Four decades of Fontan palliation

520 | SEPTEMBER 2010 | voluME 7 www.nature.com/nrcardio

Cardiothoracic Unit, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK (M. R. de Leval, J. E. Deanfield).

Correspondence to: J. E. Deanfield j.deanfield@ ich.ucl.ac.uk

Four decades of Fontan palliationMarc R. de Leval and John E. Deanfield

Abstract | The Fontan palliation was introduced in 1968 to treat cardiac malformations unsuitable for biventricular repair. This procedure has transformed the surgical management of congenital heart disease. In this Review, we reflect on the outcomes and clinical problems associated with this unique circulation after more than 40 years of experience. We also summarize the evolution of the Fontan procedure, highlight the long-term clinical issues and their management, and consider future expectations of a circulation driven by a single ventricle with the systemic and pulmonary blood flow in series rather than in parallel.

de Leval, M. R. & Deanfield, J. E. Nat. Rev. Cardiol. 7, 520–527 (2010); published online 29 June 2010; doi:10.1038/nrcardio.2010.99

IntroductionThe Fontan procedure was introduced in 1968 to treat patients with tricuspid atresia.1 This surgical approach has subsequently been applied to a range of complex congeni-tal heart malformations that are characterized by the pres-ence of only one functional ventricular chamber, in which a biventricular repair is not possible. The highly novel concept of using the right ventricle in hypo plastic left heart syndrome to serve the systemic circulation was developed by Norwood in the early 1980s.2 This discovery created a large new population of candidates for Fontan palliation, which as a result has become one of the most frequently performed operations for congenital heart defects.

The Fontan palliation is an excellent illustration of the importance of evaluating long-term follow-up to refine both patient selection and surgical procedure. The fortieth anniversary of the first Fontan procedure is a timely occa-sion to reflect on the achievements and intrinsic limitations of this circulation. In this Review, we consider the develop-ments that have moved practice closer to the optimal Fontan procedure, the patho physiology of the character-istic circulation that is created, and the evolving clinical results, particularly with regard to the consequences of both the normal aging process and speci fic diseases. We also consider future challenges and possible solutions.

Evolution of the Fontan procedureIn a normal biventricular heart, the systemic and pulmo-nary circulations are in series and each one is supported by a ventricle. In the Fontan circulation, the systemic and pulmonary circulations are separated and placed in a serial arrangement without the interposition of a normal ventricle (Figure 1).

Atrioventricular connectionIn the early years of the Fontan experience, a power source other than the main ventricular chamber was

believed to be necessary to serve the pulmonary circula-tion. The small right ventricle was used in rare instances, creating an atrioventricular connection that was usually performed in hearts with tricuspid atresia and subvalvar pulmonary stenosis, where the great arteries were con-nected to the heart.3 The procedure consisted of closing the atrial–septal defect and interposition of a valved homograft between the right atrium and the small right ventricle.3 Björk and colleagues modified this approach by creating a valveless right atrium to right ventricle con-nection using a pericardial onlay patch.4 The anticipated increase in mean pressure energy between the right atrium and the pulmonary arteries was not produced; however, favorable remodeling of the small right ven-tricle did occur in some cases, which generated posi-tive work similar to a biventricular circulation.3 In these circum stances, an atrioventricular valve was necessary to prevent heart failure owing to regurgitation into the systemic venous bed. The atrioventricular connection has now been completely abandoned because of poor results and a high incidence of reoperations.

Atriopulmonary connectionIn most cases, the right atrium was connected to the pulmo nary artery to serve as the power source (atrio-pulmonary connection). This connection was devel-oped on the basis of the concept that the hypertrophied right atrium in tricuspid atresia could act as a pump. Initially, inlet and outlet valves were incorporated, but it soon became evident that these were not necessary.5 A variety of direct atriopulmonary connections have been described. The extension of the Fontan procedure to hearts with a single ventricle and common atrio-ventricular valve or left atrioventricular valve atresia, as well as to the hypoplastic left heart syndrome, required technical modifications of the atriopulmonary connec-tion, in particular septation of the atrial chamber away from the atrioventricular valves.6,7 These changes led to the development of the lateral tunnel, suggesting that the right atrium was also dispensable.

Competing interestsThe authors declare no competing interests.

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Total cavopulmonary connectionA series of in vitro flow dynamic experiments have shown that the right atrium is often disadvantageous in the subpulmonary circulation, and can result in flow dis-turbances and consequent energy loss. This observation led to the development of a total cavopulmonary connec-tion, which generally incorporates either an intra-atrial lateral tunnel or an extracardiac conduit that connects the inferior vena cava to the pulmonary artery.8,9 The hemodynamic superior ity of the total cavopulmonary connection was confirmed by mathematical modeling using computational fluid dynamic technology.10 Besides these hemodynamic advantages, the total cavopulmonary connection prevents atrial dilatation, which occurs after atrio pulmonary connections and contributes to throm-bus formation, predisposes to a range of complex atrial arrhythmias, and sometimes causes pulmonary venous obstruction. The extracardiac total cavopulmonary connec tion has the theoretical advantage of reducing suture lines within the right atrium, excluding it com-pletely from the high venous pressure, and avoiding the placement of prosthetic material in the atrial chamber. The lateral tunnel can be performed in a relatively small heart and has the potential to grow. Technically, it has the disadvantage of requiring a period of induced myo-cardial ischemia during the intracardiac procedure and more atrial suture lines. The total cavopulmonary con-nection is now the most widely adopted Fontan approach and can be performed as a single procedure. However, a staged approach to unload the single right ventricle at a young age was introduced for hypoplastic left heart syn-drome, and is now the practice for most Fontan patients regardless of anatomy.11 This method minimizes both volume loading and acute changes in ventricular mass to volume ratio.

A further milestone in the evolution of the Fontan procedure was the creation of a fenestration to permit a controlled right to left atrial shunt in order to maintain cardiac output in high-risk patients, particularly during phasic elevation of pulmonary vascular resistance.12 This modification has become standard in many centers, but other centers either never adopted the approach or have abandoned it owing to lack of scientific evidence to support its use. In addition, policies for the late closure of fenestrations, usually by interventional catheteriza-tion, vary between centers. A randomized clinical trial would inform on both the rationale for fenestration and its subsequent closure. Hybrid procedures have started to make an impact on the management of the Fontan completion by interventional catherization.13,14

Progress in surgical practice has resulted in a more-efficient, streamlined circulation,9 with less suturing and better preparation of the systemic ventricle com-pared with the initial Fontan procedures performed in the 1970s.

Pathophysiology of the Fontan stateIn a seminal paper published after 20 years of Fontan experience, Fontan and colleagues identified the charac-teristics of a ‘perfect’ operation by use of multivariate

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The Fontan palliation is a surgical procedure that is used to repair congenitally ■malformed hearts with only one functional ventricle

The total cavopulmonary connection is the most widely adopted Fontan procedure ■

Despite considerable improvements in the prognosis of patients, the Fontan ■procedure has intrinsic limitations

Future advances, such as use of mechanical assist devices and transplantation ■technologies, could overcome or at least alleviate limitations associated with this procedure

analysis. They predicted a long-term decline in outcomes even in these ideal conditions.15 After a further 20 years, Kirklin and colleagues confirmed that, even following optimization of case selection, surgical procedure, and management, a constant hazard was still imposed by the Fontan state comparable to that predicted in the earlier report.16 As technical advances have moved practice closer to the ‘perfect’ operation, the intrinsic limitations of the Fontan circulation have become more apparent. However, difficultly remains in demonstrating with convincing evidence the role of the Fontan state in the observed late attrition, and the roles of confounding variables, such as the anatomic substrate for which the Fontan operation was performed.

Numerous theoretical, experimental, and clinical studies of the hemodynamics of a circulation driven by a single ventricle have demonstrated profound altera-tions in ventricular systolic and diastolic function and coordination, venous and arterial hemodynamics, and ventriculoarterial coupling.17–19 A considerable increase in systemic afterload has been a consistent finding, which is associated with elevation in both pulsatile and nonpulsatile impedance components of the ventricular afterload. A mismatch between myocardial contractil-ity and afterload results from changes in the systemic circulation and from limitations in ventricular perfor-mance. The key determinant of circulatory performance after Fontan remains unclear, but is an important issue as it influences treatment strategies, such as the use of drugs to reduce systemic afterload. studies of the sys-temic venous return have demonstrated reduced venous compliance and capacitance, increased microvascular filtration pressures, as well as an increase in the venous tone and abnormal splanchnic hemodynamics.20,21 These changes may be adaptive mechanisms to maintain venous return, but they also limit the ability to mobilize blood and increase preload. The infradiaphragmatic venous return after Fontan is highly influenced by activities of normal daily life, including respiration and posture.22,23

Pulmonary vascular resistance, in addition to its con-tribution to ventricular afterload, is also a key determi-nant of preload. The pulmonary vascular bed is modified as a result of the lack of pulsatile flow (raising pulmonary vascular resistance),24 abnormal regional flow distribu-tion in the lungs and consequent ventilation–perfusion mismatch, and in some cases, subclinical thrombo-embolism. many of these changes are likely to progress, which may become a major determinant of late attrition of the Fontan state.21,25,26 systemic ventricular function is




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Figure 1 | The different types of Fontan circulation. a | The atriopulmonary connection consists of closing the atrial–septal defect and connecting the right atrium directly to the right pulmonary artery. Alternatively, the superior vena caval flow can be derived directly to the pulmonary artery. The atriopulmonary connection was mainly used for the repair of tricuspid atresia, but has now been abandoned in preference to the lateral tunnel or the extracardiac cavopulmonary connection. b | The intracardiac total cavopulmonary connection, or lateral tunnel procedure, connects the superior vena cava to the right pulmonary artery, so the blood is directed from the inferior vena cava to the pulmonary artery. The use of the lateral tunnel rather than the extracardiac conduit is often a question of institutional preference. Lateral tunnel is often performed in smaller hearts, such as in patients with hypoplastic left heart syndrome who usually receive a Fontan operation at an early age. c | The extracardiac cavopulmonary connection consists of a direct anastomosis of the superior vena cava to the right pulmonary artery and in the interposition of an extracardiac prosthesis between the inferior vena cava and the right pulmonary artery. The advantage of the procedure is that it can be performed without myocardial ischemia, there are fewer suture lines in the right atrium, and no foreign material in the right atrium. Permission obtained from Nature Publishing Group © de Leval, M. R. Nat. Clin. Pract. Cardiovasc. Med. 2, 202–208 (2005).

largely determined by the resting preload limitation,25,26 which is in contrast to the normal biventricular circula-tion where cardiac output is usually dependent on myo-cardial contractility. From early in the Fontan experi ence, chronic preload deprivation has been associated with incoordinate contraction and relaxation patterns.17 Furthermore, the absence of the normal myocardial con-tractility response to increased afterload and decreased preload results in a preload/afterload mismatch, which leads to a higher energy requirement per unit of cardiac output and a reduced cardiac index. Finally, there are important consequences of chronic elevation of the systemic venous pressure on atrial size and arrhythmo-genicity (for the atrio pulmonary connections), as well as on liver and gastro intestinal structure and function.

Clinical outcomesThe short-term and medium-term results of the Fontan palliation have been excellent, particularly considering the spectrum of severe congenital cardiac malformations for which it is performed.27,28 Hypoplastic left heart syn-drome is a lethal condition without a Norwood proce-dure or transplantation. The pulmonary and systemic circulations remain in parallel following alternative pal-liations, such as pulmonary artery banding or systemic to pulmonary artery shunt; these procedures result in premature death, usually from ventricular failure owing to chronic volume overload, or cyanosis from inadequate pulmonary blood flow (Figure 2). operative mortality of the Fontan procedure has steadily decreased and is

currently <2% in the best centers, which is no higher than for many biventricular repairs.27,28 This improve-ment is a result of a number of factors, including better patient selection, improved surgical protocols such as the staged management by bidirectional cavopulmonary anastomosis and later total cavopulmonary connection, as well as better perioperative care. many of the early postoperative problems resulted from the referral of high-risk candidates who did not meet the guidelines established for Fontan suitability. Freedom from death or transplantation in the early survivors of a population of Fontan patients born before 1985 (n = 261) was reported as 93.7%, 89.9%, 87.3%, 82.6% and 69.6% at 5, 10, 15, 20 and 25 years, respectively.29 evidence is emerging that the late results of the total cavopulmonary connection are better than the atriopulmonary connection.27

Initial optimism with the results of the Fontan pal-liation has been increasingly tempered by awareness of several progressive causes of morbidity and mortality that are emerging in long-term survivors. All reported series demonstrate late attrition after Fontan, with a con-stellation of clinical problems that often occur together as part of the so-called failing Fontan complex. These adverse events include progressive decline in exercise tolerance,30–32 heart failure,33 the development of arrhyth-mias,34–37 and thromboembolic complications.29 Risk factors for late functional decline are difficult to deter-mine owing to the unquantifiable influence of patient selection, differences in operative techniques, variation in follow-up, and reporting bias. late results inevitably

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represent operations that are now obsolete, and few reports of longitudinal series have been published. similarly, assessment of the potential benefits of treat-ments, both medical and surgical, is challenging because of the lack of adequately powered randomized trials.

ArrhythmiasThe development of atrial tachyarrhythmia, most fre-quently intra-atrial re-entrant tachycardia, is a major clinical problem with a progressive increase in the likelihood of developing tachycardia over time. other supraventri cular arrhythmias have been identified, in particular atrial fibrillation, and occasionally left-sided atrial re-entrant tachycardia in patients with left atrial suture lines and dilatation. Tachyarrhythmias seem to be both the cause and consequence of clinical deteriora tion, and active attempts to restore and maintain sinus rhythm in these circumstances are, therefore, warranted. Invasive studies have revealed a complex electro physiological substrate for arrhythmia, with many potential mecha-nisms and multiple circuits. This complexity has made radio frequency catheter ablation challenging, with a high incidence of early failure.38–41

Incidence of atrial tachyarrhythmias is lower in lateral tunnel Fontan procedures than in atrioventricular con-nections, and seems to be even lower in the extracardiac conduit Fontan than in lateral tunnel.42 Atrial incisions and suture lines, and atrial distension, is likely to account for the higher incidence of arrhythmia in atrio pulmonary connections. By contrast, loss of sinus rhythm with junc-tional bradycardia, which has been reported to be as high as 30%, could be part of the underlying cardiac mal-formation, or may be a consequence of the Fontan.31,34,35 No evidence exists for a clear relationship between brady cardias and functional decline.

Exercise capacityThe hemodynamic response to exercise differs between patients with an atriopulmonary connection and those with a total cavopulmonary connection; performance augmentation with training is more likely following the total cavopulmonary connection.43 In the limited longi-tudinal studies available, decline in exercise performance with time seems to be slower after total cavopulmonary connection than after atriopulmonary connection. Patients with atriopulmonary connections and serious clinical complications, particularly arrhythmia and impaired exercise tolerance, should be considered for surgical conversion to total cavo pulmonary connection.44 This conversion has been successfully achieved in a few specialized centers, but it is challenging and long-term problems, particularly arrhythmias, may persist.

Thromboembolic eventsThromboembolic complications can cause late morbidity and mortality, and the incidence of such complications increases with time.29 The Fontan circulation results in a procoagulant state, with abnormal levels of multiple clotting factors, including protein C, protein s, and anti-thrombin III, as well as increased platelet reactivity.45,46

This state is aggravated by atrial arrhythmias, the pres-ence of prosthetic material, and sluggish flow, particu-larly in the dilated right atria. Thromboembolic events can be asymptomatic and their true incidence, there-fore, remains unknown.47 As a result, use of anti platelet therapy, anticoagulant therapy, or both after Fontan remains controversial and merits a formal clinical trial. Anticoagulation itself is not without risk in patients who are prone to developing hepatic dysfunction.

Liver dysfunctionA number of other important clinical problems after Fontan result from the chronic elevation in systemic venous pressure. They include liver dysfunction, protein- losing enteropathy, and late cyanosis. Recurrent late cyanosis may result from the pressure difference between systemic and pulmonary veins,26 or between the systemic veins and the coronary sinus, which remains at low pressure. Pulmonary arteriovenous fistulas have been described in patients with left atrial isomerism, in whom the hepatic venous return may be excluded from the pulmonary circulation. A hepatic factor has been proposed, but has not yet been identified.48 A review of the hepatopulmonary syndrome elegantly illustrates a number of other potential mechanisms of pulmonary origin that might lead to systemic arterial desatura-tion.49 These mechanisms include diffusion problems owing to capillary dilatation, and should be investi-gated in cyanosed Fontan patients (Figure 3). liver congestion, with structural and functional liver altera-tions that can lead to liver cirrhosis, have been reported as a complication of chronically elevated systemic venous pressure.50–52

Protein-losing enteropathyProtein-losing enteropathy, confirmed by low serum albumin and increased fetal alpha-1 antitrypsin levels, is a rare complication with a poor prognosis.53,54 Congestion of the gastrointestinal tract may have a role

Figure 2 | The circulation of the lung. vascular connections are present between the systemic veins and the pulmonary veins. In addition, there are direct arteriovenous shunts that also account for systemic arterial desaturation. Permission obtained from Nature Publishing Group © de Leval, M. R. Nat. Clin. Pract. Cardiovasc. Med. 2, 202–208 (2005).

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and is usually seen in failing Fontan patients. Heparin has been reported to be useful in the treatment of protein-losing entero pathy.55 Patients with protein-losing entero pathy lack heparan sulfate from the intes-tinal epithelial cells during episodes of protein-losing enteropathy, which makes the intestine more susceptible to pro inflammatory cytokines and increased venous pressure (Figure 4).56,57 Intestinal inflammation is a component of the pathophysiology of protein-losing enteropathy. A report of administration of budesonide, which has high enteric anti-inflammatory activity, to patients with protein-losing enteropathy after the Fontan operation seems to be a promising treatment of this serious complication.58

Heart failure Heart failure is a dominant cause of late morbidity and mortality in Fontan patients. The contractility– afterload mismatch and the preload/afterload mismatch of the Fontan circulation is likely a major contributory factor in the progressive decline in functional capa city and develop ment of heart failure. Contractility and after-load are rarely the major determinants of cardiac per-formance, and the progressive decline in functional capacity could be related to an increase in pulmonary vascular resistance, and thus preload limitation.21,25,26,29 As a result, conventional strategies that are effective in heart failure and a biventricular circulation, such as angiotensin-converting-enzyme inhibitors, are disap-pointing. manipulation of preload may be more reward-ing, and novel treatments such as phosphodiesterase inhibitors and endothelin antagonists, have been pro-posed but have not yet been evaluated in adequately powered trials.59–61

TransplantationPatients with a failing Fontan circulation can benefit from orthotopic cardiac transplantation.62–65 The main indications for transplantation are heart failure, intrac-table arrhythmias, protein-losing enteropathy, and plastic bronchitis, which is another rare complication of congen-ital heart defects, particularly in Fontan patients.62 The mechanism of plastic bronchitis is poorly understood and there is no consensus on the best management.66 survival following transplantation is considerably worse in patients with congenital heart disease than in children who have cardiomyopathy, and the prognosis of trans-plantation for Fontan failure is worse than for other con-genital cardiac defects.62–65 Protein-losing entero pathy has been reported to resolve in patients who survive for more than 1 month after transplantation.

In addition to the intrinsic limitations of the Fontan state, other factors, such as age at surgery31 and the ana-tomic substrate for which the Fontan operation was per-formed have a role in late morbidity and mortality. A key issue that is likely to influence long-term results is the performance of the right ventricle as a systemic ventricle in the Fontan circulation, particularly in the increas-ing number of survivors who have had treatment for hypo plastic left heart syndrome. This group is at higher risk of late failure in several, but not all, series.29,31,67,68 Atrioventricular valve regurgitation, neoaortic valve regurgitation, and right ventricular dysfunction also have a negative impact on the long-term outcome of these patients.68,69

The futureDevelopments over the past 40 years have almost achieved the perfect Fontan circulation. A continuous improvement in long-term outcomes of the patients who undergo this palliation is expected as a result of refine-ments in surgical procedures,70 as well as a better under-standing of the natural history of the underlying cardiac condition and of the Fontan state itself. The introduction of the total cavopulmonary connection has reduced the

Figure 3 | Mechanisms of arterial hypoxemia in the hepatopulmonary syndrome in a two-compartment model of gas exchange in the lung. a | In a healthy lung with uniform alveolar ventilation and pulmonary blood flow, the diameter of the capillary ranges between 8 and 15 μm, oxygen diffuses properly into the vessel, and ventilation–perfusion is well balanced. b | In patients with hepatopulmonary syndrome, capillaries become dilated and blood flow is not uniform. ventilation–perfusion mismatch emerges as the predominant mechanism, irrespective of the degree of clinical severity, either with or without intrapulmonary shunt, and coexists with restricted oxygen diffusion into the center of the dilated capillaries in the most advanced stages. Rodríguez-Roisin, R. & Krowka, M. J. Hepatopulmonary syndrome—a liver-induced lung vascular disorder. N. Engl. J. Med. 358, 2378–2387 © 2008 Massachusetts Medical Society. All rights reserved.

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need for reoperation, and the impact on arrhythmias, thromboembolic complications, and exercise capacity is encouraging. outcomes will be determined by the intrinsic limitations of this circulation, and progress in the future is likely to depend more on under standing the pathophysiology than on surgical advances. The new population of patients with a systemic right ven-tricle who have undergone Fontan palliation for hypo-plastic left heart syndrome could represent a caveat to this statement. only a few of these patients have reached adulthood so far. As patients grow older, their Fontan circulation will be exposed to the hemodynamic pro-cesses associated with normal aging, events such as preg-nancy, as well as cardio vascular and other diseases. We know that the Fontan state is compatible with success-ful pregnancy, with low risk to the mother and fetus.71,72 However, Fontan patients have limited hemodynamic reserve and are likely to be more vulnerable to aging as a result of increased arterial stiffness and pulmonary vascular resistance. The next 20 years should clarify the impact of acquired disease on Fontan patients, such as systemic hypertension, coronary artery disease, aortic stenosis, and chest infections.

The Fontan operation is undertaken for patients with extremely severe congenital anomalies, and results need to be judged against alternative strategies. The intuit-ive assumption is that a biventricular repair will lead to better long-term results than a Fontan operation. High-risk biventricular repairs, however, such as those incorporating a small left ventricle in a biventricular circulation, have displayed substantial late morbidity, including limited exercise tolerance, pulmonary hyper-tension, arrhythmias, and sudden death. Knowledge acquired in the next 20 years should help to solve the

dilemma of whether a Fontan operation or a high-risk biventricular repair is the optimum approach.

Developing strategies to manipulate the systemic and pulmonary circulation will be important in the future to prevent or treat Fontan attrition that results from the so-called Fontan paradox, consisting of systemic venous hypertension and pulmonary arterial hypo tension. Besides pharmacological treatments, the next few years are likely to see the advent of novel technologies in terms of mechanical assistance or mechanical substitution.73,74 Heart transplantation will remain part of the armamen-tarium to deal with Fontan failure. However, the expected increase in the population of those patients who would benefit from transplantation will out number the pool of potential donors. should xenografting become a clinical reality, one can speculate that a number of Fontan patients would be helped by this technology. Future discoveries in the fields of genetic engineering, stem cell research, and nanotechnology, to mention just a few, might also be applicable to the prevention and manage ment of complex congenital heart defects.

Conclusions The Fontan operation is the best palliation for most patients who are born with only one adequate ventricle. This approach has prolonged survival in association with good quality of life in many patients, including patients born with hypoplastic left heart syndrome who were inoperable before 1968.75–77 surgical evolution of the Fontan procedure has enhanced flow dynamics, reduced late complications, and improved prognosis. Nevertheless, the Fontan circulation has intrinsic limita-tions that result in suboptimal exercise performance, arrhythmias, heart failure, and probably diminished

Figure 4 | Experimental studies of intestinal barrier function. a | The normal mouse intestine provides an effective barrier against free diffusion of certain ions, nutrient solutes, proteins, bacteria, and toxins to effectively separate the intestinal lumen (outside) from the lamina propria (inside). b | Syndecan-1-deficient mice have decreased intestinal barrier function as a result of either defective intercellular junctions and increased paracellular leaks (dashed red line), or increased transcellular protein transport (solid red line). c | Syndecan-1-deficient mice treated with inflammatory cytokines (such as tumor necrosis factor and interferon-γ), or surgically treated to increase portal vein pressure, have massively defective intercellular junctions and large protein leaks (dashed red lines) consistent with protein-losing enteropathy. d | Infusions of heparan sulfate analogues completely reverse the intestinal-barrier dysfunction seen in syndecan-1-deficient mice treated with inflammatory cytokines. Lencer, W. I. Patching a leaky intestine. N. Engl. J. Med. 359, 526–528 © 2008 Massachusetts Medical Society. All rights reserved.

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long-term survival. A more thorough understanding of Fontan hemodynamics will lead to further improve-ments as a result of pharmaco logical manipulations of the pulmonary and systemic circulations, and the use of mechanical assist devices. These novel approaches will need to be assessed in formal clinical trials. manag-ing the interaction between the Fontan circulation and the consequences of aging, noncardiac and acquired cardio vascular diseases, will be a major challenge for specialist adult congenital heart disease practitioners in the future.

Review criteria

The literature was reviewed from the time of the initial Fontan operation until March 2010. Searches of the PubMed and MEDLINE databases were carried out for English language articles using the key words “Fontan physiology”, “Fontan history”, “Fontan procedures”, “Fontan results”, “Fontan complications”, ”single ventricle”, “univentricular hearts”, in combination with “physiology” and “treatment”. In addition, a personal collection of reprints dated from 1968 to 2010 was used for this Review, where both French and English literature were consulted.

1. Fontan, F. & Baudet, E. Surgical repair of tricuspid atresia. Thorax 26, 240–248 (1971).

2. Norwood, W. I. Hypoplastic left heart syndrome. Cardiol. Clin. 7, 377–385 (1989).

3. Bull, C., de Leval, M. R., Stark, J., Taylor, J. F. & Macartney, F. J. Use of a subpulmonary ventricular chamber in the Fontan circulation. J. Thorac. Cardiovasc. Surg. 85, 21–31 (1983).

4. Björk, v. O., Olin, C. L., Bjarke, B. B. & Thorén, C. A. Right atrial–right ventricular anastomosis for correction of tricuspid atresia. J. Thorac. Cardiovasc. Surg. 77, 452–458 (1979).

5. Kreutzer, G., Galíndez, E., Bono, H., De Palma, C. & Laura, J. An operation for the correction of tricuspid atresia. J. Thorac. Cardiovasc. Surg. 66, 613–621 (1973).

6. Puga, F. J., Chiavarelli, M. & Hagler, D. J. Modifications of the Fontan operation applicable to patients with left atrioventricular valve atresia or single atrioventricular valve. Circulation 76, III53–III60 (1987).

7. Jonas, R. A. & Castaneda, A. R. Modified Fontan procedure: atrial baffle and systemic venous to pulmonary anastomotic techniques. J. Card. Surg. 3, 91–96 (1988).

8. de Leval, M. R., Kilner, P., Gewillig, M. & Bull, C. Total cavopulmonary connection: a logical alternative to atriopulmonary connection for complex Fontan operations. Experimental studies and early clinical experience. J. Thorac. Cardiovasc. Surg. 96, 682–695 (1988).

9. Marcelletti, C., Corno, A., Giannico, S. & Marino, B. Inferior vena cava-pulmonary artery extracardiac conduit. A new form of right heart bypass. J. Thorac. Cardiovasc. Surg. 100, 228–232 (1990).

10. de Leval, M. R. et al. Use of computational fluid dynamics in the design of surgical procedures: application to the study of competitive flows in cavo-pulmonary connections. J. Thorac. Cardiovasc. Surg. 111, 502–513 (1996).

11. Mazzera, E. et al. Bidirectional cavopulmonary shunts: clinical applications as staged or definitive palliation. Ann. Thorac. Surg. 47, 415–420 (1989).

12. Bridges, N. D. et al. Effect of baffle fenestration on outcome of the modified Fontan operation. Circulation 86, 1762–1769 (1992).

13. Galantowicz, M. & Cheatham, J. P. Fontan completion without surgery. Semin. Thorac. Cardiovasc. Surg. Pediatr. Card. Surg. Annu. 7, 48–55 (2004).

14. Sallehuddin, A. et al. Fontan completion without surgery. Eur. J. Cardiothorac. Surg. 32, 195–201 (2007).

15. Fontan, F. et al. Outcome after a “perfect” Fontan operation. Circulation 81, 1520–1536 (1990).

16. Kirklin, J. K. et al. Is the “perfect Fontan” operation routinely achievable in the modern era? Cardiol. Young 18, 328–336 (2008).

17. Cheung, Y. F., Penny, D. J. & Redington, A. N. Serial assessment of left ventricular diastolic function after Fontan procedure. Heart 83, 420–424 (2000).

18. Szabó, G. & Bährle, S. Contractility-afterload mismatch after the Fontan operation. Cardiol. Young 15 (Suppl. 3), 35–38 (2005).

19. Macé, L. et al. Changes in venous return parameters associated with univentricular Fontan circulations. Am. J. Physiol. Heart Circ. Physiol. 279, H2335–H2343 (2000).

20. Kelley, J. R., Mack, G. W. & Fahey, J. T. Diminished venous vascular capacitance in patients with univentricular heart after the Fontan operation. Am. J. Cardiol. 76, 158–163 (1995).

21. Gewillig, M. et al. The Fontan circulation: who controls cardiac output? Interact. Cardiovasc. Thorac. Surg. 10, 428–433 (2010).

22. Hsia, T. Y. et al. Subdiaphragmatic venous hemodynamics in the Fontan circulation. J. Thorac. Cardiovasc. Surg. 121, 436–447 (2001).

23. Krishnan, U. S., Taneja, I., Gewitz, M., Young, R. & Stewart, J. Peripheral vascular adaptation and orthostatic tolerance in Fontan physiology. Circulation 120, 1775–1783 (2009).

24. Mandelbaum, I. & Burns, W. H. Pulsatile and nonpulsatile blood flow. JAMA 191, 657–660 (1965).

25. de Leval, M. R. The Fontan circulation: What have we learned? What to expect? Pediatr. Cardiol. 19, 316–320 (1998).

26. de Leval, M. R. The Fontan circulation: a challenge to William Harvey? Nat. Clin. Pract. Cardiovasc. Med. 2, 202–208 (2005).

27. d’Udekem, Y. et al. The Fontan procedure: contemporary techniques have improved long-term outcomes. Circulation 116, I157–I164 (2007).

28. Tweddell, J. S. et al. Fontan palliation in the modern era: factors impacting mortality and morbidity. Ann. Thorac. Surg. 88, 1291–1299 (2009).

29. Khairy, P. et al. Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation 117, 85–92 (2008).

30. Durongpisitkul, K. et al. Cardiorespiratory response to exercise after modified Fontan operation: determinants of performance. J. Am. Coll. Cardiol. 29, 785–790 (1997).

31. Anderson, P. A. et al. Contemporary outcomes after the Fontan procedure: a Pediatric Heart Network multicenter study. J. Am. Coll. Cardiol. 52, 85–98 (2008).

32. Giardini, A., Hager, A., Pace Napoleone, C. & Picchio, F. M. Natural history of exercise capacity after the Fontan operation: a longitudinal study. Ann. Thorac. Surg. 85, 818–821 (2008).

33. Khairy, P., Poirier, N. & Mercier, L. A. Univentricular heart. Circulation 115, 800–812 (2007).

34. Cohen, M. I. et al. Sinus node function after a systematically staged Fontan procedure. Circulation 98, II352–II358 (1998).

35. Blaufox, A. D. et al. Functional status, heart rate, and rhythm abnormalities in 521 Fontan patients 6 to 18 years of age. J. Thorac. Cardiovasc. Surg. 136, 100–107 (2008).

36. Fishberger, S. B. et al. Factors that influence the development of atrial flutter after the Fontan operation. J. Thorac. Cardiovasc. Surg. 113, 80–86 (1997).

37. Nürnberg, J. H. et al. New onset arrhythmias after the extracardiac conduit Fontan operation compared with the intraatrial lateral tunnel procedure: early and midterm results. Ann. Thorac. Surg. 78, 1979–1988 (2004).

38. Triedman, J. K., Bergau, D. M., Saul, J. P., Epstein, M. R. & Walsh, E. P. Efficacy of radiofrequency ablation for control of intraatrial reentrant tachycardia in patients with congenital heart disease. J. Am. Coll. Cardiol. 30, 1032–1038 (1997).

39. Weipert, J. et al. Occurrence and management of atrial arrhythmia after long-term Fontan circulation. J. Thorac. Cardiovasc. Surg. 127, 457–464 (2004).

40. Triedman, J. K. et al. Prospective trial of electroanatomically guided, irrigated catheter ablation of atrial tachycardia in patients with congenital heart disease. Heart Rhythm 2, 700–705 (2005).

41. Abrams, D. J. et al. Comparison of noncontact and electroanatomic mapping to identify scar and arrhythmia late after the Fontan procedure. Circulation 115, 1738–1746 (2007).

42. d’Udekem, Y. et al. How good is a good Fontan? Quality of life and exercise capacity of Fontans without arrhythmias. Ann. Thorac. Surg. 88, 1961–1969 (2009).

43. Rosenthal, M., Bush, A., Deanfield, J. & Redington, A. Comparison of cardiopulmonary adaptation during exercise in children after the atriopulmonary and total cavopulmonary connection Fontan procedures. Circulation 91, 372–378 (1995).

44. Mavroudis, C. et al. J. Maxwell Chamberlain Memorial Paper for congenital heart surgery. 111 Fontan conversions with arrhythmia surgery: surgical lessons and outcomes. Ann. Thorac. Surg. 84, 1457–1465 (2007).

45. Tomita, H. et al. Coagulation profile, hepatic function, and hemodynamics following Fontan-type operations. Cardiol. Young 11, 62–66 (2001).

46. Ravn, H. B. et al. Increased platelet reactivity and significant changes in coagulation markers after cavopulmonary connection. Heart 85, 61–65 (2001).




REviEws

47. varma, C. et al. Prevalence of “silent” pulmonary emboli in adults after the Fontan operation. J. Am. Coll. Cardiol. 41, 2252–2258 (2003).

48. Kim, S. J. et al. Inclusion of hepatic venous drainage in patients with pulmonary arteriovenous fistulas. Ann. Thorac. Surg. 87, 548–553 (2009).

49. Rodríguez-Roisin, R. & Krowka, M. J. Hepatopulmonary syndrome—a liver-induced lung vascular disorder. N. Engl. J. Med. 358, 2378–2387 (2008).

50. Ghaferi, A. A. & Hutchins, G. M. Progression of liver pathology in patients undergoing the Fontan procedure: Chronic passive congestion, cardiac cirrhosis, hepatic adenoma, and hepatocellular carcinoma. J. Thorac. Cardiovasc. Surg. 129, 1348–1352 (2005).

51. Kiesewetter, C. H. et al. Hepatic changes in the failing Fontan circulation. Heart 93, 579–584 (2007).

52. Friedrich-Rust, M. et al. Noninvasive assessment of liver fibrosis in patients with Fontan circulation using transient elastography and biochemical fibrosis markers. J. Thorac. Cardiovasc. Surg. 135, 560–567 (2008).

53. Mertens, L., Hagler, D. J., Sauer, U., Somerville, J. & Gewillig, M. Protein-losing enteropathy after the Fontan operation: an international multicenter study. PLE study group. J. Thorac. Cardiovasc. Surg. 115, 1063–1073 (1998).

54. Silvilairat, S. et al. Protein-losing enteropathy after the Fontan operation: associations and predictors of clinical outcome. Congenit. Heart Dis. 3, 262–268 (2008).

55. Donnelly, J. P., Rosenthal, A., Castle, v. P. & Holmes, R. D. Reversal of protein-losing enteropathy with heparin therapy in three patients with univentricular hearts and Fontan palliation. J. Pediatr. 130, 474–478 (1997).

56. Bode, L. et al. Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function. J. Clin. Invest. 118, 229–238 (2008).

57. Lencer, W. I. Patching a leaky intestine. N. Engl. J. Med. 359, 526–528 (2008).

58. Thacker, D. et al. Use of oral budesonide in the management of protein losing enteropathy after the Fontan operation. Ann. Thorac. Surg. 89, 837–842 (2010).

59. Khambadkone, S. et al. Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontan-type operation. Circulation 107, 3204–3208 (2003).

60. Hager, A., Fratz, S. & Hess, J. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur. Heart J. 30, 507–508 (2009).

61. Ovaert, C. et al. The effect of bosentan in patients with a failing Fontan circulation. Cardiol. Young 11, 1–9 (2009).

62. Griffiths, E. R. et al. Evaluating failing Fontans for heart transplantation: predictors of death. Ann. Thorac. Surg. 88, 558–563 (2009).

63. Bernstein, D. et al. Outcome of listing for cardiac transplantation for failed Fontan: a multi-institutional study. Circulation 114, 273–280 (2006).

64. Gamba, A. et al. Heart transplantation in patients with previous Fontan operations. J. Thorac. Cardiovasc. Surg. 127, 555–562 (2004).

65. Lamour, J. M. et al. The effect of age, diagnosis and previous surgery in children and adults undergoing heart transplantation for congenital heart disease. J. Am. Coll. Cardiol. 54, 160–165 (2009).

66. Do, T., Chu, J., Berdjis, F. & Anas, N. Fontan patient with plastic bronchitis treated successfully using aerosolized tissue plasminogen activator: a case report and review of the literature. Paediatr. Cardiol. 30, 352–355 (2009).

67. Giardini, A. & Hager, A. The effect of age at Fontan completion on long-term aerobic exercise capacity in Fontan patients. Ann. Thorac. Surg. 89, 675–676 (2010).

68. Hosein, R. B. et al. Factors influencing early and late outcome following the Fontan procedure in the current era. The ‘Two Commandments’? Eur. J. Cardiothorac. Surg. 31, 344–352 (2007).

69. Cohen, M. S. et al. Neo-aortic root dilation and valve regurgitation up to 21 years after staged reconstruction for hypoplastic left heart syndrome. J. Am. Coll. Cardiol. 42, 533–540 (2003).

70. Hsia, T. Y. et al. Computational fluid dynamic study of flow optimization in realistic models of the total cavopulmonary connections. J. Surg. Res. 116, 305–313 (2004).

71. Khairy, P. et al. Pregnancy outcomes in women with congenital heart disease. Circulation 113, 517–524 (2006).

72. Canobbio, M. M., Mair, D. D., van der velde, M. & Koos, B. J. Pregnancy outcomes after the Fontan repair. J. Am. Coll. Cardiol. 28, 763–767 (1996).

73. Throckmorton, A. L. et al. Performance of a 3-bladed propeller pump to provide cavopulmonary assist in the failing Fontan circulation. Ann. Thorac. Surg. 86, 1343–1347 (2008).

74. Bhavsar, S. S., Kapadia, J. Y., Chopki, S. G. & Throckmorton, A. L. Intravascular mechanical cavopulmonary assistance for patients with failing Fontan physiology. Artif. Organs 33, 977–987 (2009).

75. van den Bosch, A. E. et al. Long-term outcome and quality of life in adult patients after the Fontan operation. Am. J. Cardiol. 93, 1141–1145 (2004).

76. Fernandes, S. M. et al. Serial cardiopulmonary exercise testing in patients with previous Fontan surgery. Pediatr. Cardiol. 31, 175–180 (2010).

77. Ovroutski, S. et al. Long-term cardiopulmonary exercise capacity after modified Fontan operation. Eur. J. Cardiothorac. Surg. 37, 204–209 (2010).

Author contributionsM. R. de Leval and J. E. Deanfield both contributed to discussion of content for the article. M. R. de Leval wrote the majority of the article and J. E. Deanfield made substantial contributions to it. M. R. de Leval and J. E. Deanfield reviewed and edited the manuscript.



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Four decades of Fontan palliation