2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: Developed by the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG).

Table of contents

• 1. Preamble  3624

• 2. Introduction  3625

•  2.1. What is new  3625

•  2.2. Methods  3635

• 3. Definitions and classifications  3636

•  3.1. Definitions  3636

•  3.2. Classifications  3637

• 4. Epidemiology and risk factors  3638

•  4.1. Group 1, pulmonary arterial hypertension  3638

•  4.2. Group 2, pulmonary hypertension associated with left heart disease  3640

•  4.3. Group 3, pulmonary hypertension associated with lung diseases and/or hypoxia  3640

•  4.4. Group 4, pulmonary hypertension associated with chronic pulmonary artery obstruction  3640

•  4.5. Group 5, pulmonary hypertension with unclear and/or multifactorial mechanisms  3640

• 5. Pulmonary hypertension diagnosis  3640

•  5.1. Diagnosis  3640

•   5.1.1. Clinical presentation  3640

•   5.1.2. Electrocardiogram  3640

•   5.1.3. Chest radiography  3641

•   5.1.4. Pulmonary function tests and arterial blood gases  3641

•   5.1.5. Echocardiography  3642

•   5.1.6. Ventilation/perfusion lung scan  3643

•   5.1.7. Non-contrast and contrast-enhanced chest computed tomography examinations, and digital subtraction angiography  3644

•   5.1.8. Cardiac magnetic resonance imaging  3645

•   5.1.9. Blood tests and immunology  3646

•   5.1.10. Abdominal ultrasound  3646

•   5.1.11. Cardiopulmonary exercise testing  3646

•   5.1.12. Right heart catheterization, vasoreactivity, exercise, and fluid challenge  3646

•    5.1.12.1. Right heart catheterization  3646

•    5.1.12.2. Vasoreactivity testing  3647

•    5.1.12.3. Exercise right heart catheterization  3647

•    5.1.12.4. Fluid challenge  3647

•   5.1.13. Genetic counselling and testing  3648

•  5.2. Diagnostic algorithm  3648

•   5.2.1 Step 1 (suspicion)  3648

•   5.2.2. Step 2 (detection)  3648

•   5.2.3. Step 3 (confirmation)  3650

•  5.3. Screening and early detection  3652

•   5.3.1. Systemic sclerosis  3653

•   5.3.2. BMPR2 mutation carriers  3653

•   5.3.3. Portal hypertension  3653

•   5.3.4. Pulmonary embolism  3653

• 6. Pulmonary arterial hypertension (group 1)  3655

•  6.1. Clinical characteristics  3655

•  6.2. Severity and risk assessment  3655

•   6.2.1. Clinical parameters  3655

•   6.2.2. Imaging  3656

•    6.2.2.1. Echocardiography  3656

•    6.2.2.2. Cardiac magnetic resonance imaging  3656

•   6.2.3. Haemodynamics  3656

•   6.2.4. Exercise capacity  3657

•   6.2.5. Biochemical markers  3658

•   6.2.6. Patient-reported outcome measures  3658

•   6.2.7. Comprehensive prognostic evaluation, risk assessment, and treatment goals  3659

•  6.3. Therapy  3660

•   6.3.1. General measures  3660

•    6.3.1.1. Physical activity and supervised rehabilitation  3660

•    6.3.1.2. Anticoagulation  3660

•    6.3.1.3. Diuretics  3661

•    6.3.1.4. Oxygen  3661

•    6.3.1.5. Cardiovascular drugs  3661

•    6.3.1.6. Anaemia and iron status  3661

•    6.3.1.7. Vaccination  3661

•    6.3.1.8. Psychosocial support  3661

•    6.3.1.9. Adherence to treatments  3661

•   6.3.2. Special circumstances  3662

•    6.3.2.1. Pregnancy and birth control  3662

•     6.3.2.1.1. Pregnancy  3662

•     6.3.2.1.2. Contraception  3662

•    6.3.2.2. Surgical procedures  3662

•    6.3.2.3. Travel and altitude  3662

•   6.3.3. Pulmonary arterial hypertension therapies  3663

•    6.3.3.1. Calcium channel blockers  3663

•    6.3.3.2. Endothelin receptor antagonists  3664

•     6.3.3.2.1. Ambrisentan  3665

•     6.3.3.2.2. Bosentan  3665

•     6.3.3.2.3. Macitentan  3666

•    6.3.3.3. Phosphodiesterase 5 inhibitors and guanylate cyclase stimulators  3666

•     6.3.3.3.1. Sildenafil  3667

•     6.3.3.3.2. Tadalafil  3667

•     6.3.3.3.3. Riociguat  3667

•    6.3.3.4. Prostacyclin analogues and prostacyclin receptoragonists  3667

•     6.3.3.4.1. Epoprostenol  3667

•     6.3.3.4.2. Iloprost  3667

•     6.3.3.4.3. Treprostinil  3667

•     6.3.3.4.4. Beraprost  3667

•     6.3.3.4.5. Selexipag  3667

•   6.3.4. Treatment strategies for patients with idiopathic, heritable, drug-associated, or connective tissue disease-associated pulmonary arterial hypertension  3667

•    6.3.4.1. Initial treatment decision in patients without cardiopulmonary comorbidities  3668

•    6.3.4.2. Treatment decisions during follow-up in patients without cardiopulmonary comorbidities  3669

•    6.3.4.3. Pulmonary arterial hypertension with cardiopulmonary comorbidities  3670

•   6.3.5. Drug interactions  3671

•   6.3.6. Interventional therapy  3671

•    6.3.6.1. Balloon atrial septostomy and Potts shunt  3671

•    6.3.6.2. Pulmonary artery denervation  3671

•   6.3.7. Advanced right ventricular failure  3672

•    6.3.7.1. Intensive care unit management  3672

•    6.3.7.2. Mechanical circulatory support  3672

•   6.3.8. Lung and heart-lung transplantation  3672

•   6.3.9. Evidence-based treatment algorithm  3673

•   6.3.10. Diagnosis and treatment of pulmonary arterial hypertension complications  3673

•    6.3.10.1. Arrhythmias  3673

•    6.3.10.2. Haemoptysis  3673

•    6.3.10.3. Mechanical complications  3673

•   6.3.11. End-of-life care and ethical issues  3674

•   6.3.12. New drugs in advanced clinical development (phase 3 studies)  3674

• 7. Specific pulmonary arterial hypertension subsets  3674

•  7.1. Pulmonary arterial hypertension associated with drugs and toxins  3674

•  7.2. Pulmonary arterial hypertension associated with connective tissue disease  3675

•   7.2.1. Epidemiology and diagnosis  3675

•   7.2.2. Therapy  3675

•  7.3. Pulmonary arterial hypertension associated with human immunodeficiency virus infection  3676

•   7.3.1. Diagnosis  3676

•   7.3.2. Therapy  3676

•  7.4. Pulmonary arterial hypertension associated with portal hypertension  3677

•   7.4.1. Diagnosis  3677

•   7.4.2. Therapy  3677

•    7.4.2.1. Liver transplantation  3677

•  7.5. Pulmonary arterial hypertension associated with adult congenital heart disease  3678

•   7.5.1. Diagnosis and risk assessment  3678

•   7.5.2. Therapy  3679

•  7.6. Pulmonary arterial hypertension associated with schistosomiasis  3680

•  7.7. Pulmonary arterial hypertension with signs of venous/capillary involvement  3680

•   7.7.1. Diagnosis  3681

•   7.7.2. Therapy  3681

•  7.8. Paediatric pulmonary hypertension  3681

•   7.8.1. Epidemiology and classification  3681

•   7.8.2. Diagnosis and risk assessment  3683

•   7.8.3. Therapy  3683

• 8. Pulmonary hypertension associated with left heart disease (group 2)  3685

•  8.1. Definition, prognosis, and pathophysiology  3685

•  8.2. Diagnosis  3687

•   8.2.1. Diagnosis and control of the underlying left heart disease  3687

•   8.2.2. Evaluation of pulmonary hypertension and patient phenotyping  3687

•   8.2.3. Invasive assessment of haemodynamics  3687

•  8.3. Therapy  3688

•   8.3.1. Pulmonary hypertension associated with left-sided heart failure  3688

•    8.3.1.1. Heart failure with reduced ejection fraction  3688

•    8.3.1.2. Heart failure with preserved ejection fraction  3688

•    8.3.1.3. Interatrial shunt devices  3689

•    8.3.1.4. Remote pulmonary arterial pressure monitoring in heart failure  3689

•   8.3.2. Pulmonary hypertension associated with valvular heart disease  3689

•    8.3.2.1. Mitral valve disease  3689

•    8.3.2.2. Aortic stenosis  3689

•    8.3.2.3. Tricuspid regurgitation  3689

•   8.3.3. Recommendations on the use of drugs approved for PAH in PH-LHD  3689

• 9. Pulmonary hypertension associated with lung diseases and/or hypoxia (group 3)  3690

•  9.1. Diagnosis  3692

•  9.2. Therapy  3692

•   9.2.1. Pulmonary hypertension associated with chronic obstructive pulmonary disease or emphysema  3692

•   9.2.2. Pulmonary hypertension associated with interstitial lung disease  3692

•   9.2.3. Recommendations on the use of drugs approved for PAH in PH associated with lung disease  3693

• 10. Chronic thrombo-embolic pulmonary hypertension (group 4)  3693

•  10.1. Diagnosis  3694

•  10.2. Therapy  3695

•   10.2.1. Surgical treatment  3695

•   10.2.2. Medical therapy  3695

•   10.2.3. Interventional treatment  3696

•   10.2.4. Multimodal treatment  3697

•   10.2.5. Follow-up  3698

•  10.3. Chronic thrombo-embolic pulmonary hypertension team and experience criteria  3698

• 11. Pulmonary hypertension with unclear and/or multifactorial mechanisms (group 5)  3699

•  11.1. Haematological disorders  3699

•  11.2. Systemic disorders  3700

•  11.3. Metabolic disorders  3700

•  11.4. Chronic kidney failure  3700

•  11.5. Pulmonary tumour thrombotic microangiopathy  3700

•  11.6. Fibrosing mediastinitis  3700

• 12. Definition of a pulmonary hypertension centre  3701

•  12.1. Facilities and skills required for a pulmonary hypertension centre  3702

•  12.2. European Reference Network  3702

•  12.3. Patient associations and patient empowerment  3702

• 13. Key messages  3703

• 14. Gaps in evidence  3703

•  14.1. Pulmonary arterial hypertension (group 1)  3703

•  14.2. Pulmonary hypertension associated with left heart disease (group 2)  3703

•  14.3. Pulmonary hypertension associated with lung diseases and/ or hypoxia (group 3)  3704

•  14.4. Chronic thrombo-embolic pulmonary hypertension (group 4)  3704

•  14.5. Pulmonary hypertension with unclear and/or multifactorial mechanisms (group 5)  3704

• 15. ‘What to do’ and ‘What not to do’ messages from the Guidelines  3704

• 16. Quality indicators  3710

• 17. Supplementary data  3711

• 18. Data availability statement  3711

• 19. Author information  3711

• 20. Appendix  3711

• 21. References  3712

Tables of Recommendations

• Recommendation Table 1 — Recommendations for right heart catheterization and vasoreactivity testing  3648

• Recommendation Table 2 — Recommendations for diagnostic strategy  3652

• Recommendation Table 3 — Recommendations for screening and improved detection of pulmonary arterial hypertension and chronic thrombo-embolic pulmonary hypertension  3654

• Recommendation Table 4 — Recommendations for evaluating the disease severity and risk of death in patients with pulmonary arterial hypertension  3660

• Recommendation Table 5 — Recommendations for general measures and special circumstances  3662

• Recommendation Table 6 — Recommendations for women of childbearing potential  3663

• Recommendation Table 7 — Recommendations for the treatment of vasoreactive patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension  3664

• Recommendation Table 8 — Recommendations for the treatment of non-vasoreactive patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension who present without cardiopulmonary comorbiditiesa  3668

• Recommendation Table 9 — Recommendations for initial oral drug combination therapy for patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension without cardiopulmonary comorbidities  3669

• Recommendation Table 10 — Recommendations for sequential drug combination therapy for patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension  3670

• Recommendation Table 11 — Recommendations for the treatment of non-vasoreactive patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension who present with cardiopulmonary comorbiditiesa  3671

• Recommendation Table 12 — Recommendations for intensive care management for pulmonary arterial hypertension  3672

• Recommendation Table 13 — Recommendations for lung transplantation  3673

• Recommendation Table 14 — Recommendations for pulmonary arterial hypertension associated with drugs or toxins  3674

• Recommendation Table 15 — Recommendations for pulmonary arterial hypertension associated with connective tissue disease  3675

• Recommendation Table 16 — Recommendations for pulmonary arterial hypertension associated with human immunodeficiency virus infection  3676

• Recommendation Table 17 — Recommendations for pulmonary arterial hypertension associated with portal hypertension  3677

• Recommendation Table 18 — Recommendations for shunt closure in patients with pulmonary-systemic flow ratio .1.5:1 based on calculated pulmonary vascular resistance  3680

• Recommendation Table 19 — Recommendations for pulmonary arterial hypertension associated with adult congenital heart disease  3680

• Recommendation Table 20 — Recommendations for pulmonary arterial hypertension with signs of venous/capillary involvement  3681

• Recommendation Table 21 — Recommendations for paediatric pulmonary hypertension  3685

• Recommendation Table 22 — Recommendations for pulmonary hypertension associated with left heart disease  3690

• Recommendation Table 23 — Recommendations for pulmonary hypertension associated with lung disease and/or hypoxia  3693

• Recommendation Table 24 — Recommendations for chronic thrombo-embolic pulmonary hypertension and chronic thrombo-embolic pulmonary disease without pulmonary hypertension  3698

• Recommendation Table 25 — Recommendations for pulmonary hypertension centres  3702

List of tables

• Table 1 Strength of the recommendations according to GRADE  3635

• Table 2 Quality of evidence grades and their definitions  3635

• Table 3 Classes of recommendations  3636

• Table 4 Levels of evidence  3636

• Table 5 Haemodynamic definitions of pulmonary hypertension  3637

• Table 6 Clinical classification of pulmonary hypertension  3638

• Table 7 Drugs and toxins associated with pulmonary arterial hypertension  3640

• Table 8 Electrocardiogram abnormalities in patients with pulmonary hypertension  3643

• Table 9 Radiographic signs of pulmonary hypertension and concomitant abnormalities  3643

• Table 10 Additional echocardiographic signs suggestive of pulmonary hypertension  3645

• Table 11 Haemodynamic measures obtained during right heart catheterization  3646

• Table 12 Route of administration, half-life, dosages, and duration of administration of the recommended test compounds for vasoreactivity testing in pulmonary arterial hypertension  3647

• Table 13 Phenotypic features associated with pulmonary arterial hypertension mutations  3649

• Table 14 Characteristic diagnostic features of patients with different forms of pulmonary hypertension  3651

• Table 15 World Health Organization classification of functional status of patients with pulmonary hypertension  3656

• Table 16 Comprehensive risk assessment in pulmonary arterial hypertension (three-strata model)  3657

• Table 17 Suggested assessment and timing for the follow-up of patients with pulmonary arterial hypertension  3658

• Table 18 Variables used to calculate the simplified four-strata risk-assessment tool  3659

• Table 19 Dosing of pulmonary arterial hypertension medication in adults  3664

• Table 20 Criteria for lung transplantation and listing in patients with pulmonary arterial hypertension  3672

• Table 21 Clinical classification of pulmonary arterial hypertension associated with congenital heart disease  3678

• Table 22 Use of pulmonary arterial hypertension therapies in children  3684

• Table 23 Patient phenotyping and likelihood for left heart disease as cause of pulmonary hypertension  3688

• Table 24 Pulmonary hypertension with unclear and/or multifactorial mechanisms  3699

List of figures

• Figure 1 Central illustration  3639

• Figure 2 Symptoms in patients with pulmonary hypertension  3641

• Figure 3 Clinical signs in patients with pulmonary hypertension  3642

• Figure 4 Transthoracic echocardiographic parameters in the assessment of pulmonary hypertension  3644

• Figure 5 Echocardiographic probability of pulmonary hypertension and recommendations for further assessment  3645

• Figure 6 Diagnostic algorithm of patients with unexplained dyspnoea and/or suspected pulmonary hypertension  3650

• Figure 7 Pathophysiology and current therapeutic targets of pulmonary arterial hypertension (group 1)  3655

• Figure 8 Vasoreactivity testing algorithm of patients with presumed diagnosis of idiopathic, heritable, or drug-associated pulmonary arterial hypertension  3665

• Figure 9 Evidence-based pulmonary arterial hypertension treatment algorithm for patients with idiopathic, heritable, drug-associated, and connective tissue disease-associated pulmonary arterial hypertension  3666

• Figure 10 Neonatal and paediatric vs. adult pulmonary hypertension  3682

• Figure 11 Pathophysiology of pulmonary hypertension associated with left heart disease (group 2)  3686

• Figure 12 Pathophysiology of pulmonary hypertension associated with lung disease (group 3)  3691

• Figure 13 Diagnostic strategy in chronic thrombo-embolic pulmonary hypertension  3694

• Figure 14 Management strategy in chronic thrombo-embolic pulmonary hypertension  3696

• Figure 15 Overlap in treatments/multimodality approaches in chronic thrombo-embolic pulmonary hypertension  3697

• Figure 16 Pulmonary hypertension centre schematic  3701

Abbreviations and acronyms

 
• 6MWD

  6-minute walking distance

 
• 6MWT

  6-minute walking test

 
• ABG

  Arterial blood gas analysis

 
• ACEi

  Angiotensin-converting enzyme inhibitor

 
• ALAT

  Alanine aminotransferase

 
• ARB

  Angiotensin receptor blocker

 
• ARNI

  Angiotensin receptor–neprilysin inhibitor

 
• ASAT

  Aspartate aminotransferase

 
• ASIG

  Australian Scleroderma Interest Group

 
• BNP

  Brain natriuretic peptide

 
• BPA

  Balloon pulmonary angioplasty

 
• BPD

  Bronchopulmonary dysplasia

 
• CAMPHOR

  Cambridge Pulmonary Hypertension Outcome Review

 
• CCB

  Calcium channel blocker

 
• CDH

  Congenital diaphragmatic hernia

 
• cGMP

  Cyclic guanosine monophosphate

 
• CHD

  Congenital heart disease

 
• CI

  Cardiac index; Confidence interval

 
• cMRI

  Cardiac magnetic resonance imaging

 
• CO

  Cardiac output

 
• COMPERA

  Comparative, Prospective Registry of Newly Initiated Therapies for PH

 
• COPD

  Chronic obstructive pulmonary disease

 
• CpcPH

  Combined post- and pre-capillary pulmonary hypertension

 
• CPET

  Cardiopulmonary exercise testing

 
• CPFE

  Combined pulmonary fibrosis and emphysema

 
• CT

  Computed tomography

 
• CTD

  Connective tissue disease

 
• CTEPD

  Chronic thrombo-embolic pulmonary disease

 
• CTEPH

  Chronic thrombo-embolic pulmonary hypertension

 
• CTPA

  Computed tomography pulmonary angiography

 
• DECT

  Dual-energy computed tomography

 
• DLCO

  Lung diffusion capacity for carbon monoxide

 
• DPAH

  Drug- or toxin-associated pulmonary arterial hypertension

 
• dPAP

  Diastolic pulmonary arterial pressure

 
• DPG

  Diastolic pressure gradient

 
• DSA

  Digital subtraction angiography

 
• ECG

  Electrocardiogram

 
• ECMO

  Extracorporeal membrane oxygenation

 
• EHJ

  European Heart Journal

 
• EMA

  European Medicines Agency

 
• EOV

  Exercise oscillatory ventilation

 
• ERA

  Endothelin receptor antagonist

 
• ERJ

  European Respiratory Journal

 
• ERN

  European Reference Network

 
• ERN-LUNG

  European Reference Network on rare respiratory diseases

 
• ERS

  European Respiratory Society

 
• ESC

  European Society of Cardiology

 
• EtD

  Evidence to Decision

 
• FPHR

  French Pulmonary Hypertension Registry

 
• FVC

  Forced vital capacity

 
• GRADE

  Grading of Recommendations, Assessment, Development, and Evaluations

 
• HAART

  Highly active antiretroviral therapy

 
• Hb

  Haemoglobin

 
• HF

  Heart failure

 
• HFpEF

  Heart failure with preserved ejection fraction

 
• HIV

  Human immunodeficiency virus

 
• HPAH

  Heritable pulmonary arterial hypertension

 
• HPS

  Hepatopulmonary syndrome

 
• HR

  Hazard ratio

 
• HR-QoL

  Health-related quality of life

 
• ICU

  Intensive care unit

 
• IgG4

  Immunogolobulin G4

 
• ILD

  Interstitial lung disease

 
• IPAH

  Idiopathic pulmonary arterial hypertension

 
• IpcPH

  Isolated post-capillary pulmonary hypertension

 
• IP receptor

  Prostacyclin I2 receptor

 
• ISWT

  Incremental shuttle walking test

 
• i.v.

  Intravenous

 
• LA

  Left atrium/left atrial

 
• LAS

  Lung allocation score

 
• LHD

  Left heart disease

 
• LTx

  Lung transplantation

 
• LV

  Left ventricle/left ventricular

 
• LVAD

  Left ventricular assist device

 
• mPAP

  Mean pulmonary arterial pressure

 
• MR

  Magnetic resonance

 
• MRI

  Magnetic resonance imaging

 
• NOAC

  Novel oral anticoagulant

 
• NT-proBNP

  N-terminal pro-brain natriuretic peptide

 
• OR

  Odds ratio

 
• PA

  Pulmonary artery

 
• PAC

  Pulmonary arterial compliance

 
• PaCO₂

  Partial pressure of arterial carbon dioxide

 
• PADN

  Pulmonary artery denervation

 
• PAH

  Pulmonary arterial hypertension

 
• PAH-CTD

  Pulmonary arterial hypertension associated with connective tissue disease

 
• PAH-SSc

  Pulmonary arterial hypertension associated with systemic sclerosis

 
• PAH-SYMPACT

  Pulmonary Arterial Hypertension-Symptoms and Impact

 
• PaO₂

  Partial pressure of arterial oxygen

 
• PAP

  Pulmonary arterial pressure

 
• PAVM

  Pulmonary arteriovenous malformation

 
• PAWP

  Pulmonary arterial wedge pressure

 
• PCH

  Pulmonary capillary haemangiomatosis

 
• PDE5i

  Phosphodiesterase 5 inhibitor

 
• PE

  Pulmonary embolism

 
• PEA

  Pulmonary endarterectomy

 
• PET

  Positron emission tomography

 
• P_ETCO₂

  End-tidal partial pressure of carbon dioxide

 
• PFT

  Pulmonary function test

 
• PH

  Pulmonary hypertension

 
• PH-LHD

  Pulmonary hypertension associated with left heart disease

 
• PICO

  Population, Intervention, Comparator, Outcome

 
• PoPH

  Porto-pulmonary hypertension

 
• PPHN

  Persistent pulmonary hypertension of the newborn

 
• PROM

  Patient-reported outcome measure

 
• PVD

  Pulmonary vascular disease

 
• PVOD

  Pulmonary veno-occlusive disease

 
• PVR

  Pulmonary vascular resistance

 
• PVRI

  Pulmonary vascular resistance index

 
• QI

  Quality indicator

 
• Qp/Qs

  Pulmonary blood flow/systemic blood flow

 
• RA

  Right atrium/right atrial

 
• RAP

  Right atrial pressure

 
• RCT

  Randomized controlled trial

 
• REVEAL

  Registry to Evaluate Early and Long-Term PAH Disease Management

 
• RHC

  Right heart catheterization

 
• RR

  Relative risk

 
• RV

  Right ventricle/right ventricular

 
• RVEF

  Right ventricular ejection fraction

 
• RV-FAC

  Right ventricular fractional area change

 
• RVOT AT

  Right ventricular outflow tract acceleration time

 
• SaO₂

  Arterial oxygen saturation

 
• s.c.

  Subcutaneous

 
• SCD

  Sickle cell disease

 
• sGC

  Soluble guanylate cyclase

 
• SGLT-2i

  Sodium–glucose cotransporter-2 inhibitor

 
• SLE

  Systemic lupus erythematosus

 
• SPAHR

  Swedish Pulmonary Arterial Hypertension Registry

 
• sPAP

  Systolic pulmonary arterial pressure

 
• SPECT

  Single-photon emission computed tomography

 
• SSc

  Systemic sclerosis

 
• SV

  Stroke volume

 
• SVI

  Stroke volume index

 
• SvO₂

  Mixed venous oxygen saturation

 
• TAPSE

  Tricuspid annular plane systolic excursion

 
• TGF-β

  Transforming growth factor-β

 
• TPR

  Total pulmonary resistance

 
• TR

  Tricuspid regurgitation

 
• TRPG

  Tricuspid regurgitation pressure gradient

 
• TRV

  Tricuspid regurgitation velocity

 
• TSH

  Thyroid-stimulating hormone

 
• V/Q

  Ventilation perfusion

 
• VE/VCO₂

  Ventilatory equivalent for carbon dioxide

 
• VKA

  Vitamin K antagonist

 
• VO₂

  Oxygen uptake

 
• VO₂/HR

  Oxygen pulse

 
• VTE

  Venous thrombo-embolism

 
• WHO-FC

  World Health Organization functional class

 
• WSPH

  World Symposium on Pulmonary Hypertension

 
• WU

  Wood units

1. Preamble

Guidelines summarize and evaluate available evidence, with the aim of assisting health professionals in proposing the best management strategies for an individual patient with a given condition. Guidelines and their recommendations should facilitate decision-making of health professionals in their daily practice. However, guidelines are not a substitute for the patient’s relationship with their practitioner. The final decisions concerning an individual patient must be made by the responsible health professional(s), based on what they consider to be the most appropriate in the circumstances. These decisions are made in consultation with the patient and caregiver as appropriate.

Guidelines are intended for use by health professionals. To ensure that all physicians have access to the most recent recommendations, both the European Society of Cardiology (ESC) and European Respiratory Society (ERS) make their guidelines freely available in their own journals. The ESC and ERS warn non-medical readers that the technical language may be misinterpreted and decline any responsibility in this respect.

Many Guidelines have been issued in recent years by the ESC and ERS. Because of their impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The ERS and ESC guidance and procedure to formulate and issue clinical practice recommendations can be found on the societies’ relevant website or journal (https://www.escardio.org/Guidelines and https://openres.ersjournals.com/content/8/1/00655-2021). The ESC and ERS Guidelines represent the official position of the ESC and ERS on a given topic and are regularly updated.

The panel of experts of these specific guidelines comprised an equal number of ERS and ESC members, including representatives from relevant subspecialty groups involved in the medical care of patients with this pathology.

The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. Their declarations of interest were reviewed according to the ESC declaration of interest rules and can be found on the ESC website (http://www.escardio.org/Guidelines). They have been compiled in a report and co-published in a supplementary document of the guidelines. This process ensures transparency and prevents potential biases in the development and review processes. Any changes in declarations of interest that arose during the writing period were notified to the ESC and updated. The Task Force received its entire financial support from the ESC and ERS without any involvement from the health care industry.

The ESC Clinical Practice Guidelines (CPG) Committee and the ERS Guidelines Director reporting to the ERS Science Council supervise and co-ordinate the preparation of new guidelines. These Guidelines underwent extensive review by the ESC CPG Committee, the ERS Guidelines Working Group, and external experts. The guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of drafting. After appropriate revisions, the guidelines were signed off by all the experts in the Task Force. The finalized document was signed off by the ESC CPG Committee and endorsed by the ERS Executive Committee before being simultaneously published in the European Heart Journal (EHJ) and the European Respiratory Journal (ERJ). The decision to publish the guidelines in both journals was made to ensure adequate dissemination of the recommendations in both the cardiology and respiratory fields.

The task of developing the ESC/ERS Guidelines also included creating educational tools and implementation programmes for the recommendations, including condensed pocket guidelines versions, summary slides, a lay summary, and an electronic version for digital applications (smartphones, etc.). These versions are abridged and thus, for more detailed information, the user should always access the full-text version of the guidelines, which is freely available via the ESC and ERS websites, and hosted on the EHJ and ERJ websites. The National Cardiac Societies of the ESC are encouraged to endorse, adopt, translate, and implement all ESC Guidelines. Pulmonary national societies are also encouraged to share these guidelines with their members and develop a summary or editorials in their own language, if appropriate. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations.

Health professionals are encouraged to take the ESC/ERS Guidelines fully into account when exercising their clinical judgement, as well as in determining and implementing preventive, diagnostic, or therapeutic medical strategies. However, the ESC/ERS Guidelines do not override, in any way, the individual responsibility of health professionals to make appropriate and accurate decisions in considering each patient’s health condition and in consulting with that patient or the patient’s caregiver where appropriate and/or necessary. It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription and, where appropriate, to respect the ethical rules of their profession in each country.

Off-label use of medication may be presented in these guidelines if a sufficient level of evidence shows that it can be considered medically appropriate to a given condition and if patients could benefit from the recommended therapy. However, the final decisions concerning an individual patient must be made by the responsible health professional, giving special consideration to:

• The specific situation of the patient. In this respect, it is specified that, unless otherwise provided for by national regulations, off-label use of medication should be limited to situations where it is in the patient’s interest to do so, with regards to the quality, safety, and efficacy of care, and only after the patient has been fully informed and provided consent.

• Country-specific health regulations, indications by governmental drug regulatory agencies, and the ethical rules to which health professionals are subject, where applicable.

2. Introduction

Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical conditions and may be associated with a variety of cardiovascular and respiratory diseases. The complexity of managing PH requires a multifaceted, holistic, and multidisciplinary approach, with active involvement of patients with PH in partnership with clinicians. Streamlining the care of patients with PH in daily clinical practice is a challenging but essential requirement for effectively managing PH. In recent years, substantial progress has been made in detecting and managing PH, and new evidence has been timeously integrated in this fourth edition of the ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Reflecting the multidisciplinary input into managing patients with PH and interpreting new evidence, the Task Force included cardiologists and pneumologists, a thoracic surgeon, methodologists, and patients. These comprehensive clinical practice guidelines cover the whole spectrum of PH, with an emphasis on diagnosing and treating pulmonary arterial hypertension (PAH) and chronic thrombo-embolic pulmonary hypertension (CTEPH).

2.1. What is new

One of the most important proposals from the 6th World Symposium on Pulmonary Hypertension (WSPH) was to reconsider the haemodynamic definition of PH.¹ After careful evaluation, the new definitions of PH have been endorsed and expanded in these guidelines, including a revised cut-off level for pulmonary vascular resistance (PVR) and a definition of exercise PH.

The classification of PH has been updated, including repositioning of vasoreactive patients with idiopathic pulmonary arterial hypertension (IPAH) and a revision of group 5 PH, including repositioning of PH in lymphangioleiomyomatosis in group 3.

Concerning the diagnosis of PH, a new algorithm has been developed aiming at earlier detection of PH in the community. In addition, expedited referral is recommended for high-risk or complex patients. Screening strategies are also proposed.

The risk-stratification table has been expanded to include additional echocardiographic and cardiac magnetic resonance imaging (cMRI) prognostic indicators. The recommendations for initial drug therapies have been simplified, building on this revised, three-strata, multiparametric risk model to replace functional classification. At follow-up, a four-strata risk-assessment tool is now proposed based on refined cut-off levels for World Health Organization functional class (WHO-FC), 6-minute walking distance (6MWD), and N-terminal pro-brain natriuretic peptide (NT-proBNP), categorizing patients as low, intermediate–low, intermediate–high, or high risk.

The PAH treatment algorithm has been modified, highlighting the importance of cardiopulmonary comorbidities, risk assessment both at diagnosis and follow-up, and the importance of combination therapies. Treatment strategies during follow-up have been based on the four-strata model intended to facilitate more granular decision-making.

The recommendations for managing PH associated with left heart disease (PH-LHD) and lung disease have been updated, including a new haemodynamic definition of severe PH in patients with lung disease.

In group 4 PH, the term chronic thrombo-embolic pulmonary disease (CTEPD) with or without PH has been introduced, acknowledging the presence of similar symptoms, perfusion defects, and organized fibrotic obstructions in patients with or without PH at rest. Interventional treatment by balloon pulmonary angioplasty (BPA) in combination with medical therapy has been upgraded in the therapeutic algorithm of CTEPH.

New standards for PH centres have been presented and, for the first time, patient representatives were actively involved in developing these guidelines.

Questions with direct consequences for clinical practitioners regarding each PH classification subgroup were selected and addressed, namely guidance on: initial treatment strategy for group 1 PH (Population, Intervention, Control, Outcome [PICO] I); use of oral phosphodiesterase 5 inhibitors (PDE5is) for the treatment of group 2 PH (PICO II); use of oral PDE5is for the treatment of group 3 PH (PICO III); and use of PH drugs prior to BPA for the treatment of group 4 PH (PICO IV). These questions were considered to be important because: most contemporary PH registries describe variable use of initial oral monotherapy and combination therapy; large case series show widespread use of PDE5is in group 2 PH, despite a class III recommendation in the 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension; large case series show widespread use of PDE5is in group 3 PH, despite a class III recommendation in the 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension; and there is no clear guidance for therapy with PH drugs in patients with inoperable CTEPH prior to BPA.

2.2. Methods

Three main methodological approaches were used in these guidelines, depending on the type of questions addressed:

• Four questions that were considered highly important were formulated in the PICO format, and assessed with full systematic reviews and application of the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach² and the Evidence to Decision (EtD) framework³ (see Supplementary Data, Section 2.1 for full methodology description and supportive material). The resulting recommendations were rated as strong or conditional, based on four potential levels of evidence (high, moderate, low, or very low; Tables 1 and 2). All Task Force members approved the recommendations. In addition, these recommendations were also presented and voted following the usual ESC approach.

• Eight questions that were considered of key importance (key narrative questions) were assessed with systematic literature searches and application of the EtD framework.⁶ The evidence grading was performed following the usual ESC approach.

• The remaining topics of interest were assessed using the process commonly followed in ESC Guidelines. Structured literature searches were undertaken and grading tables, as outlined in Tables 3 and 4, were created to describe level of confidence in the recommendation provided and the quality of evidence supporting the recommendation. The Task Force discussed each draft recommendation during web-based conference calls dedicated to specific sections, followed by consensus modifications and an online vote on each recommendation. Only recommendations that were supported by at least 75% of the Task Force members were included in the guidelines. The recommendation tables were colour-coded for ease of interpretation.

3. Definitions and classifications

3.1. Definitions

The definitions for PH are based on haemodynamic assessment by right heart catheterization (RHC). Although haemodynamics represent the central element of characterizing PH, the final diagnosis and classification should reflect the whole clinical context and consider the results of all investigations.

Pulmonary hypertension is defined by a mean pulmonary arterial pressure (mPAP) >20 mmHg at rest (Table 5). This is supported by studies assessing the upper limit of normal pulmonary arterial pressure (PAP) in healthy subjects,^7–9 and by studies investigating the prognostic relevance of increased PAP (key narrative question 1, Supplementary Data, Section 3.1).^10–12

It is essential to include PVR and pulmonary arterial wedge pressure (PAWP) in the definition of pre-capillary PH, in order to discriminate elevated PAP due to pulmonary vascular disease (PVD) from that due to left heart disease (LHD), elevated pulmonary blood flow, or increased intrathoracic pressure (Table 5). Based on the available data, the upper limit of normal PVR and the lowest prognostically relevant threshold of PVR is ∼2 Wood units (WU).^7,8,13,14 Pulmonary vascular resistance depends on body surface area and age, with elderly healthy subjects having higher values. The available data on the best threshold for PAWP discriminating pre- and post-capillary PH are contradictory. Although the upper limit of normal PAWP is considered to be 12 mmHg,¹⁵ previous ESC/ERS Guidelines for the diagnosis and treatment of PH, as well as the recent consensus recommendation of the ESC Heart Failure Association,¹⁶ suggest a higher threshold for the invasive diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF) (PAWP ≥15 mmHg). In addition, almost all therapeutic studies of PAH have used the PAWP ≤15 mmHg threshold. Therefore, it is recommended keeping PAWP ≤15 mmHg as the threshold for pre-capillary PH, while acknowledging that any PAWP threshold is arbitrary and that the patient phenotype, risk factors, and echocardiographic findings, including left atrial (LA) volume, need to be considered when distinguishing pre- from post-capillary PH.

Patients with PAH are haemodynamically characterized by pre-capillary PH in the absence of other causes of pre-capillary PH, such as CTEPH and PH associated with lung diseases. All PH groups may comprise both pre- and post-capillary components contributing to PAP elevation. In particular, older patients may present with several conditions predisposing them to PH. The primary classification should be based on the presumed predominant cause of the pulmonary pressure increase.

Post-capillary PH is haemodynamically defined as mPAP >20 mmHg and PAWP >15 mmHg. Pulmonary vascular resistance is used to differentiate between patients with post-capillary PH who have a significant pre-capillary component (PVR >2 WU—combined post- and pre-capillary PH [CpcPH]) and those who do not (PVR ≤2 WU—isolated post-capillary PH [IpcPH]).

There are patients with elevated mPAP (>20 mmHg) but low PVR (≤2 WU) and low PAWP (≤15 mmHg). These patients are frequently characterized by elevated pulmonary blood flow and, although they have PH, they do not fulfil the criteria of pre- or post-capillary PH. This haemodynamic condition may be described by the term ‘unclassified PH’. Patients with unclassified PH may present with congenital heart disease (CHD), liver disease, airway disease, lung disease, or hyperthyroidism explaining their mPAP elevation. Clinical follow-up of these patients is generally recommended. In the case of elevated pulmonary blood flow, its aetiology should be explored.

As the groups of PH according to clinical classification represent different clinical conditions, there may be additional clinically relevant haemodynamic thresholds (e.g. for PVR) for the individual PH groups besides the general thresholds of the haemodynamic definition of PH, which are discussed in the corresponding sections.

Exercise PH, defined by an mPAP/cardiac output (CO) slope >3 mmHg/L/min between rest and exercise,¹⁷ has been re-introduced. The mPAP/CO slope is strongly age dependent and its upper limit of normal ranges from 1.6–3.3 mmHg/L/min in the supine position.¹⁷ An mPAP/CO slope >3 mmHg/L/min is not physiological in subjects aged <60 years and may rarely be present in healthy subjects aged >60 years.¹⁷ A pathological increase in pulmonary pressure during exercise is associated with impaired prognosis in patients with exercise dyspnoea¹⁸ and in several cardiovascular conditions.^19–22 Although an increased mPAP/CO slope defines an abnormal haemodynamic response to exercise, it does not allow for differentiation between pre- and post-capillary causes. The PAWP/CO slope with a threshold >2 mmHg/L/min may best differentiate between pre- and post-capillary causes of exercise PH.^23,24

3.2. Classifications

The basic structure of the classification from the 2015 ESC/ERS Guidelines for the diagnosis and treatment of PH^25,26 and the Proceedings of the 6th WSPH¹ has been kept (Table 6). The general purpose of the clinical classification of PH remains to categorize clinical conditions associated with PH, based on similar pathophysiological mechanisms, clinical presentation, haemodynamic characteristics, and therapeutic management (Figure 1). The main changes are as follows:

• The subgroups ‘non-responders at vasoreactivity testing’ and ‘acute responders at vasoreactivity testing’ have been added to IPAH as compared with the 2015 ESC/ERS Guidelines for the diagnosis and treatment of PH.^25,26 In addition to patients with IPAH, some patients with heritable PAH (HPAH) or drug- or toxin-associated PAH (DPAH) might be acute responders.

• The groups ‘PAH with features of venous/capillary (pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis [PVOD/PCH]) involvement’ and ‘persistent PH of the newborn (PPHN)’ have been included in group 1 (PAH) as compared with the 2015 ESC/ERS Guidelines for the diagnosis and treatment of PH and in line with the Proceedings of the 6th WSPH.¹

• Instead of the general term ‘sleep-disordered breathing’, the term ‘hypoventilation syndromes’ should be used within group 3 to describe conditions with increased risk of PH. Sole nocturnal obstructive sleep apnoea is generally not a cause of PH, but PH is frequent in patients with hypoventilation syndromes causing daytime hypercapnia.

4. Epidemiology and risk factors

Pulmonary hypertension is a major global health issue. All age groups are affected. Present estimates suggest a PH prevalence of ∼1% of the global population. Due to the presence of cardiac and pulmonary causes of PH, prevalence is higher in individuals aged >65 years.²⁹ Globally, LHD is the leading cause of PH.²⁹ Lung disease, especially chronic obstructive pulmonary disease (COPD), is the second most common cause.²⁹ In the UK, the observed PH prevalence has doubled in the last 10 years and is currently 125 cases/million inhabitants.³⁰ Irrespective of the underlying condition, developing PH is associated with worsening symptoms and increased mortality.²⁹ In developing countries, CHD, some infectious diseases (schistosomiasis, human immunodeficiency virus [HIV]), and high altitude represent important but under-studied causes of PH.²⁹

4.1. Group 1, pulmonary arterial hypertension

Recent registry data from economically developed countries indicate a PAH incidence and prevalence of ∼6 and 48–55 cases/million adults, respectively.³¹ It has been thought to predominantly affect younger individuals, mostly females;^32,33 this is currently true for HPAH, which affects twice as many females as males. However, recent data from the USA and Europe suggest that PAH is now frequently diagnosed in older patients (i.e. those aged ≥65 years, who often present with cardiovascular comorbidities, resulting in a more equal distribution between sexes).³² In most PAH registries, IPAH was the most common subtype (50–60% of all cases), followed by PAH associated with connective tissue disease (CTD), CHD, and portal hypertension (porto-pulmonary hypertension [PoPH]).³²

A number of drugs and toxins are associated with the development of PAH.^1,34–45 The association between exposure to drugs and toxins and PAH is classified as definite or possible, as proposed at the 6th WSPH (Table 7).¹ There is a definite association with drugs, with available data based on outbreaks, epidemiological case-control studies, or large multicentre series. A possible association is suggested by multiple case series or cases with drugs with similar mechanisms of action.¹

4.2. Group 2, pulmonary hypertension associated with left heart disease

In 2013, the Global Burden of Disease Study reported 61.7 million cases of HF worldwide, which represented almost a doubling since 1990.⁴⁶ In Europe and the USA, >80% of patients with HF are aged ≥65 years. Post-capillary PH, either isolated or combined with a pre-capillary component, is a frequent complication mainly in HFpEF, affecting at least 50% of these patients.^47,48 The prevalence of PH increases with severity of left-sided valvular diseases, and PH can be found in 60–70% of patients with severe and symptomatic mitral valve disease⁴⁹ and in up to 50% of those with symptomatic aortic stenosis.⁵⁰

4.3. Group 3, pulmonary hypertension associated with lung diseases and/or hypoxia

Mild PH is common in advanced parenchymal and interstitial lung disease. Studies have reported that ∼1–5% of patients with advanced COPD with chronic respiratory failure or candidates for lung volume reduction surgery or lung transplantation (LTx) have an mPAP >35–40 mmHg.^51,52 In idiopathic pulmonary fibrosis, an 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.⁵² Hypoxia is a public health problem for the estimated 120 million people living at altitudes >2500 m. Altitude dwellers are at risk of developing PH and chronic mountain sickness. However, it remains unclear to what extent PH and right HF are public health problems in high-altitude communities; this should be addressed with updated methodology and large-scale population studies.⁵³

4.4. Group 4, pulmonary hypertension associated with chronic pulmonary artery obstruction

The number of patients diagnosed with CTEPH is increasing, probably due to a deeper understanding of the disease and more active screening for this condition in patients who remain dyspnoeic after pulmonary embolism (PE) or who have risk factors for developing CTEPH. Registry data indicate a CTEPH incidence and prevalence of 2–6 and 26–38 cases/million adults, respectively.^31,54,55 Patients with chronic thrombo-embolic pulmonary disease (CTEPD) without PH still represent a small proportion of the patients referred to CTEPH centres.⁵⁶

4.5. Group 5, pulmonary hypertension with unclear and/or multifactorial mechanisms

Group 5 PH consists of a complex group of disorders that are associated with PH.⁵⁷ The cause is often multifactorial and can be secondary to increased pre- and post-capillary pressure, as well as direct effects on pulmonary vasculature. The incidence and prevalence of PH in most of these disorders are unknown. However, high-quality registries have recently enabled estimation of PH prevalence in adult patients with sarcoidosis.^58,59 Studies suggest that PH can be common and its presence is often associated with increased morbidity and mortality.^58,59

5. Pulmonary hypertension diagnosis

5.1. Diagnosis

The diagnostic approach to PH is mainly focused on two tasks. The primary goal is to raise early suspicion of PH and ensure fast-track referral to PH centres in patients with a high likelihood of PAH, CTEPH, or other forms of severe PH. The second objective is to identify underlying diseases, especially LHD (group 2 PH) and lung disease (group 3 PH), as well as comorbidities, to ensure proper classification, risk assessment, and treatment.

5.1.1. Clinical presentation

Symptoms of PH are mainly linked to right ventricle (RV) dysfunction, and typically associated with exercise in the earlier course of the disease.^25,26 The cardinal symptom is dyspnoea on progressively minor exertion. Other common symptoms are related to the stages and severity of the disease, and are listed in Figure 2.^60–62 Potential clinical signs and physical findings are summarized in Figure 3.^60,61 Importantly, the physical examination may also be the key to identifying the underlying cause of PH (see Figure 3).

5.1.2. Electrocardiogram

Electrocardiogram (ECG) abnormalities (Table 8) may raise suspicion of PH, deliver prognostic information, and detect arrhythmias and signs of LHD. In adults with clinical suspicion of PH (e.g. unexplained dyspnoea on exertion), right axis deviation has a high predictive value for PH.⁶³ A normal ECG does not exclude the presence of PH, but a normal ECG in combination with normal biomarkers (BNP/NT-proBNP) is associated with a low likelihood of PH in patients referred for suspected PH or at risk of PH (i.e. after acute PE).^64,65

5.1.3. Chest radiography

Chest radiography presents abnormal findings in most patients with PH; however, a normal chest X-ray does not exclude PH.⁶⁸ Radiographic signs of PH include a characteristic configuration of the cardiac silhouette due to right heart (right atrium [RA]/RV) and PA enlargement, sometimes with pruning of the peripheral vessels. In addition, signs of the underlying cause of PH, such as LHD or lung disease, may be found (Table 9).^{25,26,60,69,70}

5.1.4. Pulmonary function tests and arterial blood gases

Pulmonary function tests (PFTs) and analysis of arterial blood gas (ABG) or arterialized capillary blood are necessary to distinguish between PH groups, assess comorbidities and the need for supplementary oxygen, and determine disease severity. The initial work-up of patients with suspected PH should comprise forced spirometry, body plethysmography, lung diffusion capacity for carbon monoxide (DLCO), and ABG.

In patients with PAH, PFTs are usually normal or may show mild restrictive, obstructive, or combined abnormalities.^71,72 More severe PFT abnormalities are occasionally found in patients with PAH associated with CHD,⁷³ and those with group 3 PH. The DLCO may be normal in patients with PAH, although it is usually mildly reduced.⁷¹ A severely reduced DLCO (<45% of the predicted value) in the presence of otherwise normal PFTs can be found in PAH associated with systemic sclerosis (SSc), PVOD, in PH group 3—associated with emphysema, interstitial lung disease (ILD), or combined pulmonary fibrosis and emphysema—and in some PAH phenotypes.⁷⁴ A low DLCO is associated with a poor prognosis in several forms of PH.^75–78

Patients with PAH usually have normal or slightly reduced partial pressure of arterial oxygen (PaO₂). Severe reduction of PaO₂ might raise suspicion for patent foramen ovale, hepatic disease, other abnormalities with right-to-left shunt (e.g. septal defect), or low-DLCO-associated conditions.

Partial pressure of arterial carbon dioxide (PaCO₂) is typically lower than normal due to alveolar hyperventilation.⁷⁹ Low PaCO₂ at diagnosis and follow-up is common in PAH and associated with unfavourable outcomes.⁸⁰ Elevated PaCO₂ is very unusual in PAH and reflects alveolar hypoventilation, which in itself may be a cause of PH. Overnight oximetry or polysomnography should be performed if there is suspicion of sleep-disordered breathing or hypoventilation.⁸¹

5.1.5. Echocardiography

Independent of the underlying aetiology, PH leads to RV pressure overload and dysfunction, which can be detected by echocardiography.^82–84 When performed accurately, echocardiography provides comprehensive information on right and left heart morphology, RV and LV function, and valvular abnormalities, and gives estimates of haemodynamic parameters. Echocardiography is also a valuable tool with which to detect the cause of suspected or confirmed PH, particularly with respect to PH associated with LHD or CHD. Yet, echocardiography alone is insufficient to confirm a diagnosis of PH, which requires RHC.

Given the heterogeneous nature of PH and the peculiar geometry of the RV, there is no single echocardiographic parameter that reliably informs about PH status and underlying aetiology. Therefore, a comprehensive echocardiographic evaluation for suspected PH includes estimating the systolic pulmonary arterial pressure (sPAP) and detecting additional signs suggestive of PH, aiming at assigning an echocardiographic level of probability of PH. Echocardiographic findings of PH, including estimating pressure and signs of RV overload and/or dysfunction, are summarized in Figure 4.

Estimates of sPAP are based on the peak tricuspid regurgitation velocity (TRV) and the TRV-derived tricuspid regurgitation pressure gradient (TRPG)—after excluding pulmonary stenosis—taking into account non-invasive estimates of RA pressure (RAP). Considering the inaccuracies in estimating RAP and the amplification of measurement errors by using derived variables,^85–87 these guidelines recommend using the peak TRV (and not the estimated sPAP) as the key variable for assigning the echocardiographic probability of PH. A peak TRV >2.8 m/s may suggest PH; however, the presence or absence of PH cannot be reliably determined by TRV alone.⁸⁸ Lowering the TRV threshold in view of the revised haemodynamic definition of PH is not supported by available data (key narrative question 2, Supplementary Data, Section 5.1).^89–92 Tricuspid regurgitation (TR) velocity may underestimate (e.g. in patients with severe TR)²⁸ or overestimate (e.g. in patients with high CO in liver disease or sickle cell disease [SCD],^93,94 misinterpretation of tricuspid valve closure artefact for the TR jet, or incorrect assignment of a peak TRV in the case of maximum velocity boundary artefacts) pressure gradients. Hence, additional variables related to RV morphology and function are used to define the echocardiographic probability of PH (Table 10),^82–84,95 which may then be determined as low, intermediate, or high. When interpreted in a clinical context, this probability can be used to decide the need for further investigation, including cardiac catheterization in individual patients (Figure 5).

Echocardiographic measures of RV function include the tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RV-FAC), RV free-wall strain, and tricuspid annulus velocity (S′ wave) derived from tissue Doppler imaging, and potentially RV ejection fraction (RVEF) derived from 3D echocardiography. Furthermore, the TAPSE/sPAP ratio—representing a non-invasive measure of RV–PA coupling⁹⁶—may aid in diagnosing PH.^90,97,98 The pattern of RV outflow tract (RVOT) blood flow (mid-systolic ‘notching’) may suggest pre-capillary PH.^99,100

To separate between group 2 PH and other forms of PH, and to assess the likelihood of left ventricle (LV) diastolic dysfunction, LA size and signs of LV hypertrophy should always be measured, and Doppler echocardiographic signs (e.g. E/A ratio, E/E′) should be assessed even if the reliability of the latter is considered low.¹⁶ To identify CHD, 2D Doppler and contrast examinations are helpful, but transoesophageal contrast echocardiography or other imaging techniques (e.g. computer tomography [CT] angiography, cMRI) are needed in some cases to detect or exclude sinus venosus atrial septal defects, patent ductus arteriosus, and/or anomalous pulmonary venous return.¹⁰¹ The clinical value of exercise Doppler echocardiography in identifying exercise PH remains uncertain because of the lack of validated criteria and prospective confirmatory data. In most cases, increases in sPAP during exercise are caused by diastolic LV dysfunction.¹⁶

5.1.6. Ventilation/perfusion lung scan

A ventilation/perfusion (V/Q) lung scan (planar or single-photon emission computed tomography [SPECT]) is recommended in the diagnostic work-up of patients with suspected or newly diagnosed PH, to rule out or detect signs of CTEPH.^102,103 The V/Q SPECT is superior to planar imaging and is the methodology of choice; however, SPECT has been widely evaluated in assessing PE, but not to the same degree in CTEPH.⁶⁸ In the absence of parenchymal lung disease, a normal perfusion scan excludes CTEPH with a negative predicted value of 98%.^104,105 In most patients with PAH, V/Q scintigraphy is normal or shows a speckled pattern but no typical perfusion defects characteristic of PE or CTEPH, whereas matched V/Q defects may be found in patients with lung disease (i.e. group 3 PH). Non-matched perfusion defects similar to those seen in CTEPH may be present in 7–10% of patients with PVOD/PCH or PAH.^106,107 Deposition of the perfusion agent in extrapulmonary organs may hint to cardiac or pulmonary right-to-left shunting and has been reported in CHD, hepato-pulmonary syndrome, and pulmonary arteriovenous malformations (PAVMs).⁶⁸

5.1.7. Non-contrast and contrast-enhanced chest computed tomography examinations, and digital subtraction angiography

Computed tomography (CT) imaging may provide important information for patients with unexplained dyspnoea or suspected/confirmed PH. The CT signs suggesting the presence of PH include an enlarged PA diameter, a PA-to-aorta ratio >0.9, and enlarged right heart chambers.⁶⁸ A combination of three parameters (PA diameter ≥30 mm, RVOT wall thickness ≥6 mm, and septal deviation ≥140° [or RV:LV ratio ≥1]) is highly predictive of PH.¹⁰⁸ Non-contrast chest CT can help determine the cause of PH when there are features of parenchymal lung disease, and may also point towards the presence of PVOD/PCH by showing centrilobular ground-glass opacities (which may also be found in PAH), septal lines, and lymphadenopathy.⁶⁸

Computed tomography pulmonary angiography (CTPA) is mainly used to detect direct or indirect signs of CTEPH, such as filling defects (including thrombus adhering to the vascular wall), webs or bands in the PAs, PA retraction/dilatation, mosaic perfusion, and enlarged bronchial arteries. Importantly, the diagnostic accuracy of CTPA for CTEPH is limited (at the patient level, sensitivity and specificity are 76% and 96%, respectively),¹⁰⁹ but was reported to be higher when modern, high-quality multi-detector CT scanners were used and when interpreted by experienced readers.^109,110 Computed tomography pulmonary angiography may also be used to detect other cardiovascular abnormalities, including intracardiac shunts, abnormal pulmonary venous return, patent ductus arteriosus, and PAVMs.

In patients presenting with a clinical picture of acute PE, chest CT may be helpful in detecting signs of hitherto undetected CTEPH, which may include the presence of the above CTEPH signs, and RV hypertrophy as a sign for chronicity.^111,112 Detecting ‘acute on chronic’ PE is important, as it may impact the management of patients with presumed acute PE.

Dual-energy CT (DECT) angiography and iodine subtraction mapping may provide additional diagnostic information by creating iodine maps,¹¹³ which reflect lung perfusion, thereby possibly increasing the diagnostic accuracy for CTEPH.¹¹⁴ Although increasingly used, the diagnostic value of DECT in the work-up of patients with PH has not been established.

Digital subtraction angiography (DSA) is mainly used to confirm the diagnosis of CTEPH and to assess treatment options (i.e. operability or accessibility for BPA). Most centres use conventional two- or three-planar DSA. However, C-arm CT imaging may provide a higher spatial resolution, potentially identifying more target vessels for BPA and providing procedural guidance.^115,116

5.1.8. Cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging accurately and reproducibly assesses atrial and ventricular size, morphology, and function. Additional information on RV/LV myocardial strain can be obtained by applying tagging or by post-processing feature tracking. In addition, cMRI can be used to measure blood flow in the PA, aorta, and vena cava, allowing for quantifying stroke volume (SV), intracardiac shunt, and retrograde flow. By combining contrast magnetic resonance (MR) angiography and pulmonary perfusion imaging with late gadolinium-enhancement imaging of the myocardium, a complete picture of the heart and pulmonary vasculature can be obtained (see Supplementary Data, Table S2 for cMRI indices and normal values). A limitation is that there is no established method with which to estimate PAP. Even though the cost and availability of the technique precludes its use in the early diagnosis of PAH, it is sensitive in detecting early signs of PH and diagnosing CHD.¹¹⁷

5.1.9. Blood tests and immunology

The initial diagnostic assessment of patients with newly diagnosed PH/PAH aims to identify comorbidities and possible causes or complications of PH. Laboratory tests that should be obtained at the time of PH diagnosis include: blood counts (including haemoglobin [Hb]); serum electrolytes (sodium, potassium); kidney function (creatinine, calculation of estimated glomerular filtration rate, and urea); uric acid; liver parameters (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, γ-glutamyl transpeptidase, bilirubin); iron status (serum iron, transferrin saturation, and ferritin); and BNP or NT-proBNP. In addition, serological studies should include testing for hepatitis viruses and HIV. Basic immunology laboratory work-up is recommended, including screening tests for anti-nuclear antibodies, anti-centromere antibodies, and anti-Ro. Screening for biological markers of antiphospholipid syndrome is recommended in patients with CTEPH. Additional thrombophilia screening is not generally recommended, unless therapeutic consequences are to be expected.¹¹⁸ Pulmonary arterial hypertension and other forms of severe PH can be associated with thyroid function disorders; hence, laboratory screening should include at least thyroid-stimulating hormone.

5.1.10. Abdominal ultrasound

An abdominal ultrasound examination should be part of the comprehensive diagnostic work-up of patients with newly diagnosed PH, particularly if liver disease is suspected. A major objective is to search for liver disease and/or portal hypertension, or portocaval shunt (Abernethy malformation). During the course of the disease, patients with PH may develop secondary organ dysfunction mainly affecting the liver and kidneys.¹¹⁹ In these patients, abdominal ultrasound is needed for differential diagnostic reasons and to assess the extent of organ damage.

5.1.11. Cardiopulmonary exercise testing

Cardiopulmonary exercise testing (CPET) is a useful tool to assess the underlying pathophysiologic mechanisms leading to exercise intolerance. Patients with PAH show a typical pattern, with a low end-tidal partial pressure of carbon dioxide (P_ETCO₂), high ventilatory equivalent for carbon dioxide (VE/VCO₂), low oxygen pulse (VO₂/HR), and low peak oxygen uptake (VO₂).¹²⁰ These findings should prompt consideration of PVD. In patients with LHD or COPD, such a pattern may indicate an additional pulmonary vascular limitation.^121,122 In populations at risk of PAH, such as those with SSc, a normal peak VO₂ seems to exclude the diagnosis of PAH.¹²³

5.1.12. Right heart catheterization, vasoreactivity, exercise, and fluid challenge

5.1.12.1. Right heart catheterization

Right heart catheterization is the gold standard for diagnosing and classifying PH. Performing RHC requires expertise and meticulous methodology following standardized protocols. In addition to diagnosing and classifying PH, clinical indications include haemodynamic assessment of heart or LTx candidates¹²⁴ and evaluating congenital cardiac shunts. Interpreting invasive haemodynamics should be done in the context of the clinical picture and other diagnostic investigations. When performed in PH centres, the frequencies of serious adverse events (1.1%) and procedure-related mortality (0.055%) are low.¹²⁵ A known thrombus or tumour in the RV or RA, recently implanted (<1 month) pacemaker, mechanical right heart valve, TriClip, and an acute infection are contraindications to RHC; the risk:benefit ratio should be individually assessed before each examination and discussed with the patient. The most feared complication of RHC is perforation of a PA.

The adequate preparation of patients for RHC is of major relevance. Pre-existing medical conditions should be optimally controlled at the time of the examination (particularly blood pressure and volume control). In the supine position, the mid-thoracic level is recommended as the zero reference level, which is at the level of the LA in most patients.¹²⁶

For a complete assessment of cardiopulmonary haemodynamics, all measures listed in Table 11 must be measured or calculated. Incomplete assessments must be avoided, as this may lead to misdiagnosis. As a minimum, mixed venous oxygen saturation (SvO₂) and arterial oxygen saturation (SaO₂) should be determined. A stepwise assessment of oxygen saturation should be performed in patients with SvO₂ >75% and whenever a left-to-right shunt is suspected. Cardiac output (CO) should be assessed by the direct Fick method or thermodilution (mean values of at least three measurements). The indirect Fick method is considered to be less reliable than thermodilution;¹²⁷ however, thermodilution should not be used in the presence of shunts. Pulmonary vascular resistance ([mPAP−PAWP]/CO) should be calculated for each patient. All pressure measurements, including PAWP, should be performed at end expiration (without breath-holding manoeuvre). In patients with large intrathoracic pressure changes during the respiratory cycle (i.e. COPD, obesity, during exercise), it is appropriate to average over at least three to four respiratory cycles. If no reliable PAWP curve can be obtained, or if the PAWP values are implausible, additional measurement of LV end-diastolic pressure should be considered to avoid misclassification. Saturations taken with the catheter in the wedged position can confirm an accurate PAWP.¹²⁸

5.1.12.2. Vasoreactivity testing

The purpose of vasoreactivity testing in PAH is to identify acute vasoresponders who may be candidates for treatment with high-dose calcium channel blockers (CCBs). Pulmonary vasoreactivity testing is only recommended in patients with IPAH, HPAH, or DPAH. Inhaled nitric oxide¹²⁹ or inhaled iloprost^130,131 are the recommended test compounds for vasoreactivity testing (Table 12). There is similar evidence for intravenous (i.v.) epoprostenol, but due to incremental dose increases and repetitive measurements, testing takes much longer and is therefore less feasible.¹²⁹ Adenosine i.v. is no longer recommended due to frequent side effects.¹³² A positive acute response is defined as a reduction in mPAP by ≥10 mmHg to reach an absolute value ≤40 mmHg, with increased or unchanged CO.¹²⁹ In patients with PH-LHD, vasoreactivity testing is restricted to evaluating heart transplantation candidacy (see Section 8.1), and in patients with PH in the context of CHD with initial systemic-to-pulmonary shunting, vasoreactivity testing can be performed to evaluate the possibility of defect closure (see Section 7.5).¹⁰¹

5.1.12.3. Exercise right heart catheterization

Right heart catheterization is the gold standard method to assess cardiopulmonary haemodynamics during exercise and to define exercise PH.¹³³ The main reason to perform exercise RHC is to investigate patients with unexplained dyspnoea and normal resting haemodynamics in order to detect early PVD or left heart dysfunction. In addition, exercise haemodynamics may reveal important prognostic and functional information in patients at risk of PAH and CTEPH.^22,134,135 To maximize the amount of information, exercise RHC may be combined with CPET. According to the available data and experience, exercise RHC is not associated with an additional risk of complications compared with resting RHC and CPET.¹³³

Incremental exercise tests (step or ramp protocol) with repeated haemodynamic measurements provide the most clinical information on pulmonary circulation. The minimally required haemodynamic variables measured at each exercise level include mPAP, sPAP, diastolic PAP (dPAP), PAWP, CO, heart rate, and systemic blood pressure. In addition, RAP, SvO₂, and SaO₂ should at least be measured at rest and peak exercise. Total pulmonary resistance (TPR), PVR, and cardiac index (CI) should be calculated at each exercise level, as well as arteriovenous difference in oxygen at peak exercise. The mPAP/CO and PAWP/CO slopes should also be calculated.^136,137 In patients with early PVD, PVR may be normal or mildly elevated at rest, but may change during exercise with a steep increase in mPAP, reflected by an mPAP/CO slope >3 mmHg/L/min, while the PAWP/CO slope usually remains <2 mmHg/L/min. Patients with left heart dysfunction, such as those with HFpEF²³ and/or dynamic mitral regurgitation,¹³⁸ and a normal PAWP at rest, usually show a steep increase in mPAP and PAWP (and mPAP/CO, PAWP/CO slope) during exercise.

According to recent studies, a PAWP/CO slope >2 mmHg/L/min may be helpful in recognizing an abnormal PAWP increase and, therefore, a cardiac exercise limitation, especially in patients with PAWP 12–15 mmHg at rest.^23,24,139 A PAWP cut-off of >25 mmHg during supine exercise has been recommended for diagnosing HFpEF.¹⁶ In patients with lung disease, increased intrathoracic pressure may contribute to mPAP elevation; this is exaggerated during exercise and can be recognized by a concomitant increase in RAP.¹⁴⁰ Some exercise haemodynamics are age dependent, with healthy elderly subjects presenting with steeper mPAP/CO and PAWP/CO slopes than healthy young individuals.^9,141

5.1.12.4. Fluid challenge

Fluid challenge may reveal LV diastolic dysfunction in patients with PAWP ≤15 mmHg, but a clinical phenotype suggestive of LHD. Most available data are derived from studies aiming to uncover HFpEF (increase in PAWP) rather than identify group 2 PH (increase in PAP; see Section 8.1). It is generally accepted that rapid infusion (over 5–10 min) of ∼500 mL (7–10 mL/kg) of saline would be sufficient to detect an abnormal increase in PAWP to ≥18 mmHg (suggestive of HFpEF),¹⁴² although validation and long-term evaluation of these data are needed.¹⁴³ There are insufficient data on the haemodynamic response to fluid challenge in patients with PAH. Recent data suggest that passive leg raise during RHC may also help to uncover occult HFpEF.¹⁴⁴

5.1.13. Genetic counselling and testing

Mutations in PAH genes have been identified in familial PAH, IPAH, PVOD/PCH, and anorexigen-associated PAH (Table 13).¹⁴⁸ The screening recommendations herein specifically relate to patients with an a priori diagnosis of PAH and not ‘at-risk’ populations being screened for PAH (see Section 5.3). All patients with these conditions should be informed about the possibility of a genetic condition and that family members could carry a mutation that increases the risk of PAH, allowing for screening and early diagnosis.^33,148 Even if genetic testing is not performed, family members should be made aware of early signs and symptoms, to ensure that a timely and appropriate diagnosis is made.¹⁴⁸

Genetic counselling by appropriately trained PAH providers or geneticists should be performed prior to genetic testing, to address the complex questions related to penetrance, genetically at-risk family members, reproduction, genetic discrimination, and psychosocial issues. Careful genetic counselling with genetic counsellors or medical geneticists is critical prior to genetic testing for asymptomatic family members.¹⁴⁸

If the familial mutation is known and an unaffected family member tests negative for that mutation, the risk of PAH for that person is the same as for the general population.¹⁴⁸

Many of the less common mutations outlined have a potential additional set of syndromic features. These are summarized in Table 13 where specific clinical history, examination, and investigations are suggested. In particular, clinicians should undertake a thorough history and examination, as syndromic PAH diagnoses may be missed if not interrogated. For example, in one of the largest studies to date, TBX4, ALK1, and ENG mutations were represented in the top six most common genetic findings in adults with previously diagnosed IPAH.¹⁴⁹ These findings have been confirmed and extended in international genetics consortia in 4241 patients with PAH.¹⁵⁰ It is therefore apparent that there is either phenotypic heterogeneity of these syndromes or missed diagnostic features. As more genes associated with PAH are discovered, it will become increasingly difficult to individually test for each. Next-generation sequencing has enabled the development of gene panels to simultaneously interrogate several genes.¹⁵¹ It is, however, important to check the genes included in the panel at the time of testing, since the composition changes as genetic discoveries advance.

5.2. Diagnostic algorithm

A multistep, pragmatic approach to diagnosis should be considered in patients with unexplained dyspnoea or symptoms/signs raising suspicion of PH. This strategy is depicted in detail in Figure 6 and Table 14. The diagnostic algorithm does not address screening for specific groups at risk of PH.

5.2.1 Step 1 (suspicion)

Patients with PH are likely to be seen by first-line physicians, mainly general practitioners, for non-specific symptoms. Initial evaluation should include a comprehensive medical (including familial) history, thorough physical examination (including measurement of blood pressure, heart rate, and pulse oximetry), blood test to determine BNP/NT-proBNP, and resting ECG. This first step may raise a suspicion of a cardiac or respiratory disorder causing the symptoms.

5.2.2. Step 2 (detection)

The second step includes classical, non-invasive lung and cardiac testing. Among those tests, echocardiography is an important step in the diagnostic algorithm (Figure 6), as it assigns a level of probability of PH, irrespective of the cause. In addition, it is an important step in identifying other cardiac disorders. Based on this initial assessment, if causes other than PH are identified and/or in case of low probability of PH, patients should be managed accordingly.

5.2.3. Step 3 (confirmation)

Patients should be referred to a PH centre for further evaluation in the following situations: (1) when an intermediate/high probability of PH is established; (2) in the presence of risk factors for PAH, or a history of PE. A comprehensive work-up should be performed, with the goal of establishing the differential diagnoses and distinguishing between the various causes of PH according to the current clinical classification. The PH centre is responsible for performing an invasive assessment according to the clinical scenario.

At any time, warning signs must be recognized, as they are associated with worse outcomes and warrant immediate intervention. Such warning signs include: rapidly evolving or severe symptoms (WHO-FC III/IV), clinical signs of RV failure, syncope, signs of low CO state, poorly tolerated arrhythmias, and compromised or deteriorated haemodynamic status (hypotension, tachycardia). Such cases must be immediately managed as inpatients for initial work-up at a nearby hospital or PH centre. The presence of RV dysfunction by echocardiography, elevated levels of cardiac biomarkers, and/or haemodynamic instability must prompt referral to a PH centre for immediate assessment.

This diagnostic process emphasizes the importance of sufficient awareness and collaboration between first-line, specialized medicine and PH centres. Effective and rapid collaboration between each partner permits earlier diagnosis and management, and improves outcomes.

5.3. Screening and early detection

Despite the advent of PAH therapies that prevent clinical worsening^166–168 and effective interventions for CTEPH,¹⁰² the time from symptom onset to PH diagnosis remains at >2 years,^169,170 with most patients presenting with advanced disease. Decreasing the time to diagnosis may reduce emotional uncertainty in patients,¹⁷¹ reduce the use of health care resources, and enable treatment at an earlier stage when therapies may be more effective.¹⁷²

A proposed multifaceted approach¹⁷² to facilitate an earlier diagnosis includes: (1) screening asymptomatic, high-risk groups (with high prevalence or where the diagnosis significantly impacts the proposed intervention), including individuals with SSc (prevalence: 5–19%),^173,174BMPR2 mutation carriers (14–42%),³³ first-degree relatives of patients with HPAH,¹⁴⁸ and patients undergoing assessment for liver transplantation (2–9%);¹⁷⁵ (2) early detection of symptomatic patients in at-risk groups with conditions such as portal hypertension,¹⁷⁶ HIV infection (0.5%),¹⁷⁷ and non-SSc CTD, where the lower prevalence rates do not support asymptomatic screening; and (3) applying population-based strategies by deploying early detection approaches in PE follow-up clinics,^178,179 breathlessness clinics,¹⁷² or in at-risk patients identified from their health care behaviour and/or previous investigations.¹⁸⁰

Screening can be defined as the systematic application of a test or tests to identify at-risk, asymptomatic individuals. Screening approaches can also be extended to individuals who would not otherwise have sought medical attention on account of their symptoms, to facilitate early detection. Tools used to screen for PH have primarily been assessed, but not exclusively, in SSc,^172,174 and include blood biomarkers (NT-proBNP), ECG, echocardiography (primarily using estimates of sPAP at rest, but also exercise studies),¹⁸² PFTs (DLCO and forced vital capacity [FVC]/DLCO ratio), and exercise testing including CPET (which has been used in combination with screening algorithms to reduce the need for RHC).^123,163

5.3.1. Systemic sclerosis

In SSc, the prevalence of PAH is 5–19%,¹⁷⁴ with an annual incidence of developing PAH of 0.7–1.5%.^183–185 Evidence for the clinical value of detecting PAH early in SSc was provided by a screening programme,¹⁸⁶ which showed less severe haemodynamic impairment and better survival in screened patients compared with a contemporaneous, non-screened cohort,¹⁸⁷ providing a strong rationale for screening for PAH in patients with SSc.

The diagnostic accuracy of echocardiography or other tests alone in detecting PAH is suboptimal.¹⁷³ Several screening algorithms have been studied using a combination of clinical features, echocardiography, PFTs, and NT-proBNP to select patients with SSc for RHC (DETECT;¹⁷³ Australian Scleroderma Interest Group [ASIG]¹⁸⁸). Such combined approaches have improved diagnostic accuracy compared with the use of echocardiography, NT-proBNP, or PFTs alone, and are able to prevent unnecessary RHC and identify patients with mPAP 21–24 mmHg.¹⁸⁹ Therefore, a multimodal approach is warranted when screening patients with SSc for PAH; the echocardiographic assessment should follow the strategy described in Section 5.1.5.

Beyond initial screening, the frequency with which screening should be undertaken in asymptomatic subjects with SSc is unclear. A study from the Australian Scleroderma Study Cohort, where annual screening was recommended (some patients were screened up to 10 times), noted that most patients were diagnosed with PAH at their first screening; however, those diagnosed on subsequent screening had a lower mPAP, PVR, and WHO-FC, and better survival than those diagnosed at first screening.¹⁹⁰ Based on current evidence, annual screening for PAH in patients with SSc is sufficient. Given the financial and emotional cost associated with regular screening, stratifying subjects with SSc into those at highest and lowest risk of PAH would be desirable. Risk factors for PAH include: (1) clinical and demographic factors (i.e. breathlessness, longer disease duration, sicca symptoms, digital ulceration, older age, and male sex); and (2) the results of investigations (e.g. positive anti-centromere antibody profile, mild ILD, low DLCO, elevated FVC/DLCO ratio, or elevated NT-proBNP).^174,191 A recent meta-analysis showed that reduced digital capillary density, as assessed by video-capillaroscopy, or progression to a severe active/late pattern of vascular involvement is also a risk factor for PAH.¹⁹² In addition to identifying patients at increased risk of PAH, a simple prediction model integrating symptoms, DLCO, and NT-proBNP identified subjects at very low probability of PAH who could potentially avoid further specific testing for PH.¹⁸³ Furthermore, CPET may help to identify patients with SSc with a low risk of having PAH and thus to avoid unnecessary RHC.¹²³

The recommendations on screening for PAH in SSc have been established based on key narrative question 3 (Supplementary Data, Section 5.2).

5.3.2. BMPR2 mutation carriers

In the evolving list of genes known to be associated with PAH, experience is largely restricted to BMPR2 mutation carriers who carry a lifetime risk of developing PAH of ∼20%, with penetrance higher in female carriers (42%) compared with male carriers (14%).^33,148,193 There is currently no accepted screening strategy for evaluating PAH in BMPR2 mutation carriers. At present, based on expert consensus, asymptomatic relatives who screen positive for PAH-causing mutations are often offered yearly screening echocardiography.^25,26 The DELPHI-2 study, which prospectively screened carriers and relatives, recently demonstrated a 9.1% pick up over 47 ± 27 months of PAH, with 2/55 diagnosed at baseline and 3/55 at follow-up; this equates to an incidence of 2.3%/year.³³ The screening schedule included ECG, NT-proBNP, DLCO, echocardiography, CPET, and optional RHC; however, none of the cases would have been picked up by echocardiography alone. Screening programmes should adopt a multimodal approach, although the optimal strategy and screening period remains undefined and will require multinational, multicentre study.

5.3.3. Portal hypertension

An estimated 1–2% of patients with liver disease and portal hypertension develop PoPH,^176,194 which is of particular relevance in patients considered for transjugular portosystemic shunting or liver transplantation. In such patients, echocardiography is recommended to screen for PAH, even in the absence of symptoms. By using echocardiography, sPAP can be measured in ∼80% of patients with portal hypertension, which aids decisions to perform RHC. In patients assessed for liver transplantation, one study showed that an sPAP of >50 mmHg had 97% sensitivity and 77% specificity for detecting moderate-to-severe PAH.¹⁹⁵ Other investigators have recommended RHC when sPAP is >38 mmHg.¹⁹⁶ When screening for PoPH, it is advised to assess the echocardiographic probability of PH (see Section 5.1.5). In agreement with the International Liver Transplant Society, for patients awaiting liver transplantation, it is recommended to reassess for PAH annually, although the optimal interval remains unclear.¹⁷⁵

5.3.4. Pulmonary embolism

Chronic thrombo-embolic pulmonary hypertension is an uncommon and under-diagnosed complication of acute PE.¹¹² The reported cumulative incidence of CTEPH after acute, symptomatic PE ranges 0.1–11.8%, depending on the collective investigated.^{112,178,197–199} A systematic review and meta-analysis reported a CTEPH incidence of 0.6% in all patients with acute PE, 3.2% in survivors, and 2.8% in survivors without major comorbidities.¹⁷⁸ A multicentre, observational, screening study reported a CTEPH incidence of 3.7/1000 patient-years and a 2 year cumulative incidence of 0.79% following acute PE.²⁰⁰ A recent prospective observational study (FOCUS, Follow-up After Acute Pulmonary Embolism) showed a cumulative 2 year incidence of 2.3% and 16.0% for CTEPH and post-PE impairment, respectively, which were both associated with a higher risk of rehospitalization and death.²⁰¹ Due to insufficient awareness, some patients may have a delayed diagnosis of CTEPH because they may initially be misclassified as acute PE.¹¹² In this context, the current guidelines do not recommend routine follow-up of patients with PE by imaging methods of the pulmonary vascular tree, but suggest evaluating the index imaging test used to diagnose acute PE for signs of CTEPH. Echocardiography is the preferred first-line diagnostic test in patients with suspected CTEPH.¹⁰³

Up to 50% of patients have persistent perfusion defects after an acute PE; however, the clinical relevance is unclear.^202–204 All patients in whom symptoms can be attributed to post-thrombotic deposits within PAs are considered to have CTEPD, with or without PH.⁵⁴ While persistent dyspnoea is common after acute PE,²⁰⁵ the prevalence of CTEPD without PH is unknown and requires further study (see Section 10.1). A study exploring screening for CTEPH following acute PE identified, using echocardiography, a low yield of additional CTEPH diagnoses in asymptomatic patients.²⁰⁶ Current PE guidelines recommend that further diagnostic evaluation may be considered in asymptomatic patients with risk factors for CTEPH at 3–6 months’ follow-up.^103,207 Approaches to early detection of CTEPH following acute PE are based on identifying patients at increased risk.²⁰⁸ In patients with persistent or new-onset dyspnoea after PE, non-invasive approaches use echocardiography to assess for PH and cross-sectional imaging to assess for persistent perfusion defects. Limited data exist on strategies using DECT, CT lung subtraction iodine mapping, or 3D MR perfusion imaging. Scoring systems, including the Leiden CTEPH rule-out criteria^206,209 can be used to inform diagnostic strategies. Cardiopulmonary exercise testing may identify characteristic features of exercise limitation due to PVD, or suggest an alternative diagnosis. The optimal timing for assessing symptoms to aid early detection of CTEPH may be 3–6 months after acute PE, coinciding with the routine evaluation of anticoagulant treatment, but earlier assessment may be necessary in highly symptomatic or deteriorating patients.^54,103

6. Pulmonary arterial hypertension (group 1)

6.1. Clinical characteristics

The symptoms of PAH are non-specific and mainly related to progressive RV dysfunction (see Section 5.1.1) as a consequence of progressive pulmonary vasculopathy (Figure 7). The presentation of PAH may be modified by diseases that are associated with PAH, as well as comorbidities. More detailed descriptions of the individual PAH subsets are reported in Section 7.

6.2. Severity and risk assessment

6.2.1. Clinical parameters

Clinical assessment is a key part of evaluating patients with PAH, as it provides valuable information for determining disease severity, improvement, deterioration, or stability. At follow-up, changes in WHO-FC (Table 15), episodes of chest pain, arrhythmias, haemoptysis, syncope, and signs of right HF provide important information. Physical examination should assess heart rate, rhythm, blood pressure, cyanosis, enlarged jugular veins, oedema, ascites, and pleural effusions. The WHO-FC is one of the strongest predictors of survival, both at diagnosis and follow-up,^210–212 and worsening WHO-FC is one of the most alarming indicators of disease progression, which should trigger further investigations to identify the cause(s) of clinical deterioration.^210,213,214

6.2.2. Imaging

Imaging of the heart plays an essential role in the follow-up of patients with PAH. Several echocardiographic and cMRI parameters have been proposed to monitor RV function during the course of PAH. Table S2 provides a list of imaging parameters and relative cut-off values associated with increased and decreased risk of adverse events.

6.2.2.1. Echocardiography

Echocardiography is a widely available imaging modality and is readily performed at the patient’s bedside. It is crucial that a high-quality echocardiographic assessment by PH specialists is undertaken to reduce intraobserver and interobserver variability. Of note, estimated sPAP at rest is not prognostic and irrelevant to therapeutic decision-making.^212,215,216 An increase in sPAP does not necessarily reflect disease progression and a decrease in sPAP does not necessarily reflect improvement.

Despite the complex geometry of the right heart, echocardiographic surrogates of the true right heart dimensions, which include a description of RV and RA areas, and the LV eccentricity index, provide useful clinical information in PAH.^217,218 Right ventricular dysfunction can be evaluated measuring fractional area change, TAPSE, tissue Doppler, and 2D speckle tracking myocardial strain recording of RV free-wall motion, all of which represent isovolumetric and ejection-phase indices of load-induced RV pump failure.^219–224 The rationale for the reported measurements is strong, as RV systolic function metrics assess the adaptation of RV contractility to increased afterload, and increased right heart dimension and inferior vena cava dilation reflect failure of this mechanism, hence maladaptation.²²⁵ Pericardial effusion and tricuspid regurgitation (TR) grading further explore RV overload and are of prognostic relevance in these patients.^{218,226–228} All of these variables are physiologically interdependent and their combination provides additional prognostic information over single measurements.²²³

Echocardiography also enables combined parameters to be measured, such as the TAPSE/sPAP ratio, which is tightly linked to RV–PA coupling and predicts outcome.^96,97 Echocardiographic measurements of RV and RA sizes combined with LV eccentricity index are crucial for assessing RV reverse remodelling as an emerging marker of treatment efficacy.^220,229 Three-dimensional echocardiography may achieve better estimation than standard 2D assessment, but underestimations of volumes and ejection fraction have been reported, and technical issues are, as yet, unresolved.²³⁰

6.2.2.2. Cardiac magnetic resonance imaging

The role of cMRI in evaluating patients with PAH has been addressed in several studies, and RV volumes, RVEF, and SV are essential prognostic determinants in PAH.^{225,231–236} In patients with PAH, initial cMRI measurements added prognostic value to current risk scores.^231,232 In addition, risk assessment at 1 year of follow-up based on cMRI was at least equal to risk assessment based on RHC.²³⁷ The cMRI risk-assessment variables based on the current literature are included in Table 16.^{117,225,231–235,237} The stroke volume index (SVI) cut-off levels are based on the consensus of the literature;²³⁸ a change of 10 mL in SV (LV end-diastolic volume−LV end-systolic volume) during follow-up is considered clinically significant.²³⁹ The value of cMRI in the follow-up of patients has been shown in several studies, and cMRI enables treatment effects to be monitored and treatment strategies adapted in time to prevent clinical failure.^240–242

6.2.3. Haemodynamics

Cardiopulmonary haemodynamics assessed by RHC provide important prognostic information, both at the time of diagnosis and at follow-up.^{129,212,213,216,238,243–245,247,248} Currently available risk-stratification tools include haemodynamic variables for prognostication: RAP and PVR in REVEAL risk scores,^213,249,250 and RAP, CI, and SvO₂ in the ESC/ERS risk-stratification table.^25,26 The mPAP provides little prognostic information, except in acute vasodilator responders.¹²⁹ A recent study from France, which combined clinical and haemodynamic parameters, found that WHO-FC, 6MWD, RAP, and SVI (but not SV and SvO₂) were independent predictors of outcome.²³⁸

To refine the risk-stratification table (Table 16), SVI criteria are now added with the cut-off values of >38 mL/m² and <31 mL/m² to determine low-risk and high-risk status, respectively.²³⁸

The optimal timing of follow-up RHC has not been determined. While some centres regularly perform invasive follow-up assessments, others perform them as clinically indicated, and there is no evidence that any of these strategies is associated with better outcomes (Table 17).

6.2.4. Exercise capacity

The 6-minute walking test (6MWT) is the most widely used measure of exercise capacity in PH centres. The 6MWT is easy to perform, inexpensive, and widely accepted by patients, health professionals, and medicines agencies as an important and validated variable in PH. As with all PH assessments, 6MWT results must always be interpreted in the clinical context. The 6MWD is influenced by factors such as sex, age, height, weight, comorbidities, need for oxygen, learning curve, and motivation. Test results are usually given in absolute distance (metres) rather than the percentage of predicted values. Change in 6MWD is one of the most commonly used parameters in PAH clinical trials as a primary endpoint, key secondary endpoint, or component of clinical worsening.²⁵¹ A recent investigation showed that the best absolute-threshold values for 1 year mortality and 1 year survival, respectively, were 165 m and 440 m, respectively.²⁵² Improvements in 6MWD have had less predictive value than deterioration on key clinical outcomes (mortality and survival).^250,252,253 These results are consistent with observations from clinical trials and registries;^254,255 however, there is no single threshold that would apply to all patients.²⁵⁶ Some studies have also suggested that adding SaO₂ measured by pulse oximetry and heart rate responses may improve prognostic relevance.^246,257 Hypoxaemia observed during the 6MWT is associated with worse survival, but these findings still await confirmation in large multicentre studies.

The incremental shuttle walking test (ISWT) is an alternative maximal test for assessing patients with PAH. The ISWT has a potential advantage over the 6MWT in that it does not have a ceiling effect; furthermore, it keeps the simplicity of a simple-to-perform field test, in contrast to CPET. However, the ISWT experience in PAH is currently limited.²⁵⁸

Cardiopulmonary exercise testing is a non-invasive method for assessing functional capacity and exercise limitation. It is usually performed as a maximal exercise test, and is safe even in patients with severe exercise limitation.^259,260 Most PH centres use an incremental ramp protocol, although the test has not yet been standardized for this patient population. Robust prognostic evidence for peak VO₂ and VE/VCO₂ has been found in three studies, all powered for multivariable analysis.^261–263 When associated with SVI, peak VO₂ provided useful information to further stratify patients with PAH at intermediate risk.²⁶⁴ However, the added value of CPET on top of common clinical and haemodynamic variables remains largely unexplored.

6.2.5. Biochemical markers

Considerable efforts have been made to identify additional biomarkers of PVD, addressing prognosis,^265–272 diagnosis, and differentiation of PH subtypes,^{270,273–276} as well as PAH treatment response.²⁶⁶ Emerging proteins related to PAH and vascular remodelling include bone morphogenetic proteins 9 and 10 and translationally controlled tumour protein.^270,277,278 Proteome-wide screening in IPAH and HPAH identified a multimarker panel with prognostic information in addition to the REVEAL risk score.²⁷¹ Another study found that early development of SSc-associated PAH (PAH-SSc) was predicted by high circulating levels of C-X-C motif chemokine 4 in patients with SSc.²⁷⁶ However, none of these biomarkers have been introduced in clinical practice.

Thus, BNP and NT-proBNP remain the only biomarkers routinely used in clinical practice at PH centres, correlating with myocardial stress and providing prognostic information.²⁷⁹ Brain natriuretic peptide and NT-proBNP are not specific for PH, as they can be elevated in other forms of heart disease, exhibiting great variability. The previously proposed cut-off levels of BNP (<50, 50–300, and >300 ng/L) and NT-proBNP (<300, 300–1400, and >1400 ng/L) for low, intermediate, and high risk, respectively, in the ESC/ERS risk-assessment model at baseline and during follow-up are prognostic for long-term outcomes and can be used to predict response to treatment.²⁶⁶ Refined cut-off values for BNP (<50, 50–199, 200–800, and >800 ng/L) and NT-pro-BNP (<300, 300–649, 650–1100, and >1100 ng/L) for low, intermediate–low, intermediate–high, and high risk, respectively, have recently been introduced as part of a four-strata risk-assessment strategy (see Section 6.2.7).²⁸⁰

6.2.6. Patient-reported outcome measures

A patient-reported outcome measure (PROM) is a term for health outcomes that are ‘self-reported’ by the patient. It is the patient’s experience of living with PH and its impact on them and their caregivers, including symptomatic, intellectual, psychosocial, spiritual, and goal-orientated dimensions of the disease and its treatment. Despite treatment advances improving survival, patients with PAH present with a range of non-specific yet debilitating symptoms, which affect health-related quality of life (HR-QoL).^281,282

Patient-reported outcome measures remain an underused outcome measure. Tools validated in patients with PAH should be used to assess HR-QoL^282,283 in individual patients. There has been a reliance on generic PROMs, which have been studied in patients with PAH but may lack sensitivity to detect changes in PAH.^284,285 To address this, a number of PH-specific HR-QoL instruments have been developed and validated (e.g. Cambridge Pulmonary Hypertension Outcome Review [CAMPHOR],²⁸⁶ emPHasis-10,^282,287 Living with Pulmonary Hypertension,²⁸⁸ and Pulmonary Arterial Hypertension-Symptoms and Impact [PAH-SYMPACT]).²⁸⁹ These disease-specific PROMs track functional status, clinical deterioration, and prognosis in PAH, and are more sensitive to the differences in the risk status than generic PROMs.^290,291 In addition, HR-QoL scores provide independent prognostic information.²⁸⁷

6.2.7. Comprehensive prognostic evaluation, risk assessment, and treatment goals

In the 2015 ESC/ERS Guidelines for the diagnosis and treatment of PH, risk assessment was based on a multiparametric approach using a three-strata model to classify patients at low, intermediate, or high risk of death. Originally, these strata were based on estimated 1 year mortality rates of <5%, 5–10%, and >10%, respectively.^25,26 Since then, registry data have shown that observed 1 year mortality rates in the intermediate- and high-risk groups were sometimes higher than predicted (i.e. up to 20% in the intermediate-risk group and >20% in the high-risk group). These numbers have been updated accordingly in the revised three-strata risk model (Table 16).^292–294

Several abbreviated approaches of the 2015 ESC/ERS risk-stratification tool have been introduced and independently validated using the Swedish Pulmonary Arterial Hypertension Registry (SPAHR),²⁹² the Comparative, Prospective Registry of Newly Initiated Therapies for PH (COMPERA),²⁹³ and the French PH Registry (FPHR).²⁹⁵ Other risk-stratification tools have been developed from the US REVEAL, including the REVEAL 2.0 risk score calculator, and an abridged version (REVEAL Lite 2).^249,296 In all these studies, WHO-FC, 6MWD, and BNP/NT-proBNP emerged as the variables with the highest predictive value.

The main limitation of the 2015 ESC/ERS three-strata, risk-assessment tool is that 60–70% of the patients are classified as intermediate risk.^{292–295,297–303} An initial attempt to substratify the intermediate-risk group has been proposed, using a modified mean score in the SPAHR equation (with low–intermediate, 1.5–1.99 and high–intermediate, 2.0–2.49 as cut-offs), where the high–intermediate group was associated with worse survival.³⁰² There have also been attempts to further improve risk stratification by exploring the additional value of new biomarkers,³⁰⁴ or by measuring RV structure and function by echocardiography and cMRI.^231,305,306 Other strategies have included incorporating renal function³⁰⁷ or combining 6MWD with TAPSE/sPAP ratio;^96,97 however, all of these strategies have to be further validated.

Two recent registry studies have evaluated a four-strata, risk-assessment tool based on refined cut-off levels for WHO-FC, 6MWD, and NT-proBNP (Table 18).^280,308 Patients were categorized as low, intermediate–low, intermediate–high, or high risk. Together, these studies included >4000 patients with PAH and showed that the four-strata model performed at least as well as the three-strata model in predicting mortality. The four-strata model predicted survival in patients with IPAH, HPAH, DPAH, and PAH associated with CTD (including the SSc subgroup), and in patients with PoPH. The observed 1-year mortality rates in the four risk strata were 0–3%, 2–7%, 9–19%, and >20%, respectively. Compared with the three-strata model, the four-strata model was more sensitive to changes in risk from baseline to follow-up, and these changes were associated with changes in the long-term mortality risk. The main advantage of the four-strata model over the three-strata model is better discrimination within the intermediate-risk group, which helps guide therapeutic decision-making (see Section 6.3.4). For these reasons, the four-strata model is included in the updated treatment algorithm (see Figure 9). However, the three-strata model is maintained for initial assessment, which should be comprehensive and include echocardiographic and haemodynamic variables, for which cut-off values for the four-strata model have yet to be established.

Several studies have identified WHO-FC, 6MWD, and BNP/NT-proBNP as the strongest prognostic predictors.^293,295,296 With the abbreviated risk-assessment tools, missing values become an important limitation. REVEAL Lite 2 provides accurate prediction when one key variable (WHO-FC, 6MWD, or BNP/NT-proBNP) is unavailable, but is no longer accurate when two of these variables are missing.^293,296 The original three-strata SPAHR/COMPERA risk tool was developed with at least two variables available, while the four-strata model was developed and validated in patients for whom all three variables were available. It is therefore recommended to use at least these three variables for risk stratification. However, two components may be used when variables are missing, especially when a functional criterion (WHO-FC or 6MWD) is combined with BNP or NT-proBNP.²⁹⁶

Collectively, the available studies support a risk-based, goal-orientated treatment approach in patients with PAH, where achieving and/or maintaining a low-risk status is favourable and recommended (key narrative question 4, Supplementary Data, Section 6.1).^{298,300,303,309,310} For risk stratification at diagnosis, use of the three-strata model is recommended taking into account as many factors as possible (Table 16), with a strong emphasis on disease type, WHO-FC, 6MWD, BNP/NT-proBNP, and haemodynamics. At follow-up, the four-strata model (Table 18) is recommended as a basic risk-stratification tool, but additional variables should be considered as needed, especially right heart imaging and haemodynamics. At any stage, individual factors such as age, sex, disease type, comorbidities, and kidney function should also be considered.

6.3. Therapy

According to the revised haemodynamic definition, PAH may be diagnosed in patients with mPAP >20 mmHg and PVR >2 WU. Yet, the efficacy of drugs approved for PAH has only been demonstrated in patients with mPAP ≥25 mmHg and PVR >3 WU (see Supplementary Data, Table S1). No data are available for the efficacy of drugs approved for PAH in patients whose mPAP is <25 mmHg and whose PVR is <3 WU. Hence, for such patients, the efficacy of drugs approved for PAH has not been established. The same is true for patients with exercise PH, who, by definition, do not fulfil the diagnostic criteria for PAH. Patients at high risk of developing PAH, for instance patients with SSc or family members of patients with HPAH, should be referred to a PH centre for individual decision-making.

6.3.1. General measures

Managing patients with PAH requires a comprehensive treatment strategy and multidisciplinary care. In addition to applying PAH drugs, general measures and care in special situations represent integral components of optimized patient care. In this context, the systemic consequences of PH and right-sided HF, often contributing to disease burden, should be appropriately managed.¹¹⁹

6.3.1.1. Physical activity and supervised rehabilitation

The 2015 ESC/ERS Guidelines for the diagnosis and treatment of PH suggested that patients with PAH should be encouraged to be active within symptom limits.^25,26 Since then, additional studies have shown the beneficial impact of exercise training on exercise capacity (6MWD) and quality of life.^312–316 A large, randomized controlled trial (RCT) in 11 centres across 10 European countries, including 116 patients with PAH/CTEPH on PAH drugs, showed a significant improvement in 6MWD of 34.1 ± 8.3 m, quality of life, WHO-FC, and peak VO₂ compared with standard of care.³¹⁵ Since most of the studies included patients who were stable on medical treatment, patients with PAH should be treated with the best standard of pharmacological treatment and be in a stable clinical condition before embarking on a supervised rehabilitation programme. Establishing specialized rehabilitation programmes for patients with PH would further enhance patient access to this intervention.³¹⁷

6.3.1.2. Anticoagulation

There are several reasons to consider anticoagulation in patients with PAH. Histopathological specimens from PAH patients’ lungs have shown in situ thrombosis of pulmonary vessels. Patients with CHD or PA aneurysms may develop thrombosis of the central PAs. Abnormalities in the coagulation and fibrinolytic system indicating a pro-coagulant state have been reported in patients with PAH.³¹⁸

Data from RCTs on anticoagulation in PAH are lacking, and registry data have yielded conflicting results. The largest registry analysis so far suggested a potential survival benefit associated with anticoagulation in patients with IPAH,³¹⁹ but this finding was not confirmed by others.³²⁰ Two recent meta-analyses also concluded that using anticoagulants may improve survival in patients with IPAH;^321,322 however, none of the included studies were methodologically robust. Despite the lack of evidence, registry data obtained between 2007 and 2016 showed that anticoagulation was used in 43% of patients with IPAH.²⁹³ In PAH associated with SSc, registry data and meta-analyses uniformly indicated that anticoagulation may be harmful.^320–322 In CHD, there are also no RCTs on anticoagulation. There is also no consensus about the use of anticoagulants in patients who have permanent i.v. lines for therapy with prostacyclin analogues; this is left to local centre practice.

As anticoagulation is associated with an increased bleeding risk, and in the absence of robust data, no general recommendation has been made for or against the use of anticoagulants in patients with PAH.; therefore, individual decision-making is required.

6.3.1.3. Diuretics

Right HF is associated with systemic fluid retention, reduced renal blood flow, and activation of the renin–angiotensin–aldosterone system. Increased right-sided filling pressures are transmitted to the renal veins, increasing interstitial and tubular hydrostatic pressure within the encapsulated kidney, which decreases net glomerular filtration rate and oxygen delivery.¹¹⁹

Avoiding fluid retention is one of the key objectives in managing patients with PH. Once these patients develop signs of right-sided HF and oedema, restricting fluid intake and using diuretics is recommended. The three main classes of diuretics—loop diuretics, thiazides, and mineralocorticoid receptor antagonists—are used as monotherapy or in combination, as determined by the patient’s clinical need and kidney function. Patients requiring diuretic therapy should be advised to regularly monitor their body weight and to seek medical advice in case of weight gain. Close collaboration between patients, PH centres, especially PH nurses, and primary care physicians plays a vital role. Kidney function and serum electrolytes should be regularly monitored, and intravascular volume depletion must be avoided as it may cause a further decline in CO and systemic blood pressure. Physicians should bear in mind that fluid retention and oedema may not necessarily signal right-sided HF, but may also be a side effect of PAH therapy.³²³

6.3.1.4. Oxygen

Although oxygen administration reduces PVR and improves exercise tolerance in patients with PAH, there are no data to suggest that long-term oxygen therapy has sustained benefits on the course of the disease. Most patients with PAH, except those with CHD and pulmonary-to-systemic shunts, have minor degrees of arterial hypoxaemia at rest, unless they have a patent foramen ovale. Data show that nocturnal oxygen therapy does not modify the natural history of advanced Eisenmenger syndrome.³²⁴ In the absence of robust data on the use of oxygen in patients with PAH, guidance is based on evidence in patients with COPD;³²⁵ when PaO₂ is <8 kPa (60 mmHg; alternatively, SaO₂ <92%) on at least two occasions, patients are advised to take oxygen to achieve a PaO₂ >8 kPa. Ambulatory oxygen may be considered when there is evidence of symptomatic benefit and correctable desaturation on exercise.^326,327 Nocturnal oxygen therapy should be considered in case of sleep-related desaturation.³²⁸

6.3.1.5. Cardiovascular drugs

No data from rigorous clinical trials are available on the usefulness and safety of drugs that are effective in systemic hypertension or left-sided HF, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor–neprilysin inhibitors (ARNIs), sodium–glucose cotransporter-2 inhibitors (SGLT-2is), beta-blockers, or ivabradine in patients with PAH. In this group of patients, these drugs may lead to potentially dangerous drops in blood pressure, heart rate, or both. Likewise, the efficacy of digoxin/digitoxin has not been documented in PAH, although these drugs may be administered to slow ventricular rate in patients with PAH who develop atrial tachyarrhythmias.

6.3.1.6. Anaemia and iron status

Iron deficiency is common in patients with PAH and is defined by serum ferritin <100 µg/L, or serum ferritin 100–299 µg/L and transferrin saturation <20%.³²⁹ The underlying pathological mechanisms are complex.^330–333 In patients with PAH, iron deficiency is associated with impaired myocardial function, aggravated symptoms, and increased mortality risk.^333,334 Based on these data, regular monitoring of iron status (serum iron, ferritin, transferrin saturation, soluble transferrin receptors) is recommended in patients with PAH.

In patients with severe iron deficiency anaemia (Hb <7–8 g/dL), i.v. supplementation is recommended.^335–337 Oral iron formulations containing ferrous (Fe²⁺) sulfate, ferrous gluconate, and ferrous fumarate are often poorly tolerated, and drug efficacy may be impaired in patients with PAH.^330,331 Ferric maltol is a new, orally available formulation of ferric (Fe³⁺) iron and maltol. One small, open-label study suggested good tolerability and efficacy in patients with severe PH with mild-to-moderate iron deficiency and anaemia.³³⁸ In contrast, two small, 12 week, randomized, cross-over trials studying iron supplementation in PAH patients without anaemia provided no significant clinical benefit.³³⁹ Randomized controlled trials comparing oral and i.v. iron supplementation in patients with PAH are lacking.

6.3.1.7. Vaccination

As a general health care measure, it is recommended that patients with PAH be vaccinated at least against influenza, Streptococcus pneumoniae, and SARS-CoV-2.

6.3.1.8. Psychosocial support

Receiving a diagnosis of PH—often after a substantial delay—and experiencing the physical limitations have a substantial impact on psychological, emotional, and social aspects of patients and their families. Symptoms of depression and anxiety, as well as adjustment disorders, have a high prevalence in patients with PAH. Pulmonary arterial hypertension also has grave repercussions on ability to work and income.^{281,340–344}

Empathic and hopeful communication is essential for physicians caring for patients with PAH. Awareness and knowledge about the disease and its treatment options empower patients to engage in shared decision-making. Adequate diagnostic screening tools are the key to identifying patients in need of referral for psychological/psychiatric support, including psychopharmacological medication,³⁴⁵ or social assistance. Patient support groups may play an important role, and patients should be advised to join such groups. Given the life-limiting character of PAH, advanced care planning with referral to specialist palliative care services should be supported at the right time.³⁴⁶

6.3.1.9. Adherence to treatments

Adhering to medical therapy is key to successfully managing PAH. In general, factors that affect adherence are patient related (e.g. demographics, cognitive impairment, polypharmacy, adverse reactions/side effects, psychological health, health literacy, patient understanding of the treatment rationale, and comorbidities), physician related (expertise, awareness of guidelines, and multidisciplinary team approach), and health care system related (work setting, access to treatments, and cost).³⁴⁷

Recent studies have indicated that adherence to drug therapy in patients with PAH may be suboptimal.^348,349 Given the complexity of PAH treatment, potential side effects, and risks associated with treatment interruptions, adherence should be periodically monitored by a member of the multidisciplinary team, to identify non-adherence and any changes to the treatment regimen spontaneously triggered by patients or non-expert physicians. To promote adherence, it is important to ensure that patients are involved in care decisions and appropriately informed about treatment options and rationale, expectations, side effects, and potential consequences of non-adherence. Patients should be advised that any changes in treatment should be made in cooperation with the PH centre.

6.3.2. Special circumstances

6.3.2.1. Pregnancy and birth control

Pregnancy

Historically, pregnancy in women with PAH and other forms of severe PH has been associated with maternal mortality rates of up to 56% and neonatal mortality rates of up to 13%.³⁵⁰ With improved treatment of PAH and new approaches to managing women during pregnancy and the peri-partum period, maternal mortality has declined but remains high, ranging 11–25%.^351–355 For these reasons, previous ESC/ERS Guidelines for the diagnosis and treatment of PH have recommended that patients with PAH should avoid pregnancy.^25,26 However, there are reports of favourable pregnancy outcomes in women with PH, including, but not limited to, women with IPAH who respond to CCB therapy.^{353,354,356,357} Nonetheless, pregnancy remains associated with unforeseeable risks, and may accelerate PH progression.³⁵⁸ Women with PH can deteriorate at any time during or after pregnancy. Therefore, physicians have a responsibility to inform patients about the risks of pregnancy, so that women and their families can make informed decisions.

Women with poorly controlled disease, indicated by an intermediate- or high-risk profile and signs of RV dysfunction, are at high risk of adverse outcomes; in the event of pregnancy, they should be carefully counselled and early termination should be advised. For patients with well-controlled disease, a low-risk profile, and normal or near-normal resting haemodynamics who consider becoming pregnant, individual counselling and shared decision-making are recommended. In such cases, alternatives such as adoption and surrogacy may also be explored. Pre-conception genetic counselling should also be considered in HPAH.

Women with PH who become pregnant or present during pregnancy with newly diagnosed PAH should be treated, whenever possible, in centres with a multidisciplinary team experienced in managing PH in pregnancy. If pregnancy is continued, PAH therapy may have to be adjusted. It is recommended to stop endothelin receptor antagonists (ERAs), riociguat, and selexipag because of potential or unknown teratogenicity.³⁵⁹ Despite limited evidence, CCBs, PDE5is, and inhaled/i.v./subcutaneous (s.c.) prostacyclin analogues are considered safe during pregnancy.^356,360

Pregnancy in PH is a very sensitive topic and requires empathic communication. Psychological support should be offered whenever needed.

Contraception

Women with PH of childbearing potential should be provided with clear contraceptive advice, considering the individual needs of the woman but recognizing that the implications of contraceptive failure are significant in PH. With appropriate use, many forms of contraception, including oral contraceptives, are highly effective. In patients treated with bosentan, reduced efficacy of hormonal contraceptives should be carefully considered.³⁶¹ Using hormonal implants or an intrauterine device are alternative options with low failure rates. Surgical sterilization may be considered but is associated with peri-operative risks. Emergency post-coital hormonal contraception is safe in PH.

6.3.2.2. Surgical procedures

Surgical procedures in patients with PH are associated with an elevated risk of right HF and death. In a prospective, multinational registry including 114 patients with PAH who underwent non-cardiac and non-obstetric surgery, the peri-operative mortality rate was 2% in elective procedures and 15% in emergency procedures.³⁶² The mortality risk was associated with the severity of PH. The decision to perform surgery should be made by a multidisciplinary team involving a PH physician, and must be based on an individual risk:benefit assessment considering various factors, including indication, urgency, PH severity, and patient preferences. Risk scores to predict the peri-operative mortality risk have been developed but require further validation.³⁶³ General recommendations cannot be made. The same is true regarding the preferred mode of anaesthesia. Pre-operative optimization of PAH therapy should be attempted whenever possible (see also the 2022 ESC Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery).³⁶⁴

6.3.2.3. Travel and altitude

Hypobaric hypoxia may induce arterial hypoxaemia, additional hypoxic pulmonary vasoconstriction, and increased RV load in PAH.^365,366 Cabin aircraft pressures are equivalent to altitudes up to 2438 m,³⁶⁷ at which the PaO₂ decreases to that of an inspired O₂ fraction of 15.1% at sea level.³⁶⁵ However, evidence suggests that short-term (less than 1 day) normobaric hypoxia is generally well tolerated in clinically stable patients with PAH.^{365,368–372} In-flight oxygen administration is advised for patients using oxygen at sea level and for those with PaO₂ <8 kPa (60 mmHg) or SaO₂ <92%.^{25,26,325,369,372} An oxygen flow rate of 2 L/min will raise inspired oxygen pressure to values as at sea level, and patients already using oxygen at sea level should increase their oxygen flow rate.^25,26,373

As the effects of moderate to long-term (hours–days) hypoxia exposure in PAH remain largely unexplored,^374,375 patients should avoid altitudes >1500 m without supplemental oxygen.^25,26,369 However, patients with PAH who are not hypoxaemic at sea level have tolerated day trips to 2500 m reasonably well.³⁷⁶ Patients should travel with written information about their disease, including a medication list, bring extra doses of their medication, and be informed about local PH centres near their travel destination.^25,26

6.3.3. Pulmonary arterial hypertension therapies

6.3.3.1. Calcium channel blockers

Patients with PAH who respond favourably to acute vasoreactivity testing (Figure 8) may respond favourably to treatment with CCBs.^129,146 Less than 10% of patients with IPAH, HPAH, or DPAH are responders, while an acute vasodilator response does not predict a favourable long-term response to CCBs in patients with other forms of PAH.^129,146,378 The CCBs that have predominantly been used in PAH are nifedipine, diltiazem, and amlodipine.^129,146 Amlodipine and felodipine are increasingly being used in clinical practice due to their long half-life and good tolerability. The daily doses that have shown efficacy in PAH are relatively high and they must be reached progressively (Table 19). The most common adverse events are systemic hypotension and peripheral oedema.

Patients who meet the criteria for a positive acute vasodilator response and treated with CCBs should be closely followed for safety and efficacy, with a complete reassessment after 3–6 months of therapy, including RHC. Additional acute vasoreactivity testing should be performed at re-evaluation to detect persistent vasodilator response, supporting possible increases in CCB dosage. Patients with a satisfactory chronic response present with WHO-FC I/II and marked haemodynamic improvement (ideally, mPAP <30 mmHg and PVR <4 WU) while on CCB therapy. In the absence of a satisfactory response, additional PAH therapy should be instituted. In some cases, a combination of CCBs with approved PAH drugs is required because of clinical deterioration with CCB withdrawal attempts. Patients who have not undergone a vasoreactivity study or those with a negative test should not be started on CCBs because of potentially severe side effects (e.g. severe hypotension, syncope, and RV failure), unless prescribed at standard doses for other indications.³⁷⁹

6.3.3.2. Endothelin receptor antagonists

Binding of endothelin-1 to endothelin receptors A and B on PA smooth-muscle cells promotes vasoconstriction and proliferation (Figure 7).³⁸⁰ Endothelin B receptors are mostly expressed on pulmonary endothelial cells, promoting vasodilation through accelerated production of prostacyclin and nitric oxide, and clearance of endothelin-1.³⁸⁰ Nevertheless, selective blocking of endothelin A receptors alone or non-selective blocking of both A and B receptors has shown similar effectiveness in PAH.³⁸⁰ Endothelial receptor antagonists have teratogenic effects and should not be used during pregnancy.³⁸¹

Ambrisentan

Ambrisentan is an oral ERA that preferentially blocks the endothelin A receptors. The approved dosages in adults are 5 mg and 10 mg o.d. In patients with PAH, it has demonstrated efficacy for symptoms, exercise capacity, haemodynamics, and time to clinical worsening.³⁸² An increased incidence of peripheral oedema was reported with ambrisentan use, while there was no increased incidence of abnormal liver function.

Bosentan

Bosentan is an oral, dual ERA that improves exercise capacity, WHO-FC, haemodynamics, and time to clinical worsening in patients with PAH.³⁸³ The approved target dose in adults is 125 mg b.i.d. Dose-dependent increases in liver transaminases can occur in ∼10% of treated patients (reversible after dose reduction or discontinuation).³⁸⁴ Thus, liver function testing should be performed monthly in patients receiving bosentan.³⁸⁴ Due to pharmacokinetic interactions, bosentan may render hormonal contraceptives unreliable and lower serum levels of warfarin, sildenafil, and tadalafil.^{361,385–387}

Macitentan

Macitentan is an oral, dual ERA that has been found to increase exercise capacity and reduce a composite endpoint of clinical worsening in patients with PAH.¹⁶⁷ While no liver toxicity has been shown, a reduction in Hb to ≤8 g/dL was observed in 4.3% of patients receiving 10 mg of macitentan.¹⁶⁷

6.3.3.3. Phosphodiesterase 5 inhibitors and guanylate cyclase stimulators

Stimulating soluble guanylate cyclase (sGC) by nitric oxide results in production of the intracellular second messenger cyclic guanosine monophosphate (cGMP) (Figure 7). This pathway is controlled by a negative feedback loop through degradation of cGMP via different phosphodiesterases, among which subtype 5 (PDE5) is abundantly expressed in the pulmonary vasculature.³⁸⁸ Phosphodiesterase 5 inhibitors and sGC stimulators must not be combined with each other and with nitrates, as this can result in systemic hypotension.³⁸⁹

Sildenafil

Sildenafil is an orally active, potent, and selective inhibitor of PDE5. Several RCTs of patients with PAH treated with sildenafil (with or without background therapy) have confirmed favourable results on exercise capacity, symptoms, and/or haemodynamics.^390–392 The approved dose of sildenafil is 20 mg t.i.d. Most side effects of sildenafil are mild to moderate and mainly related to vasodilation (headache, flushing, and epistaxis).

Tadalafil

Tadalafil is a once-daily administered PDE5i. An RCT of 406 patients with PAH (53% on background bosentan therapy) treated with tadalafil at doses up to 40 mg o.d. showed favourable results on exercise capacity, symptoms, haemodynamics, and time to clinical worsening.³⁹³ The side effect profile was similar to that of sildenafil.

Riociguat

While PDE5is augment the nitric oxide–cGMP pathway by slowing cGMP degradation, sGC stimulators enhance cGMP production by directly stimulating the enzyme, both in the presence and absence of endogenous nitric oxide.³⁹⁴ An RCT of 443 patients with PAH (44% and 6% on background therapy with ERAs or prostacyclin analogues, respectively) treated with riociguat up to 2.5 mg t.i.d. showed favourable results on exercise capacity, haemodynamics, WHO-FC, and time to clinical worsening.³⁹⁵ The side effect profile was similar to that of PDE5is.

6.3.3.4. Prostacyclin analogues and prostacyclin receptor agonists

The prostacyclin metabolic pathway (Figure 7) is dysregulated in patients with PAH, with less prostacyclin synthase expressed in PAs and reduced prostacyclin urinary metabolites.³⁹⁶ Prostacyclin analogues and prostacyclin receptor agonists induce potent vasodilation, inhibit platelet aggregation, and also have both cytoprotective and anti-proliferative activities.³⁹⁷ The most common adverse events observed with these compounds are related to systemic vasodilation and include headache, flushing, jaw pain, and diarrhoea.

Epoprostenol

Epoprostenol has a short half-life (3–5 min) and needs continuous i.v. administration via an infusion pump and a permanent tunnelled catheter. A thermo-stable formulation is available to maintain stability up to 48 h.³⁹⁸ Its efficacy has been demonstrated in three unblinded RCTs in patients with IPAH (WHO-FC III and IV)^399,400 and SSc-associated PAH.⁴⁰¹ Epoprostenol improved symptoms, exercise capacity, haemodynamics, and mortality.³⁹⁹ Long-term, persistent efficacy has also been shown in IPAH,^212,245 as well as in other associated PAH conditions.^402–404 Serious adverse events related to the delivery system include pump malfunction, local site infection, catheter obstruction, and sepsis. Recommendations for preventing central venous catheter bloodstream infections have been proposed.^405,406

Iloprost

Iloprost is a prostacyclin analogue approved for inhaled administration. Inhaled iloprost has been evaluated in one RCT, in which six to nine repetitive iloprost inhalations were compared with placebo in treatment-naïve patients with PAH or CTEPH.⁴⁰⁷ The study showed an increase in exercise capacity and improvement in symptoms, PVR, and clinical events in the iloprost group compared with the placebo group.

Treprostinil

Treprostinil is available for s.c., i.v., inhaled, and oral administration. Treprostinil s.c. improved exercise capacity, haemodynamics, and symptoms in PAH.⁴⁰⁸ Infusion-site pain was the most common adverse effect, which led to treatment discontinuation in 8% of cases.⁴⁰⁸ Based on its chemical stability, i.v. treprostinil may also be administered via implantable pumps, improving convenience and likely decreasing the occurrence of line infections.^409,410

Inhaled treprostinil improved the 6MWD, NT-proBNP, and quality of life measures in patients with PAH on background therapy with either bosentan or sildenafil.⁴¹¹ Inhaled treprostinil is not approved in Europe.

Oral treprostinil has been evaluated in two RCTs of patients with PAH on background therapy with bosentan and/or sildenafil. In both trials, the primary endpoint—6MWD—did not reach statistical significance.^412,413 An additional RCT in treatment-naïve patients with PAH showed improved 6MWD.⁴¹⁴ An event-driven RCT that enrolled 690 patients with PAH demonstrated that oral treprostinil reduced the risk of clinical worsening events in patients who were receiving oral monotherapy with ERAs or PDE5is.⁴¹⁵ Oral treprostinil is not approved in Europe.

Beraprost

Beraprost is a chemically stable and orally active prostacyclin analogue. Two RCTs have shown a modest, short-term improvement in exercise capacity in patients with PAH;^416,417 however, there were no haemodynamic improvements or long-term outcome benefits. Beraprost is not approved in Europe.

Selexipag

Selexipag is an orally available, selective, prostacyclin receptor agonist that is chemically distinct from prostacyclin, with different pharmacology. In a pilot RCT in patients with PAH (receiving stable ERA and/or PDE5i therapy), selexipag reduced PVR after 17 weeks.⁴¹⁸ An event-driven, phase 3 RCT that enrolled 1156 patients⁴¹⁹ showed that selexipag alone or on top of mono or double therapy with an ERA and/or a PDE5i reduced the relative risk of composite morbidity/mortality events by 40%. The most common side effects were headache, diarrhoea, nausea, and jaw pain.

6.3.4. Treatment strategies for patients with idiopathic, heritable, drug-associated, or connective tissue disease-associated pulmonary arterial hypertension

Pulmonary arterial hypertension is a rare and life-threatening disease and should be managed, where possible, at PH centres in close collaboration with the patient’s local physicians.

This section describes drug treatment and is focused on non-vasoreactive patients with IPAH/HPAH/DPAH and on patients with PAH associated with connective tissue disease (PAH-CTD). Information on the dosing of PAH medication is summarized in Table 19. For other forms of PAH, treatment strategies have to be modified (see Section 7). The approach to vasoreactive patients with IPAH/HPAH/DPAH is described in Section 6.3.3.1.

In addition to targeted drug treatment, the comprehensive management of patients with PAH includes general measures that may include supplementary oxygen, diuretics to optimize volume status, psychosocial support, and standardized exercise training (Section 6.3.1).³¹⁵ Prior to the treatment decisions, patients and their next of kin should be provided with appropriate and timely information about the risks and benefits of the treatment options so they can make the final, informed, and joint decision about the treatment with the medical team. Treatment decisions in patients with IPAH/HPAH/DPAH or PAH-CTD should be stratified according to the presence or absence of cardiopulmonary comorbidities (Section 6.3.4.3) and according to disease severity assessed by risk stratification (Section 6.2.7).

6.3.4.1. Initial treatment decision in patients without cardiopulmonary comorbidities

The initial treatment of patients with PAH should be based on a comprehensive, multiparameter risk assessment, considering disease type and severity, comorbidities, access to therapies, economic aspects, and patient preference.

The following considerations predominantly apply to patients with IPAH/HPAH/DPAH or PAH-CTD without cardiopulmonary comorbidities, as patients with comorbidities were under-represented in the clinical studies addressing treatment strategies and combination therapy in patients with PAH. Treatment considerations for patients with PAH and cardiopulmonary comorbidities are summarized in Section 6.3.4.3.

For patients presenting at low or intermediate risk, initial combination therapy with an ERA and a PDE5i is recommended. This approach was assessed in the AMBITION study, which compared initial combination therapy using ambrisentan at a target dose of 10 mg o.d. and tadalafil at a target dose of 40 mg o.d. with initial monotherapy with either drug.¹⁶⁶ AMBITION predominantly included patients with IPAH/HPAH/DPAH or PAH-CTD. The primary endpoint was the time to first clinical failure event (a composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response). The hazard ratio (HR) for the primary endpoint in the combination-therapy group vs. the pooled monotherapy group was 0.50 (95% confidence interval [CI], 0.35–0.72; P < 0.001) and there were significant improvements in 6MWD and NT-proBNP with initial combination therapy. At the end of the study, 10% of the patients assigned to initial combination therapy had died compared with 14% of the patients assigned to initial monotherapy (HR 0.67; 95% CI, 0.42–1.08).⁴²⁰

In the TRITON study, treatment-naïve patients with PAH were assigned to initial dual-combination therapy with macitentan and tadalafil, or initial triple-combination therapy with macitentan 10 mg o.d., tadalafil at a target dose of 40 mg o.d., and selexipag up to 1600 µg o.d.⁴²¹ TRITON predominantly included patients with IPAH/HPAH/DPAH or PAH-CTD. At week 26, PVR was reduced by 52% and 54%, with double- or triple-combination therapy, respectively, and 6MWD had increased by 55 m and 56 m, respectively. The geometric means of the NT-proBNP ratio from baseline to week 26 were 0.25 and 0.26, respectively. Hence, TRITON did not show a benefit of oral triple- vs. oral double-combination therapy but confirmed that substantial improvements in haemodynamics and exercise capacity can be obtained with initial ERA/PDE5i combination therapy. Further studies are needed to determine whether oral triple-combination therapy impacts long-term outcomes.

Based on the evidence generated by these and other studies,^{303,422–424} initial dual-combination therapy with an ERA and a PDE5i is recommended for newly diagnosed patients who present at low or intermediate risk. Initial oral triple-combination therapy is not recommended, given the current lack of evidence supporting this strategy. In patients presenting at high risk, initial triple-combination therapy including an i.v./s.c. prostacyclin analogue should be considered.^426,427 While it is acknowledged that the evidence for this approach is limited to case series, there is consensus that this strategy has the highest likelihood of success, especially in view of registry data from France showing that initial triple-combination therapy including an i.v./s.c. prostacyclin analogue was associated with better long-term survival than monotherapy or dual-combination therapy.⁴²⁸ Initial triple-combination therapy including an i.v./s.c. prostacyclin analogue should also be considered in patients at intermediate risk presenting with severe haemodynamic impairment (e.g. RAP ≥20 mmHg, CI <2.0 L/min/m², SVI <31 mL/m², and/or PVR ≥12 WU).^238,426

The recommendations for initial oral double-combination therapy are based on PICO question I (Supplementary Data, Section 6.2). Although the quality of evidence is low, initial oral combination therapy with an ERA and a PDE5i achieves important targets in symptom improvement (functional class), exercise capacity, cardiac biomarkers, and reduction of hospitalizations.

6.3.4.2. Treatment decisions during follow-up in patients without cardiopulmonary comorbidities

Patients with PAH require regular follow-up, including risk stratification and an assessment of patient concordance with therapy. Patients who achieve a low-risk status have a much superior long-term survival compared with patients with intermediate- or high-risk status.^292,295,296 Achieving and maintaining a low-risk profile is therefore a key objective in managing patients with PAH.

Several clinical trials have assessed the safety and efficacy of sequential combination therapy in patients with PAH. SERAPHIN enrolled 742 patients with PAH, mostly with IPAH/HPAH/DPAH and PAH-CTD, of whom 63.7% were receiving other PAH medication at the time of enrolment, mostly sildenafil.¹⁶⁷ In the subgroup of patients with background PAH therapy, macitentan at a daily dose of 10 mg reduced the risk of clinical worsening events compared with placebo (HR 0.62; 95% CI, 0.43–0.89).¹⁶⁷

GRIPHON assessed the safety and efficacy of selexipag.⁴¹⁹ This study enrolled 1156 patients with PAH, also mostly with IPAH/HPAH/DPAH or PAH-CTD, who were treatment naïve or receiving background therapy with an ERA, PDE5i, or a combination of both. Selexipag at a dose of up to 1600 µg b.i.d. was associated with a reduced risk of clinical worsening events independent of the background medication. In patients receiving ERA/PDE5i combination therapy (n = 376), the risk of clinical worsening events was lower with selexipag than with placebo (HR 0.63; 95% CI, 0.44–0.90).⁴³¹

The effects of combination therapy on long-term survival in patients with PAH remain unclear. A 2016 meta-analysis demonstrated that combination therapy (initial and sequential) was associated with a significant risk reduction for clinical worsening (relative risk [RR] 0.65; 95% CI, 0.58–0.72; P < 0.0001);⁴³² however, all-cause mortality was not improved (RR 0.86; 95% CI, 0.72–1.03; P = 0.09) and a substantial proportion of patients had clinical worsening events or died despite receiving combination therapy. In addition, registry data showed that the use of combination therapy increased since 2015 but there was no clear improvement in overall survival rates.^428,433,434 These data were corroborated by a study showing that less than half of patients receiving initial combination therapy with an ERA and a PDE5i achieved and maintained a low-risk profile.⁴²²

Switching from PDE5is to riociguat has also been investigated as a treatment-escalation strategy.^429,435 REPLACE was a randomized, controlled, open-label study that enrolled patients on a PDE5i-based therapy who were in WHO-FC III and had a 6MWD of 165–440 m.⁴²⁹ The study predominantly included patients with IPAH/HPAH/DPAH or PAH-CTD who were randomized to continue their PDE5i or to switch from a PDE5i to riociguat up to 2.5 mg t.i.d. The study met its primary endpoint, termed ‘clinical improvement’, which was a composite of pre-specified improvements in 6MWD, WHO-FC, and NT-proBNP at week 24. Clinical improvement at week 24 was demonstrated in 41% of the patients who switched to riociguat and in 20% of the patients who maintained their PDE5i (odds ratio [OR] 2.78; 95% CI, 1.53–5.06; P = 0.0007). In addition, fewer patients in the riociguat group experienced a clinical worsening event (OR 0.10; 95% CI, 0.01–0.73; P = 0.0047).

Based on the evidence summarized above, the following recommendations for treatment decisions during follow-up are:

• In patients who achieve a low-risk status with their initial PAH therapy, continuation of treatment is recommended.

• In patients who are at intermediate–low risk despite receiving ERA/PDE5i therapy, adding selexipag should be considered to reduce the risk of clinical worsening. In these patients, switching from PDE5i to riociguat may also be considered.

• In patients who are at intermediate–high or high risk while receiving oral therapies, the addition of i.v. epoprostenol or i.v./s.c. treprostinil and referral for LTx evaluation should be considered.^309,436 If adding i.v./s.c. prostacyclin analogues is unfeasible, adding selexipag or switching from PDE5i to riociguat may be considered.

6.3.4.3. Pulmonary arterial hypertension with cardiopulmonary comorbidities

Over the past decade, the demographics and characteristics of patients with IPAH have changed, especially in industrialized countries.⁴⁴⁷ In several contemporary registries, the average age of patients diagnosed with IPAH is ∼60 years or older.^{161,295,299,447,448} Many elderly patients have cardiopulmonary comorbidities, making the distinction from group 2 and group 3 PH challenging. Among elderly patients diagnosed with IPAH, two main disease phenotypes have emerged. One phenotype (herein called the left heart phenotype) consists of elderly, mostly female patients with risk factors for HFpEF (e.g. hypertension, obesity, diabetes, or coronary heart disease) but pre-capillary PH rather than post-capillary PH;^449,450 ∼30% of these patients have a history of atrial fibrillation.¹⁶¹ The other phenotype (called the cardiopulmonary phenotype) consists of elderly, predominantly male patients who have a low DLCO (<45% of the predicted value), are often hypoxaemic, have a significant smoking history, and have risk factors for LHD.^{77,78,161,451} In a cluster analysis of 841 newly diagnosed patients with IPAH from the COMPERA registry, 12.6% had a classic phenotype of young, mostly female patients without cardiopulmonary comorbidities, while 35.8% presented with a left heart phenotype and 51.6% with a cardiopulmonary phenotype.¹⁶¹

There are no evidence-based rules for determining a patient’s phenotype. The AMBITION study used the presence of more than three risk factors for LHD together with certain haemodynamic criteria to exclude patients from the primary analysis.¹⁶⁶ However, the COMPERA cluster analysis mentioned above found that the presence of a single risk factor may change the phenotype.¹⁶¹ Pending further data, it is the overall profile that should be used to determine a patient’s phenotype.

Compared with patients without cardiopulmonary comorbidities, patients with cardiopulmonary comorbidities respond less well to PAH medication, are more likely to discontinue this medication due to efficacy failure or lack of tolerability, are less likely to reach a low-risk status, and have a higher mortality risk. While the age-adjusted mortality of patients with the left heart phenotype seems to be similar to that of patients with classical PAH, patients with a cardiopulmonary phenotype and a low DLCO have a particularly high mortality risk.^{77,78,161,450,451}

As patients with cardiopulmonary comorbidities were under-represented in or excluded from PAH trials, no evidence-based treatment recommendations can be made for this patient population. Registry data suggest that most physicians use PDE5is as primary treatment for these patients. Endothelin receptor antagonists or PDE5i/ERA combinations are occasionally used, but the drug discontinuation rate is higher than in patients with classical PAH.^447,450 A subgroup analysis from AMBITION, which assessed the response to PAH therapy in 105 patients who were excluded from the primary analysis set because of a left heart phenotype, found that these patients—compared with patients in the primary analysis set—had less clinical improvement and a higher likelihood of drug discontinuations due to safety and tolerability with both monotherapy and initial combination therapy.⁴⁴⁹ Data from the ASPIRE registry demonstrated that patients with IPAH and a cardiopulmonary phenotype had less improvement in exercise capacity and PROMs compared with patients with classical IPAH.⁴⁵¹

In patients with a left heart phenotype, ERA therapy is associated with an elevated risk of fluid retention.⁴⁴⁹ Moreover, in patients with a cardiopulmonary phenotype, PAH medication may cause a decline in the peripheral oxygen saturation.⁴⁵² There is little published experience on the use of prostacyclin analogues or prostacyclin receptor agonists in this patient population.⁴⁵³

The lack of solid evidence for treating elderly patients with PAH and cardiopulmonary comorbidities makes treatment recommendations challenging, and patients should be counselled accordingly. In the absence of evidence on treatment strategies in these patients, risk stratification is of limited usefulness in guiding therapeutic decision-making. Initial monotherapy (see Supplementary Data, Table S3) is recommended for most of these patients, with PDE5is being the most widely used compounds according to registry data.¹⁶¹ Further treatment decisions should be made on an individual basis in collaboration with the PH centre and local physicians.

The treatment algorithm for patients with PAH is shown in Figure 9 and the accompanying section describing the treatment algorithm.

6.3.5. Drug interactions

Among PAH drugs, clinically relevant pharmacokinetic interactions are observed between bosentan and sildenafil (reduced sildenafil plasma concentration³⁸⁵), bosentan and hormonal contraceptives (reduced contraception efficacy³⁶¹), and bosentan and vitamin K antagonists (VKAs) (potential need for VKA dose adjustment³⁸⁶). Additional pharmacokinetic interactions of potential clinical relevance are listed in Supplementary Data, Table S4.

6.3.6. Interventional therapy

6.3.6.1. Balloon atrial septostomy and Potts shunt

Balloon atrial septostomy,^454,455 by creating an interatrial shunt, and Potts shunt,^456–459 by connecting the left PA and descending aorta, aim to decompress the right heart and increase systemic blood flow, thereby improving systemic oxygen transport despite arterial oxygen desaturation. As these procedures are complex and associated with high risk, including substantial procedure-related mortality, they are rarely performed in patients with PAH and may only be considered in centres with experience in the techniques.

6.3.6.2. Pulmonary artery denervation

The rationale for performing a PA denervation (PADN) is based on the increased sympathetic overdrive characterizing PAH, which is associated with poor outcome.^460,461 Although the contribution of this mechanism to developing PAH is not completely understood, it is associated with vasoconstriction and vascular remodelling through a baroreflex mediated by stretch receptors located at the bifurcation of the PAs.^462,463 Applying radiofrequency at the latter acutely and chronically improves haemodynamic variables.⁴⁶⁴ However, there is little evidence yet from multicentre RCTs demonstrating a benefit of PADN in patients already receiving recommended medical therapy. A small multicentre study tested the feasibility of PADN using an intravascular ultrasound catheter in patients receiving dual or triple therapy for PAH;⁴⁶⁵ the procedure was safe and associated with a reduction in PVR, and increases in 6MWD and daily activity. Although potentially promising, PADN should be considered experimental.

6.3.7. Advanced right ventricular failure

6.3.7.1. Intensive care unit management

Patients with PH may require intensive care treatment for right HF, comorbidities (including major surgery), or both. The mortality risk is high in such patients,^466,467 and specialized centres should be involved whenever possible. In addition to basic intensive care unit (ICU) standards, RV function in these patients should be carefully monitored. Non-specific clinical signs of right HF with low CO include pale skin with peripheral cyanosis, hypotension, tachycardia, declining urine output, and increasing lactate levels. Non-invasive monitoring should include biomarkers (NT-proBNP and troponin) and echocardiography. Minimum invasive monitoring consists of an upper body central venous catheter to measure central venous pressure and central venous oxygen saturation, the latter reflecting CO. Right heart catheterization or other forms of advanced haemodynamic assessment should be considered in patients with advanced right HF or in complex situations.⁴⁶⁸

Treating right HF should focus on treatable triggers such as infection, arrhythmia, anaemia, and other comorbidities. Fluid management is of utmost importance in these patients, most of whom require a negative fluid balance to reduce RV pre-load, thereby improving RV geometry and function.⁴⁶⁸ Patients with a low CO may benefit from treatment with inotropes; dobutamine and milrinone are the most frequently used substances in this setting. Maintaining the mean systemic blood pressure >60 mmHg is a key objective when treating right HF, and patients with persistent hypotension may require vasopressors such as norepinephrine or vasopressin. Intubation and invasive mechanical ventilation should be avoided whenever possible in patients with advanced RV failure because of a high risk of further haemodynamic deterioration and death. Pulmonary arterial hypertension medication should be considered on an individual basis, taking into account underlying disease, comorbidities, and existing medication. In patients with newly diagnosed PAH presenting with low CO, combination therapy including i.v./s.c. prostacyclin analogues should be considered.⁴²⁶

6.3.7.2. Mechanical circulatory support

In specialist centres, various forms of mechanical circulatory support are available for managing RV failure, with veno-arterial extracorporeal membrane oxygenation (ECMO) being the most widely used approach. Mechanical circulatory support has become an established bridging tool to transplantation in patients with irreversible right HF, but is occasionally used as a bridge to recovery in patients with treatable causes and potentially reversible RV failure.⁴⁶⁸ No general recommendations can be made regarding the indication for mechanical circulatory support, which needs to be individualized, considering patient factors and local resources.^469,470 Long-term mechanical support analogous to left ventricular assist devices (LVADs) is not yet available for patients with PH and end-stage right HF.

6.3.8. Lung and heart–lung transplantation

Lung transplantation remains an important treatment option for patients with PAH refractory to optimized medical therapy. In patients with PAH, referral to an LTx centre should be considered early (Table 20): (1) when they present with an inadequate response to treatment despite optimized combination therapy; (2) when they present with an intermediate–high or high risk of death (i.e. 1-year mortality >10% when estimated with established risk-stratification tools)⁴⁷¹ (see Section 6.2.7), which exceeds the current mortality rate after LTx;⁴⁷² (3) when patients have a disease variant that poorly responds to medical therapy, such as PVOD or PCH.

Both heart–lung and bilateral LTx have been performed for PAH. Currently, most patients receive bilateral LTx, while combined heart–lung transplantation is reserved for patients who have additional non-correctable cardiac conditions.⁴⁷³ With the introduction of the lung allocation score (LAS), waiting list mortality has decreased and the odds of receiving a donor organ have increased.⁴⁷⁴ In some countries, an ‘exceptional LAS’ can be obtained for patients with severe PH. Some other countries not using the LAS have successfully implemented high-priority programmes for these patients.⁴⁷⁵ The patient and their next of kin should be fully engaged in the transplant assessment process and informed of the risks and benefits, and the final decision should be jointly made between the patient and medical team (see Section 6.3.1.8). For patients with PAH who survive the early post-transplant period, long-term outcomes are good. A study found that for primary transplant patients with IPAH who survived to 1 year, conditional median survival was 10.0 years.⁴⁷⁶

6.3.9. Evidence-based treatment algorithm

A treatment algorithm for patients with IPAH/HPAH/DPAH or PAH-CTD is shown in Figure 9. The evidence supporting this algorithm has mainly been generated in patients with IPAH/HPAH/DPAH or PAH-CTD who present without cardiopulmonary comorbidities. Patients with HIV-associated PAH, PoPH, and PAH associated with congenital heart disease were not enrolled or under-represented in most PAH therapy trials. Treatment recommendations for these patients are provided in Section 7.

6.3.10. Diagnosis and treatment of pulmonary arterial hypertension complications

6.3.10.1. Arrhythmias

The most common types of arrhythmias observed in PAH are supraventricular, mainly atrial fibrillation and atrial flutter, while the frequency of ventricular arrhythmias and bradyarrhythmias appears to be considerably lower.^477–479 Of note, age is an independent risk factor for atrial arrhythmias. In prospective studies, the incidence of atrial arrhythmias was 3–25% over an observation time of 5 years in cohorts primarily containing patients with IPAH.^479–481

In the absence of specific evidence for PAH, managing anticoagulation in patients with PAH and atrial arrhythmia should follow the recommendations for patients with other cardiac conditions.⁴⁷⁷

Patients with PAH are especially sensitive to haemodynamic stress during atrial arrhythmias due to tachycardia and loss of atrioventricular synchrony. Maintaining sinus rhythm is an important treatment objective in these patients. New-onset arrhythmias frequently lead to clinical deterioration and are associated with increased mortality.⁴⁸¹ Observational studies have shown that a variety of rhythm control strategies are feasible, including pharmacological cardioversion with anti-arrhythmic drugs, electrical cardioversion, and invasive catheter ablation procedures. To achieve or maintain a stable sinus rhythm, prophylaxis with anti-arrhythmic drugs without negative inotropic effects, such as oral amiodarone, should be considered, even if specific data regarding their efficacy are lacking. Low-dose beta-blockers and/or digoxin may be used on an individual patient basis.

Catheter ablation is the preferred approach in managing atrial flutter and some other atrial tachycardias, although catheter ablation in patients with PAH is often more technically challenging than in patients with a structurally normal right heart chamber.⁴⁸² The safety and efficacy of ablation techniques for atrial fibrillation specifically in the PAH population are uncertain, and it is possible that, due to remodelling of the RA, non-pulmonary vein triggers may play a more important role than in patients without PAH.⁴⁸³

6.3.10.2. Haemoptysis

Haemoptysis, ranging from mild to life-threatening, may occur in all forms of PH but is particularly common in HPAH and PAH associated with CHD. Pulmonary bleeding frequently originates from enlarged bronchial arteries;^484–486 hence, the diagnostic evaluation of patients with PAH and haemoptysis should include a contrast-enhanced CT scan with an arterial phase. Even if the source of bleeding cannot be determined, embolization of enlarged bronchial arteries is recommended in patients who present with moderate-to-severe haemoptysis or recurrent episodes of mild haemoptysis. Lung transplant should be considered in patients with recurrent and severe haemoptysis despite optimized treatment.

6.3.10.3. Mechanical complications

Mechanical complications in patients with PAH usually arise from progressive dilatation of the PA and include PA aneurysms, rupture, and dissection, and compression of adjacent structures such as the left main coronary artery, pulmonary veins, main bronchi, and recurrent laryngeal nerves.^487–492

Pulmonary artery aneurysm was independently related to an increased risk of sudden cardiac death in one study.⁴⁹² Symptoms and signs are non-specific; in most cases, patients are asymptomatic and these complications are incidentally diagnosed. Pulmonary artery aneurysms are usually detected during echocardiography and best visualized by contrast-enhanced CT or MRI. Treatment options for asymptomatic PA aneurysm or PA dissection are not well defined. LTx has to be considered on an individual basis.^490,493

For patients with left main coronary artery compression syndrome, percutaneous coronary stenting is an effective and safe treatment.⁶² For patients with asymptomatic left main coronary artery compression or non-severe compromise of its anatomy, evaluation with intravascular ultrasound or coronary pressure wire may help to avoid unnecessary interventions.⁴⁹⁴

6.3.11. End-of-life care and ethical issues

The clinical course of PAH may be characterized by progressive deterioration and occasional episodes of acute decompensation. Life expectancy is difficult to predict, as patients may either die slowly because of progressive right HF or experience sudden death.

Patient-orientated care is essential in managing PAH. Information about disease severity and possible prognosis should be provided at initial diagnosis but empathic and hopeful communication, as well as yielding hope, is essential, in line with Section 6.3.1.8. At the right time, open and sensitive communication will enable advanced planning and discussion of a patient’s fears, concerns, and wishes, and will ultimately contribute to making the final, well-informed, and joint decision about treatment with the medical team.

Patients approaching end of life require frequent assessment of their full needs by a multidisciplinary team. In advanced stages, recognizing that cardiopulmonary resuscitation in severe PAH has a poor outcome may enable a do not resuscitate order; this may facilitate patients being in their preferred place of care at end of life. Attention should be given to controlling distressing symptoms and prescribing appropriate drugs while withdrawing medication that is no longer needed, which may include PAH medication. Well-informed psychological, social, and spiritual support is also vital. Specialist palliative care should be consulted for patients whose needs are beyond the expertise of the PH team.³⁴⁶

6.3.12. New drugs in advanced clinical development (phase 3 studies)

Pulmonary arterial hypertension remains an incurable condition with a high mortality rate, despite use of PAH drugs mainly targeting imbalance of vasoactive factors. Novel agents, which are currently in phase 3 development, are ralinepag and sotatercept. Ralinepag is an orally available prostacyclin receptor agonist, which, in a phase 2 RCT that included 61 patients with PAH, improved PVR compared with placebo after 22 weeks of therapy.⁴⁹⁵ Sotatercept—a fusion protein comprising the extracellular domain of the human activin receptor type IIA linked to the Fc domain of human immunoglobulin G1—acts as a ligand trap for members of the transforming growth factor (TGF)-β superfamily, thus restoring balance between growth-promoting and growth-inhibiting pathways.⁴⁹⁶ In a phase 2 RCT that included 106 patients with PAH treated over 24 weeks, s.c. sotatercept reduced PVR in patients receiving background PAH therapy;⁴⁹⁶ improvements were also observed in 6MWD and NT-proBNP.⁴⁹⁶

7. Specific pulmonary arterial hypertension subsets

7.1. Pulmonary arterial hypertension associated with drugs and toxins

Several drugs and toxins are associated with developing PAH or PVOD/PCH. Historically, certain appetite suppressants and toxic rapeseed oil were the most prominent examples, whereas methamphetamines, interferons, and some tyrosine kinase inhibitors are more common causes nowadays (Table 7). Pulmonary arterial hypertension is a rare complication in patients exposed to these drugs, and many of these drugs have also been linked to other pulmonary complications such as parenchymal lung disease or pleural effusions. These pulmonary complications may occur concurrently.

Methamphetamine-associated PAH has mainly been reported from the USA, where some centres have found that 20–29% of their otherwise idiopathic cases of PAH were associated with methamphetamine use.^497,498 Compared with patients with IPAH, those with methamphetamine-associated PAH had more severe haemodynamic impairment and a higher mortality risk.⁴⁹⁸ Alpha and beta interferons have also been associated with developing PAH.⁴⁹⁹ The same is true of some tyrosine kinase inhibitors, especially dasatinib, but also bosutinib and ponatinib.^40,500

Drug- or toxin-induced PAH should always be considered in patients presenting with unexplained exertional dyspnoea or other warning signs. The diagnostic approach should be the same as in other forms of PH, and the diagnosis is usually made by excluding other forms of PH in patients who have been exposed to drugs associated with developing PAH.

Treatment of DPAH follows the same basic principles as treating other forms of PAH. Importantly, partial or full reversal of PAH has been reported after discontinuing the causative agent, at least for interferons and dasatinib.^499,500 Hence, multidisciplinary management of the patient should include discontinuing the presumed causative agents once PAH is diagnosed (also see the 2022 ESC Guidelines on Cardio-Oncology).⁵⁰¹ In patients with mild PH and a low-risk profile, discontinuing the trigger alone may be sufficient, and it is recommended that these patients be observed over 3–4 months before considering PAH therapy. Pulmonary arterial hypertension therapy should be initiated in patients who do not normalize their haemodynamics after withdrawing or in patients presenting with more advanced PAH at diagnosis. Unlike in other forms of PAH, de-escalation of PAH therapy is often possible during the course of the disease.⁵⁰⁰ Physicians should bear in mind that DPAH may have features of PVOD/PCH, especially in patients treated with alkylating agents such as mitomycin C or cyclophosphamide. Health professional awareness is essential in identifying cases of DPAH and reporting adverse effects of pharmaceutical products.

7.2. Pulmonary arterial hypertension associated with connective tissue disease

Pulmonary arterial hypertension is a well-known pulmonary vascular complication of SSc,^{173,502–504} systemic lupus erythematosus (SLE),^505–507 mixed CTD,⁵⁰⁶ and, rarely, dermatomyositis⁵⁰⁸ and Sjögren’s syndrome.⁵⁰⁹ Conversely, the relationship between rheumatoid arthritis and PAH is not established.⁵¹⁰ After IPAH, PAH-CTD is the second most prevalent type of PAH in western countries.⁵¹¹

Systemic sclerosis, particularly in its limited variant, represents the main cause of PAH-CTD in Europe and the USA (SLE being more common in Asia).^173,502,506 The prevalence of pre-capillary PH in large cohorts of patients with SSc is 5–19%.^173,502 In these patients, PH may occur in association with ILD^504,512 or as a result of PAH,^{173,502–504,506} sometimes with features of venous/capillary involvement.^504,513 Moreover, group 2 PH-LHD is also common due to myocardial SSc involvement.^504,514 Of note, patients with SLE may also present with PAH, LHD, ILD, and CTEPH (mostly in the setting of antiphospholipid syndrome). It is therefore essential to carefully determine which mechanism is operative in a given patient, since this will dictate treatment in the context of a multifaceted disease.

Cluster analysis performed in patients with SSc has shown that pre-capillary PH can be characterized into distinct clusters that differ in prognosis.⁵⁰³ One cluster, characterized by the presence of extensive ILD, and another by severely impaired haemodynamics carried a dismal prognosis, while the two others showed either the absence of ILD or the presence of limited ILD, with mild-to-moderate risk PAH and a relatively favourable overall prognosis.⁵⁰³

7.2.1. Epidemiology and diagnosis

There is a strong female predominance in PAH-CTD (female/male ratio 4:1), and mean age at diagnosis is commonly >50 years, especially in SSc.^{173,502–511,513,515,516} In the setting of a CTD, patients may present with concomitant disorders such as ILD, and have shorter survival compared with patients with IPAH.⁵⁰³ The unadjusted risk of death for PAH-SSc compared with IPAH is 2.9, and the predictors of outcome are broadly similar to those for IPAH.^516,517 Symptoms and clinical presentation are also similar to IPAH, and some patients thought to have IPAH can be identified as having an associated CTD by careful clinical examination and immunological screening tests. Chest CT is recommended for evaluating the presence of associated ILD or PVOD/PCH.^504,513,515 An isolated reduction of DLCO is common in PAH-CTD.^{173,502–504}

Resting echocardiography combined with other tests is recommended as a screening test in asymptomatic patients with SSc, followed by annual assessments. Screening/early detection is discussed in Section 5.3.1. In other CTDs, PH screening in the absence of suggestive symptoms is not recommended, while echocardiography should be performed in the presence of symptoms. As in other forms of PAH, RHC is recommended in all cases of suspected PAH-CTD to confirm diagnosis, determine severity, and rule out LHD.⁵⁰⁴

7.2.2. Therapy

Drugs for PAH should be prescribed in PAH-CTD according to the same treatment algorithm as in IPAH (Figure 9). Patients with PAH-CTD have been included in most of the major RCTs for regulatory approval of PAH therapy.⁵¹⁸ Some aspects of PAH-CTD treatment differ according to the associated CTD.⁵⁰⁶ Immunosuppressive therapy combining glucocorticosteroids and cyclophosphamide may result in clinical improvement in patients with SLE- or mixed CTD-associated PAH,⁵⁰⁶ while it is not recommended in PAH-SSc.⁵¹⁹ Patients with SSc and other CTDs may have ILD and/or HFpEF, which needs to be considered when initiating PAH therapy.^504,515 In SSc, the long-term risk/benefit ratio of oral anticoagulation is unfavourable because of an increased risk of bleeding, while VKAs are recommended in PAH-CTD with a thrombophilic predisposition (e.g. antiphospholipid syndrome).³¹⁹

Subgroup analyses of patients with PAH-SSc enrolled in RCTs performed with monotherapy or combination therapy of ERAs, PDE5is, sGC stimulators, prostacyclin receptor agonists, epoprostenol, and prostacyclin analogues have shown positive effects vs. placebo.^{301,401,519,520} In some of these trials, the magnitude of the response in the PAH-CTD subgroup was lower than in the IPAH subgroup.^519,520 Continuous i.v. epoprostenol therapy improved exercise capacity, symptoms, and haemodynamics in a 3-month RCT in PAH-SSc.⁴⁰¹ However, a retrospective analysis showed a better effect of i.v. epoprostenol on survival in IPAH compared with PAH-SSc.⁵²¹ The choice of PAH therapy in the context of SSc and its systemic manifestations may consider other vascular damage such as digital ulcers.⁵²²

Connective tissue disease should not be considered as an a priori contraindication for LTx.⁵²³ This has been extensively studied in SSc, where a multidisciplinary approach optimizing SSc management before, during, and after surgery is recommended.⁵²³ Indications and contraindications for transplantation have to be adapted to the specificities of CTD, with a special focus on digestive (gastro-oesophageal reflux disease and intestinal disease), cardiac, renal, and cutaneous involvement.⁵²³

7.3. Pulmonary arterial hypertension associated with human immunodeficiency virus infection

The use of highly active antiretroviral therapy (HAART), and advances in managing opportunistic infections have contributed to increased life expectancy in patients with HIV.^525,526 Consequently, the spectrum of complications has shifted towards other long-term conditions, including PAH. Clinical and histopathological findings in PAH associated with HIV infection (PAH-HIV) share many similarities with IPAH.^1,527 With the availability of HAART given in combination with PAH therapies, the prognosis of PAH-HIV has markedly improved in recent years.^526,528 In addition, the incidence of PAH-HIV has declined in parallel with the increasing availability of HAART.⁵²⁸ Taken together, these effects on survival and incidence have resulted in a stable PAH prevalence in patients with HIV over recent decades. A French population study indicated that the prevalence of PAH in individuals with HIV infection was 0.46%, which is very similar to the prevalence before the HAART era.¹⁷⁷

The pathogenesis of PAH-HIV remains unclear. There is no evidence of a direct role of HIV in the pathogenesis of PAH and, although present in inflammatory cells in the lungs, the virus itself has never been found in pulmonary vascular lesions of patients with PAH-HIV.⁵²⁹ This suggests that an indirect action of viral infection on inflammation and growth factors may act as a trigger in a predisposed patient.

7.3.1. Diagnosis

Pulmonary arterial hypertension associated with HIV shares a clinical presentation with IPAH. Before the availability of HAART most patients were in WHO-FC III or IV at diagnosis. Nowadays, patients are diagnosed with much less severe symptoms and haemodynamics. Patients may present with other risk factors for PAH such as liver disease (chronic viral hepatitis B or C) or exposure to drugs or toxins. Patients with PAH-HIV are more likely to be male and i.v. drug abusers.^403,526 There is no correlation between the severity of PAH and the stage of HIV infection or the degree of immunodeficiency.^403,530 Because of its low prevalence, asymptomatic patients with HIV should not be screened for PAH. However, echocardiography should be performed in patients with unexplained dyspnoea to detect HIV-related cardiovascular complications such as myocarditis, cardiomyopathy, or PAH. Right heart catheterization is mandatory to confirm the diagnosis of PAH-HIV and to rule out LHD.⁵²⁷

Pulmonary arterial hypertension is an independent risk factor for death in patients with HIV. In the 1990s, before the availability of HAART, patients with PAH-HIV had poor outcomes, with a 3 year survival of <50%.⁴⁰³ The overall survival has now improved and patients with PAH-HIV have a better prognosis than most patients with other forms of PAH.⁵²⁶

7.3.2. Therapy

Current recommendations for the treatment of PAH-HIV are largely based on data from IPAH.^25,26

Treatment of PAH-HIV with HAART has improved functional status and survival in some retrospective studies.^525,526,531 The use of HAART in PAH-HIV is therefore recommended, irrespective of viral load and CD4+ cell count.

Anticoagulation is not recommended because of an increased risk of bleeding and drug interactions.^319,527 Patients with PAH-HIV are usually non-responders to acute vasoreactivity testing and therefore should not receive CCBs.³⁷⁸

The prospective, open-label, BREATHE-4 study showed that bosentan markedly improved WHO-FC, exercise capacity, quality of life, and haemodynamics after 16 weeks in patients with PAH-HIV.⁵³² In a long-term, retrospective series, bosentan therapy was associated with haemodynamic normalization in 10/59 patients.⁵³³ Bosentan potentially interacts with antiretroviral drugs, and close monitoring is required when combined with HAART. Very few patients with PAH-HIV have been included in RCTs with ambrisentan and macitentan, and no definite conclusion can be drawn from those studies.

Positive effects of sildenafil and tadalafil in PAH-HIV have been established in case studies.^534,535 Interactions have been reported between PDE5is and protease inhibitors, resulting in major increases in PDE5i concentrations; these drugs should be introduced at low dosages with careful monitoring of potential side effects, including hypotension.^536,537 There are no data on the use of the sGC stimulator riociguat in PAH-HIV.

Treatment with i.v. epoprostenol resulted in significant improvement in WHO-FC, exercise capacity, haemodynamics, and survival in selected patients with PAH-HIV.^403,538 There are very few data on the use of i.v. or s.c. treprostinil or inhaled iloprost in PAH-HIV.^539,540

There are no clinical trial data on the use of combination therapy for PAH-HIV. Given the lack of supporting evidence and potential safety concerns when PAH drugs are co-administered with antiretroviral drugs, initial monotherapy with PAH medication is recommended, followed by an individualized use of combination therapy in patients who do not reach a low-risk profile.

7.4. Pulmonary arterial hypertension associated with portal hypertension

Pulmonary arterial hypertension associated with portal hypertension, commonly referred to as PoPH, develops in 2–6% of patients with portal hypertension, with or without liver disease. In PAH registries, PoPH represents 5–15% of the patients.^543–545 Rarely, some patients with PoPH have portosystemic shunts in the absence of portal hypertension (congenital extrahepatic cavoportal shunts).⁵⁴⁶ However, PoPH is distinct from hepatopulmonary syndrome (HPS), which is characterized by intrapulmonary vascular dilatations and hypoxaemia. Of note, HPS and PoPH can occur sequentially or concurrently in patients with portal hypertension.⁵⁴⁷

7.4.1. Diagnosis

The diagnosis of PoPH is based on the presence of otherwise unexplained pre-capillary PH in patients with portal hypertension or a portosystemic shunt. The diagnostic approach is the same as in other patients with suspected or newly detected PH. Transthoracic echocardiography is usually the first non-invasive assessment in patients with suspected PH, and echocardiography is also recommended as a screening tool in patients evaluated for liver transplantation. As patients with liver disease often have an elevated CO, TRV tends to overestimate PAP in these patients. Hence, RHC with comprehensive haemodynamic assessment is essential to confirm the diagnosis of PH and to distinguish PAH (with elevated PVR) from unclassified PH (with a normal PVR).

7.4.2. Therapy

Patients with unclassified PH (i.e. mPAP >20 mmHg, elevated CO, and PVR ≤2.0 WU) should be regularly followed-up but should not be treated with drugs approved for PAH.

In patients with an established diagnosis of PoPH, treatment should follow the same general principles as in other patients with PAH, taking into account the severity of underlying liver disease, the indication for liver transplantation, and the potential effects of PAH medication on gas exchange, which may deteriorate with vasodilators in patients with PoPH.^548,549 All drugs approved for PAH can principally be used to treat patients with PoPH, bearing in mind that these patients are usually excluded from registration studies. Nevertheless, various case series support the use of approved PAH medication in patients with PoPH. The largest series published so far reported on 574 patients with PoPH treated with various PAH drugs, mostly PDE5is or ERAs, alone and in combination.⁵⁴⁵ Most patients (56.8%) were in Child–Pugh class A at the time of PAH diagnosis. At the first follow-up, which took place 4.5 months after starting treatment, improvements were seen in haemodynamics, WHO-FC, 6MWD, and BNP/NT-proBNP; survival at 5 years was 51%. In patients presenting with mild liver disease, the main causes of death were PAH progression and malignancy, whereas complications of liver disease were the most common causes of death in patients with advanced liver disease. The 5 year survival of patients who underwent liver transplantation (n = 63) was 81%.

The only RCT dedicated to the treatment of PoPH was PORTICO, a 12 week study that randomized 85 patients to macitentan (n = 43) or placebo (n = 42).¹⁶⁸ PORTICO met its primary endpoint, demonstrating a significant reduction in PVR from baseline (ratio of geometric mean 0.65; 95% CI, 0.59–0.72; P < 0.0001). There were, however, no differences between the two treatment groups in secondary outcome measures, including WHO-FC, 6MWD, and NT-proBNP.

7.4.2.1. Liver transplantation

Porto-pulmonary hypertension is not per se an indication for liver transplantation. Pulmonary arterial hypertension poses a major threat to patients who undergo liver transplantation when indicated for the severity of liver disease. In a historical series from the Mayo Clinic, severe PAH with mPAP ≥50 mmHg was associated with a 100% peri-operative mortality rate. In patients with mPAP 35–50 mmHg and PVR >3.0 WU, mortality was still 50%.⁵⁵⁰ In liver transplantation candidates with PAH, targeted medical therapy successfully improves haemodynamics and establishes eligibility for transplantation.^{545,551–554} However, haemodynamic criteria for successful liver transplantation have not been firmly established. The International Liver Transplant Society proposed haemodynamic targets of mPAP <35 mmHg and PVR <5 WU, or mPAP ≥35 mmHg and PVR <3 WU in patients receiving PAH therapy, while acknowledging that these criteria need to be further validated.¹⁷⁵ An mPAP ≥45 mmHg is regarded as an absolute contraindication to liver transplantation.¹⁷⁵

In patients with PoPH who successfully underwent liver transplantation, de-escalation or discontinuation of PAH medication is often feasible, but this has to be performed on an individual basis.^551,554

7.5. Pulmonary arterial hypertension associated with adult congenital heart disease

The presence of PH in adults with CHD has a negative impact on the natural course of CHD, and worsens clinical status and overall outcome.⁵⁵⁵ Pulmonary arterial hypertension associated with adult CHD is included in group 1 of the PH clinical classification (Table 6) and represents a heterogeneous patient population. Post-capillary PH in adult CHD (e.g. systolic or diastolic, systemic, ventricular dysfunction in combination with shunt lesions or complex adult CHD, and systemic atrioventricular valve dysfunction) should be excluded to determine further management. A specific clinical classification (Table 21) is provided to better characterize PAH associated with adult CHD. Some complex CHDs are associated with congenital abnormalities of the pulmonary vascular tree leading to segmental PH. In segmental PH, one or more, but not all, segments of the lung(s) are hypertensive and each hypertensive area may present with PH of different severity, while other parts of the lung vasculature may be hypoplastic. Pulmonary atresia with ventricular septal defect and systemic-to-pulmonary collaterals is the most frequent condition, but other complex CHDs may also lead to segmental PH.

Approximately 3–7% of patients with adult CHD will eventually develop PAH; it is more frequently encountered in females, and the incidence depends on the underlying lesion and increases with age and age at defect closure.⁵⁵⁶ The estimated prevalence of PAH in patients after correcting a simple cardiac defect is 3%.⁵⁵⁷ The epidemiology of PAH associated with adult CHD is expected to change due to advances in diagnostic and therapeutic paediatric cardiology, resulting in fewer patients with simple adult CHD and more patients with complex lesions and/or closed defects who develop PAH in adulthood.⁵⁵⁸

The clinical presentation of Eisenmenger syndrome, an advanced form of adult CHD-associated PAH, is characterized by the multiorgan effects of chronic hypoxaemia, including cyanosis, and haematological changes, including secondary erythrocytosis and thrombocytopenia; the main symptoms are dyspnoea, fatigue, and syncope. Eisenmenger syndrome may also present with haemoptysis, chest pain, cerebrovascular accidents, brain abscesses, coagulation abnormalities, and sudden death. Patients with adult CHD and Down syndrome are at an increased risk of developing Eisenmenger syndrome.

7.5.1. Diagnosis and risk assessment

The diagnostic work-up of PAH associated with adult CHD should be based on the presence of symptoms and includes medical history, physical examination, PFTs, ABG, imaging (especially echocardiography), and exercise and laboratory testing. Of note, standard echocardiographic criteria for detecting PH may not be applicable in complex adult CHD.⁵⁵⁹ Right heart catheterization with compartmental oximetry for calculating pulmonary blood flow/systemic blood flow (Qp/Qs) is required to confirm PAH diagnosis and guide therapeutic interventions. Thermodilution should be avoided in the presence of intracardiac shunts, and direct Fick is the most accurate method. Pulmonary vascular resistance may be overestimated due to erythrocytosis.⁵⁶⁰ Interpreting invasive haemodynamics (see Section 5.1.12) should be made in the context of multiparametric assessment of exercise capacity, laboratory testing, and imaging.

Predictors of worse outcomes in adult CHD-associated PAH are WHO-FC III–IV, exercise intolerance assessed by 6MWD or peak VO₂, history of hospitalization for right HF, biomarkers (NT-proBNP >500 pg/mL, C-reactive protein >10 mg/mL, high serum creatinine, and low albumin levels), iron deficiency, and echocardiographic indices of RV dysfunction.^559,561 When compared with patients with IPAH, patients with Eisenmenger syndrome may have a relatively stable long-term clinical course. The right ventricle is unloaded by the right-to-left shunt, sustaining CO at the expense of hypoxaemia and cyanosis. However, due to immortal time bias, prognosis of Eisenmenger syndrome is not as favourable as previously thought.⁵⁶²

As in other forms of PAH, risk assessment is important to guide therapy, and specific risk factors have been described in Eisenmenger syndrome. A large multicentre study showed that mortality in adults with Eisenmenger syndrome was predicted by the presence of pre-tricuspid shunt, advancing age, low rest oxygen saturation, absence of sinus rhythm, and presence of pericardial effusion.⁵⁶³

7.5.2. Therapy

Outcomes in adult CHD-associated PAH have improved with the availability of new PAH therapies, advances in surgical and peri-operative management, and a team-based, multidisciplinary approach in PH centres. These patients should be managed by specialized health professionals. Patient education, behavioural modifications, and social and psychological support are all important aspects of management.

Shunt closure (surgical or interventional) may only be considered in patients with prevalent systemic-to-pulmonary shunting without significantly increased PVR. Criteria for defect closure based on Qp/Qs ratio and (baseline and/or after targeted PAH treatment) PVR have been proposed by the 2020 ESC Guidelines for the management of adult congenital heart disease.¹⁰¹ Decisions on shunt closure should not be made on haemodynamic numbers alone, and a multiparametric strategy should be followed. For instance, shunt closure is not indicated in the case of desaturation during exercise in the 6MWT or CPET, or when there is secondary erythrocytosis suggesting dynamic reversal of shunt. There is no evidence for a long-term benefit of a treat-and-repair approach in patients with adult CHD-associated PAH with prevalent systemic-to-pulmonary shunts; therefore, there is a need for future prospective studies.⁵⁶⁴ Defect closure is contraindicated in all patients with Eisenmenger syndrome, and may also adversely affect patients with small/coincidental defects that behave similarly to IPAH.⁵⁶⁵ There are no prospective data available on the usefulness of vasoreactivity testing, balloon closure testing, or lung biopsy for assessing operability and normalization of PVR after closure.⁵⁶⁶

Patients with adult CHD-associated PAH may present with clinical deterioration in different circumstances, such as arrhythmia, during non-cardiac surgery requiring general anaesthesia, dehydration or bleeding, thrombo-embolism, and lung infections. Surgeries should be limited to those deemed essential, and performed in specialized centres with anaesthetists experienced in adult CHD and PAH. Endocarditis should be suspected in patients with sepsis, whereas a cerebral abscess should be excluded in those with neurological symptoms or new headache, especially in those with low oxygen saturations and complex anatomies. It is recommended to avoid strenuous exercise, but mild and moderate activities seem to be beneficial.⁵⁶⁷ Patients should receive all recommended vaccinations and endocarditis prophylaxis in the presence of cyanosis. Although pregnant patients with left-to-right shunts and stable, well-controlled PAH have tolerated pregnancy well under specialized care, pregnancy is still associated with both high maternal mortality and foetal complications in Eisenmenger syndrome and should be discouraged in this setting;^568,569 hence, effective contraception is highly recommended. Levonorgestrel-based, long-acting, reversible contraception implants or intrauterine devices have been recommended for these patients.⁵⁷⁰

Secondary erythrocytosis is beneficial for adequate oxygen transport and delivery, and routine phlebotomy should be avoided whenever possible. Symptoms of hyperviscosity in the presence of haematocrit >65% should be approached with appropriate hydration. Iron deficiency should be corrected. When i.v. iron supplementation is administered, special care should be taken to avoid air emboli during administration.⁵⁷¹ Supplemental oxygen therapy has not been shown to impact survival.

Oral anticoagulant treatment with VKAs may be considered in patients with large PA aneurysms with thrombus, atrial arrhythmias, and previous thrombo-embolic events, but with low bleeding risk. In patients with very high Hb levels (>20 mg/dL), standard international normalized ratio measures are less accurate, and citrate-adjusted blood bottles must be used. Regarding using novel oral anticoagulants (NOACs), a large, nationwide, German, adult CHD database (including 106 NOAC-treated patients with Eisenmenger syndrome) showed that NOAC users had higher long-term risk of bleeding, major adverse cardiovascular events, and mortality compared with those on VKAs, suggesting that initiating NOACs should be reserved for experienced adult CHD centres, carefully weighing potential benefits and risks.^572,573

Compared with other group 1 subgroups, limited data exist on the use of drugs approved for PAH in patients with adult CHD-associated PAH. Bosentan improved 6MWD and decreased PVR in patients with Eisenmenger syndrome in WHO-FC III.⁵⁷⁴ Patients with more complex lesions were less likely to respond to PAH therapies compared with patients with simple lesions. An RCT investigating the efficacy of macitentan found no effect on 6MWD in a mixed cohort of patients with Eisenmenger syndrome (6MWD improved in both treatment and placebo arms), although decreases in NT-proBNP and PVR were noted in the macitentan arm.⁵⁷⁵

Experiences with other ERAs and PDE5is have shown favourable functional and haemodynamic results in Eisenmenger syndrome.⁵⁷⁶ In a small, single-centre, pilot study, adding nebulized iloprost to a background of oral PAH therapy failed to improve 6MWD in Eisenmenger syndrome.⁵⁷⁷ In case symptoms persist or in clinical deterioration, a sequential and symptom-orientated treatment strategy is recommended in Eisenmenger syndrome, starting with an oral ERA (or PDE5i) and escalating therapy. Should symptoms not adequately improve with oral therapies, i.v./s.c. options should be proactively considered.⁵⁷⁸ There is a theoretical risk of paradoxical embolism in right-to-left shunt lesions with the presence of a central venous catheter for i.v. therapy; therefore, s.c. prostacyclin analogue infusion may be considered.

The effect of PAH therapies in patients with prevalent systemic-to-pulmonary shunts is less well established. Patients with small/coincidental defects should be treated with PAH medication.⁵⁵⁷ This is also the case for patients with PAH after defect correction who have increased mortality compared with those with Eisenmenger syndrome.⁵⁷⁹ These patients were included in major RCTs with PAH therapies and should be evaluated based on comprehensive risk assessment (Table 16).⁵⁸⁰ The effect of PAH therapies in patients with segmental PH remains a matter of debate.^101,581 While some series have reported promising results, there have been cases where therapies were not tolerated.⁵⁸¹ Similarly, using PAH therapies in Fontan circulation has yielded conflicting results, and results of further studies are awaited.^582–584

Heart–lung transplantation or LTx with heart surgery is an option in highly selected cases not responsive to medical treatment; however, it is limited by organ availability and lesion complexity. Mortality is high during the first year after surgery, especially after heart–lung transplantation, but remains relatively low thereafter.⁵⁸⁵

7.6. Pulmonary arterial hypertension associated with schistosomiasis

Schistosomiasis is one of the most common chronic infectious diseases worldwide, affecting around 200 million people.^586,587 Schistosomiasis-associated PAH is present in 5% of patients with the hepatosplenic form of the disease.⁵⁸⁶ It is thus a leading cause of PAH, especially in some regions of South America, Africa, and Asia. Compared with patients with IPAH, patients with schistosomiasis-associated PAH present with higher CO and lower PVR, and have a better survival.⁵⁸⁷ Registry data suggest that survival in schistosomiasis-associated PAH has improved in recent years with the use of PAH drugs.⁵⁸⁸

7.7. Pulmonary arterial hypertension with signs of venous/capillary involvement

The common risk factors, identical genetic substrate, and indistinguishable clinical presentations of PCH and PVOD necessitate their consideration as a single disease belonging to the group 1 PH spectrum of diseases (PAH with signs of venous/capillary involvement).^1,425,589 In PVOD/PCH, post-capillary lesions affecting septal veins and pre-septal venules consist of loose, fibrous remodelling of the intima that may totally occlude the lumen.^{1,425,589,590} These changes are frequently associated with PCH consisting of capillary ectasia and proliferation, with doubling and tripling of the alveolar septal capillary layers that may be focally distributed within the alveolar interstitium.^425,590

The proportion of patients with IPAH that fulfil the criteria for PVOD/PCH is ∼10%, resulting in a lowest estimate of PVOD/PCH incidence and prevalence of <1 case/million.⁴²⁵ In contrast to IPAH, there is a male predominance in PVOD/PCH and its prognosis is worse.^425,589,591 Familial PVOD/PCH typically occurs in the young siblings of one generation, with unaffected and sometimes consanguineous parents, indicating that the disease segregates as a recessive trait.^158,425,591 Biallelic mutations in the EIF2AK4 gene cause heritable PVOD/PCH.¹⁵⁸ In addition, PVOD/PCH can complicate the course of associated conditions, such as SSc,⁴²⁵ or be associated with exposure to environmental triggers, such as alkylating agents (cyclophosphamide, mitomycin C)³⁴ and solvents (trichloroethylene).³⁸

7.7.1. Diagnosis

Most patients complain of non-specific dyspnoea on exertion and fatigue.⁵⁹⁰ Physical examination may reveal digital clubbing and bibasal crackles on lung auscultation.⁵⁹⁰ Pulmonary arterial hypertension and PVOD/PCH share the same haemodynamic profile as pre-capillary PH.^590,591 The PAWP is not elevated because the pulmonary vascular changes occur in small venulae and capillaries, while the LA filling pressure remains normal.^590,591 A diagnosis of PVOD/PCH is based on the results of tests suggesting venous post-capillary involvement, chronic interstitial pulmonary oedema, and capillary proliferation.^1,590,591 These tests include PFTs (decreased DLCO, frequently <50% theoretical values), ABG (hypoxaemia), and non-contrast chest CT (subpleural thickened septal lines, centrilobular ground-glass opacities, and mediastinal lymphadenopathy).^{1,425,589,591,592} Importantly, these patients are at risk of drug-induced pulmonary oedema with PAH therapy, a finding suggestive of PVOD/PCH.^425,591 Detecting biallelic EIF2AK4 mutations is sufficient to confirm a diagnosis of heritable PVOD/PCH.^158,591,592 Lung biopsy is hazardous in PH and is not recommended for diagnosing PVOD/PCH.^1,425

7.7.2. Therapy

There is no established medical therapy for PVOD/PCH.⁴²⁵ Compared with IPAH, PVOD/PCH has a poor prognosis and limited response to PAH therapy, with a risk of pulmonary oedema due to pulmonary venous obstruction.^425,591 However, there are reports of incomplete and transient clinical improvement in individual patients with PVOD/PCH treated with PAH therapy, which should be used with great caution in this setting.^425,591 Diuretics, oxygen therapy, and slow titration of PAH therapy can be used on an individual basis.⁴²⁵ Therefore, therapy for PVOD/PCH should be undertaken at centres with extensive experience in managing PH, and patients should be fully informed about the risks.⁴²⁵ Anecdotal reports suggest a potential benefit of immunomodulatory treatments, but this approach requires further study.⁵⁹³ The only curative therapy for PVOD/PCH is LTx, and eligible patients should be referred to a transplant centre for evaluation upon diagnosis.^425,591 Pathological examination of the explanted lungs will confirm the diagnosis.⁵⁹⁰

7.8. Paediatric pulmonary hypertension

Pulmonary hypertension may present at all ages, including in infants and children. Pulmonary hypertension in childhood shares many common features with PH in adulthood; however, there are also important differences, which concern epidemiology, aetiology, genetic background, age-dependent diagnostic and treatment approaches, and disease monitoring. An important and conceptually distinctive feature of paediatric PH is injury to developing foetal, neonatal, or paediatric lung circulation.

7.8.1. Epidemiology and classification

The reported annual incident rate for paediatric PH is 64/million children.⁵⁹⁴ The distribution of the various aetiologies of PH in childhood differs from PH in adulthood.^594–596 Pulmonary arterial hypertension is the most frequent type of PH in children, with the vast majority (82%) of cases being infants with transient PAH (i.e. PPHN or repairable cardiac shunt defects). Of the remaining children with PAH, most have either IPAH, HPAH, or irreversible CHD-associated PAH. The reported incidences of IPAH/HPAH and (non-transient) CHD-associated PAH are 0.7 and 2.2/million children, respectively, with a prevalence of 4.4 and 15.6/million children, respectively.⁵⁹⁴ Other conditions associated with PAH (Table 6) do occur in children but are rare.

Another significant proportion (34–49%) of children with non-transient PH are neonates and infants with PH associated with respiratory disease, especially developmental lung diseases, including bronchopulmonary dysplasia (BPD), congenital diaphragmatic hernia (CDH), and congenital pulmonary vascular abnormalities.^594–598 These children form a prominent and distinctive group in paediatric PH and are currently classified as PH group 3 associated with developmental lung disease (Table 6; Table S7). A significant and growing proportion of children with PH associated with respiratory disease is made up of pre-term infants with BPD. Also, newly recognized genetic developmental lung disorders—including alveolar capillary dysplasia, TBX4-mutation-related lung disorders, and surfactant abnormalities—are currently classified in this category (Figure 10).⁵⁹⁹

Another distinctive feature of PH in children is the high burden of genetic disorders. Childhood PH is often associated with chromosomal, genetic, and syndromic anomalies (11–52%). Like in adults, gene mutations implicated in the pathogenesis of HPAH are found in 20–30% of sporadic cases, where paediatric HPAH seems to be characterized by an enrichment in TBX4 and ACVRL1 variations.^600,601 Additionally, 17% of children with PAH have other disorders known to be associated with PAH, including trisomy 21. Finally, 23% of children with PAH have copy number variations not previously associated with PH.^600,602,603

Given the frequent association of paediatric PAH with chromosomal, genetic, and syndromic anomalies (for which the mechanistic basis for PAH is generally uncertain), genetic testing may be considered for defining aetiology and comorbidities, stratifying risk, and identifying family members at risk; however, this should be after appropriate expert genetic counselling for the child and family (see Section 5.1.13).

The clinical PH classification (Table 6) is also followed for paediatric PH. To improve applicability of this classification in infants and children with PH, it has been adapted to give room to PH associated with various congenital cardiovascular and pulmonary diseases or specific paediatric conditions (Tables S5–S8).⁵⁹⁹

7.8.2. Diagnosis and risk assessment

Historically, the definition of PH in children aged >3 months has been the same as in adults. The definition for PH has now been redefined to mPAP >20 mmHg in adults as well as in children. The impact of an mPAP 21–24 mmHg on outcomes in children is unknown. However, in the interest of consistency and to facilitate transition from paediatric to adult PH care, it is recommended that the updated definition for PH also be followed in children. No treatment recommendations currently exist for this group of children (mPAP 21–24 mmHg).

Regarding the newly introduced criterion to include PVR >2 WU to identify pre-capillary PH in adults, PVR had previously been included in the definition for PAH in children. In children, blood flows are traditionally indexed assuming that systemic and pulmonary blood flows change proportionally with body size, while the transpulmonary pressure gradient does not. Since blood flow is the denominator in the equation for calculating PVR, the need for indexing of PVR in children is emphasized, and the criterion of pulmonary vascular resistance index (PVRI) ≥3 WU·m² in the definition for PAH in children remains unchanged.⁵⁹⁹

Since the aetiology of paediatric PH is very diverse, a methodical and comprehensive diagnostic approach is crucial to reach an accurate diagnosis and treatment plan. As in adults, IPAH is a diagnosis ‘per exclusion’. A diagnostic work-up, similar to that in adults but customized for paediatric PH, is recommended.⁵⁹⁹ Pre-term infants with BPD should be screened for PH, since PH is prevalent in this population and seriously affects outcome.⁶⁰⁴

Also in children, RHC is the gold standard for definitively diagnosing and establishing the nature of PH, and provides important data for stratifying risk.^604a,605 To identify those suitable for high-dose CCB treatment, acute vasoreactivity testing is recommended in children with IPAH/HPAH. The criteria used in adults for a positive acute response have identified children who will show sustained benefit from CCB therapy; however, these criteria do not define reversibility of PAH or operability in children with CHD. Since RHC in children with PH may be associated with major complications (in 1–3% of cases, especially in young infants and those in worse clinical condition), risks and benefits have to be balanced in the individual child.⁶⁰⁵ Heart catheterization in children with PAH should be exclusively performed in experienced paediatric PH centres. Indications for repeated RHC in children with PH are currently not well defined.

Treatment of children with PAH is based on risk stratification.⁵⁹⁹ Predictors of worse outcome in paediatric PAH are similar to those in adults, and include clinical evidence of RV failure, progression of symptoms, WHO-FC III–IV, certain echocardiographic parameters (e.g. TAPSE), and elevated serum NT-proBNP. A 6MWD <350 m has also been suggested as a predictor of worse outcome in paediatric PH, but its value in young children is less established. Further prognosticators identified in paediatric PAH are failure to thrive and haemodynamic variables, such as RAP >10 mmHg, the ratio of mean pulmonary-to-systemic blood pressure >0.75, and PVRI >20 WU·m².^602,606,607 Paediatric risk-assessment tools based on these parameters have been retrospectively validated in observational paediatric registries.^599,604a

7.8.3. Therapy

The ultimate goal of treatment should be to improve survival and facilitate normal childhood activities without limitations. In the absence of RCTs in paediatric PAH, recommended treatment algorithms are extrapolated from those in adults and enhanced with data from observational studies in children with PAH.⁵⁹⁹

Observational cohort studies support treatment algorithms designed for adults to be used for children (including the superiority of combination therapy over monotherapy).⁶⁰⁸ Drugs investigated in children, with or without formal approval by the European Medicines Agency (EMA) for treating children with PAH, are shown in Table 22.

A paediatric treatment algorithm, derived from that for adults, is based on risk stratification, recommending general measures, high-dose CCB therapy for responders to acute vasoreactivity testing (where close follow-up is mandatory, as some patients may fail long-term therapy), oral or inhaled combination therapy for children at low risk, and combination therapy with i.v./s.c. prostacyclin analogues for those at high risk.⁵⁹⁹

In the case of insufficient response to recommended drug therapy, or when drugs are unavailable, a Potts shunt (a surgical or interventional connection between the left PA and the descending aorta), BAS, or LTx may be considered in children with severe PH (see Sections 6.3.6.1 and 6.3.8).⁵⁹⁹ Reported clinical experience with Potts shunts is limited to just over 100 patients, predominantly children, with a mortality of 12–25% and long-term clinical benefit in a subset of children with long-term follow-up.^456–459

Monitoring of treatment effect and disease course is pivotal in managing all patients with PAH (adults and in children). In children with PAH, clinical risk scores including WHO-FC, TAPSE, and serum NT-proBNP are potential treatment targets for goal-orientated treatment.^604a,609

Contemporary treatment algorithms for infants with PPHN have been proposed but are outside the scope of these guidelines.⁶¹⁰

The recommendations discussed above apply to children with PAH, whereas the specific group of infants with neonatal PVD, mostly classified as PH associated with developmental lung disease and with heterogeneous aetiology, require a distinct and customized approach (Figure 10).

In pre-term infants with BPD and PH, the underlying lung disease should primarily be treated. Frequently, these infants are additionally treated with therapies for PAH, including sildenafil and bosentan; however, these are not approved by the EMA for use in infants with group 3 PH and developmental lung diseases (BPD, CDH). Their effects on outcomes in this population are unclear, and data enabling robust treatment recommendations are lacking. These children should be treated by multidisciplinary teams involving cardiologists, neonatologists, pulmonologists, and nutritionists. Pulmonary hypertension in these infants may disappear with lung healing, although long-term cardiovascular sequelae have been reported.^611,612

8. Pulmonary hypertension associated with left heart disease (group 2)

8.1. Definition, prognosis, and pathophysiology

Among patients with LHD, PH and RV dysfunction are frequently present and associated with high mortality.⁴⁷ This includes patients with HF with reduced, mildly reduced, or preserved ejection fraction (HFrEF, HFmrEF, or HFpEF), left-sided valvular heart disease, and congenital/acquired cardiovascular conditions leading to post-capillary PH.^13,631–635 Arguably, PH-LHD represents the most prevalent form of PH, accounting for 65–80% of cases.⁴⁷

Consistent with the general definitions of PH, PH-LHD (group 2 PH) is defined by an mPAP >20 mmHg and a PAWP >15 mmHg. Within this haemodynamic condition of post-capillary PH, IpcPH is defined by PVR ≤2 WU and CpcPH by PVR >2 WU (Table 5). The diastolic pressure gradient (DPG) (calculated as the difference between dPAP and PAWP) is no longer used to distinguish between IpcPH and CpcPH because of conflicting data on prognostication in LHD.¹⁴²

Across the spectrum of LHD, increases in PAP and PVR are associated with an increased disease burden and a worse outcome.^{13,631,633,635} In a large patient cohort—predominantly with post-capillary PH—a PVR ≥2.2 WU was associated with adverse outcomes and considered abnormal.¹³ However, even within this subgroup of patients with LHD and CpcPH, the risk of mortality increases with progressive elevation in PVR. In patients with advanced HFrEF and those with HFpEF or valvular heart disease, a PVR >5 WU carries additional prognostic information and is considered clinically meaningful by physicians.^{142,450,631–639} Elevated PVR also appears to be associated with decreased survival in special situations, such as in patients undergoing interventions for correcting valvular heart disease,⁶³⁴ heart transplantation,^142,633 or LVAD implantation.^142,637 Based on available data, a PVR >5 WU may indicate a severe pre-capillary component, the presence of which may prompt physicians to refer patients to PH centres for specialized care.

The prevalence of PH in patients with LHD is difficult to assess and depends on the methodology of diagnostic testing (echocardiography or invasive haemodynamics), cut-off values used to define PH, and populations studied. Observational studies suggest an estimated prevalence of PH of 40–72% in patients with HFrEF and 36–83% in those with HFpEF.^48,639–643 When PVR is used to define a pre-capillary component in patients with HF and post-capillary PH, ∼20–30% of patients are categorized as having CpcPH.^47,644,645 In patients with valvular heart disease, echocardiographic studies have shown that PH is present in up to 65% of patients with symptomatic aortic stenosis,^646–651 while virtually all patients with severe mitral valve stenosis develop PH,⁶⁵² which can also be found in most patients with significant degenerative or functional mitral regurgitation.

The pathophysiology of PH-LHD combines several mechanisms (Figure 11): (1) an initial passive increase in LV filling pressures and backward transmission into the pulmonary circulation; (2) PA endothelial dysfunction (including vasoconstriction); (3) vascular remodelling (which may occur in both venules and/or arterioles); (4) RV dilatation/dysfunction and functional TR;^653–656 and (5) altered RV–PA coupling.^655–657 The haemodynamic profile of CpcPH vs. IpcPH and elevated PVR reflects pulmonary vascular abnormalities, which contribute to an increased RV afterload. Resulting dysfunction of the RV is frequent and associated with a worse prognosis in patients with PH-LHD. In HFpEF, where RV dysfunction may occur via distinct mechanisms (Figure S1), deterioration of RV, but not LV systolic function, has been observed over time, and both prevalent and incident RV dysfunction are predictors of mortality.⁶⁵⁸

The occurrence of PH in patients with LHD may also be due to other causes, including undetected CTEPH or PAH. Further, respiratory comorbidities such as COPD and sleep apnoea are also common in patients with LHD and may contribute to PH and impact prognosis. Patients with HFpEF and PH associated with HFpEF^75,76 may also present with a low DLCO, which is an independent predictor of outcome.⁷⁵

8.2. Diagnosis

In patients with LHD, symptoms (e.g. exertional dyspnoea) and physical signs of PH (e.g. peripheral oedema) frequently overlap with those of the underlying left heart condition and are mostly non-specific. However, while pulmonary congestion or pleural effusion indicate LHD as the underlying cause of PH, other features may suggest the presence of relevant PH (see Section 5.1.1).

Routine diagnostic tests including BNP/NT-proBNP, ECG, and echocardiography may show signs of underlying LHD, but may also indicate PH. While BNP/NT-proBNP cannot discriminate between left- or right-sided HF, ECG findings such as right axis deviation or RV strain may suggest the presence of PH in patients with LHD. Echocardiography can diagnose HFrEF and HFpEF; identify specific cardiac conditions, including those with restrictive filling pattern; and diagnose additional valvular heart disease; it may also detect elevated sPAP and other features of PH (RA area, PA enlargement, RV/LV ratio, LV eccentricity index, RV forming the apex), leading to an echocardiographic probability of PH (see Section 5.1.5). A stepwise, composite echocardiographic score may discriminate pre- vs. post-capillary PH and predict PVD in patients with LHD.^659,660 Additional information may be gathered from further testing, including biomarkers, imaging-derived markers of RV dysfunction, and CPET-derived variables.¹⁴²

Given the complexity and variability of cardiopulmonary haemodynamics in patients with LHD, the distinction between post- and pre-capillary PH and the diagnosis of PH-LHD vs. other forms of PH can be challenging. Diagnostic clues in the evaluation of suspected PH in LHD include: (1) diagnosis and control of the underlying LHD; (2) evaluation for PH and patient phenotyping; and (3) invasive haemodynamic evaluation, when indicated.

8.2.1. Diagnosis and control of the underlying left heart disease

Patients with suspected PH-LHD will have an established diagnosis of LHD, such as HFrEF/HFmrEF, HFpEF, valvular heart disease, and/or CHD. The distinction between PH associated with HFpEF and other forms of PH (e.g. PAH, CTEPH) may be challenging, particularly given the increased burden of cardiovascular comorbidities in real-world PAH populations.^142,450,661 In this context, validated scores for diagnosing HFpEF (HFA-PEFF, H2FPEF)^16,662,663 may be helpful for detecting it as an underlying condition in PH, and the presence or absence of risk factors for PAH or CTEPH should be determined. Patients with signs of predominant RV strain and/or PH should be further evaluated. Patients should be assessed or reassessed when they are fully recompensated and in a clinically stable condition.

8.2.2. Evaluation of pulmonary hypertension and patient phenotyping

Patients with LHD and suspected PH should be evaluated following the diagnostic strategy for PH (see Section 5). This requires identifying clinical features and a multimodal approach using non-invasive diagnostic tests such as echocardiography, ECG, and BNP/NT-proBNP levels. In the presence of mild PH and predominant LHD, no further testing may be necessary. Otherwise, CTEPH and significant lung disease should be ruled out by V/Q scan and PFTs, and additional cardiac imaging including cMRI may be considered in selected cases. For phenotyping, a combination of variables may help to determine the likelihood of LHD, and HFpEF in particular, vs. other causes of PH (Table 23). Pulmonary hypertension associated with left heart disease is likely in the presence of known cardiac disease, multiple cardiovascular comorbidities/risk factors, atrial fibrillation at diagnosis, and specific imaging findings (LV hypertrophy, increased LA size, and reduced LA strain). Although exercise echocardiography has been proposed to uncover HFpEF, it is unable to diagnose or classify PH in this context. A combination of clinical findings and phenotyping is required to decide about the need for further invasive assessment.

8.2.3. Invasive assessment of haemodynamics

The decision to perform cardiac catheterization and to invasively assess cardiopulmonary haemodynamics should depend on the presence of an intermediate to high echocardiographic probability of PH, and should be determined by the need to obtain relevant information for prognostication or management. In patients with a high likelihood of LHD as the main cause of PH, or with established underlying LHD and mild PH (Table 23), invasive assessment for PH is usually not indicated. Indications for RHC in LHD include: (1) suspected PAH or CTEPH; (2) suspected CpcPH with a severe pre-capillary component, where further information will aid phenotyping and treatment decisions (Figure S2); and (3) advanced HF and evaluation for heart transplantation. While several haemodynamic measures (mPAP, PVR, pulmonary arterial compliance [PAC], transpulmonary pressure gradient, and DPG) are associated with outcomes in PH-LHD,^142,632,635 the most robust and consistent data are available for PVR. Invasive assessment should be conducted in experienced centres, when management of the underlying LHD has been optimized and patients are in a clinically stable condition. With respect to respiratory variations of intrathoracic pressures, all pressure readings should be taken at end-expiration.

Additional testing during RHC may be useful for distinguishing between PAH and HFpEF,^{18,23,664–669} and to uncover LHD in patients with a high likelihood of PH-LHD and normal resting PAWP;^670–673 both exercise testing and fluid challenge may be considered in special situations (see Section 5.1.12). Conditions associated with reduced LV diastolic compliance or valvular heart disease may be associated with a rapid increase in PAWP when challenged with increased systemic venous return.⁶⁷⁴ While the upper limit of normal remains controversial,^{142,143,665,667} a PAWP cut-off of >18 mmHg has been suggested to identify HFpEF as the underlying cause of PH, despite normal PAWP at baseline.¹⁴³ While this may help to classify PH, therapeutic consequences of such testing remain to be determined.

As differentiating between severe PH associated with HFpEF and IPAH with cardiac comorbidities is challenging, patients with an unclear diagnosis, particularly those with a predominant pre-capillary component (e.g. PVR >5 WU), should be referred to a PH centre for individualized management.

8.3. Therapy

The primary strategy in managing PH-LHD is optimizing treatment of the underlying cardiac disease. Nevertheless, a pathophysiological sequence ranging from left-sided heart disease via pulmonary circulation to chronic right heart strain (at rest or exercise) is present in many patients.⁴⁷ Since deterioration of RV function over time is associated with poor outcomes in HFpEF,⁶⁵⁸ preserving RV function should be considered an important treatment goal. Diuretics remain the cornerstone of medical therapy in the presence of fluid retention due to PH-LHD.

There is limited and conflicting evidence for the use of drugs approved for PAH in patients with group 2 PH. Some medications may have variable and potentially detrimental effects in such patients and are therefore not indicated in PH-LHD. Management strategies for PH in various left heart aetiologies are described below.

8.3.1. Pulmonary hypertension associated with left-sided heart failure

8.3.1.1. Heart failure with reduced ejection fraction

Patients with HFrEF or HFmrEF require guideline-directed treatment including established medical and interventional therapies.²⁷ In patients with advanced HFrEF, implanting an LVAD may significantly reduce or even normalize mPAP,⁶⁷⁵ although this is not achieved in all patients,⁶⁷⁶ and an increased DPG emerged as a negative prognostic factor after LVAD implantation.⁶⁷⁷ With regards to PAH drugs, bosentan was assessed in an RCT of patients with PH associated with HFrEF,⁶⁷⁸ showing no efficacy but an increase in adverse events compared with placebo, predominantly related to fluid retention. Small studies have suggested that sildenafil may improve haemodynamics and exercise capacity in PH and HFrEF,^679–681 but RCTs are lacking.

8.3.1.2. Heart failure with preserved ejection fraction

In patients with HFpEF, blood pressure, volume load, and risk factors should be controlled, which may lower filling pressures and PAP.²⁷ Recently, the SGLT-2i empagliflozin improved outcomes in patients with an LV ejection fraction of 40–60%.⁶⁸² Endothelin receptor antagonists have not proved successful in this population, as both bosentan⁶⁸³ and macitentan⁶⁸⁴ failed to show efficacy but rather led to more adverse events (fluid retention) vs. placebo in patients with HFpEF-associated PH and HF with ejection fraction >35%-associated CpcPH, respectively. Phosphodiesterase 5 inhibitors were assessed in two small RCTs in patients with HFpEF and PH with distinct haemodynamic characteristics. In patients with a predominantly IpcPH profile, sildenafil had no effect on mPAP (primary endpoint) or other haemodynamic and clinical measures vs. placebo.⁶⁸⁵ In patients with a predominantly CpcPH profile, sildenafil improved haemodynamics, RV function, and quality of life at 6 and 12 months vs. placebo.⁶⁸⁶ Furthermore, retrospective analyses and registry data suggested improvements in exercise capacity with PDE5i therapy in patients with HFpEF-associated CpcPH and with a severe pre-capillary component (PVR mostly >5 WU).^450,687

8.3.1.3. Interatrial shunt devices

Recent data suggest that specific interventions may be considered in selected cases of HFpEF, such as interatrial shunt devices to unload the left heart. While this was associated with short-term improvements in pulmonary vascular function,⁶⁸⁸ the long-term effect on the pulmonary circulation remains unknown. The recent REDUCE LAP-HF II trial failed to show a reduction in HF events after placement of an atrial shunt device in a population of HF patients with LVEF ≥40%,⁶⁸⁹ with worse outcomes in the presence of PVD.⁶⁹⁰ In addition, a sustained increase in PA blood flow may be a matter of concern, as this may trigger vascular remodelling in patients with pre-existing PH.

8.3.1.4. Remote pulmonary arterial pressure monitoring in heart failure

The importance of decongestion in patients with HF is underscored by the use of implantable pressure sensors, remotely monitoring PAP as a surrogate of left-sided filling pressure. Pulmonary arterial pressure-based adjustment of HF therapy substantially reduced HF hospitalizations and improved outcomes in both patients with HFpEF and HFrEF,^691–694 with adjustment of diuretic therapy being the most prominent therapeutic consequence. Further strategies to optimize management depending on the haemodynamic phenotype in PH-LHD remain to be established. In HFrEF, novel medical therapies such as ARNIs and SGLT-2is reduced remotely monitored PAP and diuretic use,^695–698 potentially providing opportunities to further optimize PAP-guided HF therapy.

8.3.2. Pulmonary hypertension associated with valvular heart disease

Pulmonary hypertension frequently occurs as a consequence of valvular heart disease. While surgical or interventional approaches for valvular repair improve cardiopulmonary haemodynamics by reducing PAWP and PAP and improving forward SV,⁶⁹⁹ persistent PH after correcting valvular heart disease is frequent and associated with adverse outcomes.^634,700

8.3.2.1. Mitral valve disease

Both mitral stenosis and regurgitation regularly lead to post-capillary PH. Functional (secondary) mitral regurgitation occurs in both HFrEF and HFpEF, and is an important contributor to PH in LHD. Reducing mitral regurgitation according to the recommendations of the 2021 ESC/EACTS Guidelines for the management of valvular heart disease²⁸ has a crucial role in improving haemodynamics in patients with HFrEF, as this reduces mPAP and PAWP and improves the CI.⁶⁹⁹ Nevertheless, registry data have demonstrated that even moderately elevated sPAP negatively impacts post-procedural outcomes after catheter-based therapy.⁷⁰⁰

8.3.2.2. Aortic stenosis

In patients with aortic stenosis undergoing surgical or catheter-based aortic valve repair, pre-interventional PH is associated with a higher risk of in-hospital adverse events and adverse long-term outcomes.^646–651 Although post-procedural improvement in PH correlates with symptom relief and favourable outcomes, persistence of PH is common, and even moderate PH is associated with a higher all-cause mortality.^646–651

Of note, medical therapy of PH post-valvular repair may be harmful. A randomized study of 231 patients with surgically corrected valvular heart disease and persistent PH showed that sildenafil therapy vs. placebo was associated with worse outcome when compared with placebo;⁷⁰¹ however, this study did not distinguish between different types of PH (pre-capillary, IpcPH, and CpcPH).

8.3.2.3. Tricuspid regurgitation

Severe TR is associated with volume overload, increased RV workload, and maladaptive remodelling, leading to symptomatic right HF and impaired survival.^702,703 While primary TR is relatively rare, functional TR may arise from annular dilation in the presence of both PH and LHD. Transcatheter tricuspid valve interventions have recently emerged, aiming at reducing TR and RV volume overload. Of note, correcting TR in patients with PAH or PH in (non-valvular) LHD with significantly elevated PVR and/or RV dysfunction must be considered with great caution, as this may be hazardous.⁷⁰⁴ Right ventricle–PA coupling is an independent predictor of all-cause mortality in such patients.⁷⁰⁵ Patient selection appears crucial, and a comprehensive diagnostic approach integrating imaging modalities and invasive haemodynamic assessment is necessary in the evaluation process prior to tricuspid valve repair, particularly since echocardiography underestimates sPAP in the presence of severe TR.

8.3.3. Recommendations on the use of drugs approved for PAH in PH-LHD

The recommendations on the use of drugs approved for PAH in patients with PH-LHD have been established based on key narrative question 5 (Supplementary Data, Section 8.3).

The recommendations on the use of PDE5is in patients with CpcPH associated with HFpEF are based on PICO question II (Supplementary Data, Section 8.4). Two RCTs that enrolled patients with HFpEF and PH were identified, but no study that specifically enrolled patients with HFpEF and CpcPH. Harmful effects cannot be excluded, even if the available data from clinical studies, case series, and registries suggest that PDE5is may be safely administered to patients with HFpEF-associated CpcPH. As a result, a general recommendation for or against the use of PDE5is in patients with HFpEF and CpcPH cannot be made. However, it is clinically relevant to make a recommendation against their use for patients with HFpEF and IpcPH.

9. Pulmonary hypertension associated with lung diseases and/or hypoxia (group 3)

Pulmonary hypertension is frequently observed in patients with COPD and/or emphysema, ILD, combined pulmonary fibrosis and emphysema (CPFE), and hypoventilation syndromes.^{52,165,707,708} Pulmonary hypertension is uncommon in obstructive sleep apnoea unless other conditions coexist, such as COPD or daytime hypoventilation.⁷⁰⁹ At high altitude (>2500 m) hypoxia-induced PH is thought to affect >5% of the population, the development of PH being related to geography and genetic factors.⁷¹⁰

A PH screening study performed on a large cohort of >100 patients with lymphangioleiomyomatosis confirmed that PH is usually mild in that setting: from six patients (5.7%) presenting with pre-capillary PH, none had mPAP >30 mmHg and PH was associated with PFT alteration, suggesting that the rise in mPAP is associated with parenchymal involvement.⁷¹¹ Thus, PH in lymphangioleiomyomatosis is now classified in group 3 PH.¹

In patients with lung disease, PH is categorized as non-severe or severe, depending on haemodynamic findings (Figure 12). In the 2015 ESC/ERS Guidelines for the diagnosis and treatment of PH, severe PH was defined by mPAP >35 mmHg or mPAP ≥25 mmHg with CI <2.5 L/min/m².^25,26 However, two recent studies have demonstrated that a PVR >5 WU is a better threshold for predicting worse prognosis in patients with PH associated with both COPD and ILD.^712,713 Based on these data, the current guidelines used PVR to distinguish between non-severe PH (PVR ≤5 WU) and severe PH (PVR >5 WU). Whereas non-severe PH is common in advanced COPD and ILD defined by spirometric criteria, severe PH is uncommon, occurring in 1–5% of cases of COPD and <10% of patients with advanced ILD, with limited data in obesity hypoventilation syndrome.^714,715 Even non-severe PH in lung disease negatively impacts symptoms and survival, and is associated with increased hospitalization.^715–717 Patients with lung disease and severe PH have a worse outcome than those with non-severe PH, providing evidence that this distinction has clinical significance.^{51,712,713,718,719} It is noteworthy that developing severe PH is largely independent of spirometry but usually accompanied by hypoxaemia, low PaCO₂, and a significant reduction in DLCO.^{51,714,718,719}

Pulmonary hypertension presenting in patients with lung disease may be due to a number of causes, including undiagnosed CTEPH or PAH.^714,720 Cardiac comorbidities are also common in patients with lung disease and may contribute to PH. A number of distinct phenotypes of PH in patients with lung disease, including a pulmonary vascular phenotype, have been proposed.^51,720 The pulmonary vascular phenotype is characterized by better preserved spirometry, low DLCO, hypoxaemia, a range of parenchymal involvement on lung imaging, and a circulatory limitation to exercise.^{51,714,718–722} Recent studies have shown that the clinical characteristics, disease trajectory, response to treatment,^451,718,719 and histological correlates^723,724 of patients with severe PH and minor lung disease are different to those in patients with IPAH, including a poorer prognosis.

9.1. Diagnosis

In patients with lung disease, symptoms of PH, especially exertional dyspnoea, overlap with those of the underlying condition. Physical findings may also be non-specific, for example: ankle swelling is common during episodes of ventilatory failure in COPD, where activation of the renin–angiotensin–aldosterone system may cause fluid retention, usually in the setting of preserved RV function.

Non-invasive tests—such as ECG showing right axis deviation or RV strain, elevated levels of BNP/NT-proBNP, CPET, or features on cross-sectional imaging—may suggest the diagnosis of PH in patients with lung disease.^725,726 Echocardiography remains the most widely used non-invasive diagnostic tool for assessing PH; however, the accuracy of echocardiography in patients with advanced respiratory diseases is low, with a TRV unmeasurable in >50% of patients in some studies, and there is a tendency to overestimate PAP and misclassify patients with PH.^86,87,727 More recent data suggest that a stepwise, composite, echocardiographic score can identify patients with severe PH, with and without an estimate of TRV, using other echocardiographic features including RA area, RV:LV ratio, and LV eccentricity index.⁷²⁸ Where PH is suspected, combining echocardiography with a contrast-enhanced CT may aid diagnostic assessment and disease classification.^{108,729–731} Pulmonary artery enlargement, RV outflow hypertrophy, and increased RV:LV ratio may suggest a diagnosis of PH.¹⁰⁸ Ideally, assessments should be made or repeated when the patient is clinically stable, as exacerbations can significantly raise PAP.

Key parts of evaluating suspected PH in lung disease include integrating: (1) the presence or absence of risk factors for PAH, CTEPH, or LHD; (2) clinical features, including disease trajectory (e.g. rapid recent deterioration vs. gradual change over years, and oxygen requirements); (3) PFTs, including DLCO and blood gas analysis; (4) NT-proBNP measurements, ECG, and echocardiography; and (5) cross-sectional imaging with contrast-enhanced CT, SPECT, or V/Q lung scan and, in selected cases, cMRI⁷³² to assess the need for RHC. Cardiopulmonary exercise testing may be helpful in assessing ventilatory or cardiac limitation in patients with lung disease,^121,733 although data are limited regarding its clinical use in identifying patients with PH in lung disease.

Indications for RHC in lung disease include assessment for surgical treatments (selected patients considered for LTx and lung volume reduction surgery), suspected PAH or CTEPH, and where further information will aid phenotyping of disease and consideration of therapeutic interventions (Figure S3).^712,718,734 Such testing should ideally be conducted in PH centres when patients are clinically stable and treatment of underlying lung disease has been optimized. Consideration should be given to how pressure measurements are made, due to the impact of changing intrathoracic pressures on pulmonary haemodynamics during the respiratory cycle (see Section 5.1.12).⁷³⁵

9.2. Therapy

The therapeutic approach to group 3 PH starts with optimizing the treatment of the underlying lung disease, including supplementary oxygen and non-invasive ventilation, where indicated, as well as enrolment into pulmonary rehabilitation programmes.⁷³⁶ There is limited and conflicting evidence for the use of medication approved for PAH in patients with group 3 PH, and these drugs may have variable and sometimes detrimental effects on haemodynamics, exercise capacity, gas exchange, and outcomes in this patient population.^{181,737–740}

9.2.1. Pulmonary hypertension associated with chronic obstructive pulmonary disease or emphysema

Studies using drugs approved for PAH in patients with PH associated with COPD or emphysema have yielded conflicting results and are mostly limited by small sample size, short duration, and insufficient haemodynamic characterization of PH.^739,741,742 In a 16 week RCT of 28 patients with COPD and severe PH confirmed by RHC, sildenafil therapy resulted in statistically significant improvements in PVR and quality of life.⁷⁴³ Registry data identified that ∼30% of patients with COPD and severe PH, predominantly treated with PDE5is, had improved WHO-FC, 6MWD, and PVR vs. baseline, and those with a treatment response had improved transplant-free survival.^51,718 However, in the absence of large randomized trials, the evidence is insufficient to support the general use of medication approved for PAH in patients with COPD and PH. Patients with COPD and suspected or confirmed severe PH should be referred to PH centres for individual decision-making.

9.2.2. Pulmonary hypertension associated with interstitial lung disease

Numerous phase 2 and phase 3 studies have investigated the use of ERAs to treat ILD, all with negative results.^740,744,745 In addition, the PDE5i sildenafil has been investigated in phase 3 trials of patients with ILD, also with negative results.^746,747 Few data from RCTs are available for patients with PH associated with ILD, and many of the studies performed for this indication^748,749 suffered from the same limitations as the aforementioned studies in PH associated with COPD. In addition, there were several adverse safety signals: ambrisentan was associated with an increased risk of clinical worsening in patients with ILD with and without PH,^740,750 while riociguat was associated with an increased risk of clinical worsening events, including potential excess mortality, in patients with PH associated with idiopathic interstitial pneumonia.¹⁸¹

In contrast, promising results have been obtained with the use of inhaled treprostinil. A phase 3 RCT (INCREASE) examined inhaled treprostinil at a target dose of 72 µg given four times daily in 326 patients with PH associated with ILD.^734,751 The PH diagnosis was confirmed by RHC within 1 year prior to enrolment. At week 16, the placebo-corrected 6MWD improved by 31 m with inhaled treprostinil. There were also improvements in NT-proBNP and clinical worsening events, the latter driven by a lower proportion of patients whose 6MWD declined by >15% from baseline.

Given the significant impact of even non-severe PH in patients with lung disease, eligible patients should be referred for LTx evaluation. In patients with ILD and PH, inhaled treprostinil may be considered based on the findings from the INCREASE study, but further data are needed, especially on long-term outcomes. The routine use of other medication approved for PAH is not recommended in patients with ILD and non-severe PH. For patients with severe PH and/or severe RV dysfunction, or where there is uncertainty regarding the treatment of PH, referral to a PH centre is recommended for careful evaluation, to facilitate entry into RCTs, and consider PAH therapies on an individual basis (Figure S3). Registry data show that some patients with group 3 PH are being treated with PAH medication, predominantly PDE5is,^718,752,753 but it is unclear if and to what extent these patients benefit from this treatment.

9.2.3. Recommendations on the use of drugs approved for PAH in PH associated with lung disease

The recommendations on the use of drugs approved for PAH in patients with PH associated with COPD and ILD have been established based on key narrative questions 6 and 7 (Supplementary Data, Sections 9.1 and 9.2, respectively).

The recommendations on the use of PDE5is in patients with severe PH associated with ILD are based on PICO question III (Supplementary Data, Section 9.3). There are no direct data from RCTs on the safety, tolerability, and efficacy of PDE5is in patients with PH associated with ILD. The indirect data included in the guidelines do not enable firm conclusions to be drawn. Given the lack of robust evidence, the Task Force members felt unable to provide a recommendation for or against the use of PDE5is in patients with ILD and severe PH, and recommend that these patients are referred to a PH centre for individualized decision-making.

Recommendation Table 23B

10. Chronic thrombo-embolic pulmonary hypertension (group 4)

All patients whose symptoms can be attributed to post-thrombo-embolic fibrotic obstructions within the PA are considered to have CTEPD with or without PH; CTEPH remains the preferred term for patients with PH, as defined in Section 3.1 (Table 5).⁵⁴ Chronic thrombo-embolic pulmonary disease describes symptomatic patients with mismatched perfusion defects on V/Q scan and with signs of chronic, organized, fibrotic clots on CTPA or DSA, such as ring-like stenoses, webs/slits, and chronic total occlusions (pouch lesions or tapered lesions), after at least 3 months of therapeutic anticoagulation. Pulmonary hypertension in this setting is not only a consequence of PA obstruction by organized fibrotic clots but can also be related to the associated microvasculopathy. In those patients without PH at rest, breathlessness could be due to exercise PH (see definition in Section 3.1, Table 5) and/or increased dead space ventilation.⁵⁴ Excluding ventilatory limitation, deconditioning and psychogenic hyperventilation syndrome by CPET and LV myocardial or valvular disease by echocardiography is of upmost importance when making therapeutic decisions in patients with CTEPD without PH.

10.1. Diagnosis

Chronic thrombo-embolic pulmonary hypertension is a common and important cause of PH, with a distinct management strategy. Thus, the possibility of CTEPH should be carefully considered in all patients with PH (Figure 13). In the context of acute PE, CTEPH should be considered: (1) if radiological signs (detailed in Section 5.1.7) suggest CTEPH on the CTPA performed to diagnose PE,¹¹² and/or if estimated sPAP is >60 mmHg¹¹² on echocardiogram; (2) when dyspnoea or functional limitations persist in the clinical course post-PE;⁷⁵⁴ and (3) in asymptomatic patients with risk factors for CTEPH or a high CTEPH prediction score.⁷⁵⁵ Clinical conditions such as permanent intravascular devices (pacemaker, long-term central lines, ventriculoatrial shunts), inflammatory bowel diseases, essential thrombocythaemia, polycythaemia vera, splenectomy, antiphospholipid syndrome, high-dose thyroid hormone replacement, and malignancy are risk factors for CTEPH.^54,103,756

Alternative causes of PA obstructions (also included in group 4 of the PH classification)—including PA sarcomas, other malignant tumours (e.g. renal carcinoma, uterine carcinoma, and germ-cell tumours of the testis), non-malignant tumours (e.g. uterine leiomyoma), arteriitis without CTD, congenital or acquired PA stenoses, parasites (hydatid cyst), and foreign-body embolism—have to be considered in the differential diagnosis of CTEPD.⁷⁵⁷ They can be explored by specific additional imaging such as ¹⁸F-2-fluoro-2-deoxy-D-glucose-positron emission tomography (PET) scan, which can provide additional information when PA sarcoma is suspected.⁷⁵⁸

Ventilation/perfusion scintigraphy²⁰⁷ remains the most effective tool in excluding CTEPD. Alternative perfusion imaging techniques—such as iodine subtraction mapping, DECT, and MRI perfusion—have numerous theoretical advantages over V/Q but are more technically challenging and expensive, have limited availability, and currently lack multicentre validation.

Computed tomography pulmonary angiography with bi-planar reconstruction is broadly used for diagnosing CTEPD and assessing operability, but a negative CTPA, even if high quality, does not exclude CTEPD, as distal disease can be missed. Digital subtraction angiography is still used to assess treatment options when CTPA is inconclusive. Selective segmental angiography, cone-beam CT, and area detector CT allow for more accurate visualization of subsegmental vasculature and are useful for procedural guidance for BPA. The benefits of the new technologies require validating in prospective trials before being recommended for routine clinical use; a large, European, multicentre study is currently ongoing.⁷⁵⁹

10.2. Therapy

The CTEPH treatment algorithm includes a multimodal approach of combinations of pulmonary endarterectomy (PEA), BPA, and medical therapies to target the mixed anatomical lesions: proximal, distal, and microvasculopathy, respectively (Figures 14 and 15).

General measures recommended for PAH also apply to CTEPH, including supervised exercise training, which is effective and safe in inoperable CTEPH patients,⁷⁶⁰ as well as early after PEA.⁷⁶¹

Lifelong therapeutic anticoagulation is recommended for patients with CTEPH, as recurrent pulmonary thrombo-embolism accompanied by insufficient clot resolution are key pathophysiological features of this disease. There are no RCTs in CTEPH with any of the approved anticoagulants; however, despite this lack of evidence, VKAs are recommended by experts, and are most widely used as background therapy for patients with CTEPH. More recently, NOACs have more frequently been used as alternatives to VKAs, again, lacking evidence from RCTs. A retrospective case series from the UK and a multicentre prospective registry (EXPERT) showed comparable bleeding rates for VKAs and NOACs in CTEPH, but recurrent venous thrombo-embolism rates were higher in those receiving NOACs.^762,763 In patients with antiphospholipid syndrome (10% of the CTEPH population), VKAs are recommended.^103,764,765 Screening for antiphospholipid syndrome should be performed at CTEPH diagnosis. In the absence of any evidence in favour or against prolonged anticoagulation in patients with CTEPD without PH, long-term anticoagulant therapy is based on individual decision-making. It is recommended when the risk of PE recurrence is intermediate or high, thereby following the 2019 ESC/ERS Guidelines for the diagnosis and management of acute pulmonary embolism (Table 11).¹⁰³

10.2.1. Surgical treatment

Surgical PEA is the treatment of choice for patients with accessible PA lesions.¹⁰² As surgery may normalize pulmonary haemodynamics (65% decrease in PVR)⁷⁶⁶ and functional capacity, an expert multidisciplinary team including an experienced PEA surgeon (on-site or closely collaborating) is mandatory for evaluating operability and deciding final treatment.¹⁰²

Operability is based on team experience, accessibility of PA lesions, correlation between severity of PH and degree of PA obstructions, and comorbidities.⁷⁶⁷ The surgical technique is complex but well standardized with >30 years of experience. It consists of a complete bilateral endarterectomy of the PAs down to segmental and subsegmental levels in phases of deep hypothermic circulatory arrest (Figure 15).^767,768 In CTEPH centres, surgical outcomes are favourable, with peri-operative mortality rates <2.5% due to improved management of cardiac and pulmonary complications and well-established use of ECMO.⁷⁶⁸ Post-operative PH is frequently observed (∼25%),⁷⁶⁶ but long-term outcomes after PEA surgery are excellent regarding survival (averaging 90% at 3 years) and quality of life,^769–771 even in patients with distal PA obstructions.⁷⁷² On the other hand, patients with proximal operable disease declining surgery have a poor long-term outcome, with a 5 year survival of 53% compared with 83% in patients undergoing PEA.⁷⁷³ Therefore, PEA should be offered to all operable patients with a favourable risk:benefit ratio, ideally during a personal consultation between the patient and the PEA surgeon.¹⁰²

Selected symptomatic patients with CTEPD without PH can be successfully treated by PEA, with clinical and haemodynamic improvements at rest and exercise.^135,774 Those patients would require careful discussion to balance risk and benefit.

10.2.2. Medical therapy

To manage the microvascular component of CTEPH (Figure 15), medical therapies have been used off-label based on uncontrolled studies and/or regional approvals. Meanwhile, three RCTs have successfully been conducted. The first phase 3 RCT investigated the efficacy of riociguat in patients with inoperable CTEPH or those with persistent/recurrent PH after PEA.⁷⁷⁵ Riociguat, after 16 weeks of therapy, improved 6MWD and reduced PVR by 31% compared with placebo, and is approved for this indication. Treprostinil s.c. was investigated in a phase 3 RCT, which showed improved 6MWD at week 24 in patients with inoperable CTEPH or those with persistent/recurrent PH after PEA receiving a high dose compared with a low dose;⁷⁷⁶ s.c. treprostinil is approved for this indication. In a phase 2 study including only patients with inoperable CTEPH, macitentan 10 mg improved PVR and 6MWD vs. placebo at 16 and 24 weeks, respectively.⁷⁷⁷ A phase 3 RCT is ongoing to evaluate the safety and efficacy of macitentan 75 mg in inoperable or persistent/recurrent CTEPH (NCT04271475).

Other medical therapies—PDE5is (e.g. sildenafil) and ERAs (e.g. bosentan)—have been used off-label, as their efficacy in inoperable CTEPH has not been proven by RCTs or registry data.^769,778,779 However, oral combination therapy, including PDE5is and ERAs, is common practice in patients with CTEPH with severe haemodynamic compromise.⁷⁸⁰

10.2.3. Interventional treatment

Balloon pulmonary angioplasty (Figure 15) has become an established treatment for selected patients with inoperable CTEPH or persistent/recurrent PH after PEA, improving haemodynamics (PVR decrease 49–66%), right heart function, and exercise capacity.^781–794 Long-term outcomes are promising, but evidence is still scarce.⁷⁹⁵

A staged interventional procedure with a limited number of dilated PA segments per session is preferred.^102,788 The number of sessions needed and haemodynamic results are dependent on experience.⁷⁸¹ While BPA is effective, it is associated with serious complications, which may be fatal. Procedural and post-interventional complications include vascular injury due to wire perforation, and lung injury with haemoptysis and/or hypoxia.^{102,781,796,797} As with all interventional procedures, a significant learning curve has been shown, with reducing complication rates over time;⁷⁸¹ therefore, this procedure should be performed in high-volume CTEPH centres. As the rates of interventional complications can be reduced by medical pre-treatment, patients with a PVR >4 WU should be treated before BPA (Figure 15).⁷⁹⁸

Selected symptomatic patients with CTEPD without PH and segmental/subsegmental lesions can successfully be treated by BPA, with clinical and haemodynamic improvements at rest and exercise.⁷⁹⁹

Preliminary data on PADN point towards improved exercise capacity and pulmonary haemodynamics in patients with persistent PH after PEA;⁸⁰⁰ further confirmation is being awaited.

10.2.4. Multimodal treatment

Multimodal therapy including surgery, medication, and intervention is offered to selected patients with CTEPH (Figure 15).¹⁰²

Using medical therapy in patients with high pre-operative PVR to improve pulmonary haemodynamics before PEA is common practice but still controversial, as it is felt to delay timely surgical referral and therefore definitive treatment.^801–803

A significant proportion of symptomatic patients may have persistent or recurrent PH following PEA, which may also benefit from medical and/or interventional therapies (Figure 15).^804–806 An mPAP ≥30 mmHg has been associated with initiation of medical therapies post-PEA, and an mPAP ≥38 mmHg and PVR ≥5 WU with worse long-term survival.⁸⁰⁶

Some patients with CTEPH may have mixed anatomical lesions, with surgically accessible lesions in one lung and inoperable lesions in the other lung. Such patients might benefit from a combined approach with BPA (prior to or at the same time as surgery) and PEA to decrease the surgical risk and improve the final result.⁸⁰⁷

The recommendations on BPA and medical therapy in patients with inoperable CTEPH have been established based on key narrative question 8 (Supplementary Data, Section 10.1).

The recommendation on the use of medical therapy before interventional therapy in patients with CTEPH who are considered inoperable but candidates for BPA is based on PICO question IV (Supplementary Data, Section 10.2). The included evidence suggests that pre-treatment improves pulmonary haemodynamics and safety of the procedure. This is confirmed by the clinical experience of Task Force members. However, due to the low certainty of the evidence, the recommendation is conditional.

10.2.5. Follow-up

Regardless of the result of PEA/BPA, patients should be regularly followed-up, including invasive assessment with RHC 3–6 months after intervention, allowing for consideration of a multimodal treatment approach. After successful treatment, yearly non-invasive follow-up, including echocardiography and an evaluation of exercise capacity, is indicated because recurrent PH has been described (Figure 14).⁸⁰⁶

Risk assessment with either the ESC/ERS or REVEAL risk score developed for PAH has been validated in medically treated patients with CTEPH,^300,808,809 but it is unknown if its use has any therapeutic implication or affects outcome.

There are no data or consensus on what is the therapeutic target after PEA/BPA or medical therapy in CTEPH. Most experts accept achieving a good functional class (WHO-FC I–II) and/or normalization or near normalization of haemodynamics at rest, obtained at RHC 3–6 months post-procedure (PEA or last BPA), and improvement in quality of life.

10.3. Chronic thrombo-embolic pulmonary hypertension team and experience criteria

To optimize patients’ outcomes, CTEPH centres should fulfil criteria for a PH centre (Section 12) and have a CTEPH multidisciplinary team consisting of a PEA surgeon, BPA interventionist, PH specialist, and thoracic radiologist, trained in high-volume PEA and/or BPA centres. The team should meet regularly to review new referrals and post-treatment follow-up cases. Ideally, CTEPH centres should have PEA activities (>50/year)⁸¹⁰ and BPAs (>30 patients/year or >100 procedures/year),⁷⁸¹ as these figures have been associated with better outcome. The CTEPH centres should also manage medically treated patients. Based on regional requirements, these numbers may be adjusted for the country’s population, ideally concentrating care and expertise in high-volume centres.

Recommendation Table 24B

11. Pulmonary hypertension with unclear and/or multifactorial mechanisms (group 5)

Pulmonary hypertension with unclear and/or multifactorial mechanisms (Table 24) includes several conditions that may be complicated by complex and sometimes overlapping pulmonary vascular involvement. Although group 5 PH represents less-studied forms of PH, it constitutes a significant part of the worldwide burden of PH.¹ Group 5 PH includes: haematological disorders, such as SCD and chronic myeloproliferative neoplasms; systemic disorders, such as sarcoidosis; metabolic diseases, such as glycogen storage disease; and others, such as chronic renal failure, pulmonary tumour thrombotic microangiopathy, and fibrosing mediastinitis. A common feature of these diseases is that the mechanisms of PH are poorly understood and contributing factors may include, alone or in combination: hypoxic pulmonary vasoconstriction, pulmonary vascular remodelling, thrombosis, fibrotic destruction and/or extrinsic compression of pulmonary vasculature, pulmonary vasculitis, high-output cardiac failure, and left HF. These patients need careful assessment and treatment should be directed to the underlying condition.

11.1. Haematological disorders

In haemoglobinopathies and chronic haemolytic anaemias, including SCD, PH has emerged as a major cause of morbidity and mortality. The prevalence of PH confirmed by RHC was 6–10% in studies of adult patients with stable SCD.^93,94,813 Patients with SCD with pre-capillary PH are more commonly homozygous for haemoglobin S, while some have S-β0 thalassaemia (S-β0 thal) or haemoglobin SCD.⁸¹⁴ Thrombotic lesions are a major component of PH related to SCD, more frequently in haemoglobin SCD.⁸¹⁴ Patients with PH and SCD should be followed by multidisciplinary SCD and PH teams, since treatment of the anaemia is a key part of management.⁸¹⁴ There is a lack of data to support the use of PAH drugs in patients with SCD-associated PH. In a study in patients with SCD with TRV ≥2.7 m/s and a 6MWD of 150–500 m, sildenafil showed no treatment effect on 6MWD, TRV, or NT-proBNP, but appeared to increase hospitalization rates for pain.⁸¹⁵ Preliminary evidence supports the short- and long-term benefits of chronic blood-exchange transfusions in patients with pre-capillary PH complicating SCD.⁸¹⁶ Pre-capillary PH complicating SCD has an important impact on survival, with an overall death rate of 2.0–5.3% in different populations with similar follow-up (26 months and 18 months, respectively).^94,817 In β-thalassaemia, invasive haemodynamic evaluation confirmed pre-capillary PH in 2.1% of cases, while a post-capillary profile was found in 0.3%.⁸¹⁸ Potential treatment strategies are awaiting an enhanced understanding of the pathophysiological mechanisms. In spherocytosis, splenectomy is a risk factor for CTEPH.⁸¹⁹

Multiple causes of PH have been described in patients with chronic myeloproliferative disorders.⁸²⁰ In chronic myelogenous leukaemia, spleen enlargement and anaemia can give rise to hyperkinetic syndrome. Hepatosplenic enlargement can also cause PoPH. Cases of potentially reversible DPAH have been described with dasatinib, bosutinib, and ponatinib. In polycythaemia vera and essential thrombocythaemia, there is an increased risk of venous thrombo-embolic disease and CTEPH; moreover, a blood clot within the hepatic veins can lead to Budd–Chiari syndrome and subsequent PoPH. Pulmonary extramedullary haematopoiesis complicating idiopathic or secondary myelofibrosis may also contribute to dyspnoea and PH.

Group 5 PH may be described in other haematological disorders, such as common variable immunodeficiency; immunoglobulin G4 (IgG4)-related disease; Castleman disease; and polyneuropathy, organomegaly, endocrinopathy, monoclonal immunoglobulin, skin changes (POEMS) syndrome.^821–823

11.2. Systemic disorders

The reported prevalence of PH in patients with sarcoidosis is 6–20%.⁸²⁴ The causes are multifactorial, including fibrosing lung disease, granulomata in the PAs and/or pulmonary veins, fibrosing mediastinitis and/or extrinsic compression by lymph nodes, pulmonary vasculitis, CTEPH, and PoPH.^58,825 It is associated with significant morbidity and increased mortality compared with sarcoidosis without PH.^58,825 In a registry, factors independently associated with outcomes included physiological (forced expiratory volume in 1 s/FVC ratio and DLCO) and functional (6MWD) parameters.⁵⁸ In a large study of severe, sarcoidosis-associated PH, PAH drugs improved short-term pulmonary haemodynamics without improving 6MWD.⁵⁹ Small RCTs have suggested efficacy of PAH drugs in these patients, which requires confirmation in larger studies.⁸²⁶ Corticosteroids or immunosuppressive therapy may improve haemodynamics in selected patients with active granulomatous disease. Of note, when pulmonary vascular compression is suspected (fibrosing mediastinitis and/or extrinsic compression by lymph nodes), results from pulmonary angiography and PET scans provide additional information justifying endovascular and/or anti-inflammatory approaches. Long-term survival remains poor in sarcoidosis-associated PH, which makes LTx a reasonable option for selected severe cases.

In pulmonary Langerhans’s cell histiocytosis, diminished exercise capacity does not appear to be due to ventilatory limitation but may be related to pulmonary vascular dysfunction. In 29 patients with PH associated with pulmonary Langerhans’s cell histiocytosis, PAH drugs improved haemodynamics without worsening oxygen levels.⁸²⁷

Pulmonary hypertension associated with neurofibromatosis type 1 is a rare but severe complication characterized by female predominance (female/male ratio 3.9:1).⁸²⁸ Specific pulmonary vascular involvement exists in these patients, and despite a potential short-term benefit of PAH drugs, prognosis remains poor, and LTx should be considered in selected patients with severe disease. In the presence of dyspnoea, screening for ILD by non-contrast CT and for PH by echocardiography is required.⁸²⁸

11.3. Metabolic disorders

Glycogen storage diseases are caused by genetic alterations of glycogen metabolism, and PH case reports have been related to glycogen storage disease type 1 and 2.⁸²⁹ The occurrence of PH has predominantly been described in glycogen storage disease type 1, where it may partly be due to vasoconstrictive amines such as serotonin. Drugs for PAH have been used in some cases.⁸³⁰

Untreated patients with Gaucher disease may develop PH, which is caused by a combination of factors, including asplenia, plugging of the vasculature by abnormal macrophages, and pulmonary vascular remodelling. Treatment with enzyme-replacement therapy may improve PH.

11.4. Chronic kidney failure

Although commonly recognized in chronic renal failure, the pathogenesis of PH remains poorly understood and PH is observed in patients prior to and while receiving different dialysis modalities.⁸³¹ A recent RHC study of 3504 patients with chronic kidney disease found that CpcPH was the most common phenotype, and the phenotype with the highest mortality.⁸³² Post-capillary PH has been described in 65% of patients receiving haemodialysis and 71% of patients without kidney replacement.⁸³³

11.5. Pulmonary tumour thrombotic microangiopathy

Pulmonary tumour thrombotic microangiopathy describes tumour-cell microemboli with occlusive fibrointimal remodelling in small PAs, pulmonary veins, and lymphatics. It is a rare cause of PH, which arises due to multiple mechanisms, but probably remains under-diagnosed, as evidenced by autopsy findings.⁸³⁴ The disorder is associated with carcinomas, notably gastric carcinoma. Progressive vessel occlusion ultimately results in PH, which is often severe, of sudden onset, rapidly progressive, and accompanied by progressive hypoxaemia. Chest CT may show patchy ground-glass and septal markings (masquerading as PVOD).

11.6. Fibrosing mediastinitis

Fibrosing mediastinitis is caused by fibrous tissue proliferating in the mediastinum, encasing mediastinal viscera and compressing mediastinal bronchovascular structures.⁸³⁵ Pre- or post-capillary PH can complicate the course of fibrosing mediastinitis due to extrinsic compression of the PAs and/or pulmonary veins. Fibrosing mediastinitis can be idiopathic or caused by irradiation, infection (tuberculosis, histoplasmosis), and systemic diseases, such as sarcoidosis and IgG4-related disease, a fibroinflammatory disease characterized by elevated serum IgG4 levels with infiltration of IgG4+ plasma cells and severe fibrosis in affected tissues.⁸²¹ Treatment should be directed to the underlying condition. No clear clinical improvement has been described with PAH drugs. Surgical and endovascular procedures have been proposed to de-obstruct or bypass the arterial and/or venous compressions.

In the absence of positive RCTs studying the use of PAH drugs for treating group 5 PH, treating the underlying disorder remains the standard of care.⁸³⁶ Importantly, some of the diseases described in Table 24 may have a pulmonary venous component that could be made worse with PAH drugs, implying that off-label use of drugs approved for PAH should be considered with great caution, if at all. Placebo-controlled, randomized trials are currently recruiting in well-phenotyped subgroups of PH with unclear and/or multifactorial mechanisms, such as sarcoidosis-associated PH.

12. Definition of a pulmonary hypertension centre

While PH is not an uncommon condition, severe forms of PH, especially PAH and CTEPH, require highly specialized management. Since medical centres with multidisciplinary teams and a high volume of patients generally offer best standard of care, which translates into better clinical outcomes, establishing PH centres is clinically and economically highly desirable and is supported by patient organizations and scientific societies. The purpose of a PH centre is to: receive new referrals; assess and investigate the cause of PH; carefully phenotype and routinely manage patients with medical, interventional, and surgical approaches; work closely with other health care providers to achieve the best outcomes for patients; undertake audits (reporting patient case mix and quality indicators); and be involved in clinical and translational research, and education. The requirements—comprising definition, multidisciplinary structure, number of cases, procedures, and staffing levels, as well as the skills and resources needed in a PH referral centre—are described below and in Figure 16. Criteria for paediatric and CTEPH centres are described elsewhere (Sections 7.8.3 and 10.3, respectively).

12.1. Facilities and skills required for a pulmonary hypertension centre

Pulmonary hypertension centres care for a sufficient number of patients on PH therapy, as well as new referrals, to warrant this status. According to the 2015 ESC/ERS Guidelines for the diagnosis and treatment of PH and the European Reference Network on rare respiratory diseases (ERN-LUNG) competency requirements, the ideal number of patients seen by an adult centre each year is no fewer than 200, of which at least half have a final diagnosis of PAH; a PH centre follows at least 50 patients with PAH or CTEPH and receives at least two new referrals per month with documented PAH or CTEPH.^{25,26,837–839} These numbers can be adapted according to specific country characteristics (small population, large geographical area) provided that strong working collaborations are established with high-volume centres. This is currently facilitated by the availability of secure virtual platforms (e.g. ERN clinical patient management system).⁸⁴⁰

Proper training of staff members includes core competencies, such as those outlined in the ERS Pulmonary Vascular Diseases Continuing Professional Development framework,⁸⁴¹ and builds on entrustable professional activities, described in the ESC Core Curriculum.⁸⁴²

Clinical, laboratory, and imaging facilities include: a ward where health care providers have expertise in PH; a specialist outpatient service; an intermediate/ICU; 24/7 emergency care; an interventional radiology unit; diagnostic investigations, including echocardiography, CT scanning, nuclear medicine, MRI, exercise tests, and PFTs; a cardiac catheterization laboratory; access to genetic counselling and testing; and fast and easy access to cardiothoracic and vascular surgery. Key diagnostic procedures are performed in sufficient numbers to guarantee expertise (e.g. ERN-LUNG requirements).⁸³⁷ In analogy with the ‘advanced heart failure units’,⁸⁴³ PH centres offer the full range of PAH therapies available in their country (including i.v./s.c. prostacyclin derivatives) and have early referral protocols to CTEPH, LTx, and rehabilitation centres. Since evaluation and early availability of new drugs and techniques are critical, PH centres participate in collaborative clinical research.

Regular multidisciplinary team meetings, including core members and on-demand invited members (extended multidisciplinary team) as needed (Figure 16), are required to establish and adapt individual patient care pathways. Case management (co-ordination of individual patient pathways) should include administrative, social, and care support. Remote accessibility of the PH centre by phone, mail, or other is a vital part of the care. Strategies have to be implemented in order to improve health literacy and shared decision-making, with the support of dedicated patient decision tools. Transitioning from a paediatric PH centre to an adult PH centre requires adequate planning to prevent gaps in care. Involving national and/or international patient associations helps to design patient-centric care and to spread medical knowledge among patients and their carers.

Pulmonary hypertension centres should record patients’ data using local, national, or international patient registries, and be able to report process indicators (compliance with diagnostic and treatment guidelines, including LTx) and outcome indicators, such as WHO-FC, exercise capacity, haemodynamics, quality of life, complications, and survival. They should undergo regular audits to assess the quality of delivered care.

12.2. European Reference Network

In 2017, the European Commission launched European Reference Networks (ERNs) for rare diseases that included the ERN-LUNG with a PH core network. European Reference Networks are patient-centred networks of commissioned centres offering guidance and cross-border best standard of care in the European Union. The PH network includes over 20 full members, contributing each year ∼1500 new patients with PAH or CTEPH.⁸⁴⁴ It also includes UK supporting centres, and affiliated partners (who do not necessarily have to fulfil the minimum competency criteria of the ERN-LUNG PH network). The ERN-LUNG requires and monitors standards for these centres.

12.3. Patient associations and patient empowerment

Pulmonary hypertension centres should inform patients about patient associations and encourage them to join such groups. Patient associations are a valuable resource for managing patients, as they provide educational and emotional support, and can have positive effects on coping, confidence, and outlook.⁸⁴⁵ It is recommended that PH centres collaborate with patient associations on initiatives to empower patients and improve the patient experience, addressing issues such as health literacy, digital skills, healthy lifestyles, mental health, and self-management. Health care can be delivered more effectively and efficiently if patients are full partners in the process.

13. Key messages

1. The haemodynamic definition of PH has been updated as mPAP >20 mmHg. The definition of PAH also implies a PVR >2 WU and PAWP ≤15 mmHg. These cut-off values better reflect the limits of normal ranges, but do not yet translate into new therapeutic recommendations, since the efficacy of PAH therapy in patients with PVD and an mPAP 21–24 mmHg and/or PVR 2–3 WU is still unknown.

2. The main diagnostic algorithm for PH has been simplified following a three-step approach, from suspicion by first-line physicians, detection by echocardiography, and confirmation with RHC in PH centres. Warning signs associated with worse outcomes have been identified, which justify immediate referral and management in PH centres.

3. Screening strategies for PAH in patients with SSc and in those at risk of HPAH are proposed based on the results of published cohort studies. Their implementation may shorten the time from symptom onset to diagnosis of PAH.

4. An improved recognition of CT and echocardiographic signs of CTEPH at the time of an acute PE event, together with a systematic follow-up of patients with acute PE, as indicated in the 2019 ESC/ERS Guidelines for the diagnosis and management of acute pulmonary embolism, should help to remediate the underdiagnosis of CTEPH.

5. The three-strata risk-stratification assessment in PAH has been refined after being validated in multiple registries. The MRI and echocardiographic criteria have been added to the ESC/ERS table, refining non-invasive evaluation at diagnosis.

6. A four-strata risk stratification, dividing the large, intermediate-risk group into intermediate–low and intermediate–high risk, is proposed at follow-up.

7. The treatment algorithm for PAH has been simplified, with a clear focus on risk assessment, cardiopulmonary comorbidities, and treatment goals. Initial combination therapy and treatment escalation at follow-up when appropriate are current standards.

8. The Task Force has attempted to close the gap between paediatric and adult PAH care, with therapeutic and follow-up strategies based on risk stratification and treatment response, extrapolated from that in adults but adapted for age.

9. The recommendations on sex-related issues in patients with PAH, including pregnancy, have been updated, with information and shared decision-making as key points.

10. The recommendations for rehabilitation and exercise programmes in PH have been updated following the release of additional supportive evidence.

11. For the first time, there is a recommendation for PH medical therapy in group 3 PH, based on a single positive RCT in patients with ILD.

12. The concept of CTEPD with or without PH has been introduced, enabling further research on the natural history and management in the absence of PH.

13. The treatment algorithm for CTEPH has been modified, including multimodal therapy with surgery, PH drugs, and BPA.

14. Gaps in evidence

14.1. Pulmonary arterial hypertension (group 1)

• The efficacy and safety of PAH drugs in group 1 patients with an mPAP 21–24 mmHg, PVR 2–3 WU, and exercise PH has to be established.

• The role of PAH drugs in different PAH subgroups, including schistosomiasis-associated PAH, needs to be explored.

• Risk-stratification assessment in PAH needs to be further prospectively validated through goal-orientated outcome studies, and optimized for patients with PAH and comorbidities.

• New PAH phenotypes observed in patients with significant cardiopulmonary comorbidities are common and should be the focus of more research.

• The importance of PAH patient phenotypes and the relevance of comorbidities on treatment goals and outcomes must be further evaluated.

• The impact of PAH therapies and treatment strategies on survival needs to be further assessed.

• Pulmonary arterial hypertension drugs targeting novel pathways are emerging and the impact of add-on use of this medication on outcomes has to be evaluated in RCTs.

• The role of RV imaging techniques (echocardiography, cMRI) in diagnosing and stratifying risk in PAH needs to be further studied. The proposed cut-off values for risk stratification need to be properly validated in multicentre studies.

• The role of CPET in the early diagnosis of PAH in populations at risk of developing PAH, and in assessing prognosis in PAH on top of clinical and haemodynamic data, needs further investigation.

• The role of exercise echocardiography and exercise RHC in patients at risk of developing PAH, with abnormal CPET but normal rest echocardiogram, also needs further evaluation.

• The use of mechanical circulatory support, particularly in reversible PH or in patients with advanced right HF with an exit strategy (such as LTx), has to be further studied.

• Differences in natural history and treatment response between adults and children should be further investigated.

• Further studies are needed on the effects of PADN in PAH and in other PH groups.

• The impact of centre volume, organization, and expertise on treatment outcome needs further investigation.

14.2. Pulmonary hypertension associated with left heart disease (group 2)

• The management of patients with group 2 PH needs further study with RCTs.

• Additional research is needed to facilitate non-invasive diagnosis of HFpEF-associated PH and distinguishing it from PAH.

• The role of fluid challenge and exercise testing to reveal left HF needs further validation.

• Further studies focusing on PDE5is in patients with HFpEF and a CpcPH phenotype are needed and currently underway.

• The effects that new HF medication (ARNIs, SGLT-2is) has on PH, through reverse remodelling of the LV, need further investigation.

14.3. Pulmonary hypertension associated with lung diseases and/or hypoxia (group 3)

• The management of patients with group 3 PH has to be further studied in RCTs.

• Refining phenotypes will be crucial, as this will inform development of trials.

• Clinical relevance and therapeutic implications of severe PH in lung disease need to be investigated.

• Long-term data on the effects of inhaled treprostinil (and other PAH drugs) in patients with PH associated with lung disease are needed.

• The impact of the hypobaric and hypoxic environment of the >150 million people living at >2500 m altitude has to be clarified, and studies need to be performed to assess potential treatment strategies for PH.

14.4. Chronic thrombo-embolic pulmonary hypertension (group 4)

• The differentiation between acute and chronic PE in imaging (CTPA) has to be improved.

• In patients with suspected CTEPH, the diagnostic role of DECT or iodine subtraction mapping vs. V/Q lung scintigraphy has to be validated.

• The effect of drug therapy on the outcome of patients with CTEPH needs to be established.

• The treatment goals in patients with CTEPH have to be clarified, as it is still unclear if normalizing mPAP and PVR translates into improved outcomes.

• The role of BPA vs. PEA should be further clarified: which treatment in which patient? Are they equivalent for the treatment of segmental/subsegmental disease?

• In inoperable CTEPH or persistent/recurrent PH after PEA, the potential role of combination therapy of PH drugs must be assessed.

• The role of medical treatments as bridges to interventional and operative treatments needs to be formally tested.

• Randomized controlled trials are needed to discriminate the effects of PEA and early follow-up rehabilitation.

• The effect of PEA, BPA, and medical therapy on patients with CTEPD without PH is not established.

14.5. Pulmonary hypertension with unclear and/or multifactorial mechanisms (group 5)

• Further research needs to inform management of group 5 PH, such as SCD-associated PH and sarcoidosis-associated PH.

15. ‘What to do’ and ‘What not to do’ messages from the Guidelines

16. Quality indicators

Quality indicators (QIs) are tools that may be used to evaluate care quality, including structural, process, and outcomes of care.⁸⁴⁷ They may also serve as a mechanism for enhancing adherence to guideline recommendations through associated quality-improvement initiatives and benchmarking of care providers.^848,849 As such, the role of QIs in improving care and outcomes for cardiovascular disease is increasingly being recognized by health care authorities, professional organizations, payers, and the public.⁸⁴⁷

The ESC understands the need for measuring and reporting quality and outcomes of cardiovascular care, and has established methods for developing the ESC QIs for the quantification of care and outcomes for cardiovascular diseases.⁸⁴⁷ To date, the ESC has developed QI suites for a number of cardiovascular diseases^850–852 and embedded these in respective ESC Clinical Practice guidelines.^{27,477,853,854} Furthermore, the ESC aims to integrate its QIs with clinical registries such as the EurObservational Research Programme and the European Unified Registries On Heart Care Evaluation and Randomized Trials (EuroHeart) project⁸⁵⁵ to provide real-world data about the patterns and outcomes of care for cardiovascular disease across Europe.

In parallel with the writing of this Clinical Practice Guideline, a process has been initiated to develop QIs for patients with PH using the ESC methodology and through collaboration with domain experts and the Heart Failure Association of the ESC. Such QIs may be used for evaluating the quality of care for patients with PH, and enable important aspects of care delivery to be captured. These QIs, alongside their specifications and development process, will be published separately.

17. Supplementary data

Supplementary data is available at European Heart Journal online including key narrative question (1-8) and PICO questions (I-IV).

18. Data availability statement

No new data were generated or analysed in support of this research.

19. Author information

Author/Task Force Member Affiliations: Marc Humbert*, Faculty of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France, Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France, INSERM UMR_S 999, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France; Gabor Kovacs, University Clinic of Internal Medicine, Division of Pulmonology, Medical University of Graz, Graz, Austria, Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Marius M. Hoeper, Respiratory Medicine, Hannover Medical School, Hanover, Germany, Biomedical Research in End-stage and Obstructive Lung Disease (BREATH), member of the German Centre of Lung Research (DZL), Hanover, Germany; Roberto Badagliacca, Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Roma, Italy, Dipartimento Cardio-Toraco-Vascolare e Chirurgia dei Trapianti d’Organo, Policlinico Umberto I, Roma, Italy; Rolf M.F. Berger, Center for Congenital Heart Diseases, Beatrix Children’s Hospital, Dept of Paediatric Cardiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; Margarita Brida, Department of Sports and Rehabilitation Medicine, Medical Faculty University of Rijeka, Rijeka, Croatia, Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton & Harefield Hospitals, Guys & St Thomas’s NHS Trust, London, United Kingdom; Jørn Carlsen, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, Department of Clinical Medicine; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Andrew J.S. Coats, Faculty of Medicine, University of Warwick, Coventry, United Kingdom, Faculty of Medicine, Monash University Melbourne, Australia; Pilar Escribano-Subias, Pulmonary Hypertension Unit, Cardiology Department, Hospital Universitario 12 de Octubre, Madrid, Spain, CIBER-CV (Centro de Investigaciones Biomédicas En Red de enfermedades CardioVasculares), Instituto de Salud Carlos III, Madrid, Spain, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Pisana Ferrari (Italy), ESC Patient Forum, Sophia Antipolis, France, AIPI, Associazione Italiana Ipertensione Polmonare, Bologna, Italy; Diogenes S. Ferreira, Alergia e Imunologia, Hospital de Clinicas, Universidade Federal do Parana, Curitiba, Brazil; Hossein Ardeschir Ghofrani, Department of Internal Medicine, University Hospital Giessen, Justus-Liebig University, Giessen, Germany, Department of Pneumology, Kerckhoff Klinik, Bad Nauheim, Germany, Department of Medicine, Imperial College London, London, United Kingdom; George Giannakoulas, Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece; David G. Kiely, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom, Sheffield Pulmonary Vascular Disease Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom, Insigneo Institute, University of Sheffield, Sheffield, United Kingdom; Eckhard Mayer, Thoracic Surgery, Kerckhoff Clinic, Bad Nauheim, Germany; Gergely Meszaros (Hungary), ESC Patient Forum, Sophia Antipolis, France, European Lung Foundation (ELF), Sheffield, United Kingdom; Blin Nagavci, Institute for Evidence in Medicine, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; Karen M. Olsson, Clinic of Respiratory Medicine, Hannover Medical School, member of the German Center of Lung Research (DZL), Hannover, Germany; Joanna Pepke-Zaba, Pulmonary Vascular Diseases Unit, Royal Papworth Hospital, Cambridge, United Kingdom; Jennifer K. Quint, NHLI, Imperial College London, London, United Kingdom; Göran Rådegran, Department of Cardiology, Clinical Sciences Lund, Faculty of Medicine, Lund, Sweden, The Haemodynamic Lab, The Section for Heart Failure and Valvular Disease, VO. Heart and Lung Medicine, Skåne University Hospital, Lund, Sweden; Gerald Simonneau, Faculté Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France, Centre de Référence de l’Hypertension Pulmonaire, Hopital Marie-Lannelongue, Le Plessis-Robinson, France; Olivier Sitbon, Faculty of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France, Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France, INSERM UMR_S 999, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France; Thomy Tonia, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Mark Toshner, Heart Lung Research Institute, Dept of Medicine, University of Cambridge, Cambridge, United Kingdom, Royal Papworth NHS Trust; Jean-Luc Vachiery, Department of Cardiology, Pulmonary Vascular Diseases and Heart Failure Clinic, HUB Hôpital Erasme, Brussels, Belgium; and Anton Vonk Noordegraaf, Pulmonology, Amsterdam UMC, Amsterdam, Netherlands.

* Marc Humbert is supported by the Investissement d’Avenir programme managed by the French National Research Agency under the grant contract ANR-18-RHUS-0006 (DESTINATION 2024).

20. Appendix

ESC/ERS Scientific Document Group

Includes Document Reviewers and ESC National Cardiac Societies.

Document Reviewers: Markus Schwerzmann (ESC Review Coordinator) (Switzerland), Anh-Tuan Dinh-Xuan (ERS Review Coordinator) (France), Andy Bush (United Kingdom), Magdy Abdelhamid (Egypt), Victor Aboyans (France), Eloisa Arbustini (Italy), Riccardo Asteggiano (Italy), Joan-Albert Barberà (Spain), Maurice Beghetti (Switzerland), Jelena Čelutkienė (Lithuania), Maja Cikes (Croatia), Robin Condliffe (United Kingdom), Frances de Man (Netherlands), Volkmar Falk (Germany), Laurent Fauchier (France), Sean Gaine (Ireland), Nazzareno Galié (Italy), Wendy Gin-Sing (United Kingdom), John Granton (Canada), Ekkehard Grünig (Germany), Paul M. Hassoun (United States of America), Merel Hellemons (Netherlands), Tiny Jaarsma (Sweden), Barbro Kjellström (Sweden), Frederikus A. Klok (Netherlands), Aleksandra Konradi (Russian Federation), Konstantinos C. Koskinas (Switzerland), Dipak Kotecha (United Kingdom), Irene Lang (Austria), Basil S. Lewis (Israel), Ales Linhart (Czech Republic), Gregory Y.H. Lip (United Kingdom), Maja-Lisa Løchen (Norway), Alexander G. Mathioudakis (United Kingdom), Richard Mindham (United Kingdom), Shahin Moledina (United Kingdom), Robert Naeije (Belgium), Jens Cosedis Nielsen (Denmark), Horst Olschewski (Austria), Isabelle Opitz (Switzerland), Steffen E. Petersen (United Kingdom), Eva Prescott (Denmark), Amina Rakisheva (Kazakhstan), Abilio Reis (Portugal), Arsen D. Ristić (Serbia), Nicolas Roche (France), Rita Rodrigues (Portugal), Christine Selton-Suty (France), Rogerio Souza (Brazil), Andrew J. Swift (United Kingdom), Rhian M. Touyz (Canada/United Kingdom), Silvia Ulrich (Switzerland), Martin R. Wilkins (United Kingdom), and Stephen John Wort (United Kingdom).

ESC National Cardiac Societies actively involved in the review process of the 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: Algeria: Algerian Society of Cardiology, Messaad Krim; Armenia: Armenian Cardiologists Association, Hamlet Hayrapetyan; Austria: Austrian Society of Cardiology, Irene Lang; Azerbaijan: Azerbaijan Society of Cardiology, Oktay Musayev; Belarus: Belorussian Scientific Society of Cardiologists, Irina Lazareva; Bosnia and Herzegovina: Association of Cardiologists of Bosnia and Herzegovina, Šekib Sokolović; Bulgaria: Bulgarian Society of Cardiology, Vasil Velchev; Croatia: Croatian Cardiac Society, Maja Cikes; Cyprus: Cyprus Society of Cardiology, Ioannis Michaloliakos; Czechia: Czech Society of Cardiology, Pavel Jansa; Denmark: Danish Society of Cardiology, Søren Mellemkjær; Egypt: Egyptian Society of Cardiology, Ahmed Hassan; Estonia: Estonian Society of Cardiology, Ly Anton; Finland: Finnish Cardiac Society, Markku Pentikäinen; France: French Society of Cardiology, Nicolas Meneveau; Georgia: Georgian Society of Cardiology, Mikheil Tsverava; Germany: German Cardiac Society, Mareike Lankeit; Greece: Hellenic Society of Cardiology, Athanasios Manginas; Hungary: Hungarian Society of Cardiology, Istvan Hizoh; Ireland: Irish Cardiac Society, Vincent Maher; Israel: Israel Heart Society, Rafael Hirsch; Italy: Italian Federation of Cardiology, Nazzareno Galié; Kazakhstan: Association of Cardiologists of Kazakhstan, Murat A. Mukarov; Kosovo (Republic of): Kosovo Society of Cardiology, Pranvera Ibrahimi; Kyrgyzstan: Kyrgyz Society of Cardiology, Sooronbaev Talant, Latvia: Latvian Society of Cardiology, Ainars Rudzitis; Lebanon: Lebanese Society of Cardiology, Ghassan Kiwan; Lithuania: Lithuanian Society of Cardiology, Lina Gumbienė; Luxembourg: Luxembourg Society of Cardiology, Andrei Codreanu; Malta: Maltese Cardiac Society, Josef Micallef; Moldova (Republic of): Moldavian Society of Cardiology, Eleonora Vataman; Montenegro: Montenegro Society of Cardiology, Nebojsa Bulatovic; Morocco: Moroccan Society of Cardiology, Said Chraibi; Netherlands: Netherlands Society of Cardiology, Marco C. Post; North Macedonia: North Macedonian Society of Cardiology, Elizabeta Srbinovska Kostovska; Norway: Norwegian Society of Cardiology, Arne Kristian Andreassen; Poland: Polish Cardiac Society, Marcin Kurzyna; Portugal: Portuguese Society of Cardiology, Rui Plácido; Romania: Romanian Society of Cardiology, Ioan Mircea Coman; Russian Federation: Russian Society of Cardiology, Oksana Vasiltseva; San Marino: San Marino Society of Cardiology, Marco Zavatta; Serbia: Cardiology Society of Serbia, Arsen D. Ristić; Slovakia: Slovak Society of Cardiology, Iveta Šimkova; Slovenia: Slovenian Society of Cardiology, Gregor Poglajen; Spain: Spanish Society of Cardiology, María Lázaro Salvador; Sweden: Swedish Society of Cardiology, Stefan Söderberg; Switzerland: Swiss Society of Cardiology, Silvia Ulrich; Syrian Arab Republic: Syrian Cardiovascular Association, Mhd Yassin Bani Marjeh; Tunisia: Tunisian Society of Cardiology and Cardio-Vascular Surgery, Fatma Ouarda; Turkey: Turkish Society of Cardiology, Bulent Mutlu; Ukraine: Ukrainian Association of Cardiology, Yuriy Sirenko; United Kingdom of Great Britain and Northern Ireland: British Cardiovascular Society, J. Gerry Coghlan; and Uzbekistan: Association of Cardiologists of Uzbekistan, Timur Abdullaev.

ESC Clinical Practice Guidelines (CPG) Committee: Colin Baigent (Chairperson) (United Kingdom), Magdy Abdelhamid (Egypt), Victor Aboyans (France), Sotiris Antoniou (United Kingdom), Elena Arbelo (Spain), Riccardo Asteggiano (Italy), Andreas Baumbach (United Kingdom), Michael A. Borger (Germany), Jelena Čelutkienė (Lithuania), Maja Cikes (Croatia), Jean-Philippe Collet (France), Volkmar Falk (Germany), Laurent Fauchier (France), Chris P. Gale (United Kingdom), Sigrun Halvorsen (Norway), Bernard Iung (France), Tiny Jaarsma (Sweden), Aleksandra Konradi (Russian Federation), Konstantinos C. Koskinas (Switzerland), Dipak Kotecha (United Kingdom), Ulf Landmesser (Germany), Basil S. Lewis (Israel), Ales Linhart (Czech Republic), Maja-Lisa Løchen (Norway), Richard Mindham (United Kingdom), Jens Cosedis Nielsen (Denmark), Steffen E. Petersen (United Kingdom), Eva Prescott (Denmark), Amina Rakisheva (Kazakhstan), Marta Sitges (Spain), and Rhian M. Touyz (Canada/ United Kingdom).

Independent Research Methodologists: Rebecca L. Morgan (United States of America) and Kapeena Sivakumaran (Canada).

21. References

Author notes