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Diagnosis and management of pulmonary arterial hypertension

Sarah Cullivan, Margaret Higgins, Sean Gaine
Breathe 2022 18: 220168; DOI: 10.1183/20734735.0168-2022
Sarah Cullivan
National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland
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  • For correspondence: sarah.cullivan@ucdconnect.ie
Margaret Higgins
National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland
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Sean Gaine
National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland
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    FIGURE 1

    Transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling pathways in pulmonary arterial hypertension (PAH). In the extracellular space, ligands such as such as BMP9 or BMP10 bind to BMP receptor 2 (BMPR2). This forms a heteromeric complex with ALK1 (activin receptor-like kinase 1 or ACVRL1) and associates with the co-receptor endoglin, to trigger a cascade of intracellular events, including the phosphorylation of receptor-regulated SMADs (small mothers against decapentaplegic), SMADs 1, 5 and 8 proteins. These proteins form a complex with the common mediator SMAD, named SMAD4, and translocate to the nucleus to modulate gene transcription. This pathway is disrupted in PAH, with resultant increased signalling via the TGFβR2/ALK-5/SMAD2 and SMAD3 pathway, and subsequent pro-proliferative signalling. This figure was created with BioRender.com.

Tables

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  • TABLE 1

    An overview of the clinical classification of pulmonary hypertension (PH), with associated conditions and important investigations to consider

    Group 1 Pulmonary arterial hypertension (PAH)
     1.1 Idiopathic PAH
      1.1.1 Non-responders at vasoreactivity testingImportant to exclude alternative causes of PAH before assigning this diagnosis
      1.1.2 Acute responders at vasoreactivity testingDiagnosed during vasoreactivity testing at RHC:
    • mPAP reduction of ≥10 mmHg (to <40 mmHg)
    • Cardiac output is increased/maintained
     1.2 Heritable PAHEnquire regarding family history of PAH
    • Offer genetic counselling and consider gene panel
    • e.g. gene mutations in BMPR2, EIF2AK4, TBX4, ACVRL1, ENG [6]
     1.3 Associated with drugs and toxinsEnquire regarding specific drug and toxin exposure at home and at work (e.g. aminorex, fenfluramine, methamphetamines)
     1.4 Associated with:
      1.4.1 Connective tissue disease (CTD)CTDs associated with PAH include SSc-PAH, SLE, mixed CTD, rheumatoid arthritis, dermatomyositis, Sjögren syndrome [3]
    Considerations for subjects with SSc and suspected PAH:
    • Ask regarding symptoms of Raynaud's, GORD, etc.
    • Examine for features such as digital ulcers, sclerodactyly, calcinosis, telangiectasia, microstomia; consider nailfold capillaroscopy
    • Request serum ANA and CTD panel
    • Exclude comorbid LHD, and ILD in suspected SSc-PAH
      1.4.2 HIV infectionAssess for infection with HIV
      1.4.3 Portal hypertensionPortal hypertension with or without cirrhosis is associated with PAH
    Investigate with:
    • Liver screen including autoimmune serology, viral hepatitis screen and HIV
    • Doppler ultrasound of liver and portal system
    • A hepatic venous pressure gradient >5 mmHg during invasive catheterisation (may be normal in subjects with extrahepatic portal hypertension)
      1.4.4 Congenital heart diseaseEisenmenger syndrome; PAH associated with prevalent systemic-to-pulmonary shunts, PAH-with small/coincidental defects, PAH after defect correction [3, 7]
    Consider investigation with:
    • Doppler and contrast echocardiography
    • Cardiac MRI
    • Stepwise assessment of oxygen saturations at RHC if left-to-right shunt suspected
      1.4.5 SchistosomiasisPresent in 5% of patients with hepatosplenic schistosomiasis infection
    Consider investigation with:
    • Confirm infection, e.g. through the detection of parasite eggs in the stool or urine
    • Doppler ultrasound of liver and portal system to assess for portal hypertension
     1.5 PAH with features of venous/capillary (PVOD/PCH) involvementConsider family history, medical history (e.g. prior chemotherapy), occupational exposures (e.g. organic solvents)
    Consider genetic screening for EIF2AK4
    Suspect if:
    • Often accompanied by severe hypoxia and marked reductions in DLCO (<50%)
    • Treatment with PAH specific therapy may be complicated by pulmonary oedema
    • CT thorax: septal lines, centrilobular ground-glass opacities, mediastinal adenopathy
     1.6 Persistent PH of the newbornFailed circulatory adaptation at birth with sustained elevation in PVR; diagnosed in neonates and often resolves
    Group 2 PH associated with left heart disease
    Consider the pre-test probability of LHD and ensure adequate imaging of left heart, such as echocardiography, cardiac MRI. If suspected, consider fluid challenge at RHC [2, 8].
     2.1 Heart failure:
      2.1.1 With preserved ejection fraction
      2.1.2 With reduced or mildly reduced ejection fraction
     2.2 Valvular heart disease
     2.3 Congenital/acquired cardiovascular conditions leading to post-capillary PH
    Group 3 PH associated with lung diseases and/or hypoxia
    Investigate with ABG, PFTs, chest imaging such as high-resolution CT thorax, polysomnography.
     3.1 Obstructive lung disease or emphysema
     3.2 Restrictive lung disease
     3.3 Lung disease with mixed restrictive/obstructive pattern
     3.4 Hypoventilation syndromes
     3.5 Hypoxia without lung disease (e.g. high altitude)
     3.6 Developmental lung disorders
    Group 4 PH associated with pulmonary artery obstructions
    CTPA and Vʹ/Qʹ imaging are important investigations. Consider invasive pulmonary angiogram if Group 4 PH suspected.
     4.1 Chronic thromboembolic PH
     4.2 Other pulmonary artery obstructions
    Group 5 PH with unclear and/or multifactorial mechanisms
    Guided by individual history and assessment.
     5.1 Haematological disorders
     5.2 Systemic disorders
     5.3 Metabolic disorders
     5.4 Chronic renal failure with or without haemodialysis
     5.5 Pulmonary tumour thrombotic microangiopathy
     5.6 Fibrosing mediastinitis

    RHC: right heart catheterisation; mPAP: mean pulmonary artery pressure; BMPR2: bone morphogenetic protein receptor type 2; EIF2AK4: eukaryotic translation initiation factor 2 alpha kinase 4; TBX4: T-box 4; ACVRL1: activin receptor-like kinase 1 (ALK1); ENG: endoglin; SSc: systemic sclerosis; SLE: systemic lupus erythematosus; GORD: gastro-oesophageal reflux disease; ANA: antinuclear antibody; LHD: left heart disease; ILD: interstitial lung disease; MRI: magnetic resonance imaging; PVOD: pulmonary veno-occlusive disease; PCH: pulmonary capillary haemangiomatosis; DLCO: diffusion capacity of the lung for carbon monoxide; CT: computed tomography; PVR: pulmonary vascular resistance; ABG: arterial blood gas; PFTs: pulmonary function tests; CTPA: computed tomography pulmonary angiogram; Vʹ/Qʹ: ventilation/perfusion. Reproduced and modified from [2], with permission.

    • TABLE 2

      Important pulmonary arterial hypertension (PAH) susceptibility genes

      GenesOverviewReferences
      BMPR2Member of the TGF-β receptor superfamily
      Ubiquitously expressed, important for vascular homeostasis
      Autosomal dominant inheritance, with incomplete penetrance (estimated 14% penetrance in male carriers and 42% in female carriers)
      Mutations associated with paediatric and adult PAH
      [22]
      ALK1/ACVRL1Member of the TGF-β receptor superfamily
      Forms a heteromeric complex with BMPR2
      Causes PAH associated with HHT
      Mutations are associated with paediatric and adult PAH
      [24, 25]
      EndoglinMember of the TGF-β receptor superfamily
      Co-receptor to BMPR2/ALK1 receptors
      Causes PAH associated with HHT
      [25]
      SMAD9Important protein in the BMP signalling pathway
      Encodes the transcription factor Smad8
      [25]
      BMP9/GDF2Mediator in the BMP signalling pathway
      Encodes the BMP9 ligand
      [22]
      TBX4Associated with small patella/coxopodopatellar syndrome
      Mutations are associated with paediatric and adult PAH
      Its precise role in the development of PAH is unclear
      [25, 26]
      CAV1Encodes the protein caveolin-1, which is responsible for the integrity of caveolae; these are specialised invaginations in endothelial plasma membranes that are rich in cell surface receptors, including BMPR2 and endothelial nitric oxide synthase
      This is important for vascular homeostasis and is implicated in proliferative, apoptotic signalling
      Mutations in this gene are a rare cause of HPAH
      [22, 25]
      KCNK3Also called TASK-1 (TWIK-related acid-sensitive K+ channel 1)
      This was the first identified channelopathy in PAH
      Encodes a pH-sensitive potassium channel, which is important for the regulation of plasma membrane resting potential
      Reduced function of KCNK3 in PAH may affect vascular tone
      [25]
      EIF2AK4Encodes GCN2 (general control nonderepressible 2) which is a serine-threonine kinase with a role in cellular adaptation to stress and amino acid deprivation
      Mutations are associated with paediatric and adult PAH
      Autosomal recessive inheritance, with near complete penetrance
      Results in pulmonary veno-occlusive disease/PCH
      The exact mechanism by which this leads to pulmonary vascular disease is unclear
      [27]

      An overview of gene mutations in heritable PAH (HPAH). These mutations are inherited in an autosomal dominant fashion, with reduced penetrance, apart from EIF2AK4 (eukaryotic translation initiation factor 2α kinase 4), which is inherited in an autosomal recessive pattern, with suspected near complete penetrance. BMPR2: bone morphogenetic protein receptor 2; TGF-β: transforming growth factor-β; ALK1/ACVRL1: activin A receptor-like type 1; HHT: hereditary haemorrhagic telangiectasia; SMAD: small mothers against decapentaplegic; BMP: bone morphogenetic protein; GDF2: growth and differentiation factor 2; TBX4: T-box 4; CAV1: caveolin-1; KCNK3: potassium channel two-pore domain subfamily K member 3; PCH: pulmonary capillary haemangiomatosis.

      • TABLE 3

        Overview of some of the risk assessment tools for pulmonary arterial hypertension (PAH)

        Risk assessment toolYear of publicationPatients includedPAH subgroupVariables includedSurvival estimation
        ClinicalExerciseLaboratoryImagingHaemodynamic
        NIH equation [37]1991IncidentIPAH####1. mPAP
        2. mRAP
        3. CI
        1-, 3-, 5-year
        PH connection registry [38]2010Incident and prevalentIPAH
        HPAH
        APAH
        ####1. mPAP
        2. mRAP
        3. CI
        1-, 3-, 5-year
        FPHN registry risk equation [39, 40]2010Incident and prevalentIPAH
        HPAH
        APAH
        1. Sex2. 6MWD##3. CO1-, 2-, 3-year
        REVEAL registry [41]2010Incident and prevalentGroup 1 PAH1. Age
        2. Sex
        3. PAH subgroup
        4. Renal insufficiency
        5. FC
        6. SBP
        7. HR
        8. 6MWD9. BNP10. Pericardial effusion
        11. DLCO
        12. PVR
        13. mRAP
        1-year
        Scottish composite score [42]2012IncidentGroup 1 PAH (CHD-PAH and CCB-R excluded)1. Age
        2. Sex
        3. PAH subgroup
        4. 6MWD##5. mRAP
        6. CO
        1-, 2-, 3-year
        Nickel et al. [43]2012IncidentIPAH#
        FC, NT-proBNP, CI, SvO2 at follow-up
        1. 6MWD2. NT-proBNP#3. CI
        4. SvO2
        1-, 3-, 5-year
        ESC/ERS 2015 Guidelines [3]2015#Group 1 PAH1. Progression of symptoms
        2. Syncope
        3. FC
        4. Clinical signs RHF
        5. 6MWD
        6. Peak VʹO2 (CPET)
        7. VʹE/ VʹCO2 slope (CPET)
        8. BNP/NT-proBNP9. RA area
        10. Pericardial effusion
        11. RAP
        12. CI
        13. SvO2
        1-year
        FPHN registry [44]2017IncidentIPAH
        HPAH
        DPAH
        1. FC
        FC, 6MWD, BNP/NT-proBNP at first follow-up
        2. 6MWD##3. mRAP
        4. CI
        1–5 years
        COMPERA registry [45]2017IncidentGroup 1 PAH1. FC2. 6MWD3. BNP/NT-proBNP#4. mRAP
        5. CI
        1–5 years
        SAPHR registry [46]2018IncidentGroup 1 PAH1. FC2. 6MWD3. NT-proBNP4. RA area
        5. Pericardial effusion
        6. mRAP
        7. CI
        8. SvO2
        1-, 3-, 5-years
        Modified Risk Assessment Score of PAH [47]2018Incident and prevalentGroup 1 PAH1. FC2. 6MWD3. BNP4. RA area#1-year
        COMPERA 2.0 [48]2021IncidentGroup 1 PAH1. FC2. 6MWD3. BNP/NT-proBNP##1-, 3-, 5-years
        ESC/ERS 2022 Guidelines [2]2022#Group 1 PAH1. Progression of symptoms
        2. Syncope
        3. FC
        4. Clinical signs RHF
        5. 6MWD
        6. Peak VʹO2 (CPET)
        7. VʹE/ VʹCO2 slope (CPET)
        8. BNP/NT-proBNP9. Echocardiography: RA area
        Pericardial effusion
        TAPSE/PASP
        10. cMRI:
        RVEF
        SVI
        RVESVI
        11. RAP
        12. CI
        13. SvO2
        14. SVI
        1-year

        NIH: National Institutes of Health; PH: pulmonary hypertension; FPHN: French PH Network; REVEAL: US Registry to Evaluate Early and Long-term PAH Disease Management; ESC/ERS: European Society of Cardiology/European Respiratory Society; COMPERA: Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension; SAPHR: Swedish PAH register; IPAH: idiopathic PAH; HPAH: hereditary PAH; APAH: anorexigen-associated PAH; CHD: congenital heart disease; CCB-R: long-term responder to calcium channel blockers; DPAH: drug-associated PAH; FC: functional class; SBP: systolic blood pressure; HR: heart rate; RHF: right heart failure; 6MWD: 6-min walk distance; BNP: B-type natriuretic peptide; NT-proBNP: N-terminal pro-brain natriuretic peptide; DLCO: diffusion capacity of the lung for carbon monoxide; RA area: right atrium area; mPAP: mean pulmonary artery pressure; mRAP: mean right atrial pressure; CI: cardiac index; CO: cardiac output; PVR: pulmonary vascular resistance; SvO2: mixed venous oxygen saturation; TAPSE/PASP: tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure; RVEF: right ventricular ejection fraction; SVI: stroke volume index; RVESVI: right ventricular end-systolic volume index; VʹO2: oxygen uptake; CPET: cardiopulmonary exercise testing; VʹE: minute ventilation. #: absent data.

        • TABLE 4

          An overview of the three major therapeutic pathways in pulmonary arterial hypertension

          Therapeutic pathwaysNitric oxide (NO)Prostacyclin (PGI2)Endothelin 1 (ET1)
          Levels in PAHReducedReducedIncreased
          Aim of therapyTo increase NOTo increase PGI2To reduce ET1
          Current available drugsSildenafilEpoprostenolMacitentan
          TadalafilTreprostinilAmbrisentan
          RiociguatIloprostBosentan
          Selexipag
          Routes of administrationOralOral, parenteral, inhaledOral
          Method of actionTo increase cGMP via the inhibition of PD5 or by direct stimulation of sGCTo increase the conversion of ATP to cAMPTo inhibit ETA receptors ± ETB receptors
          Side-effects
           Common side-effectsSystemic vasodilation resulting in hypotension, flushing, light-headedness, gastrointestinal side-effects (e.g. nausea, diarrhoea)
           Specific drug side-effectsSildenafil and tadalafil: ocular side-effectsParenteral prostacyclin: thrombocytopenia, bone marrow suppressionMacitentan: anaemia Bosentan: deranged transaminases
          Rash

          The aim of therapy is to promote vasodilation in the pulmonary circulation. Within the nitric oxide pathway, sildenafil and tadalafil are phosphodiesterase type-5 (PD5) inhibitors and riociguat is a soluble guanylate cyclase (sGC) stimulator. In the endothelin (ET) pathway, bosentan and macitentan are dual ET receptor antagonists (i.e. they block both ETA and ETB receptors) and ambrisentan is a selective ETA receptor antagonist. Modern therapy typically consists of double or triple combination therapy, using one drug from each therapeutic pathway. Monotherapy is uncommon and should only be considered in patients with low-risk profiles. cGMP: cyclic guanosine monophosphate.

          •   RHCPre nitric oxidePost nitric oxide
              mRAP (mmHg)22
              mPAP (mmHg)3821
              PAWP (mmHg)87
              Cardiac output (L·min−1)4.335.33
              PVR (Wood units)6.922.6
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          Diagnosis and management of pulmonary arterial hypertension
          Sarah Cullivan, Margaret Higgins, Sean Gaine
          Breathe Dec 2022, 18 (4) 220168; DOI: 10.1183/20734735.0168-2022

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          Diagnosis and management of pulmonary arterial hypertension
          Sarah Cullivan, Margaret Higgins, Sean Gaine
          Breathe Dec 2022, 18 (4) 220168; DOI: 10.1183/20734735.0168-2022
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          • Article
            • Abstract
            • Abstract
            • Introduction
            • Epidemiology
            • Pathology
            • Pathobiology
            • Assessment and investigations in PAH
            • Screening in specific populations
            • Risk assessment in PAH
            • Management and treatment
            • Conclusion
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          • Idiopathic pulmonary fibrosis and lung cancer
          • Diagnosis and management of PH related to chronic respiratory disease
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