Figures
- 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
- 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 testing Important to exclude alternative causes of PAH before assigning this diagnosis 1.1.2 Acute responders at vasoreactivity testing Diagnosed during vasoreactivity testing at RHC:
• mPAP reduction of ≥10 mmHg (to <40 mmHg)
• Cardiac output is increased/maintained1.2 Heritable PAH Enquire 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 toxins Enquire 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-PAH1.4.2 HIV infection Assess for infection with HIV 1.4.3 Portal hypertension Portal 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 disease Eisenmenger 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 suspected1.4.5 Schistosomiasis Present 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 hypertension1.5 PAH with features of venous/capillary (PVOD/PCH) involvement Consider 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 adenopathy1.6 Persistent PH of the newborn Failed 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
Genes Overview References BMPR2 Member 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/ACVRL1 Member 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] Endoglin Member of the TGF-β receptor superfamily
Co-receptor to BMPR2/ALK1 receptors
Causes PAH associated with HHT[25] SMAD9 Important protein in the BMP signalling pathway
Encodes the transcription factor Smad8[25] BMP9/GDF2 Mediator in the BMP signalling pathway
Encodes the BMP9 ligand[22] TBX4 Associated 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] CAV1 Encodes 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] KCNK3 Also 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] EIF2AK4 Encodes 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 tool Year of publication Patients included PAH subgroup Variables included Survival estimation Clinical Exercise Laboratory Imaging Haemodynamic NIH equation [37] 1991 Incident IPAH # # # # 1. mPAP
2. mRAP
3. CI1-, 3-, 5-year PH connection registry [38] 2010 Incident and prevalent IPAH
HPAH
APAH# # # # 1. mPAP
2. mRAP
3. CI1-, 3-, 5-year FPHN registry risk equation [39, 40] 2010 Incident and prevalent IPAH
HPAH
APAH1. Sex 2. 6MWD # # 3. CO 1-, 2-, 3-year REVEAL registry [41] 2010 Incident and prevalent Group 1 PAH 1. Age
2. Sex
3. PAH subgroup
4. Renal insufficiency
5. FC
6. SBP
7. HR8. 6MWD 9. BNP 10. Pericardial effusion
11. DLCO12. PVR
13. mRAP1-year Scottish composite score [42] 2012 Incident Group 1 PAH (CHD-PAH and CCB-R excluded) 1. Age
2. Sex
3. PAH subgroup4. 6MWD # # 5. mRAP
6. CO1-, 2-, 3-year Nickel et al. [43] 2012 Incident IPAH #
FC, NT-proBNP, CI, SvO2 at follow-up1. 6MWD 2. NT-proBNP # 3. CI
4. SvO21-, 3-, 5-year ESC/ERS 2015 Guidelines [3] 2015 # Group 1 PAH 1. Progression of symptoms
2. Syncope
3. FC
4. Clinical signs RHF5. 6MWD
6. Peak VʹO2 (CPET)
7. VʹE/ VʹCO2 slope (CPET)8. BNP/NT-proBNP 9. RA area
10. Pericardial effusion11. RAP
12. CI
13. SvO21-year FPHN registry [44] 2017 Incident IPAH
HPAH
DPAH1. FC
FC, 6MWD, BNP/NT-proBNP at first follow-up2. 6MWD # # 3. mRAP
4. CI1–5 years COMPERA registry [45] 2017 Incident Group 1 PAH 1. FC 2. 6MWD 3. BNP/NT-proBNP # 4. mRAP
5. CI1–5 years SAPHR registry [46] 2018 Incident Group 1 PAH 1. FC 2. 6MWD 3. NT-proBNP 4. RA area
5. Pericardial effusion6. mRAP
7. CI
8. SvO21-, 3-, 5-years Modified Risk Assessment Score of PAH [47] 2018 Incident and prevalent Group 1 PAH 1. FC 2. 6MWD 3. BNP 4. RA area # 1-year COMPERA 2.0 [48] 2021 Incident Group 1 PAH 1. FC 2. 6MWD 3. BNP/NT-proBNP # # 1-, 3-, 5-years ESC/ERS 2022 Guidelines [2] 2022 # Group 1 PAH 1. Progression of symptoms
2. Syncope
3. FC
4. Clinical signs RHF5. 6MWD
6. Peak VʹO2 (CPET)
7. VʹE/ VʹCO2 slope (CPET)8. BNP/NT-proBNP 9. Echocardiography: RA area
Pericardial effusion
TAPSE/PASP
10. cMRI:
RVEF
SVI
RVESVI11. RAP
12. CI
13. SvO2
14. SVI1-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 pathways Nitric oxide (NO) Prostacyclin (PGI2) Endothelin 1 (ET1) Levels in PAH Reduced Reduced Increased Aim of therapy To increase NO To increase PGI2 To reduce ET1 Current available drugs Sildenafil Epoprostenol Macitentan Tadalafil Treprostinil Ambrisentan Riociguat Iloprost Bosentan Selexipag Routes of administration Oral Oral, parenteral, inhaled Oral Method of action To increase cGMP via the inhibition of PD5 or by direct stimulation of sGC To increase the conversion of ATP to cAMP To inhibit ETA receptors ± ETB receptors Side-effects Common side-effects Systemic vasodilation resulting in hypotension, flushing, light-headedness, gastrointestinal side-effects (e.g. nausea, diarrhoea) Specific drug side-effects Sildenafil and tadalafil: ocular side-effects Parenteral prostacyclin: thrombocytopenia, bone marrow suppression Macitentan: 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.
RHC Pre nitric oxide Post nitric oxide mRAP (mmHg) 2 2 mPAP (mmHg) 38 21 PAWP (mmHg) 8 7 Cardiac output (L·min−1) 4.33 5.33 PVR (Wood units) 6.92 2.6
