The systemic ventricle

Several factors contribute to systemic ventricular dysfunction following Fontan procedure.^E44–E46

• The dominant systemic ventricle of right ventricular or indeterminate morphology with unfavourable fibre arrangements that is mechanically insufficient to sustain adequate cardiac output has a higher incidence of failure than morphologic left ventricle.^E44–E54

• Associated cardiomyopathy of underlying CHD.^E44

• Multiple surgeries pre-Fontan with accumulated periods of myocardial ischaemia.

• Periods of neonatal palliation with pressure overload related to restrictive ventricular septal defect in discordant connection, pulmonary artery band, and recoarctation.^E219–E222

• Shunt-induced volume overload.^E219–E222

• Recruitment of the systemic ventricle through two vascular beds resulting in eventual ventricular dysfunction.^E44

• Following Fontan procedure, the preload of systemic ventricle is reduced from 25% to 70% leading to systolic and diastolic dysfunction.^E46–E54 Secondly, chronotropic incompetence may occur due to scar-related sinus node dysfunction, and thirdly, increase in ventricular end-diastolic pressure lead to higher Fontan circuit pressure and eventual failure (Table E1).^E223–E224

Ventricular function

Systolic ventricular function is relatively preserved in the first decade after Fontan procedure but declines progressively over time.^E228,E229 A substantial number of patients with Fontan circulation have heart failure with preserved ejection fraction.^{Reference Hebson, McCabe and Elder10,Reference Book and Shaddy11,E71} These patients have features of venous congestion and its attendant compendium of complications such as ascites, protein-losing enteropathy, plastic bronchitis, liver cirrhosis, limited exercise capacity, and growth failure.^E230,E231

It is indeed difficult to distinguish Fontan failure with preserved ejection fraction from Fontan failure with normal Fontan pressure. Studies have shown that catheterisation findings can be masked when systemic chamber volume is low.^{Reference Hebson, McCabe and Elder10,Reference Book and Shaddy11,E69–E72} However, the diastolic function may be unmasked with volume challenge.^E221,E235

Diastolic dysfunction can be difficult to assess non-invasively in patients with a single ventricle because of lack of normal values for systemic ventricle in this subset of patients.^{E51,E232–E234} Estimates of pressure-volume loop relationships indicate evidence of diastolic dysfunction early post-operatively following Fontan operation.^E234

Ascites

Ascites following Fontan procedure may develop secondary to elevated right atrial pressure, hepatic congestion with centrilobular necrosis, or protein-losing enteropathy. Ascites without hypoalbuminemia is an indicator of a failing Fontan circulation (Table E1).^{Reference Fontan, Kirklin and Fernandez1–Reference Deal and Jacobs9}

Lymphatic dysfunction

Increased pressures in systemic veins and splanchnic circulation following Fontan operation result in impaired lymphatic reabsorption. It may also occur in the setting of failed Fontan with normal systemic venous pressure. Elevated thoracic duct pressure following Fontan procedure results in chylous effusion in early post-operative period and plastic bronchitis/protein-losing enteropathy in late post-operative period.^{Reference Akbari Asbagh, Navabi Shirazi and Soleimani22–Reference Meadows, Gauvreau and Jenkins26}

Protein-losing enteropathy occurs in 3 to 15% patients following Fontan procedure with a higher incidence after atriopulmonary Fontan compared to extracardiac Fontan.^{Reference Ostrow, Freeze and Rychik27–Reference Mertens, Hagler and Sauer29} It presents as vague gastrointestinal symptoms, ascites, pleural effusions, and generalised anasarca. With the development of severe gut oedema, diarrhoea becomes a common event.^E325 This complication is diagnosed by low serum albumin and presence of faecal α-1 antitrypsin levels.^{Reference Hess, Kruizinga and Bijleveld25,Reference Rychik, Goldberg and Rand30,E189,E190}

Factors resulting in protein-losing enteropathy include low cardiac output, abnormal mesenteric vascular pressure, intestinal lymphangiectasia, enterocyte membrane dysfunction, aberrant lymphatic channels adjacent to gut lumen, diminished heparan sulphate proteoglycans in enterocyte membrane, intestinal cellular wall damage, and auto-immune reactions.^{Reference Hess, Kruizinga and Bijleveld25–Reference Rychik, Goldberg and Rand30,E189–E191} Serum proteins, immunoglobulins, and coagulation factors are lost in intestinal tract inciting infections and thromboembolic events. Protein-losing enteropathy and plastic bronchitis with normal venous pressure constitute 10% of Fontan failure and are reported to cause 50% mortality at 5 years.^{Reference Rychik, Goldberg and Rand30}

Plastic bronchitis is the pulmonary corollary to the gastrointestinal lymphatic derangements seen in protein-losing enteropathy. It is reported to occur in less than 5% of patients with Fontan circulation.^E236 Non-inflammatory protein-rich mucinous material leaks into the airway through mucosal defects producing bronchial casts obstructing airway.^E237,E238 Clinical manifestations include dyspnoea, cough, tachypnoea, wheezing, and expectoration of bronchial casts that may cause severe respiratory distress with asphyxia, cardiac arrest, or death. Its exact cause is unknown. It is conjectured that high intrathoracic lymphatic pressure may lead to development of lymphoalveolar fistula and leakage of proteinaceous material into airways resulting in bronchial casts.^E192 The determination of pre-Fontan risk factors for prediction of post-Fontan protein-losing enteropathy and plastic bronchitis has been elusive (Table E1).^{Reference Hess, Kruizinga and Bijleveld25–Reference Rychik, Goldberg and Rand30,E189–E192}

Pulmonary arteriovenous malformations

Pulmonary arteriovenous malformations complicate the post-operative course of many patients following staged univentricular palliation.^E203 Although the aetiology is unknown, it has been linked to non-pulsatile pulmonary blood flow and lack of hepatic-derived factor.^E201,E203 Pulmonary arteriovenous malformations have been noted to regress following completion Fontan procedure. Sometimes, these arteriovenous malformations persist following Fontan procedure resulting in hypoxia and significant morbidity. At times, it is related to differential perfusion to one lung and is managed on an individualised basis (Table E2).

Cyanosis and collateral formation

A mild degree of desaturation is present in most Fontan patients. Cyanosis may result from incomplete closure of a residual atrial septal defect, fenestrated Fontan pathway, diversion of coronary sinus to left atrium, veno-venous collateral formation between systemic and pulmonary venous circulation, pulmonary arteriovenous malformations, and a classic Glenn.^E46,E203 Resting saturation of less than 90% suggests the presence of a right-to-left shunt or a pulmonary arteriovenous fistula (Table E2).^E46,E203

Hepatic effects

In the absence of right heart pressures in Fontan circulation, the liver acts as a “capacitor” for venous blood, causing hepatic sinusoidal congestion and necrosis with activation of inflammation in some cases.^E239 Long-term hepatic effects of Fontan circulation include increased stiffness, centrilobular necrosis, cardiac cirrhosis with occasional development of hepatic adenoma, and hepatocellular carcinoma.^{E72,E240–E248} The prevalence of post-Fontan hepatocellular carcinoma is around 1.3%.^E249–E255 Physiologically, hepatic perfusion is largely dependent on portal venous flow. Following Fontan circulation, the portal venous blood flow is reduced, resulting in reflex rise of hepatic arterial supply.^E205–E211 Reduction of portal pulsatility index in more than 50% of patients following Fontan operation has additive effects on hepatic dysfunction.^E205–E212 There is dilation of splanchnic and systemic circulation and increased circulatory blood volume to augment the cardiac output and compensate for the decreased systemic vascular resistance (Table E2).^E213–E218

Studies by Chaloupecky and associates demonstrated reduced mean concentrations of factor V, factor VII, protein C, and fibrinogen following Fontan procedure due to decreased protein production in liver.^E4–E7,E214 Bradycardia, reduced cardiac index, and portal vein thrombosis are other contributing factors for selective impairment of clotting factors in the presence of normal liver function test.^E4–E10 Thus post-operatively, these patients should undergo monitoring of hepatic function, abdominal ultrasound, hepatic fibroscan, CT, or MRI to evaluate the degree of Fontan-associated liver disease (Table E2).^{E240,E249,E250,E254–E261}

Atrioventricular valve dysfunction and outflow obstruction

A restricted ventricular septal defect, atrioventricular valvular stenosis, or regurgitation may cause Fontan circuit failure. Subaortic stenosis may result in ventricular hypertrophy and diastolic dysfunction. Atrioventricular valvular regurgitation results in elevated right atrial pressures and late Fontan failure even with normal pulmonary vascular resistance (Table E2).^E267–E271 Atrioventricular valvular regurgitation may result from prior volume overload with systemic-to-pulmonary artery shunt, annular dilation and abnormal chordo-papillary apparatus, and conversion of tricuspid valve to systemic atrioventricular valve.^E267–E271

Thrombotic Fontan pathway occlusion

Causative factors for thrombotic occlusion of Fontan pathway include hypercoagulability, low-velocity flow through the circuit, presence of foreign material including patches, conduits, fenestration closure devices, and suture lines.^E40,E41 Circuit thrombosis may cause chronic pulmonary thromboembolism and paradoxic thromboembolism. Thrombotic circuit occlusion is difficult to treat; only 50% of microemboli resolve completely and mortality approaches 25%.^E42 The differential thrombotic risk of various circuits and materials remains ill-defined (Table E2).^E43

Arrhythmias

Post-Fontan arrhythmias include sinus node dysfunction, junctional atrial dysrhythmias, atrioventricular block, supraventricular and ventricular arrhythmias, and risk of arrhythmic sudden death. Incidence of sinus node dysfunction varies from 40 to 60% following atriopulmonary connection to approximately 15 to 44% following lateral tunnel and extracardiac Fontan on long-term follow-up.^E8–E18 Atrial reentrant tachycardia accounts for approximately 75% of supraventricular tachycardia with focal atrial tachycardia in up to 15% of patients.^E18,E19 In lateral tunnel pathway, the reentrant circuit may reside in pulmonary venous atrium.

The atrial arrhythmias increase the pressure in pulmonary venous atrium leading to reduction in the pressure gradient along which the pulmonary blood flows. Reduction in pulmonary blood flow further depletes the preload in systemic ventricle and leads to low cardiac output.^E20,E21

Risk factors for developing post-operative supraventricular arrhythmias include older age at Fontan, dilation and surgical scars within atrial mass, preoperative bradycardia, atriopulmonary connection, lack of sinus rhythm, atrioventricular valvular regurgitation, completion Fontan procedure, and heterotaxy syndrome.^E17–E21 Atrioventricular block may occur due to intrinsic conduction system abnormalities or as a consequence of surgery. Ambulatory 24-hour electrocardiographic monitoring, event monitoring, and exercise testing should be included in post-operative surveillance protocol.^E20,E22

Although catheter-based arrhythmia ablation has an immediate success rate of 40 to 75%, around 60% reoccur within the first year.^E23–E35 The incidence of pacemaker implantation for complete heart block ranges from 3 to 18%.^{Reference Caneo, Turquetto and Neirotti2–Reference Zentner, Celermajer and Gentles5,Reference Deal, Costello and Webster17–Reference Akbari Asbagh, Navabi Shirazi and Soleimani22,E5,E35,E53} Non-sustained and less frequently sustained ventricular tachycardia and sudden death are reported in 2 to 12% of patients; the time-related risk of sudden death appears to be 0.15 to 0.2% per year.^{E187,E188,E262–E266} The reported prevalence of implantation of defibrillator for secondary prevention is 1.4 to 2% of Fontan survivors (Table E3).^{E187,E188,E228,E265,E267}

Somatic growth and bone health

In general, Fontan patients are shorter in height and fail to gain weight due to suboptimal cardiac output.^E55 Children and adolescents with Fontan physiology have abnormal bone structure in addition to linear growth delay.^E272–E280 They have decreased vitamin D levels, increased levels of parathyroid hormone, decreased growth hormone, low lean body mass, and decreased cortical bone mineral density.^E272–E280

Secondary hyperparathyroidism is common in these children owing to alterations in calcium metabolism resulting from altered renal perfusion or poor gastrointestinal absorption.^E281,E282 Overweight and obesity seen in up to 50% of adult patients contribute to increased morbidity.^E283–E286

Kidney

Hepatic, cardiac, and renal dysfunctions may result from poor perfusion. Cardiorenal and hepatorenal syndrome portend a poor prognosis.^E57,E58 The kidneys receive 20 to 25% of cardiac output at rest.^{Reference Rychik, Atz and Celermajer4} Following Fontan operation, acute kidney injury occurs in up to 40% of children.^E287 Chronic renal dysfunction develops in at least 10% of younger patients with increasing prevalence in adolescence and adulthood.^E288 Measured glomerular filtration rate reveals abnormality in nearly 50%, with one-third of patients over 18 years of age demonstrating albuminuria.^E289 The prevalence of proteinuria and albuminuria is 10% to 37% in patients with Fontan circulation.^E290,E291

Ohuchi and associates demonstrated that high renal resistive index (≥0.81) reflects heart failure severity, renal dysfunction, and mortality.^E292,E294 Serum biomarkers such as creatinine, cystatin C, urine albumin-creatinine ratio, kidney injury molecule 1, neutrophil gelatinase-associated lipocalin may be used for regular surveillance.^{Reference Rychik, Atz and Celermajer4}

Hepatorenal insufficiency in failed Fontan may result from sepsis and low cardiac output.^E59 At Mayo clinic over a period of 40 years after Fontan procedure, renal insufficiency was the cause of death in 30% of patients.^E59

Brain

Brain MRI in Fontan survivors has identified widespread abnormalities in white and grey matter microstructure including increased stiffness of cerebral vasculature, periventricular leukomalacia, generalised atrophy, focal tissue loss, ventriculomegaly, acute or chronic intracranial haemorrhage, reduced cortical and subcortical grey matter volume, reduced cortical thickness, and widespread white matter injury involving major fibre tracts.^{E67,E121,E244,E247,E248,E293–E299} Bellinger and colleagues demonstrated an increased incidence of structural brain abnormality by MRI among Fontan adolescents compared to references (66 versus 6%).^E67

Numerous studies over the past two decades have identified a high prevalence of executive functioning challenges, attention-deficit/hyperactivity disorder, and social cognition problems in Fontan survivors.^E67,E300

The potential causes of brain injury include genetic abnormalities, disturbed foetal cerebral haemodynamics, multiple operations with risk of hypoxic-ischaemic injury, microemboli, longer circulatory support, and lower gestational age.^E85,E301

Fontan failure with reduced ejection fraction (Phenotype 1; systolic dysfunction)

This pattern is characterised by features of heart failure, low ejection fraction regardless of ventricular morphology, elevated ventricular end-diastolic and pulmonary venous pressures, hepatic congestion, limited ability to augment cardiac output, and in later stages, elevated systemic vascular resistance and decreased resting cardiac output.^E68 Cyanosis may develop due to veno-venous collaterals from the chronically elevated central venous pressures. Fontan failure with systolic dysfunction is more commonly seen in paediatric population.^E68,E69

Fontan failure with preserved ejection fraction (Phenotype 2; diastolic dysfunction)

Maurer and colleagues identified a phenotypically diverse population of Fontan failure with preserved ejection fraction and pulmonary venous congestion closely resembling diastolic heart failure, characterised by normal or low cardiac output, elevated ventricular end-diastolic pressure, and elevated systemic vascular resistance. The causative mechanisms are inclusion of coronary sinus into Fontan pathway with elevated right atrial pressure, cardiac fibrosis especially in adults, and coronary atherosclerosis.^{E1–E68–E71}

Fontan failure with normal Fontan pressures (Phenotype 3; Fontan circulatory failure)

These patients exhibit “reasonably” normal Fontan pressures, preserved ejection fraction, normal end-diastolic pressure, elevated pulmonary vascular resistance, normal or low systemic vascular resistance, elevated cardiac output, and cirrhosis. In cirrhotic patients without a Fontan, cardiac output is elevated in response to splanchnic arterial vasodilation. Fontan patients in contrast have a limited ability to increase cardiac output; thus, circulatory failure is potentiated. When decompensated, the pathophysiology devolves into renal failure, refractory ascites, and oedema. The pathophysiology is unclear but may be related to elevated central venous pressure and portopulmonary hypertension.^E326

Fontan failure with abnormal lymphatics (Phenotype 4; lymphatic failure)

In this phenotype, the haemodynamics are often “normal” but lymphatic pathology is present. Clinically, this presents as plastic bronchitis, more commonly seen in children, and protein-losing enteropathy, seen in both children and adults.^{Reference Hess, Kruizinga and Bijleveld25–Reference Rychik, Goldberg and Rand30,E189–E192} In patients with plastic bronchitis, magnetic resonance lymphatic imaging or lymphangiography may show dilated lymphatics forming a plexus, often in left or right upper lobes of lungs.^E74

Management

Management of Fontan failure is based on phenotype. Other treatment modalities are targeted at specific adverse events like arrhythmia and thrombosis. However before assigning a phenotype, a diligent search should be made to exclude any surgically correctable cause of Fontan failure and treated accordingly.^{Reference Hebson, McCabe and Elder10–Reference Mori, Park and Yamagishi14}

Pharmacological and non-pharmacological management of Fontan failure include sodium restriction and regular exercise to increase venous capacitance, respiratory exercises, compression stockings to treat varicose veins, maintenance of sinus rhythm with atrioventricular synchrony, and correction of residual or structural valvular complications.^E75–E87 Beta-adrenergic blockers and amiodarone are the drugs of choice for treatment and prevention of supraventricular arrhythmias.

Abdominal problems, due to the high central venous pressures, protein-losing enteropathy, plastic bronchitis, lymphatic problems, hepatic cirrhosis, and carcinoma, are exclusive phenomena of Fontan failure; therefore, medical treatment of normal cardiac failure has no effect in the Fontan circulation.

Following experimentation in animal models, three alternative surgical approaches have been performed in patients with failing Fontan. The first alternative approach is to return to bi-directional Glenn physiology with or without augmented pulmonary blood flow.

The second alternative approach is to replicate “Kawashima physiology.” The extracardiac Fontan was created utilising infrahepatic inferior caval vein, rather than suprahepatic inferior caval vein. Thus, the liver and intestines which are often the major drivers of Fontan circulatory failure are excluded from the Fontan pathway.^E327–329

The third alternative approach is to anastomose the transected brachiocephalic vein to either the right atrium or left atrium depending on the available length, thus decompressing the thoracic duct in failing Fontan. At this stage, one may consider these alternatives when no other treatment options other than cardiac transplantation are available as a last resort therapy. Evidence in support for the efficacy of second and third approaches is limited.^{Reference Hraška24}

Fontan failure with reduced ejection fraction

The management strategy for these patients has been largely extrapolated from the large trials on treatment for left ventricular failure in bi-ventricular physiology. Loop diuretics, aldosterone antagonists, heart failure-specific beta-blockers, such as carvedilol, metoprolol succinate, and bisoprolol and angiotensin-converting enzyme inhibitors, form the core of medical management.^{E56,E115,E306}

However, in cases of late-stage Fontan failure with advanced hepatic dysfunction and liver cirrhosis, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may further decrease systemic vascular resistance leading to renal failure, similar to hepatorenal syndrome, and are potentially harmful.^E80

Fontan failure with preserved ejection fraction

These patients benefit from measures to control pulmonary venous congestion, sodium restriction, loop diuretics, aldosterone antagonists, and perhaps antihypertensives. As these patients have predominantly pulmonary venous congestion, indiscriminate use of pulmonary vasodilators may be harmful.^E79

Fontan failure with “normal Fontan pressures”

Cardiac catheterisation with haemodynamic assessment is necessary to discriminate Fontan failure with preserved ejection fraction from Fontan failure with normal Fontan pressures. Studies have shown that if systemic vasodilators such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are added, there may be a decrease in renal perfusion, precipitating renal failure.^E78 These medications possibly result in a reduced glomerular filtration rate in spite of increasing renal blood flow, since angiotensin II acts on the efferent arteriole causing vasoconstriction with increase in filtration fraction.^E78 Midodrine which raises systemic vascular resistance has been found useful.^E80,E81

A subset of these patients has elevated pulmonary vascular resistance. There is conflicting evidence in literature on the use of pulmonary vasodilators.^E82–E85 Several investigators have observed mixed results with Bosentan in failing Fontan, possibly due to inclusion of multiple Fontan failure phenotypes.^E82–E85 The indications of isolated cardiac or combined cardiac and liver transplantation are unclear.

Fontan failure with abnormal lymphatics

The best-studied medications in patients with protein-losing enteropathy include oral budesonide, and pulmonary vasodilators and cardiac transplantation when appropriate.^{E86,E170,E180–E182} Plastic bronchitis is treated with thoracic duct ligation and percutaneous lymphatic interventions.^E74 Inhaled tissue plasminogen activator and VEST therapy have been used to mobilise bronchial casts with variable success.^E180–E182

Management of early Fontan failure

Early post-operatively, fenestration of Fontan circuit may break the cycle, and if fenestration does not help, deterioration occurs rapidly.^{Reference Stout, Broberg and Book8–Reference Murphy, Glatz and Goldberg16} Rapid recognition and correction of any residual anatomic problems may enable preservation of Fontan circuit. Other options include Fontan takedown to an intermediate circulation like superior cavopulmonary connection, hemi-Fontan, use of extracorporeal membrane oxygenation, or urgent cardiac transplantation. Each option carries risk. Fontan takedown involves additional bypass time and may cause haemodynamic instability. The end result is a still cyanosed patient with borderline cardiopulmonary function and prolonged post-operative course. While a subset of these patients may qualify for a later Fontan procedure, cardiac transplantation provides a more definitive solution.^{Reference Caneo, Turquetto and Neirotti2–Reference Deal and Jacobs9,E109} Since rapid availability of an allograft is the main impediment to cardiac transplantation, “bail out” strategies have been applied by few investigators with limited success.^{Reference Caneo, Turquetto and Neirotti2–Reference Deal and Jacobs9}

Several investigators in the Extracorporeal Life Support Organization Registry have used veno-venous or venoarterial extracorporeal membrane oxygenation as a temporary support in patients with early Fontan failure with a mortality ranging between 35 and 50%.^E330–338 Other investigators have used ventricular assist device including Berlin Heart EXCOR and total artificial heart as a bridge to transplantation with limited success.^{Reference Stout, Broberg and Book8–Reference Murphy, Glatz and Goldberg16,E88–E95,E339–E359}

Management of “failed” Fontan circulation

The surgical options for failed Fontan circulation include Fontan revision, Fontan conversion, and cardiac transplantation. Any correctable anatomic causes should be promptly treated by Fontan revision.^{Reference Stout, Broberg and Book8,Reference Deal, Costello and Webster17,Reference Mavroudis, Backer and Deal20–Reference Akbari Asbagh, Navabi Shirazi and Soleimani22,E37–E39} Surgical or catheter-based interventions have been performed by investigators.^{Reference Stout, Broberg and Book8,Reference Deal, Costello and Webster17,Reference Mavroudis, Backer and Deal20–Reference Akbari Asbagh, Navabi Shirazi and Soleimani22,E37–E39} Morbidity (25%) and mortality (8 to 10%) following Fontan conversion continue to improve but are not insignificant.^{Reference Rychik, Atz and Celermajer4–Reference Khairy, Fernandes and Mayer6,Reference Mavroudis, Backer and Deal20,Reference Mavroudis and Deal21,E91} Despite extensive experience with Fontan conversion, Mavroudis and colleagues found that 5.4% of the 135 patients required cardiac transplantation.^{Reference Mavroudis, Backer and Deal20,Reference Mavroudis and Deal21} Thus, conversion surgery merely delays the inevitable.

Definitive palliation

Cardiac transplantation is a definitive palliation in Fontan journey. It may be the only viable alternative when all follow-up measures to improve ventricular function or Fontan pathway haemodynamics have failed, if exercise intolerance/cyanosis occurs despite acceptable haemodynamics, or presence of multi-organ system complications not reversible by surgical or catheter interventions at acceptable risk.^E88–E95

Cardiac transplantation has been performed with steadily improving outcomes for patients with failed Fontan conversion and arrhythmia surgery; protein-losing enteropathy and plastic bronchitis unresponsive to medical measures; primary systemic ventricular dysfunction unresponsive to medical manipulation; extensive pulmonary arteriovenous malformations; hepatic failure unresponsive to medical measures; and early Fontan failure in absence of a surgically correctable cause, requiring mechanical circulatory assistance.^{E88–E103,E107,E108}

Cardiac transplantation following a Fontan procedure may require reconstruction of systemic or pulmonary venous pathways, aortic arch, and pulmonary arteries. Patients with a Bjork’s modification frequently have inadequate central pulmonary arteries. Reconstruction of pulmonary arteries using donor vascular tissue is preferable. Over 90% of post-Fontan cardiac transplantation required pulmonary artery or venous reconstruction in Children’s Hospital of New York Paediatric Transplantation Registry.^E107,E108

Bridge to definitive palliation

Upon developing Fontan failure with end-organ damage, patients are destined for a cardiac transplant or death. Mechanical support devices have been used as a bridge to transplantation.^E329–E59 In general, patients with early Fontan failure and refractory arrhythmias have been subjected to extracorporeal membrane oxygenation. In the setting of incomplete decompression and desire to maintain pulsatile flow with oxygenated blood in the Fontan circuit, one could choose a venoarterial venous strategy.^E330–E338

Patients with Fontan circulation pose unique challenges to extracorporeal membrane oxygenation support. High cerebral venous pressures in combination with low systemic blood pressure result in decreased cerebral perfusion pressure contributing to neurologic injury. Particular attention should be given to maximising venous drainage decompressing both upper and lower compartments using multiple venous cannula, specifically with the initial cannula placed above and the second cannula below.

In order to achieve continuous decompression of a failing Fontan circuit, continuous-flow ventricular assist device, bi-ventricular assist devices, or total artificial heart has been used as a bridge to cardiac transplantation.^E339–359

Despite the recognition of an increasing population of Fontan patients who would potentially benefit from mechanical support devices, reports of success of ventricular assist devices are uncommon.^E339–359 A recent report of the Berlin Heart EXCOR (Berlin Heart Inc., The Woodlands, Tx) in 204 children included 19 patients with a single ventricle physiology with a mortality of 42%.^E339–359

Stem cells and tissue engineering in Fontan failure

Preclinical and clinical studies indicate that stem cell therapy with a subset of cell lineages has the potential to mitigate the deterioration of systemic right ventricular function by promoting angiogenesis and decreasing oxidative stress.

Cardiac progenitor cells or stem cells that have committed to a cardiac fate were first delivered to patients with hypoplastic left heart syndrome in the transcoronary infusion of cardiac progenitor cells in patients with univentricular physiology . Clinical trial phase I and II results demonstrated significant improvement in ejection fraction compared to baseline values. Results of phase III trials are awaited.^E360,E361

In addition to cardiac progenitor cells, several groups have investigated the benefit of multipotential mesenchymal stem cells on systemic ventricular function.^E362 However, results from meta-analysis of 16 stem cell clinical trials reported only a small improvement in ejection fraction.^E362

Poor cell retention has limited stem cell efficacy in vivo, and biocompatible materials that can support cells in vivo may increase their therapeutic benefit in younger patients. Tissue engineering utilises cells, scaffolds, and bioactive molecules to develop biological substitutes for damaged tissues.^E363

Tissue-engineered conduits for use in Fontan-Kreutzer procedure have been evaluated in Japanese clinical trial 84 and Nationwide Children’s Hospital trial in United States of America.^E364–E367 These patients demonstrated exceptional graft growth and patency when the cells are delivered to the scaffold in a dose-dependent manner.^E368 However, 25% of patients experienced stenosis in the late-term, and this solution does not address the long-term complications associated with passive flow and congestion within the Fontan circuit.^E369–E377

A group of Tokyo women’s Medical University utilised cell sheet technology for application to Fontan.^E378,E379 Pacing and engraftment failure have been the main concern. Recently, a report out of Yale University details the design and in vitro performance of a modular tissue-engineered pulsatile conduit.

A main takeaway from the mesenchymal stem cells and cord-derived cell-based clinical trials is the safety and efficacy of autologous stem cells in the single ventricle population and the ability to modulate tissue-engineered structures by delivering cells to scaffold in doses.^E376

Arrhythmia surgery

The most common indication is refractory supraventricular arrhythmias with or without haemodynamic abnormalities.^{Reference Mavroudis, Backer and Deal20,Reference Mavroudis and Deal21} The combination of revision or conversion of atriopulmonary or atrioventricular type of Fontan circuit to either a lateral tunnel or an extracardiac Fontan procedure, appropriate modified maze procedure, and routine dual-chamber pacing has been performed with steadily improving short- and long-term outcomes.^{Reference Mavroudis, Backer and Deal20,Reference Mavroudis and Deal21,E115}

Arrhythmia surgery involves intraoperative epicardial electrophysiological studies and cryoablation of lesions identified in right and occasionally in left atrium. The advances in multisite pacing have also been applied to dyskinetic systemic ventricles.^E119 Some authors support presumptive strategy of atrial lead placement at Fontan repair owing to limitations of post-operative venous access to the atrium, risk of endocardial lead thrombosis, and morbidity of repeat sternotomy.^{Reference Caneo, Turquetto and Neirotti2–Reference Schilling, Dalziel and Nunn7,Reference Mavroudis, Backer and Deal20,Reference Mavroudis and Deal21,E37–E39}

Pulmonary vasodilators

The utility of pulmonary vasodilators in Fontan failure is controversial.^35–39,E120 In selected cases of Fontan failure with normal pressures with raised pulmonary vascular resistance, sildenafil (phosphodiesterase type-5 inhibitor) improved symptoms and no other features of Fontan failure.^E120–E128 This effect appears dependent on reduction on pulmonary vascular resistance rather than direct effects on ventricular function.^{Reference Elder, McCabe and Hebson12,E121,E122}

Results of endothelin receptor antagonists, namely bosentan and macitentan, have been equivocal, with two small randomised trials showing improved exercise capacity, oxygen consumption, and functional status, whereas a third trial showed no benefit.^{E151–E153,E120–E128,E183–E185}

Kim and associates demonstrated the beneficial effects of inhaled iloprost in limited patients with failing Fontan.^E11,E129 Presently, use of prostanoids is not widespread and requires further clinical evaluation.