Fontan Circulation Failure

Fontan circulation failure is the progressive loss of the ability of a Fontan circulation to deliver adequate cardiac output at an acceptable venous pressure. Systemic venous blood reaches the lungs passively, with no subpulmonary ventricle, so any rise in resistance or fall in ventricular performance is poorly tolerated.

Survivors of Fontan completion are a large and ageing population. Transplant free survival is roughly 85% at 20 years and 70 to 75% at 30 years in large series, and failure becomes frequent after the second decade.

Causes are ventricular systolic or diastolic dysfunction (earlier and more often with a systemic right ventricle), atrioventricular valve regurgitation, atrial tachyarrhythmia, sinus node dysfunction, raised pulmonary vascular resistance, obstruction of the conduit or branch pulmonary arteries, venovenous and aortopulmonary collaterals, thrombus, and chronotropic incompetence.

Two phenotypes occur. Failure with reduced ejection fraction responds partly to heart failure drugs. Failure with preserved ejection fraction is commoner, shows high venous pressure, low output and lymphatic failure, and responds poorly to them.

Complications are protein losing enteropathy (up to about 10 to 15% in long term series), plastic bronchitis (1 to 5%), liver fibrosis and cirrhosis, renal dysfunction, thromboembolism, cachexia and sudden death.

Pathophysiology.

Cardiac output depends on the pressure gradient from systemic veins to the left atrium, on pulmonary vascular resistance, on ventricular filling and on rhythm. Central venous pressure in a stable Fontan is about 10 to 14 mmHg, which leaves little reserve.

Chronic venous hypertension and low output congest the liver and gut, raise lymphatic pressure and reduce renal perfusion. Protein loss through the gut and cast formation in the airways are expressions of lymphatic failure.

Absent pulsatile pulmonary flow lowers nitric oxide production, and the pulmonary vascular bed remodels over time. Skeletal muscle wasting reduces the peripheral pump and exercise capacity.

Loss of sinus rhythm causes a sharp fall in output because atrial contraction contributes to ventricular filling and pulmonary flow.

Falling exercise tolerance, fatigue, exertional dyspnoea, palpitations, peripheral oedema, ascites, abdominal pain and distension, and early satiety. Diarrhoea with hypoalbuminaemia suggests protein losing enteropathy. Recurrent cough with expectoration of branching bronchial casts indicates plastic bronchitis.

Cyanosis suggests a fenestration, venovenous collaterals or pulmonary arteriovenous malformations. Stroke or limb ischaemia suggests thromboembolism. Signs are raised jugular venous pressure, hepatomegaly, ascites, atrioventricular valve regurgitation murmur and low saturations.

• ECG and ambulatory ECG: atrial tachycardia or flutter (often subtle, with slow rates), junctional rhythm, sinus node dysfunction.
• Echocardiography and cardiac MRI: ventricular volumes and ejection fraction, atrioventricular valve regurgitation, conduit and pulmonary artery flow, thrombus, aortic and venous collateral flow.
• Cardiopulmonary exercise testing: reduced peak oxygen uptake (under 50% of predicted indicates significant limitation), chronotropic incompetence.
• Blood tests: NT-proBNP, albumin (under 35 g/L suggests protein loss), immunoglobulins, lymphocyte count, full blood count, ferritin and transferrin saturation, creatinine and eGFR, liver tests with GGT, INR, platelets and AFP. Stool alpha-1 antitrypsin clearance for protein losing enteropathy.
• Catheterisation (the decisive test): Fontan pressure (over 15 mmHg is high), transpulmonary gradient (over 6 mmHg suggests obstruction or raised resistance), ventricular end diastolic pressure (over 12 mmHg is high), indexed pulmonary vascular resistance (over 3 Wood units x m2 is high), cardiac index, and angiography of the conduit, pulmonary arteries, venovenous collaterals and aortopulmonary collaterals.
• Liver ultrasound with elastography, and multiphasic MRI or CT.

Differential diagnosis.

• Obstruction of the Fontan conduit or branch pulmonary arteries as the sole cause.
• Constrictive pericarditis and pulmonary embolism.
• Other causes of protein loss (inflammatory bowel disease, coeliac disease, infection) and of cirrhosis (viral, metabolic, drug induced).
• Primary cardiomyopathy of the single ventricle.

Find and correct reversible lesions at catheterisation first. Stent obstructions of the conduit, pulmonary arteries or pulmonary veins; coil or plug venovenous and aortopulmonary collaterals; treat atrioventricular valve regurgitation (repair or replacement); remove thrombus.

Rhythm.

• Atrial tachyarrhythmia is poorly tolerated. Synchronised cardioversion 120 to 200 J (biphasic) when unstable or early, after transoesophageal echocardiography or 3 weeks of anticoagulation.
• Amiodarone: load 200 mg orally three times daily for 1 week, then twice daily for 1 week, then 200 mg daily; thyroid and liver tests every 6 months; reduces warfarin requirement by 30 to 50%.
• Sotalol 80 to 160 mg orally twice daily (maximum 320 mg daily); ECG for QTc at baseline and after changes, stop if QTc over 500 ms; extend the interval at eGFR 30 to 60 and avoid under 30 mL/min/1.73 m2. Avoid class I drugs.
• Catheter ablation (specialist centre), and atrial or atrioventricular sequential pacing for sinus node dysfunction and bradycardia.

Antithrombotic therapy. Aspirin 75 to 100 mg daily after Fontan, or warfarin to INR 2.0 to 3.0 for thrombus, atrial arrhythmia, a fenestration with right-to-left shunt, or low flow. Apixaban 5 mg twice daily is used in selected adults, with limited data (2.5 mg twice daily if two of age 80 or over, weight 60 kg or under, creatinine 133 micromol/L or over).

Congestion.

• Furosemide 20 to 80 mg orally daily, titrated to weight, with spironolactone 25 to 100 mg daily (potassium under 5.0 mmol/L, eGFR over 30; check at 1 and 4 weeks). Avoid over diuresis because the circulation is preload dependent. Electrolytes and creatinine within 1 week of changes.
• Large volume paracentesis with 6 to 8 g of albumin for each litre removed when ascites is tense.

Ventricular dysfunction (reduced ejection fraction). ACE inhibitor (ramipril 2.5 mg daily titrated to 10 mg), beta blocker (carvedilol 3.125 mg twice daily titrated to 25 mg twice daily, once euvolaemic and with a protected heart rate), spironolactone, and, with caution, an SGLT2 inhibitor (dapagliflozin 10 mg daily at eGFR 25 or over) while watching for volume depletion. Evidence for these drugs in the Fontan circulation is limited.

Raised pulmonary vascular resistance. Pulmonary vasodilators give modest gains in exercise capacity: sildenafil 20 mg three times daily, or tadalafil 20 to 40 mg once daily (avoid when creatinine clearance is under 30 mL/min; contraindicated with nitrates), or bosentan 62.5 mg twice daily for 4 weeks then 125 mg twice daily (monthly ALT and AST), or macitentan 10 mg daily. Endothelin receptor antagonists are teratogenic, so exclude pregnancy before starting and monthly.

Protein losing enteropathy.

• High protein diet with medium chain triglycerides and low long chain fat intake.
• Budesonide 9 mg orally once daily (adults), with monitoring of glucose, blood pressure and infection.
• Unfractionated heparin 5000 units subcutaneously twice daily by specialist decision.
• Albumin 20% infusion 0.5 to 1 g/kg for symptomatic hypoalbuminaemia, and immunoglobulin replacement when IgG is low with recurrent infection.
• Search for and relieve obstruction, close collaterals, and consider fenestration creation or lymphatic intervention.

Plastic bronchitis. Bronchoscopic cast removal, dornase alfa 2.5 mg nebulised once or twice daily, inhaled alteplase (dose set by the specialist centre), and lymphatic imaging with thoracic duct decompression or embolisation.

Fenestration, conversion and support. Creation of a fenestration lowers venous pressure at the cost of desaturation and is used for preserved ejection fraction failure with refractory effusions. Surgical conversion to an extracardiac conduit with arrhythmia surgery suits atriopulmonary Fontan connections. Mechanical circulatory support is limited in Fontan physiology.

Transplantation. Refer early, at the onset of protein losing enteropathy, refractory ascites, falling ejection fraction, renal dysfunction or cachexia. Combined heart and liver transplantation when cirrhosis with portal hypertension is established. Palliative care input for those not eligible.

Prevention of 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).

Monitoring. Clinical review, weight, saturation and ECG every 3 to 6 months. NT-proBNP, albumin, creatinine, liver tests and full blood count every 3 to 6 months. Echocardiography yearly, cardiopulmonary exercise testing every 1 to 3 years, and MRI every 3 to 5 years. Liver imaging yearly from 10 years after the operation.

Referral and escalation. All patients need an adult congenital heart disease centre. Urgent referral for new atrial tachycardia, thromboembolism, ascites, falling albumin, haemoptysis or cast expectoration, cyanosis, or declining exercise capacity. Early referral for transplantation assessment.

Special groups.

• Pregnancy: possible in selected women with good function and sinus rhythm, but risk of miscarriage, preterm birth, arrhythmia and thrombosis is increased. Plan before conception, stop ACE inhibitors, endothelin receptor antagonists and warfarin from 6 to 12 weeks (enoxaparin 1 mg/kg subcutaneously every 12 hours with anti-Xa monitoring instead).
• Children and adolescents: weight based dosing and growth monitoring; budesonide dosing by paediatric specialists.
• Kidney or liver impairment: avoid NSAIDs, adjust sotalol and apixaban by renal function, and monitor bosentan closely.
• Region specific: where transplantation and catheter interventions are unavailable, rhythm control, diuretics, anticoagulation and nutritional support are the main measures.