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Review
Factors associated with long-term mortality after Fontan procedures: a systematic review
  1. Tarek Alsaied1,
  2. Jouke P Bokma2,3,
  3. Mark E Engel4,
  4. Joey M Kuijpers2,3,
  5. Samuel P Hanke1,
  6. Liesl Zuhlke5,
  7. Bin Zhang6,
  8. Gruschen R Veldtman7
  1. 1Children's Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  2. 2Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands
  3. 3The Netherlands Interuniversity Cardiology Institute of the Netherlands—Netherlands Heart Institute, Utrecht, The Netherlands
  4. 4Department of Medicine, Groote Schuur Hospital, Cape Town, South Africa
  5. 5Department of Paediatrics, Red Cross War Memorial Children's Hospital and University of Cape Town, Cape Town, South Africa
  6. 6Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio USA
  7. 7Adolescent and Adult Congenital Program, Children's Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  1. Correspondence to Professor Gruschen R Veldtman, Adolescent and Adult Congenital Program, Children's Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; Gruschen.veldtman{at}cchmc.org

Abstract

Background Despite an ageing Fontan population, data on late outcomes are still scarce. Reported outcome measures and determinants vary greatly between studies making comprehensive appraisal of mortality hazard challenging.

Methods We conducted a systematic review to evaluate causes and factors associated with late mortality in patients with Fontan circulation. Late mortality was defined as mortality beyond the first postoperative year. Studies were included if they had ≥90 patients or ≥20 late mortalities and/or transplants. Studies with overlapping patients were rationalised to include only the most recent studies to avoid duplication.

Results From 28 studies, a total of 6707 patients with an average follow-up time of 8.23±5.42 years was identified. There were 1000 deaths. Causes of late death were reported in 697 cases. The five most common causes were heart/Fontan failure (22%), arrhythmia (16%), respiratory failure (15%), renal disease (12%) and thrombosis/bleeding (10%). Factors associated with late mortality were evaluated and classified into 9 categories.

Conclusions Causes and factors associated with late mortality after the Fontan operation are summarised in this study. The presented information will aid in identifying patients at highest risk for mortality and guide our risk stratification efforts in this patient population.

https://doi.org/10.1136/heartjnl-2016-310108

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    Introduction

    The Fontan procedure has transformed the lives of patients born with single ventricle physiology and offered them the potential for survival and good quality of life well into adulthood.1 ,2 Since it was first performed in 1968, surgical techniques have evolved enormously2 as have the perioperative landscape including intensive care and cardiac catheter based interventions. As this patient population is ageing multiple morbidities are encountered which lead to premature death. Given the large number of patients with Fontan circulation reaching adulthood, we sought to systematically review and describe late mortality outcomes and its determinants in Fontan patients.

    Methods

    A systematic review of published studies that evaluated long-term mortality and/or heart transplantation in Fontan circulation was performed. Randomised, prospective and retrospective non-randomised studies were considered eligible for inclusion, provided that the study population included at least 90 patients with a Fontan circulation or at least 20 mortalities and/or transplants to maintain statistical power. We excluded studies that focused on short-term mortality within the 1st year of the Fontan procedure. We searched PubMed and the Cochrane Library for studies published in English with no restriction on date of publication. Search strategies for each database are presented in the online supplementary data. Two independent investigators conducted the search for studies initially, reaching agreement on the studies to be included by consensus among the entire group (figure 1). The risk of bias was assessed using the Cochrane risk of bias tool for randomised controlled trials3 and the modified Newcastle Ottawa scale for non-randomised studies.4 When more than one study included the same patients we excluded the studies with overlapping patients and we included only the most recent study that included these patients in the final analysis.

    Figure 1
    Figure 1

    PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram—study identification, selection and exclusions.

    The factors associated with long-term mortality were divided into nine different categories as detailed in the results section. Each article was assigned to one or more category, depending on the mortality risk factors reported in the study. Each category of predictors was summarised by one or two researchers depending on their area of expertise and experience.

    Results

    Our search identified 28 studies eligible for inclusion (figure 1). These encompassed a total of 6707 patients with an average follow-up time of (8.23±5.42) years (table 1). Overall there were 1000 mortalities and 138 heart transplantations. The overall pooled mortality rate was 2.1% per year of follow-up. Additional characteristics are presented in online supplementary table S1.

    View this table:
    Table 1

    Characteristics of included studies for mortality risk after Fontan procedure

    Causes of long-term mortality

    Causes of mortality were inconsistently reported between studies. A cause of late mortality was reported in 697 (70%) of the 1000 late mortalities. Of the reported causes, heart failure including Fontan failure was the leading cause accounting for 151 patients (22% of late mortality). Sudden death/arrhythmia was the cause of death in 112 patients (16%). Respiratory failure and renal disease were the most common non-cardiac causes of late mortality and accounted for 105 and 85 cases of mortality (15% and 12% of late mortality) (figure 2).

    Figure 2
    Figure 2

    Causes of late mortality after Fontan procedure.

    Predictors of long-term mortality

    Era of operation

    Earlier date of operation, that is, those operated on in the 1970s and early 1980s was associated with worse long-term outcomes including mortality, Fontan takedown and/or heart transplantation.5–8 This appears to be mainly related to changes in myocardial protection and surgical techniques.6 A recent large study showed a 10-year survival rate after the Fontan procedure of 79% for patients operated on before 1990 compared with 95–98% beyond 1990.9

    Preoperative risk factors

    The preoperative risk factors reported include age at operation, gender, type of congenital heart defect, single ventricular anatomy (right or left ventricle) and function and atrioventricular (AV) valve regurgitation.

    The observation that older age at Fontan operation is associated with worse survival was first denoted by Fontan in 1990.10 In a large Australian/New Zealand popula`tion-based registry, follow-up data of 1006 hospital survivors were collected. Patients operated at >7 years of age had worse long-term survival (HR=2.7, 95% CI 1.2 to 5.7) in multivariable analysis.11 More specifically, in a recent large study of 1052 patients, optimal late survival was observed in patients operated between 2 years and 4 years of age using univariate analysis, although age of operation was not a statistically significant predictor of outcomes in multivariable analysis.9 Some studies reported worse long-term outcomes in men compared with women11 ,12 although a recent large study did not support such sex based differences.9

    The type of congenital heart defect was reported to impact late mortality.13–15 Hypoplastic left heart syndrome is associated with worse late outcomes (including death or Fontan failure) in a large contemporary cohort of 529 patients with Fontan circulation. After adjustment for other significant covariates, hypoplastic left heart syndrome had an almost threefold increased risk for late Fontan mortality (HR=2.8, 95% CI 1.1 to 7.5).16 In the same cohort, AV septal defect was not found to predict long-term mortality and this observation was attributed to the more aggressive management of AV valve regurgitation.11 Importantly, heterotaxy syndrome was associated with decreased survival in a number of studies.5 ,13 ,17–19 In a Japanese study that included 335 Fontan patients, heterotaxy syndrome was shown to be an important risk factor for late mortality in multivariate analysis (HR=12.70, 95% CI 1.68 to 150).17

    Haemodynamic status prior to Fontan surgery was associated with long-term outcomes in several studies. Higher preoperative pulmonary artery pressure was associated with worse survival with 15 mm Hg reported as a threshold in most studies.12 ,20 ,21 Impaired preoperative ventricular function also correlated with worse long-term survival.20 AV valve regurgitation prior to Fontan completion had an almost twofold increased risk for late mortality (HR=1.9, 95% CI 1.15 to 3.20).13 Additionally patients who had a pacemaker prior to Fontan completion and patients who were not in sinus rhythm prior to Fontan completion, appear to have worse outcomes.9

    Operative factors

    Long-term outcomes were superior in patients with cavopulmonary Fontan (lateral tunnel and extracardiac conduit) compared with atriopulmonary Fontan.11 ,12 ,18 ,22 In a recent large study 10-year survival for patients who survived 30 days post Fontan procedure was 80% after atriopulmonary connection, 84% after lateral tunnel Fontan and 97% after extracardiac conduit Fontan.9 The survival difference between lateral tunnel and extracardiac conduit was however not statistically significant and was attributed to using lateral tunnel techniques in patients with heterotaxy syndromes in combination with a significant era effect.9 Some studies suggested worse survival in patients with longer aortic cross-clamp time23 or cardiopulmonary bypass time which can be a surrogate for more complex anatomy or concomitant procedures during Fontan surgery.6 Concomitant replacement of the AV valve was associated with worse long-term survival in two studies (HR=4, 95% CI 2.1 to 7.8) in the latter.9

    Postoperative factors

    Only relatively few postoperative factors influencing late mortality could be identified. These included elevated left atrial pressure, persistent postoperative pleural effusions and elevated postoperative Fontan pressures.

    Increased postoperative right atrial pressure (>13 mm Hg) was frequently reported to be associated with increased late mortality or a combined end point of mortality or heart transplantation with (HR=2.05, 95% CI 1.48 to 2.82) in early Fontan survivors in a recent large review of North American experience.9 Persistent pleural effusions (>30 days or requiring reoperation) increased late mortality in hospital survivors (HR=2.9, 95% CI 1.1 to 7.4) in a population-based registry.11 Prolonged pleural drainage (>3 weeks) was also recently confirmed to be associated with increased risk of late mortality in patients who survived at least 30 days after the Fontan procedure on multivariate analysis (HR=1.2, 95% CI 1.05 to 1.26).9 Increased postoperative Fontan pressures >20 mm Hg was a predictor of mortality with an HR=2.14, 95% CI 1.63 to 2.81.9

    Long-term cardiac complications

    Long-term cardiac complications after the Fontan procedure that may lead to late mortality include arrhythmias, thromboembolic events and heart failure.15

    Heart failure/Fontan failure was found to be the most common cause of long-term mortality in our systematic review.15 ,24 Though delayed diastolic filling and time related progressive ventricular stiffness is now well recognised as part of failing Fontan pathophysiology,25 late outcomes data for those with diastolic dysfunction do not yet exist.

    Arrhythmia is an important risk factor for long-term mortality in Fontan circulation (HR=1.79, 95% CI 1.18 to 2.72).9 A population based study from Denmark found a steady increase of arrhythmia with age.26 The most common arrhythmia is intra-atrial re-entry tachycardia and is more common in atriopulmonary Fontan due to the dilation of the atrium.27

    A composite cardiac risk factor score that included patient age, older style Fontan (atriopulmonary connection and AV), arrhythmia and/or heart failure was indeed strongly predictive of mortality and/or transplant outcomes in a large multi-institutional cohort.28 The presence of two cardiac risk factors was associated with a 4-fold increased risk, whereas three cardiac risk factors was associated with a 10-fold increased risk of mortality or transplantation.

    Thromboembolic events account for a significant portion of late mortality (up to 25% in some studies).15 Risk factors for thrombosis include haemodynamic factors with low cardiac output and less pulsatile pulmonary flow in addition to a hypercoagulable state in Fontan patients.29 A recent meta-analysis showed a pooled incidence of 11% and that prophylaxis with aspirin or warfarin decreases the risk significantly (OR 0.4, 95% CI 0.19 to 0.92).29 The location of thrombus is most commonly in the Fontan conduit, intracardiac or in the pulmonary arteries.15 ,29 ,30

    Non-invasive cardiac imaging factors

    Few studies reported imaging markers predictive of long-term mortality or transplant.31 One study showed that global circumferential strain on transthoracic echocardiogram is predictive of long-term mortality (HR=1.3 per unit change, 95% CI 1.1 to 1.5).32 Ejection fraction was significantly lower in patients who died but did not reach statistical significance on multivariate analysis.32 The same investigators reviewed cardiac MRI in 215 adolescents with Fontan circulation. After a follow-up period of 4 years, 24 (11%) died or were transplanted. The study found that ventricular indexed end-diastolic volume >125 mL/m2 body surface area was a predictor of late mortality (HR=7.7, 95% CI 2.8 to 21.1).31

    Cardiopulmonary exercise testing factors

    Cardiopulmonary exercise tolerance decreases greatly over the life span of Fontan patients.17 ,28 ,33 ,34 In a large study 321 adult Fontan survivors had cardiopulmonary exercise testing and were then observed for the combined study end point of death or transplantation or cardiac hospitalisation over 21 months. Though almost all peak exercise and anaerobic threshold parameters (VO2, % of predicted VO2, heart rate reserve, anaerobic threshold, minute ventilation (VE)/carbon dioxide production (VCO2 slope), were able to predict unscheduled cardiovascular hospital admissions, only peak VO2 was able to independently predict mortality HR=0.88 for each 1% increase in peak VO2.17 Another study showed that a peak VO2 of <16.6 mL/kg/min and peak-exercise heart rates of <122.5 bpm were predictors for long-term mortality with an HR=7.5, CI 2.6 to 21.6 and HR=10.6, CI 3 to 37.1, respectively.

    Non-cardiac predictors of late mortality

    Non-cardiac risk factors evaluated in the literature include plastic bronchitis (PB), hepatic disease, protein losing enteropathy (PLE), high altitude and renal dysfunction.11 ,35–37 A case–control study looking at 25 patients with PB compared with 45 Fontan patients without PB revealed a 32% mortality in patients with PB with a median transplant-free survival of 8.3 years post diagnosis.36 PB was significantly associated with mortality (OR 5.0, 95% CI 1.1 to 26.8).36 Respiratory failure is an important cause of death in the Fontan population. The mechanisms by which the lungs exert their mortality effect in this patient population are not well understood.

    Few studies examined the effect of hepatic disease on mortality.38–41 A recent study reviewed liver data including histopathology and biochemistry.40 Cirrhosis was found to be a late complication with a high mortality (1-year, 43%; 2-year, 65%). The strongest predictor of developing cirrhosis was a previous diagnosis of hypoplastic left heart syndrome. The recently reported VAST score (Varices, Ascites, Splenomegaly or Thrombocytopenia, 1 point each), highlighting the importance of portal hypertension, demonstrated that a VAST score ≥2 confers a ninefold risk for a major adverse event.39 PLE is an important risk factor for mortality and/or transplantation.42 A multi-institutional study in 1998 showed that mortality in patients with PLE was at least 50% over 5 years.35 Given this devastating prognosis, the authors suggest that instead, early transplantation should be considered.35 More recently a single institution study showed improved 5-year survival (88%) and attributed these more favourable late PLE outcomes to early detection and more aggressive management strategies.43

    High altitude has a significant impact on Fontan patients, reducing transplant-free survival and significantly increasing (by more than twofold) the incidence of PLE and clinical decompensation. This was attributable to increased pulmonary vascular resistance at high altitude.21

    Although renal insufficiency was found to be an important non-cardiac cause of death in a number of publications, there is limited literature to describe the spectrum and the exact pathology of renal dysfunction in this population. A recent study showed that postoperative renal insufficiency is associated with increased risk of late mortality (HR=2.5, 95% CI 1.7 to 3.9).9 Another study showed a rate of acute kidney injury of 42% after the Fontan procedure.44

    Serological biomarkers

    Hyponatraemia and elevated brain natriuretic peptide (BNP) have been studied in Fontan patients.

    Hyponatraemia is a well established mortality marker for non-congenital heart disease associated heart failure.45 In a retrospective study of 1004 patients with adult congenital heart disease, including 54 adult Fontan patients, the presence of hyponatraemia (<136 mmol/L) was observed in 29.6% of Fontan patients.46 Hyponatraemia was associated with a significant increase in risk of death in this study (HR=2.59, 95% CI 1.68 to 3.97).46

    Several studies report data on BNP levels in the Fontan physiology.47 In a study that included 369 patients with Fontan circulation, elevated BNP was a predictor of mortality (HR=1.13 per 10 pg/mL; 95% CI 1.02 to 1.25).48 Other studies suggested an association between elevated BNP levels and worse functional status in Fontan patients as expressed by NYHA class rather than mortality.47

    Discussion

    For this systematic review, 28 relevant articles which described late mortality in Fontan patients were evaluated. Overall, late mortality in Fontan patients was 2.1% per year and largely attributable to Fontan/heart failure (22%) and sudden cardiac/arrhythmic death (16%). Overall, we found considerable differences between studies in design and reported risk factors. To facilitate better and more uniform risk stratification risk factors were classified into nine different categories.

    Patients with congenital heart disease and a Fontan circulation are at serious risk for late complications such as arrhythmias, Fontan failure and early death.9 Theoretically, this unfavourable course may be improved by risk appropriate surveillance leading to timely intervention such as Fontan revision surgery, invasive arrhythmia management and/or cardiac transplantation.27 Thus appropriate identification of high-risk patients is important for improving long-term care.

    In this systemic review, we found a large number of risk factors reported in literature. The 35 risk factors (see table 2) identified were divided into the following predefined categories: (1) era-related, (2) preoperative factors, (3) operative factors, (4) postoperative factors (5) long-term cardiovascular complications, (6) cardiac imaging, (7) exercise stress testing, (8) non-cardiac factors, (9) serological factors (table 2). Preoperative anatomical factors such as hypoplastic left heart are likely disadvantageous because a morphological Right ventricle (RV) is more likely to become dysfunctional during long-term follow-up.16 High pulmonary or Fontan pressures preoperatively or postoperatively may reflect early vascular changes in the pulmonary vasculature, which may further progress over time.9 Atriopulmonary Fontan is associated with high rates of supraventricular arrhythmias, after which further clinical deterioration is common.22 Extracardiac manifestations such as PLE or hepatic fibrosis can be considered a sign of Fontan failure, and increasing central venous pressures.9 In stress testing, reduced peak heart rate emerged as the most promising factor. This may reflect autonomic dysfunction and the inability to enhance pulmonary blood flow during exercise.34 Although cardiac imaging and serological testing are potentially very useful in risk stratification, only two papers investigated the prognostic value of these parameters.

    View this table:
    Table 2

    Summary of factors associated with long-term mortality classified into categories

    Future directions

    Retrospective, large data repositories such as the multi-institutional Australian and New Zealand Registry have proven enormously effective in lending statistical power to assess multiple unanswered questions.11 ,13 ,49 Large multinational collaboration will allow analysis of currently employed surveillance techniques and their utility in identifying at-risk Fontan patients.50 Ideally, these collaborations will produce a risk score that helps clinicians in outpatient settings. Identifying patients at high risk will guide interventions and resource utilisation in this patient population.

    Limitations

    Most of the studies reviewed in this systematic review, were retrospective, single-centre registries. Although these studies provided valuable outcomes information, selection or follow-up bias cannot be excluded. Importantly, across different studies, there was large variation in underlying defects, previous palliation, timing of surgery, surgical techniques used and perioperative care.

    Conclusions

    This systematic review provides an overview of late Fontan mortality and factors associated with late mortality across nine different categories. To facilitate and improve decision making, the factors associated with long-term mortality were classified into nine different categories. Further studies may lead to creation of a Fontan risk score for mortality to further help risk stratification and resource utilisation in this patient population.

    References

    1. ↵
      1. Gersony WM
      . Fontan operation after 3 decades: what we have learned. Circulation 2008;117:13–15. doi:10.1161/CIRCULATIONAHA.107.748566
      OpenUrlFREE Full Text
    2. ↵
      1. Mondesert B,
      2. Marcotte F,
      3. Mongeon FP, et al
      . Fontan circulation: success or failure? Can J Cardiol 2013;29:811–20. doi:10.1016/j.cjca.2012.12.009
      OpenUrlCrossRefPubMed
    3. ↵
      1. Higgins JPT,
      2. Green S, eds
      . Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.2 (updated September 2009). The Cochrane Collaboration, 2009. http://www.cochrane-handbook.org
    4. ↵
      1. Wells GA,
      2. Shea B,
      3. O'Connell D, et al
      . The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses (cited 19 January 2016) 2008. http://wwwohrica/programs/clinical_epidemiology/oxfordhtm
    5. ↵
      1. Driscoll DJ,
      2. Offord KP,
      3. Feldt RH, et al
      . Five- to fifteen-year follow-up after Fontan operation. Circulation 1992;85:469–96. doi:10.1161/01.CIR.85.2.469
      OpenUrlAbstract/FREE Full Text
    6. ↵
      1. Bartz PJ,
      2. Driscoll DJ,
      3. Dearani JA, et al
      . Early and late results of the modified fontan operation for heterotaxy syndrome 30 years of experience in 142 patients. J Am Coll Cardiol 2006;48:2301–5. doi:10.1016/j.jacc.2006.07.053
      OpenUrlFREE Full Text
    7. ↵
      1. Dabal RJ,
      2. Kirklin JK,
      3. Kukreja M, et al
      . The modern Fontan operation shows no increase in mortality out to 20 years: a new paradigm. J Thorac Cardiovasc Surg 2014;148:2517–23.e1. doi:10.1016/j.jtcvs.2014.07.075
      OpenUrlCrossRefPubMed
    8. ↵
      1. Mair DD,
      2. Puga FJ,
      3. Danielson GK
      . The Fontan procedure for tricuspid atresia: early and late results of a 25-year experience with 216 patients. J Am Coll Cardiol 2001;37:933–9. doi:10.1016/S0735-1097(00)01164-5
      OpenUrlFREE Full Text
    9. ↵
      1. Pundi KN,
      2. Johnson JN,
      3. Dearani JA, et al
      . 40-year follow-up after the Fontan operation: long-term outcomes of 1,052 patients. J Am Coll Cardiol 2015;66:1700–10. doi:10.1016/j.jacc.2015.07.065
      OpenUrlFREE Full Text
    10. ↵
      1. Fontan F,
      2. Kirklin JW,
      3. Fernandez G, et al
      . Outcome after a “perfect” Fontan operation. Circulation 1990;81:1520–36. doi:10.1161/01.CIR.81.5.1520
      OpenUrlAbstract/FREE Full Text
    11. ↵
      1. d'Udekem Y,
      2. Iyengar AJ,
      3. Galati JC, et al
      . Redefining expectations of long-term survival after the Fontan procedure: twenty-five years of follow-up from the entire population of Australia and New Zealand. Circulation 2014;130(Suppl 1):S32–8. doi:10.1161/CIRCULATIONAHA.113.007764
      OpenUrlAbstract/FREE Full Text
    12. ↵
      1. Burkhart HM,
      2. Dearani JA,
      3. Mair DD, et al
      . The modified Fontan procedure: early and late results in 132 adult patients. J Thorac Cardiovasc Surg 2003;125:1252–9. doi:10.1016/S0022-5223(03)00117-X
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      1. d'Udekem Y,
      2. Xu MY,
      3. Galati JC, et al
      . Predictors of survival after single-ventricle palliation: the impact of right ventricular dominance. J Am Coll Cardiol 2012;59:1178–85. doi:10.1016/j.jacc.2011.11.049
      OpenUrlFREE Full Text
    14. ↵
      1. Iyengar AJ,
      2. Brizard CP,
      3. Konstantinov IE, et al
      . The option of taking down the Fontan circulation: the Melbourne experience. J Thorac Cardiovasc Surg 2010;139:1346–8. doi:10.1016/j.jtcvs.2009.12.029
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Khairy P,
      2. Fernandes SM,
      3. Mayer JE, Jr.., et al
      . Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation 2008;117:85–92. doi:10.1161/CIRCULATIONAHA.107.738559
      OpenUrlAbstract/FREE Full Text
    16. ↵
      1. Iyengar AJ,
      2. Winlaw DS,
      3. Galati JC, et al
      . The extracardiac conduit Fontan procedure in Australia and New Zealand: hypoplastic left heart syndrome predicts worse early and late outcomes. Eur J Cardiothorac Surg 2014;46:465–73. discussion 73. doi:10.1093/ejcts/ezu015
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Ohuchi H,
      2. Negishi J,
      3. Noritake K, et al
      . Prognostic value of exercise variables in 335 patients after the Fontan operation: a 23-year single-center experience of cardiopulmonary exercise testing. Congenit Heart Dis 2015;10:105–16. doi:10.1111/chd.12222
      OpenUrl
    18. ↵
      1. Wolff D,
      2. van Melle JP,
      3. Ebels T, et al
      . Trends in mortality (1975–2011) after one- and two-stage Fontan surgery, including bidirectional Glenn through Fontan completion. Eur J Cardiothorac Surg 2014;45:602–9. doi:10.1093/ejcts/ezt461
      OpenUrlAbstract/FREE Full Text
    19. ↵
      1. Ohuchi H,
      2. Kagisaki K,
      3. Miyazaki A, et al
      . Impact of the evolution of the Fontan operation on early and late mortality: a single-center experience of 405 patients over 3 decades. Ann Thorac Surg 2011;92:1457–66. doi:10.1016/j.athoracsur.2011.05.055
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. Hosein RB,
      2. Clarke AJ,
      3. McGuirk SP, et al
      . Factors influencing early and late outcome following the Fontan procedure in the current era. The ‘Two Commandments’? Eur J Cardiothorac Surg 2007;31:344–52; discussion 53. doi:10.1016/j.ejcts.2006.11.043
      OpenUrlAbstract/FREE Full Text
    21. ↵
      1. Johnson JT,
      2. Lindsay I,
      3. Day RW, et al
      . Living at altitude adversely affects survival among patients with a Fontan procedure. J Am Coll Cardiol 2013;61:1283–9. doi:10.1016/j.jacc.2013.01.008
      OpenUrlFREE Full Text
    22. ↵
      1. d'Udekem Y,
      2. Iyengar AJ,
      3. Cochrane AD, et al
      . The Fontan procedure: contemporary techniques have improved long-term outcomes. Circulation 2007;116(11 Suppl):I157–64. doi:10.1161/CIRCULATIONAHA.106.676445
      OpenUrlPubMedWeb of Science
    23. ↵
      1. Hirsch JC,
      2. Goldberg C,
      3. Bove EL, et al
      . Fontan operation in the current era: a 15-year single institution experience. Ann Surg 2008;248:402–10. doi:10.1097/SLA.0b013e3181858286
      OpenUrlPubMed
    24. ↵
      1. Nakano T,
      2. Kado H,
      3. Tatewaki H, et al
      . Results of extracardiac conduit total cavopulmonary connection in 500 patients. Eur J Cardiothorac Surg 2015;48:825–32. doi:10.1093/ejcts/ezv072
      OpenUrlAbstract/FREE Full Text
    25. ↵
      1. Gewillig M,
      2. Goldberg DJ
      . Failure of the fontan circulation. Heart Fail Clin 2014;10:105–16. doi:10.1016/j.hfc.2013.09.010
      OpenUrlCrossRefPubMed
    26. ↵
      1. Idorn L,
      2. Juul K,
      3. Jensen AS, et al
      . Arrhythmia and exercise intolerance in Fontan patients: current status and future burden. Int J Cardiol 2013;168:1458–65. doi:10.1016/j.ijcard.2012.12.055
      OpenUrlCrossRefPubMed
    27. ↵
      1. Deal BJ,
      2. Mavroudis C,
      3. Backer CL
      . Arrhythmia management in the Fontan patient. Pediatr Cardiol 2007;28:448–56. doi:10.1007/s00246-007-9005-2
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      1. Diller GP,
      2. Giardini A,
      3. Dimopoulos K, et al
      . Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients. Eur Heart J 2010;31:3073–83. doi:10.1093/eurheartj/ehq356
      OpenUrlAbstract/FREE Full Text
    29. ↵
      1. Alsaied T,
      2. Alsidawi S,
      3. Allen CC, et al
      . Strategies for thromboprophylaxis in Fontan circulation: a meta-analysis. Heart 2015;101:1731–7. doi:10.1136/heartjnl-2015-307930
      OpenUrlAbstract/FREE Full Text
    30. ↵
      1. Monagle P,
      2. Cochrane A,
      3. Roberts R, et al
      . A multicenter, randomized trial comparing heparin/warfarin and acetylsalicylic acid as primary thromboprophylaxis for 2 years after the Fontan procedure in children. J Am Coll Cardiol 2011;58:645–51. doi:10.1016/j.jacc.2011.01.061
      OpenUrlFREE Full Text
    31. ↵
      1. Rathod RH,
      2. Prakash A,
      3. Kim YY, et al
      . Cardiac magnetic resonance parameters predict transplantation-free survival in patients with fontan circulation. Circ Cardiovasc Imaging 2014;7:502–9. doi:10.1161/CIRCIMAGING.113.001473
      OpenUrlAbstract/FREE Full Text
    32. ↵
      1. Ghelani SJ,
      2. Harrild DM,
      3. Gauvreau K, et al
      . Comparison between echocardiography and cardiac magnetic resonance imaging in predicting transplant-free survival after the fontan operation. Am J Cardiol 2015;116:1132–8. doi:10.1016/j.amjcard.2015.07.011
      OpenUrl
    33. ↵
      1. Ohuchi H,
      2. Ono S,
      3. Tanabe Y, et al
      . Long-term serial aerobic exercise capacity and hemodynamic properties in clinically and hemodynamically good, “excellent”, Fontan survivors. Circ J 2012;76:195–203. doi:10.1253/circj.CJ-11-0540
      OpenUrlCrossRefPubMedWeb of Science
    34. ↵
      1. Fernandes SM,
      2. Alexander ME,
      3. Graham DA, et al
      . Exercise testing identifies patients at increased risk for morbidity and mortality following Fontan surgery. Congenit Heart Dis 2011;6:294–303. doi:10.1111/j.1747-0803.2011.00500.x
      OpenUrlCrossRefPubMedWeb of Science
    35. ↵
      1. Mertens L,
      2. Hagler DJ,
      3. Sauer U, et al
      . Protein-losing enteropathy after the Fontan operation: an international multicenter study. PLE study group. J Thorac Cardiovasc Surg 1998;115:1063–73. doi:10.1016/S0022-5223(98)70406-4
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      1. Schumacher KR,
      2. Singh TP,
      3. Kuebler J, et al
      . Risk factors and outcome of Fontan-associated plastic bronchitis: a case-control study. J Am Heart Assoc 2014;3:e000865. doi:10.1161/JAHA.114.000865
      OpenUrlAbstract/FREE Full Text
    37. ↵
      1. Johnson ES,
      2. Finch CA
      . High-altitude adaptation and maximum work performance. Am J Physiol 1984;246(Pt 2):R619–23.
      OpenUrl
    38. ↵
      1. Assenza GE,
      2. Graham DA,
      3. Landzberg MJ, et al
      . MELD-XI score and cardiac mortality or transplantation in patients after Fontan surgery. Heart 2013;99:491–6. doi:10.1136/heartjnl-2012-303347
      OpenUrlAbstract/FREE Full Text
    39. ↵
      1. Elder RW,
      2. McCabe NM,
      3. Hebson C, et al
      . Features of portal hypertension are associated with major adverse events in Fontan patients: the VAST study. Int J Cardiol 2013;168:3764–9. doi:10.1016/j.ijcard.2013.06.008
      OpenUrlCrossRefPubMed
    40. ↵
      1. Pundi K,
      2. Pundi KN,
      3. Kamath PS, et al
      . Liver disease in patients after the fontan operation. Am J Cardiol 2016;117:456–60. doi:10.1016/j.amjcard.2015.11.014
      OpenUrl
    41. ↵
      1. Elder RW,
      2. McCabe NM,
      3. Veledar E, et al
      . Risk factors for major adverse events late after Fontan palliation. Congenit Heart Dis 2015;10:159–68. doi:10.1111/chd.12212
      OpenUrlCrossRefPubMed
    42. ↵
      1. Kim SJ,
      2. Kim WH,
      3. Lim HG, et al
      . Outcome of 200 patients after an extracardiac Fontan procedure. J Thorac Cardiovasc Surg 2008;136:108–16. doi:10.1016/j.jtcvs.2007.12.032
      OpenUrlCrossRefPubMedWeb of Science
    43. ↵
      1. John AS,
      2. Johnson JA,
      3. Khan M, et al
      . Clinical outcomes and improved survival in patients with protein-losing enteropathy after the Fontan operation. J Am Coll Cardiol 2014;64:54–62. doi:10.1016/j.jacc.2014.04.025
      OpenUrlFREE Full Text
    44. ↵
      1. Esch JJ,
      2. Salvin JM,
      3. Thiagarajan RR, et al
      . Acute kidney injury after Fontan completion: Risk factors and outcomes. J Thorac Cardiovasc Surg 2015;150:190–7. doi:10.1016/j.jtcvs.2015.04.011
      OpenUrl
    45. ↵
      1. Gheorghiade M,
      2. Abraham WT,
      3. Albert NM, et al
      . Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry. Eur Heart J 2007;28:980–8. doi:10.1093/eurheartj/ehl542
      OpenUrlAbstract/FREE Full Text
    46. ↵
      1. Dimopoulos K,
      2. Diller G-P,
      3. Petraco R, et al
      . Hyponatraemia: a strong predictor of mortality in adults with congenital heart disease. Eur Heart J 2010;31:595–601. doi:10.1093/eurheartj/ehp495
      OpenUrlAbstract/FREE Full Text
    47. ↵
      1. Koch AM,
      2. Zink S,
      3. Singer H, et al
      . B-type natriuretic peptide levels in patients with functionally univentricular hearts after total cavopulmonary connection. Eur J Heart Fail 2008;10:60–2. doi:10.1016/j.ejheart.2007.11.001
      OpenUrlCrossRefPubMed
    48. ↵
      1. Ohuchi H,
      2. Yasuda K,
      3. Miyazaki A, et al
      . Comparison of prognostic variables in children and adults with Fontan circulation. Int J Cardiol 2014;173:277–83. doi:10.1016/j.ijcard.2014.03.001
      OpenUrlCrossRefPubMed
    49. ↵
      1. Iyengar AJ,
      2. Winlaw DS,
      3. Galati JC, et al
      . The Australia and New Zealand Fontan Registry: description and initial results from the first population-based Fontan registry. Intern Med J 2014;44:148–55. doi:10.1111/imj.12318
      OpenUrlCrossRefPubMed
    50. ↵
      1. Atz AM,
      2. Zak V,
      3. Mahony L, et al
      . Survival data and predictors of functional outcome an average of 15 years after the Fontan procedure: the pediatric heart network Fontan cohort. Congenit Heart Dis 2015;10:E30–42. doi:10.1111/chd.12193
      OpenUrlCrossRefPubMed

    Footnotes

    • Contributors TA wrote the first draft of the manuscript. TA, JPB, LZ, JMK, SPH and GRV reviewed the included studies in the systematic review. GRV, JPB, LZ, JMK, SPH critically revised the manuscript. BZ and MEE provided statistical support.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.