State of the art of the Fontan strategy for treatment of univentricular heart disease

In patients with a functionally univentricular heart, the Fontan strategy achieves separation of the systemic and pulmonary circulation and reduction of ventricular volume overload. Contemporary modifications of surgical techniques have significantly improved survival. However, the resulting Fontan physiology is associated with high morbidity. In this review, we discuss the state of the art of the Fontan strategy by assessing survival and risk factors for mortality. Complications of the Fontan circulation, such as cardiac arrhythmia, thromboembolism, and protein-losing enteropathy, are discussed. Common surgical and catheter-based interventions following Fontan completion are outlined. We describe functional status measurements such as quality of life and developmental outcomes in the contemporary Fontan patient. The current role of drug therapy in the Fontan patient is explored. Furthermore, we assess the current use and outcomes of mechanical circulatory support in the Fontan circulation and novel surgical innovations. Despite large improvements in outcomes for contemporary Fontan patients, a large burden of disease exists in this patient population. Continued efforts to improve outcomes are warranted. Several remaining challenges in the Fontan field are outlined.


Introduction
Functionally univentricular congenital heart disease (CHD), in which only one ventricle is fully developed, poses a complex clinical problem. Estimates of the incidence of this disease entity range from 0.08 to 0.4 per 1,000 births 1-3 . Functionally univentricular CHD entails different morphological diagnoses, the most common of which are hypoplastic left heart syndrome (HLHS) (25 to 67% of functionally univentricular hearts), tricuspid atresia (15 to 24%), and double inlet left ventricle (14 to 18%) 1,3-5 . It is estimated that currently there are about 22,000 patients in Europe and about 50,000 in the US 6 . Recent advancements in prenatal screening have increased the rates of prenatal diagnosis and possibly termination of pregnancy in patients with univentricular hearts 1,7 . Despite the low incidence, improvements in treatment have reduced the mortality to the point where a large number of patients survive into adulthood.
Palliation can be achieved with the Fontan strategy. A series of operations is performed to palliate the adverse effects of a univentricular heart. The Fontan strategy refers to the landmark surgery for tricuspid atresia by Fontan and Baudet 8 . In the "early days" of this procedure, it was attempted to replace the function of the right ventricle with the right atrium by connecting the right atrium to the pulmonary artery. Although short-term results were unprecedented, this strategy caused dilation of the right atrium, resulting in arrhythmia and thromboembolism due to sluggish blood flow 9 . Modifications of this surgery are referred to as atriopulmonary connections (APCs). In a later era, de Leval et al. found that atrial contractions did not contribute significant power to the APC circuit and proposed the intra-atrial lateral tunnel (ILT), a transatrial connection using an intra-atrial baffle connecting the inferior caval vein to the pulmonary artery in a more energetically favorable manner 10 . Currently, most centers employ an extracardiac conduit (ECC), a prosthetic conduit that bypasses the atrium completely. Both ILT and ECC are referred to as total cavopulmonary connection (TCPC) Fontan modifications.
A Fontan circuit was originally created in a single surgical setting. This resulted in relatively high mortality. A staged TCPC, in which a series of operations is performed at different ages, is the current standard of care. These operations are tailored to the individual anatomy of the patient. First, the single ventricle (SV) needs to be connected to the aorta, which may require extensive surgery, such as the Norwood procedure for HLHS. At about 3 to 6 months of age, a partial cavopulmonary connection (PCPC), connecting the superior caval vein to the pulmonary artery (that is, bidirectional Glenn procedure), is performed. Completion of the TCPC is usually performed between 18 months and 4 years of age 4 . The connections and circulatory pattern after these operations are illustrated in Figure 1.
These patients require a lifetime of highly specialized care and significant health-care resources. In Oceania, the mean hospital costs across all stages of palliation are about $200,000 per patient 12 . Following Fontan palliation, hospital admission rates for patients are eight times higher than for the general population 13 , and both length of stay and hospital costs are higher compared with those of other CHDs, including tetralogy of Fallot 14-16 .

Physiology
In unpalliated univentricular CHD, cyanosis occurs because of mixing of saturated and unsaturated blood in the heart. The SV is also exposed to volume overload as it drains both systemic and pulmonary venous return at the same time. The Fontan strategy reduces volume overload and restores normoxemia. Following PCPC surgery, some volume unloading of the SV is achieved. Following TCPC, the volume load of the SV is further reduced 17 . Furthermore, after TCPC, the systemic and pulmonary blood flows are connected in series rather than parallel as before this strategy has been deployed. This comes at the expense of the lack of a ventricle supplying energy to the pulmonary circulation. This is illustrated in Figure 2. The SV provides the energy needed to attain blood flow through the systemic as well as the pulmonary vascular bed and is subjected to increased afterload. After TCPC, central venous pressures are higher than normal. Pulsatility in the pulmonary artery is mostly lost and there is preload insufficiency of the SV. This highly abnormal circulation is called the Fontan circulation. The resulting physiology has been referred to as a "Fontan paradox", where systemic venous pressure is high in the presence of relative pulmonary artery hypotension 18 . This might augment lymphatic outflow and impede lymphatic inflow from the thoracic duct. Several complications of the Fontan strategy have been linked to abnormalities in lymphatic drainage. Because of the multiple inherent hemodynamic challenges of the Fontan circulation, it is generally considered a palliative procedure 19 .
The aim of this article is to provide an overview of current outcomes, treatment options, and remaining challenges to improve outlook for patients with univentricular heart disease.

State of the art
Overall survival Survival following the Fontan procedure has increased dramatically in the past few decades. We will discuss data from recently published reports of large cohorts with long follow-up intervals. An overview of studies assessing survival is presented in Figure 3, obtained from Kverneland et al. 21 .
In a recent study from Oceania, perioperative mortality decreased from 8% between 1975 and 1990 to 1% in 2001-2010 22 . In this cohort, early Fontan takedown occurred in 2% of patients. Ten-year survival among patients discharged with a Fontan circulation was 89% following APC and 97% for both ECC and ILT 23 . Survival at 25 years was 76%. This group was composed only of APC patients.
In a retrospective study from the Mayo Clinic of 40 years and 1,052 Fontan patients, overall survival rates were 74% at 10 years, 61% at 20 years, and 43% at 30 years 24 . Survival was significantly higher in later surgical eras, and 10-year survival was 95% for patients operated on after 2001. Interestingly, patients operated on with the ECC technique showed better overall survival over ILT. It should be taken into account that patients with cardiac defects with worse prognosis were more frequently operated on using the ILT technique. A Danish national registry described outcomes for SV patients from 1977 to 2009 1 . Fifty percent of patients died before Fontan completion. Overall survival improved in later birth eras. Five-year survival for any univentricular CHD increased from 22% in 1977-1989 to 51% in 2000-2009. One should note that follow-up studies after Fontan procedures reflect results of an earlier surgical era and do not necessarily represent the outlook of Fontan patients undergoing surgery in the current era.

Determinants of survival
Several factors have been associated with survival after the Fontan procedure. Of preoperative factors, male gender 23 and specific CHD diagnosis, most strikingly for HLHS 25 , have been associated with worse long-term survival. Perioperative risk factors for mortality include APC type procedure, earlier surgical era, older age at procedure, concomitant valve replacement, and prolonged postoperative pleural effusion 25 . Postoperative factors that affect survival include elevated central venous pressure and lower arterial saturation 26 ; imaging-derived parameters such as lower global longitudinal strain on echocardiography and higher end-diastolic volume measured by magnetic resonance imaging (MRI) 25 ; peak heart rate and peak oxygen uptake during cardiopulmonary exercise testing 25,27,28 ; and serum levels of sodium, creatinine, and brain natriuretic peptide 25,29,30 .

Cardiac complications
Although survival following Fontan completion has increased over time, the Fontan strategy has been associated with important morbidity, most likely related to extensive surgical procedures and the highly abnormal circulatory state after these procedures. In recent cohorts, event-free survival has ranged from 59 to 81% at 15 years 23,31 .
The most commonly reported event is cardiac arrhythmia. Supraventricular tachycardia (SVT) contributes significantly to late mortality in Fontan patients 32 . SVT has been associated with Fontan type; the highest risk is for APC type, followed by ILT, and the lowest is for ECC 23,33 . Results may have improved for the ILT technique after introduction of the prosthetic modification 35 . The incidence of SVT increases during follow-up, and after 20 years of follow-up, 10 to 60% of patients have experienced some form of SVT 34,35 .
Failure of the Fontan circulation can occur even in long-standing uncomplicated Fontan circulations. The definition of Fontan failure varies but generally includes excessive constitutional limitations of the Fontan physiology, abnormal parameters of hemodynamic function, poor functional status, or the presence of Fontan sequelae 36 . Fontan failure occurs in 2 to 13% of patients, depending on definitions and follow-up period 36 . A 56% 25-year freedom of Fontan failure for APC connections has been reported 23 .

Extracardiac complications
Abnormalities of coagulation. Blood flow can be slow in the Fontan circuit because of the absence of a prepulmonary pump. This promotes coagulation. Furthermore, coagulation factor abnormalities have been described in the SV patient, even before PCPC palliation 37 . Thromboembolic events are more common following APC surgery than TCPC 37 . The prevalence of thrombi is particularly high in those who develop atrial arrhythmias 38 . Up to 65% of thrombi are detected within the first year following TCPC (early thromboembolic events) 39 . Early thromboembolic events probably relate to perioperative factors, such as extracorporeal membrane oxygenation (ECMO) use and altered hemodynamics. Beyond 10 years after Fontan completion, incidence of late thromboembolism steadily increases 39 . Reports of the incidence of thromboembolism are complicated by different definitions and methods of detection. Studies report incidences of late thromboembolism of between 1 and 25% 31,40 . Silent thrombi are detected with transesophageal echocardiography in up to 33% of patients 41 . Thromboembolic events have been reported to account for 8% of Fontan deaths 42 .
Liver function abnormalities, cirrhosis, and even hepatocellular carcinoma have been reported following Fontan surgery 43 . The elevated systemic venous pressures encountered in the Fontan circulation lead to chronic venous congestion in the liver. However, the exact mechanism for Fontan-associated liver disease remains unknown, as does how best to monitor progression 44,45 . The American College of Cardiology recently provided a position statement on the subject, advising laboratory and imaging screening at least every 3-5 years in children and at least every 1-3 years in adult Fontan patients 46 . Preventive strategies need to be developed.
Protein-losing enteropathy (PLE) is a devastating complication of the Fontan circulation in which loss of protein in the gastrointestinal tract occurs, leading to low albumin levels, edema, pleural effusions, and ascites. Incidences of between 3 and 29% have been reported 24,31,35,47 . It is thought to be caused, in part, by impairments in the lymphatic drainage. Hepatoduodenal lymphatic connections exist in some patients as a normal anatomic variant, which might induce competition in lymphatic flow in the presence of elevated venous pressure, diverting lymphatic flow to the gastrointestinal tract.
Plastic bronchitis is a serious pulmonary complication of the Fontan circulation in which large gelatinous casts are formed in the airways. It is thought to be related to abnormal lymphatic drainage directly into the airways, resulting in cast formation. Reported incidences range from 0.5 to 4% 48-50 .
Chronic kidney disease is estimated to be present in up to 50% of adult Fontan patients and is associated with adverse outcomes 30,51 . With the increasing availability of cystatin C-determined glomerular filtration rate (GFR), a muscle massindependent estimate, the prevalence of clinically significant renal dysfunction appears to be lower 52 . GFR estimates based on serum creatinine concentrations probably overestimate renal function in Fontan patients 51 .
Psychological, psychiatric, and cognitive defects have been described in Fontan patients. Cerebral MRI has shown morphological differences in some cerebral structures of Fontan patients compared with those of healthy controls 53,54 . Interestingly, the pituitary gland, supplied by a portal venous system similar to the liver, appears to be enlarged following Fontan surgery 55 . The relevance of this possible congestion on the endocrine system remains unclear.

Re-interventions
Many patients require additional surgical and catheter-based interventions following Fontan completion. Twenty-year freedom of re-operation following TCPC procedures in recent eras ranges from 86 to 92% 56 . In older cohorts, higher re-operation rates have been reported 24,57,58 . The most common surgical re-intervention procedures, in order of incidence, are pacemaker implantation in 9 to 23% of patients 23,24 , Fontan revision or conversion in 3 to 18% of patients 9,24,59 , and atrioventricular (AV) valve repair in 1 to 14% of patients 24,59,60 .
Fontan conversion, from APC to TCPC, can improve functional status and exercise tolerance in the failing Fontan circulation 61 . AV valve repair after Fontan completion is considered in patients with moderate to severe regurgitation, but survival following successful repair remains inferior to that of patients without prior AV regurgitation 62,63 .
For several reasons, re-interventions by catheter may be required. A fenestration in the atrial tunnel, inducing a rightto-left atrial shunt, can be created during surgery to decrease systemic venous pressure, increase ventricular preload, and improve cardiac output at the cost of lower arterial saturation. This fenestration sometimes closes spontaneously or can be closed via catheter at a later time 64 .
Hemodynamically significant obstruction in the Fontan pathway may occur, most commonly in the left pulmonary artery 57,65 . In the absence of a prepulmonary pump, this can severely affect the Fontan circulation, and obstructions are routinely dilated or stented.
Systemic to pulmonary venous collaterals can produce a right-to-left shunting which often worsens in time. Coiling of these collaterals is routinely performed in some centers, although no survival benefit has been demonstrated 66 .
Aortopulmonary collaterals are common in the Fontan circulation. They increase pulmonary blood flow but induce a volume overload on the SV and might increase pulmonary artery pressure, limiting flow from the caval veins 65 . During exercise, aortopulmonary flow increases, possibly augmenting loading conditions of the ventricle 67 . A large aortopulmonary collateral burden has been associated with worse short-term outcomes 68 . No clear consensus regarding the long-term effects and management of these collaterals exists 65 .
Catheter ablation of an arrhythmogenic substrate is common. Long-term success rates vary between 15 and 72% 69,70 .

Other outcomes and functional status
Most studies report a diminished quality of life in Fontan patients compared with healthy controls 74-78 . Physical and emotional functioning are the most severely affected domains 74,79 . Low perceived health status can lead to unnecessary restrictions in daily life. Furthermore, increased rates of developmental disorders and lower intelligence scores have been reported in the Fontan population 53,76 .
Fontan patients have a moderately decreased exercise capacity compared with healthy controls 80 . Mean peak oxygen uptake ranges from 61 to 74% of predicted values 80-82 . A small fraction of Fontan patients have normal exercise capacity 83 . Exercise capacity in the Fontan patient has been shown to decrease over time 81,82 . Exercise capacity is predictive of hospital admissions, quality of life, and late mortality 25,28,79,82 . Exercise training can be done successfully in Fontan patients and can improve quality of life, functional class, and health perception in a short-term follow-up 84-87 . Whether exercise training has a role in optimizing long-term outcome is currently not clear 84,86-89 . Resistance training can be used to increase muscle mass. In the Fontan patient, this could augment peripheral venous return, augment ventricular preload, and improve cardiac output 90 . Similarly, a benefit of inspiratory muscle training has been demonstrated 91 .
Despite high morbidity and suboptimal outcomes, most patients with a well-functioning Fontan circulation manage to lead fulfilling lives, are employed, may attain academic achievements, can participate in sports, and are able to successfully carry pregnancy to term 92-94 .

Assessment techniques
Fontan patients are routinely assessed for health and functional status. Diagnostic cardiac catheterization has been standard practice in the pre-TCPC evaluation, as it provides excellent anatomic and necessary hemodynamic information regarding the pulmonary artery pressure, pulmonary vascular resistance, and end-diastolic SV pressure 95 . There is recent interest in omitting cardiac catheterization in the pre-TCPC assessment for low-risk SV patients [95][96][97] . No consensus regarding this policy has been reached, as long-term outcomes are currently unavailable. Catheter-based interventions are discussed above.
Cardiac magnetic resonance imaging (CMR) is routinely performed during follow-up after TCPC, particularly to assess ventricular size and function and to quantify large vessel flow, including the amount of collateral flow 98-102 . Death and (being listed for) heart transplantation have been associated with higher end-diastolic volume index (EDVi) (>125 mL/m 2 ) as assessed with CMR in adolescents with a Fontan circulation 103,104 . Combined with a computational fluid dynamics approach, CMR might provide very useful information on the Fontan circulation and can aid in the evaluation of modifications in treatment strategies 104,105 . Echocardiographic strain measurements have been shown to predict survival in the Fontan population and predict length of hospital stay following TCPC 104,106 . Assessment of ventriculoarterial (VA) coupling may be another important parameter, as it is independent of the (often impaired) ventricular load. VA coupling has been shown to be suboptimal in some Fontan populations 107 . Currently, VA coupling has not been associated with long-term outcomes in the Fontan population.
Lymphangiography could play an important role in the management of Fontan complications with a suspected lymphatic pathogenesis, such as PLE and plastic bronchitis. In patients with PLE or plastic bronchitis, increased diameters of major lymphatic vessels have been noted 108 . Abnormal lymphatic depositions in the lungs and liver have been visualized in patients with plastic bronchitis and PLE, respectively 109,110 .

Medical therapy
Anticoagulation, in the form of anti-platelet drugs or vitamin K antagonists (VKAs), is commonly indicated considering the increased risk for thromboembolic events, as discussed above in the "Extracardiac complications" section 111 . A metaanalysis by Alsaied et al. showed that both acetylsalicylic acid and VKA were equally effective in preventing thromboembolic complications 112 . However, if international normalized ratio (INR) is not properly controlled, outcomes on VKA are worse compared with acetylsalicylic acid 113 . Novel oral anticoagulants (NOACs) do not require frequent monitoring and have mostly outperformed VKA in the adult population. Thirty-day outcomes following NOAC initiation show no major adverse events in the adult CHD population 114 . However, no NOAC agent currently has US Food and Drug Administration approval for use in children.
Medical prevention of circulatory failure in the Fontan circulation Various medications have been assessed in the management of Fontan failure. No studies have shown benefit of angiotensinconverting enzyme (ACE) inhibitor therapy on survival, ventricular function, or cardiopulmonary exercise outcomes 115,116 .
Vasodilator drugs have been used to lower pulmonary vascular resistance 117,118 . Sildenafil has increased ventricular function, exercise capacity, and New York Heart Association (NYHA) status after 6 weeks of follow-up 119,120 . The effects of bosentan, an endothelin antagonist, in the Fontan population have varied [121][122][123][124][125][126] . No long-term survival benefit of vasodilator therapy has yet been demonstrated 119 .

Mechanical circulatory support for the failing Fontan circulation
The failing Fontan circulation can be supported by mechanical assist devices. Despite increasing use and the development of novel devices specifically for the pediatric and CHD population, experience in this population is still limited 127 . Mechanical support devices are mostly used as a bridge to transplant in the failing Fontan 128 . Recent reports showed a 60% 12month survival in 48 Fontan patients with a ventricular assist device, proving viability of longer mechanical circulatory support 129,130 . A total biventricular artificial heart, the SynCardia, has been used to bridge a failing Fontan patient to transplant 131 . A registry of mechanical circulatory support specifically for SV patients has been initiated 132 . Currently, mechanical circulatory support in Fontan patients is associated with worse survival compared with mechanical circulatory support patients with a biventricular circulation 133-135 .

Cardiac transplantation
Cardiac transplantation is the only treatment that truly corrects Fontan physiology, and it is employed in the failing Fontan circulation. In large cohorts, 1.6 to 3.6% of patients ultimately underwent cardiac transplant 23,24 . Survival following cardiac transplantation in Fontan patients is generally worse compared with other types of CHD 136,137 . Five-year survival ranges from 60 to 67% 136-138 .

Surgical innovations
Continual efforts are made to improve the surgical techniques used in Fontan surgery. Recently, a Y-shaped graft was proposed for the connection of the inferior vena cava to the left and right pulmonary artery 139 . Theoretically, this graft is more energetically favorable and provides better distribution of hepatic blood flow between the left and right pulmonary artery, distributing "hepatic factors" that may prevent the formation of intrapulmonary collaterals more equally. Worse energetic performance and pulmonary flow distributions in comparison with ECC connections have been noticed in practice 140,141 .
Fontan completion without cardiopulmonary bypass, particularly with the ECC technique, is an attractive option. However, experience is still limited and reported rates of conduit replacement and outcomes following off-pump procedures differ across centers 142-145 .
Less-invasive surgical approaches such as lateral thoracotomy have been described in this population 146 . Hybrid procedures, which combine transcatheter and surgical approaches, have been implemented in the initial management of HLHS 147 . Long-term outcomes are favorable, and some centers have adopted this hybrid approach as the standard for selected patient populations 148 .

Remaining challenges
A contemporary Fontan strategy uses either the ILT or the ECC modification. Two large meta-analyses have recently compared surgical strategies and found no differences in early or late mortality and Fontan takedown between ECC and ILT 33,149 . Theoretical advantages of both techniques have been discussed extensively in the literature 150,151 . Further research should assess contemporary differences in outcomes between modifications and help guide the preferred procedure for future Fontan patients. This may include alternative concepts, like the Y-graft or combinations with external energy supply (pumps).
Remodeling of the SV, which is exposed to volume overload at birth and is volume-deprived following the TCPC procedure, is not very well understood. A better understanding of mechanisms of remodeling during these stages and the interaction of ventricular size and function with the Fontan baffle function, pulmonary circulation, atrial function, and VA interaction is required to find better means to preserve cardiac function. The search for new targets for drugs that may help to preserve cardiac and circulatory function continues.
Some controversy regarding the timing of TCPC surgery exists. Proponents of early TCPC argue that a prolonged period of volume overload leads to adverse cardiac remodeling and reduced cardiac function 152 . Others argue that the Fontan circulation inherently leads to complications and that surgery should be delayed to reduce the amount of time in Fontan physiology 153 . Other factors to be considered are the techniques used; ILT allows TCPC at lower body weight than ECC since small-sized conduits (<18 mm) need to be avoided 152,154 . Studies assessing the optimal timing of ECC procedures are currently being performed.
The effect of systemic to pulmonary venous and aortopulmonary collaterals on the Fontan circulation remains poorly understood. These collaterals could provide some benefit in patients with a suboptimal Fontan circuit. How these collaterals develop and why some patients seem more prone to this development remain to be determined. Increasing our understanding of the role of collaterals could help guide the selection of patients who will benefit from intervention. This requires well-designed (multicenter) studies. Several treatment modalities of PLE have been described in small series, including catheter-based strategies of both blood and lymphatic vessels and surgical re-implantation of the innominate vein into the common atrium [155][156][157][158][159] . More comprehensive analysis is needed to determine the efficacy and safety of these procedures.
Drug therapy has been shown to be able to decrease pulmonary vascular resistance in the short-term, making this a promising therapy for the Fontan patient. However, currently, no long-term benefit has been demonstrated. The role of drug therapy in the Fontan circulation needs to be studied more extensively.
These questions require answers to make better-informed decisions in the management of these challenging patients, who have some of the most severe kinds of CHD. We have an opportunity to help this growing patient population not just to survive but also to thrive and live full and satisfying lives.

Conclusions
The modern Fontan strategy has significantly transformed outcomes for patients with univentricular CHD. This has led to a large and growing population of Fontan patients surviving into adulthood. However, morbidity remains high and increases as this population ages and grows in proportion. Efforts to reduce morbidity and improve quality of life in these patients are ongoing. These efforts are focused on improving surgical techniques, developing novel diagnostic and therapeutic tools, and increasing our understanding of the highly abnormal Fontan physiology.

Competing interests
No competing interests were disclosed.

Grant information
The author(s) declared that no grants were involved in supporting this work.
with functional single-ventricle physiology: impact of ventricular and valve resonance imaging: role in pediatric congenital heart disease. Asian

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