Evaluation and Management of the Child and Adult With Fontan Circulation: A Scientific Statement From the American Heart Association

The normal subpulmonary ventricle (normally the right ventricle) keeps systemic venous and right atrial pressures low at rest and during exertion, accelerates pulmonary flow in a pulsatile manner, and increases cardiac output by both heart rate and augmented stroke volume. Pulmonary pressures can normally increase up to 50 mm Hg (or even more) during exercise, leading to recruitment of lung vessels.⁴⁸ The normal subpulmonary ventricle will also allow some compensation in disease states such as pulmonary pathway obstruction or any lung disease that may result in increased pulmonary vascular resistance. The absence of a subpulmonary ventricle results in increased venous pressure at rest and at exercise, with a greater dependency on the skeletal and respiratory muscle pumps for preload augmentation during exercise. In addition, lack of pulsatility and marked attenuation of the normal high-pressure high-flow pulmonary arterial circulation during exercise occur. Consequently, there is less recruitment of collapsible pulmonary vessels, especially at low exercise levels. This results in diminished ventricular preload, with decreased volume-induced ventricular stretch downstream during exercise.

Excessive flow restriction in this passive flow system can occur at any level of the Fontan circuit or the lungs: the Fontan venous connections; the pulmonary arteries; the pulmonary capillary network, including precapillary sphincters; the pulmonary veins; or the venoatrial connection. These impediments include, but are not limited to, stenosis, hypoplasia, distortion, vasoconstriction, pulmonary vascular disease, loss or exclusion of large vessels or microvessels, turbulence or competitive flow collision, flow mismatch, and obstruction by external compression. Impediment at any level of this circuit can profoundly affect cardiac output in Fontan circulation, to a greater degree than in a 2-ventricle circulation.

From even before birth, the single ventricle is subject to abnormal hemodynamic demands and morphological abnormalities that can predispose to systolic or diastolic dysfunction.⁴⁹ Palliation of the single ventricle with an aortopulmonary shunt or pulmonary artery band in the neonatal period results in increased ventricular volume load, a condition caused by the presence of pulmonary and systemic circulations existing in parallel, with mixing within the single ventricle. Valvular regurgitation (atrioventricular or semilunar) can also add to the hemodynamic stress on the myocardium. As a result of intracardiac mixing, arterial oxygen saturation is low, and the myocardium is subject to a chronically hypoxic environment. A significant proportion of patients with a single ventricle have either morphological right or indeterminate anatomy.⁵⁰ However, even in those with single left ventricle, normal geometry as in a 2-ventricle system is not preserved. Myocardial fiber arrangement in the single ventricle is often disturbed and myocardial fibrosis is present. As a consequence, ventricular energetics and the mechanics of contraction can be deranged, with ventricular systolic and diastolic dyssynchrony possible.^51,52

At the time when the Fontan procedure is performed, the ventricle commonly evolves from being volume overloaded, overgrown, and overstretched to volume deprived with a smaller cavity and increased wall thickness.^49,53 In the short term, this can create a ventricular mass-to-volume mismatch that can deleteriously influence both systolic and diastolic function. Shifting volume load and ventricular mass ratios early in the course of surgical reconstruction may also carry long-term implications for ventricular mechanics.⁵⁴

During exercise, individuals with a normal heart increase their stroke volume by 20% to 50%; in contrast, such an exercise-induced increase may be completely absent in patients with Fontan circulation, most likely as a result of preload restriction.⁴⁸ Chronic volume deprivation with lack of fiber stretch is known to decrease contractility and to increase muscle stiffness, resulting in increasing filling pressures.⁵⁵ Moreover, abnormal ventriculo-vascular coupling may further compound ventricular stiffness.^56,57

Throughout the first years of life for the child with a single ventricle, the pulmonary vasculature is subjected to multiple alterations likely to affect growth and function. During fetal life, pulmonary flow is altered from normal, and pulmonary vascular development can be affected. Neonatal palliation will frequently result in further alterations (usually an increase) in pulmonary blood flow, whereas the staged cavopulmonary connections will decrease pulmonary blood flow. Flow distribution to the lungs may not be uniform. As a result, acquired hypoplasia or vascular disease of the pulmonary vascular bed may occur. Stenosis resulting from ductal constriction, abnormal connections, or surgical scarring can further compromise the pulmonary architecture. The Fontan circulation itself imposes multiple abnormal physiological features onto the pulmonary vasculature such as chronically decreased volume of flow, minimally to mildly desaturated bronchial flow, increased aortopulmonary collateral flow, suboptimal mixing of inferior and superior caval flow streams, endothelial dysfunction, absence of pulsatility, and absence of episodic high flow and high pressure, as is normally seen during exercise, all required for exercise-associated vessel recruitment and vasodilation. In combination, these factors contribute to a burden of pulmonary vascular trauma, resulting in an elevated and increasing pulmonary vascular resistance, which can itself contribute to Fontan circulatory failure.^58,59

A well-accepted definition of heart failure is the inability of the heart to meet resting and exercise demands at low filling pressures. By such a definition, essentially all patients with Fontan circulation have a physiological form of chronic heart failure from the first day after the operation, yet we know that this circulation sufficiently sustains life for decades. The defining thresholds for characterizing failure in a patient with Fontan circulation differ from other cardiovascular conditions. Within the context of physiological failures inherent in the Fontan circulation, some patients develop classic heart failure symptoms such as fluid retention and exercise intolerance. The consequences of progressive heart failure in the patient with Fontan circulation are substantial and result in cardiac and noncardiac morbidities that affect long-term survival and quality of life.

An important distinction to make is the presence of 2 categories of heart failure in the patient with Fontan circulation with a single ventricle: the classic ventricular pump failure phenomenon with its clinical manifestations and Fontan circulatory failure, which is unique as a physiological consequence of chronically elevated systemic venous pressure and low cardiac output. In other words, symptoms of heart failure may exist despite reasonable ventricular performance of the single ventricle, simply as a consequence of venous hypertension and its end-organ consequences inherent in the pathophysiology of every patient with Fontan circulation.

Within 15 years of the introduction of the first Fontan procedure, early survival improved markedly; however, a 1%/y continuous hazard for failure was present throughout the follow-up period.⁶⁰ A recent report of patients who underwent the atriopulmonary Fontan indicates that only 45% of patients remain free of death, heart transplantation, or New York Heart Association class III to VI heart failure over a 28-year follow-up period.⁶¹ Evidence suggests that long-term survival has improved in patients who have undergone the lateral tunnel or extracardiac conduit. However, circulatory failure remains an important cause of death in this population.³¹ Clinical heart failure signs and symptoms are among the leading causes of hospital admission in the Fontan population, and once such heart failure is apparent, it is a strong predictor for worse outcomes.^44,62 In a report from the Dutch CONCOR registry, mortality in the patient with Fontan circulation admitted with heart failure was 24% at 1 year and 35% at 3 years from presentation.⁶³

Systolic or diastolic dysfunction is the underlying cause of circulatory failure in the general population, and the diagnosis and treatment of affected individuals are focused primarily on measures that evaluate and improve myocardial performance.⁶⁴ In contrast, the causes of heart failure in the Fontan population are substantially more heterogeneous and complex. They result in varying phenotypes of heart failure that may represent complex interactions among variables such as systolic and diastolic ventricular performance, structural cardiac or valvular abnormalities, rhythm disorders, and the pathophysiology of passive venous flow through the pulmonary circulation.⁶⁵

Systolic ventricular function is relatively preserved in the first decades after the Fontan procedure⁵⁰ but declines over time.⁴⁴ In the presence of atrial arrhythmias, ventricular dysfunction can improve once rhythm control is achieved.⁶⁶ Systolic ventricular dysfunction is present in 40% to 60% of patients with Fontan circulation undergoing evaluation for heart transplantation.^67,68 These patients often have the manifestations of chronic low cardiac output, including exercise intolerance, poor somatic growth, and fatigue. Systolic ventricular dysfunction can be difficult to assess in the patient with Fontan circulation with a non–left ventricular systemic ventricle because normal values of functional indexes for the right ventricle or the univentricular heart are not uniformly agreed on or readily available. Cardiac magnetic resonance imaging (MRI) is a standard and reliable means for providing serial information on ventricular performance, valvular function, and flow data in the patient with a single ventricle after Fontan.⁶⁹ Although 2-dimensional echocardiography is limited in its ability to evaluate a morphologically abnormal ventricle, fair correlation was demonstrated between the 2-dimensional echocardiographic and cardiac MRI determinations of ejection fraction in a large multicenter study.⁷⁰ Thus, 2-dimensional echocardiography may be adequate to monitor serial changes in ventricular function on a more frequent basis and may complement the application of serial cardiac MRI.

Similar to the adult noncongenital heart failure population, a substantial number of patients with Fontan circulation have evidence of heart failure with preserved ejection fraction. These patients manifest the signs and symptoms of venous congestion and its attendant consequences such as ascites, PLE, and liver cirrhosis, and they may exhibit growth failure as an indicator of low cardiac output.^67,68 Diastolic dysfunction can be difficult to assess noninvasively in the single-ventricle population because of the lack of normal values for systemic right ventricles and univentricular hearts. Estimates of pressure-volume loop relationships indicate evidence for diastolic dysfunction early in the postoperative period after the Fontan operation.⁷¹ A volume challenge can often elicit “occult” diastolic dysfunction late after Fontan, highlighting the sensitivity of the single-ventricle heart to volume loads.^72,73

Ventricular performance can be gauged through functional assessments such as exercise performance. Baseline exercise performance in patients with Fontan circulation is significantly impaired, with a mean maximal peak oxygen consumption of 60% predicted.^74,75 In a large multicenter study, no relationship was found between ejection fraction and exercise performance, whereas a lower resting oxygen saturation, lower oxygen pulse, and chronotropic incompetence were associated with worse exercise performance, highlighting the importance of factors other than systolic ventricular function on exercise capacity.⁷⁵ Key take-away points for heart failure and ventricular dysfunction are listed in Table 1.

PLE is the abnormal loss of serum proteins into the intestinal lumen. It occurs in 5% to 12% of individuals after Fontan palliation.^39,44,164 Morbidity stemming from the disease is marked, and although improved in the current era, mortality remains high.^164–166

The pathophysiology of PLE remains incompletely characterized, but several factors appear to contribute in varying combinations for each individual case. Recent investigation into lymphatic anatomy and function in patients with PLE has revealed an increase in abnormal lymphatic vessels throughout the intestinal tract.¹⁶⁷ Lymphatic congestion, likely present in every patient with Fontan circulation, can lead to overflow or leak of these channels, resulting in spillage of lymph-rich material into the low-pressure intestinal tract and thus enteric protein loss. Lymphatic leak may be worsened by several factors, including the degree of pressure elevation in the systemic veins into which the lymphatic vessels must drain.^167,168 Variability in the anatomic configuration of the lymphatic system may predispose to intestinal or bronchial lymphatic leakage when chronic venous congestion is present. For example, some individuals may have lymphatic channels and decompression pathways that run adjacent to the gut lumen or airway and, when in the presence of elevated venous pressure and lymphatic congestion, manifest spillage into these low-pressure passages. This may explain why only select patients with similar degrees of venous hypertension develop PLE or plastic bronchitis (PB) and others do not. Exaggeration of elevated pressure secondary to anatomic obstruction or cardiac dysfunction can accentuate the problem of luminal protein loss.^164,169 Altered intestinal mucosal perfusion may also play a role. Chronically limited cardiac output demonstrated in patients with Fontan circulation can result in a state of persistently elevated systemic vascular resistance with redistribution of blood flow, along the lines of chronic heart failure. A selective increase in mesenteric vascular resistance may be present as part of flow redistribution. Increased mesenteric vascular resistance has been demonstrated in patients with Fontan circulation and is also increased in those with PLE.¹⁷⁰ Furthermore, chronically low cardiac output leads to a proinflammatory state that may alter enterocyte membrane permeability, predisposing to PLE.¹⁷¹ Finally, a subset of patients with PLE have diminished HSPGs (heparan sulfate proteoglycans), a protein present in the enterocyte membrane that normally assists in enteral protein trafficking, and its absence can result in protein leakage.¹⁷² The overall result of these derangements is leakage or spillover of the intestinal lymphatics and loss of protein into the intestinal lumen. As a result of protein loss, serum oncotic pressure decreases, leading to systemic edema. When the intestinal wall becomes edematous, malabsorption occurs, and protein loss can worsen, leading to a vicious cycle of intestinal symptoms and edema often referred to as a PLE flare. These sporadic periods of worsening PLE often follow a viral infection, further suggesting that inflammation plays a role in bowel wall leak in this condition.

PLE often persists as a chronic condition for extended periods of months to years. Subclinical PLE may also exist with low levels of enteric protein loss that may not manifest as ostensible tissue edema but may nevertheless contribute to perturbations in somatic growth and development of abnormalities in the coagulation cascade, processes that depend on proper protein balance. Transient PLE has been identified in select patients with spontaneous remission and periods of wellness for extended periods of time. However, when sustained PLE is present, complications from chronic protein loss lead to significant systemic morbidity. Chronic diffuse edema leads to symptoms of abdominal and extremity swelling, as well as diminished tissue integrity and difficulty in wound healing.¹⁷³ Coagulation abnormalities result from dysregulation of clotting mechanisms (eg, factor loss or altered production), with an increased risk for thromboembolic complications above and beyond the already increased risk present in every patient with Fontan circulation. Bone density can be profoundly diminished as a consequence of chronic hypocalcemia secondary to low levels of albumin, an essential protein for calcium transport.¹⁷⁴ Linear growth failure occurs frequently.¹⁷³ Immune abnormalities, including low immunoglobulin levels and lymphopenia with profoundly low CD4 T-cell counts, are typically present. Individuals with PLE have a greater likelihood and increased persistence of cutaneous virally mediated processes such as warts and molluscum contagiosum.^175,176 Emerging data suggest that lymphopenia may be present in a substantial number of patients with Fontan circulation without clinically overt PLE and that lymphopenia worsens with greater duration from the Fontan operation. The process of chronic low-level lymphocyte loss resulting from enteric lymphatic congestion and intestinal spillage may explain this finding. Gastrointestinal bleeding can also occur in PLE, with resulting anemia worsening the clinical symptoms.¹⁷⁷

The gold standard test to diagnose PLE is an elevated α-1 antitrypsin clearance in a 24-hour stool collection.¹⁷⁸ Given the challenges in collecting adequate specimen samples for this test, it is also acceptable to base a PLE diagnosis on an elevated α-1 antitrypsin level in a single stool sample together with the presence of serum hypoalbuminemia and symptoms of edema without another identified cause. Tracking serum albumin periodically may detect laboratory-based subclinical albumin loss, act as a marker for subtle deterioration of hemodynamics and strain on a congested lymphatic system, and gauge nutritional status before the onset of full-blown clinical PLE. After a confirmed PLE diagnosis, evaluation for potentially correctable derangements in the Fontan circulation should be undertaken with appropriate assessments.

At this time, treatment of PLE is primarily symptomatic. Heart transplantation has been reported to be an effective strategy in several reports. However, the ravages of long-standing PLE can lead to chronically ill, poorly nourished, frail individuals, a common picture for those with PLE. These patients are often poor candidates for transplantation and may not survive the wait for an organ. The mainstay of symptomatic treatment is aimed at decreasing fluid overload, with aggressive diuresis often augmented by intravenous albumin replacement to replenish oncotic pressure and to drive fluid out of tissue and into the vascular space. Even after a flare is resolved, most individuals will require ongoing maintenance diuretics, and some will require ongoing long-term albumin replacement.¹⁷³ In addition to being useful for sparing renal potassium losses with diuresis, spironolactone may improve symptoms via improved natriuresis or as an anti-inflammatory agent and is often included in a maintenance regimen.^179,180 Dietary modifications, including a high-protein, low-fat diet with a greater-than-normal proportion of medium-chain triglycerides, may be considered as an adjunct to symptomatic therapy,¹⁸¹ although diet alone is typically insufficient to overcome the process. Diarrhea may be present primarily as a result of intestinal lymphatic leak or secondary to gut microbial overgrowth, with loperamide therapy anecdotally reported as helpful.¹⁸² Intravenous immunoglobulin may be administered to raise oncotic pressure in addition to replacing chronically low serum immunoglobulin. Although there are reports of PLE remission associated with intravenous immunoglobulin administration,¹⁸³ this response to treatment is not widespread. Enteral corticosteroids, most often oral controlled-release budesonide, have been demonstrated to help maintain serum albumin levels and to decrease symptoms.^184,185 Although helpful in select patients, steroid therapy can result in cushingoid features, hypertension, dyslipidemia, and suppression of the adrenocortical axis and may contribute to poor growth, poor tissue integrity, and bone demineralization. A strategy of a time-limited course of high-dose steroids with weaning to low maintenance levels can be considered. Phosphodiesterase-5 inhibitors can be used to lower Fontan pathway pressures and to decrease mesenteric vascular resistance, thereby potentially increasing normal lymphatic drainage and improving tissue perfusion, but their efficacy in PLE is not well established.¹⁸⁶ Exogenous unfractionated heparin, either intravenous or subcutaneous, has been reported to induce remission, perhaps in the select subset of individuals with PLE complicated by abnormal or absent cell membrane heparin sulfate proteoglycan. A trial of heparin therapy may therefore be considered, but as with other therapies, if improvement of the disease state is not achieved in the time span of weeks to months, it should be discontinued.^187,188 Dopamine infusion appears to induce remission of protein loss in a small series of patients bridged to transplantation.¹⁸⁹

Invasive procedures may provide the best opportunity for true disease improvement and should be considered on a case-by-case basis. Some individuals with PLE improve with transcatheter fenestration creation, which reduces impedance to forward venous flow at the expense of increased cyanosis resulting from right-to-left shunting.^169,190 Lymphatic interventional procedures aimed at interrupting lymphointestinal connections originating from the liver have achieved remission in a small number of patients with PLE and appear promising.¹⁶⁷ Surgical innominate vein exclusion with rerouting of the innominate vein and the thoracic ductal return directly to the low-pressure pulmonary venous atrium has resulted in remission of PLE at the expense of increased cyanosis.¹⁹¹ Lymphatic pathway drainage-altering therapies may prove to be safe and effective strategies for management of PLE as these procedures evolve and more experience is broadly achieved. Currently, such therapies are most commonly considered in the patient with PLE deemed at high risk or thought not to be a candidate for heart transplantation. To date, only orthotopic heart transplantation has been demonstrated to consistently and effectively treat PLE, with the tradeoff of a relatively high, but in most cases acceptable, risk of mortality.¹⁹² The precise timing of referral for invasive procedures such as fenestration creation, catheter-based lymphatic intervention, surgical thoracic duct rerouting, and heart transplantation remains a challenge when balanced against the potential efficacy of medical management.

PB is a disease characterized by the production of thick, tenacious casts within the airway lumen. It is reported to occur in <5% of individuals with Fontan circulation, although the prevalence of subclinical PB may be higher.^166,193 It confers significant morbidity, most often chronic cough and hypoxemia, with expectoration of proteinaceous casts and increased risk of mortality.¹⁹⁴ Fontan-associated PB is believed to be caused by the spillage of protein-rich lymph through lymphatic-to-bronchial communications.^195–197 Both PLE and PB may be considered part of the clinical spectrum of lymphatic insufficiency associated with chronically elevated venous pressure. Lymphatic system overflow and congestion are in search of natural decompression. In select patients, perhaps related to an individual’s unique lymphatic vascular architecture, lymph decompresses into the airway lumen, causing PB. In PB, an airway inflammatory reaction, precipitated either via a concurrent respiratory infection or secondary to individual abnormalities of inflammatory response, results in fibrin cross-linking within the lymph, causing it to coagulate into a rubbery, solid cast.¹⁹⁸ Bronchial casts can partially or completely obstruct the airway in which it forms and in severe cases may lead to severe hypoxemia, asphyxiation, and death.

PB is diagnosed after production of an airway cast either by patient expectoration or via bronchoscopic removal. Although not diagnostic, symptoms of chronic cough, wheezing, or respiratory symptoms not responsive to bronchodilator therapy in a patient with Fontan circulation may prompt consideration of possible PB. Imaging with MRI T2-weighted techniques that allow visualization of high-water-content structures may help define patterns of lymphatic vascular architecture within the chest or abdomen either before or shortly after the Fontan operation that may be more highly associated with PB or PLE.¹⁹⁹

Initial treatment should target symptomatic therapies aimed at airway clearance. However, a vigorous investigation of the state of the Fontan circulation is warranted to rule out cardiovascular anatomic considerations. Similar to PLE, pulmonary vasodilator therapy and diuretic treatment, particularly with aldosterone inhibition, can be helpful.²⁰⁰ Treatment with bronchodilators and aggressive chest physiotherapy should be started for any patient regularly producing casts.^200,201 Anti-inflammatory therapy with inhaled steroids may be considered, although the effectiveness of this therapy is unclear.²⁰² Therapy with mucolytics such as dornase-α or N-acetylcysteine has been reported to be efficacious in improving cast mobilization in small series and may be considered.²⁰¹ Nebulized and inhaled tissue plasminogen activator therapy can be very effective in clearing obstructive airway material in acutely symptomatic individuals because it targets the fibrin cross-links that lead to cast formation.^203,204 Long-term therapy with tissue plasminogen activator for cast prevention has also been reported.²⁰⁰ In addition to medical therapy, dietary modifications that decrease lymphatic flow such as a low-fat diet have been associated with symptomatic improvement or resolution in some patients.²⁰⁵ Any significant hypoxemia, respiratory distress, or shock in a patient with PB should be treated with urgent bronchoscopy with the goal of clearing the obstructed airway.²⁰⁶ Until recently, the most effective therapy for PB was heart transplantation and elimination of the Fontan circulation. Survival after heart transplantation for PB is relatively favorable and commonly results in disease remission.²⁰⁷ Currently, catheter-based intervention to embolize and eliminate lympho-bronchial airway communications has resulted in durable remission of the disease with excellent outcomes, including low morbidity and mortality.¹⁹⁷ Catheter-based occlusion of lymphatic leaks in PB can be lifesaving; however, such interventions do not influence the underlying deleterious pathophysiology of the Fontan circulation. Therapies targeting venous and lymphatic decongestion with diuretics and pulmonary vasodilators are often still necessary to optimize the circulation in hopes of preventing recurrence. Table 5 lists the various management and treatment strategies for PLE and PB. Key take-away points for PLE and PB are listed in Table 6.

FALD is in part, if not predominantly, related to hepatic flow characteristics unique to the Fontan circulation.²¹³ Infradiaphragmatic hemodynamics change profoundly from the moment the Fontan circulation is installed. Venous pressures rise; lymphatic overflow and congestion ensue; and cardiac output decreases from baseline. Exertional stress exaggerates these phenomena with precipitous increases in central venous pressures to levels ≥25 mm Hg when the individual is awake and active.^214,215 The earliest manifestations of these profound hemodynamic changes are reflected in the universal acute increase in liver stiffness. Hepatic stiffness persists during late follow-up in the vast majority.²¹⁶ The high central venous pressures mimic hepatic venous outlet obstruction, giving rise to arterialization of hepatic blood flow through the so-called hepatic arterial buffer response. The arterial buffer response has long been recognized as an intricate regulatory mechanism through which overall hepatic blood inflow is maintained through autoregulation of the 2 hepatic inflows: hepatic arterial flow (normally contributing ≥25% of inflow) and portal venous flow (normally ≈75% of hepatic inflow).^217,218 Hypervascular nodules within the body of the liver are seen frequently during late follow-up but do not necessarily correlate with worse FALD.²¹⁹ Increased volume of hepatic venous return is associated with a greater degree of fibrosis.²²⁰ This may be a consequence of hepatic arterialization associated with worsening fibrosis, thus leading to increased venous return.

A number of potential mechanisms may contribute to the development of this unique condition, FALD.²²¹ Figure 4 demonstrates some of the mechanisms for the development of liver fibrosis in the patient with Fontan circulation.

All patients with Fontan circulation should undergo regular hepatic screening with assessments that are age dependent and may include laboratory serum screening and imaging (see the Surveillance Strategies: Proposed Schema of How to Monitor the Patient With Fontan Circulation section). Serum α-fetoprotein is a valuable early biomarker for conversion from liver fibrosis to carcinoma and may be incorporated into a regular screening scheme in older patients. A marked or sudden increase in abnormalities of liver parameters should prompt hemodynamic assessment. All potentially important hemodynamic derangements such as significant AVV regurgitation, pathway obstruction, diastolic dysfunction, pulmonary vascular disease, or aortic arch obstruction should be carefully evaluated for possible interventional approaches. Creative surgical strategies such as hepatic vein exclusion, although potentially of short-term promise, are hitherto unproven as a good long-term tactic and may carry adverse consequences such as cyanosis. The use of pharmacological agents such as pulmonary vasodilator therapy, vascular decongestant agents such as diuretics, or antifibrotic therapies such as aldosterone inhibition or angiotensin-converting enzyme (ACE) inhibition is theoretically of potential benefit but as of yet is unproven to prevent the development or to halt the progression of FALD. Considering the ubiquity of FALD, evidence for progression with age, and overall growing concern, study of these strategies is warranted.

General liver preventive health should be advised to all patients with Fontan circulation. These include avoidance of liver toxins when possible, including alcohol and high-dose acetaminophen. The risks and benefits of potential hepatotoxic drugs such as amiodarone should be weighed carefully. Patients with Fontan circulation should be strongly advised to be vaccinated for hepatitis B, to avoid smoking, and to prevent overweight/obesity.²⁴³ End-stage hepatic disease with liver cirrhosis is generally associated with diminished systemic vascular resistance, although this has not been extensively studied in the Fontan circulation. Nevertheless, agents that lower systemic vascular resistance (eg, milrinone, dobutamine) should be used with caution because they may be ineffective or potentially harmful in the critically ill patient with cirrhosis. Liver cirrhosis and end-stage disease may profoundly influence liver performance, leading to an increase in serum ammonia and a decrease in circulating albumin because hepatic clearance and synthetic function are affected. Key take-away points for FALD are listed in Table 8.

The longitudinal development of obesity is similar to that of the general population but poses particularly hazardous consequences for patients with Fontan circulation.^281,282 At the time of Fontan surgery, ≈10% of patients are overweight or obese, increasing to 20% to 30% by 12 years of age and 38% to 50% in adulthood.^281–284 Similar to other populations, childhood overweight or obesity markedly increases the risk for obesity in adulthood for the Fontan population.²⁸² Obesity imposes uniquely negative factors for the Fontan circulation that contribute to heart failure: increased pulmonary vascular resistance, increased ventricular mass, diastolic and ultimately systolic ventricular dysfunction, atrial fibrillation, and elevated blood pressure.^285–287 Obesity contributes to nonalcoholic liver disease and an increased risk of cancer development, including HCC.^{243,288–291} For the general population, recent data suggest that a body mass index of < 25 kg/m² is optimal for cardiovascular health, which should also be a target for patients with Fontan circulation.²⁹² The prevention of overweight and obesity may be a critically important and modifiable risk factor for the long-term health of the patient with Fontan circulation.^{163,287,292,293} Key take-away points for growth and development are listed in Table 10.

Living with a chronic health condition carries potential psychosocial impact, and having undergone a Fontan procedure is certainly no exception. Compared with healthy peers, individuals with Fontan physiology face potential psychosocial challenges in childhood, adolescence, and adulthood. As a group, many children and adolescents with CHD are at risk of psychosocial maladjustment, particularly according to parental report.³³⁴ A recent study compared the psychiatric and psychosocial status of 156 patients (mean age, 15 years) who had undergone Fontan procedures with that of 111 healthy peers.³³² The patient cohort had a significantly higher rate of lifetime psychiatric diagnosis (65% versus 22%); anxiety and attention-deficit/hyperactivity disorder were most common. Furthermore, as a group, patients had worse outcomes on measures of global psychosocial functioning, anxiety, depressive symptoms, posttraumatic stress, and disruptive behavior. Risk factors of poorer psychiatric/psychosocial outcomes include male sex, lower birth weight, longer duration of deep hypothermic circulatory arrest, and lower intelligence.

In adults, a meta-analysis of international studies using survey assessment of psychological distress revealed no consistent evidence of poorer outcomes among adults with CHD of various subtypes, although methodological heterogeneity was evident.³³⁵ The results of 3 North American studies, however, suggest that one-third of adults with CHD meet diagnostic criteria for a mood or anxiety disorder when clinical interviews are administered.^336–338 Although depression has received much of the attention in the behavioral cardiology literature, adults with CHD are also at risk of elevated anxiety and posttraumatic stress disorder.^339–341 Patients’ subjective health status has been more strongly associated with psychosocial outcomes than objective assessment,^{337,342–345} an important consideration for physicians faced with the symptomatic adult patient with Fontan circulation. Among adolescents and young adults with Fontan physiology, elevated symptoms of depression have been reported (28% with mild symptoms, 32% with moderate symptoms) and demonstrated to be a negative predictor of quality of life.³⁴⁶ Furthermore, more than half of patients endorsed worry about current health, employment, and living independently.³⁴⁷ Anxiety is common; an Italian study revealed that anxiety symptoms were more elevated than depressive symptoms and that more than half of the patients were considered to have possible anxiety.³⁴⁸ MRI of the brain in adolescents with a single ventricle reveals injury in select areas that control anxiety and depression, suggesting a structural basis for the functional deficits seen.³⁴⁹

Qualitative research offers a rich understanding of post-Fontan life. In-depth interviews with adolescents and young adults with Fontan circulation (17–32 years of age) revealed difficulties and challenges, as well as 3 positive themes: feeling happiness in being themselves (eg, feeling proud, mature, healthy, and special), focusing on possibilities (eg, managing physical restrictions and medical procedures), and being committed to life (eg, living with uncertainty and making the most out of life).³⁵⁰

Improving the understanding and management of cognitive and psychiatric outcomes in adults with CHD was identified as a research priority in a working group of the National Heart, Lung, and Blood Institute and the Adult Congenital Heart Association.³⁵¹ Patients who have undergone Fontan repairs represent a subgroup of patients with CHD for whom increased research and clinical resources targeting psychosocial outcomes are paramount. This is a group for whom the question is typically when, not if, significant medical sequelae will present, and the complex interplay between physical and psychosocial outcomes warrants attention. Congenital cardiology teams are encouraged to be proactive in their approach to the growing cohort of patients with Fontan circulation by developing efficient ways to identify psychosocial maladjustment, collaborating with mental health professionals, and developing pediatric-based preventive approaches to encourage positive psychosocial adaptation.

Although the Fontan procedure has certainly extended life spans and mortality has largely shifted from the pediatric to adult setting, a mortality risk remains that is associated with the original Fontan procedure and a Fontan conversion. Research has suggested that many adolescents and adults with CHD, including those with complex disease, overestimate their life expectancy.³⁵² Qualitative research revealed that adolescents and adults with Fontan circulation “made a pledge to themselves that they would stay alive as long as possible”³⁵⁰ yet also expressed uncertainty about the future and were aware of the possibility of shortened life expectancy. Thus, it is critical that patients, families, and healthcare providers are well prepared for the premature mortality facing individuals with Fontan circulation.

Advance directives provide the valuable opportunity for patients to decide whom they want to convey their preferences for medical and palliative care should they become unable to speak for themselves. These directives benefit not only patients nearing the end of their lives but also family members and health providers facing this difficult phase. Guidelines recommend completion of advance directives and addressing end-of-life matters as part of the routine care of adolescents and adults with CHD.^353,354 Patients should be encouraged to complete advance directives “ideally at a time during which they are not morbidly ill or hospitalized, so that they can express their wishes in a less stressful setting.”³⁵³ Although many deaths among patients with Fontan physiology occur after a period of decline, some deaths occur unexpectedly. Thus, waiting for the end stage of disease to initiate advanced care planning is discouraged.

North American studies that surveyed adults with CHD in the outpatient setting revealed that <15% recalled discussing advanced care planning with their provider, only 5% to 21% had completed advance directives, and the majority preferred advanced care planning discussions to be initiated when healthy.^355–358 On a scale from 0 to 10, with 10 being most important, the average rating for discussing advanced care planning with providers was 7, and participants preferred a median age of 18 years (range, 5–60 years) as the most appropriate age to initiate the discussions.³⁵⁸ Variables for timing of discussions include the patients’ expressed wishes and cognitive functioning, familiarity with the physician, and timing in relation to transitioning care to a new provider. Thus, these conversations should not be postponed until end-stage disease progression. Room for improvement in clinical care was similarly demonstrated in a study of adults with CHD, most with advanced disease who died during a hospital admission.³⁵⁹ Very few had documented end-of-life discussions. Attempted resuscitation was less likely among patients with documented end-of-life discussions and did not occur at all among patients referred to palliative care.

In summary, documentation of advanced care planning discussions and the completion of advance directives occur for a minority of adults with CHD who, as a group, value these discussions and wish for them to occur earlier in the disease course. A common provider-reported barrier to end-of-life discussions is being unable to reliably estimate life expectancy.³⁵⁷ However, challenges in prognostication can be shared directly with patients and families, and providers may be reassured to know that it is general information on the life expectancy of patients with their form of CHD that most patients are seeking.^356,358

Recommendations for patients with Fontan circulation include normalizing conversations about advanced care planning and end-of-life care, scheduling separate visits to discuss these important matters with patients (and their chosen loved ones) with later-stage disease approaching the end of their lives, using patient-friendly language to discuss health expectations and prognoses, and exploring patient preferences for end-of-life care while recognizing that they might shift over time.³⁶⁰ Soliciting guidance from mental health professionals and providers experienced in how best to approach these conversations is important. When working with adolescents and young adults, it is important to be mindful of neurodevelopmental abilities, capacity for decision-making, and cultural background.^{354,360–362} Providers are encouraged to partner with palliative care providers to manage symptoms and patient and family distress.³⁶⁰ It is also important for healthcare teams to recognize their own emotional reactions that often accompany the death of a younger person in whose care they may have been involved for years or even decades.³⁶⁰ Key take-away points for psychological, mental health, and social challenges are listed in Table 12.

Adults are the group of patients who have old-style atriopulmonary Fontan operations and are thus the population for whom surgical conversion remains a treatment option. The primary indications for Fontan conversion include difficult atrial arrhythmias, atrial clots, and hemodynamic derangements (eg, AVV regurgitation) that require surgical intervention. The procedure involves takedown of the atriopulmonary connection, reduction of the right atrium, creation of an extracardiac TCPC, and modifications of atrial arrhythmia surgery. A report of 140 patients who underwent Fontan conversion describes a freedom of atrial arrhythmias of 77% and survival free of death or transplantation at 5, 10, and 15 years of 90%, 84%, and 66%, respectively.¹²⁵ Fontan conversion with arrhythmia surgery is successful in reducing arrhythmias and improving symptoms, but as more children are treated with lateral tunnel or TCPC repairs, the number of patients for whom a Fontan conversion is indicated is decreasing over time.⁶ With the more recent advent of extracardiac conduit–type Fontan operations, some have speculated that a small-diameter conduit (<16 mm), although satisfactory for a child, might increase inferior vena caval pressure and potentially exacerbate FALD when patients grow to adulthood.^367,368 There are currently few data to refute or support this hypothesis; more elapsed time is needed before we can determine whether a relatively small extracardiac conduit may ultimately require future surgical revision or catheter-based intervention.³⁶⁹

The coexistence of other medical or surgical problems is more typical in adulthood, and management of these problems may be complicated by underlying Fontan physiology. In 1 series, adult patients with Fontan palliations had more periprocedural complications (15%) than patients with CHD and a biventricular repair or patients without CHD.³⁷⁰ In an administrative study of costs of admissions for noncardiac reasons, adult patients with CHD in general had higher costs, longer stays overall, higher rates of intensive care unit stay, and higher mortality.³⁷¹ There is a paucity of robust data on the impact of Fontan physiology on the outcomes of other medical problems. For example, the risk of cancer is increased in the adult with CHD and is a considerable challenge to manage in the patient with Fontan circulation.²³⁶ More data on the impact of Fontan physiology on the management of common conditions are needed to provide guidance on optimal management strategies. Care in adult CHD centers has been demonstrated to reduce mortality in patients with moderate to complex CHD.³⁷² Evaluation and care by adult CHD specialists is of benefit in optimizing management strategies for the unique and complex aspects of caring for the adult with Fontan circulation. Guidelines for the general management of adults with CHD were updated for 2018.³⁷³

Women with Fontan circulation may desire contraception and may consider the possibility of pregnancy. Counseling on pregnancy can be a challenge because there are few data on the long-term cardiovascular impact of the circulatory changes of pregnancy, particularly volume overload, on Fontan physiology. Nevertheless, because of the strong natural desire to have a family, there is growing experience with women with Fontan circulation experiencing pregnancy. Maternal complications of pregnancy include arrhythmias, heart failure, and thromboembolic complications, which can occur in up to 25% of women. Strikingly high rates of fetal loss are demonstrated in the few series of women with Fontan circulation who achieved pregnancy. In a study of 50 women with 124 pregnancies, the miscarriage rate was nearly 55%.³⁷⁴ Women who are cyanotic are more likely to have miscarriage.³⁷⁵ In a meta-analysis of pregnancies reported in women with Fontan circulation, arrhythmias and heart failure were more common than in the normal populations or in those with simpler forms of CHD; fetal complications were dramatically higher, with up to 50% of pregnancies ending in miscarriage.³⁷⁶

Counseling women with Fontan circulation about pregnancy should take into account the cardiovascular status, hepatic status, thromboembolic risk, potential heritability of the CHD, and potential for a long-term decrease in cardiovascular function as a result of pregnancy. An important, but difficult, conversation concerns the life expectations for women with Fontan physiology, in terms of both morbidity and mortality. In a study of outcomes of preconception counseling of women with a Fontan palliation, most women agreed to participate; however, the majority chose to pursue pregnancy even after being given information about the higher rates of maternal and fetal complications.³⁷⁷

Women with Fontan circulation have higher rates of primary amenorrhea; thus, menarche may be delayed.³⁷⁸ For some women, assisted reproduction may be considered. The hormonal manipulations needed for various forms of assisted reproduction may be poorly tolerated by a woman with Fontan circulation because of the potential for thrombosis and blood volume shifts. Pregnancy surrogacy may be a desirable alternative for some women. Ethical considerations related to maternal longevity concerns are also present when the use of advanced technology-based assisted reproductive technologies is considered. Assisted reproduction also carries a risk of multiple embryos, which can produce an even greater hemodynamic burden on the pregnant woman with Fontan circulation.

Cardiopulmonary exercise testing (CPET) can be particularly useful in patients with Fontan circulation to quantify (serially) maximum exercise capacity and to infer the reason(s) for any exercise limitation observed. On CPET, key parameters of interest include max to assess aerobic capacity and the ratio of to to assess respiratory efficiency and anaerobic threshold. Impaired CPET parameters are associated with increased risk of hospitalization in patients with Fontan circulation,⁶² and both maximal and submaximal exercise data appear to have prognostic value in this population.³⁸⁰ Deterioration in CPET parameters on serial study identifies a population at increased risk for later cardiovascular events.¹³³ Other specific parameters can provide insights into respiratory reserve, stroke volume, and ventilation-perfusion matching. Detailed knowledge of contributors to exercise limitation in patients with Fontan circulation can suggest potential therapeutic strategies for consideration such as fenestration closure for excessive hypoxemia or atrial pacing for important chronotropic incompetence.

Invasive CPET testing has also been applied in patients with Fontan circulation. Although this involves the insertion of pulmonary and radial artery catheters, which can alter resting physiology, such studies have clearly shown (inter alia) rapid and dramatic increases in systemic venous pressures in exercising patients with Fontan circulation, often exceeding 30 mm Hg at relatively modest workloads.²¹⁴ This phenomenon is associated with poor systemic oxygen delivery.

Because maximal exercise capacity is so often limited in those with Fontan circulation, ranges of normal CPET parameters for children and teenagers are now published (at age 12±3 years).³⁸¹

Exercise training may have particular benefits in patients with Fontan circulation for physical and psychological well-being. Given the importance of peripheral venous return, increased muscle mass may augment venous return and thus influence heart preload. Investigators have shown that leg muscle resistance training can significantly augment peripheral muscle mass, venous return, cardiac output, and max in adults with Fontan circulation.³⁸² Similarly, given the importance of the thoracic bellows to drive inspiratory venous return to the heart, investigators have found that inspiratory muscle training (for 6 weeks) improves resting cardiac output and ventilatory efficiency during exercise.³⁸³ In contrast, results from aerobic training programs have been less encouraging.³⁸⁴ Further studies will be informative concerning the optimal type or combination, frequency, and duration of exercise training for patients with Fontan circulation.

Exercise training certainly appears safe for patients with Fontan circulation. A review of 23 articles on exercise training found only 3 adverse events in >200 participants, all of which were transient.³⁸⁵ When measured, quality of life improved with exercise training in the majority of studies. The main physical benefits documented were improved muscle strength and stroke volume. Key take-away points for exercise are listed in Table 17.

The applicability of agents that modulate pulmonary vascular resistance has generated a great deal of interest for the Fontan population.³⁹⁰ Agents include phosphodiesterase-5 enzyme inhibitors (sildenafil, tadalfil), endothelin receptor antagonists (bosentan, ambrisentan), and prostacyclins (iloprost). A recent systematic review of pharmacological therapy for patients with Fontan circulation examined 9 studies with a total of 267 patients, 8 of which studied a pulmonary vasodilator: 4 studies with sildenafil, 3 with bosentan, and 1 with iloprost.³⁹¹ Most of these studies were small and short term, but a trend toward a positive impact on exercise capacity and hemodynamics was noted. The largest study, a randomized placebo-controlled trial of bosentan in 75 patients treated for 14 weeks, showed an increase in peak oxygen consumption, exercise time, and functional class without serious adverse events.³⁹² The authors concluded that although the results were promising, further study was necessary. After completion of a pharmacokinetic dose-finding study of udenafil (a relative long-acting phosphodiesterase-5 inhibitor) in 36 patients with Fontan circulation,³⁹³ a larger efficacy and safety placebo-controlled trial of treatment for 26 weeks of 400 patients is currently in progress (Fontan Udenafil Exercise Longitudinal Assessment Trial; URL: ClinicalTrials.gov. Unique identifier: NCT02741115), with a primary outcome of change in peak oxygen consumption. A 52-week open-label extension study will further assess safety outcomes (A Extension Study of Udenafil in Adolescents; URL: ClinicalTrials.gov. Unique identifier: NCT03013751). A placebo-controlled trial of 52 weeks of macitentan (an endothelin receptor antagonist) in 134 patients with Fontan circulation is underway (Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-Palliated Subjects; URL: ClinicalTrials.gov. Unique identifier: NCT03153137), also with a primary outcome of change in peak oxygen consumption. These studies will inform the evidence base to support a clinical recommendation, weighing benefit, safety, and cost.

Thrombosis is an important and unpredictable complication, not only after Fontan operation but also associated with each stage of single-ventricle palliation.³⁹⁴ It is an important cause of morbidity, particularly when it leads to pulmonary embolism or stroke, and contributes to mortality. The predominant predisposing factor for thrombosis is stasis of blood flow. Venous stasis is often evident in the cavopulmonary circuit in light of the absence of a pump for systemic venous return and pulmonary blood flow. Congenital or acquired anatomic areas of stasis may be present such as a hypoplastic left ventricle with poor inflow and outflow or the creation of a blind-ended pulmonary artery stump. A number of reports have described altered levels of clotting and fibrinolysis factors at all stages of palliation but below the clinical threshold for abnormality. However, these altered levels have been associated with features specific to Fontan palliation, including lower systemic oxygenation, low cardiac output, and hepatic congestion. Furthermore, some patients may have inherited or intrinsic alterations in thrombophilia factors. Most alterations in clotting factor levels likely reduce the reserve of the clotting system, whereby an inciting stimulus such as cardiopulmonary bypass or an indwelling central line increases the risk of both bleeding and thrombosis. The presence of further disturbance of the coagulation system such as through excessive factor loss through PLE or synthetic impairment resulting from severe liver fibrosis or cirrhosis increases the risk of thromboembolic complications.

A targeted approach to thromboprophylaxis is not yet feasible, although patients with a history of thrombosis are at increased risk of recurrence. Additional factors such as atriopulmonary Fontan connection type, Kawashima connection type, dilated atrium, presence of thrombogenic foreign material, ventricular dysfunction, arrhythmias, prolonged immobilization, and PLE have been variously reported. Although clinicians remain concerned about the potential for paradoxical emboli in patients with atrial fenestration, this has not been reported as a risk factor for thrombosis or thromboembolic events.

Both antiplatelet and anticoagulation agents have been used. Some thromboprophylaxis has been shown to be better than none, but the superiority of acetylsalicylic acid (ASA) versus warfarin remains unclear, as was noted in a meta-analysis of 20 observational studies.³⁹⁵ An underpowered randomized clinical trial of ASA versus warfarin failed to show a significant difference in the incidence of thrombosis over a 2-year period immediately after the Fontan procedure,³⁹⁶ although a secondary analysis showed that poorly controlled warfarin was associated with a high risk of thrombosis.³⁹⁷ A small trial of ASA versus warfarin showed greater deposition of material, presumed laminar thrombus, within the extracardiac conduit cavopulmonary connection for those on ASA.³⁹⁸ Current guidelines suggest that it is reasonable for all patients with Fontan circulation to receive ASA, with anticoagulation reserved for those with presumed risk factors or previous thrombosis or older patients.³¹⁶ With either agent, an important residual risk of thrombosis remains; hence, there is an ongoing unmet need for better strategies.³⁹⁹ Newer direct oral anticoagulants are currently being studied in pediatric cardiac populations, including patients with Fontan circulation. They are likely to be an attractive alternative to warfarin, although their comparative efficacy and safety have yet to be determined. Key take-away points for thrombosis are listed in Table 18.

To develop novel strategies, a better foundation of scientific understanding is necessary. A scientific summit was held at Stanford University in April 2018 in which a number of research objectives were summarized. Insights into the genetics of single-ventricle CHD are required. Models of single-ventricle CHD are necessary to elucidate the mechanisms of arrested ventricular development. Processes such as decreased cell proliferation, increased apoptosis, and mitotic cell cycle arrest and associated metabolic and mitochondrial changes in both the fully formed ventricle and the hypoplastic ventricle should be investigated. Exploring the common developmental pathways of the placental and fetal cardiovascular systems may offer clues to the origins of single-ventricle CHD. Investigation of the relationship between genotype and phenotype to elucidate mechanisms of heart failure and to guide counseling for individual families could be accelerated by the development of large clinical registries, modeling single ventricles with induced pluripotent stem cells, high-throughput screening for mechanisms of single-ventricle failure, and identification of biomarkers to serve as a plasma signature of myocardial events. Strategies using stem cell-based therapies to prevent or treat ventricular failure are being explored. Further work in computer modeling, 3D printing, and tissue engineering would help to drive the design and creation of vessels, heart valves, organs, and auxiliary pumps. A large-animal model of Fontan circulation would be of tremendous benefit in further experimental design of the circulation and new surgical and mechanical support therapies.

To achieve progress in the care of this growing population, we need to deepen our understanding of the basic physiological mechanisms underlying this extraordinary circulation. Understanding the physiological “critical bottleneck” in the circulation (ventricular dysfunction, valvular dysfunction, Fontan cavopulmonary connection, pulmonary vasculature, etc) will allow a targeted therapeutic strategy, which may vary from patient to patient and within individual patients over time. We now understand how dilatation of the atrial chamber in the classic atriopulmonary Fontan is associated with atrial arrhythmias, thromboembolic events, and ultimately ventricular failure.^420,421 We now also understand that patients with Fontan circulation live with decreased cardiac output and increased systemic vascular resistance, but it is still uncertain whether lowering systemic vascular resistance will be beneficial or deleterious to these patients.⁴²² The decline of the Fontan circulation is often associated with decreased oxygen saturation, increased cardiac volumes, and altered mesenteric blood flow, but how these factors interact is unclear.^44,423–425 We understand that patients who have adverse characteristics such as decreased ventricular function, distorted or small pulmonary arteries, AVV regurgitation, and arrhythmias will have a worse outcome. However, we do not yet know whether patients who do not have any such adverse features will be affected by rapid deterioration of their Fontan circulation and, if so, in what time frame. It is suspected that all patients are at risk to be impaired because of the gradual increase of their pulmonary vascular resistance and their decreased diastolic ventricular function, but the evidence for when and how these impairments occur is weak.^58,426,427

The main parameters helping us to identify the quality of a cavopulmonary circulation are invasive measurements of central pulmonary artery pressures and end-diastolic pressure of the systemic ventricle. Unless grossly abnormal, these parameters have been poorly correlated with adverse outcomes. It is likely that these parameters are unreliable and highly variable even within individual patients because they are measured in only 1 instance when most patients are fasted, in a supine position, and frequently under sedation or general anesthesia. A more real-life, dynamic mode of characterization of the Fontan circulation that better reflects the natural, daily state is necessary.

A large proportion of patients will incur hepatic and renal end-organ damage driven likely in combination by the excessive venous pressure and altered cardiac output characterizing this circulation.⁸ Differences from normal in baseline substrate organ state as a consequence of altered development may increase vulnerability to the rigors of the Fontan circulation and thus place specific organs at risk. The model of a different-from-normal organ structure at birth, with acquired, additive insult along the way, is likely the process in play in neurological injury and its clinical manifestations. Such a model may similarly apply for other organ systems in the single ventricle. The potential for reversibility of these organ system damages is still unknown. A deeper understanding of the pathophysiology of end-organ damage will allow the development of specific treatments that may mitigate or alter the trajectory of decline and further inform the optimal timing to offer heart transplantation.

Emerging knowledge indicates that the lymphatic circulation is under significant duress in the Fontan circulation. Increased venous pressure leads to increased production in organs such as the liver, as well as impediment to drainage. New imaging techniques for the first time allow visualization of the severe degree of lymphatic channel abnormalities present.⁴²⁸ The most feared complications after Fontan operation—PLE, PB and, in terminal patients, ascites and edema—are clearly driven by the incapacity of the lymphatic circulation to drain this increased lymphatic flow.^167,197 Lymphocytes are depleted and specific T-cell populations are perturbed in patients with Fontan circulation.¹⁷⁶ Defining the pathophysiology behind the trajectory from mild lymphopenia, common and progressive after Fontan operation, to the life-threatening conditions of PLE or PB is important. Exploring the relationship between lymphatic congestion and end-organ dysfunction such as liver fibrosis and intestinal absorptive abnormalities that may be the source of nutritional and vitamin deficiencies would be of great value. Whether there are individual variations in the lymphatic circulation—inherent, acquired, or a combination—is unknown. Research should be focused on studying the capacity for the lymphatic circulation to sustain these abnormal flows. Mechanical or medical interventions for decompression or reducing production may affect the function of the lymphatic circulation and thus profoundly influence outcomes after Fontan operation.^429–431

There is clearly a subset of patients with Fontan circulation who are doing well from both the physiological and the psychosocial perspective. Discovering what factors contribute to resilience and sustained success is critically important. Despite the heterogeneity of this population, practitioners still try to establish management strategies that would fit the entire population. There seems to be little doubt that the variation in innate and acquired characteristics of these patients necessitates a more balanced approach to management and treatment. It is reasonable to believe that the characteristics of the circulation such as cyanosis and increased venous pressures, as well as lymphatic circulatory variation and organ system vulnerabilities, are tolerated in various ways by individual patients, but this possibility is still unexplored. Exploring the genetic basis of ostensible phenotypic variability is essential to understanding this individual variability.

There is a continuity spectrum of incremental health status between the perfectly well-appearing, well-functioning patient with Fontan circulation and progressive degradation leading to failure and risk of premature death. However, we are lacking appropriate metrics for characterization specific to the state of patients with this unique circulation. Such metrics would provide a capacity to stratify risk and to better gauge prognosis and the best time to initiate therapies. A validated risk stratification scheme could likely be based on a rich host of features such as morphological and functional characteristics, cardiopulmonary fitness indexes, biological parameters, and estimates of end-organ functionality.

Neurodevelopmental status and psychological function are some of the most important factors that influence outcome and quality of life in patients with Fontan circulation. Today, the determinants of only 30% of the variations in neurodevelopmental outcomes are elucidated.^295,296 Psychosocial well-being is a major concern voiced by families of a patient with Fontan circulation. Mental health concerns affect not just the patient but also parents and siblings, with potential influence on family socioeconomics and quality of life. Mental health therapies for active problems and preventive measures along the therapeutic trajectory starting early in life may improve outcomes but have not yet been clearly identified. Social integration of those born with a single ventricle is a goal, with education, gainful employment, and creation of a meaningful, productive life. Strategies to achieve these goals must emerge as the population grows further into adulthood. Although major physiological changes may not yet be readily available, we should exert greater efforts at the earliest possible points of care to promote wellness through strategies of optimizing exercise, nutrition, and mental health—factors that may very well prove to be readily modifiable and could have great impact on improving quality of life.

Achieving these goals and objectives will require collaboration and the development of multicenter networks. Registries can provide a data resource that may facilitate answering many of the above questions and provide further insight into the design of clinical trials evaluating drugs, exercise regimens, or other interventions. Adherence to the proposed surveillance toolkit suggestions may lead to a reduction in clinical practice variability with learning and discovery of optimal clinical practice strategies. Finally, building a culture of research investigation among patients is important. Healthcare providers should convey to those with single-ventricle heart disease that the best path forward to wellness and a long and healthful life is evolving, and thus, their participation in discovery and investigational research endeavors is essential and should be encouraged. This approach can allow the best evolution of optimal treatment strategies moving forward.

The survival of patients undergoing the Fontan procedure has been an extraordinary success. At the outset, it was never suspected that patients with such life-threatening birth defects could live for such extended periods in such relatively good condition. A substantial number of patients are now entering their fifth decade and beyond.^61,364 We had not predicted the burden that this circulation would have on the physical and psychological health of our patients because at first the focus was on survival. The fear of death remains the highest concern of patients and their families.⁴³² Nevertheless, the extraordinary survival of most born with this condition today is a testimony to the perseverance of numerous practitioners, patients, and their families and should be considered an amazing achievement of modern cardiovascular medicine.

Today, we are in the early phase of characterizing this circulation and its consequences. One should realize that we are reporting population averages with relatively small numbers in most of our investigational studies and that individual patient measures will be spread along a wide variation spectrum. As an example, it was previously suspected that the Fontan circulation was incompatible with a normal exercise capacity. It is now reported that a substantial proportion of patients have better than normal, normal, or near-normal exercise capacity.⁴³³ The same is likely possible to hold true for liver, kidney, and brain function. Characterization of the condition in every patient is therefore a necessary step to discover care pathways that can allow the individualization of management and improve personal well-being. This is the fundamental principle underlying our consensus on suggested schema for surveillance.

Interventional and preventive strategies of care are evolving for the patient with Fontan circulation. For example, we know that better psychological support of families from the early stages of life may improve psychological well-being of patients, their parents, and their siblings.⁴³⁴ Of great promise but not yet fully tested is the impact of cardiac rehabilitation programs, enhanced nutrition, and interventions aimed at improving neurodevelopmental outcomes. Programs targeting patient education and health self-awareness may be of great value. Trials testing various medications are underway with anticipation of identifying optimal drug therapies to enhance and sustain cardiovascular and end-organ wellness.^392,435 Instead of a reactive approach to complications, an era of proactive health maintenance is emerging as experiences unfold and understandings improve.

As healthcare practitioners, we may often lose perspective and not appreciate that the life of our patients is not necessarily limited to their medical condition. Between hospitalizations, complications, and fears, our patients enjoy a rich and satisfying life. Although some studies show patients to have a decreased quality of life, others identify patients with Fontan circulation to have a quality of life similar to that of their peers.^436–438 Even among some of the oldest patients, many attain higher levels of education, have jobs, and build their own families with satisfying and fulfilling lives.⁶¹

We are now entering a new phase in the management of patients born with single-ventricle CHD. Provided that patients undergo regular follow-up, adopt a healthy lifestyle, and are encouraged to participate in investigational clinical protocols and research, healthcare providers and patients can share an optimistic view for a brighter future.