about impact on others

Need for informationInability to perform activities others take for granted

Financial impact: earning and medical costsAccess to care

Conc

erns

dur

ing

man

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Conc

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dur

ing

diag

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FIGURE 1 Surveys of patients and caregivers suggest that traditional parameters of pulmonary hypertensionseverity may be the “tip of the iceberg” when the broader range of patient concerns is considered.

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Current status“Patient perspective” can be viewed through two different but related lenses: 1) the individual’s perspectiveas it relates to each patient’s individual situation and 2) the aggregate perspective of the PH population,i.e. a perspective of common denominators despite unique individual variations.

Individual patient perspectiveRecognition of the importance of the individual patient’s perspective regarding their experience of PH isexemplified by the evolving patient/HCP clinical interaction. The traditional model of this relationship(exploration of symptoms and physical findings with tests culminating in a diagnosis and treatmentrecommendations) has been the subject of algorithms and guidelines [45, 52–54]. The management of PHis increasingly complex, including medications administered by different routes with unpredictable degreesof beneficial and adverse effects, options for invasive or surgical interventions, differences in practicesettings and access to treatment from centres to community practices, decreased time spent with patients,and considerations of cost and follow-up. Increasing recognition of this complexity of PH and itstreatment, and of the importance of the individual patient’s perspective, including their understanding ofPH and appreciation of the burden of their illness and impact on their HRQoL, requires a bidirectionalexchange of opinions and objectives between patients and HCPs, in order to promote integration of thepatient perspective into the patient/HCP relationship. This patient-centred collaborative care approach isfinding expression in concepts such as narrative medicine, shared decision making and palliative care,leading to greater patient engagement, involvement and empowerment in management of their illness [55].

Narrative medicineA key feature of patient-centred medicine in chronic conditions such as PH is that the patient presentswith a spectrum of symptoms and associated psychological responses which occur within a sociologicaland cognitive framework unique to that patient, and which contribute to the patient’s fears, copingmechanisms and goals. Treatment focused exclusively on the underlying disease often fails to address theripples of impact provoked by PH which may become the main source of concern to the patient. Theability of HCPs to “acknowledge, absorb, interpret, and act on the stories and plights of others” has beenreferred to as narrative competence, the foundation of narrative medicine [56]. The intention of narrative

TABLE 1 Summary of measures of health-related quality of life used in pulmonary arterialhypertension (PAH)

Measure [ref.] Domains Items n Recall period

GenericSF-36 [9] Physical functioning, role limitations physical, bodily

pain, general health, vitality, social functioning, rolelimitations emotional, mental health

36 Now to past4 weeks

EQ-5D [10] Health state description: mobility, self-care, usualactivities, pain/discomfort, anxiety/depression; overall

health status (visual analogue scale)

51 Today

NHP [11] Mobility, pain, social isolation emotional reactions,energy level, sleep

38 At the moment

HADS [12] Anxiety, depression 14 At the momentPAH specificCAMPHOR [13] Overall symptoms (energy, breathlessness, mood),

functioning, quality of life65 Today

MLHFQ [14] Physical, emotional 21 4 weeksLPH [15] Physical, emotional 21 1 weekCHFQ [16] Dyspnoea, fatigue, emotional function, mastery 20 2 weeksemPHasis-10 [17] Unidimensional 10 At the momentPAH-SYMPACT [18] Respiratory symptoms, tiredness, cardiovascular

symptoms, other symptoms, physical activities, dailyactivities, social impact, cognition, emotional impact

41 24 h forsymptoms;

7 days for imacts

SF-36: Medical Outcomes Study 36-item short form; EQ-5D: EuroQol Group 5-Dimension Self-ReportQuestionnaire; NHP: Nottingham Health Profile; HADS: Hospital Anxiety and Depression Scale; CAMPHOR:Cambridge Pulmonary Hypertension Outcome Review; MLHFQ: Minnesota Living with Heart FailureQuestionnaire; LPH: Living with Pulmonary Hypertension questionnaire; CHFQ: Chronic Heart FailureQuestionnaire; emPHasis-10: 10-question survey proposed by the Pulmonary Hypertension Association UK.Information based on and expanded from [6].

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TABLE 2 Effect of pulmonary arterial hypertension (PAH) medications on health-related quality of life (HRQoL) measures

Study [ref.] Subjectsn

Drug HRQoLmeasurement

Time tomeasurement

Domains significantly improved#

ERAsARIES-1 [26] 201 Ambrisentan

2.5–10 mgSF-36 Physical: none; mental: none

ARIES-2 [26] 192 Ambrisentan2.5–5.0 mg

SF-36 12 weeks Physical: function; mental: none

EARLY [27] 185 Bosentan SF-36 24 weeks Physical: none; mental: none; healthtransition index

SERAPHIN [29] 742 Macitentan 3 or 10 mg SF-36 version 2 6 months Physical: function, role, pain; mental:vitality, social function, emotional

role, mental healthPDE5 inhibitors andsGC stimulatorsSildenafil in PPH [32] 22 Sildenafil 25, 50 or

100 mgCHFQ 6 weeks Dyspnoea, fatigue

SUPER-1 [31] 278 Sildenafil (pooled 20,40 or 80 mg doses)

SF-36 12 weeks Physical: function, general health;mental: vitality

EQ-5D Utility index score

PHIRST [30] 405 Tadalafil 40 mg SF-36 Physical: function, role, pain, generalhealth; mental: vitality, social function

EQ-5D Visual analogue scale; UK utility indexscore; USA utility index score

PATENT-1 [28] 443 Riociguat EQ-5D NS

LPH SignificantProstanoids andprostacyclin receptoragonistsEpoprostenol in

PPH [34]81 Epoprostenol CHFQ Dyspnoea, fatigue, emotional function,

masteryNHP Emotional reaction, sleep

Treprostinil s.c. inPAH [39]

470 Treprostinil MLHFQ Physical score

Iloprost for severePH [37]

203 Inhaled iloprost EQ-5D Overall health status (visualanalogue scale)

SF-12 NS

Beraprost forPAH [33]

116 Beraprost MLHFQ 3, 6, 9 and12 months

NS

Treprostinil inCTD-PAH [38]

90 Treprostinil MLHFQ NS

GRIPHON [41] 1156 Selexipag None reportedCombination therapyPACES [40] 267 Sildenafil added to

epoprostenolSF-36 Physical: function, role, general

health; mental: vitality, socialfunctioning, mental health

TRIUMPH [36] 235 Treprostinil added tooral bosentan orsildenafil therapy

MLHFQ Global, physical scores

AMBITION [35, 42] 500 Upfront ambrisentanand tadalafil

None initiallyreported;

CAMPHOR, SF-36

Improved only health transition scorein SF-36 versus monotherapy; botharms improved all domains of both

instruments

ERA: endothelin receptor agonist; SF-36: Medical Outcomes Study 36-item short form; PDE5: phosphodiesterase type 5; sGC: soluble guanylatecyclase; PPH: primary pulmonary hypertension; CHFQ: Chronic Heart Failure Questionnaire; EQ-5D: EuroQol Group 5-Dimension Self-ReportQuestionnaire; NS: non-significant; LPH: Living with Pulmonary Hypertension questionnaire; NHP: Nottingham Health Profile; MLHFQ:Minnesota Living with Heart Failure Questionnaire; CTD: connective tissue disease; SF-12: Medical Outcomes Study 12-item short form;CAMPHOR: Cambridge Pulmonary Hypertension Outcome Review. #: compared with placebo. Information condensed and updated from [22].

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medicine is to adopt a broad perspective in terms of appreciating the entire spectrum of the patient’spresentation and also by enlisting elements of other disciplines (such as the humanities and literature) tobest understand that spectrum [57, 58]. The contribution of narrative knowledge is to provide a balance orcontext for the scientific dimension of medicine [59, 60]. Narrative medicine addresses the issue of how aunique individual under unique circumstances can be uniquely helped, whereas scientific medicine askshow the features of patients’ presentations make them statistically similar or dissimilar to a demographicwhich responds in a given way to a particular management strategy.

In a practical sense, patients should be able to discuss with HCPs not only symptoms, but their experienceof their individual illness in terms of functional burden and psychosocial impact, as well as their objectivesof treatment. HCPs should encourage patients to express their perspective, be receptive to and attempt tocomprehend and incorporate their views into management. An interaction of this type is crucial since theHCPs’ goals for PH therapy tend towards achieving symptomatic and functional improvement, delayingworsening of disease, and extending life expectancy. Patients may emphasise quality of life, capability forcoping with daily demands and minimising the burdens of complex therapies [61]. This mutually respectfulbidirectional interaction would establish common ground for the process of shared decision making.

Shared decision makingThe definition of shared decision making is succinctly stated in commonsense terminology: “aconversation between the clinician [and others, such as pastoral counsellor and social worker] and thepatient in which they figure out together what to do to address the patient’s situation” [62]. This conceptincorporates components that are “iterative and interactive steps in a conversational dance”, which include:clarifying the patient’s situation; identifying the aspect of the situation that requires action; recognisingthat more than one way of addressing the situation exists; discussing the pros and cons of the availableapproaches with the patient and caregivers; and gaining understanding of what the patient values aboutthese options, and why [62].

For the patient perspective to be valid and relevant, it must be informed by an accurate comprehension bythe patient of the facts of the situation. In some medical disciplines, decision aid tools have beendeveloped to facilitate the patient’s understanding of the clinical context and potential outcomes ofalternative treatment strategies, including those which are probabilistic in nature. Decision aids promotethe patient’s knowledge, estimation of treatment risk and engagement in the discussion. However, therehas not yet been a demonstrable benefit in terms of outcome [62]. Standardised decision aids have notbeen developed for PH management.

Palliative carePalliative care was traditionally a change in the focus of care at the end of life away from therapiesintended to cure or slow the progression of disease, to management of physical symptoms (e.g. pain) andemotional distress. Palliative care is currently better understood as an interdisciplinary approach topromoting quality of life and reducing suffering at any stage of chronic disease [63]. Palliative care hasbeen defined as “patient and family-centered care that optimizes quality of life by anticipating, preventing,and treating suffering. Palliative care throughout the continuum of illness involves addressing physical,intellectual, emotional, social, and spiritual needs and to facilitate patient autonomy, access to information,and choice” [64].

In a survey of 774 PAH patients, 276 analysable responses revealed that awareness of and access topalliative care resources were low despite marked impairment of HRQoL, physical and emotionalwellbeing, social activity, and pain control [49]. This degree of diminished HRQoL is consistent with thatfound in other studies [20, 49, 65–69]. Since PH-targeted therapies do not usually alleviate all physicalsymptoms or necessarily improve patients’ psychosocial function, a role for integrating palliative caretechniques and expertise early to optimise HRQoL has been advocated [70].

Obstacles to expanding the use of palliative care in PH patients are lack of awareness of its purpose(e.g. symptom management and psychological wellbeing), inadequate local medical payer coverage,misunderstanding palliative care as synonymous with hospice care and implies “giving up” or beingresigned to an imminent death, and not understanding that PH-targeted medications can continue withina palliative care strategy [63]. Therapies for PH have side-effects which may negatively impact HRQoLdespite achieving benefits in terms of haemodynamics and some symptoms. Thus, strategies to focus onHRQoL during otherwise beneficial treatment arguably become even more imperative.

PAH population perspectivePatients and caregivers need support from others, which can take many different forms: awareness thatothers are confronting similar struggles, sharing experiences and information, suggesting solutions to

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shared challenges, attending formal educational events, participating in collaborative efforts to advancecare, and unifying around shared needs and goals to raise awareness.

Patient associationsOrganisations have been created to facilitate the expression of the PH population perspective and to aid indealing with the needs of PH patient communities worldwide (table 3).

Support groupsSupport groups are smaller local patient networks with less infrastructure and expense which provideinformal interactions to offer empathetic sharing of experiences and education. Support groups may beindependent or promoted by medical institutions or pharmaceutical companies, and may receive logisticalor financial assistance from national patient associations. Such local/regional support groups exist in manycountries especially in North America (e.g. more than 240 identified by the Pulmonary HypertensionAssociation (PHA) in the USA), but also in a number of European, Latin American, Asian and Africannations.

Education/awarenessAcquiring information about PH is an essential coping mechanism for many patients. In addition, theperception that others lack awareness and knowledge about their disease is distressing. Insights provided topatients in subspecialty clinics by dedicated staff helps address these needs [50, 71], but publicdissemination of information also is central to patient organisations’ mission. A pivotal component of thiseffort has been to increase awareness of PH both in HCPs and the general population in order to improvethe timeliness and accuracy of PH diagnosis in patients presenting with suggestive symptoms (e.g. the“Early Diagnosis” campaign of the US PHA), catalysed by observations that there is a significant intervalbetween symptom onset and definitive diagnosis [4, 5, 72].

The annual World Pulmonary Hypertension Day was first held on May 5, 2012 in Madrid, Spain to raiseglobal awareness and this was adopted by PHA Europe (http://worldphday.org). The World PulmonaryHypertension Day has gained increasing momentum, with 86 global partner organisations involved in aninternational awareness campaign in 2018. Through its involvement of national political and healthauthorities, academia, HCPs, and celebrities, World Pulmonary Hypertension Day has generated mediainterest and awareness across the world.

Evaluation of patients at referral centres frequently identifies aspects of pre-referral management that donot align with best practices and guidelines [73]. Concerned physicians and patients in the PH communityre-emphasised the need for professional education, including periodic international symposia (e.g. theWorld Symposia on Pulmonary Hypertension (WSPH) [74] and the European Society of Cardiology(ESC)/European Respiratory Society (ERS) guidelines for PH [45], culminating in publications ofstate-of-the-art knowledge summaries, management guidelines and algorithms), web-based educationalprogrammes, on-site preceptorships and PH-focused publications.

Access to healthcare/coverageDisparity in healthcare access is a worldwide issue which patient organisations address on behalf of theirconstituencies. A major concern of patients, their families and primary HCPs is where the patient shouldbe most effectively managed. This concern embodies many elements: how can qualified experts andwell-resourced medical facilities be identified; how can geographical and financial constraints be navigated;by whom are complex treatment strategies best prescribed, managed and followed; and what is the bestapproach to medical emergencies? The answers are largely dependent on the geographical location andnationality of the patient.

In the USA, under the aegis of the PHA, the PH Care Centers (PHCC; https://phassociation.org/phcarecenters) programme of site accreditation was developed to identify facilities which are staffed andequipped to deliver patient management that meets expert consensus for best practices.

The European Reference Networks (ERNs; https://ec.europa.eu/health/ern_en) for rare diseases, launchedin 2017, introduced a European Union (EU) accreditation system for centres of expertise for rare diseasesto whom referrals can be made for “virtual” consults. The EU initiative is intended to facilitatecross-border sharing of knowledge, experience, medical research, teaching, training and resources. Patientsare closely involved and each ERN has a Patient Advisory Group (ePAG) which advises on strategy, policyand organisational processes. PHA Europe has three representatives on ERN Lung.

Latin American and Asian countries also confront difficulties with early diagnosis and access to treatmentfor PH patients due to lack of knowledge and insufficient legal frameworks to protect the right to good

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TABLE 3 Representative pulmonary hypertension (PH)-focused patient organisations#

Organisation (website) Region; beginning Constituency Mission Major activities

Pulmonary HypertensionAssociation(https://phassociation.org)

USA; 1991 PAH and CTEPH patients, caregivers,physicians and allied health professionals,

researchers; membership: >16000

“To extend and improve the lives of thoseaffected by PH”

Research funding support; advocacy; patientsupport and education, medical educationand public awareness and education; PH

care centre accreditation

Pulmonary HypertensionAssociation Canada(www.phacanada.ca)

Canada; 1999 asPulmonary Hypertension

Society of Canada,renamed PHA Canada in

2008

All PH patients and their caregivers,physicians and allied healthcare

professionals; engagement: >1000 (note noformal membership)

“To empower the Canadian PH communitythrough awareness, advocacy, education,

research and patient support”

Patient/caregiver support and education;advocacy; medical education; public

awareness and education; research fundingsupport

Pulmonary HypertensionAssociation Japan(www.pha-japan.ne.jp)

Japan; 1999 PAH and CTEPH patient, caregivers;membership: >200

“Promotion of social awareness andunderstanding about PH”

Advocacy; patient support and education,public awareness; promoting early diagnosis

and access to new drugs

Pulmonary HypertensionAssociation UK(www.phauk.org)

UK; 2000 PAH and CTEPH patients, caregivers,physicians and allied health professionals,researchers; membership: >4000 patients

and >200 HCPs

To advance the education and awarenessof the general public and medical

professionals of the condition known asPH; the relief of need of sufferers of PH,their families and carers through the

provision of financial assistance towards,but not exclusively, respite care, travelgrants and equipment grants at the

discretion of the executive committee, asand when resources allow

Patient and family support, high-qualityonline/printed support materials, supportand advocacy for all patients with all formsof PH, increasing disease awareness withinall areas of healthcare and general public;

reduce the time to diagnosis for PH;improve the health wellbeing and quality oflife of patients with PH and their kinship;

ensure equity of access in the UK toevidence-based PH treatments for all;

reduce the financial hardship incurred byliving with PH

Pulmonary HypertensionAssociation Europe(www.phaeurope.org)

Europe; 2003 Umbrella organisation for 40 patientassociations in 33 countries

“Promotion of social awareness andunderstanding about PH”

Improve access to expert care, improveawareness and screening, encourage

clinical research and innovation, empowerpatient groups, ensure the availability of

psychosocial support

Latin Society of PulmonaryHypertension (SociedadLatina de HipertensiónPulmonar)(www.sociedadlatinahp.org)

Latin America; 2005 Umbrella organisation for 21 LatinAmerican patient associations in 16

countries

“To raise awareness about PH throughoutLatin America”

Promoting optimal level of care for PAHpatients, availability of quality treatments,research on new drugs and therapies,

awareness and public policies; umbrellaorganisation supporting regional patientorganisations; awareness campaignsinclude: “Labios Azules” (“Blue Lips”)(2011); “Sin Aliento” (“Short of Breath”)(2012); “Quedate sin Aliento” (“Stay

Breathless”) (2014) and “Un Aliento paraVencer” (“Breathe to Win”) (2016)

Continued

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TABLE 3 Continued

Organisation (website) Region; beginning Constituency Mission Major activities

Pulmonary HypertensionAssociation of Australia(www.phaaustralia.com)

Australia; 2005 All categories of PH patients, caregivers,family and supporters, pre- and

post-transplant patients; HCPs arenon-participant members trying to

understand the patient/family side of thedisease; membership >7000

“To provide hope, support and education,and to promote awareness and toadvocate for the PH community”

Administered by volunteers for 18 years (nopaid staff ); patient, caregiver and family

education; public awareness and educationthrough website and several social mediaplatforms; advocate for the PH community;bereavement support; immediate phonesupport for those in a PH-related crisis;immediate online support through theirsecure Facebook support group; work

closely with Australian specialists throughthe Pulmonary Hypertension Society

of Australia and New Zealand(www.phsanz.org) to ensure best outcome

for patients

iSEEKPH Hope Center(www.iseek.org.cn)

China; 2011 Patients, caregivers, physicians, medicalprofessionals, researchers; membership:

>5000

“To advocate for patients’ equal rights andimprove their quality of life”

Advocacy; patient education and support;public awareness; education; research

PAH: pulmonary arterial hypertension; CTEPH: chronic thromboembolic PH; HCP: healthcare professional. #: for a comprehensive listing of international PH associations, see https://phassociation.org/phinternational.

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healthcare by World Health Organization criteria. Scarcity of referral centres, inconsistency among healthsystems, wide distribution of patients, geographical barriers, economic disparity and limited accessibility tomedical records have made it difficult to generate awareness of PH.

Advocacy and empowermentPatient-centred organisations acknowledge patients’ needs within a supportive environment and provideopportunities for patients and caregivers to advocate for themselves by being proactive in defining theirsituations, proposing solutions, participating in political activity to promote those solutions, being engagedin their own self-care and counselling each other [55]. Patients’ understanding of their illness andengagement in the care process appears to contribute to improved coping ability [71] and outcomes [75,76] in a variety of chronic diseases. Patient associations and individual patients in many parts of the worldare active advocates for better access to treatment, organ transplant and greater attention to quality of life.

PHA Europe has been successful in involving members of the European Parliament, top EU officials,members of the ESC and ERS, and representatives of influential public health European non-governmentalorganisation in PH-related issues, including for two European Parliament meetings (2012 and 2016). PHAEurope is also active in the context of larger European organisations, and gives support and strategicadvice to national advocacy activities.

Lacking a national single-payer system, the US PHA undertakes simultaneous efforts to educate policymakers at both the federal and state levels, and inform and educate federal and state regulatory agencies(e.g. Centers for Medicare & Medicaid Services and the US Food and Drug Administration (FDA), andstate health and insurance agencies) and commercial payers. The US PHA uses a combination of advocacystaff, volunteer PH patients and caregivers, and coalitions of patient organisations with similar advocacygoals to influence policy makers.

The Latin Society of Pulmonary Hypertension (Sociedad Latina de Hipertensión Pulmonar (SLHP)) hassupported improved living conditions of patients. One result of this is the Framework Law approved bythe Health Commission of the Latin Parliament in 2015 and by other legislative forums to promotenational laws that protect the Human Right to Health. This law regulates the healthcare for people withrare diseases in Latin America. However, the diversity, complexity, fracture and corruption of the healthsystems make it difficult to achieve a direct impact.

Role in research/registriesPatients have had a vital role in PAH-related clinical trials and registries, almost exclusively as studysubjects. An early manifestation of the relevance of the patient perspective in research is the concept ofpatient-reported outcome (PRO) as a meaningful measurement of treatment effect of investigational drugs.In 2009, the US FDA stated that “A PRO is any report of the status of a patient’s health condition thatcomes directly from the patient, without interpretation of the patient’s response by a clinician or anyoneelse” [77]. The 4th and 5th WSPH, in 2008 and 2013, respectively, advocated that PROs be included as asecondary end-point in clinical drug studies [78, 79]. Patient input is needed to understand theirperspective and experience so that PROs can be developed as relevant end-points in clinical trials [80].The US FDA launched the Patient-Focused Drug Development initiative to assess and integrate patientperspectives into the early phases of drug development in a range of diseases [81]. A meeting involvingPAH patients and representatives was held in 2014, and emphasised the impact of PAH on the individualpatient’s life beyond the physical burden of symptoms, including loss of independence, inability toperform routine daily activities and fully participate in relationships with significant others and children,embarrassment, fear of being alone, and impact of treatment side-effects on HRQoL [82]. This initiativerepresents an important step in incorporating patient perspective and engagement at an early stage ofclinical trial design.

Future directionsIn order to advance the role of patients, both as individuals and as a demographic group, to a position ofempowerment and engagement in all aspects of their PAH experience with the goal of enhancing overallwellbeing [55], we suggest several areas in which to focus future attention (table 4). The commondenominator of these suggestions is to cultivate the importance of HRQoL in the care PH patients.

Clinical managementPromote access to optimal managementOptimal care must be multidimensional to address the physical, psychological, social and informationalneeds of patients and caregivers, alongside their clinical needs. This approach is suggested by the latestESC/ERS clinical guidelines: “[expert] Referral centres are recommended to provide care by an

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interprofessional team …” [45]. Nevertheless, guidelines are largely silent about the desirability of patient/HCP bidirectional interactions that address patients’ need for emotional support conducted by acollaborative team at a “tempo” which permits the patients to understand the HCP’s information and toconvey their perspectives, concerns and goals. Future guidelines should point out that HRQoL objectivesrequire a culture of shared decision making and narrative competence to support patient and caregiveremotional resilience. This should include access to focused psychological management, social work,palliative care, spiritual counselling and physical therapy (figure 2).

Optimal care must be accessible to the patient. Mechanisms, such as ERNs and the PHCC, to evaluate andidentify sites able to provide clinical management consistent with consensus guidelines are importantsteps. The next challenge is to promote restriction of care to such centres once sufficient numbers havebeen identified to serve the PH population. This is most likely to be achieved in systems with a singlepayer/commissioner, usually state provided.

In Latin America and in developing countries, future advances are particularly challenging because of thebarriers noted earlier. A primary objective of patient organisations both in Latin America and worldwidewill be to overcome these barriers and advocate for social, political and legal measures to procureaccessible healthcare for PH patients. “Twinning relationships” between individual centres of expertise andcentres seeking consultative input could be a means of promoting optimal care in needy regions. Theregional disparity of care available to PH patients mandates that governments, insurers, the pharmaceuticalindustry, and patient and professional organisations promote global accessibility and affordabletreatment for all PH patients. For a compelling narrative regarding the need for globalisation of PH care,please watch the Jenna Lowe Trust video at: https://phassociation.us13.list-manage.com/track/click?u=acd152c7c169b59aaec993284&id=4874e4af3a&e=99080b0e01.

Empower patients’ participation in their managementPH patients and HCPs collaboratively make decisions which have a major impact and require anunderstanding by all parties of the components and priorities involved in achieving an appropriate courseof action. To achieve the necessary mutual understanding requires a complexity, duration and frequency ofinteraction that poses a challenge within the time constraints of medical practices. The process may befacilitated by incorporating formal principles of shared decision making, including the use of decision aidtools. A synthesis of the qualitative precepts of narrative medicine and the implementation of morequantitative HRQoL instruments in clinical practice might also enhance the physician’s awareness of thepatient’s needs and systematically reflect aspects of illness that are not otherwise measured.

Patient associations frequently offer educational materials which complement the role of the HCP byproviding information about the disease, treatment options and day-to-day issues in living with PH. Since2015, over 200 resources in 24 languages have been collected in the “PH Library” (www.ourphlibrary.com),

TABLE 4 Cultivate the importance of health-related quality of life (HRQoL) in the care of thoseaffected by pulmonary hypertension (PH)

Clinical managementPromote access to optimal careExpand MDT approachAccreditation of PH centresTwinning of expert and developing centres

Empower patient participation in managementMultimedia patient information/materialsCreate and endorse methods to enhance HCP and patient/caregiver communication:Shared decision makingNarrative-based medicinePalliative care techniques

Provider developmentIntegrate concepts of narrative-based medicine, shared decision making and HRQoL into clinical training

Clinical researchSupport, expand and harmonise HRQoL databasesPrioritise HRQoL as a distinct end-point in clinical trialsFoster patients’ input into clinical study design and outcome measurements

Patient associationsPromote the mission and role of PH patient organisations worldwide

MDT: multidisciplinary team; HCP: healthcare provider.

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an online joint project of PHA in the USA and PHA Europe, which should be continued and expanded.An additional role that patient organisations and support groups might play is to help patients developnarrative medicine knowledge and skills so they can be more effective during their limited timewith HCPs.

Role and timing of palliative careThe assimilation of palliative care principles into the PH management strategy at an earlier phase ofdisease should be encouraged to promote all means of improving HRQoL by pain management,symptomatic improvement of dyspnoea, addressing psychological issues and sleep disturbances, andassisting in end-of-life concerns. Equating the term “palliative care”, which is currently burdened with thenotion of “end-of-life” care, with “holistic” or “quality-of-life” care will be an important strategy forreorienting perceptions about this discipline.

Provider developmentIntegrate concepts of patients’ perspectives into medical educationMedical education has recognised the importance of the patient perspective to a degree, incorporatingconcepts of shared decision making, narrative-based medicine and HRQoL into educational curricula.Narrative medicine can potentially increase efficiency and bring economic benefits to healthcare systems.A closer and more collaborative patient–doctor relationship can improve treatment compliance andsatisfaction, and reduce unnecessary tests and medicolegal disputes.

It is important to further integrate these concepts into all clinical disciplines, including PH management,at all levels of medical education from medical school to continuing medical education of all HCPs.

Clinical researchSupport, expand and harmonise HRQoL databasesSurveys of patient perspectives are an important source of information by which HCPs can orientthemselves to their patients’ multiple and complex needs. Since perspectives may vary as the treatmentmilieu changes over time, it will be important to periodically reassess using updated survey instruments.

Psychologicalsupport

Shar

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mak

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Shar

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Shared decis

ion mak

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Shared decis

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Shared decision makingShared decision making

Shared decision making

Shared decision making

Rehabilitation Spiritualsupport

Palliativecare

Socialsupport

Diagnostics/therapies/medical/nursing

Health coaching/

goal setting

Patientassociations/

groups/information

Patientand

carer

FIGURE 2 Representation of components of a multidimensional approach to care of the pulmonaryhypertension patient.

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Information derived from patient surveys can differ by geographical location. This suggests that the use ofsurveys in other regions of the world would be informative in terms of comparisons and would alsoprovide new insights into the attitudes of previously unexamined populations, including those in LatinAmerica, the Middle East, Africa and Asia.

Surveys of patient perceptions should be integrated with traditional clinical database registriesIncorporation of these variables into a single or cross-linked case report form would potentially simplify(unify) data collection. Ultimately data analyses might better determine whether treatment strategies andtraditional outcome measures (e.g. hospitalisation and survival) correlate with HRQoL. It is likely thatthese analyses would be hypothesis generating and lead to further formal study.

It would be useful if registries and/or patient surveys were designed to prospectively harmonise datavariables in such a way that global analyses could be performed without resorting to post hoc statisticaladjustment.

Incorporate patients’ perspectives early into clinical study design and outcome measurementsBased on information gleaned from surveys, including patients in the clinical trial design process mayincrease the importance of “overall wellbeing” as a central objective of medical care and potentially as aclinical trial outcome on an equal footing with more traditional end-points. HRQoL could be included asan end-point by itself or as part of a multiparameter score, rather than simply a surrogate for otherend-points such as survival or clinical deterioration.

The PAH patient and caregiver community needs to be cognisant of the developing opportunity toparticipate in relevant advisory and steering committees in order to advocate for the patients’ perspectivein clinical trial design. This might be best pursued by patient organisations by advocating for andfacilitating patients to serve as steering committee members, patient liaisons or focus group members forstudy designs, as an outgrowth of US FDA and European Medicines Agency initiatives to promote“patient-focused drug development”.

Patient associationsRecognise and enhance the role of PAH patient organisations/professional organisationsAs noted, existing patient organisations (e.g. in the USA, Europe and elsewhere) work as a looseconfederation with a similarity of general objectives adapted to their constituencies’ specific realities andneeds (table 3). Such patient associations have a track record of providing a voice and support for the PHpatient community. Thus, continued development of these organisations should be supported and similarassociations should be established in underserved areas. Obstacles to globalisation of PH patientorganisations are significant and include: funding, geographic dispersion of rare disease patients,communication barriers, questions of organisational governance and substantial differences in delivery ofmedical care. The commonality of objectives and needs of PH patients suggest that stronger networkingfor the purposes of educational efforts and sharing of productive strategies should be promoted. Animportant step forward in this direction was taken in 2017 when the US PHA, SLHP and PHA Europedecide to join forces for the first time in organising the World Pulmonary Hypertension Day, which, inturn rallied many other associations from other parts of the world, including from Canada, Africa, Asiaand Australia. Social media can play an increasing role in the future in breaking down geographicalbarriers and having a unifying function, and other avenues for collaboration should be explored.

Conflict of interest: M.D. McGoon reports personal fees for advisory committee work from United Therapeutics, andpersonal fees for data monitoring committee work from Pfizer and Acceleron, outside the submitted work. P. Ferrarihas nothing to disclose. I. Armstrong has nothing to disclose. M. Denis has nothing to disclose. L.S. Howard reportsspeaker fees, honoraria for scientific advice and congress/travel support from Actelion and MSD, speaker fees, honorariafor scientific advice, congress/travel support and research grant support from Bayer, and honoraria for scientific advicefrom GSK, Third Pole, Gossamer, Arena and Endotronix, outside the submitted work. G. Lowe has nothing to disclose.S. Mehta has nothing to disclose. N. Murakami has nothing to disclose. B.A. Wong has nothing to disclose.

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