709

Chapter 86 Manifestations and Management of Failing Fontan AMIT MISRI

that the pulmonary circulation and the systemic circulation be separated in a case of univentricular heart. The drawback of this physiology is that a series circuit with two pumping chambers as is case with normal heart gets converted to a series circuit with single energy or pumping source. Moreover, the energy generated by the dominant ventricle gets dissipated because of the resistance offered at different levels of circuit. Systemic vas-cular bed, systemic venous bed and pulmonary vascular bed all exert some amount of resistance in a system which is already compromised. Absence of ventricular thrust and creation of passive ve-nous fl ow through the cavopulmonary circuit leads to development of two things. First, the cen-tral venous pressure gets raised up to three times the normal and secondly this also leads to a rela-tively low cardiac output state.

FONTAN FAILURE

The end points that indisputably describe Fontan failure are death or cardiac transplantation. Studies have shown that freedom from death or transplan-tation at 20 years is about 85% (see ref 4). Major causes of death have been attributed to ventricular dysfunction, thromboembolism or sudden death secondary to arrhythmias. Before actually reaching the stage of Fontan failure, two inherent features of Fontan circulation namely chronic elevated sys-temic venous pressures and decreased cardiac out-put result in most physiological impairments and their many manifestations. These symptoms usu-ally occur over years and represent the stage termed as failing Fontan. Timely intervention of a compro-mised circulatory state before patients overtly mani-fest themselves is the main principle of Fontan management strategies.

INTRODUCTION

The fi rst description of an alleged single ventricle heart in fetus was given by Chemineau in 1699 (see ref 1). Subsequently diverse morphological entities of congenital heart disease have been rec-ognized which fall under the group termed as uni-ventricular heart. The prevalence rate is thought to be 1 in 10,000 live births 2 . In the absence of any intervention during early life, these patients rarely reach adulthood and most of them die during childhood.

A new era started in 1968 when Francis Fontan did a double-valved atriopulmonary connection in a patient with tricuspid atresia 3 . This was based on the assumption that the ventriculized right atrium will act as a pumping chamber to the pulmonary circulation. Moreover, Fontan surgery during the last fi ve decades has been subjected to many modi-fi cations. The atriopulmonary connection has been replaced by total cavopulmonary connections with the belief that this will reduce the haemodynamic pitfalls inherent to the original Fontan surgery. In current era, patients with univentricular heart un-dergoing Fontan surgery can reach adulthood and have reasonably decent quality of life. Since Fontan physiology is an unnatural physiology and just a palliative surgery, life expectancy remains far below the projected normal values. These patients also develop myriad of complications with time. Of late, newer modalities of treatment are being developed and used to treat such complications so as to de-crease the associated morbidity and mortality.

PARADOXICAL FONTAN PHYSIOLOGY

The main aim of the original Fontan surgery was to treat cyanosis. To achieve this, it is necessary

710 SECTION X — Pediatric Cardiology

CAUSES OF FONTAN FAILURE

Factors that are responsible for failure of Fontan circulation lie in the anatomic variant of congenital heart disease for which the surgery has been done, surgical modifi cation of Fontan undertaken and the inevitable effects of the altered physiology. Fontan circuit is composed of venoarterial connection, pulmonary arteries, pulmonary capillary system, pulmonary veins and venoatrial connection. Resis-tance of any kind either anatomical like stenosis, hypoplasia, kinking or physiological in the form of vasoconstriction, pulmonary vascular disease, fl ow alterations have catastrophic effects on output sta-tus of Fontan. In addition, development of ven-tricular diastolic and systolic dysfunction jeopar-dizes an already compromised state. In univentricular heart, a single source of kinetic en-ergy has to pump against resistance generated by systemic arteries, venous bed and pulmonary bed thus leading to early systolic dysfunction. The de-creased preload after Fontan surgery in a ventricle which was previously dilated secondary to shunt surgery or atrioventricular valve regurgitation re-sults in diastolic dysfunction. This resembles an overgrown heart whereby the ventricle looks hyper-trophied but underfi lled.

MANIFESTATIONS OF FONTAN FAILURE

The manifestations of Fontan failure encompass a varied spectrum ranging from growth failure to car-diac failure.

(1) Fontan patients are generally shorter than the normal population but inability to gain weight appropriately may be an early sign of inade-quate cardiac output.

(2) Some amount of exercise intolerance is inherent part of Fontan physiology. This is because the factors that help in increasing cardiac output in normal person like increase in preload, heart rate, chronotropic competence, decrease in pul-monary vascular resistance are all altered in Fon-tan physiology. Serial assessment of exercise tolerance becomes mandatory and it objec-tively identifi es haemodynamic status. Factors responsible for deterioration should be timely addressed.

(3) Although the main aim of Fontan surgery is to alleviate cyanosis, saturations near 90% are ex-pected because the desaturated coronary sinus blood is still mixing with pulmonary venous

blood and reaching the systemic circulation. Presence of profound cyanosis should lead to suspicion of other causes. Venous collaterals which either drain into pulmonary veins or pul-monary atrium and shunt via fenestrations can lead to desaturation. Hepatic veins in patients with heterotaxy syndrome may drain separately into the heart. If they are not incorporated into the Fontan baffl e they can cause cyanosis by shunting desaturated hepatic blood to systemic circulation. Also, defi ciency of hepatic factor reaching the pulmonary bed in such situation is believed to cause formation of pulmonary AV malformations resulting in cyanosis.

(4) Arrhythmias remain a major cause of morbidity and can even lead to sudden death. Develop-ment of rhythm abnormalities are related to atrial incisions and multiple suture lines. Sinus node dysfunction has a prevalence rate of as high as 40% (see ref 5). Ventricular dysfunction, atrioventricular valve regurgitation and high right atrial pressures can lead to grossly enlarged atrium which then acts as a substrate for ar-rhythmia generation. Older age at the time of Fontan surgery, sinus node dysfunction, atrio-pulmonary anastomosis and long postoperative interval are all risk factors for development of atrial tachycardias.

(5) Thromboembolic events are one of the leading causes of death in Fontan patients and its inci-dence varies from 3% to 33%. Dilated Fontan path-ways, sluggish fl ow in the circuit, atrial arrhyth-mias and altered coagulation profi le secondary to hepatic dysfunction create a milieu conducive for thrombus formation. Small emboli which get dis-lodged from the main thrombus reach the pulmo-nary capillaries causing elevation in central venous pressure and Fontan circulation. Presence of fenes-tration in such a scenario may lead to emboli reaching the systemic circulation causing cerebro-vascular accident.

(6) Protein-losing enteropathy (PLE) is a serious manifestation of Fontan failure with a 3-year mortality rate of 30% and 5-year mortality rate of about 50% (see refs 6, 7). Mean age of devel-opment of this complication is 7 years. Onset may range from 1 month to two decades after Fontan surgery. As with most other symptoms of Fontan failure, the root cause of this compli-cation is elevated venous pressure which gets transmitted to abdominal veins leading to in-testinal congestion and enteric loss of protein. Chronic congestive failure over a period of time leads to mesenteric ischaemia and intestinal

711Chapter 86 — Manifestations and Management of Failing Fontan

mucosal injury facilitating protein loss. Inci-dences of PLE in patients who have normal central venous pressure points towards infec-tious aetiology affecting the intestinal mucosa but this remains to be proven.

(7) Plastic bronchitis is a rare but dreaded compli-cation of Fontan failure. Its incidence is thought to be less than 2% (see ref 8). Patients develop-ing this complication are at risk of airway ob-struction because of branching bronchial casts. Pathogenesis remains unclear but increased central venous pressure leading to endobron-chial leakage has been implicated as a causative factor.

(8) Heart failure is a well-recognized risk factor for death in Fontan patients. Since a single source of energy has to propel blood against two cir-culations in a Fontan circulation it tends to give way early. Morphological single right ventricle fails much earlier as compared to morphological single left ventricle. Both sys-tolic dysfunction and diastolic dysfunction are detrimental to Fontan haemodynamics. Presence of diastolic dysfunction decreases the sucking power of the ventricle leading to de-creased preload. On the other hand, pumping of blood against already increased resistance is markedly reduced because of systolic dysfunc-tion. Early manifestation of heart failure may be decreasing exercise intolerance, mildly al-tered liver enzymes but later present as frank ascites, pedal oedema and decreased urine output.

MANAGEMENT OF FONTAN FAILURE

Patients who have been early recipients of Fontan surgery are now entering their fi fth decade. Due to abnormal physiology of Fontan circulation they are facing the various symptoms of failure as they age. Over time, the patients who do not fi t the original Chausset’s criteria and are not ideal candi-dates for Fontan are also taken for Fontan surgery but they tend to develop failure symptoms early. Many other compounding factors like the inability to understand the importance of regular follow-up, defi ciency of composite health centres, lack of per-sonal who have a proper understanding of the consequences of this abnormal physiology and availability of limited resources in developing countries only add to the problem. Management guidelines recommend that centres with experi-ence in adult congenital heart disease should man-age them 9 , 10 .

Early Fontan failure: Early failure of Fontan surgery is usually charac-terized by inability to come off cardiopulmonary bypass, not able to wean the patient of ventilator, prolonged or persistent pleural effusion. Reports from Australia and New Zealand have shown an early failure rate of about 6% in all patients un-dergoing Fontan surgery. Reconversion to stage one or stage two of palliation is associated with signifi cant morbidity and a mortality rate close to 50%. Some of the factors considered to be respon-sible for early failure are right ventricular mor-phology of single ventricle and early age at the time of Fontan completion. Surgical take down of Fontan to previous palliative stage remains the line of management. Although some of these un-derwent a new Fontan completion but cardiac transplantation remains the defi nite treatment in such situations.

Late Fontan failure: In perioperative survivors, freedom from all-cause death or transplantation was reported to be 90% at 10 years, 83% at 20 years and 70% at 25 years 11 . However, during the survival pe-riod these patients may not be completely symptom free and manifest one or other com-plications of failing Fontan requiring medical management, cardiac intervention or a surgical procedure.

Medical Management

This modality of treatment is used to alter the various factors causing Fontan failure namely ven-tricular dysfunction, increased pulmonary resis-tance and arrhythmias. Heart failure secondary to ventricular dysfunction in single ventricle physi-ology is believed to be different from acquired heart failure in adults. Angiotensin converting enzyme inhibitors (ACE-I) have been frequently used in ventricular dysfunction in Fontan patients despite a lack of evidence supporting the same. In the Australia and New Zealand, Fontan registry indications for initiation of therapy were ventricu-lar systolic or diastolic dysfunction, atrioventricu-lar valve regurgitation, preservation of normal ventricular function, prolonged effusions after Fontan and hypertension. The reason for using ACE-I is that Fontan patients have chronically el-evated levels of renin and angiotensin. Activation of the renin–angiotensin system and subsequent increased angiotensin II cause vasoconstriction of both systemic and pulmonary vasculature, which results in higher ventricular end-diastolic pressure

712 SECTION X — Pediatric Cardiology

and progressive low- cardiac output. ACE inhibi-tion may therefore be effective therapy for pa-tients with failing Fontan. In acute and severe cases of ventricular dysfunction, phosphodiester-ase inhibitors are used. Their inotropic, lusitropic and vasodilatory actions are widely used in treat-ing and preventing low-cardiac output syndrome. Sometimes chronic intravenous milrinone ther-apy is used in failing Fontan because of its well-suited haemodynamic profi le. Another problem faced by failing Fontan population because of ac-tivation of renin–angiotensin system is that of abnormal fl uid homeostasis. Combination of spi-ronolactone, an aldosterone antagonist, along with furosemide, a potent loop diuretic, in a guarded manner is shown to be quite effective in such patients. High doses may lead to dehydra-tion and electrolyte imbalance in a critically balanced situation. Nesiritide – a recombinant B natriuretic pepitide – is used in heart failure pa-tients. Although clinical experience of its use in congenital heart disease is limited, its arterial and venodilator effect without causing refl ex tachycar-dia may enormously benefi t this group of pa-tients. Another group of drugs used in heart fail-ure are beta blockers. Data on the use of beta blocker in paediatric heart failure are limited. On one hand, by decreasing the heart failure–induced adrenergic activation, they prevent myocardial hypertrophy and apoptosis, while on other hand, their negative chrono- and dromotropic effects may be harmful. Multicentric review of use of carvedilol in paediatric heart failure has shown clinical improvement in two-third of patients but only 11% of the study population had undergone Fontan procedure 12 . Inappropriate use of beta blockers may affect the systemic perfusion be-cause cardiac output in these patients is predomi-nantly dependent on higher heart rates as im-paired preload cannot generate adequate stroke volume. Kurishima and colleagues report a small series of eight patients treated with isosorbide di-nitrate (ISDN) after Fontan surgery 13 . They found a considerably lower Fontan baffl e pressures, lower mean arterial pressures and lower systemic vascu-lar resistance in their patients. Systemic hypoten-sion remains the most signifi cant side effect of ISDN and its use along with phosphodiesterase inhibitors is contraindicated.

Pulmonary vasodilators are increasingly being used in failing Fontan physiology. One of the char-acteristic features of Fontan circulation is the non-pulsatile fl ow in pulmonary arteries which results in decreased release of endogenous nitric oxide.

This can cause elevated pulmonary pressure and resistance as nitric oxide is a potent endothelial vasodilator. This may manifest as low-cardiac out-put or excessive hypoxaemia. Khambadkone re-ported a decrease in basal pulmonary vascular resis-tance with exogenous nitric oxide suggesting the presence of endothelial dysfunction 14 . Pulmonary vasodilators like sildenafi l, bosentan and prostacy-clin can decrease the deleterious effects of high pulmonary vascular resistance. Inhaled prostacy-clins have also been used with the advantage that they cause fewer systemic side effects such as sys-temic vasodilatation. While short-term use of pros-tacyclin analogues may be benefi cial in improving exercise capacity, effects of chronic administration are not clear at present 15 .

Arrhythmias remain a cause of concern in Fon-tan patients, as they can have signifi cant haemody-namic effects. Nonsinus rhythm, atrial tachycardia, AV block in l-transposition and ventricular tachy-cardia all can manifest in cases of Fontan surgery. Incision over the atria during surgery can also lead to generation of atrial arrhythmia. Arrhythmia per se results in atrial enlargement creating a viscous cycle. So aggressive management of arrhythmia is indicated which otherwise leads to increased sys-temic venous pressure causing thromboembolic events, ascites and hepatic fi brosis. Increasing risk of sudden death has been attributed to either atrial re-entrant tachycardia with 1:1 conduction or ventricular arrhythmia and warrants urgent cardio-version without a typical prior anticoagulative pro-tocol. Due to limited studies regarding evidence-based management of arrhythmia in this group treatment is generally empirical. Preference is given to both beta blocker and digoxin because of their negative inotropic effects. However, reduction in heart rate may decrease cardiac output which is poorly tolerated. Use of amiodarone may have side effects on thyroid and lungs but it does not impair systolic ventricular function. Modifi cations of Fon-tan procedure has resulted in decline in arrhythmia incidence in Fontan procedure. Atriopulmonary Fontan has 60% risk of atrial arrhythmias which is quite high as compared to extracaval total cavopul-monary Fontanor lateral tunnel Fontan surgery 16 .

Thrombotic events have the highest incidence in Fontan patients compared to all other congenital heart diseases. They also are a signifi cant cause of morbidity and mortality. Raised systemic venous pressure, sluggish fl ow in Fontan circuit, altered hepatic functions and arrhythmia are all causes for its development. Heparin, aspirin, coumarin deriva-tives all have been tried either individually or in

713Chapter 86 — Manifestations and Management of Failing Fontan

combination. Individual institutional experiences have shown varying results. Some have advocated anticoagulation therapy during the fi rst 3 years after Fontan completion followed by a break and then re-initiation at 10 years based on the period at which the risk of thromboembolism is maximum.

PLE is a serious complication of Fontan surgery with a mortality rate of about 50% within 5 years of its occurrence. As the exact cause of this presenta-tion is not well understood, treatment is mainly empirical. Before initiating medical therapy, a com-prehensive workup should be done to rule out causes which are amenable to surgical or catheter intervention. The mainstay of treatment is to ad-dress ventricular dysfunction, intestinal membrane stabilization and establish protein homeostasis. Drugs that are used to treat heart failure can be tried. By decreasing the systemic venous pressure and augmenting cardiac output, mesenteric isch-aemia can be controlled which is thought to be a causative factor. Intestinal membrane stabilization can be achieved using prednisone or enteral budesonide, as they attenuate the infl ammatory reactions. The drawback with steroid therapy is that effectiveness remains only as long as steroids are continued. Fontan patients have heparin sulphate defi ciency whose production and distribution are affected by high central venous pressure. Since it is believed that these sulphated glycosaminoglycans regulate protein loses, heparin infusion has shown good symptomatic and biochemical results in PLE patients. To compensate for heavy loss of proteins, exogenous albumin therapy may become necessary. This can provide temporary relief from ascites, pleu-ral effusions and peripheral oedema. High-protein diet along with medium-chain triglycerides can im-prove the nutritional state and decrease lymphatic congestion. Both hypoprotenaemia and fat malab-sorption lead to vitamin D defi ciency and second-ary hypocalcaemia. Supplementation of calcium and vitamin D has shown to decrease protein loss but mechanism remains unknown.

As is the case with other manifestations of fail-ing Fontan, treatment of plastic bronchitis re-mains empirical and multipronged. Short-term therapy involves removing the casts by adminis-tering mucolytics, chest physiotherapy and bron-choscopy in severe cases. Pulmonary toilet, use of inhaled steroids and inhaled tissue plasminogen activators, hypertonic saline all have been tried. Long-term treatment is aimed at treating heart failure and arrhythmia which leads to decrease in endobronchial leakage by reducing systemic ve-nous pressures.

Cath Lab Management

With advancements in technology and hardware, catheter-based interventions are increasingly being performed to address factors that cause failure of Fontan. A detailed cardiac catheterization helps in unravelling haemodynamic factors that are respon-sible for failing Fontan. Angiography can be done to look for anatomic obstructions at various sites, arterial or venovenous collaterals and fenestrations. High central venous pressures secondary to ana-tomical obstructions leading to Fontan failure can be treated with placements of stents at site of obstruction ( Fig. 86-1 ). If no cause of elevated sys-temic venous pressure is found, creation of fenestra-tion can decompensate the circuit albeit at cost of some desaturation ( Fig. 86-2 ). Placement of stent in the fenestration not only helps in keeping it patent but also in maintaining the adequate size of the same. High pressure in pulmonary arteries along with ventricular dysfunction can occur because of presence of arterial collaterals or antegrade fl ow into pulmonary arteries. Various types of devices or coils can be used to obliterate these shunts thereby im-proving the haemodynamic parameters ( Fig. 86-3 ). These procedures may be contemplated in situations of prolonged pleural drainage, ascites or PLEs. Mild cyanosis is often seen in patients of Fontan comple-tion but higher degrees of desaturation may be because of presence of large fenestration or venove-nous collateral. Obliteration of fenestration using devices and coil occlusion of venous collaterals will ameliorate the cyanosis. Proper prior haemodynamic assessment is of utmost importance in such condi-tions. Pulmonary arteriovenous malformations can lead to cyanosis in cases of unidirectional Fontan,

Figure 86-1. Stent dilatation (arrow) of Fontan pathway.

714 SECTION X — Pediatric Cardiology

and transcatheter pulmonary artery reconstruction has been successfully performed in such patients. Newer methods of cardiac catheterizations are be-ing developed to address varied issues related to Fontan failure. Reports of successful transcatheter take down of Fontan in patients of Fontan failure have emerged 17 . In patients where the cause of Fon-tan failure has been attributed to chronic atrioven-tricular valve regurgitation, placement of Melody valve has shown promising results.

Surgical Interventions for Failing Fontan

Repeat surgery remains the last mode of treatment in cases of failing Fontan. Dense adhesions due to multiple previous surgeries not only make it diffi cult for surgeons to operate but also increase morbidity and mortality. Even then surgery may be the only hope to salvage a failing Fontan. Many patients who have undergone classical Fontan surgery are coming with complications inherent to it. These include developing arrhythmias, obstruction to pulmonary veins or compression to pulmonary artery all sec-ondary to dilated atrium. Fontan conversion along with arrhythmia surgery has been shown to be of much benefi t to the patient. There is a signifi cant effect on symptoms like pleural effusion, ascites and arrhythmias. The 15-year freedom from cardiac transplantation or death after Fontan conversion with arrhythmia surgery has been shown to be 80% (see ref 18). Patients who have discontinuous pul-monary arteries tend to manifest cyanosis due to development of pulmonary arteriovenous malfor-mations because of lack of hepatic blood fl ow to one lung. In such cases, Fontan revision, whereby both pulmonary arteries are connected so that both lungs receive hepatic blood fl ow, may be of help. Other factors which are surgically amenable to treatment in failing Fontan are atrioventricular valve regurgita-tion, hepatic vein drainage directly to heart in cases of Kawashima, pulmonary artery stenosis or distor-tions, incessant arrhythmias. Transvenous implan-tation of pacemaker in Fontan patients is diffi cult since systemic veins are not connected to heart. In such a scenario, surgical implantation of pacemaker may be necessary. When ventricular dysfunction is thought to be primarily responsible for Fontan fail-ure, ventricular assist devices (VADs) may act as res-cue therapy. VADs for systemic ventricle are used in cases of systolic dysfunction but they are not of much benefi t in conditions were the primary cause is decreased preload. Augmentation of preload which indirectly improves diastolic dysfunction can

A

B

Figure 86-2. Fenestration creation in a patient of Fontan failure. (A) Dilator (arrow) in pulmonary venous atrium; (B) fenestration jet (arrow, seen faintly in this image) decom-pressing Fontan pathway.

Figure 86-3. Percutaneous closure of antegrade pulmonary fl ow using a ‘patent ductus arteriosus occluder’ (arrow).

715Chapter 86 — Manifestations and Management of Failing Fontan

be achieved by using right-sided cavopulmonary as-sist device. Early Fontan failure patient may need take down of the Fontan circuit to either previous fi rst or second stage of univentricular pathway. When all of the above-mentioned treatment mo-dalities have been performed and still patient does not improve, heart transplant remains the only op-tion. Risks as compared to transplants conducted for reasons other than Fontan are signifi cantly higher. The 90-day mortality rate in patients undergoing heart transplantation for Fontan failure has been found to be signifi cantly higher than heart trans-plantation for other congenital heart diseases 19 . This is not only because of the technical diffi culty result-ing from dense adhesions secondary to previous surgeries but also due to HLA sensitization conse-quent to multiple blood transfusions received in the past.

CONCLUSION

While Fontan surgery has helped many children reach their adulthood, inherent physiological limi-tations of this circulation are bound to cause failure of this circuit sooner or later. Proper case selection, use of newer drugs, advanced catheter procedures and modifi cations in surgical techniques have helped to prolong the occurrence of symptoms of failure in these cases. As this patient population grows in number, novel methods of treatment will have to be developed to help them achieve a pro-ductive symptom free life and improve their sur-vival.

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2. Qu, Y., Liu, X., Zhuang, J., Chen, G., Mai, J., Guo, X., et al . ( 2016 ). Incidence of congenital heart disease: The 9-year experience of the Guangdong Registry of Con-genital Heart Disease, China . PLoS one , 11 , e0159257 .

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5. Kim, S. J., Kim, W. H., Lim, H. G., & Lee, J. Y. ( 2008 ). Outcome of 200 patients after an extracardiac Fontan procedure . Journal of Thoracic and Cardiovascular Surgery , 136 , 108 – 116 .

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8. Costello, J. M., Steinhorn, D., McColley, S., Gerber, M. E., & Kumar, S. P. ( 2002 ). Treatment of plastic bronchi-tis in a Fontan patient with tissue plasminogen activa-tor: A case report and review of the literature . Pediat-rics , 109 , e67 .

9. Warnes, C. A., Williams, R. G., Bashore, T. M., Child, J. S., Connolly, H. M., Dearani, J. A., et al . ( 2008 ). ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: A report of the American College of Cardiology/American Heart As-sociation Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Manage-ment of Adults With Congenital Heart Disease). De-veloped in collaboration with the American Society of Echocardiography, Heart Rhythm Society, Interna-tional Society for Adult Congenital Heart Disease, So-ciety for Cardiovascular Angiography and Interven-tions, and Society of Thoracic Surgeons . Journal of the American College of Cardiology , 52 , e143 – e263 .

10. Silversides, C. K., Salehian, O., Oechslin, E., Schwerz-mann, M., Vonder Muhll, I., Khairy, P., et al . ( 2010 ). Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with con-genital heart disease: Complex congenital cardiac le-sions . Canadian Journal of Cardiology , 26 , e98 – 117 .

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12. Bruns, L. A., Chrisant, M. K., Lamour, J. M., Shaddy, R. E., Pahl, E., Blume, E. D., et al . ( 2001 ). Carvedilol as therapy in pediatric heart failure: An initial multi-center experience . Journal of Pediatrics , 138 , 505 – 511 .

13. Kurishima, C., Saiki, H., Masutani, S., & Senzaki, H. ( 2015 ). Tailored therapy for aggressive dilatation of systemic veins and arteries may result in improved long-term Fontan circulation . Journal of Thoracic and Cardiovascular Surgery , 150 , 1367 – 1370 .

14. Khambadkone, S., Li, J., de Leval, M. R., Cullen, S., Deanfi eld, J. E., & Redington, A. N. ( 2003 ). Basal pul-monary vascular resistance and nitric oxide respon-siveness late after Fontan-type operation . Circulation , 107 , 3204 – 3208 .

15. Snarr, B. S., Paridon, S. M., Rychik, J., & Goldberg, D. J. ( 2015 ). Pulmonary vasodilator therapy in the failing Fontan circulation: Rationale and effi cacy . Cardiology in the Young , 25 , 1489 – 1492 .

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17. Hallbergson, A., Mascio, C. E., & Rome, J. J. ( 2015 ). Transcatheter Fontan takedown . Catheterization and Cardiovascular Interventions , 86 , 849 – 854 .

18. Deal, B. J., & Jacobs, M. L. ( 2012 ). Management of the failing Fontan circulation . Heart , 98 , 1098 – 1104 .

19. Davies, R. R., Sorabella, R. A., Yang, J., Mosca, R. S., Chen, J. M., & Quaegebeur, J. M. ( 2012 ). Outcomes after transplantation for “failed” Fontan: A single-in-stitution experience . Journal of Thoracic and Cardiovas-cular Surgery , 143 , 1183 – 1192.e4 .