Heritable Pulmonary Arterial Hypertension

Heritable pulmonary arterial hypertension is pulmonary arterial hypertension caused by a pathogenic germline variant, with or without a family history. It behaves as IPAH, but it presents earlier, is more severe and needs genetic counselling for the whole family.

BMPR2 variants account for 70 to 80% of familial cases and for 10 to 20% of apparently idiopathic cases. Other genes are ACVRL1 and ENG (hereditary haemorrhagic telangiectasia), SMAD9, CAV1, KCNK3, TBX4 (often in children), SOX17, ATP13A3, AQP1, GDF2, and biallelic EIF2AK4 (pulmonary veno occlusive disease and capillary haemangiomatosis).

Inheritance is autosomal dominant with reduced penetrance. BMPR2 lifetime penetrance is about 14% in male carriers and 42% in female carriers. Anticipation and genetic modifiers influence age of onset.

Compared with IPAH, BMPR2 carriers are diagnosed about 10 years earlier, have worse haemodynamics, are rarely vasoreactive, and have a higher risk of death or transplantation.

Pathophysiology.

Loss of function in BMPR2 and related genes reduces bone morphogenetic protein signalling, which shifts endothelial and smooth muscle cells toward proliferation, apoptosis resistance and inflammation. A second hit (infection, hormonal change, drug, hypoxia) is probably needed.

In HHT-associated disease (ACVRL1, ENG), abnormal vascular signalling causes arteriovenous malformations in the lung, liver and brain, in addition to pulmonary arterial hypertension.

Biallelic EIF2AK4 variants cause venous and capillary involvement with widespread pulmonary oedema on vasodilator exposure and poor response to specific therapy.

Presentation is with exertional dyspnoea, fatigue, syncope, chest pain and right heart failure, usually in the 20s to 40s. Children present with failure to thrive, syncope or heart failure, and TBX4 disease may come with small patella syndrome or lung developmental disease.

HHT features: recurrent epistaxis, mucocutaneous telangiectasia, gastrointestinal bleeding, iron deficiency anaemia, and pulmonary or cerebral arteriovenous malformations. EIF2AK4 disease presents with severe hypoxaemia and low diffusing capacity.

• Right heart catheterisation: mean pulmonary artery pressure over 20 mmHg, wedge pressure of 15 mmHg or less, pulmonary vascular resistance over 2 Wood units. Vasoreactivity testing with inhaled nitric oxide 10 to 20 ppm. A positive response is a fall in mean pressure of 10 mmHg or more to under 40 mmHg with preserved output, and it is rare in carriers.
• Genetic testing after counselling: a panel including BMPR2 (with deletion and duplication analysis), ACVRL1, ENG, SMAD9, CAV1, KCNK3, TBX4, EIF2AK4, SOX17, ATP13A3, AQP1 and GDF2. Test the proband first, then offer cascade testing to first degree relatives who are adults (children by specialist decision).
• Workup includes echocardiography, ventilation perfusion scan, pulmonary function with diffusing capacity, high resolution CT, NT-proBNP, blood tests for secondary causes.
• EIF2AK4 suspicion: diffusing capacity under 50%, centrilobular ground glass opacities, septal lines and mediastinal lymph node enlargement on CT. Diagnosis rests on genotype, and lung biopsy is avoided.
• HHT: contrast (bubble) echocardiography and CT for pulmonary arteriovenous malformations, brain MRI, and haemoglobin and ferritin.
• Risk stratum (annual mortality under 5%, 5 to 10%, over 10%):
  • Low risk: functional class I or II, 6-minute walk over 440 m, NT-proBNP under 300 ng/L, right atrial pressure under 8 mmHg, cardiac index 2.5 or more.
  • Intermediate: class III, 165 to 440 m, NT-proBNP 300 to 1100, right atrial pressure 8 to 14, cardiac index 2.0 to 2.4.
  • High: class IV, under 165 m, NT-proBNP over 1100, right atrial pressure over 14, cardiac index under 2.0, syncope.

Differential diagnosis.

• Idiopathic pulmonary arterial hypertension and acquired forms (connective tissue disease, drugs, HIV, portal hypertension, congenital shunts).
• Pulmonary hypertension from left heart or lung disease and chronic thromboembolic disease.
• Pulmonary veno occlusive disease without a variant, sarcoidosis and pulmonary arteriovenous malformations without pulmonary hypertension.
• Hepatopulmonary syndrome and high output states in HHT.

Genetic counselling and family screening.

• Pre-test and post-test counselling, with explanation of reduced penetrance. Offer cascade testing.
• Carriers without disease: annual clinical review, NT-proBNP and echocardiography from adulthood (earlier when family onset was young). Proceed to right heart catheterisation for tricuspid regurgitation velocity over 2.8 m/s, symptoms, or unexplained fall in exercise capacity.
• Counsel on reproductive options including prenatal and preimplantation testing, and on pregnancy risk.

Specific therapy. All drugs are continued long term. Risk based therapy follows IPAH, with a lower threshold for early combination or parenteral treatment.

• Low or intermediate risk: ambrisentan 5 mg orally once daily, increased to 10 mg (maximum 10 mg; haemoglobin and liver tests at baseline and when indicated; avoid in moderate to severe hepatic impairment) with tadalafil 40 mg once daily (start 20 mg in mild to moderate renal or hepatic impairment; avoid when creatinine clearance is under 30 mL/min). Alternative: macitentan 10 mg once daily with tadalafil 40 mg once daily.
• High risk: add parenteral prostacyclin. Epoprostenol intravenously from 2 ng/kg/min, increased by 2 ng/kg/min at intervals of at least 15 minutes in hospital, with a usual chronic dose of 20 to 40 ng/kg/min; never interrupt abruptly. Or treprostinil subcutaneously or intravenously from 1.25 ng/kg/min, increased by 1.25 ng/kg/min weekly for 4 weeks and then 2.5 ng/kg/min weekly.
• Escalation: selexipag 200 microgram orally twice daily increased weekly by 200 microgram twice daily to a maximum of 1600 microgram twice daily (start 200 microgram once daily in Child-Pugh B; avoid in severe hepatic impairment), or sotatercept 0.3 mg/kg then 0.7 mg/kg subcutaneously every 3 weeks with haemoglobin and platelet monitoring. Sotatercept increases bleeding and telangiectasia, so use caution in HHT.
• Calcium channel blockers are used only after a positive acute vasoreactivity test (nifedipine modified release up to 240 mg daily or diltiazem up to 720 mg daily), which is rare in BMPR2 carriers.
• Endothelin receptor antagonists and riociguat are teratogenic: exclude pregnancy before starting and monthly afterwards.

EIF2AK4-related disease. Refer for lung transplantation assessment at diagnosis. Specific therapy can cause pulmonary oedema, so start only in a specialist centre with very low doses and close monitoring, and expect limited benefit.

HHT-associated disease. Avoid anticoagulation and antiplatelet drugs unless essential. Treat iron deficiency (ferrous sulphate 200 mg orally once daily, or ferric derisomaltose 20 mg/kg intravenously, maximum 1000 mg). Embolise pulmonary arteriovenous malformations of 3 mm or larger feeding vessel diameter. Give antibiotic prophylaxis before dental procedures (amoxicillin 2 g orally 30 to 60 minutes before) while arteriovenous malformations persist, and use air filters on intravenous lines.

General measures. As for IPAH: diuretics (furosemide 40 to 120 mg daily with spironolactone 25 to 100 mg daily), oxygen for PaO2 under 8 kPa, iron correction, vaccination, supervised rehabilitation, and avoidance of pregnancy.

Transplantation. Refer early, because heritable disease progresses faster.

Monitoring. Clinical review, NT-proBNP and 6-minute walk every 3 to 6 months. Echocardiography every 6 to 12 months. Right heart catheterisation at baseline, 3 to 6 months after any change and with deterioration. Haemoglobin and ferritin every 3 months in HHT.

Referral and escalation. Refer all patients to a pulmonary hypertension centre and a clinical genetics service. Urgent referral for syncope, haemoptysis, rapid decline, high risk, or suspected pulmonary veno occlusive disease.

Special groups.

• Pregnancy: maternal mortality is about 20 to 30%, and pregnancy is advised against. Heritable disease passes to 50% of offspring.
• Children: weight based dosing under paediatric pulmonary hypertension teams. TBX4 and ACVRL1 disease can present in infancy.
• Kidney or liver impairment: adjust or avoid drugs as set out.
• Region specific: genetic testing may not be available, so use family history and clinical features, and still apply caution with anticoagulation in suspected HHT.