Key Facts

Pulmonary hypertension (PH) is defined as an elevation in mean pulmonary artery pressure ≥20 mmHg at rest, measured by right heart catheterisation. It encompasses a heterogeneous group of conditions classified into 5 WHO groups based on aetiology and haemodynamic profiles.

Epidemiology

• Group 2 (left heart disease) is the most common cause overall
• Idiopathic PAH (Group 1): incidence ~2-7 per million per year
• PAH prevalence: ~15-50 per million
• Female predominance in idiopathic PAH (~4:1)
• Mean age at diagnosis of idiopathic PAH: ~50 years
• CTEPH (Group 4): develops in ~2-4% of PE survivors

Aetiology

WHO Classification:

• Group 1 (PAH): idiopathic, heritable (BMPR2 mutation), drug-induced (anorexigens, methamphetamine), connective tissue disease (scleroderma), HIV, portal hypertension, congenital heart disease, schistosomiasis
• Group 2: left heart disease (HFrEF, HFpEF, valvular disease)
• Group 3: chronic lung disease (COPD, ILD, OSA, high altitude)
• Group 4: CTEPH
• Group 5: multifactorial/unclear (sarcoidosis, haematological disorders, metabolic)

Pathophysiology

• PAH (Group 1): pulmonary arterial vasoconstriction, vascular remodelling (intimal fibrosis, medial hypertrophy), in-situ thrombosis, plexiform lesions
• Endothelial dysfunction: reduced nitric oxide and prostacyclin, excess endothelin-1 and thromboxane
• Progressive increase in PVR → RV pressure overload → RV hypertrophy → RV failure
• Group 2: passive congestion from elevated left atrial pressure; may develop reactive (combined pre- and post-capillary) component
• Group 4: organised thrombus causes mechanical obstruction + secondary small vessel arteriopathy

Typical Presentation

• Progressive exertional dyspnoea (most common symptom)
• Fatigue and lethargy
• Exertional syncope or presyncope
• Chest pain (RV ischaemia)
• Peripheral oedema

Clinical Signs

• Raised JVP with prominent a-wave (RV hypertrophy) or v-wave (tricuspid regurgitation)
• Right ventricular heave (left parasternal)
• Loud P2 (pulmonary component of second heart sound)
• Pansystolic murmur of tricuspid regurgitation
• Hepatomegaly, ascites, peripheral oedema (right heart failure)
• Cyanosis in advanced disease

WHO Functional Classification

• Class I: no limitation of physical activity
• Class II: slight limitation; comfortable at rest
• Class III: marked limitation; comfortable only at rest
• Class IV: symptoms at rest; unable to carry out any physical activity

Red Flags

• Syncope (indicates severe disease/low cardiac output)
• Rapidly progressive symptoms
• Signs of decompensated RV failure
• Pericardial effusion on echo
• Low cardiac output (cool peripheries, low BP, oliguria)

Bedside

• ECG: right axis deviation, RV hypertrophy (tall R waves V1-V3), P pulmonale, RBBB
• Pulse oximetry: desaturation (especially on exercise)
• 6-minute walk test: functional capacity and prognosis

Bloods

• BNP/NT-proBNP: elevated in RV dysfunction; prognostic marker
• FBC: polycythaemia (chronic hypoxia)
• Autoimmune screen: ANA, anti-centromere, anti-Scl-70, RF (connective tissue disease)
• TFTs: thyroid disease associated with PAH
• HIV test: HIV-associated PAH
• LFTs: hepatic congestion, portopulmonary hypertension screen
• Thrombophilia screen: if CTEPH suspected

Imaging

• Echocardiography: screening tool; estimates PA systolic pressure (PASP) from tricuspid regurgitation velocity, RV size/function, RA size, septal bowing, pericardial effusion
• CTPA: exclude CTEPH, assess cardiac chambers
• V/Q scan: gold standard to screen for CTEPH (higher sensitivity than CTPA for chronic thrombus)
• HRCT: parenchymal lung disease (Group 3)
• CXR: enlarged pulmonary arteries, pruning of peripheral vessels, RV enlargement

Special Tests

• Right heart catheterisation (RHC): gold standard for diagnosis and classification
  • mPAP ≥20 mmHg confirms PH
  • PAWP ≤15 mmHg: pre-capillary (Groups 1, 3, 4, 5)
  • PAWP >15 mmHg: post-capillary (Group 2)
  • PVR ≥2 Wood units: confirms elevated resistance
• Vasoreactivity testing: during RHC for idiopathic PAH; positive if mPAP drops ≥10 mmHg to ≤40 mmHg with preserved cardiac output (inhaled NO or IV epoprostenol)
• Pulmonary function tests: spirometry, TLCO, lung volumes
• Cardiac MRI: gold standard for RV assessment

Non-pharmacological

• Specialist PH centre referral for all suspected PAH/CTEPH
• Supervised exercise rehabilitation (improves functional capacity)
• Supplemental oxygen if PaO₂ <8 kPa
• Fluid restriction and low-salt diet
• Avoid pregnancy (high mortality risk 30-50%)
• Contraception counselling (avoid oestrogen-containing)
• Annual influenza and pneumococcal vaccination

Pharmacological

Group 1 (PAH) — targeted therapy:

Vasoreactive patients: high-dose CCB (nifedipine 120-240mg/day or diltiazem 240-720mg/day) — only ~10% of idiopathic PAH

Non-vasoreactive (majority):

• PDE5 inhibitors: sildenafil 20mg TDS (SUPER-1 trial) or tadalafil 40mg OD
• Endothelin receptor antagonists (ERAs): bosentan 125mg BD (BREATHE-1 trial), ambrisentan 5-10mg OD, macitentan 10mg OD (SERAPHIN trial)
• Prostanoids: epoprostenol IV continuous (gold standard for severe PAH), iloprost nebulised, treprostinil SC/IV/inhaled, selexipag PO (GRIPHON trial)
• sGC stimulator: riociguat 2.5mg TDS (PATENT-1 trial) — for PAH or inoperable CTEPH
• Combination therapy: initial or sequential combination is standard of care (AMBITION trial: ambrisentan + tadalafil superior to monotherapy)

Group 2 (left heart disease): treat underlying cardiac condition; PAH-specific therapies not recommended

Group 3 (lung disease): optimise treatment of underlying lung disease; supplemental oxygen; inhaled treprostinil for PH-ILD (INCREASE trial)

Group 4 (CTEPH):

• Pulmonary endarterectomy (PEA): potentially curative; gold standard for operable CTEPH
• Balloon pulmonary angioplasty (BPA): for inoperable CTEPH
• Riociguat: for inoperable/persistent CTEPH (CHEST-1 trial)

Surgical/Interventional

• Pulmonary endarterectomy for CTEPH (specialist centres; UK: Papworth)
• Balloon pulmonary angioplasty
• Atrial septostomy: palliative, creates R→L shunt to decompress RV
• Lung transplantation: end-stage PAH refractory to medical therapy
• Heart-lung transplantation: Eisenmenger syndrome

Referral Criteria

• All suspected PH: echocardiography → if PASP >40 mmHg or RV dysfunction, refer to specialist PH centre
• National PH centres in UK: Papworth, Hammersmith, Sheffield, Newcastle, Glasgow, Cardiff
• Urgent referral for syncope, rapid functional decline, or signs of RV failure

• Untreated idiopathic PAH: median survival ~2.8 years
• With modern combination therapy: median survival >7 years
• WHO FC I/II at diagnosis: better prognosis than FC III/IV
• 6MWD <300m, BNP >300 pg/mL, cardiac index <2 L/min/m²: poor prognostic markers
• CTEPH: PEA has ~95% 10-year survival if successful
• Scleroderma-associated PAH: worse prognosis than idiopathic PAH (~3-year survival ~50%)
• Group 2 PH: prognosis determined by underlying cardiac disease
• Pregnancy in PAH: maternal mortality ~30-50%; strongly advised against

WHO PH Classification Summary

Targeted PAH Drug Classes