Surgery Insight: late complications following repair of tetralogy of Fallot and related surgical strategies for management

Transcription

1 Surgery Insight: late complications following repair of tetralogy of Fallot and related surgical strategies for management Tara Karamlou, Brian W McCrindle and William G Williams* SUMMARY Biventricular correction of tetralogy of Fallot was devised more than 50 years ago. Current short-term outcomes are excellent. The potential for late complications is, however, an important concern for the growing number of postrepair survivors. Progressive pulmonary valve regurgitation leading to right heart failure and arrhythmia are centrally important problems faced by these patients. New techniques are, however, likely to change the future outcomes for postrepair survivors. These techniques include percutaneous valve replacement, arrhythmia ablation surgery, and strategies that emphasize preservation of the pulmonary valve even at the cost of leaving some residual valvular stenosis. The objectives of this Review are to outline the major complications that arise late after repair of tetralogy of Fallot, to describe the surgical approaches that have been developed to avoid and manage arising complications, and to briefly explore how novel treatment paradigms could change the future long-term outlook for patients following tetralogy repair. KEYWORDS arrhythmia, cyanotic congenital heart disease, outcomes, pulmonary valve, tetralogy of Fallot REVIEW CRITERIA A search for original articles published between 1945 and 2005 and focusing on tetralogy of Fallot and its related complications was performed in MEDLINE and PubMed. The search terms used were tetralogy of Fallot, outcomes, natural history, complications and long-term outcomes. We also included data, when applicable, from our experience with tetralogy of Fallot at the Hospital for Sick Children and the Toronto Congenital Cardiac Center for Adults. All papers identified were English-language, full-text papers. We also searched the reference lists of identified articles for further papers. T Karamlou is the current John W Kirklin Fellow of the Congenital Heart Surgeons Society and WG Williams is a professor of surgery in the Division of Cardiovascular Surgery, Hospital for Sick Children and the Toronto Congenital Cardiac Center for Adults, Toronto, ON, Canada. BW McCrindle is a professor of pediatrics in the Division of Cardiology, Hospital for Sick Children, Toronto. Correspondence *Division of Cardiovascular Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada bill.williams@sickkids.ca Received 14 December 2005 Accepted 19 June doi: /ncpcardio0682 INTRODUCTION Biventricular correction of tetralogy of Fallot (ToF) was devised more than five decades ago. The potential for late complications is an important concern for the growing number of postrepair survivors, although short-term outcomes with current procedures are excellent In line with the dynamic history that has shaped the field of congenital heart surgery, techniques such as percutaneous valve replacement and arrhythmia ablation surgery will provide future outcome benchmarks. The objectives of this Review are to outline the important complications that arise late after repair of ToF, to describe the surgical approaches that have been developed to address them, and to briefly explore how novel treatment paradigms could change the future long-term outlook for patients following repair. MORPHOLOGY The original description of ToF by Etienne-Louis Fallot, 11 as the name implies, included four abnormalities: a large peri membranous ventricular septal defect adjacent to the tricuspid valve; an over-riding aorta; a variable degree of right ventricular outflow tract (RVOT) obstruction, which might include hypoplasia and dysplasia of the pulmonary valve as well as obstruction at the subvalvular and pulmonary artery level; and right ventricular hypertrophy. Van Praagh et al. 12 have since pointed out that ToF could be more correctly termed monology of Fallot, since the four components are explained by the mal position of the infundibular septum. Anterior and leftward displacement of the infundibular septum causes the RVOT to narrow, and the anterior deviation of the infundibular septum results in failure of fusion of the ventricular septum between the arms of the trabeculo- septo-marginalis (Figure 1). The morphology of ToF is markedly heterogeneous and includes an absent pulmonary valve, concomitant atrioventricular septal defects, pulmonary artery branch stenosis, and pulmonary atresia with major aortopulmonary NOVEMBER 2006 VOL 3 NO 11 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE 611

2 A B C AO TV VSD RV RVOT Infundibular septum PA Infundibular septum RVOT RV Infundibular septum RVOT RV Figure 1 Monology of Fallot. (A) Pathologic specimen showing the monology of Fallot. The infundibular septum is displaced anterior and leftward (arrow). When displaced in this way, the right ventricular outflow tract becomes narrowed and fusion of the ventricular septum fails between the arms of the trabeculo-septo-marginalis. (B) Angiogram showing the monology of Fallot. The arrow marks the displaced infundibular septum. The catheter is introduced through the inferior vena cava into the right ventricle. (C) Echocardiogram showing the monology of Fallot. The large solid arrow marks the infundibular septum that is displaced anterior and leftward. Abbreviations: AO, aorta; PA, pulmonary artery; RV, right ventricle; RVOT, right ventricular outflow tract; TV, tricuspid valve; VSD, ventricular septal defect. Permission for Part A obtained from Elsevier Ltd Van Praagh R et al. (1970) Am J Cardiol 26: collaterals. The present Review will focus only on the so-called classic presentation of ToF without coexisting intracardiac defects. HISTORICAL PERSPECTIVE Evolutionary paradigms in the understanding and surgical treatment of congenital heart disease are perhaps best exemplified by ToF, which was originally termed la maladie bleu (Box 1). 11 ToF Box 1 Evolution of surgical treatment of tetralogy of Fallot over time Palliation for tetralogy of Fallot introduced (systemic pulmonary artery shunt) : era of staged corrective surgery a 1954: Intracardiac repair introduced : Transatrial repair introduced : Primary repair at any age advocated : Prostaglandin E introduced 1980s to present day: era of primary repair and transatrial repair 1980s: Doppler color flow mapping introduced 1980s: Pulmonary artery indices (Nakata Index) defined 1992: Two-institution comparative study found primary repair equal or preferable to the staged approach : Excellent results for transatrial and transpulmonary repair reported by Karl et al. 22 a Primary repair was adopted by some centers as early as 1969, but most continued to use staged repair until the late 1980s. is a complex congenital cardiac abnormality; it accounts for 9.7% of all cardiac malformations in children seen at our center. 13 Without the availability of surgical intervention, only 10 15% of patients survived past the age of 20 years. 1,14 The dismal natural history was dramatically altered in 1944 when the first palliative procedure was reported by Blalock and Taussig, 15 and further altered by intracardiac repair, which was introduced 10 years later by Lillehei et al. 16 A shift has since been seen towards early primary repair in infancy, which has improved early survival and might have an impact on late results. 17 Currently, surgical mortality following complete repair is less than 3% and 36-year survival is 96%. 1 SURGICAL REPAIR John Deanfield 18 said long follow-up inevitably means surgery in an earlier era: more recent surgery, at a younger age, with better pre operative, operative, and postoperative care, will improve long-term results. Data from the former (earlier) era will be overly pessimistic. This statement is particularly pertinent as surgical correction of ToF has evolved from a staged approach of antecedent palliation in infancy followed by intracardiac repair to primary repair during the first few months of life without prior palliative surgery. Intracardiac repair consists of patch closure of the ventricular septal defect and relief of RVOT obstruction. Management of the ventricular septal defect has been more consistent than management of the RVOT throughout the history of tetralogy 612 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE KARAMLOU ET AL. NOVEMBER 2006 VOL 3 NO 11

3 Table 1 Reported prevalence of mortality and morbidity from selected series. Study and time period a Number of patients Mean FU (years) Late mortality Reoperation (%) b rate (%) Norgaard et al. 1 ( ) Gatzoulis et al. 48 ( ) Nollert et al. 14 ( ) Roos-Hesselink et al. 37 ( ) Hamada et al. 68 ( ) Nakazawa et al. 5 ( ) NR 10.5 Atik et al. 69 ( ) 39 d Faidutti et al. 70 ( ) NR Knott-Craig et al. 25 ( ) NR Erdogan et al. 3 ( ) NR Murphy et al. 2 ( ) Zhao et al. 71 ( ) Alexiou et al. 46 ( ) e <1.0 Karl et al. 22 ( ) NR Proportion with arrhythmia c (%) a Refers to the era of intracardiac repair. b Calculated as the number of patients who survived operation but died during follow-up, divided by the total number of operative survivors. c Calculated as the maximum number of patients with either atrial or ventricular arrhythmia identified by echocardiography or by Holter monitoring, divided by the total number of operative survivors or the proportion of patients who died from sudden cardiac death. d All patients older than 18 years at time of intracardiac repair. e All patients younger than 2 years at time of intracardiac repair. Abbreviations: FU, follow-up; NR, not reported. repair, except that repair of the ventricular septal defect has evolved in most centers from transventricular closure to transatrial repair. In addition, current surgical repair is by both transatrial and transventricular approach, thereby avoiding and negating the need for a ventriculotomy, or at least keeping ventriculotomy length to a minimum Although a comprehensive discussion of all possible complications is beyond the scope of this Review, we will highlight those that have arguably the most important impact on longterm outcome, including late mortality and right-sided and left-sided cardiac complications. The right-sided complications include pulmonary valve regurgitation, arrhythmia (atrial and ventricular), tricuspid valve regurgitation, and residual RVOT obstruction. The left-sided complications included aortic root dilation and aortic valve regurgitation. Reported late mortality and complication rates from selected large series are shown in Table 1. Mortality trends over time Unsurprisingly, mortality has decreased over time as management of influential risk factors has improved (Figure 2). Lillehei and Survival (%) s a 1990s a 1980s 1970s 1960s 1950s n = 2, s Time after admission to HSC (years) Figure 2 Kaplan Meier curves showing improvements in estimated survival for patients with tetralogy of Fallot enrolled in the continuing Global Outcomes Tracking in Congenital Heart Adults study, stratified by decade of birth. Participants are entered into the study at admission to the Hospital for Sick Children, Toronto, ON, Canada, and, therefore, deaths occurring before intervention are included in the analysis. a Survival estimates are calculated following operative intervention rather than admission. Abbreviation: HSC, Hospital for Sick Children. NOVEMBER 2006 VOL 3 NO 11 KARAMLOU ET AL. NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE 613

4 colleagues 24 reported actuarial survival among 106 patients discharged from hospital after intracardiac repair in the 1980s: rates were 92%, 80%, and 77% at 10, 20, and 30 years, respectively. By contrast, Knott-Craig et al. 25 reported their 26-year experience in 294 patients who underwent repair between 1971 and 1997, with actuarial survival of 98% at 20 years. Timing of intracardiac repair The optimum age for ToF repair has not been established. Older age at definitive repair is a well-known risk factor for death, but very early repair (before age 3 months) is associated with raised risks of postoperative morbidity. 26,27 Early repair probably also increases the need for transannular patching, although data on this point are conflicting. 25,28,29 Two studies at our institution, done by van Dongen et al. 26 and Van Arsdell et al., 27 found that primary repair in children younger than 3 months was associated with a longer stay in intensive care and ventilation duration after surgery, whereas repair in children older than 12 months was associated with increased postoperative mortality. Our current approach based on these studies is to undertake elective complete repair in children aged between 3 and 11 months (Figure 3A). The favorable impact of our change in protocol can be clearly seen (Figure 3B). Fraser and colleagues 30 have used 40 years of experience in more than 2,175 patients to create an empirically based management protocol. Their current strategy also involves complete primary repair at age younger than 6 months in patients with classic ToF. Their results are encouraging, with no operative mortality, less than 1% late mortality, and a 3% reoperation rate. A study by Seliem et al., 31 in which recovery of right ventricular hypertrophy was reported to be improved when intracardiac repair was performed before age 6 months, validates our current protocol of elective repair at age 5 6 months. COMPLICATIONS OF SURGERY Right-sided cardiac complications Pulmonary valve regurgitation Pulmonary valve regurgitation after repair of ToF is relatively well tolerated in the short term, partly because the hypertrophied right ventricle usually adapts to the altered hemo dynamic load. 32 The detrimental effects of chronic pulmonary valve regurgitation are, however, numerous, and include progressive right ventricular dilatation and failure, tricuspid valve regurgitation, exercise intolerance, arrhythmia, and sudden death. 6,9,19,32 35 Mechanoelectrical interaction, by which a dilatated right ventricle provides the substrate for electrical instability, might underlie the propensity toward ventricular arrhythmia. 6 In support of this contention, Gatzoulis and colleagues 6,9 found that the risk of symptomatic arrhythmia was high in patients with marked right ventricular enlargement and QRS prolongation on resting electrocardiogram of more than 180 ms. We have shown that similar structural and hemodynamic abnormalities, including a larger right atrial volume and right ventricular chamber size, are also related to atrial arrhythmias in patients following ToF repair. 10 We found that prolongation of the QRS duration beyond a threshold of 160 ms increased the risk of atrial arrhythmias, albeit at an average age 10 years older than in patients with ventricular arrhythmia. 36 Together, these data show that a similar mechanism could be responsible for both atrial and ventricular arrhythmias after repair in patients with ToF. Arrhythmia Arrhythmia is potentially the most serious late complication following ToF repair. In a multicenter cohort of 793 patients studied by Gatzoulis et al., 9 a steady increase was documented in the prevalence of ventricular and atrial tachyarrhythmia and sudden cardiac death in the first 5 10 years after intracardiac repair. Clinical events were reported in 12% of patients at 35 years after repair. The prevalence of atrial arrhythmia from other studies, however, ranges from 1% to 11%, 10,37 which is a reflection of the strong time dependence of arrhythmia onset. Underlying causes of arrhythmia following repair are complex and multifactorial, resulting in poorly defined optimum screening and treatment algorithms. Older repair age has been associated with an increased frequency of both atrial and ventricular arrhythmia. 7,9,38,39 Impaired ventricular function secondary to a protracted period of cyanosis before repair might contribute to the propensity for arrhythmia in older patients. 40 Although early primary repair of ToF can eliminate one arrhythmogenic substrate, other potential long-term implications exist with this approach. Transannular patch placement, which causes pulmonary valve incompetence, 614 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE KARAMLOU ET AL. NOVEMBER 2006 VOL 3 NO 11

5 is more frequently required for complete relief of RVOT obstruction in those undergoing early repair than in those having either initial palliation or later repair. 25 Early primary repair could, therefore, create a different arrythmogenic substrate, and whether late arrhythmia prevalence will be decreased by the current paradigm remains uncertain. Tricuspid valve regurgitation Clinically important tricuspid valve regurgitation is also common late after ToF repair. 41,42 Mahle et al. 41 reported a 10-year prevalence of 32% among a cohort of 56 school-aged children who had undergone repair before age 5 years; these findings were in agreement with those from another published report. 43 The mechanism of tricuspid valve regurgitation is multifactorial, including intraoperative injury and postoperative ventricular remodeling, leading to annular dilatation and compromise of tricuspid valve chordal support. Tricuspid valve regurgitation often coexists with clinically important pulmonary valve regurgitation, prolonged QRS duration, and increased arrhythmia vulnerability because of the shared pathogenetic mechanism of right ventricular dilation. 6,9,35,44,45 Recurrent or residual right ventricular outflow tract obstruction Residual gradients at the level of the right ventricular infundibulum, pulmonary valve annulus, and peripheral pulmonary arteries following ToF repair have been described. 46,47 The potential impact of residual or recurrent RVOT obstruction has, however, been downplayed by the increased awareness of the adverse effect of pulmonary valve incompetence and the shift towards early repair. The relative tolerance of residual RVOT obstruction is age dependent because the right ventricle in infants is physiologically adapted to higher pressures than in older children. Infants might, therefore, be better equipped than child ren to cope with higher right ventricular pressures after repair. The potential protective effects of mild residual stenosis led to modifications of contemporary surgical practice: aggressive resection of the RVOT is now avoided, and preservation of the pulmonary valve is improved. 48,49 Kaushal et al. 50 studied 166 consecutive children undergoing transatrial repair at a median age of 7 years, 21% of whom were younger than 2 years old. Most of the A Mean age at repair (years) B Cumulative in-hospital mortality after ToF repair (%) Birth cohort Protocol change immediate postoperative gradient was dynamic, and gradients declined notably. Karamlou and colleagues 36 reported a series of 249 patients who had undergone late re operation (>1 year) after ToF repair and found that reoperation for isolated RVOT was unusual (necessary in 8 patients). Nevertheless, reintervention for recurrent RVOT obstruction is a potential 7 months ,000 Consecutive patients with ToF undergoing repair Figure 3 Timing and operative mortality for repair of tetralogy of Fallot at the Hospital for Sick Children, Toronto, ON, Canada. (A) The mean age at repair of patients with tetralogy of Fallot has decreased over time and is currently 7 months. (B) Cumulative sum graph to illustrate the change in in-hospital mortality risk at the Hospital for Sick Children following introduction of early primary repair. The curve reflects the birth cohorts after 1979 shown in Part A. The arrow indicates the time at which the protocol changed to primary repair, resulting in a decline in operative mortality risk from 3.5% to <1.0%, related to the age at repair progressively decreasing. Abbreviation: ToF, tetralogy of Fallot. NOVEMBER 2006 VOL 3 NO 11 KARAMLOU ET AL. NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE 615

6 problem, and could become more prevalent as the number of infant repairs rises. 46 Alexiou and colleagues 46 reported a significantly higher 10-year rate of reintervention for RVOT obstruction among infants who had undergone transatrial repair than among infants who had undergone transventricular repair (72%, SD 6% were free from repair at 10 years compared with 98%, SD 2%; P <0.0001). Left-sided cardiac complications Aortic root dilation and aortic valve regurgitation Aortic root dilatation is known to be a feature of ToF, and is more common in patients with pulmonary atresia than in those without, especially among those undergoing repair at older ages. 51 The pathophysiologic mechanisms are unproven, but are thought to be related to increased flow through the aorta from overriding of the infundibular septum and right-toleft shunting before repair. 51,52 Progressive aortic root dilation might result in aortic regurgitation in 15 18% of operative survivors, some of whom will require valve replacement. 52 Intrinsic abnormalities in the media of the aortic wall have been observed, but whether these are intrinsic to tetralogy or secondary to the hemodynamic load of increased aortic flow is unknown. SURGICAL TECHNIQUES TO LIMIT AND TREAT COMPLICATIONS Limitation of pulmonary valve regurgitation and reduction of arrhythmia Method of RVOT reconstruction The morphology of the pulmonary valve and the method of RVOT reconstruction are arguably the most important determinants of later pulmonary valve competence. Giannapoulos and colleagues 53 described ideal RVOT reconstruction, which involves finding the delicate balance whereby the surgeon avoids both inadequate resection (which would lead to residual RVOT obstruction) and excessive transannular patching (which would lead inevitably to severe pulmonary valve regurgitation). Current evidence suggests that residual mild RVOT obstruction is less harmful than pulmonary valve regurgitation. Present surgical techniques err on the wrong side of this balance. 48,54 Studies have demonstrated that mild residual obstruction and consequent restrictive physiology is protective against pulmonary valve regurgitation and ventricular dilation. Gatzoulis et al. 48 showed that compared with patients with a compliant ventricle, a poorly compliant right ventricle leads to improved exercise performance. Investigation of 67 patients undergoing repair at a mean age of 1.8 years by Uebing et al. 49 showed that pulmonary valve competence could be maintained by limiting the enlargement of the pulmonary annulus to the second lower SD of normal without an increased prevalence of residual RVOT obstruction. These researchers found also that right and left ventricular pressures were not elevated even in the subset of patients with very small indexed pulmonary annulus diameters (between the second and fourth SDs). Transatrial repair Transatrial repair has gained favor in preference to the transventricular approach. Avoidance of a ventriculotomy or limitation in ventriculotomy size should presumably preserve right ventricular structure and function. Visualization of the ventricular septal defect through the tricuspid valve is usually adequate for repair, and can be improved further by division of obstructing RVOT muscle bundles. Additional access to the RVOT can be obtained by use of a limited incision in the main pulmonary artery. 22 The transatrial and transpulmonary approach has been used successfully by many groups, even in infants younger than 6 months, and has been associated with improved right ventricular function and reduced right ventricular volumes in the short term Kawashima et al. 23 reported improved right ventricular function and a decreased prevalence of ventricular arrhythmia with the transatrial approach relative to transventricular repair. Similarly, Dietl et al. 55 showed that the transatrial approach decreased the prevalence of both right ventricular dysfunction and pulmonary regurgitation, and also reduced the risk of ventricular arrhythmia without a concomitant increase in atrial arrhythmia. Direct comparison between the transatrial approach and the transventricular approach is, however, hampered by the non contemporaneous nature of the groups; favorable outcomes with the former might well be because of the improved early results and, of necessity, a shorter postrepair follow-up duration. Whether adoption of the transatrial approach will provide durable long-term benefit without increasing the prevalence of tricuspid valve incompetence or RVOT obstruction remain unanswered. Given these data, a rational algorithm can be developed to achieve optimum balance between 616 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE KARAMLOU ET AL. NOVEMBER 2006 VOL 3 NO 11

7 reaching normal right ventricular pressure and preserving pulmonary competence: avoid where possible ventriculotomy by using the transatrial approach; preserve the pulmonary valve, if possible; adopt discretionary use of a transannular patch for patients with a Z score for pulmonary annulus of 2 or less, or when rightto-left ventricular pressure ratio after repair exceeds 0.7; completely correct all intra cardiac defects and peripheral pulmonary arterial stenoses guided by intraoperative echocardiography; and undertake complete primary repair in the first 6 months of life whenever possible. Use of a monocusp valve to limit regurgitation cannot be uniformly recommended, as this technology has poor longevity and has limited long-term benefit. 1,56 Treatment of pulmonary valve regurgitation and arrhythmia Pulmonary valve replacement Pulmonary valve replacement improves pulmonary regurgitation and is protective against the development of recurrent ventricular and atrial arrhythmia. 35,36 The salutary effects of pulmonary valve replacement before arrhythmia clinically manifests could be related to a reduction of the QRS duration, as documented by a study by Hooft van Huysduynen and colleagues. 57 An alternative explanation is stabilization of the QRS duration, as shown by Therrien and colleagues. 35 Correlation between small right ventricular size and reduced vulnerability to arrhythmia indicates that a measurable reduction in right ventricular size is an important precursor to favorable QRS changes. Reoperation rates for pulmonary valve insufficiency in ToF patients vary depending on the morphological substrate involved, the repair type, and the duration of follow-up. Rates of 98% freedom from pulmonary valve replacement 10 years after initial ToF repair probably underestimate the actual prevalence, since they reflect the historically conservative approach to pulmonary valve replacement. 46 Currently available data on the indications for pulmonary valve replacement are variable and subjective (Box 2). Patients are generally referred when they have symptomatic exercise intolerance or clinical arrhythmia, or severe right ventricular dilatation or dysfunction. 34,35,45,58 Reports suggest that the appearance of clinical signs indicates that right ventricular functional recovery is limited and, therefore, the Box 2 Published indications for pulmonary valve replacement. Clinical symptoms 45 Exercise intolerance Exertional dyspnea Arrhythmia Echocardiographic criteria Right ventricular hypokinesia 34 Isolated severe pulmonary valve regurgitation 32 Pulmonary valve regurgitation associated with tricuspid valve regurgitation, pulmonary artery stenosis, or residual VSD 35 Preoperative right ventricular ejection fraction 40% 45 Progressive right ventricular dilatation 72 Severe right ventricular dilatation 34 Right ventricular end-diastolic volume >170 ml/m 2 Right ventricular end-systolic volume >85 ml/m 2 Severe right ventricular dilatation and right ventricular dysfunction 35 Moderate to severe RVOT obstruction (peak Doppler gradient >50 mmhg) 68 Electrocardiographic criteria QRS duration 180 ms 73 Increased QRS duration rate of change (>3.5 ms/year) 73 Recurrent or sustained arrhythmia 32 Elapsed time interval from repair >2 years 58 Abbreviations: RVOT, right ventricular outflow tract; VSD, ventricular septal defect. benefits of restoring pulmonary competence are minimal. 32,45 Therrien and colleagues 34 attempted to define more-exact criteria for pulmonary valve replacement. They studied 17 patients with MRIobtained indices of right ventricular volumes. The researchers reported that no patients with a right ventricular end-diastolic volume greater than 170 ml/m 2 or an end-systolic volume greater than 85 ml/m 2 achieved normalization of right ventricular volume. 34 Additional compelling evidence that supports adjustment of the current indications for pulmonary valve replacement comes from a study by Hooft van Huysduynen et al. 57 These researchers demonstrated a significant decrease in both right ventricular end-diastolic volume and QRS duration following pulmonary valve replacement. Other studies by Bove et al. 59 have shown right ventricular recovery to be independent of the interval between repair and pulmonary valve replacement, but the study population NOVEMBER 2006 VOL 3 NO 11 KARAMLOU ET AL. NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE 617

8 Freedom from late arrhythmia Time from reoperation (years) Number of patients at risk Freedom from de novo late arrythmia 1 year 99% 5 years 98% 10 years 92% Figure 4 A risk-adjusted nomogram generated from the multivariable equation for de novo arrhythmia after late reoperation among 174 patients. Only 8% of the patients without arrhythmia developed a de novo arrhythmia within 10 years of reoperation. By contrast, the 74 patients who presented with arrhythmia before late reoperation had a 25% prevalence of arrhythmia recurrence or persistence within 10 years of their reoperation. Survival after late reoperation is 92% at 10 years, and is not affected by whether or not the patients had an arrhythmia before reoperation. The solid lines represent the parametric point estimates, and the dashed lines show 70% CI. was significantly younger at the time of valve replacement than in the study by Therrien and colleagues 45 (mean age 14.6 years versus 33.9 years). The potential for right ventricular mechanical and electrical remodeling following pulmonary valve replacement might diminish over time, and earlier replacement could have real benefit after ToF repair. 32 Equilibrium must be sought, however, between the potential benefits of early intervention and the inevitable failure rate of the implanted prosthetic valve leading to one or more reoperations. New modalities for measuring right ventricular volume and assessing right ventricular function, such as MRI and echocardiographic isovolumic myocardial acceleration, might allow improved selection of patients for pulmonary valve replacement. Frigiola and colleagues 44 used the recently validated isovolumic myocardial acceleration, a novel load- independent tissue Doppler-based index of systolic right ventricular function, to correlate the degree of contractile dysfunction with the degree of pulmonary valve regurgitation. In 124 post-repair ToF survivors, they noted a strong correlation between both right and left ventricular function and the isovolumic myo cardial acceleration. Their conclusion was that isovolumic myocardial acceleration could be a suitable clinical tool for assessing right ventricular function in the presence of altered loading conditions. A robust marker of pre clinical right ventricular dysfunction would facilitate decision-m aking regarding optimum timing for pulmonary valve replacement following ToF repair. Accurate patient triage is even more important with the recent introduction of transcatheter valve implantation. 60 The indications for pulmonary valve replacement late after tetralogy repair are evolving, and our current practice is to recommend inter vention for moderate to severe pulmonary regurgitation as follows: at onset of clinical symptoms, when exercise capacity is reduced (myocardial oxygen consumption <50% predicted), or both; at onset of arrhythmia especially with QRS duration longer then 180 ms; before the right ventricular volume increases to 170 ml/m 2 ; and in association with residual lesions (shunt or pulmonary artery stenosis). An implantable defibrillator as primary therapy for life-threatening arrhythmia is indicated only in the absence of residual hemodynamic lesions. Arrhythmia ablation surgery The role of ablation in reducing arrhythmia recurrence has been investigated. 7,36,61 Arrhythmia surgery effectively reduces the frequency of recurrent atrial arrhythmias at our institution. 7,61 In a study by Karamlou et al. 36 of late reoperations in patients who had previously undergone ToF repair (Figure 4), pulmonary valve replacement among those with late ventricular tachycardia resulted in a very low incidence of postoperative ventricular tachycardia, irrespective of whether an ablative procedure was performed (Figure 5A). Among patients with late atrial arrhythmia, however, surgical ablation was clearly beneficial in preventing recurrence of this arrhythmia (Figure 5B). These data suggest that, in contrast to sustained ventricular arrhythmias, which resolve after repair of residual hemo dynamic lesions, atrial arrhythmias tend to persist after reoperation, unless concomitant ablation is performed. 618 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE KARAMLOU ET AL. NOVEMBER 2006 VOL 3 NO 11

9 We recommend, therefore, that patients with atrial arrhythmia need ablation combined with correction of the hemodynamic lesions to decrease their late prevalence of atrial tachycardia. For ToF patients with late ventricular tachycardia, correction of the hemodynamic abnormality alone results in a very low prevalence of ventricular tachycardia and, although the addition of ablation is safe, more experience and longer follow-up are needed to fully assess its efficacy. 10,36 The type of ablative surgery in our series was not associated with risk of recurrent arrhythmia. A modified right-sided maze procedure is super ior to anatomic isthmus block in treating most re-entrant atrial arrhythmias. 61 The management paradigm for atrial arrhythmia at our center is an isthmus block for typical atrial flutter, a right-sided maze procedure for patients with atypical atrial flutter or atrial fibrillation, and a biatrial maze procedure for those with atrial fibrillation in whom concomitant leftsided hemo dynamic heart lesions are present. In the absence of hemo dynamic lesions, atrial arrhythmias can be treated successfully by radiofrequency catheter ablation. If patients have residual hemo dynamic abnormalities, however, as is common after ToF repair, integra tion of catheter ablation and surgical repair could provide the most efficient care at a reduced risk. Reduction of tricuspid valve regurgitation Strategies to prevent clinical deterioration from tricuspid regurgitation include frequent evaluation with echocardiography, MRI, and cine- MRI to identify patients with preclinical right ventricular dysfunction or dilatation. Early pulmonary valve replacement with or without tricuspid valve repair is recommended. Judicious use of tricuspid valve annuloplasty, valve repair, and right atrial reduction is indicated when there is evidence of more than mild valvular incompetence, to prevent further deterioration and the onset of atrial arrhythmia. 9,32,35,44,45 Some authors also recommend prophylactic cryoablation to decrease the risk of late arrhythmia in patients with severe tricuspid valve regurgitation and right atrial enlargement. 32 Although no conclusive evidence exists, preferential use of the trans atrial approach at initial repair could increase the risk of tethering of the septal leaflet during ventricular septal defect closure, and could potentially increase the prevalence of important tricuspid valve regurgitation. 41 Results A 100 P = 0.50 % survival free of VT Ablation (n = 31) No ablation (n = 13) Years after re-operation late after ToF repair B 100 P = 0.50 % survival free of VT Ablation (n = 34) No ablation (n = 9) Years after re-operation late after ToF repair Figure 5 Freedom from ventricular and supraventricular tachycardia after late reoperation. (A) Among patients who presented with ventricular tachycardia before reoperation, freedom from this tachycardia is 90% at 10 years. The addition of arrhythmia ablation at reoperation had no significant effect on subsequent arrhythmia compared with no ablation (31 versus 13 patients). We conclude that repair of the hemodynaic lesions substantially reduces the risk of arrhythmia. (B) Freedom from supraventricular arrhythmia is markedly affected by whether or not a surgical ablation is performed at reoperation. Freedom from subsequent arrhythmia is 85% at 5 years (31 patients) compared with 37% without ablation (9 patients). Unlike the outcome for patients with ventricular tachycardia, repair of the hemodynamic lesions alone is insufficient to alleviate arrhythmia. Abbreviations: SVT, supraventricular tachycardia; ToF, tetralogy of Fallot; VT, ventricular tachycardia. of ongoing long-term studies will motivate future innovation in the conduct of intracardiac repair, as has been seen for other procedures in ToF. 7.5 NOVEMBER 2006 VOL 3 NO 11 KARAMLOU ET AL. NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE 619

10 Reduction of aortic root dilatation and aortic valve regurgitation Early primary repair, by elimination of increased aortic flow and avoidance of the additional volume-load imposed by palliative shunts, should decrease the prevalence of later aortic root dilatation and aortic valve regurgitation. Niwa and colleagues 52 compared 32 patients with aortic root dilatation (defined as a ratio of observed to expected aortic root size >1.5 by standard nomogram) with 54 age-matched ToF controls without aortic root dilatation. Longer shunt-torepair interval was associated with more rapid progression of aortic dilatation, an increased prevalence of aortic valve regurgitation, and larger left ventricular dimension on follow-up echocardiogram. Niwa et al. observed the lack of a relationship between left ventricular size and severity of aortic valve regurgitation, and, therefore, inferred that left ventricular dilatation was attributable to chronic volume-loading from longstanding palliative shunts rather than the direct effect of aortic valve regurgitation. Ishizaka and associates 62 also documented a positive correlation between older age at repair and progression of aortic valve regurgitation in their review of 427 patients who survived operative correction. Eight patients in their series underwent nine aortic valve procedures, including valvuloplasty (n = 5) or replacement (n = 4), either before (n = 1), during (n = 4), or late after (n = 4) ToF repair. Early repair might not offer a complete solution, however, as progressive aortic root dilation can occur despite uncomplicated repair. Of 16 patients reported by Dodds et al., developed progressive aortic valve regurgitation following repair. Our indications for replacing a dilating aortic root (diameter >55 mm or moderate insufficiency) are more conservative than those for Marfan patients. When pulmonary valve replacement, pulmonary arterioplasty or other surgery is required, the indications for concomitant aortic root replacement are more liberal. CONCLUSIONS The outlook for patients with ToF has dramatically improved in the past 60 years, reflecting the evolution in treatment of all forms of congenital heart disease. Enthusiasm regarding the decreased operative mortality and the near-normal life expectancy for postrepair survivors, however, is tempered by remaining late morbidity and rare sudden death in the long term. Amnon Rosenthal 64 expressed the situation of current ToF survivors succinctly: Adults with tetralogy of Fallot repaired yes, cured no. Perhaps many of the complications intrinsic to repair of the older patient will be abrogated by earlier primary repair. The evidence suggests that current emphasis on avoiding excessive muscle resection, preserving pulmonary valve function, and minimizing or avoiding a right ventriculotomy will decrease the prevalence of late arrhythmia and sudden cardiac death. Pulmonary valve regurgitation, potentially the most important and inevitable sequel of ToF repair, demands meticulous follow-up and early valve replacement before clinical symptoms become manifest. Promising new techniques will undoubtedly influence the approach to many of these complications, but cautious implementation in concert with prospective randomized studies that include long-term follow-up are mandatory in order to achieve the best possible outcome. KEY POINTS The outlook for patients with tetralogy of Fallot has dramatically improved in the past 60 years Pulmonary valve regurgitation and arrhythmia are the major problems faced by long-term survivors following repair of tetralogy of Fallot Guidelines for optimum timing of pulmonary valve replacement remain unclear New catheter-based procedures and an emphasis on sparing the pulmonary valve, even at the cost of leaving some residual stenosis, could change postrepair outcomes in the future The interaction between residual hemodynamic lesions and arrhythmia is becoming clearer Long-term studies of survivors following repair of tetralogy of Fallot are required to direct care References 1 Norgaard MA et al. (1999) Twenty-to-thirty-sevenyear follow-up after repair for Tetralogy of Fallot. Eur J Cardiothorac Surg 16: Murphy JG et al. (1993) Long-term outcome in patients undergoing surgical repair of tetralogy of Fallot. N Engl J Med 329: Erdogan HB et al. (2005) Long-term outcome after total correction of tetralogy of Fallot in adolescent and adult age. J Card Surg 20: Hennein HA et al. (1995) Intermediate results after complete repair of tetralogy of Fallot in neonates. J Thorac Cardiovasc Surg 109: Nakazawa M et al. (2004) Arrhythmias late after repair of tetralogy of Fallot: a Japanese multicenter study. Circ J 68: NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE KARAMLOU ET AL. NOVEMBER 2006 VOL 3 NO 11

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