The Lymphatic Circulation in Adaptations to the Fontan Circulation
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Failing Fontan continues to be major problem for patients on the univentricular pathway. Failing Fontan is often complicated by chylothorax, plastic bronchitis and protein loosing enteropathy. The role of lymphatic circulation in Fontan circulation is still being researched. Newer imaging modalities give insight into the role of abnormal dilatation and retrograde flow in lymphatic channels post Fontan. Interventional strategies targeting abnormal lymphatic channels, provides an alternative management strategy for patients with failing Fontan. This review focuses on the role of lymphatic system in adaptations to Fontan circulation
KeywordsFontan Fontan failure Lymphatics Lymphatic disorders Congenital heart disease Single ventricle physiology
The Fontan operation, first introduced in 1971, is the final stage procedure for a variety of congenital cardiac defects, principally for univentricular hearts and when a biventricular repair is not possible. This procedure involves redirecting the systemic venous return to the pulmonary arteries. The concept of bypassing the pulmonary ventricle—although extraordinarily effective for many patients—is associated with a number of short and long-term problems. Prolonged pleural drainage and chylothorax early post-Fontan, and plastic bronchitis and protein loosing enteropathy (PLE) in the later stages are some of the most serious complications that are associated with the Fontan circulation.
The focus of this overview is the role of the lymphatic system in adaptations to the Fontan circulation, development of post-Fontan complications, new approaches and insights. Development of new imaging approaches as well as therapeutic techniques targeting abnormal lymphatics are emerging as useful strategies to manage patients with a failing Fontan circulation and, in the future, may inform the optimal management of patients entering the single ventricle pathway.
Fontan physiology can be classically described as a circulation ‘in series’ with only the single systemic ventricle as the energy source for forward flow . The resistance to this single energy source is present at various levels in the form of the ventricle chamber itself, the systemic vascular resistance, systemic venous resistance and pulmonary vascular resistance . Although inherently inefficient, good functional performance is achieved, partly through augmentation of flow because of negative intrathoracic pressure generated during inspiration and the effect of the skeletal ‘muscle pump’. The systemic ventricle, which may have been exposed to chronic volume or pressure overload and cyanosis, is subjected to significant unloading and a suboptimal preload at time of Fontan creation. Reduction in the preload, which is one of the primary aims of Fontan completion, may also turn out to be counterproductive in the long run as it results in a significant increase in ventricular mass and impairs the ventricular relaxation leading to significant diastolic dysfunction [2, 3]. This was demonstrated in dogs, who showed a significant increase in posterior wall thickness after removal of experimentally induced chronic volume overload . Serial assessment of ventricular diastolic function after Fontan completion has shown progressive development of diastolic dysfunction with reduced ventricular compliance and impaired early relaxation .
The systolic ventricular function in the early years post Fontan is often good. The systolic wall stress restores to normal in most individuals if the Fontan procedure is done before 10 years of age . However, long-term systolic ventricular dysfunction is seen in patients with a Fontan circulation. This is attributed to chronic hypoxia and volume overload, right ventricle morphology of the single ventricle and ventriculotomy during various palliative procedures .
Therefore, both systolic and diastolic ventricular dysfunction may occur in the long term in Fontan patients. The inherent chronic low cardiac output state in Fontan physiology results in chronically elevated systemic vascular resistance . Neurohormonal activation and a resultant increase in systemic vascular resistance have been documented in post-Fontan patients even when the patient is in NYHA Class I and despite the absence of severe ventricular systolic dysfunction . Such changes are analogous to adaptations to chronic heart failure in the normal circulation.
There are many reasons why progressive increases in pulmonary vascular resistance may be seen in patients with a Fontan. These include abnormal morphology of pulmonary arteries or veins, abnormal pulmonary endothelial function, non-pulsatile flow and multiple silent thromboembolic episodes. Elevations in pulmonary vascular resistance may occur as a secondary consequence of progressive ventricular systolic or diastolic dysfunction, AV valve regurgitation and collateral circulation .
The Role of the Lymphatics in Acute Adaptation to the Fontan Circulation
The human body is normally in a state of ‘capillary filtration equilibrium’ . Fluid filters into tissue spaces at the arteriolar end of capillaries and is reabsorbed at the venous end of the capillary. Approximately 10% of tissue fluid, which fails to reabsorb, is taken up by small lymphatic capillaries, which then drain into larger lymphatic channels. These lymphatic channels ultimately drain into the thoracic duct, the most important lymphatic channel in the body which itself drains into the innominate vein. The major source of lymph to the thoracic duct is the liver and the intestines. Capillary filtration equilibrium depends on mean capillary hydrostatic pressure which is greatest at the arteriolar end leading to filtration and least at the venular end leading to reabsorption  (Fig. 1). Raised arteriolar resistance can decrease the capillary hydrostatic pressure at the arteriolar end resulting in decreased filtration. Any rise of pressure at the venous end would result in raised capillary hydrostatic pressure at the venular end, preventing reabsorption of the filtrate  (Fig. 2).
To allow the Fontan circulation to work, the systemic venous pressure needs to be elevated to maintain forward flow into the pulmonary vasculature and necessarily needs to be higher than the systemic atrial pressure. Typically, the SVC pressure prior to Fontan completion is around 12 mm Hg and the atrial pressure is around 7 mm Hg . A near doubling of lower body systemic venous pressure occurs acutely at the time of Fontan creation, as the lower body venous pressure rises to reflect the pulmonary artery pressure. Acutely, elevated systemic venous pressure is a necessary part of the Fontan circulation. However, chronic systemic venous hypertension may have detrimental effects on the splanchnic, hepatic and portal circulation culminating in increased lymphatic pressures and its sequelae.
The raised central venous pressure post Fontan results in raised mean capillary hydrostatic pressure at the venular end, and hence decreased reabsorption of the interstitial fluid. Failure of capillary filtration equilibrium results in development of pleural and pericardial effusions in the early post-Fontan operative period. This is usually seen in those patients who have high mean capillary hydrostatic pressure and low systemic arteriolar resistance index . This loss of filtration equilibrium is compensated for, to a certain extent, by dilatation of lymphatic channels. This adaptation of lymphatics has been demonstrated by MR lymphangiography in post-Fontan patients .
The Failing Fontan and the Role of the Lymphatic Circulation
Perioperative mortality for the Fontan operation in the current era is around 1–2% . Despite excellent early survival in the current era, there is ongoing attrition possibly related to the inherent compromise of the Fontan physiology. Data from the Australia and New Zealand Fontan Registry show that the freedom from all causes of death and transplant at 15, 20 and 25 years is 93, 90 and 83%, respectively. Freedom from failure at 15, 20 and 25 years is, respectively, 83, 70 and 56% . Current approaches, including contemporary pre-Fontan care and utilization of the extra cardiac conduit, yield a survival of 97% at 13 years .
Late Fontan failure usually presents insidiously. The systemic complications secondary to a failing Fontan include cyanosis, hepatic dysfunction, protein-losing enteropathy (PLE), ascites, plastic bronchitis and coagulation abnormalities. Plastic bronchitis (PB) and protein-losing enteropathy (PLE) are serious complications associated with significant morbidity and mortality. They occur in 5–15% of patients after palliation of the single ventricle .
Fontan patients have an elevated systemic venous pressure and failure of the Fontan circulation is associated with further increases. Increased systemic venous pressure results in increased lymph production predominantly from the liver and also from the extrahepatic portal system . In addition to increased lymph production, elevations of venous pressure make it more difficult for chyle in the thoracic duct to empty into the great veins. The effect of increased systemic venous pressure on thoracic duct drainage has been studied experimentally and has shown that as the outflow pressure of thoracic duct increases above zero, the lymph flow decreased linearly and lymph flow stops at high outflow pressures [15, 16]. This leads to significant lymphatic congestion, dilatation of the thoracic duct, chylous pleural effusions, impaired drainage and formation of new lymphatic collaterals .
Clearly, the lymphatic circulation is fundamental to early adaptations to, and chronic complications of, the Fontan circulation. It is not yet established if all patients have similar adaptive capabilities of the lymphatic circulation and the extent to which congenital anomalies of the lymphatic circulation may explain early failures of the Fontan pathway.
Certainly, variations in normal lymphatics have been described. However, complex lymphatic anomalies remain poorly understood . Anomalies of major lymphatic channels such as thoracic duct and cisterna chyli termed as central conducting lymphatics anomalies (CCLAs) have been described. These may include stenosis, obstruction or dilatation of the lymphatic trunks, associated with reflux and leakage from dysfunctional channels .
They may manifest as abnormalities such as lymphedema, lymphangiectasia and chylous fluid accumulations (chylothorax and chylous ascites, depending on the anatomical location of the abnormality). CCLAs are distinct from other complex lymphatic anomalies such as generalized lymphatic anomalies (GLA) and Gorham Stout Disease (GSD). It remains unclear whether these anomalies of the lymphatic channels may coexist with congenital cardiac defects, and potentially contribute to the lymphatic complications of Fontan circulation.
Plastic Bronchitis and Protein-Losing Enteropathy
Plastic bronchitis is a rare and severe respiratory disorder characterized by the formation of gelatinous plugs in the airways that take the shape of bronchial “casts”. It is classified into two types based on the histology of the casts: Type I (inflammatory) and Type II (non-inflammatory / mucin casts) . Protein-losing enteropathy is seen in 5–15% of patients post Fontan . The reported mortality is 50% from the onset of diagnosis. The exact aetiology for PLE is still not clear, although raised central venous pressures and subsequent intestinal lymphangiectasia has been demonstrated by intestinal biopsies . The fact that plastic bronchitis and protein-losing enteropathy are seen in some Fontan patients with normal PA pressures, and many Fontan patients with elevated PA pressures do not develop these complication, points to the multi-factorial aetiology. A higher incidence of plastic bronchitis and PLE is seen in patients with prolonged chylous effusion in the early post-operative period, irrespective of PA pressures. This points to the interrelationship between the mean capillary hydrostatic pressure, systemic arteriolar resistance index and the lymphatic vasculature in maintaining the filtration equilibrium, the loss of which leads to progressive lymphatic disorder.
The lymphatic disorder can be either abnormal dilation of the lymphatic channels (lymphangiectasia) or an abnormal proliferation of lymphatics (lymphangiogenesis) . Post-Fontan patients have been demonstrated to develop secondary lymphangiectasia and lymphangiogenesis. Lymphatics in normal lung drain along the bronchovascular bundles to the hilum and then into the mediastinum. In the mediastinum, they drain either directly to systemic veins or via mediastinal lymph trunks into the thoracic duct. The direction of flow is central, regulated by the presence of valves. The high central venous pressure in post-Fontan patients, along with incompetence of valves secondary to lymphangiectasia, promotes retrograde flow in the thoracic duct, which has been shown conclusively by MR lymphangiography .
With regard to PLE in patients with a Fontan circulation, endoscopic small bowel biopsy has shown the presence of intestinal lymphangiectasia either localized, or non-uniform in distribution.
Conventional Medical Management of Failing Fontan
Conventional medical management for patients with failing Fontan, who eventually present with plastic bronchitis or PLE includes dietary modifications (high protein, low fat and low salt diet), diuretics, corticosteroids, pulmonary vasodilators, use of inotropes and after load reducing agents to improve the cardiac output . Selective use of inhalational acetylcysteine, DNase, Urokinase, tPA in patients with plastic bronchitis and subcutaneous heparin therapy for PLE has yielded varied results . In spite of aggressive medical management, many patients continue to be refractory and warrant surgical or interventional management.
Optimization of the Fontan circulation involves identification of structural and functional impediments including thrombus in the venous pathways, pulmonary arterial obstruction, pulmonary venous abnormalities, loss of AV synchrony and AV valve regurgitation . Stenosis in the central or branch pulmonary arteries can be corrected surgically or by dilatation and stenting. Discrete stenosis of the pulmonary veins is also usually amenable to stenting. Cardiac resynchronization and valve repair or replacement is done if identified as the cause of failing Fontan. In patients with high systemic venous pressures, fenestration, Fontan take-down or cardiac transplantation may be required [21, 22, 23].
Nevertheless, many patients with a failing Fontan do not have high central venous pressures at cardiac catheterization, and most Fontan failure occurs in patients well beyond the initial period of hospitalization for Fontan completion.
Diagnostic and Therapeutic Interventions Targeting Lymphatics in Post-Fontan Patients
Lymphatics are difficult structures to evaluate because of their small size and variable location. Traditionally, lymphangiography is used to study abnormalities of lymphatic circulation. Lymphangiography involves the use of X-rays, CT or MRI to study the lymphatic channels after contrast is injected into the lymphatic channels. MRI is a rapidly evolving imaging modality for evaluation of thoracic duct. Non-contrast T2-weighted MR lymphatic mapping is a recently developed technique that allows non-invasive evaluation of the thoracic duct . This may delineate the whole thoracic duct along with all its tributaries. MR Lymphangiogram in patients with single ventricle palliation, shows evidence of lymphangiectasia and lymphatic collateralization . In patients with plastic bronchitis, significant dilatation of peri bronchial lymphatics has also been demonstrated. Dynamic contrast MR Lymphangiography (DCMRL), developed by Dori et al. at The Children’s hospital of Philadelphia has demonstrated abnormal dilated lymphatic channels arising from thoracic duct and the retrograde flow of contrast in these channels towards the carina or hilum of the lung . This new imaging technique has enabled them to describe 5 lymphangiographic patterns of retrograde lymphatic flow towards lung parenchyma or bronchi  (Table 1).
Pattern of retrograde lymphatic flow
Patent thoracic duct with retrograde flow in 1 branch
Patent thoracic duct with retrograde flow in multiple branches
Double thoracic duct with left supplying the lungs
Complete occlusion of the thoracic duct with retrograde flow in multiple branches
Absence of any identifiable thoracic duct with diffuse perfusion of lungs
Dori et al. have termed this phenomenon of retrograde lymphatic flow from thoracic duct to lung parenchyma as Pulmonary Lymphatic Perfusion Syndrome .
Scintigraphy using either indium 111-labelled transferrin, technetium 99-labelled human serum albumin or technetium dextran is the most sensitive and reliable non-invasive imaging modality for PLE. Radiolabelled isotopes like chromium 51 and iodine 125 conjugated to serum proteins like albumin, globulin and transferrin can be used for confirmation of diagnosis. Nuclear Scintigraphy also demonstrates the dilated thoracic duct and perihilar lymphangiectasia .
Early evidence of lymphatic abnormalities (lymphangiectasia and lymphatic collaterals) has been demonstrated in patients after bi-directional cavo-pulmonary connection or Fontan procedure even in the absence of plastic bronchitis or PLE [13, 25]. In patients who develop plastic bronchitis or PLE, the thoracic duct dimensions have been demonstrated to be significantly enlarged.
Therapeutic/Palliative Lymphatic Intervention
Several strategies have been utilized in an attempt to treat the failing Fontan by addressing lymphatic abnormalities. These include thoracic duct ligation, decompression of the thoracic duct, thoracic duct embolization and selective embolization of abnormal lymphatic collaterals.
Thoracic duct ligation has been well described for treatment of chylothorax and can be done surgically or thoracoscopically with good results . Successful resolution of plastic bronchitis has also been reported after thoracic duct ligation . This procedure involves mass ligation of all tissues to the right of the oesophagus and aorta overlying the vertebral column. Careful assessment of the bronchial casts appears to be important prior to the procedure, as plastic bronchitis fails to resolve after thoracic duct ligation in patients with predominant Type I cast. There is considerable reluctance to ligate the thoracic duct in Fontan patients because of the established importance of this structure in handling of abdominal chyle and the possibility that duct ligation could initiate or worsen ascites and/or PLE.
A novel technique for decompression of the thoracic duct by diverting the innominate vein to the right or left atrial appendage appears promising . The innominate vein is detached from the SVC and anastomosed to the atrial appendage. The thoracic duct in this procedure hence drains to the low-pressure atrium and thus prevents the abnormal dilatation of the duct and resultant incompetence of the valve and retrograde flow of lymph. This procedure also helps in improving the preload to the ventricle and improves cardiac output at the cost of desaturation. Further experience with this procedure and evaluation is required.
Thoracic duct embolization was developed as a minimally invasive alternative to thoracic duct ligation. Traumatic and non-traumatic chyle leaks have been successfully treated by this technique. Imaging techniques like nuclear scintigraphy or MR lymphangiography allows identification of the exact areas of lymph leak or the abnormal lymphatic channels with retrograde flow .Under fluoroscopic guidance, the cisterna chyli is accessed using a 22G Chiba needle and guide wire introduced into the thoracic duct. A micro catheter is advanced over the guide wire, and the thoracic duct embolized using Lipiodol, metallic coils and/or Glue.
Selective embolization of the abnormal lymphatic channel or isolation of the branches of the thoracic duct with covered stents has been described by Dori et al. [25, 26]. They have demonstrated a high incidence of significant clinical improvement (88%) in patients in whom the abnormal lymphatics were embolized or isolated . Transient abdominal pain and hypotension were the most common complications following the procedure. Patients, in whom no clinical improvement was noticed, had either no retrograde flow or no thoracic duct on Lymphangiography or DCMRL. 15 of 17 patients were also weaned off respiratory medicines and other therapies with the exception of sildenafil . This procedure, being minimally invasive, appears to be associated with less morbidity than thoracic duct ligation and selective embolization of the involved lymphatics maintains the patency of the thoracic duct.
Our experience with use of lymphangiography as a diagnostic and therapeutic target for patients with plastic bronchitis post Fontan is limited to 2 patients. Plastic bronchitis was successfully treated in a 4-year-old boy by disruption of the cisterna chyli . Lymphangiogram demonstrated the dilated and tortuous thoracic duct with retrograde flow to perihilar lymphatics (Figs. 3, 4).The thoracic duct could not be catheterized. His plastic bronchitis and pleural effusion resolved shortly after the procedure and he was expediently discharged to ward after a 4-month stay in PICU. Lymphangiography in a second child showed absence of the thoracic duct with diffuse perfusion of the lungs, and hence no intervention was performed. Lymphatic interventions have a definite palliative role in patients with a failing Fontan who present with plastic bronchitis, with complete resolution of plastic bronchitis possible after selective embolization.
Resection of localized intestinal Lymphangiectasia has been reported suggesting that a careful search for localized intestinal lymphangiectasia is warranted in cases of PLE which are refractory to medical management . Successful management of PLE in a child with failing Fontan, by thoracic duct decompression, has been described recently. The thoracic duct was decompressed by diverting the innominate vein to the atrium through a 8 mm Gore-Tex graft . This shows the need for further study of lymphatics in patients with PLE and the probable role of thoracic duct decompression by stenting in future.
The Fontan circulation places significant additional demands on the lymphatic circulation and in most patients adaptations to augment lymph flow are effective and sustained. In a small proportion of patients, an abnormality of the lymphatic system contributes to Fontan failure, and presentations with PB and PLE. The reason for development of these complications in specific patients with acceptable pulmonary artery pressures remains unexplained. Identification of patients likely to develop these complications before and after Fontan could aid in prevention of complications and assist in decision making regarding which patients will benefit most from fenestration. MR Lymphangiography has potential as a screening tool to detect patients at risk of developing PLE or plastic bronchitis. Further evaluation and prospective studies are required to confirm the diagnostic and therapeutic benefit of lymphangiography and embolization.
This work is funded by the Fontan Partnership Grant; NHMRC 1076849.
Compliance with Ethical Standards
Conflict of interest
There are no conflicts of interest for all authors.
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