Congenital Heart Disease-associated Pulmonary Arterial Hypertension

Congenital heart disease associated pulmonary arterial hypertension is pulmonary arterial hypertension that develops in patients with a systemic-to-pulmonary shunt, either unrepaired or after repair. It includes Eisenmenger syndrome, the most advanced form, in which the shunt has reversed and the patient is cyanosed.

About 5 to 10% of adults with congenital heart disease have pulmonary arterial hypertension. Eisenmenger syndrome affects about 1% of this population. It is more common with large defects at the ventricular or arterial level (ventricular septal defect, patent ductus arteriosus, aortopulmonary window, atrioventricular septal defect) than with atrial defects, and it is common in Down syndrome.

Four clinical groups are recognised: Eisenmenger syndrome; pulmonary arterial hypertension with prevalent systemic-to-pulmonary shunts (moderate to large defects with mild to moderate rises in resistance); pulmonary arterial hypertension with small or coincidental defects (ventricular septal defect under 1 cm, atrial septal defect under 2 cm effective diameter); and pulmonary arterial hypertension after defect correction.

Survival of Eisenmenger syndrome is better than in IPAH, and many patients live to the 4th to 6th decade. Shunt reversal with cyanosis, multi-organ effects and haemoptysis dominate later disease.

Pathophysiology.

High pulmonary flow and pressure cause shear injury and obliterative remodelling of small pulmonary arteries, which raises resistance until the shunt reverses. Once the arteriopathy is advanced, it does not regress after shunt closure.

Right-to-left shunting causes chronic hypoxaemia, secondary erythrocytosis, iron deficiency, hyperviscosity, bleeding, thrombosis, renal impairment, gout and cerebral abscess risk.

Right ventricular function in Eisenmenger syndrome is relatively preserved because the right ventricle has been exposed to high pressure since birth.

Dyspnoea, fatigue, cyanosis, clubbing (differential in patent ductus arteriosus: toes affected more than fingers), haemoptysis, palpitations, headaches, syncope and right heart failure. Examination: loud single second heart sound, right ventricular heave, murmur of tricuspid or pulmonary regurgitation (Graham Steell murmur), and the original shunt murmur is typically absent or soft.

Complications: paradoxical embolism and stroke, brain abscess, endocarditis, gallstones, gout, haemoptysis, arrhythmia, and sudden death.

• Echocardiography with agitated saline: defect type and size, shunt direction, pulmonary pressure and ventricular function. MRI for shunt quantification and right ventricular volumes.
• Pulse oximetry at rest and exercise (including pre-ductal and post-ductal in ductus). Haemoglobin, haematocrit, ferritin, transferrin saturation, creatinine, urate, liver tests, coagulation and platelets.
• Right heart catheterisation: measure pulmonary and systemic flow, resistances and the effect of vasodilators.
• Shunt closure decision, based on indexed pulmonary vascular resistance and the ratio of pulmonary to systemic flow:
  • Close the defect when indexed resistance is under 4 Wood units x m2 (resistance under about 2.3 to 3 Wood units) and the shunt is still left-to-right with a flow ratio over 1.5.
  • Do not close when indexed resistance is over 8 Wood units x m2 (resistance over about 4.6 Wood units), or with Eisenmenger syndrome.
  • Between these bands (4 to 8 Wood units x m2), decide individually in a specialist centre, often with a supervised test of treatment and repeat catheterisation.
• Risk stratum: low (functional class I or II, 6-minute walk over 440 m, NT-proBNP under 300 ng/L), intermediate (class III, 165 to 440 m, 300 to 1100 ng/L), high (class IV, under 165 m, over 1100 ng/L, syncope).

Differential diagnosis.

• Cyanotic congenital heart disease with reduced pulmonary flow and high pulmonary flow without pulmonary vascular disease.
• Pulmonary hypertension from left heart disease, lung disease, thromboembolism or hypoxia.
• Idiopathic pulmonary arterial hypertension with coincidental small defect.
• Polycythaemia from other causes and sleep disordered breathing.

Specific therapy. All drugs are continued long term.

• Bosentan 62.5 mg orally twice daily for 4 weeks, then 125 mg twice daily (maximum 250 mg daily), improves exercise capacity in Eisenmenger syndrome. Monthly ALT and AST. Contraindicated with ciclosporin and glibenclamide. Avoid in Child-Pugh B or C.
• Macitentan 10 mg orally once daily is an alternative with an acceptable safety record (haemoglobin and ALT at baseline and when indicated).
• Ambrisentan 5 mg once daily, increased to 10 mg (maximum 10 mg), is used in associated pulmonary arterial hypertension.
• Sildenafil 20 mg three times daily, or 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), added for inadequate response. Contraindicated with nitrates and riociguat.
• Treprostinil, epoprostenol, selexipag (200 microgram twice daily titrated weekly to a maximum of 1600 microgram twice daily) and riociguat (1 mg three times daily, increased by 0.5 mg every 2 weeks to a maximum of 2.5 mg three times daily, not with phosphodiesterase-5 inhibitors) are used for high risk or inadequate response. Intravenous routes carry paradoxical embolism and sepsis risks, so subcutaneous or inhaled routes are preferred in shunt patients.
• Endothelin receptor antagonists and riociguat are teratogenic: exclude pregnancy before starting and monthly.

Eisenmenger specific measures.

• Maintain hydration. Avoid dehydration, high altitude, strenuous exercise and hot baths.
• Iron deficiency: ferrous sulphate 200 mg orally once daily or on alternate days, with haemoglobin and ferritin monitored at 4 weeks. Intravenous iron is used cautiously. Iron deficiency worsens symptoms and should not be tolerated.
• Phlebotomy only for symptoms of hyperviscosity (headache, fatigue, visual disturbance, paraesthesia) with haematocrit over 65% and euvolaemia: remove 250 to 500 mL and replace with equal volume of isotonic saline over 30 to 45 minutes. Do not use routine phlebotomy.
• Use air filters on all intravenous lines to prevent paradoxical embolism.
• Prevent endocarditis: amoxicillin 2 g orally 30 to 60 minutes before dental procedures involving gingival manipulation (azithromycin 500 mg or doxycycline 100 mg with penicillin allergy), with good dental hygiene.
• Avoid NSAIDs and drugs that lower systemic vascular resistance (dihydropyridine calcium channel blockers, ACE inhibitors) because they increase right-to-left shunting.
• Anticoagulation is not routine. Use it for atrial fibrillation or pulmonary thrombus with attention to bleeding, especially haemoptysis.
• Oxygen is used for symptomatic relief of nocturnal desaturation, but does not improve survival.
• Haemoptysis: minor episodes settle with rest and tranexamic acid 1 g orally three times daily for 3 days (avoid in severe renal impairment, reduce dose when creatinine clearance is under 50 mL/min). Major haemoptysis needs admission and bronchial artery embolisation.
• Non-cardiac surgery and anaesthesia carry high risk (mortality over 5%), and need a specialist centre.

Defect closure and transplantation. Close the defect only when resistance criteria are met. For intermediate resistance, a treat-and-repair strategy with specific therapy followed by repeat catheterisation may allow closure. Heart lung or lung transplantation with repair in selected patients with progressive disease.

Monitoring. Clinical review, oxygen saturation, haemoglobin, ferritin, creatinine and urate every 3 to 6 months. Echocardiography yearly. NT-proBNP and 6-minute walk every 6 months. Liver tests monthly on bosentan.

Referral and escalation. Refer to an adult congenital heart disease centre with pulmonary hypertension expertise. Urgent referral for haemoptysis, stroke, syncope, endocarditis, pregnancy, or planned surgery.

Special groups.

• Pregnancy: maternal mortality is 30 to 50% in Eisenmenger syndrome, so pregnancy is contraindicated. Use progestogen only implants or intrauterine devices (or two methods) because bosentan reduces hormonal contraceptive effect. Termination counselling.
• Children: weight based dosing under paediatric services, and close attention to early repair of large defects before 1 to 2 years to prevent arteriopathy.
• Down syndrome: higher risk of early pulmonary vascular disease; specific therapy is as effective.
• Region specific: late presentation with established Eisenmenger syndrome is frequent where early repair is unavailable, so reliable sildenafil or bosentan, hydration advice and endocarditis prevention are the main supports.