Abstract
Patients with Fontan circulation are now surviving longer into adulthood and experience a multitude of extracardiac, non-hepatic sequelae that impact their quality of life and prognosis. These sequelae include pulmonary complications (pulmonary vascular disease, sleep-disordered breathing, restrictive lung disease, plastic bronchitis), gastrointestinal manifestations (protein losing enteropathy), chronic venous insufficiency, kidney abnormalities, reproductive issues (pregnancy, contraception and sexual dysfunction), neurocognitive changes, endocrinopathies (glycemic abnormalities, thyroid disorders) and hematological abnormalities (thromboembolic complications and secondary erythrocytosis). This review article aims to present a contemporary overview of the extracardiac, non-hepatic sequelae observed in adults with Fontan circulation.
Keywords: Fontan, Single ventricle, Pulmonary vascular disease, Kidney dysfunction, Thromboembolic events
1. Introduction
Although most patients undergoing Fontan palliation are now living into adulthood, their long-term outcomes are often complicated by cardiac and extra-cardiac end-organ sequelae [1]. While Fontan Associated Liver Disease is the most commonly discussed non-cardiac sequela, clinicians need to be familiar with the multitude of non-cardiac sequelae. We present a review of hemodynamics in patients with Fontan circulation followed by a clinically oriented review of the extracardiac, non-hepatic sequelae of the Fontan circulation including pulmonary complications, gastrointestinal manifestations, chronic venous insufficiency, kidney abnormalities, reproductive issues, neurocognitive changes, endocrinopathies and hematological abnormalities (Fig. 1).
Fig. 1.
Overview of extracardiac, extra-hepatic sequelae in adult patients with Fontan circulation. Image credit: Cristiana Iosef, PhD.
2. The fontan operation
The initial technique for Fontan operations involved a direct connection between the right atrial appendage to the right pulmonary artery, called the atrio-pulmonary Fontan. The technique was subsequently modified due to issues with significant right atrial dilation which was associated with atrial arrhythmias, thrombi and inefficient forward flow. The first modification was the lateral tunnel, an intra-atrial tunnel using native atrial tissue or prosthetic material, to connect the inferior vena cava to the pulmonary arteries. The second modification was the extracardiac Fontan, where a Dacron graft tube is used to connect the inferior vena cava to the pulmonary arteries external to the atria. Both the lateral tunnel and extracardiac Fontans are typically preceded by a Glenn shunt connecting the superior vena cava to the pulmonary arteries. The combination of a Glenn shunt and either a lateral tunnel or extracardiac Fontan is described as a total cavo-pulmonary connection (TCPC). A fenestration may be placed in the lateral tunnel or extracardiac Fontan to decompress the systemic venous circulation, increase preload to the systemic ventricle and sustain cardiac output in the immediate post-operative period. Some fenestrations close spontaneously, and others can be closed percutaneously provided hemodynamics are suitable.
3. Hemodynamics
The defining feature of the Fontan circulation is the absence of a subpulmonic pumping chamber. Blood follows passively from the systemic veins into the pulmonary arteries. The passive pulmonary flow in the Fontan circulation is primarily dependent on the pressure gradient between the upstream systemic venous pressure, the pulmonary vascular resistance (PVR) and the downstream pulmonary venous pressure. This passive flow is augmented by negative inspiratory intrathoracic pressure (the “thoracic pump”) and suction from ventricular diastole. This arrangement results in elevated systemic venous pressures, pulmonary artery hypotension and reduced cardiac output. These hemodynamic changes may contribute to the end-organ dysfunction observed in adults with Fontan circulation.
4. Pulmonary manifestations
4.1. Pulmonary vascular disease (PVD)
Maintaining low pulmonary vascular resistance is crucial to maintain pulmonary venous return and cardiac output. Even minimal increases in the PVR may decrease preload to the single ventricle and cardiac output.
Different forms of pulmonary vascular remodeling can occur throughout the stages of the Fontan palliation ranging from increased wall thickness and muscularization of the medial layer (early on and before Fontan completion) to loss of vascular smooth muscle cells and intimal fibrosis later in the course (after Fontan completion) [2].
Diagnosing PVD in Fontan circulation can be problematic as accurate quantification and interpretation of PVR in Fontan patients by standard techniques can be challenging due to hemodynamic limitations inherent in the Fontan circulation. The presence of decompressing veno-venous collaterals may impose an additional challenge for the accurate evaluation of PVR. Well established cut-offs to inform when a PVR is abnormal in Fontan circulation have not been defined. It is possible that even the commonly accepted cut off for PVR of 3 Wood Units for patients with biventricular circulation may be too high for adequate forward flow in this passive circulation.
The role of pulmonary vasodilator therapy in Fontan circulation is debated. Targeting the nitric oxide (NO) and endothelin-1 pathways through use of phosphodiesterase-5 inhibitors (PDE5-I) and endothelin-receptor antagonists (ERA) has been of recent interest in patients with Fontan circulation with a potential benefit to lower the PVR, resulting in augmentation of single ventricle preload and cardiac output. However, critics highlight that the loss of vascular smooth muscle cells in pulmonary arteries of patients with Fontan circulation may attenuate the benefit of pulmonary vasodilators.
Accordingly, studies have reported differential effects on hemodynamics and exercise capacity with the use of pulmonary vasodilators in patients with Fontan circulation. Bosentan has been associated with improved functional status in the TEMPO trial [3] and improvements in 6 min walk test distance and resting cardiac output in another study [4]. Conversely, in a prospective multicenter randomized trial, no significant improvement in functional capacity was noted after 6-months of bosentan therapy [5]. Sildenafil has also been shown to increase exercise tolerance, increase cardiac output and decrease PVR during exercise [6]. Most recently, the FUEL trial [7], a prospective multicentre randomized trial of 400 patients with Fontan circulation (12–18 years of age) who received the long-acting PDE5-I udenafil for 26 weeks, demonstrated no significant difference in the oxygen consumption at peak exercise.
Future multicentre studies, including the ongoing, prospective RUBATO trial evaluating the effect of macitentan on functional capacity, may provide further insights to reconcile the differential clinical outcomes with use of pulmonary vasodilators in patients with Fontan circulation, including exploring subgroups that benefit from their use.
4.2. Sleep disordered breathing
Sleep disordered breathing is often poorly tolerated in patients with Fontan circulation as it entails a rise in intrathoracic pressure and reduced preload in addition to its known risks of heart failure, hypertension, and arrhythmia [8], which may have further detrimental consequences in patients with Fontan circulation.
Patients with Fontan circulation have a higher prevalence of obstructive sleep apnea (OSA) as compared to general population [8]. Clinicians should have a high index of suspicion for sleep disordered breathing in patients with Fontan circulation presenting with symptoms of worsening arrhythmia or progressive exercise intolerance.
Although continuous positive airway pressure (CPAP) may seem harmful for the Fontan physiology, the hemodynamic effects of periodic obstruction are likely more harmful. The goal of using CPAP in this population is to provide the lowest positive pressure ventilation that can relieve the airway obstruction without compromising the systemic venous return [9]. CPAP titration could be established clinically or guided by invasive hemodynamics.
4.3. Restrictive lung disease (RLD)
Nearly 60% of adult patients with Fontan circulation have an FEV1 of less than 80% predicted. Risk factors for RLD include diaphragmatic palsy, scoliosis, previous thoracotomy, and lower BMI [10,11]. RLD compromises functional capacity and quality of life, even when correcting for peak VO2 [11]. From a hemodynamic perspective, RLD could attenuate negative intrathoracic pressure and reduce the “thoracic pump” that augments systemic venous return. Exercise and inspiratory muscle training may improve exercise capacity and increase lung function [10].
4.4. Plastic bronchitis
Plastic bronchitis is a rare complication of Fontan circulation characterized by formation of large casts in the tracheobronchial tree that usually presents in childhood. Management strategies with marginal benefits include systemic steroids, dornase-alpha, inhaled tissue plasminogen activator and removal of the casts via bronchoscopy [12]. Heart transplant is reserved for cases refractory to medical treatment. Transcatheter lymphatic vessel occlusion has been recently introduced with variable success [12].
5. Gastrointestinal manifestations
5.1. Protein-losing enteropathy (PLE)
PLE is a devastating complication of the Fontan circulation associated with a poor prognosis [13]. There is a 5–15% lifetime risk of PLE. It is characterized by enteric loss of albumin, immunoglobulins, and clotting factors leading to a clinical presentation of chronic diarrhea, peripheral edema, ascites, and immune deficiency. The exact pathophysiology is poorly understood. Several factors have been proposed including congestion of lymphatic drainage from elevated venous pressures, obstruction of the thoracic duct, increased mesenteric resistance, and diminished mesenteric flow leading to distention of hepatoduodenal lymphatic channels and dysfunction of intestinal mucosa [14,15].
Confirmatory diagnostic testing includes low serum albumin level <3.0 g/dl and elevated fecal α-1 antitrypsin level (>50 ml/24 h or spot fecal α-1 antitrypsin concentration >100 mg/ml) [16].
Once the diagnosis is confirmed, potential causes of elevated Fontan pressures should be investigated including mechanical obstruction in the Fontan anastomosis sites or pulmonary arteries. Visualization and mapping of the lymphatic system through magnetic resonance lymphangiography can be considered to assess obstruction of the thoracic duct.
For patients with symptomatic hypervolemia, diuretic agents with or without albumin infusions should be considered. Medical therapies targeting the intestinal mucosa have been introduced with variable clinical response including subcutaneous heparin and oral budesonide. Subcutaneous unfractionated heparin acts as a mechanical barrier by decreasing permeability of the basal membrane to large molecules such as albumin. It may decrease inflammation and potential micro-thrombi to the mesenteric arteries. Budesonide, an oral controlled release steroid, provides a local anti-inflammatory effect with unique pharmacokinetics of limited systemic absorption and less systemic side effects [17]. Finally, dietary modifications should be considered including high-protein (>2 g/kg/day), low-fat diet (<25% of calories from fat) with medium-chain triglyceride supplementation. Medium-chain triglycerides absorbed directly into the bloodstream, bypassing the damaged lymphatic system.
In patients with elevated Fontan pressures, efforts should be made to lower the Fontan pressures including relieving any obstruction in the Fontan circulation, occlusion of aorto-pulmonary collateral arteries, or creation of fenestration to decrease the Fontan pressures [18]. Decompressing the thoracic duct is an evolving strategy being studied to improve symptoms of PLE [19]. Take down of the Fontan circulation and heart transplantation can be considered as a last resort [20].
6. Kidney abnormalities
The prevalence of kidney dysfunction in adult patients with Fontan circulation ranges between 10 and 50% [21,22] with the primary predictor being time since Fontan completion [23]. There are multiple factors which may contribute to the pathogenesis of kidney dysfunction in patients with Fontan circulation including (1) decreased renal perfusion pressure in the setting of low cardiac output and increased renal venous pressure, (2) cardiopulmonary bypass injury during the multiple surgeries, and (3) possible right-to-left shunts and chronic hypoxia which may result in secondary erythrocytosis and hyperviscosity that can be associated with altered glomerular blood flow, the so called “cyanotic nephropathy” [24].
Controversy exists as to the most accurate method to estimate kidney function, with the commonly used creatinine-based calculated GFR potentially overestimating renal function due to low muscle mass [24]. Cystatin-C may provide advantages because its production is less variable across ages, heights and body compositions [24], however its use has not yet been widely accepted in clinical practice.
Microalbuminuria, defined as microalbumin/creatinine ratio >30 μg/mg, is highly prevalent (up to 43%) in patients with Fontan circulation [25]. It is likely related to chronically elevated central venous pressure even in the absence of intrinsic renal disease. This suggests microalbuminuria is not always a pathological finding in patients with Fontan circulation [24].
While ACE inhibitors have shown a protective effect for development of microalbuminuria [25], future studies are required to further study the prognostic impact of kidney dysfunction and further explore therapies to mitigate development and progression of kidney dysfunction in patients with Fontan circulation.
7. Chronic venous insufficiency
Nearly two-thirds of patients with Fontan circulation have chronic venous insufficiency (CVI) [26], primarily due to underlying systemic venous hypertension resulting in distention and engorgement of the veins with subsequent inflammatory reaction in the vascular wall and venous valves leading to loss of function of the venous valves and reflux [27].
CVI presents with chronic pain and decreased physical function. Leg elevation, compression stockings and lower extremity muscle training may have a role in alleviating the symptoms of CVI, although the efficacy of these strategies has not been studied in patients with Fontan circulation.
8. Reproductive issues
8.1. Pregnancy
Most women with Fontan circulation are now living to reproductive age and some desire to have children. The hemodynamic changes of pregnancy may be poorly tolerated in patients with Fontan circulation and impose risk of heart failure (4%), and arrhythmias (8%, predominantly supraventricular arrhythmias) [28]. In addition, obstetric and fetal complications are of considerable risk including miscarriage (45%), prematurity (60%), intrauterine growth restriction (20%), post-partum hemorrhage (14%) and pulmonary embolism [28].
Care during around pregnancy involves a multidisciplinary team to provide pre-conception counselling, establishing maternal cardiac, obstetrical and neonatal risks, antepartum management, peripartum management and postpartum management.
Anticoagulation during pregnancy carries a class IIa indication in the presence of atrial thrombus, atrial arrhythmia, or history of thromboembolic events [29]. The role of antiplatelet or anticoagulant agents during pregnancy in the absence of these risk factors is less defined and must be carefully weighed with the risks of bleeding. Many centres provide at least prophylactic doses of anticoagulants in the immediate postpartum period given the considerable risk for life-threatening pulmonary emboli [30].
Fetal echocardiography is recommended at 18–22 weeks gestational age to screen for congenital heart disease.
8.2. Contraception
Contraceptive agents containing estrogen should be avoided in Fontan patients due to the increased risks of thrombosis with their use and the potential catastrophic nature of venous thromboembolism [29]. There is a potential risk of a vasovagal reaction with insertion of an intrauterine device (IUD) which would be poorly tolerated in a patient with Fontan circulation. In our experience, this risk is low with an experienced operator and with local anesthesia of the cervix prior to IUD insertion.
8.3. Sexual function
Adults with Fontan circulation have reported erectile dysfunction, low self-esteem and avoidance of sexual intercourse, with symptoms of sexual dysfunction increasing with age [31]. In the absence of robust studies to establish prevalence of low fertility in patients with Fontan circulation, all patients with congenital heart disease should be counselled regarding the potential for low fertility and referred to specialists when appropriate [32].
9. Neurocognitive function
Understanding the prevalence, etiology and impact of neurocognitive issues such anxiety, depression, learning disabilities and issues with executive function in adults with Fontan circulation has recently become a priority. Given up to 50% of children with Fontan circulation experience neurocognitive issues [33], an equal or greater prevalence may be expected in adults. Patients with Fontan circulation have lower neurocognitive function than other patients with complex congenital heart disease [34,35]. Predictors of poor cognitive function include older age at Fontan surgery, longer time since Fontan completion and more inpatient days in childhood [34,35]. Adults have more deficits in psychomotor function and working memory than children [34]. All Fontan patients have structural changes on their brain MRIs, with approximately 20% being acquired changes (e.g. strokes) [34]. White matter changes are associated with worse paired associated learning [34]. Patients with Fontan circulation also had smaller global brain volumes, with the volume being associated with neurocognitive functioning. Global brain volume correlated with resting oxygen saturation [34], suggesting cyanosis may contribute to the neurocognitive issues.
10. Endocrinopathies
10.1. Glycemic abnormalities
Ohuchi et al. [36,37] demonstrated abnormal glucose metabolism in patients with Fontan circulation. Impaired fasting glucose, occurring in 43% of patients with Fontan circulation, was associated with lower maximal oxygen consumption and increased risks of heart failure and arrhythmias [36]. Lower fasting plasma glucose has been as associated with higher rates of hospitalizations and all-cause mortality [37], potentially mediated by cardiomyocyte dysfunction and QTc prolongation.
10.2. Thyroid disorders
Up to 30% of adult patients with Fontan circulation have thyroid dysfunction, with hypothyroidism being more common than hyperthyroidism [38]. Recognition of thyroid dysfunction is important given the potential hemodynamic sequelae of hypo- and hyperthyroidism may not be well tolerated in patients with Fontan circulation.
11. Hematological abnormalities
11.1. Thromboembolic complications
Thromboembolic complications occur in 3–20% of adult patients with Fontan circulation [39]. The risk of thromboembolic complications is highest in the immediate post-operative period and >10 years following Fontan completion [40].
11.1.1. Clinical presentation of thromboembolic events
Thromboembolic complications may manifest in the venous or arterial systems. There is a wide range of presentations of venous thrombi: from insidiously as incidental findings on routine cross-sectional imaging to symptomatic presentations with dyspnea or pre-syncope related to low output to dramatic presentations of cardiovascular collapse [41]. Furthermore, venous thrombi may paradoxically embolize to the arterial system in the presence of a patent Fontan fenestration or leak in the Fontan connections. In the arterial system, thrombus formation in the systemic ventricle in patients with severely depressed systolic function or pulmonary venous atrium and systemic atrial appendages in patients with atrial arrhythmias has the potential risk for ischemic cerebrovascular or peripheral embolic events.
11.1.2. Multiple mechanisms of increased thrombotic events in patients with fontan circulation
Virchow's triad of abnormalities in blood flow, pro-thrombotic state and endothelial damage provides some insights on the mechanisms of thromboembolic events. The non-laminar flow in the Fontan circulation may result in stasis of blood. Furthermore, stasis from atrial arrhythmias increases thrombotic risk. Atrial arrhythmias, including atrial fibrillation, atrial flutter and intra-atrial re-entrant tachycardia, have been shown to confer higher risks of thrombotic complications, morbidity and mortality [42]. Potential clotting factor deficiencies (deficiency of protein C, protein S, and antithrombin III) and increased platelet activity are pro-thrombotic. Lastly, endothelial dysfunction, NO dysregulation, increased venous pressure and prosthetic material may result in endothelial damage [43].
Other factors that have been explored are the type of Fontan circulation and the presence of a fenestration. An observational study identified the risk of thromboembolic complications was highest in patients with atriopulmonary Fontans and lowest in patients with extracardiac Fontans, even after controlling for atrial arrhythmias and thromboprophylaxis [44]. Although there is a potential risk of paradoxical embolism through a patent Fontan fenestration, the presence of a fenestration has not been consistently shown to be a risk factor for systemic embolism [45].
11.1.3. Approach to thromboprophylaxis
The need and type of thromboprophylaxis has been a controversial topic for patients with Fontan circulation, particularly given the high risk of thromboembolic events, high prevalence liver disease and hemodynamic consequences of major bleeding. While historical decisions focused on when warfarin was indicated as a thrombophylactic agent, the decisions have since expanded to additionally consider aspirin and direct oral anticoagulants (DOACs) as alternatives to warfarin. Warfarin has been conceptualized as the most efficacious, however concerns of its use include lower time in therapeutic range and increased bleeding risk. These risks may be potentially offset by the use of aspirin or DOACs, provided they have equal efficacy for preventing thromboembolic events.
Recent data provides some insights on the risks and benefits of different agents. A propensity-matched study based in New Zealand reported similar rates in thromboembolic complications between aspirin and warfarin in patients with extracardiac Fontans [46]. In a retrospective, multicentre observational study of patients with mostly extracardiac Fontans, direct oral anticoagulants (predominantly rivaroxaban) were associated with less major adverse events than warfarin or an antiplatelet agent [47]. However, a large registry of 44,000 patients with congenital heart disease recently identified higher risks of longer term adverse events, including thromboembolism and mortality, in patients taking direct oral anticoagulants as compared to warfarin [48], albeit lesion-specific subgroups were not provided. Unfortunately, the evidence to guide selection of which agent to use remains limited and somewhat conflicting. Multicentre prospective studies, such as the PROTECT AR study, and randomized trials comparing thromboprophylaxis agents in adults will be of benefit in determining the efficacy of DOACs in patients with Fontan circulation.
An additional consideration when contemplating use of a DOAC is end-organ dysfunction. DOACs are considered contraindicated in patients with advanced liver disease, particularly if the INR is abnormal. Dose modifications or altered therapeutic targets may be contemplated in patients with advanced liver disease, however guidelines on thromboprophylaxis in this group have yet to address this issue. Furthermore, reductions in DOAC doses are required in patients with kidney impairment and there is limited data to guide use of DOACs in patients with severe kidney impairment or patients on dialysis.
Given the nature of the data around thromboprophylaxis in patients with Fontan circulation, guideline recommendations do not provide specific recommendations on which agent to use. Both the ACC/AHA Guideline for Management of Adults with Congenital Heart Disease and the 2020 European Society of Cardiology (ESC) Guidelines for the Management of Adult Congenital Heart Disease state that anticoagulation is indicated in the presence or with a history of prior thromboembolic event, atrial arrhythmias or thrombus (Class 1). However, the ACC/AHA guidelines specify the use of a vitamin K antagonist whereas the ESC guidelines do not specify which agent is preferred. Additionally, the ACC/AHA guidelines include a class IIB indication for use of thromboprophylaxis in patients without prior thromboembolism or arrhythmia, either antiplatelet or anticoagulation. The New Zealand Position Statement for Caring for Patients with Fontan circulation provides a less selective approach, outlining most patients should receive thromboprophylaxis and noting that there is no consensus on which agent to use.
Until robust studies comparing thromboprophylaxis agents can inform more specific guideline recommendations, shared decision making will likely guide many decisions particularly in patients without a prior history of thrombosis or arrhythmias.
11.2. Secondary erythrocytosis
The presence of an elevated hemoglobin or exertional intolerance in patients with Fontan circulation with normal resting oxygen saturations should raise suspicion of occult cyanosis and trigger an exercise test to assess for exertional desaturations. Patients may experience resting or exertional desaturations due to venovenous collaterals, arteriovenous malformations, or Fontan fenestrations, resulting in increased production of erythropoietin, secondary erythrocytosis and increased hematocrit. However, not all patients with increased hemoglobin and hematocrit will experience symptoms of hyperviscosity (headaches, visual changes, myalgias, mucosal bleeding and fatigue). Patients with concomitant iron deficiency are most prone to developing symptoms of hyperviscosity [49]. Consequently, patients with secondary erythrocytosis should be screened for iron deficiency.
Treatment of hyperviscosity symptoms first focuses on ensuring the patient is both iron and fluid replete. Iron is often replaced with low dose oral supplementation (e.g. ferrous sulfate 325 mg daily) with close monitoring of iron indices during supplementation to avoid an excessive erythropoietic response. Iron supplementation should be stopped when iron stores are replete, which can be identified by a transferrin saturation of >20% or an increasing reticulocyte count.
Treating the underlying cause of the hypoxia is also a priority when possible, including occlusion of collaterals. Arteriovenous malformations or fenestrations after careful evaluation of Fontan hemodynamics.
12. Concluding remarks
Patients with Fontan circulation commonly encounter a diverse spectrum of sequelae beyond the heart and liver. Strategies for screening for these extracardiac manifestations and their management are evolving. The prevalence and breadth of extracardiac manifestations highlight the importance of integrated multidisciplinary approach to care for adult patients with Fontan circulation.
Funding
None to declare.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Footnotes
This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
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