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1462 www.thelancet.com Vol 374 October 24, 2009

Tetralogy of FallotChristian Apitz, Gary D Webb, Andrew N Redington

Tetralogy of Fallot is the most common form of cyanotic congenital heart disease, and one of the fi rst to be successfully repaired by congenital heart surgeons. Since the fi rst procedures in the 1950s, advances in the diagnosis, perioperative and surgical treatment, and postoperative care have been such that almost all those born with tetralogy of Fallot can now expect to survive to adulthood. The startling improvement in outcomes for babies born with congenital heart disease in general—and for those with tetralogy of Fallot in particular—is one of the success stories of modern medicine. Indeed, in many countries adults with tetralogy of Fallot outnumber children. Consequently, new issues have emerged, ranging from hitherto unpredicted medical complications to issues with training for caregivers and resource allocation for this population of survivors. Therefore, evolution of treatment, recognition of late complications, research on disease mechanisms and therapies—with feedback to changes in care of aff ected children born nowadays—are templates on which the timely discussion of organisation of care of those aff ected by congenital heart diseases from the fetus to the elderly can be based. Here, we focus on new developments in the understanding of the causes, diagnosis, early treatment, and late outcomes of tetralogy of Fallot, emphasising the continuum of multidisciplinary care that is necessary for best possible lifelong treatment of the 1% of the population born with congenital heart diseases.

IntroductionTetralogy of Fallot was fi rst described by Niels Stenson in 1671, although its precise anatomical description was elegantly illustrated by William Hunter at St Georges Hospital Medical School in London in 1784: “…the passage from the right ventricle into the pulmonary artery, which should have admitted a fi nger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”.1,2 His description of a large outlet ventricular septal defect together with subpulmonary and pulmonary valve stenosis, and its resulting physiology, was refi ned by Etienne-Louis Fallot in 1888 in his description of L’anatomie pathologique de la maladie bleu, but the term tetralogy of Fallot (a tetrad of (i) ventricular septal defect with (ii) over-riding of the aorta, (iii) right ventricular outfl ow obstruction, and (iv) right ventricular hyper-trophy) is attributed to Canadian Maude Abbott in 1924.

We now regard tetralogy as a family of diseases, all characterised by a similar intracardiac anatomy (fi gure 1),

but highly variable in terms of pulmonary artery anatomy, associated abnormalities, and outcomes. Here, we focus on the most common form, in which the heart has normal segmental anatomical structure, the right ventricular outfl ow tract is patent at birth, and no other major intracardiac abnormalities, such as atrioventricular septal defect, exist.

About 3·5% of all infants born with a congenital heart disease have tetralogy of Fallot, corresponding to one in 3600 or 0·28 every 1000 livebirths, with males and females being aff ected equally.3 Its precise cause is unknown, as for most congenital heart diseases. Most cases seem sporadic, although the risk of recurrence in siblings is about 3% if there are no other aff ected fi rst-degree relatives.

However, a strong and increasingly recognised genetic substrate to tetralogy can aff ect the outcome after surgical repair.4 One study showed that a microdeletion of the q11 region of chromosome 22 was present in up to 25% of patients, suggesting that investigation with fl uorescent in-situ hybridisation for such a deletion should be undertaken in all patients when diagnosed.5 Indeed, tetralogy is closely associated with, and frequently diagnosed in those with, overt Di George syndrome or velo cardiofacial syndrome, both of which have 22q11 deletions.6,7 In those without an overt syndrome, the prevalence of deletions has been estimated at 6%.8 22q11 deletion is becoming increasingly important not only because of its cardiac and syndromic associations, but also because of its association with late-onset neuro psychiatric disorders. Bassett and colleagues9 showed that adults with 22q11.2 deletion syndrome have a rate of schizophrenia of almost 25%; about 1% of patients with schizophrenia therefore have an associated 22q11.2 deletion.10

PathophysiologyThe ventricular septal defect is almost always large and non-restrictive in tetralogy of Fallot, ensuring that the

Lancet 2009; 374: 1462–71

Published OnlineAugust 17, 2009

DOI:10.1016/S0140-6736(09)60657-7

Division of Cardiology, Labatt Family Heart Centre, Hospital

for Sick Children, Toronto, ON, Canada (C Apitz MD,

Prof A N Redington MD); and Philadelphia Adult Congenital

Heart Center, Hospital of the University of Pennsylvania,

Philadelphia, PA, USA (Prof G D Webb MD)

Correspondence to:Prof Andrew N Redington,

Division of Cardiology, Labatt Family Heart Centre, Hospital for

Sick Children, 555 University Avenue Toronto, ON M5G 1X8,

[email protected]

Search strategy and selection criteria

We searched PubMed with the search term “tetralogy of Fallot”. We mainly selected publications from the past 5 years, but did not exclude commonly referenced and highly regarded older publications. We also searched the reference lists of articles identifi ed by this search strategy and selected those we judged relevant. Several reviews or book chapters were included because they provide comprehensive overviews that are beyond the scope of this Seminar. The reference list has been modifi ed during the peer-review process on the basis of comments from reviewers.

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www.thelancet.com Vol 374 October 24, 2009 1463

pressure is equal in the two ventricles. Consequently, the loud systolic murmur typical in aff ected infants originates from the dynamic narrowing of the right ventricular outfl ow tract. The direction and magnitude of fl ow through the defect depends on the severity of the obstruction of the right ventricular outfl ow tract. If obstruction to right ventricular outfl ow is severe, or if there is atresia, a large right-to-left shunt with low pulmonary blood fl ow and severe cyanosis requiring intervention at birth are present.11

However, most patients have adequate pulmonary blood fl ow at birth but develop increasing cyanosis during the fi rst few weeks and months of life. In countries with well developed paediatric cardiac services, severe cyanosis, recurrent hypercyanotic spells, squatting, and other consequences of severely reduced pulmonary blood fl ow are nowadays rare because diagnosis is seldom delayed and infants undergo palliative procedures, or frequently complete repair within the fi rst few days, weeks, or months of life. Temporary treatment with propranolol, which decreases right ventricular hypercontractility and heart rate and increases systemic vascular resistance, is sometimes used to reduce the incidence of hypercyanotic spells before surgery.

DiagnosisSimilar to many complex congenital heart diseases, tetralogy of Fallot is frequently diagnosed during fetal life (fi gure 2). For those with severely obstructed pulmonary blood fl ow, fetal diagnosis allows better planning of perinatal management and facilitates early prostaglandin therapy to maintain ductal patency, thus avoiding life-threatening cyanosis in the early newborn period.

Nonetheless, most children present with the condition after birth. Although an experienced paediatrician or cardiologist usually suspects the diagnosis clinically, transthoracic cross-sectional echocardiography provides a comprehensive description of the intracardiac anatomy (fi gure 3). With the exception of patients with major aortopulmonary collateral arteries and rare cases in whom echocardiographic assessment is incomplete, any other diagnostic investigations (eg, cardiac catheterisation) are now rarely done before palliative or corrective surgery.

ManagementBefore the advent of surgical intervention, about 50% of patients with tetralogy of Fallot died in the fi rst few years of life, and it was unusual for a patient to survive longer than 30 years.12 Nowadays, almost all those born with this disease in all its variants can expect to survive surgical correction and reach adult life. Since the fi rst reported intracardiac repair of tetralogy in 1955,13 the age of patients receiving primary corrective surgery has gradually decreased, with some units advocating surgery at diagnosis, even within the fi rst few days of life. Most centres prefer to operate on children aged 3–6 months,

reserving earlier open-heart surgery for those presenting with severe cyanosis or hypercyanotic spells. Some centres continue to off er surgical palliation by construction of a systemic-to-pulmonary arterial shunt, balloon dilation, or placement of a stent in the right ventricular outfl ow, in neonates and young infants, thereby deferring intracardiac repair.14

Potential disadvantages of this staged approach include long-lasting pressure overload of the right ventricle and persistent cyanosis. Long-term hypoxaemia contributes to cardiomyocytic degeneration and interstitial fi brosis, which have been implicated in myocardial dysfunction and ventricular arrhythmias.15 However, the opponents of early palliation point to the frequent need for aggressive outfl ow tract procedures, the adverse eff ects of early bypass surgery on the neonatal brain,16 the often complicated and lengthy postoperative recovery in small infants, and implications of all these factors for late adverse outcomes.

The best age for repair has been previously discussed in a review17 of results obtained at the Hospital for Sick Children in Toronto (Canada) during the transitional period towards a policy of primary complete repair. Between 1993 and 1998, 227 consecutive children underwent complete repair, with the incidence of previous palliation with a systemic-to-pulmonary artery shunt falling from 38% to 0% during that time. The overall mortality was only 2·6%, but this also fell with transition to primary repair, becoming 0% in 1996–98. Nonetheless, primary repair in babies younger than 3 months of age has been associated with longer intensive care and hospital stay than in those older than 3 months, suggesting that the optimum age of elective repair is 3–6 months of age.

Whenever done, reparative surgery should ideally result in complete closure of the ventricular septal

Pulmonary trunk

Aorta

VSD

Right atrium

Right ventricle

Figure 1: Morphological features of tetralogy of FallotThe subpulmonary narrowing (arrow) is formed between the malaligned muscular outlet septum (asterisk), which is deviated anterocephalad relative to the limbs of the septomarginal trabeculation and the hypertrophied septoparietal trabeculations. There is a large ventricular septal defect with over-riding of the aorta, which is partly committed to the hypertrophied right ventricle. Note the dysplastic and stenotic pulmonary valve. VSD=ventricular septal defect. Image kindly provided by Robert H Anderson.

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defect, preservation of right ventricular form and function, with an unobstructed right ventricular outfl ow tract in corporating a competent pulmonary valve. Unfortunately, the nature of the subpulmonary obstruction rarely makes this possible. Surgical repair has made consistent progress over the past 50 years. Early techniques included repair of the ventricular septal defect via a large right ventriculotomy and extensive resection of the right ventricular outfl ow musculature and pulmonary valve leafl ets. Improvements of the transatrial–transpulmonary approach have benefi ted early and middle-term outcomes by avoiding right ventriculotomy and its associated scarring and dysfunction.18 Furthermore, in the past 20 years a shift from the need for complete relief of obstruction19 towards a policy to preserve the pulmonary valve, even at the expense of a modest residual stenosis, has occurred.20 This shift might keep adverse late eff ects of pulmonary incompetence to a minimum and retain the integrity of the outfl ow tract, avoiding late aneurysmal dilation. Changes in the management of children born with tetralogy of Fallot in the 21st century are being guided by results of surgery done in the second half of the 20th century.

Indeed, the evolution of complications in adult life, their careful cataloguing, and the new understanding of their mechanisms provide ample evidence that follow-up of patients with congenital heart disease needs to be a continuous process, not only because of the burgeoning needs of adult survivors but also as a responsibility to the children requiring treatment today. Understanding the causes of complications during the early postoperative period and the late postoperative period after repair of tetralogy of Fallot has led to the description of unique pathophysiological changes and development of novel treatments that have implications for cardiovascular diseases as a whole, and are important for the progress of research on adult congenital heart disease as its own subspecialty.

ComplicationsThe early postoperative periodMost children undergoing complete repair have an uncomplicated postoperative recovery and are discharged within a week of surgery. For a minority, the early postoperative course is complicated by a low cardiac output syndrome despite an apparently adequate repair with preserved biventricular systolic function. Echo-cardiographic doppler studies in these patients often show evidence of what is known as restrictive right ventricular physiology.21 Occurrence of restrictive physiology is related to the degree of myocardial damage that takes place during repair.

Chaturvedi and colleagues22 showed that the devel-opment of restrictive physiology was associated with signifi cantly increased troponin concentrations on release of the aortic cross clamp and throughout the early postoperative period. Interestingly, it does not seem to be related to age at operation, but is more common on follow-up of patients in whom a trans-annular patch had been inserted across the ventriculo-pulmonary junc tion.23,24 Early postoperative restrictive physiology requires a longer duration of inotropic support, longer stay in an intermediate care station, and higher doses of diuretics.25 However, it is a transient phenomenon, usually resolving within 72 h, although reappearance in the later postoperative follow-up period can occur.23,26

Pulmonary incompetenceNot long ago, residual pulmonary incompetence was regarded as an inevitable, but unimportant, late sequel of repair. Much emphasis was placed on the need for complete relief of obstruction, often at the expense of a freely regurgitant and ever-dilating outfl ow tract. Although data for the relation between residual outfl ow tract obstruction and early postoperative mortality were concerning,19 they are not anymore. Indeed, during the past decade the degree of residual pulmonary incompetence has been related to the most severe adverse outcomes of progressive exercise intolerance, right heart failure, ventricular arrhythmia, and sudden death.

The misguided assertions of investigators that pulmonary incompetence was an unimportant late outcome of tetralogy can be understood when one considers the time course of the eff ects of postoperative pulmonary regurgitation. The problems of tetralogy occur decades after repair and might be incompletely defi ned because of the expected decades of further survival, even for the earliest cohorts of survivors of surgical repair. This prolonged time course also illustrates the need for continuous and vigilant follow-up of all patients in whom intracardiac repairs have been done in childhood. Even so, there was circumstantial evidence more than two decades ago that the late outcome of tetralogy might be adversely aff ected by the degree of pulmonary incompetence.

Aorta

Right ventricle

Right ventricle

Outlet septum

Pulmonary trunk

Leftventricle

A B

Figure 2: Prenatal diagnosis of tetralogy of FallotThe long-axis view of the fetal echocardiogram (A) shows a large ventricular septal defect with over-riding of the aorta. The typical anterocephalad deviation of the outlet septum is seen (B), causing obstruction to the fl ow into the pulmonary trunk. Image kindly provided by Edgar Jaeggi.

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In 1984, Shimazaki and colleagues27 showed that symptom-free survival was decreased in patients with isolated (ie, no other major cardiac lesions) pulmonary incompetence. Interestingly, almost no complication was seen during the fi rst 30 years of life, but thereafter a rapidly progressive condition of right heart failure, exercise intolerance, and death evolved, all of which resonate with late problems of tetralogy. In the 1970s and 1980s, right heart dysfunction was known to be more likely if an outfl ow tract patch was needed at the time of repair,28 as was the fact that exercise dysfunction was related to the cardiothoracic ratio (as a surrogate of right heart dilation) on chest radiograph.29 Nonetheless, only in the past 10 years has direct quantifi cation of pulmonary regurgitation by the gold standard cardiac magnetic resonance been possible (fi gure 4).

A clear relation between the amount of pulmonary regurgitation and right ventricular dilation was established with one of the fi rst quantitative methods—videodensitometry—described in 1981 by Falliner and colleagues.30 In 1988, we described a technique to quantify pulmonary regurgitation from right ventricular pressure–volume loops measured with angiograms,31 or with a conductance catheter technique.32 We showed a correlation between the volume of pulmonary regurgitation during isovolumic relaxation, and right ventricular volumes and exercise dysfunction.33 In another study,32 we used the uniquely dynamic nature of conductance catheter recordings to show the relation between increased right ventricular afterload and the degree of pulmonary regurgitation. These data strongly support the notion that substantial branch pulmonary artery stenosis, especially in the setting of free pulmonary regurgitation, should be treated aggressively by balloon dilation with or without implantation of an endoluminal stent.

Although restrictive physiology, characterised by antegrade diastolic fl ow in the pulmonary artery throughout the respiratory cycle, is associated with reduced cardiac output and slowed early postoperative recovery in children,21 its presence as a primary phenomenon in adults is mainly benefi cial. In the fi rst study of restrictive physiology, in adults 15–35 years

after repair, Gatzoulis and colleagues34 showed that those with a restrictive right ventricle had a smaller cardiothoracic ratio on chest radiograph and better exercise performance (both of which might be entirely normal) than those without restrictive physiology. This is because the poorly compliant right ventricle prevents adverse remodelling (dilation) of the right ventricle that occurs in response to pulmonary regurgitation when diastolic function is less abnormal. In turn, in many studies the amount of pulmonary regurgitation has been directly related to right heart dilatation and exercise performance. Although these fi ndings have been confi rmed by others,35,36 additional studies, mainly using magnetic resonance, have failed to show a consistent relation between restrictive physiology, as evidenced by antegrade diastolic fl ow, and either right ventricular volumes or exercise performance.37,38

Another important observation in the study by Gatzoulis and colleagues34 was that QRS duration on the electrocardiogram in those with restrictive physiology was shorter than in those without restrictive physiology. We also showed a relation between the duration of the QRS and both right ventricular volumes and propensity to symptomatic arrhythmia and sudden death.39 We proposed the term mechanoelectrical interaction to describe the relation between the degree and type of right ventricular remodelling and its electrophysiological properties, and showed a threshold for QRS prolongation of 180 ms, and the occurrence of symptomatic ventricular tachycardia and sudden death in a single centre analysis. This phenomenon has been confi rmed by us and others,40–42 albeit with diff erent thresholds of QRS dura tion, and improved methods of describing the relation between mechanical and electrical function.

However, the most comprehensive assessment comes from a multicentre study43 that showed in 793 patients from fi ve centres that pulmonary regurgitation was the most important haemodynamic determinant of symptomatic arrhythmia. Furthermore, not only was absolute duration of QRS an important predictor, but also rate of change of duration (>3 ms per year over the 10-year assessment period) was strongly associated with

A CB

RVIVS

LVRV

RPA

RPALPA

PT

PT

RV

LA

AO

AO

AO

Figure 3: Postnatal diagnosis of tetralogy of Fallot by transthoracic echocardiography(A) The parasternal long-axis view shows the aortic valve over-riding the crest of the ventricular septum (IVS) and severe hypertrophy of the right ventricular myocardium. (B) Subcostal right oblique view of the obstruction of the subpulmonary infundibulum due to the anterocephalad deviation of the malaligned outlet septum (long arrow) and the abnormal arrangement of the septoparietal trabeculations (short arrows). (C) Parasternal short-axis view shows small peripheral pulmonary arteries (RPA and LPA) with supravalvular narrowing of the pulmonary trunk (PT). LV=left ventricle. RV=right ventricle. AO=over-riding aorta. LA=left atrium.

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poor outcomes. Ventricular dysrhythmia is not the only problem that characterises the late electrophysiological outcome of these patients. Although often less dramatic in terms of haemodynamic sequelae, atrial arrhythmias are almost equally as frequent.43–45

Although attention has been focused on the right ventricle, there is emerging awareness of the eff ect of biventricular dysfunction on late outcomes. The right ventricle is anatomically integrated with the left ventricle through subepicardial bundles of aggregated myocytes that run from the free wall of the right ventricle to the anterior wall of the left ventricle. Moreover, the ventricles share the septum and are enclosed in the same pericardial cavity. Interaction of the two ventricles results in alterations of both diastolic and systolic function.46 Experimental studies have shown that part of the external mechanical work generated by the right ventricle is a direct consequence of left ventricular contraction or contraction of shared myocytes,47 and conversely that dilation of the right ventricle undermines left ventricular systolic per-formance.48,49 Therefore, a strong correlation between right and left ventricular ejection fractions exists in patients after repair of tetralogy of Fallot.50 Furthermore, those with substantial coexisting left ventricular dysfunction have a high risk of sudden death late after repair.51 The mechanisms for this interaction are incompletely understood but might in part be related to increasing dys-synchrony between contraction of the two ventricles. Indeed, D’Andrea and colleagues52 showed that patients with the longest delay between onset of contraction of the two ventricles had worse exercise performance and a high incidence of ventricular arrhythmia.

Although pacing of the right ventricle might improve the intraventricular dys-synchrony of right ventricular contraction,53 biventricular resynchronisation might be valuable in postoperative tetralogy patients with overt interventricular dys-synchrony. We reported extraordinary functional improvement after biventricular pacing under these circumstances.54

Thus, follow-up of adults and teenagers late after repair of tetralogy of Fallot focuses on the assessment of the degree of pulmonary regurgitation, its secondary eff ects on ventricular remodelling, and risk stratifi cation for arrhythmia and sudden death. Having almost ignored the possibility of needing pulmonary valve replacement in the past, the assessment of need and optimum timing of pulmonary valve implantation is one of the present hot topics in this research area.

Timing and eff ects of pulmonary valve replacementPulmonary regurgitation as an important determinant of many late complications of early repair set the scene for various important studies reporting the eff ectiveness, or otherwise, of surgical pulmonary valve replacement. Although most would agree that those with new onset symptomatic sustained ventricular tachycardia and those with overt symptoms of exercise intolerance or right heart failure are almost all candidates for surgery, many more potential candidates who do not fulfi l such criteria exist.

In 2000, Therrien and colleagues55 reported the eff ects of pulmonary valve replacement in 25 consecutive patients attending the Toronto congenital cardiac centre for adults. The investigators concluded that operations had taken place too late. In these adults with grossly dilated ventricles, pulmonary valve replacement did not have any eff ect on right ventricular volumes or ejection fraction. A subsequent study56 from the same group but in younger patients with lower degree of right ventricular dilation suggested a threshold for adequate reverse remodelling, measured by cardiac magnetic resonance, of 170 mL/m² for end-diastolic volume and 85 mL/m² for end-systolic volume. Similar results, but with somewhat diff erent thresholds, have been obtained by other groups.57,58 Recovery of function is less likely to happen above a certain degree of right ventricular dilation.

However, many questions remain unanswered. For example, what should we recommend to asymptomatic patients with a borderline-sized right ventricle? Although at low risk, surgery is not entirely favourable and long-term viability of implanted valves is inconsistent. What is the role for formal exercise testing in the timing of surgery? The lack of a relation between symptoms and measured performance is one of the most pervasive dilemmas in the fi eld of adult congenital heart disease, but the usefulness of formal exercise testing remains to be defi ned. And fi nally, is there a threshold above which surgery is too risky or futile? One of the reasons why these questions remain mainly unanswered is that too little is known about functional responses to surgery. Exercise performance might improve by valve replace ment and seems unrelated to the degree of ventricular remodelling,59–61 but there are no defi nitive data on which to base preoperative recommendations and decision making.

1 2–200

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0

400

600

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1000

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–600

–800

3 4 5 6 7 8 9 10 11 12 13141516171819

A B

PT

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LV

Phase number

Aver

age

flow

(mL/

min

)

Figure 4: Magnetic resonance imaging in a patient with tetralogy of Fallot late after surgical correction(A) Greatly dilated right ventricle (RV) and pulmonary trunk (PT) and (B) corresponding fl ow profi le in the right ventricular outfl ow tract measured with phase-contrast imaging. Note that the pathological fl ow profi le of pulmonary regurgitation (PR) is about 40% of the systolic forward fl ow (SFF). LV=left ventricle.

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Percutaneous pulmonary valve replacementDevelopment of percutaneous approaches to valve disease is one of the most exciting areas of research and clinical innovation in cardiovascular research. The main development has been that of transcatheter pulmonary valve replacement for the rehabilitation of conduits between the right ventricle and pulmonary artery in patients after surgery for tetralogy. Although fi rst reported by a Danish investigator as an experimental technique in the early 1990s,62 this approach failed to capture the imagination of clinicians (who were then ignorant of the adverse eff ects of pulmonary regurgitation) and industry representatives (who understandably were unconvinced of its commercial viability). 10 years later, our understanding of the issues of pulmonary incompetence has changed considerably. The device and technique had been improved and, after careful experimental and proof-of-principle studies, were introduced clinically in 2000 by Phillip Bonhoeff er (fi gure 5).63–65 His percutaneous pulmonary valve implantation system (Melody valve, Medtronic, USA) is composed of a bovine internal jugular vein, with its native valve, mounted in a platinum stent. This valved stent is advanced into the right ventricular outfl ow conduit via a long sheath under fl uoroscopic control, and fi xed in place by infl ation of a balloon-in-balloon system that allows precise placement. The device has been implanted in about 700 patients worldwide, with encouraging early to mid-term results.66,67 The largest published report includes 155 patients treated between 2000 and 2007. There was no periprocedural mortality and the overall late mortality has been very low; the freedom from reoperation was in 93%, 86%, 84%, and 70% of patients at 10, 30, 50, and 70 months, respectively.68

Percutaneous pulmonary valve replacement is not without unwanted eff ects and complications, however. Care must be taken during deployment to avoid compression of coronary arteries, which might be adjacent to the right ventricular outfl ow tract. The most common complication is fracture of the stent,69 but this is rarely a problem clinically. Valve failure occurs but usually can be treated by implantation of a second valve.70 The major limitation of the technique is that it is unsuitable for most patients with patch reconstruction of the right ventricular outfl ow tract and those with a grossly dilated native outfl ow tract. Techniques are being developed to deal with this issue, but the development of this technique has already fed back to size and type of conduit being chosen for those currently needing surgery, anticipating the use of this device, or one of the other similar devices under development,71,72 in the future.

Pulmonary valve replacement and arrhythmia35 years after corrective surgery, the rate of clinical sustained ventricular tachycardia and sudden death is estimated at 11·9% and 8·3%, respectively.43 Right ventricular enlargement from chronic pulmonary

regurgitation is the most common haemodynamic sub-strate. Pulmonary valve replacement reduces right ventricular size, stabilises QRS duration, and can lead to a substantial reduction in the incidence of subsequent monomorphic ventricular tachycardia.73 The latter is inconsistent however,74 and most would include an additional anti-arrhythmia procedure before, during, or after valve replacement. This additional procedure can take the form of preoperative electrophysiological study with transcatheter ablation, intraoperative arrhythmia mapping and cryoablation, postoperative implantation of an automatic defi brillator, or their combination. Patients undergoing concomitant cryotherapy or surgical ablation for ventricular or atrial arrhythmia have the greatest chance of remaining arrhythmia-free after operation.73,75,76 The exact indications for primary or secondary insertion of an implantable defi brillator is a topic of continuous investigation and debate, although patients with tetralogy of Fallot are the largest subgroup of implantable cardioverter defi brillator recipients with congenital heart disease.77,78

Other considerations for adults with tetralogy of FallotIncreasing specialisation of paediatric cardiologists and lack of appropriate training of adult cardiologists have led to inadequate follow-up for many patients, with inevitable casualties even in the best developed health-care systems. Many eff orts have been made over the past 20 years to establish training criteria for physicians working with adult patients with congenital heart disease and to provide recommendations for treatment of their most common problems.79–82 However, even with an immediate response by training bodies and a massive injection of resources (both of which are unlikely), inadequate care will go on for many years, or even decades, which is a terrible indictment of medical

A BValve ring Percutaneousvalve

PTPTRVOT

Figure 5: Percutaneous pulmonary valve replacementLateral still-frame pulmonary artery angiograms showing the pulmonary trunk (PT) and the right ventricular outfl ow tract (RVOT) before (A) and after (B) percutaneous pulmonary valve replacement. The patient has previously undergone surgical placement of a valved conduit between the right ventricle and the pulmonary artery. Note the residual obstruction within the valve leafl ets (arrow), just above the valve ring. There is also dense opacifi cation of the right ventricular outfl ow tract due to the pulmonary regurgitation (arrowheads) in the preimplantation image. The obstruction is completely relieved, and there is no residual regurgitation after percutaneous implantation of a stented valve within the previous valved conduit.

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planning that undermines the much-lauded success story of care of children with congenital heart disease.

These issues are further amplifi ed by the need for a multidisciplinary approach in adult patients with repaired congenital heart disease. So far, we have emphasised the haemodynamic consequences of tetralogy repair. How-ever, physicians caring for these patients should also be able to advise patients on other issues arising in adulthood, such as associated medical problems, pregnancy and prevention, insurance and employment, and recommendations about exercise activities. The importance of this inclusive expert model of care is exemplifi ed by a recent study of outcomes in adults with congenital heart disease undergoing cardiac surgery,83 in which those operated on by non-dedicated congenital cardiac surgeons were more than twice as likely to die than those operated on by surgeons specialised in congenital heart abnormalities. The key to a successful programme is a focused and dedicated approach to the care of people with congenital heart disease that spans the age range and incorporates expertise from all subspecialties, no matter what their traditional orientation (paediatric or adult) might be.

Other medical complicationsAortic root dilation is an increasingly recognised feature of late postoperative tetralogy of Fallot and can lead to aortic regurgitation, which in turn could necessitate surgery. Increased aortic fl ow attributable to right-to-left shunting before repair and adverse intrinsic properties of the aortic root seem to be the underlying mechanisms.84 Prevalence of aortic root dilation varies between 15% and 87% depending on the method and defi nition used in the studies.85,86 Currently, no agreement exists on which patient or at what stage aortic root surgery should be done, although progressive aortic regurgitation and aortic root dilation more than 55 mm are widely accepted as criteria for aortic root surgery, especially when the primary indication for surgery is pulmonary valve implantation.

A growing number of patients with tetralogy of Fallot are reaching late adulthood and become at risk of coronary artery disease, but only a few cases have been reported and the exact prevalence remains unknown.87,88 However, even if rare, typical or atypical symptoms of coronary artery disease should be investigated thoroughly. If revascularisation surgery is required, additional residual lesions should be carefully documented before surgery and addressed at revascularisation, unless contraindicated by haemodynamic instability or emergency.

Pregnancy and contraceptionThe risk of pregnancy in postoperative women with tetralogy of Fallot depends on their haemodynamic state. The risk is low—similar to that of the general population—in patients with good underlying haemodynamics. In patients with substantial residual

obstruction across the right ventricular outfl ow tract, severe pulmonary regurgitation, tricuspid regurgitation, and right and left ventricular dysfunction, the increased volume load of pregnancy could lead to right heart failure and arrhythmias.89 Because the right ventricle might be vulnerable to the additional volume load of pregnancy, being already compromised from previous surgery, and because pregnancy in these patients is associated with persisting midterm dilatation of the subpulmonary ventricle, patients with repaired tetralogy of Fallot and severe pulmonary regurgitation should be considered for pulmonary valve replacement before becoming preg nant.90,91 Vaginal delivery is the recom-mended mode of delivery for most women with tetralogy of Fallot. In rare cases of right ventricular failure during pregnancy, delivery should be considered before term,92 but this is an unusual situation. Pre-pregnancy assessment and counselling by an appropriately trained specialist, and delivery in a unit specialised in the care of high-risk mothers with cardiac disease, are highly desirable.

Exercise activitiesFor young adults with congenital heart disease, exercise capacity and participation in competitive sports are important considerations. Sport might contribute to improved quality of life and life expectancy. Common sporting activities can be grouped into static or dynamic, graded as low, moderate, or high intensity. Limitations on sport participation vary with symptoms and extent of residual defects. Decisions need to be made on an individual basis. Sports should be avoided by individuals with exercise-induced life-threatening arrhythmias. In patients with high right ventricular pressure (>50% of systemic values), severe pulmonary regurgitation with right ventricular dilatation, or rhythm disturbances, restriction to low dynamic and low static sport activities is advised (eg, hiking, golfi ng, or bowling), although these recommendations can vary and are likely to change after reoperation. Full exercise activity should be encouraged for patients with only minimal residual abnormalities.93,94 In some patients, exercise testing is helpful to assess eff ort tolerance and to defi ne functional class, but no general recommendations exist.

Insurance and employmentAccess to health and life insurance and full employment are issues for many adolescents and adults with congenital heart disease. Specifi c advocacy has been lacking, especially when compared with that of other patient groups. Ideally, the health-care team—including both physicians and specialised social workers—should work to provide appropriate advice and to fi nd eff ective solutions for each individual.79

Although resources are limited, government-sponsored comprehensive health-care systems of some countries are hugely helpful to adults with congenital heart disease.

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In other systems, adequate health insurance, and therefore care, might be diffi cult to obtain in adulthood, partly because of uncertainties and misconceptions about the cost of care for adults with congenital heart disease. Actual costs of medical care seem to be low in these patients compared with those of survivors with other chronic diseases that begin in childhood.80

Similarly, employment opportunities for adults with congenital heart disease are scarce. Although some patients require special counselling and support, most of them can sustain normal employment. Patient advocacy groups should have a major role in raising awareness and emphasising discrimination when it occurs, and in shaping social policy through pressure on governments.

ConclusionsThe care of children with tetralogy of Fallot and their transition to adult life has been a success of modern medicine. Most of them now survive early repair and have an essentially normal childhood. However, great challenges have come with this success. One is that many adverse outcomes only become apparent decades after surgery. Hitherto unanticipated complications are now increasingly understood, and their recognition is feeding back to improve care of infants born with the disease. This success story has also created a resource gap for care that urgently needs attention. Paradoxically, this societal conundrum might be the greatest threat to the adequate care of this population.

ContributorsCA did the literature search and wrote the fi rst draft of the manuscript.

ANR planned, organised, and reviewed the manuscript. GDW revised

the manuscript and made important additional contributions to its

content and structure.

Confl icts of interestWe declare that we have no confl icts of interest.

AcknowledgmentsCA is supported by a research scholarship of Deutsche Herzstiftung eV,

Frankfurt, Germany.

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