Current Treatment Options for the Failing Fontan Circulation

Abstract

The Fontan operation was introduced in 1968. For congenital malformations, where biventricular repair is unsuitable, the Fontan procedure has provided a long-term palliation strategy with improved outcomes compared to the initially developed procedures. Despite these improvements, several complications merely due to a failing Fontan circulation, including myocardial dysfunction, arrhythmias, increased pulmonary vascular resistance, protein-losing enteropathy, hepatic dysfunction, plastic bronchitis, and thrombo-embolism, may occur, thereby limiting the life-expectancy in this patient cohort. This review provides an overview of the most common complications of Fontan circulation and the currently available treatment options.

1. INTRODUCTION

The Fontan procedure was introduced in 1968 to treat patients with tricuspid atresia [1]. Since then, various patients with a single ventricle (SV) have undergone staged surgical palliation, resulting in so-called Fontan anatomy and physiology. An atrioventricular connection (AVC) is initially created by closing the atrial septal defect and inserting a valved homograft between the right atrium (RA) and right ventricle (RV) [2], followed by an atriopulmonary connection (APC). Subsequent efforts to improve hemodynamics have led to the introduction of the total cavopulmonary connection (TCPC) with an intra-atrial lateral tunnel (ILT) or extracardiac conduit (ECC), connecting the inferior vena cava directly to the pulmonary artery (PA) [3, 4]. The ECC is currently the most widely used TCPC technique (Figs. 1-4).

Fig. (4).

4-dimensional flow magnetic resonance image of IVC-conduit mismatch; flow acceleration at 16mm conduit in a adolescent. Courtesy of FM Rijnberg, AAW Roest, Leiden University Medical Center, Leiden, The Netherlands.

Nowadays, a staged approach with a series of operations is used to palliate SV lesions. The first stage is performed in the neonatal period in which the aorta is connected to the SV if required (for instance, the Norwood procedure in hypoplastic left heart syndrome), followed by a partial cavopulmonary connection (PCPC) after ~ 3-6 months (in which the superior vena cava is connected to the PA) and the TCPC at ~1.5-4 years, thereby creating a Fontan circulation.

The perioperative mortality of TCPC completion has decreased over time from 8% to 1%, and the current overall 10-year survival is estimated to be between 89-97% [5, 6]. Long-term survival was recently reported as 86% for AP versus 93% for TCPC at 30 years of age and 78% versus 81% at 40 years of age [7]. Although more than 90% of hospital survivors remain in NYHA class I-II for decades [8], diminished quality of life is reported, and many suffer from a range of complications and require recurrent re-interventions [9, 10].

The most common complications encountered are myocardial dysfunction, arrhythmias, increased pulmonary vascular resistance, protein-losing enteropathy (PLE), hepatic dysfunction, plastic bronchitis (PB), and thromboembolism. This review will focus on the etiology of these complications of the Fontan circulation and the currently available treatment options.

1.1. Myocardial Dysfunction

Myocardial dysfunction is common in Fontan patients [11]. Ischemia-reperfusion injury during previous surgery [12, 13] and RV morphology of the SV are related to late ventricular dysfunction [8, 14]. Myocardial dysfunction can also be caused by adverse myocardial remodeling as expressed by hypertrophy, dilatation, and spherical reconfiguration due to volume overloading in the early stages of Fontan palliation [8]. Pressure overloading may occur if banding of the pulmonary artery is performed or if aortic narrowing occurs in cases of prior aortic arch reconstruction [12]. Take- down of the aorta-pulmonary shunt during the PCPC operation will normalize volume loading conditions, hence providing the possibility for the ventricle to remodel with reduced compliance and filling pressures [8, 12]. Frequently present atrioventricular valve insufficiency and, to a less frequent extent, (neo-) aortic valve insufficiency will also contribute to adverse loading conditions and an often compromised ventricular performance [15, 16]. Different types of valve repair or replacement during planned Fontan surgery or between stages seem beneficial to prevent progressive ventricular dysfunction [15, 17, 18]. Medical treatment includes diuretics and afterload reduction [15].

Cardiac systolic (dys-)function can be assessed with routine echocardiography. Serial cardiac magnetic resonance (CMR) can be used to quantify myocardial dysfunction, valve insufficiency and measure myocardial replacement fibrosis with T1 mapping and delayed enhancement [19, 20]. Cardiac catheterization is warranted in search of correctable lesions aforementioned (12). In the absence of good methods for assessing single ventricle filling, little data exist on diastolic (dys-)function in Fontan. Diastolic dysfunction is reported to be prevalent in 72% of patients [14]. Prolonged isovolumic relaxation time (IVRT), deceleration time of the early AV valve inflow (DT), the ratio of mitral peak velocity of the early filling (E) to early diastolic mitral annular velocity (E') (E/E' ratio) and reduced E wave deceleration time, E and A wave velocities, and E:A velocity ratio are reported [14, 21].

1.1.1. Pharmacotherapeutics

The choice for heart failure pharmacotherapy in Fontan patients is empiric, considering the lack of evidence and resembling that of heart failure in acquired heart disease Table 1 [22]. Diuretics may be considered in the setting of heart failure symptoms but have not been extensively studied [23]. Spironolactone was not found to improve endothelial function or alter serum cytokine levels as suggested in other disease entities [24]. Despite limited and sometimes conflicting evidence, many Fontan patients are empirically treated with ACE inhibitors and/or beta-blockers [25-28]. The use of sacubitril/valsartan is promising [29]. Recently a multi- center, international cohort registry (ENTRUSTACHD HF) was designed to study the effect of sacubitril-valsartan in ACHD patients with heart failure [30]. In the case of overt ventricular dysfunction, inotropic support (milrinone) has shown good short-term effects [31, 32]. Caution with the use of diuretics and renin-angiotensin-aldosterone system blockers is warranted, as they may compromise ventricular filling and increase right-to-left shunting in patients with an intra- cardiac shunt [23].

Table 1.

Heart failure.

Treatment	Main qualities
Pharmacotherapy	By lack of evidence empiric and resembling treatment for heart failure in acquired heart disease. ACE-inhibitors, betablockers, diuretics, inotropes.
Surgical	Fontan Conversion from AP to extracardiac TCPC can be achieved with low morbidity and mortality.
Mechanical circulatory support	ECMO may allow time for evaluation, diagnosis, treatment, and sometimes, recovery. Adverse events: bleeding, end-organ injury, systemic air thromboembolism, infection, and poor neurologic outcomes. VAD is a longer-term treatment option as bridge to recovery or bridge to transplant Adverse events: respiratory failure (42.3%), bleeding (38.5%), infection (23.1%), neurologic dysfunction (15.4%), pump change due to thrombus

1.1.2. Pacing

Hemodynamic improvement and outcome have been reported on atrioventricular sequential pacing [33-37]. Over 10% of Fontan patients require a pacemaker during long-term follow-up for sinus node dysfunction or AV-block [38]. The classic transvenous access for endocardial leads is missing after an APC, and associated risks of thromboembolism with endocardial leads in systemic ventricles have resulted in epicardial pacing as a procedure of choice [39]. Importantly, epicardial procedures are frequently hampered by surgical adhesions and increased pacing thresholds, thus leading to early battery depletion and frequent lead fractures [39]. Epicardial leads are associated with a high rate of pacemaker re-interventions but similar device-related complication rates compared to endocardial leads [40].

1.1.3. Transcatheter

Significant obstruction of the Fontan pathway may develop early or during midterm follow-up after Fontan completion and may cause heart failure and PLE [41]. Obstruction causes abnormal flow patterns, which can be visualized and quantified with 3-dimensional blood flow data derived from computational fluid dynamics and 4-dimensional flow magnetic resonance imaging [42].

Percutaneous transcatheter stenting of ILT or ECC obstruction is feasible and safe with good short-term patency [41, 43, 44].

1.1.4. Surgical

1.1.4.1. Fontan Conversion

Conversion from AP to extracardiac TCPC can be achieved with low morbidity and mortality, reducing energy loss in the Fontan circuit and improving clinical status in selected cases [4, 45]. Coronary perfusion may improve if the coronary sinus is situated in the lower pressure atrium.

1.1.5. Mechanical Circulatory Support

Mechanical circulatory support (MCS) in failing Fontan is used to augment cardiac output and decrease systemic venous pressure [45]. Currently, there are three types of MCS available for Fontan. Extracorporeal membrane oxygenation (ECMO) may be used for short-term cardiac support. Ventricular assist devices (VAD’s) may be used for mid- and long-term support, bridge to recovery, and typically bridge to transplant. For long-term support, a Total Artificial Heart (TAH) can be implanted [45].

1.1.6. Extracorporeal Membrane Oxygenation (ECMO)

ECMO initiation may provide time for evaluation, diagnosis, treatment, and occasionally recovery after an adverse event, leading to overt circulatory compromise [46-48]. ECMO carries high risks, such as bleeding, end-organ injury, systemic air thromboembolism, infection, and poor neurologic outcomes, and should be considered a temporary measure to support the circulation [46].

1.1.7. Ventricular Assist Device (VAD)

Growing experience with the use of VAD provides a longer-term alternative to ECMO as bridge-to-recovery or bridge-to-transplant. CHD patients have higher early mortality after VAD insertion but similar adverse event rates and improved functional capacity and quality of life compared to non-CHD patients [49]. Survival to transplantation on VAD- support for the systemic ventricle is reported as 60-75% [50] [51, 52]. Incidence of adverse events rates after VAD implantation has been reported as 73%, including respiratory failure (42%), bleeding (39%), infection (23%), neurologic dysfunction (15%), and pump change due to thrombus (27%) [50]. After VAD implantation, potential worsening of PLE and hepatic dysfunction may be expected due to increased systemic venous pressures related to improved cardiac output [51]. TAH may then be a better option as the systemic venous pressure will be lower after TAH [53].

1.1.8. Biventricular Assist and Total Artificial Heart (TAH)

Biventricular support or TAH may be considered in patients with ventricular failure and elevated venous pressure and pulmonary vascular resistance [52], thereby supporting the SV output and the Fontan circuit. Small case series are reported with successful bridge-to-transplant with biventricular support [54, 55] and TAH [51, 53].

1.2. Arrhythmias

Fontan patients are at increased risk of atrial arrhythmias (AA) at a young age [56], with the highest risk for an AP Fontan circulation [57]. Atrial tachyarrhythmias occur in >50% of patients at 20 years after Fontan surgery [58-61], involving intra-atrial reentrant tachycardia, type I typical atrial flutter, and atrial fibrillation. Scar tissue, prosthetic material, and malformed anatomic structures within the Fontan circuit allow for macro reentrant circuits [56]. Tachyarrhythmias affect the quality of life and can cause complications, such as thrombo-embolisms, hemodynamic deterioration, cardiac dysfunction, and sudden death [56, 62]. The mortality risk is 23 times higher when AA arises [63], and the presence of arrhythmia is a strong predictor of Fontan failure [57, 64].

1.2.1. Antiarrhythmic Drug Therapy

Antiarrhythmic drug therapy is the initial treatment strategy but has a low success rate Table 2 [65]. Arrhythmia control can be obtained only in half of the patients, often requiring multiple antiarrhythmic drugs [66]. A 90% recurrence rate of arrhythmias within 36 months has been reported [65]. Sodium-channel blocking agents, digoxin, and verapamil have demonstrated some effect when used alone or combined [66]. The use of sodium-channel blocking agents in heart failure patients may not be suitable considering the negative inotropic effect, and a potassium blocking agent may then be a better choice.

Table 2.

Treatment options for arrhythmias.

Treatment	Main qualities
Anti-arrhythmic drugs	Initial treatment strategy, but with low success rate. Sodium-channel blocking agents, digoxin and verapamil are effective alone or combined. Caution with sodium-channel blocking agents in heart failure given the negative inotropic effect. Alternative: potassium blocking agents.
Direct current cardioversion	Safe, but with significant failure and recurrence rate. Concomitant use of class I or III anti-arrhythmic drugs increase success rate.
Anti-tachypacing	Success rate of 7-69%. Acceleration of AT or conversion to AF may occur.
Catheter-ablation	High success rate (54-94%) with very low complication rate. Recurrence rate 20-50%.
Fontan Conversion	Consider in refractory atrial arrhythmia. Low risk of morbidity and mortality.

1.2.2. Direct Current Cardioversion

Direct current cardioversion (DCCV) is safe but has significant procedural failure and recurrence rates. Simultaneous use of class I or III antiarrhythmic medication is associated with an increased likelihood of success of DCCV [67]. Therapeutic anticoagulation is required when the arrhythmia is present >48hours [67].

1.2.3. Anti-tachypacing

Fontan patients frequently experience sinus node dysfunction (5-40%), and 3-18% of patients need to receive a pacemaker [68-70]. Pacemaker patients may use anti-tachypacing for the treatment of atrial tachycardia. A variable success rate of 7-69% for atrial tachycardia termination by anti- tachypacing is reported, but atrial tachycardia acceleration or conversion to atrial fibrillation may occur [71, 72].

1.2.4. Catheter ablation

Catheter ablation has a reasonably high procedural success rate (54-94%) with low complication risk, but recurrence of arrhythmias (20-50%) is common [59, 65, 73-75] and related to progressive atrial cardiomyopathy and the often multifocal etiology of atrial arrhythmias [56].

1.2.5. Fontan Conversion

Fontan conversion can be considered in refractory AA and converts an AVC or APC to a TCPC. Fontan conversion can be combined with partial excision of a dilated atrium or MAZE procedure and the implantation of epicardial pacemaker leads. Arrhythmia surgery is effective for refractory AA and has improved overall survival, despite an increased risk of sinus node dysfunction [65, 76-78]. Epicardial pacemaker leads during arrhythmia surgery can be considered even when rate response and anti-tachypacing are not indicated yet but can be foreseen at a later stage [77].

1.3. Increased Pulmonary Vascular Resistance

Systemic venous return can be hindered by increased pulmonary vascular resistance (PVR) [8], and even a minor PVR increase may lead to a low cardiac output state, hepatic congestion, and extravascular fluid accumulation [79]. Increased PVR is explained by adverse pulmonary vascular remodeling [80, 81] and underdevelopment of the vascular bed in the early stages of Fontan palliation. A great emphasis has been placed on avoiding volume overload for the ventricle, and pulmonary blood supply has been restricted [82]. Pulsatile flow plays a role in reducing PVR by passive capillary recruitment [83]. Inversely, the absence of pulsatile flow induces endothelial dysfunction with impaired pulmonary vasodilation in the Fontan circuit.

1.3.1. Pulmonary Vasodilators

Pulmonary vasodilators may improve symptoms, hemodynamics, and exercise capacity in Fontan patients with no or only mild side effects Table 3 [84-92]. In the landmark FUEL trial, adding udenafil to standard therapy did not statistically improve peak exercise oxygen consumption but did demonstrate significant improvements in multiple measures of exercise performance at the ventilator anaerobic threshold [92]. No effects on mortality or BNP/NT-proBNP have been observed yet [84].

Table 3.

Increased pulmonary vascular resistance.

	Increased pulmonary vascular resistance
Etiology	Multifactorial; adverse pulmonary remodeling, endothelial dysfunction, absence of passive capillary recruitment.
Treatment	-
Pulmonary vasodilators	Improve hemodynamics, reduce NYHA class and increase exercise capacity. No or only mild side effects.
Fenestration	Increases cardiac output, but also desaturation. Improves survival in high risk patients. Debate about the appropriate use because of the higher risk of cerebrovascular events.

1.3.2. Fenestration

The creation of a baffle fenestration between the systemic and pulmonary venous chambers can be considered to reduce systemic venous pressure [93]. Right-to-left shunting across the fenestration will decompress increased systemic venous pressure related to increased PVR, and will improve ventricular loading conditions at the cost of systemic arterial blood oxygen desaturation. Improved survival was demonstrated in selected cases [94]. Fenestration can be performed surgically or using a blade or balloon septostomy, balloon dilatation, or insertion of a stent or Amplatzer-fenestrated ASD device [95]. Transcatheter fenestration attempts have a low success rate and a high rate of spontaneous closure (63%) [95] but could be considered as a bridge to Fontan takedown or transplantation in severely ill patients.

1.3.3. Aortopulmonary Collaterals

Aortopulmonary collaterals (APC’s) are common (before and) after Fontan completion and can result in increased pulmonary arterial and left atrial pressure with subsequent heart or respiratory failure [96, 97]. In Fontan patients with prolonged effusions and no other correctable anatomic defects, catheterization for identification and closure of APC’s is reasonable [97, 98].

1.4. Protein-losing Enteropathy

Protein-losing enteropathy is characterized by enteric loss of proteins, including albumin, immunoglobulins, and clotting factors. Protein-losing enteropathy pathophysiology is incompletely understood but is probably multifactorial and may be related to reduced cardiac output, elevated central venous pressure, increased mesenteric vascular resistance, systemic inflammation, and altered enterocyte function [99]. Protein loss and malabsorption may result in bloating, abdominal pain, steatorrhea, effusions, diarrhea, edema, and failure to thrive. Although uncommon (3-18%), PLE has significant morbidity and mortality with frequent hospitalization [100-103]. A 24-hour stool alpha-1-antitrypsin (AAT) clearance study is the gold standard for PLE diagnosis. For surveillance, a single sample stool AAT is sufficient, which, combined with normal plasma protein levels and low clinical suspicion, may assure the physician of PLE absence [100]. When PLE occurs, a full diagnostic work-up of the Fontan circulation is required to assess ventricular performance, atrioventricular valve regurgitation, and Fontan pathway obstruction. Noncontrast magnetic resonance lymphangiography can be used to image both the peripheral and central lymphatic systems. T2 imaging can show thoracic duct dilatation, lymphangiectasia, lymphatic collateralization, and tissue edema. Intranodal lymphangiography is the standard method for imaging the central lymphatic system, where Lipiodol contrast is injected in the inguinal lymph nodes under ultrasound guidance. Intranodal and intrahepatic dynamic contrast magnetic resonance lymphangiography (IS/IN-DCMRL) are newer techniques to image flow disorders using gadolinium injection followed by dynamic and static contrast-enhanced MR imaging [104].

1.4.1. Diet

In patients with PLE, a high protein, low-fat diet is advised with increased medium-chain triglycerides, which can be absorbed more easily, to support the nutritional status Table 4 [105-107].

Table 4.

Treatment options for protein-losing enteropathy.

Treatment	Main qualities
Diet	High protein, low-fat diet to support the nutritional status, which should not be considered therapeutic.
Pharmacologic	Oral budesonide, octreotide, high dose i.v. immunoglobulins, s.c. heparin, high dose i.v. prednisone, high dose spironolactone, and loperamide.
Lymphatic embolization	Liver lymphangiography to demonstrate liver lymph leakage as a cause of PLE. Subsequent lymphatic embolization to relieve symptoms and increasing serum albumin levels.
Surgical	Creation of a fenestration.
Transcatheter	Low interventional risk. Relief obstructions in the venous flow pathway by balloon angioplasty and stenting, the creation of fenestration or perform a Fontan take-down. Transcatheter fenestration has low success rate and hight rate of spontaneous closure. Complete exclusion of hepatic venous return. Thoracic duct decompression.

1.4.2. Pharmacology

Oral budesonide can be used to increase serum albumin level and decrease fluid overload [108-112] in PLE [110]. Careful assessment of hepatic function should be performed before initiation of therapy, as systemic side effects can limit treatment. Case reports and small cohort studies also indicate favorable results for the use of octreotide [101], intravenous administration of high dose immunoglobulins [113], subcutaneous injections of heparin, high dose intravenous prednisone [114], and loperamide [115].

1.4.3. Lymphatic Embolization

Liver lymphangiography can be used to demonstrate liver lymph leakage as a cause or expression of PLE. Subsequent lymphatic embolization can be performed to (temporarily) relieve symptoms and increase serum albumin levels, as reported in selected cases [116]. IN/IH DCMRL cannot only be used diagnostically but also therapeutically. Lipidiol can cause mechanical occlusion to the distal lymphatic vessels over weeks [104].

1.4.4. Transcatheter and Surgical Treatment

Selective lymphatic duct embolization of lymphatic collaterals branching from the thoracic duct can be performed using a microcatheter. When there are too many or too small collaterals, covered stents can be placed in the thoracic duct [104]. Surgical or transcatheter Fontan takedown can be considered to temporarily improve PLE symptoms and may be considered if PLE occurs shortly after Fontan surgery as a palliative measure [117]. Inferior vena cava flow is redirected into the atrium by occluding the Fontan conduit with a vascular plug between the pulmonary arteries and fenestration, thereby bypassing the pulmonary vascular bed. Unrestrictive inferior vena cava flow into the atrium can be facilitated by stenting of the fenestration. A surgical takedown of the Fontan circuit is associated with very high operative mortality (62%), whilst PLE only resolves in half of the surviving patients [118]. Medical treatment only (without transcatheter or surgical intervention) results in the complete resolution of symptoms in 25% with a mortality rate of 46% [117].

1.5. Hepatic Dysfunction

Chronic liver disease is increasingly recognized in Fontan patients [119-125], with an increasing incidence over time [121, 126-129]. The etiology of hepatic dysfunction is incompletely understood, but is probably related to diminished portal flow, cyanosis, elevated central venous pressure, and a low perfusion state due to often limited cardiac performance [122, 130]. Hepatic complications include abnormalities in biochemical liver function and coagulation profile, liver fibrosis, which may progress to liver cirrhosis, and even hepatocellular carcinoma (HCC) [120-122]. The AHA/ACC and ESC CHD guidelines recommend yearly follow-up for hepatic congestion and dysfunction after TCPC [120, 131], including laboratory markers, algorithms like Fibrotest or MELD score [121, 132, 133], and liver ultrasound. Alpha-foetoprotein can be used to assess the risk for HCC. When HCC is suspected, computed tomography, magnetic resonance imaging, or liver biopsy are required to exclude HCC [120]. Liver biopsy is the gold standard [122], while catheterization should be considered to measure pulmonary vascular resistance, intracardiac and transhepatic pressures, and identify any obstruction within the Fontan circuit [119, 134].

1.5.1. Treatment Options

Catheter intervention for aggressive relief of any Fontan obstruction is recommended to address an elevated posthepatic pressure Table 5 [134, 135]. Pulmonary vasodilator drugs may be considered in case of elevated Fontan pressures (>15mmg) in the absence of an anatomic obstruction that cannot be relieved by catheter intervention [81, 129, 135, 136]. Transplantation of the liver, heart or combined transplantation may be considered [118, 120, 125, 137-142] if there are no interventional/surgical options to improve a failing Fontan circulation with end-stage liver disease [134, 143].

Table 5.

Hepatic dysfunction.

-	Hepatic dysfunction
Etiology	Probably related to diminished portal flow, cyanosis, elevated central venous pressure and low perfusion state.
Abnormalities	Biochemical liver function and coagulation profile, liver fibrosis, cirrhosis and ultimately hepatocellular carcinoma.
Diagnosis	Laboratory markers, algorithms (i.e. Fibrotest, MELD score), alpha-foetoprotein to assess risk of HCC. Imaging (US, CT, MRI) to assess liver stiffness and/or fibrosis. Liver biopsy.
Follow-up	Yearly biomarkers and US. CT, MRI or biopsy when HCC is suspected. Consider catheterization.
Treatment	Relief of venous pathway obstruction. Pulmonary vasodilators. Consider liver, heart or combined transplantation if no interventional or surgical options exist.

1.6. Plastic Bronchitis

Plastic bronchitis (PB) is characterized by the exudation of proteinaceous material into the airways leading to branching bronchial casts formation, primarily composed of fibrin [144, 145]. Spontaneous expectoration is often the presenting symptom, increasing the risk of asphyxiation and pulmonary failure [146-148]. PB pathogenesis is poorly understood, but low cardiac output, elevated Fontan pressures, and abnormal lymphatic flow patterns may play a role [148-150]. PB is rare (1-2%) [103, 151, 152], has high morbidity and mortality (50-60%) [103, 151, 153-159], and frequently requires hospitalization [103]. Chest X-ray may show opacification due to atelectasis [160], and bronchoscopy can confirm the diagnosis [148]. Combining CMR and lymphangiography, abnormal lymphatic flow in the lungs can be visualized to reveal the underlying PB pathophysiology [148, 150]. New lymphatic imaging modalities include intranodal-, intrahepatic-, and intra-mesenteric dynamic contrast magnetic resonance lymphangiography (IN/IH/IM-DCMRL), allowing for visualization of the central lymphatic system and identification of abnormal flow patterns. They are considered the first step in characterizing the problem and guiding management and interventions [104].

1.6.1. Bronchoscopy

Bronchoscopy can be performed to confirm PB diagnosis and for treatment with lavage or extraction of casts. Rigid bronchoscopy provides better visualization of casts when compared to flexible bronchoscopy [161]. Cast removal can be challenging due to the firm consistency of the casts, and casts can fragmentize during manipulation leading to airway obstruction [161, 162].

1.6.2. Treatment Options

The main objectives of PB treatment are lowering central venous pressure and preventing cast formation and lymphatic embolization. Airway clearance therapy by facilitating cast expectoration [160] can be done using chest physiotherapy, bronchodilators, and nebulized hypertonic saline Table 6 [159, 160, 163]. Inhaled and systemic corticosteroids are useful for acute and chronic treatment of PB [160, 164]. Aerosolized fibrinolytic (t-PA) has been reported to decrease cast burden and improve respiratory symptoms [148, 163, 165-169]. Small case series have described successful treatment with inhaled mucolytics [144, 162].

Table 6.

Treatment options for plastic bronchitis.

Treatment	Main qualities
Airway clearance	Chest physiotherapy. Bronchodilators. Nebulized hypertonic saline.
Anti-inflammatory	Inhaled and systemic corticosteroids. Systemic corticosteroids should be limited to the acute treatment because of the side effects.
Cast reduction	Aerosolized fibrinolytics (t-PA). Inhaled mucolytics.
Bronchoscopy	Confirm diagnosis and lavage or extraction of casts. Best performed under general anesthesia (by cardio-anesthetist) by a skilled bronchoscopist in a tertiary center.
Reduction of pulmonary pressure	Sildenafil and Bosentan reported in single cases.
Surgical and catheter intervention	Stenting of pulmonary artery stenosis. Lowering venous pressure with fenestration. Resolution or reduction of cast formation by atrial pacing reported in three single cases. Interruption/ligation of retrograde lymphatic from the thoracic duct to the lung parenchyma.

1.6.3. Reduction of Pulmonary Pressure

In several case reports, reduction of pulmonary pressure with sildenafil and bosentan and subsequent clinical improvement have been described [170, 171].

1.6.4. Catheter and Surgical Intervention

Clinical improvement of PB and cast reduction have been reported after stenting pulmonary artery stenosis [151] and lowering systemic venous pressure with fenestration [154, 172]. Resolution or reduction of cast formation has also been described after atrial pacing by improving cardiac performance [169, 173, 174]. Retrograde lymphatic flow from the thoracic duct to the lung parenchyma can be interrupted by percutaneous lymphatic embolization or covered stenting of the thoracic duct as a palliative measure [104, 148, 150]. Successful ligation of the thoracic duct and subsequent relief of symptoms have also been reported [175-178].

1.7. Thrombo-embolic Complications

Patients with a Fontan circulation have an increased risk of thrombo-embolic complications (TECs) with a prevalence of 25% [179] and an overall incidence of 11% [180]. TECs include pulmonary embolisms, deep venous thrombosis, and cerebrovascular thromboembolism [180]. Pulmonary thrombi may impair TCPC blood flow [180] and occur more frequently in the setting of a failing Fontan [181]. TEC risk factors are chronic systemic venous hypertension, PLE, AA, conduit stenosis, prosthetic material use, coagulation factor abnormalities [182-186], and APC [179].

1.7.1. Treatment Options

The optimal thromboprophylaxis strategy has not been defined yet for Fontan patients [134, 180], as aspirin and vitamin K antagonists similarly reduce TEC incidence with >50% and a 9% failure rate for both strategies Table 7 [180] . Anticoagulation is associated with lower TEC rates, mortality, and hospitalization, without an increased bleeding risk [187]. In the 2018 AHA/ACC guideline, prophylaxis with vitamin K antagonists is recommended with Class I recommendations for patients with Fontan circulation and known or suspected TEC or AA in the absence of contraindications. There is a class IIb recommendation to consider antiplatelet or anticoagulation therapy in Fontan patients without or suspected thrombus, thromboembolic events, or prior arrhythmia [188]. If TEC occurs, most cases can be managed by anticoagulation alone without surgical or catheter intervention [179]. When anticoagulation for TEC is discontinued due to bleeding events, a high incidence of a second TEC event is reported [179]. Importantly, anticoagulation should be considered when a fenestration is present, considering the high risk of (cerebral) thromboembolic events.

Table 7.

Thrombo-embolic complications.

Treatment	Main qualities
Thromboprophylaxis	Both aspirin and VKA reduce TEC with >50% without one agent being superior to the other. Prophylaxis with VKA class I recommended for Fontan circulation and known or suspected TEC or atrial arrhythmia in the absence of contraindications.
TEC	Most cases can be managed with anticoagulation alone. Surgical or transcatheter embolectomy.

1.8. End-stage Fontan Failure

1.8.1. Heart Transplantation

After Fontan, indications for heart transplantation (HTX) are described in the AHA 2007 statement and are similar to indications for other CHD or acquired heart diseases [188]. Heart transplantation is indicated in symptomatic heart failure, growth failure in pediatric patients, life-threatening arrhythmias, development of fixed, irreversible elevation in PVR, and several specific conditions, including severe stenosis (stenoses) or atresia in proximal coronary arteries, moderate to severe stenosis, and/or insufficiency of the atrioventricular and/or systemic semilunar valve(s), and severe ventricular dysfunction. Conditions in which HTX may be considered are severe aortic or systemic atrioventricular valve insufficiency that is not considered amenable to a surgical correction, severe arterial oxygen desaturation (cyanosis) that is not considered amenable to a surgical correction, and persistent PLE or PB, despite optimal medical-interventional-surgical therapy [189].

Transplantation has an increased risk of early mortality [190, 191], with increased PVR as a strong predictor of mortality [192]. Overall, Fontan HTX patients with preserved ventricular function but with sequelae of failed Fontan physiology (PLE, PB, refractory ascites, and edema) have a threefold greater risk of death in the first year after HTX compared to the group with impaired ventricular function alone [192]. One- and five-year survival rates after HTX are 80% and 71%, respectively [193]. Finding a suitable donor is challenging due to the high rate of sensitization in patients after multiple prior surgeries, blood transfusions, pregnancies, or ECMO/VAD [194]. In patients with irreversible renal- or liver dysfunction, combined heart-kidney and heart-liver transplantations are performed [195-197]

2. FUTURE RESEARCH AND PERSPECTIVES

With the increasing survival of Fontan patients, the impact of its morbidity grows. In many areas, future research might aid in improving follow-up and treatment. Improved understanding of the basic science, physiology, parameters of the state of the Fontan circulation, the mechanism of hepatic and renal damage, the lymphatic circulation, and improved risk stratification has been stated as goals for future research [15].

Future perspectives include the increased use of four-dimensional flow cardiac magnetic resonance and computational fluid dynamics, which will help to visualize and evaluate the Fontan circulation [198]. Wider use of three-dimensional imaging and printing will aid in procedural planning and communication between physicians, patients, and families [199].

New developments in ventricular assist devices include smaller devices, like HeartMate 3, HVAD, and Jarvik 2015 [200-205]. Rodefeld and colleagues have proposed a viscous impeller pump for cavopulmonary support [201, 202]. Other innovations include a modified HeartMateII for cavopulmonary circulatory support [203-205], the development of a cavopulmonary low-pressure high flow device with a transcutaneous chargeable battery [206] as destination therapy [52], valves in the IVC at diaphragm level [134], and hepatic vein exclusion [207].

CONCLUSION

Over the 50 years since the first Fontan surgery, survival has significantly improved. However, several complications continue to limit life expectancy and quality of life, including myocardial dysfunction, arrhythmias, increased pulmonary vascular resistance, protein-losing enteropathy (PLE), hepatic dysfunction, plastic bronchitis (PB), and thromboembolism. Several pharmacological, percutaneous, and surgical treatment options are available in the failing Fontan circulation. With the increasing number of surviving/ageing Fontan patients, the impact of Fontan circulation is growing not only in numbers but also in disease burden. Stringent and frequent follow-up is crucial to enable timely treatment of potential complications in order to improve life expectancy and quality of life for this complex patient cohort.

Fig. (1).

Variations of Fontan circulation (with permission from Springer Valente AM, Landzberg MJ, Powell AJ Adult congenital heart disease. Edited by Libby P).

Fig. (2).

Echocardiographic image of Partial Cavo-Pulmonary Connection (PCPC).

Fig. (3).

Echocardiographic image of Fontan tunnel originating from the inferior vena cava.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.