Management of the failing Fontan: Medical, interventional and surgical treatment

    Management of the failing Fontan: Medical, interventional and surgical treatment Gabrielle Vaughn, John Moore, John Lamberti, Charles Canter PII: DOI: Reference:

S1058-9813(16)30051-0 doi: 10.1016/j.ppedcard.2016.07.007 PPC 917

To appear in:

Progress in Pediatric cardiology

Please cite this article as: Vaughn Gabrielle, Moore John, Lamberti John, Canter Charles, Management of the failing Fontan: Medical, interventional and surgical treatment, Progress in Pediatric cardiology (2016), doi: 10.1016/j.ppedcard.2016.07.007

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ACCEPTED MANUSCRIPT Management of the failing Fontan: medical, interventional and surgical treatment Gabrielle Vaughna, John Moorea, John Lambertia, Charles Canterb bSt.

Children’s Hospital, University of California, San Diego Louis Children’s Hospital, Washington University

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aRady

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Introduction

The number and types of patients undergoing Fontan completion for single ventricle

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palliation have increased significantly since Francis Fontan performed an atriopulmonary connection in 1968.1 The original procedure was conceived for a systemic left ventricle in a

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patient with tricuspid atresia, but the Fontan procedure is now applied for all types of univentricular hearts and is commonly used for palliation of hypoplastic left heart

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syndrome. Patients with single ventricle anatomy and physiology are now experiencing improved survival after the Fontan operation due to modification of the surgical techniques and improved perioperative management and patient selection. 2 The first Fontan

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recipients are now entering into their fifth decade. Registry data from Australia and New 83% respectively.3

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Zealand estimates survival at 15, 20 and 25 years after Fontan completion to be 93, 90 and

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As the palliated single ventricle population ages, they will struggle with functional decline due to the non-physiologic Fontan circulation. The Fontan circulation performs without a subpulmonary ventricle and the patient is at risk for hemodynamic sequelae including systemic venous hypertension, ventricular preload deficiency, increased ventricular afterload, abnormal pulmonary vascular resistance, systolic dysfunction and diastolic dysfunction.4 These patients are at risk of numerous complications related to the Fontan physiology including cyanosis, arrhythmias, thromboembolism, plastic bronchitis, protein losing enteropathy (PLE), edema, varicosities, hepatic dysfunction, renal dysfunction, persistent effusions and death. 4, 5 As patients develop complications and symptoms related to the Fontan physiology they enter a state of “Fontan failure”. Failure can be from several different factors. In a review of 500 consecutive Fontan patients, the etiology of late failure was found to be due to systemic ventricular failure (30.6%), intractable effusions (22.2%), probable or definite arrhythmia (16.7%), reoperation (8.3%), pulmonary venous obstruction (5.6%) and high pulmonary vascular resistance (2.8%). 6. The onset of failing Fontan can be insidious and may be evidenced clinically by growth failure, weight loss, exercise intolerance, depression, abdominal distention, bloating,

ACCEPTED MANUSCRIPT diarrhea, cardiomegaly, hepatomegaly, or laboratory evaluation including low albumin, thrombocytopenia, hyperbilirubinemia, coagulopathy.7 Once a patient reaches a state of failure of the Fontan circulation various approaches can be considered including medical

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management, catheter-based or surgical intervention. Herein we present a summary of the

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current treatment options.

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Medical Management

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The etiology of Fontan failure is diverse and multi-factorial. It may result from ventricular systolic dysfunction, arrhythmia, sinus node dysfunction, diastolic dysfunction,

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elevated transpulmonary gradient, or anatomic lesions such as stenosis along the Fontan pathway, atrioventricular valve regurgitation or subaortic obstruction. Traditional adult heart failure therapies may not be applicable to the failing Fontan patient and the data

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regarding the routine use of ACE inhibitors or beta-blockers in single ventricle patients is

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inconclusive. 8 A double-blind, placebo controlled trial of enalapril in Fontan patients did not enhance exercise capacity or improve baseline hemodynamic variables. 9 Likewise, a

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short course of spironolactone in a healthy cohort of adult Fontan patients did not improve endothelial function or alter serum cytokine levels and long term benefits of aldosterone antagonism remain to be determined. 10 Although it seems intuitive to treat pump failure in a Fontan patient with the typical heart failure therapies, the current literature does not support this conclusion and further investigation is needed to determine the optimal heart failure therapy for Fontan patients. Pulmonary vasodilators are becoming an important target for failing Fontan physiology. Pulmonary vascular resistance is a key factor in cardiac output in the Fontan circulation. Increases in pulmonary vascular resistance can lead to decreases in ventricular preload and cardiac output. Thus, low pulmonary vascular resistance is imperative for optimal Fontan physiology. Patients with Fontan circulation may be at risk for pulmonary vascular disease. Mitchell and colleagues demonstrated a high incidence of pulmonary vascular disease in patients with late Fontan failure. 11 Analysis of post-mortem lung tissue from Fontan patients demonstrates adverse pulmonary vascular remodeling. 12 Presumably the adverse remodeling is due to pulmonary endothelial dysfunction from the non-pulsatile pulmonary blood flow in the Fontan circulation. 13 As such, therapies

ACCEPTED MANUSCRIPT directed at pulmonary vascular reactivity are gaining popularity and undergoing investigations. PDE5 inhibitors are an emerging therapy in single ventricle patients status post Fontan operation. In a healthy cohort of Fontan patients, sildenafil has been shown to

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improve ventricular performance in the short-term. 14 Sildenafil has also been shown to improve the cardiac index during exercise in Fontan patients and therefore pulmonary

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vasodilation may be a target to improve exercise hemodynamics. 15

Other pathways under investigation to improve pulmonary vascular resistance

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include prostacyclin and Endothelin-1. The TEMPO trial studied the effects of bosentan, an Endothelin-1 receptor antagonist, on exercise capacity and NYHA functional class in Fontan

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patients. Patients in the bosentan treatment group demonstrated improved exercise capacity and functional class in the medium-term. Though it should be noted that this was a

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healthy cohort of Fontan patients.16 Patients with liver or renal dysfunction, critical heart failure, cyanosis and hypotension were excluded. Therefore, it is difficult to draw conclusions on the safety and efficacy for the failing Fontan population, especially in light of

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the potential for hepatotoxicity in an at-risk population.

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The prostacyclin analogues improve pulmonary vascular resistance by modulating pulmonary vasoreactivity. There are many routes of administration for the prostacyclin

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analogues including epoprostenol (IV infusion), trepostinil (subcutaneous administration), iloprost (inhalation), Beraprost (oral) and Orenitram (oral). Iloprost, an inhaled prostacyclin, was found to improve peak oxygen consumption and oxygen pulse in patients with Fontan compared to placebo. 17 While short term administration may be beneficial, chronic administration of prostacyclin analogues in Fontan patients is not clear at the present time. 18

Thrombotic events are a well-described complication after the Fontan operation and a cause of significant morbidity and mortality. 19 While the risk for clot formation is highest in the immediate postoperative period, patients remain at risk years after the Fontan procedure and thrombosis has been shown to be an important cause of latemortality. 20 Therapeutic warfarin and aspirin have both been shown to decrease the risk of thrombosis in patients after the Fontan procedure.21 Patients without antiplatelet or anticoagulation therapy are at a higher risk of death from a thrombotic event. 20 The choice of antiplatelet or anticoagulation for thromboprophylaxis is often based on physician or institutional practice. Multiple studies have compared aspirin to warfarin and found no significant difference in outcomes or incidence of thromboembolism.22,23 A recent meta-

ACCEPTED MANUSCRIPT analysis showed that while the incidence of thromboembolism is lower in patients treated with aspirin and warfarin, failure rates still approximate 9% in these patients. This suggests that thromboprophylaxis in Fontan patients warrants continued investigation.

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Novel oral anticoagulants are gaining popularity in the adult population, but have not been described or investigated in Fontan patients.

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Protein losing enteropathy is a complication of the Fontan physiology resulting in intestinal loses of serum proteins including albumin, immunoglobulins and coagulation

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factors. The onset of PLE portends a poor prognosis.24 The precise cause of PLE in Fontan patients is elusive and so targeted therapy has been difficult to establish. Furthermore, due

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to the low number of patients with the disease there are no large, randomized trials evaluating the efficacy of the various therapies. Treatment should involve a

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multidisciplinary approach involving the cardiologist, interventional cardiologist, electrophysiologist, cardiovascular surgeon as well as other pediatric subspecialists such as nutrition, gastroenterology, immunology, and hematology. The role of the interventional

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cardiologist and surgeon is to address the anatomic obstructions, atrioventricular

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dyssynchrony and valvar regurgitation to improve Fontan hemodynamics. 25 Current medical therapies are varied. In a recent survey of 76 patients with PLE, the patients

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reported treatment with high protein diet (53%), enteral budesonide (36%), sildenafil (32%), prednisone (12%), IV or subcutaneous heparin (5%) and octreotide (4%). Twenty four percent of patients received chronic albumin infusions as an outpatient. The most common combination therapy was high protein diet and budesonide.26 Oral budesonide was the most frequently used therapy. It has been shown to increase serum albumin levels in PLE after Fontan, however patients must remain on therapy for continued response.27 Subcutanous heparin and octreotide have been shown to subjectively improve the symptoms of PLE but not alter the course of the disease 28,29 There is little reported on the use of sildenafil in PLE, although one case series reported improvement in PLE and alpha-1 antitrypsin stool levels in three patients. 30 Despite a lack of published data, sildenafil is frequently used as reported in the survey of PLE fontan patients above. 26 Plastic bronchitis is an important cause of morbidity and mortality in Fontan patients. It is characterized by the development of casts in the tracheobronchial tree that can progress to airway obstruction and death. 25, 31 In the survey by Schumacher et al, 46 patients with plastic bronchitis responded and reported treatment with inhaled albuterol (41%), chest physiotherapy (26%), inhaled budesonide (26%), inhaled dornase-alpha

ACCEPTED MANUSCRIPT (24%), inhaled tissue-plasminogen activator (22%) hypertonic saline (20%) and oral steroids (20%). 26 Avitabile et al have proposed a treatment algorithm for plastic bronchitis which follows a step-wise progression of therapy based on response. 31 Initial

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therapy involves relief of any anatomic abnormalities, bronchodilators, mucolytics, inhaled steroids, pulmonary toilet, PDE 5 inhibitors followed by endotheilin-1 receptor antagonists.

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If inadequate response to therapy, patients are referred for fenestration creation and started on beta-blockade with carvedilol. The last and final phase of therapy is Fontan

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takedown or heart transplantation. A report of selective lymphatic embolization leading to resolution of plastic bronchitis has been published and is a novel approach to the treatment

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of plastic bronchitis. 32

Failing Fontan physiology is a difficult problem to treat in part because of the

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various etiologies and complex interplay of multi-organ involvement. There is no panacea for failing Fontan patients and in the late stages of the disease process, the goal of medical management may ultimately be to make patients better candidates for transplantation. 5

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Future directions should focus on prevention of disease progression to Fontan failure.

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Catheter-based intervention

The role of congenital interventional cardiology is becoming more important for monitoring and rehabilitating patients with failing Fontan circulation. Scheduled surveillance catheterizations are becoming part of some congenital cardiology practices. Hemodynamic assessment, angiography of the Fontan circuit, arteries and collaterals, as well as trans-jugular liver biopsy may be performed. These studies provide key physiologic data, unmask sub-clinical or “minor” anatomic problems and help define the severity of liver pathology. Hebson at el recently described the “Hemodynamic Phenotype of the Failing Fontan” in adult patients as assessed by catheterization and compared these data to surveillance catheterization data in a group of largely asymptomatic pediatric patients after Fontan surgery.33 Important difference in Fontan pressure, pulmonary artery wedge pressure, rates of fenestration, and vascular resistance were identified.

ACCEPTED MANUSCRIPT The Hebson study provides a possible basis for systematic assessment and maintenance of favorable Fontan hemodynamics. Elevations in Fontan pressure may be reduced by correcting residual anatomic lesions or obstructions in the venous and the

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arterial circulations. Ventricular function, pulmonary vascular resistance and cardiac output may be optimized by reducing or eliminating arterial collaterals causing systemic

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ventricular volume load, elevated pulmonary artery pressure and resistance, and steal from the systemic circulation. There is evidence that such interventions are presently common

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as one institutional review of 137 consecutive Fontan patients reported the most common interventions performed after the Fontan procedure were collateral occlusion and

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angioplasty or stenting of the pulmonary artery. 34 However, it is fair to say that regular chronic surveillance catheterizations and systematic interventional elimination of

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obstructions and collaterals is not at present part of common community practice. Interventional techniques have evolved significantly and currently there are many opportunities to optimize Fontan physiology without major surgery. Catheter-based

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techniques to close, create or enlarge fenestrations, to close collateral vessels (both venous

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and arterial), to relieve anatomic obstructions in the Fontan Circuit, pulmonary arteries or aorta, to manage thrombosis and to manage arteriovenous malformations are now

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commonplace.

Fontan Fenestration may be needed in the early postoperative period if there is early Fontan failure, however it should also be considered for late Fontan failure. Creation of a fenestration via percutaneous techniques has been performed to relieve symptoms of right heart failure, mainly edema, ascites and PLE. The multicenter PLE study group reported success with fenestration creation in a small number of patients.24 More contemporary reports discussing long-term follow-up have results that are less promising. While fenestration may be helpful for the reduction of edema and ascites, PLE may relapse and this measure may only be temporizing. 35,36 However, one important consideration is maintenance of adequate size of the fenestration. It is one author’s (J Moore) unpublished experience that Fontan fenestrations often must be stented or undergo re-dilations in order to maintain adequate caliber. This strategy may facilitate longer-term results which are better than those cited above. Early reports suggested that occlusion of significant arterial collaterals reduced volume of post-operative pleural effusions, and durations of ventilation, ICU stay and hospitalization after Fontan operations. 37-39 However, Pediatric Heart Network data

ACCEPTED MANUSCRIPT refuted these reports by suggesting no significant advantages from this practice.40 MRI studies have demonstrated that after Fontan as much as 43% of pulmonary blood flow and 35% of cardiac output may be accountable to arterial collaterals.41, 42 Clearly, significant

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superfluous pulmonary blood flow through collaterals may have adverse effects on pulmonary vascular pressure and resistance, ventricular function through chronic volume

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loading, and on blood flow to vital organs such as the liver. Thus, there is rationale for arterial collateral occlusion late post Fontan surgery. However, there are no studies

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demonstrating benefit from such occlusion.

Stenosis and obstruction of the Fontan pathway can be problematic. In a review

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from Rome, torsion of the extracardiac conduit occured from somatic growth.43 Late pulmonary artery stenosis may also develop, more commonly in the left pulmonary artery.

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In the event of stenosis along the pathway (IVC, conduit or pulmonary arteries), catheter based techniques such as stent implantation or balloon angioplasty have lead to significant clinical improvement and resolution of ascites.44 Additionally, obstruction from

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thrombosis can be effectively treated with interventional techiniques including

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thrombolysis, balloon angioplasty and stent implantation. 45 Aortic arch obstruction may also be problematic for the single ventricle patient at

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any stage of palliation. Recurrent coarctation in HLHS patients has been shown to result in systolic ventricular dysfunction between stage I and II palliation. Intervention on the coarctation results in improvement in systolic function.46 Aortic arch obstruction in single ventricle patients leads to ventricular hypertrophy and worsening diastolic function which contributes to failure of the Fontan circulation. 47 Thus, one can postulate that intervention on residual aortic arch lesions would be beneficial by preserving ventricular function and optimizing Fontan hemodynamics. Many Fontan patients will be mildly desaturated at baseline, but more significant cyanosis may signify a larger problem and one that may be difficult to diagnose by echocardiography. Cardiac catheterization is useful for both diagnosis and intervention. Veno-venous collaterals can lead to progressive cyanosis. Coil occlusion of the collateral results in an increase in oxygen saturation and resolution of cyanosis in the short term. 48 More importantly, angiography and hemodynamic assessment can evaluate the underlying cause for collateral formation and allow for definitive therapy. Cyanosis can also develop from pulmonary arteriovenous malformations (AVM). In a patient with a unidirectional

ACCEPTED MANUSCRIPT Fontan, transcatheter pulmonary artery reconstruction has been described with technical success and improvement in oxygen saturations suggesting regression of AVMs.49 Interventional cardiology technologies and techniques continue to expand and

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improve, and applications to failing Fontan continue to evolve. Novel approaches for managing anatomic lesions and hemodynamic complications are emerging. Recently,

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percutaneous transcatheter Fontan takedown was reported with success in three patients with early Fontan failure.50 Two patients had improvement in plastic bronchitis and one of

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PLE. In addition, Melody valve implantation in the neoaortic and AV valve position has been reported with success in patients with failing Fontan physiology due to valvular

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regurgitation. 51, 52 As reports emerge of technical feasibility, percutaneous valve

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implantation may see broader application in the Fontan population. Surgical intervention

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When medical and interventional strategies have been exhausted, surgical

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intervention may be the only option left and in some instances surgery may be the best therapeutic approach for the patient. There are a variety of factors that can affect the

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performance of the Fontan circulation. Residual anatomic lesions, cyanosis, valvular dysfunction, arrhythmias and ventricular dysfunction may be treatable by surgical intervention. A review from Children’s Hospital of Philadelphia evaluated surgical reintervention following the Fontan procedure and reported the most common surgical procedures as pacemaker insertion or revision (48%), reinclusion of previously excluded hepatic veins (13%), Fontan conversion (11%), cardiac transplantation (7%), enlargement or creation of a baffle fenestration (5%), AVV operation (2%), and other procedures (14%).53 A recent 40-year review of Fontan outcomes at the Mayo clinic found that among survivors of the operation, 23% went on to have pacemaker insertion/revision, 13% had Fontan revision/conversion, 7% had AVV repair/replacement, 2% had implantable cardioverter-defibrillators placed and 2% had late Fontan takedown.54 Surgical Fontan conversion or revision has been very successful for many patients presenting with “classic” atriopulmonary Fontan failure. Patients with a classic atriopulmonary Fontan are prone to develop atrial dilation, arrhythmias and exercise intolerance. Dilation of the atrium can lead to pulmonary venous obstruction and narrowing at the pulmonary artery connection. Surgical conversion to an extracardiac

ACCEPTED MANUSCRIPT Fontan should be considered whenever a patient with an atriopulmonary connection presents with arrhythmias, residual anatomic lesions or mild-moderate ventricular dysfunction. 55 The intermediate-term results of Fontan conversion combined with an

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arrhythmia operation has been reported with favorable outcomes. The 10-year freedom from cardiac death or transplant was 84% and the 10-year freedom from arrhythmia was

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77% after Fontan conversion. 56 Patients with PLE, multiorgan dysfunction and poor ventricular function are not good candidates for an ablation/conversion procedure. These

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patients may be better served with heart transplantation. 7 Whether or not the asymptomatic atriopulmonary connection patient with a dilated right atrium and other

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sub-clinical anatomic abnormalities that are free of arrhythmias should be offered “prophylactic” conversion is debatable. Since the natural history of the atriopulmonary

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Fontan connection is now well defined in the literature, a reasonable case for prophylactic surgery can be made. Fontan revision may also be a useful adjunct in the cyanotic patient. Cyanosis can develop from pulmonary arteriovenous malformation due to discontinuous

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pulmonary arteries or streaming of hepatic blood flow to one lung. Surgery to address the

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pulmonary arteries or revise the conduit and direct hepatic blood flow to both lungs can improve saturations. 57, 58 Takedown of the Fontan circuit to a systemic-to-pulmonary

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artery shunt or superior cavopulmonary anastamosis has been well described for early Fontan failure. 59-61 Outcomes of late takedown for Fontan failure are not well described. Atrioventricular valve regurgitation is associated with worse outcomes after the Fontan operation.62 Moderate-to-severe A-V valve regurgitation is generally accepted as an indication for intervention. Valve repair is more commonly performed than valve replacement (62% vs 38%) and early mortality is not significantly different between the two surgical options. 63 The operation is usually technically successful at decreasing the degree of regurgitation however patients requiring valve intervention have higher late mortality and a greater need for transplantation.64 They also have a higher incidence of PLE than the general Fontan population. 63 Patients with other residual obstructive anatomic lesions in the pulmonary arteries, pulmonary veins, subaortic area or aortic arch should be considered for early corrective surgery . The original “Ten Commandments” for a successful Fontan connection proposed by Choussat, and Fontan are still useful in analyzing late post-Fontan patients that are candidates for an intervention. 65 If a conversion or corrective operation is contemplated, all anatomic and physiologic abnormalities should be addressed at operation.

ACCEPTED MANUSCRIPT Sinus node dysfunction and other arrhythmias are frequent developments after the Fontan operation. Most of the common arrhythmias can have adverse hemodynamic effects on the Fontan circulation. Junctional rhythm produces increased atrial pressure and

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impairs ventricular filling which can impact the Fontan hemodynamics, even at acceptable heart rates. Permanent pacemaker implantation for sinus node dysfunction and

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bradyarrhythmias has been shown to provide symptomatic relief and hemodynamic improvement. 66 The development of arrhythmia portends a poor prognosis and is

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associated with increased mortality.67,68 The atriopulmonary Fontan has the highest risk of atrial arrhythmias.69 In the Mayo clinic analysis of Fontan outcomes, arrhythmias occur

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in 41% of patients and the most common arrhythmias are atrial flutter (74%), atrial fibrillation (39%), atrial tachycardia (26%), re-entrant supraventricular tachycardia (9%)

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and ventricular tachycardia (10%). 56 Catheter ablation of atrial tachycardia in Fontan patients is less successful in comparison to other forms of congenital heart disease and has a high recurrence rate. 70, 71 Thus, surgical intervention should be considered when

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patients fail catheter therapies. Results of Fontan conversion with arrhythmia surgery have

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been associated with good outcomes. Arrhythmia surgery at the time of conversion may include right atrial reduction, a modified right atrial maze procedure for right atrial macro-

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reentrant tachycardia and left atrial Cox Maze III for atrial fibrillation or left atrial macroreentrant tachycardia. 7

Mechanical circulatory support is now widely used for left-sided heart failure. Ventricular assist devices (VAD) are designed to provide systemic support and thus application to failing Fontan physiology remains challenging. VAD is a viable option if Fontan failure is the result of ventricular dysfunction. However, ventricular assist may not overcome failing Fontan physiology if low cardiac output is a result of inadequate preload through passive pulmonary blood flow. 72 There are case reports of the successful implementation of ventricular assist devices in patients with failing Fontan as a bridge to transplantation however successful outcomes are rare in the reported literature.73-77 The development of a right-sided pump for cavopulmonary support is now underway. The goal of such support is to augment ventricular filling and decrease venous pressures. 78

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application of such support could be used to stabilize the circulation in the early perioperative period or alleviate the symptoms and hemodynamic sequelae of late Fontan failure. 79 Animal Fontan models have been created to test the feasibility of right-sided support with short term success. 78, 80-82 As VAD technology advances, cavopulmonary

ACCEPTED MANUSCRIPT support could be used as a bridge to transplantation or destination therapy. Rodefeld and colleagues have proposed an algorithm to guide assist strategies in the failing Fontan circulation. 83 In summary, ventricular or left-sided support should be considered for

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systemic support when there is ventricular systolic dysfunction. Cavopulmonary or rightsided support should be used to stabilize the Fontan circulation when there is diastolic patient with combined systolic and diastolic dysfunction.

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dysfunction. Both ventricular and cavopulmonary support should be considered for a

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Heart transplantation is the final option for patients that have failed all other treatment strategies for end stage heart failure and/or PLE. However, transplant is an

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imperfect solution due to the inadequate supply of donor hearts and unpredictable waiting period. Additionally, this subset of patients often has multi-organ dysfunction and HLA

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sensitization from previous exposure to blood product and homograft material, which adds additional risk to the transplant outcome. The surgical procedure is complex owing to the difficult dissection from multiple prior procedures and carries a risk of significant bleeding

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and complicated arterial and venous reconstructions. As such, cardiopulmonary bypass and

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aortic cross clamp times are often longer in Fontan patients undergoing transplantation. 84 Recent examinations of transplant outcomes in Fontan patients have shown that they are at

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increased risk for early mortality after transplantation, but that medium and long-term mortality is similar to patients with other forms of congenital heart disease. 85-87 Therefore, heart transplantation should be considered an effective therapy for end stage Fontan failure and PLE is expected to improve in most cases. 85

ACCEPTED MANUSCRIPT Conclusion Introduction of the Fontan procedure and subsequent modifications have created a

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palliative strategy for patients with single ventricle anatomy and physiology. The Fontan circulation is not as efficient as a biventricular circulation and patients are subject to

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chronic venous hypertension, abnormal pulmonary vascular resistance and low cardiac output. Despite the inherent drawbacks, the Fontan operation remains the best palliative

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strategy for single ventricle patients at the current time. The limitations of this palliative approach are becoming evident as more patients are presenting with failing Fontan

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physiology. There are multiple causes of Fontan failure which makes this a challenging group of patients to treat. The lack of effective therapies highlights the need for continued

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investigation into treatments and interventions that will preserve optimal Fontan

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hemodynamics and prevent the progression to failure.

ACCEPTED MANUSCRIPT References 1. Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax 1971; 26: 240-248

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2. d’Udekem Y, Iyengar A ,Cochrane A et al. The Fontan procedure contemporary techniques have improved tong-term outcomes. Circulation 2007; 116: 157-164

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3. d’Udekem Y, Ivengar A, Galati J et al. Redefining expectations of long term turvival after Fontan. Circulation 2014; 130: 532-538

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4. Rychik J, Goldberg D. Late consequences of the Fontan operation. Circulation 2014; 130: 1525-1528

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5. De Rita F, Crossland D, Griselli M et al. Management of the failing Fontan. Semin Thorac Cardiovasc Surg Pediatr Card Surg Ann 2015; 18: 2-6

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6. Gentles T, Mayer J, Gauvreau K et al. Fontan operation in five hundred consecutive patients: factors influencing early and late outcome. J Thorac Cardiovasc Surg 1997; 114: 376-391

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7. Deal B, Jacobs M. Management of the failing Fontan circulation. Heart 2012; 98: 10981104

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8. Simpson K, Canter C. Can adult heart failure regimens be applied to children: What works and what does not? Curr Opin Cardiol 2012; 27:98-107

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9. Kouatli A, Garcia J, Zellers T et al. Enalapril does not enhance exercise capacity in patients after fontan procedure. Circulation 1997; 96: 1507-1512 10. Mahle W, Wang A, Quyyumi A et al. Impact of spironolactone on endothelial function in patients with single ventricle heart. Congenit Heart Dis. 2009; 4:12-16 11. Mitchell M, Campbell D, Ivy D et al. Evidence of pulmonary vascular disease after heart transplantation for Fontan circulation failure. J Thorac Cardiovasc Surg 2004; 128: 693-702 12. Ridderbos F, Wolff D, Timmer A et al. Adverse pulmonary vascular remodeling in the Fontan circulation. J Heart Lung Transplant 2015; 34: 404-413 13. Hambadkone S, Li J, de Leval M et al. Basal pulmonary vascular resistance and nitric oxide responsiveness later after fontan-type operation. Circulation 2003; 107: 3204-3208 14. Goldberg D, French B, Szwast A et al. Impact of sildenafil on echocardiographic indices of myocardial performance after Fontan operation. Pediatr Cardiol 2012; 33: 689-696 15. Van De Brauene A, La Gerche A, Claessen G et al. Sildenafil improves exercise hemodynamics in fontan patients. Circ Cardiovasc Imaging 2014; 7: 265-273 16. Herbert A, Mikkelsen U, Thilen U et al. Bosentan improves exercise capacity in adolescents and adults after Fontan operation. The TEMPO (treatment with endothelin

ACCEPTED MANUSCRIPT receptor antagonist in Fontan patients, a randomized, placebo-controlled, bouble-blind study measuring peak oxygen consumption) study. Circulation 2014; 130: 2021-2030

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17. Rhodes J, Ubeda-Tikkanen A, Clair M et al. Effect of inhaled Iloprost on the exercise function of Fontan patients: a demonstration of concept. Int J Cardiol 2013; 168: 2435-2440

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18. Sharr B, Paridon S, Rychik J. Pulmonary vasodilator therapy in the failing Fontan circulation: rationale and efficacy. Cardiol Young 2015; 25: 1489-1492

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19. Monagle P, Cochrane A, McCrindle B et al. Thromboembolic complications after Fontan procedures-the role of prophylactic anticoagulation. J Thorac Cardiovas Surg 1998; 115: 493-498

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20. Khairy P, Fernandes S, Mayer J et al. Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation 2008; 117:85-92

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21. McCrindle B, Manlhiot C, Cochrane A et al. Factors associated with thrombotic complications after the Fontan procedure. A secondary analysis of a multicenter, randomized trial of primary thromboprophylaxis for 2 years after the Fontan procedure. JACC 2013; 61: 346-353

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22. Potter B, Leong-Sit P, Fernandes S et al. Effect of aspirin and warfarin therapy on thromboembolic events in patients with univentricular hearts and Fontan palliation. Int J Cardiol 2013; 168: 3940-3943

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23. Alsaied T, Alsidawi S, Allen C et al. Strategies for thromboprohylaxis in Fontan circulation: a meta-analysis. Heart 2015; 101: 1731-1737 24. Mertens L, Hagler D, Sauer U et al. Protein-losing enteropathy after the Fontan operation: an international multicenter study. PLE study group. J Thorac Cardiovasc Surg 1998; 115: 1063-1073 25. Goldberg D, Shaddy R, Ravishankar C et al. The failing Fontan: etiology, diagnosis and management. Expert Rev Cardiovasc Ther 2011; 9: 785-793 26. Schumacher K, Stringer K, Donohue J et al. Fontan-associated protein-losing enteropathy and plastic bronchitis. J Pediatr 2015; 166: 970-977 27. Thacker D, Patel A, Dodds K. Use of oral budesonide in the management of proteinlosing enteropathy after the Fontan operation. Ann Thorac Surg 2010; 89: 837-842 28. Ryerson L, Goldberg C, Rosenthal A et al. Usefulness of heparin therapy in protein-losing enteropathy associated with single ventricle pallliation. Am J Cardiol 2008; 101: 248-251 29. John A, Phillips S, Driscoll D et al. The use of octreotide to successfully treat proteinlosing enteropathy following the Fontan operation. Congenit Heart Dis 2011; 6: 653-656 30. Reinhardt Z, Uzu O, Bhloe V et al. Sildenafil in the management of the failing Fontan circulation. Cardiol Young 2010; 20: 522-525

ACCEPTED MANUSCRIPT 31. Avitabile C, Goldberg D, Dodds K et al. A multifaceted approach to the management of plastic bronchitis after cavopulmonary palliation. Ann Thorac Surg 2014; 98: 634-640

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32. Dori Y, Keller M, Rychik J et al. Successful treatment of plastic bronchitis by selective lymphatic embolization in a fontan patient. Pediatrics 2014; 134: 590-595

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33. Hebson C, McCabe N, Elder R et al. Hemodynamic phenotype of the failing Fontan in an adult population. Am J Cardiol 2013; 112:1943-1947

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34. Hannan R, Zabinsky J, Salvaggio J et al. The Fontan operation: the pursuit of associated lesions and cumulative trauma. Pediatr Cardiol 2011: 32: 778-784

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35. Vyas H, Driscoll D, Cabalka A et al. Results of transcatheter Fontan fenestration to treat protein losing enteropathy. Cath Cardiovasc Interv 2007; 69: 584-589

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36. Meadows J, Jenkins K. PLE: Integrating a new disease paradigm into recommendations for prevention and treatment. Cardiol Young 2011; 21: 363-377

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37. Ichikawa H, Yagihara T, Kishimoto H et al. Extent of aortopulmonary collateral blood flow as a risk factor for Fontan operations. Ann Thorac Surg 1995; 59:433-437

TE

38. Spicer R, Uzark K, Moore J et al. Aortopulmonary collateral vessels and prolonged pleural effusions after modified Fontan procedures. Am Heart J 1996; 131:1164-1168

AC CE P

39. Kanter K, Vincent R, Raviele A. Importance of acquired systemic-to-pulmonary collaterals in the Fontan operation. Ann Thorac Surg 1999; 68: 969-974 40. Banka P, Sleeper L, Atz A et al. Practice variability and outcomes of coil embolization of aortopulmonary collaterals before Fontan completion: a report from the Pediatric Heart Network Fontan cross-sectional study. Am Heart J 2011; 162:125-130 41. Grosse-Wortmann L, Drolet C, Draqulescu A et al. Aortopulmonary collateral flow volume affects early postoperative outcome after Fontan completion: a multimodality study. J Thorac Cardiovasc Surg 2012; 144: 1329-1336 42. Odenwald T, Quail M, Giardini A et al. Systemic to pulmonary collateral blood flow influences early outcomes following the total cavopulmonary connection. Heart 2012; 98:934-940 43. Giannico S, Hammad F, Amodeo A et al. Clinical outcomes of 193 extracardiac Fontan patients the first 15 years. JACC 2006; 47: 2065-2073 44. Ovroutski S, Ewert P, Alexi-Mekishvili et al. Dilation and stenting of the Fontan pathway: impact of the stenosis treatment on chronic Ascites. J Interv Cardiol 2007: 21: 38-43 45. Kammeraad J, Sreerman N. Acute thrombosis of an extracardiac Fontan conduit. Heart 2004; 90: 70

ACCEPTED MANUSCRIPT 46. Larrazabal L, Tierney E, Brown D et al. Ventricular function deteriorates with recurrent coarctation in hypoplastic left heart syndrome. Ann Thorac Surg 2008; 86: 869-874

PT

47. Lee M, Brizard C Galati J et al. Outcomes of patients born with single ventricle physiology and aortic arch obstruction: the 26 year Melbourne experience. J Thorac Cardiovasc Surg 2014; 148: 194-201

SC

RI

48. Sugiyama H, Yoo S, Williams W et al. Characterization and treatment of systemic venous to pulmonary venous collaterals seen after the Fontan operation. Cardiol Young 2003; 13: 424-430

NU

49. Aboulhosn J, Danon S, Levi D et al. Regression of pulmonary arteriovenous malformations after transcatheter reconnection of the pulmonary arteries in patients with unidirectional Fontan. Congenit Heart Dis 2007; 2: 179-184

MA

50. Hallberson A, Mascio C, Rome J. Transcatheter Fontan Takedown. Cath Cardiovasc Interv 2015; 86: 849-854

D

51. Moysih A, Kerst G, Akinturk H et al. Transapical valve-in-valve implantation to treat a regurgitant mitral bioprothesis in a child with failing Fontan circulation. J Thorac Cardiovasc Surg. 2015; 150: 23-25

TE

52. Martin M, Gruber P, Gray R. Transcatheter neoaortic valve replacement utilizing the Melody Valve in hypoplastic left heart syndrome. Cath Cardiovasc Interv 2015; 85:615–619

AC CE P

53.Petko M, Myung R, Wernovsky G et al. Surgical reinterventions following the Fontan procedure. Eur J Cardiothorac Surg 2003; 24: 255-259 54. Pundi K, Johnson J, Dearani J et al. 40-year follow-up after the Fontan operation longterm outcomes of 1,052 Patients. JACC 2015; 66: 1700-1710 55. Kogon B. Surgery for the failing Fontan. Prog Pediatr Cardiol 2012; 34: 27-30 56. Deal B, Costello J, Webster G et al. Intermediate term outcome of 140 Fontan conversion with arrhythmia operations. Ann Thorac Surg 2016; 101: 717-724 57. Sernich S, Ross-Ascuitto N, Dorotan J et al. Surgical improvement of hepatic venous mixing to resolve systemic arterial hypoxemia associated with post-Fontan pulmonary arteriovenous fistula. Tex Heart Inst J 2009; 36: 480-482 58. Imoto Y, Sese A, Joh K. Redirection of the hepatic venous flow for the treatment of pulmonary arteriovenous malformations after Fontan operation. Pediatr Cardiol 2006; 27: 490-492 59. Murphy M, Glatz A, Goldberg D et al. Management of early Fontan failure: a single institution experience. Eur J Cardiothorac Surg 2014; 46: 458-464 60. Iyengar A, Brizard C, Konstantinov I et al. The option of taking down the Fontan circulation: the Melbourne experience. J Thorac Cardiovasc Surg 2010; 139: 1346-1348

ACCEPTED MANUSCRIPT 61. Almond C, Mayer J, Thiagarajan R et al. Outcome after Fontan failure and takedown to an intermediate palliative circulation. Ann Thorac Surg 2007; 84: 880-887

PT

62. Yoshimura N, Yamaguchi M, Oshima Y et al. Risk factors influencing early and late mortality after total cavopulmonary connection. Eur J Cardiothorac surg 2001; 20: 598-602

RI

63. Menon S, Dearani J Cetta F. Long-term outcome after atrioventricular valve surgery following modified Fontan operation. Cardiol Young 2011; 21: 83-88

SC

64. Liu V, Yong M, d’Udekem Y et al. Outcomes of atrioventricular valve operation in patients with Fontan circulation. Ann Thorac Surg 2015; 99: 1632-1638

NU

65. Stern H. Fontan “Ten Commandments” revisited and revised. Pediatr Cardiol. 2010; 31: 1131-1134

MA

66. Heinemann M, Gass M, Breuer J et al. DDD Pacemaker Implantation After Fontan-Type Operations. PACE 2003; 26: 492-495 67. Quinton E, Nightingale P, Hudsmith L et al. Prevalence of atrial tachyarrhythmia in adults after Fontan operation. Heart 2015; 101:1672-1677

TE

D

68. Giannakoulas G, Dimopoulos K, Yuksel S et al. Atrial tachyarrhythmias late after Fontan operation are related to increase in mortality and hospitalization. Int J Cardiol 2012; 157: 221-226

AC CE P

69. Stephenson E, Lu M, Berul C et al. Arrhythmias in a contemporary Fontan cohort: prevalence and clinical associations in a multi-center cross-sectional study . JACC 2010; 56: 890-896 70. Yap S, Harris L, Silversides C et al. Outcome of intra-atrial re-entrant tachycardia catheter ablation in adults with congenital heart disease : negative impact of age and complex atrial surgery. JACC 2010; 56: 1589-1596 71. Correa R, Sherwin E, Kovach J et al. Mechanism and ablation of arrhythmia following total cavopulmonary connection. Circ Arrhythm Electrophysiol. 2015; 8: 318-325 72. Fuller S. Surgical revisions and mechanical circulatory support of the failing Fontan. Cardiol Young 2013; 23: 847-851 73. Morales D, Adachi I, Heinle J et al. A new era: use of an intracorporeal systemic ventricular assist device to support a patient with failing Fontan circulation. J Thorac Cardiovasc Surg 2011; 142: 138-149 74. Halaweish I, Ohye R, Si M. Berlin heart ventricular assist device as a long-term bridge to transplantation in a Fontan patient with failing single ventricle. Pediatr Transplant 2015;19:193-195 75. Hoganson D, Boston U, Gazit A et al. Successful bridge through transplantation with berlin heart ventricular assist device in a child with Failing fontan. Ann Thorac Surg 2015; 99: 707-709

ACCEPTED MANUSCRIPT

76. Davide C, Ocello S, Salviato N et al. Implantation of a berlin heart as single ventricle bypass on Fontan circulation in univentricular heart failure ASAIO J 2007; 53: e1-2

PT

77. Russo P, Wheeler A, Russo J et al. Use of a ventricular assist device as a bridge to transplantation in a patient with single ventricle physiology and total cavopulmonary anastomosis. Paediatr Anaesth. 2008;18: 320-324

SC

RI

78. Rodefeld M, Boyd J, Myers C et al. Cavopulmonary assist: circulatory support of the univentricular Fontan circulation. Ann Thorac Surg 2003; 76: 1911-1916

NU

79. Rodefeld M, Coats B, Fisher T et al. Cavopulmonary assist for the univentricular Fontan circulation: von Karman Viscous Impeller Pump (VIP). J Thorac Cardiovasc Surg 2010; 140: 529-536

MA

80. Reimer R, Amir G, Reichenbach S et al. Mechanical support of total cavopulmonary connection with an axial flow pump. J Thorac Cardiovasc Surg 2005; 130: 351-354 81. Derk G, Laks H, Biniwale R et al. Novel techniques of mechanical circulatory support for the right heart and Fontan circulation. Int J Cardiol 2014; 176: 828-832

TE

D

82. Zhu J, Kato H, Fu Y et al. Cavopulmonary support with a microaxial pump for the failing Fontan physiology. ASAIO J 2015; 61: 49-54

AC CE P

83. Giridhara G, Ising M, Sobieski M et al. Cavopulmonary assist for the failing Fontan circulation: impact of ventricular function on mechanical circulatory support strategy. ASAIO J 2014; 60: 707-715 84. Davies R, Sorabella R, Yang J et al. Outcomes after transplantation for “failed” Fontan: A single-institution experience. J Thorac Cardiovasc Surg 2012; 143: 1183-1192 85. Bernstein D, Naftel D, Chin C et al. Outcome of listing for cardiac transplantation for failed Fontan a multi-instiutional study. Circulation 2006; 114: 273-280 86. Kovach J, Naftel D, Pearce F et al. Comparison of risk factors and outcomes for pediatric patients listed for heart transplantation after bidirectional Glenn and after Fontan: An analysis from the Pediatric Heart Transplant Study. J Heart Lung Trans 2012; 31: 133-139 87. Kanter K, Mahle W, Vincent R et al. Heart Transplantation in children with a fontan procedure. Ann Thorac Surg 2011; 91: 823-830