Increased survival rates after corrective or palliative surgery for complex congenital heart disease (CHD) in infancy and childhood are now being coupled with increased numbers of patients who survive to adulthood with various residual lesions or sequelae. These patients are likely to deteriorate in cardiac function or end-organ function, eventually requiring lifesaving treatment including heart transplantation. Although early and late outcomes of heart transplantation have been improving for adult survivors of CHD, outcomes and pretransplant management could still be improved. Survivors of Fontan procedures are a vulnerable cohort, particularly when single ventricle physiology fails, mostly with protein-losing enteropathy and hepatic dysfunction. Therefore, we reviewed single-institution and larger database analyses of adults who underwent heart transplantation for CHD, to enable risk stratification by identifying the indications and outcomes. As the results, despite relatively high early mortality, long-term results were encouraging after heart transplantation. However, further investigations are needed to improve the indication criteria for complex CHD, especially for failed Fontan. In addition, the current system of status criteria and donor heart allocation system in heart transplantation should be arranged as suitable for adults with complex CHD. Furthermore, there is a strong need to develop ventricular assist devices as a bridge to transplantation or destination therapy, especially where right-sided circulatory support is needed.
In the surgical treatment of congenital heart disease (CHD), salvage rates for reparative or palliative surgery in infancy and childhood have markedly improved . Consequently, the number of patients who develop chronic heart failure or who die during follow-up with CHD has been increasing . Adult patients with CHD (ACHD) are likely to carry residual lesions or postoperative sequelae that make them a distinct cohort as grown-ups with CHD (GUCH) . While heart transplantation (HTx) has long been adopted as a rescue therapy for infants and children with complex CHD , its extension to adult cohort with CHD has been limited until recently [5, 6].
Heart failure in ACHD is related to the persistence of structural disorders of the cardiovascular system, and is very different to failure that occurs in acquired heart disease . Notably, during the late follow-up of children who receive the Fontan operation , various end-organ failures and complications develop from circulatory impairment, causing failed Fontan [2, 7, 9, 10]. In this review, we analyze the literature related to CHD and HTx, focusing mainly on adult cohort, to delineate our current understanding of the issues that need to be resolved. Because the issue of HTx for CHD is continuing from childhood to adult age, the review of the literature had to include some relevant reports covering both pediatric and adult HTx. The issue of combined heart and lung transplantation is not considered in this review.
General trend and status: early and late outcomes of HTx
Reports from the pediatric HTx registry of the International Society for Heart and Lung Transplantation (ISHLT) show that the number of pediatric patients who received HTx for CHD has been increasing. In a recent report of pediatric HTx spanning 2009–2015, the overall percentage with CHD was about 40%, with the highest prevalence in infants younger than 1 year (55%), followed by adolescents (23%) . In a recent adult ISHLT registry , the percentage of patients with CHD was 3.2% with about 110 HTx operation per year for other adult population.
Early research of clinical outcomes of HTx for ACHD focused on single institutional experiences, as summarized by Bhama et al. in 2013 . In this review, key reports were gathered for analysis, as summarized in Table 1 [13–22]. Among these, a report by Mori et al. showed excellent results in 12 adult patients including 7 failed Fontan with zero early mortality. The have stressed the importance of the team in adult cardiac center with experienced pediatric cardiac surgeon. On the other hand, the first major analysis of a national multi-institutional or international database was done by Patel et al. . They analyzed United Network for Organ Sharing (UNOS) data for HTx in a cohort of ACHD, and two other UNOS-based reports have followed [24, 25]. Other multicenter registries have been created, one from the Scientific Registry of Transplant Recipients (SRTR) and the other from ISHLT registries [26, 27]. The results of these reports are summarized as follows: early mortalities were 10–17% and long-term survival rates were around 80% at 1 year, 70% at 5 year, and 55% in 10 year, respectively. The leading study by Burchill et al.  was the largest (over 1800 patients), showing superior late survival in ACHD HTx recipients when survived over 30 days compared to those adult patients without CHD. The overall survival rates for ACHD recipients were 77% in 1 year, 67% in 5 years, 57% in 10 years, and 53% in 15 years, respectively, and this result compared with control (non-CHD) is added to Table 1. The better late outcomes instead of higher early mortality after HTx in ACHD compared to non-CHD group have been described as “survival paradox”.
Profile of adult patients with CHD who require HTx
Ross et al.  released an American Heart Association (AHA) Statement for the management of CHD by HTx and mechanical circulatory support, and provided an overview of how to treat heart failure in these patients including ACHD. Coupled with a previous AHA Statement , it provides key factors to consider before deciding on HTx for ACHD patients. For example, the following prognostic variables are listed: age, arrhythmia, hospitalization, ventricular function, pulmonary hypertension (PH), pulmonary function, biomarkers, and exercise testing.
The basic clinical profiles of adult patients with CHD listed for HTx in multi-institutional analyses are summarized in Table 2 [12, 25, 29–31]. The trends were shown as UNOS Status 1 in about one-third of cases, prior cardiac surgery in over four-fifths, and inotropic support in about one-quarter. In the UNOS data, the ACHD group had lower age, lower UNOS Status, longer waiting period, and longer ischemia time compared with other adult patients . In a multi-institutional analysis  comparing the trend in disease severity between early (1998–2005) and late (2006–2012) periods, the late era was associated with more advanced disease in terms of pretransplant hospitalization, use of intravenous inotropes, assist devices, and UNOS Status in spite of no apparent change in anatomical complexity between the periods. Therefore, it has been a clear trend toward more advanced disease in adults undergoing HTx for CHD.
Regarding the anatomical diagnosis, complex lesions dominate, with single or univentricular hearts accounting for 28–36% of cases [26, 32, 33]. In a series of Lamour et al. , which included children, the last major surgery before HTx was most often four-chamber repair (29%), followed by the Fontan operation (22%). Here, we must understand many differences in patient selection policies that exist among institutions and that multi-institutional data lacked detailed anatomical diagnosis.
Indications for HTx in adult patients with CHD
A key factor in deciding whether HTx is indicated for adults with CHD is the assessment of life expectancy, as 1-year survival of <80%, by judging the extent of heart or other end-organ failure [6, 28]. However, this is very different to that in patients without CHD, who typically have cardiomyopathy with left ventricular dysfunction. The decision to perform HTx for CHD has traditionally been empiric because of the lack of guideline-supported medical therapy for heart failure. Recently, Goldberg et al.  outlined the following prognostic factors for ACHD HTx: univentricular or biventricular anatomy, progressive cyanosis, and other objective measures of declining quality of life, including right heart failure and failure to thrive.
The ISHLT have also released their 10-year update of the listing criteria for HTx in 2016 . In this report, recommendations (Class I–III) are provided in a special section for CHD, covering both children and adults. In Class I, it is stated that HTx should only be performed at centers with established medical and surgical experience for CHD in both pediatric and adult patients, and HTx. In addition, detailed assessments of anatomical and vascular abnormalities are essential. The importance of cardiopulmonary exercise testing even in ACHD is described quoting a report indicating peak VO2 as to relate to 5-year survival after HTx.
Patients with univentricular hearts have complex cardiovascular abnormalities necessitating additional surgical procedures at the time of HTx, including pulmonary artery reconstruction and rerouting the abnormal systemic venous return [15, 16, 36]. The aorto-pulmonary collaterals, pulmonary artery and/or portal to systemic venous collaterals, and pulmonary arteriovenous malformations have frequently been seen in post-Fontan patients [35, 36]. In addition, protein-losing enteropathy (PLE) and plastic bronchitis often develop in failed Fontan patients. Although these conditions can be resolved by HTx, peri-transplant morbidly is usually increased. These complications of failed Fontan occur in higher rates among those with preserved ventricular systolic function, as described in the following [37, 38].
Regarding the PH, ISHLT guideline has advised pulmonary vascular resistance (PVR) below 3 WU and transpulmonary pressure gradient (TPG) below 15 mmHg as acceptable levels for HTx . Actually, in the ISHLT registry study , the average PVR in ACHD group was lower as 1.9 WU (Wood unites) compared to 2.1 WU for non-CHD group. In another analysis from the UNOS database , PH was defined as ≥12 mmHg in terms of TPG and the mortality on the waiting lists was higher in PH group compared to non-PH group. In addition, in cases with irreversible PH, combined heart–lung transplantation or lung transplantation with intracardiac repair becomes the more appropriate option .
In summary, indications for HTx in patients with ACHD can be based on whether there is uni- or biventricular anatomy, the extent of heart failure and PH, the complexity of anatomical and vascular abnormalities, the degree of end-organ dysfunction, and the status of ventricular function . Burchill et al.  presented a guideline following the above-mentioned AHA Statement , as partly shown in Table 3.
Risk stratification in early and late phases of HTx
Delisting or death on waiting lists
It must be realized that a significant number of patients with CHD are likely to be lost while on waiting lists, with rates reported to be as much as 40% higher than for non-CHD cohorts [29, 30]. Although this primarily relates to the donor organ allocation system described later, it is also affected by clinical factors such as decreased glomerular filtration rates (GFR), low serum albumin level (<3.2 g/dl), and hospitalization at the time of listing . Cardiac and other-organ failure or infection was the main causes of delisting or death on waiting lists in other reports [13, 29].
The causes of early death among adult patients undergoing HTx for CHD include primary graft failure, stroke, hemorrhage, and multi-organ failure [23, 28, 34]. In the 2016 AHA Statement about chronic heart failure in CHD , specific risk factors at the time of HTx were listed as sensitization, PH, surgical challenges, liver issues, Fontan physiology, and Eizenmenger syndrome.
The risks for early and late mortality have been indicated in the large database reports, as summarized in Table 4 [23–27, 30, 32]. As a peri-transplant factor, long ischemic time has often been raised as the strongest predictor of mortality, but other factors include donor–recipient mismatches (cytomegalovirus, gender), sternotomy over three times, and a score >18 on the Model for End-stage Liver Disease, excluding the International Normalized Ratio) . Sensitization to HLA is a critical matter in HTx for ACHD, and only a slightly higher incidence (panel reactive antibody test >10%) is seen in CHD cohort compared to non-CHD (13 vs 8%) .
Kavarana et al.  summarized the composite risk factors predicting survival after HTx in young children, showing that the presence of a univentricular heart plus the use of dialysis was a strong predictor of death after HTx. Although the details are not presented here, Doumouras et al.  published a well-organized systematic review and meta-analysis covering most of the previously reported single institutional and database analyses.
In practical concerns in surgical strategy, the number of re-do patients is dominating and re-sternotomy increases morbidity and mortality by bleeding and infection from prolonged cardiopulmonary bypass. In univentricular hearts, anomalies of the great vessels and of the systemic and pulmonary venous returns are encountered when atrial isomerism or heterotaxy syndrome is associated, with a couple of relevant case reports in the literature [42, 43].
Failure of the Fontan physiology
Prognosis of the Fontan operation
Although the total cavopulmonary connection (TCPC) has provided better early and intermediate outcomes for Fontan conversion , patients are at increased risk of heart failure or end-organ dysfunction during long-term follow-up [7, 9, 10, 45]. The persistence of low cardiac output with elevated systemic venous pressure in single ventricle physiology is the base of failed Fontan or univentricular physiology. PLE is one of the main manifestations of Fontan failure [10, 28, 36, 46, 47] and liver cirrhosis is also another critical consequence [10, 45, 48, 49]. On the other hand, a robust definition for failed Fontan is still lacking, and this complex situation of end-organ dysfunction has been investigated whether it relates to the status of ventricular function [7, 37, 38]. In addition, long-term follow-up confirms that gradual attrition occurs from thromboembolism, heart failure-related comorbidities, and sudden death . In the report from Boston Children’s Hospital, the predictors of heart failure death after Fontan operation were found as the existence of PLE, a single right ventricle, and a high right atrial pressure . In addition, arrhythmia particularly of supraventricular origin has been well recognized to develop late after atriopulmonary Fontan operation triggering the development of heart failure, with 1.5-fold increase in mortality risk [6, 28, 45]. Therefore, aggressive treatment, such as catheter ablation or TCPC conversion, is indicated during post-Fontan follow-up.
Profile of patients undergoing HTx
Following early experiences in Chicago , there have been an increasing number of reports, which are summarized in Table 5 [36, 47, 50–54]. The interval from Fontan operation to HTx averaged 6–11 years, with inotrope use in about 50% (one report gave this at a rate of 14%). The prevalence of PLE varies considerably (20–60%), as does the rate of ventricular dysfunction (42–78%). Atrioventricular valve regurgitation was described in two reports: one showing a high prevalence (95%) and the other reporting that 11 out of 34 patients (32%) had moderate-to-severe regurgitation, with all but one of these seen in the group with impaired ventricular function . Plastic bronchitis was documented in two reports, and the use of mechanical circulatory support was described in very few. Regarding the type of operation, classic or atriopulmonary connection has often been seen among the failed Fontan as expected . However, patients with TCPC including extracardiac conduit have also developing late failure not in a small number [38, 47].
Fontan-associated liver disease
Fontan-associated liver disease (FALD) [45, 48, 49] has been increasingly recognized as a major potential end-organ dysfunction after Fontan operations, and the main pathophysiological finding is liver fibrosis leading to cirrhosis. For liver cirrhosis, Pundi et al.  followed the post-Fontan patients by liver biopsies, and out of 195 patients 21% had the diagnosis of liver cirrhosis, and freedom form cirrhosis was 99% at 10, 94% at 20, and 54% at 30 years, respectively. In the review by Greenway et al. , FALD is defined as abnormalities in liver structure and function resulting from the abnormal circulation of the Fontan state not related to another process, such as viral infection, medication, or alcohol toxicity. Fontan circulation exposes the liver to higher hepatic venous pressure which creates chronic congestion and decreases portal blood flow. However, low cardiac output combined with elevated venous pressure has not been understood as an exclusive cause of FALD and the cause has been recognized as multifactorial. In our previous clinical research in acute phase after Fontan operation, hepatic venous oxygen saturation was found very low suggesting the inappropriate portal blood flow causing hypoxic hepatic injury . Although it may be controversial, if the hepatic hypoxia early after Fontan operation continues, this might contribute to the development of late FALD.
In clinical setting considering HTx for patients with failed Fontan, meticulous assessment of hepatic functions, whether it is reversible or not, should be conducted by specific laboratory examinations and hepatic biopsy, as necessary. Child–Pugh class, MELD or MELD-XI scores , liver ultrasound score, ultrasonic liver elastography, and various imaging studies have been introduced to assess the degree of liver fibrosis. However, in FALD, the role of these modalities except biopsy appears to be still controversial . Nevertheless, liver function should be reversible, and if it is not, combined heart and liver transplantation is needed. Therefore, HTx alone may be justified when FALD is not advanced, and as the consequence, HTx may be reserved for those patients with stable in liver dysfunction. This situation, however, makes the decision difficult, because such candidates may have lower listing statuses and less chance of HTx.
The results of HTx for post-Fontan patients are summarized in Table 6 [15, 36, 51–54]. Early mortality was 14–39%, and the survival rates were 62–86% at 1 year, 59–77% at 5 years, and 48–69% at 10 years. In the report by Davies et al. (mean age 15.8 years) , the results showed higher early mortality in the Fontan than non-Fontan group (35 vs 20%) but comparable early mortality rates in the later era (28 vs 22%).
PLE is an established concern when making decisions and doing pretransplant management for those with failed Fontan, regardless of patient age. This complication has been recognized to have a negative effect on the early and midterm outcomes of HTx by increasing susceptibility to infection from malnutrition . However, current case series have shown that PLE is not always a predictor of early death [36, 50], and most reports have shown that PLE can resolve after successful HTx. Thus, HTx may be justified in failed Fontan patients under careful assessment of indication even when PLE is the dominant clinical manifestation. By contrast, renal dysfunction, as shown by elevated serum creatinine and decreased GFR, is a significant predictor of early and late death [27, 30, 36].
Preserved vs. impaired ventricular function
Post-Fontan patients can usually be divided into those with preserved or those with impaired systolic ventricular function. Those with preserved ventricular function tend to have worse outcomes from both medical treatment and HTx because of high prevalence of associated PLE [37, 38, 52, 57]. However, this issue is controversial under improved pretransplant management and refined indications for HTx, with recent data showing comparable outcomes between groups with impaired and preserved ventricular functions . Backer et al. postulated that patients with PLE are relatively immunocompromized, which may increase the risks associated with transplantation . Therefore, for those with preserved ventricular function and PLE, a multidisciplinary approach is needed for successful HTx.
The underlying hemodynamic derangement in patients with preserved ventricular function is persistent volume overload to the ventricle mainly by aorto-pulmonary collaterals [28, 37, 38]. At the time of HTx, this circulation remains and new heart cannot accommodate the acute volume overload, which causes primary graft failure. The introduction of coil embolization for aorto-pulmonary collaterals has been an important strategy for reducing volume load before transplantation; however, it requires careful assessment because of the risk of increased hypoxia .
Outcomes of HT
Michielon et al. demonstrated the excellent outcome after HTx in those with impaired ventricular function when the onset of Fontan failure was delayed . In the recent report by Murtuza et al. , the group with preserved ventricular function had higher Varices, Ascites, Splenomegaly, or Thrombocytopenia-Score (VAST)  and liver ultrasound scores, and lower serum albumin level compared to the group with impaired ventricular function. Furthermore, liver fibrosis accounted for two-thirds of the total mortality, confirming that patients with preserved ventricular function may represent a distinct subset with more disturbed failure of Fontan physiology and higher transplant mortality risk, as described in the Griffiths's report . By contrast in the Miller’s report  as described above, recent advances have made the improvement even in the preserved ventricular function group comparable to non-CHD cohort. Although the discussion about this issue may continue, the preserved ventricular function per se may not be a discriminating factor in failed Fontan indicated to HTx.
Mechanical circulatory support and ventricular assist devices
Progress in mechanical circulatory support for the management of end-stage heart failure has been remarkable, particularly with development of implantable ventricular assist devices (VADs). On the other hand, data from the UNOS in 2008 indicated that mechanical circulatory support did not improve the waiting list survival, because patients were already too ill, indicating that the importance of early use before end-stage disease comes apparent . Nevertheless, mechanical circulatory support is now a key issue in HTx for patients with CHD, including those with failed Fontan, because of the severe donor shortage and long waiting times . In the last report of the ISHLT, 14% of adult recipients had pretransplant mechanical circulatory support in a cohort of 763 patients with CHD . Pulsatile paracorporeal VADs have been increasingly applied in mostly pediatric patients with CHD , and for ACHD patients, implantable devices can be applicable in the setting of bridge to HTx or destination (DT) therapy . Maxwell et al.  analyzed the organ procurement and transplant network (OPTN) database for mechanical supports including left ventricular VAD in 81% in ACHD patients prior to HTx, and the number was still small, but outcomes were favorable with 30-day mortality after HTx as 10.8% in 83 patients comparable to the control group.
Application of implantable HeartMate-II® VAD has been growing in patients with complex CHD for functional left-side ventricular support in such patients with corrected transposition  and d-transposition of the great arteries with atrial switch operation . For failed Fontan, left-sided ventricular support has also been reported using an implantable axial flow VAD . Furthermore, the application of VAD for right-sided circulatory support in post-Fontan patient had been attempted using extracorporeal pulsatile VAD (Berlin Heart®) for total right heart support . In animal experiments, Jarvik 2000® and Heart Mate-II® axial flow VADs were used in TCPC model, either total or partial right heart support [67, 68]. In particular, Riemer et al. demonstrated the feasibility of inferior vena cava to pulmonary artery partial support using HeartMate-II® in a TCPC sheep acute model .
Continuous-flow axial VADs to augment the systemic venous return in TCPC
We propose an application of continuous-flow VAD to augment systemic venous return to the pulmonary circulation in TCPC using Jarvik® 2000 axial flow pump (Fig. 1). The idea is simple as dividing the extracardiac conduit into inflow and outflow grafts, and interposing the device in the place of TCPC leaving the bidirectional Glenn anastomosis intact. This represents a one-and- half repair of sorts for univentricular hearts, and small continuous-flow implantable VAD may be suitable to in situ application to TCPC conduit. This strategy needs experimental studies examining whether clinically applicable in size-match between the device and the TCPC conduit and also how to manage the thrombotic obstruction of the inflow conduit.
The needs of reliable VAD in univentricular hearts have been increasing , and the concept of partial mechanical support of systemic venous return in cavopulmonary connection has been examined in experimental approaches [70–72]. In this context, the application of a small VAD, such as pediatric Jarvik axial flow pump and Impella®, is promising in post-TCPC failed Fontan and also in the place of HTx for failed Fontan, total artificial heart may be an option in the near future .
Recipient prioritization and donor heart allocation in HTx for ACHD
The listing criteria for HTx and the allocation system for donor hearts in UNOS seem challenging toward the current complex clinical demands. However, the current prioritization system is underdeveloped for ACHD cohort, with most falling into Status 2 because of the limited VAD use [28, 74]. The risk scoring and prioritization system for HTx mostly targets non-CHD groups, and this requires amendment to be more suitable for CHD cohorts [6, 28]. After the 2006 revision of the OPTN and UNOS heart allocation policy, modifying the previous criteria for Status 1A, the number of candidates with VADs reaching to HTx has increased . However, patients with CHD are less likely to get VAD support, so this change has had limited effect in the ACHD population. Last year, a new OPTN/UNOS adult heart allocation policy was proposed, and has just started to be rolled out in the end of 2016 [75, 76]. The UNOS statuses have now been revised to six Tiers instead of previous three statuses adding a Tier for those with CHD including post-Fontan patients. However, this new Tier for CHD is in the fourth level if mechanical or respiratory support is not accompanied, and therefore, it still seems unclear how the new system attends to the merits in ACHD HTx candidates.
In Japan, legislation in 1997 allowed organ transplantation to take place from brain-dead donors smoothly ; however, the number of donors has been limited even after the law was revised in 2010. Currently, HTx is performed in around 50 cases per year with an average waiting period of nearly 3 years . In addition, over 90% of patients are bridged by VADs. Regarding the ACHD issue, the first HTx for CHD was done in 2005 for an adult patient with a univentricular heart and heterotaxy . Recently, an adult patient with corrected transposition of the great arteries received HTx (unpublished data). In addition, there is a report about application of implantable VAD to a 60-year-old patient with corrected transposition of the great arteries . At present, however, few ACHD recipients have been registered to the Japan Organ Transplant Network. The reason may be the poor understanding about HTx for ACHD because of the very severe donor shortage.
In Fontan operation, there have been excellent early and late results in the current strategy of early TCPC application which provided very limited late failure [80, 81]. However, because of the rapid increase of Fontan survivors, we must manage the compromised post-Fontan patients as expected [82–84]. However, there is a lack of the basic data about risk stratification of long-term outcome for ACHD and also specific or separate listing criteria for HTx in ACHD cohort are not provided at present. With the support of allied medical professionals, some important actions are desirable: the introduction of a national ACHD registration system; the development of CHD-oriented listing criteria for HTx, particularly for adult cohorts; and the modification of donor allocation systems that currently follow classic UNOS Status 1 or 2, with no higher or urgent statuses. In the specialism of lung transplantation in Japan, there is a move toward modifying the lung allocation system, so that it is adjusted to the disease-specific risk of pretransplant death. Such action should be reminded in cardiac transplant professionals.
In spite of remarkable advanced in the current medical and surgical strategies for heart failure in ACHD, there are still many issues to be solved . In failed Fontan, although the current approaches have provided improved results , we must understand and preempt the “Fontan epidemic” , and multidisciplinary approaches are needed to provide integrated strategy supported by innovative VADs. In addition, also it is crucial to delineate the pathophysiology of univentricular circulation and also of FALD establishing the specific risk assessment for late deterioration.
It is also needed to evaluate the indication criteria for HTx and the organ allocation system adequate for ACHD patients. Furthermore, we should aim to explore a reliable VAD therapy that can either be a bridge to transplant or destination therapy for ACHD patients including pot-Fontan patients . Finally, we have to recognize the increasing number of compromised ACHD patients unresponsive to advanced therapies and also the fact that ACHD patients are in unequitable situation as the HTx candidates compared to non-CHD patients.
Addendum The new UNOS adult heart allocation system has not been activated yet as of April 8, 2017.
Jacobs JP, Pasquali SK, Jeffries H, Jones SB, Cooper DS, Vincent R. Outcomes analysis and quality improvement for the treatment of patients with pediatric and congenital cardiac disease. World J Pediatr Congenit Heart Surg. 2011;2:620–33.
Diller GP, Kempny A, Alonso-Gonzalez R, Swan L, Uebing A, Li W, et al. Survival prospects and circumstances of death in contemporary adult congenital heart disease patients under follow-up at a large tertiary centre. Circulation. 2015;132:2118–25.
Sommerville J. Management of adults with congenital heart disease: an increasing problem. Ann Rev Med. 1997;40:283–93.
Hsu DT, Lamour JM. Changing indications for pediatric heart transplantation. Complex congenital heart disease. Circulation. 2015;31:91–9.
Hosseinpour AR, Cullen S, Tsang VT. Transplantation for adults with congenital heart disease. Eur Cardiothorac Surg. 2006;30:508–14.
Burchill LJ. Heart transplantation in adult congenital heart disease. Heart. 2016;102:1871–7.
Stout KK, Broberg CS, Book WM, Cecchin F, Chen JM, Dimopoulos K, et al. Chronic heart failure in congenital heart disease: a scientific statement from the American Heart Association. Circulation. 2016;133:770–801.
Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax. 1971;26:140–8.
Engelfriet P, Boersma E, Oechslin E, Tijssen J, Gatzoulis MA, Thilén U, et al. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. Eur Heart J. 2005;26:2325–33.
Khairy P, Femandes SM, Mayer JE Jr, Triedman JK, Walsh EP, Lock JE, Landzberg MJ. Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation. 2008;117:85–92.
Rossano JW, Dipchand AI, Edwards LB, Goldfarb S, Kucheryavaya AY, Levvey BJ, et al. The Registry of the International Society for Heart and Lung Transplantation: nineteenth pediatric heart transplantation report-2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant. 2016;35:1185–206.
Lund LH, Edwards LB, Dipchand AI, Goldfarb S, Kucheryavaya AY, Levvey BJ, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-third adult heart transplantation report-2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant. 2016;35:1159–69.
Bhama JK, Shulman J, Bermudez CA, Bansal A, Ramani R. Heart transplantation for adults with congenital heart disease: results in the modern era. J Heart Lung Transplant. 2013;32:499–504.
Speziali G, Driscoll DJ, Danielson GK, Julsrud PR, Porter CJ, Dearani JA, et al. Cardiac transplantation for end-stage congenital heart defects: the Mayo Clinic experience. Mayo Cardiothoracic Transplant Team. Mayo Clin Proc. 1998;73:923–8.
Lamour JM, Addonizio LJ, Galantowicz ME, Quaegebeur JM, Mancini DM, Kichuk MR, et al. Outcome after orthotopic heart transplantation in adults with congenital heart disease. Circulation. 1999;100(SupplII):II200–5.
Chen JM, Davies RR, Mital SR, Mercando ML, Addonizio LJ, Pinney SP, et al. Trends and outcomes in transplantation for complex congenital heart disease: 1984–2004. Ann Thorac Surg. 2004;78:1352–61.
Coskun O, Coskun T, El-Arousy M, Parsa MA, Reiss N, Blanz U, Knyphalisen V, et al. Heart transplantation in adults with congenital heart disease. Experience with 15 patients. ASAIO J. 2007;53:103–6.
Greutmann M, Pretre R, Furrer L, Bauersfeld U, Turina M, Noll G, et al. Heart transplantation in adolescence and adult with congenital heart disease: a case–control study. Transplant Proc. 2009;41:3821–6.
Irving C, Parry G, O’Sullivan J, Dark JH, Kirk R, Crossland DS, et al. Cardiac transplantation in adults with congenital heart disease. Heart. 2010;96:1217–22.
Cheng RK, Depasquale M, Allaredy M, Cadeiras M, KhuuT Baas A, et al. Post-heart transplant survival for adult congenital heart disease. J Hear Lung Transplant. 2013;31:S206.
Mori M, Vega D, Book W, Kogon BE. Heart transplantation in adults with congenital heart disease: 100% survival with operations performed by a surgeon specializing in congenital heart disease in an adult hospital. Ann Thorac Surg. 2015;99:2173–8.
Besik J, Szarszoi O, Hegarova M, Konarik M, Smetana M, Netuka I, et al. Non-Fontan adult congenital heart disease transplantation survival is equivalent to acquired heart disease. Ann Thorac Surg. 2016;101:1768–73.
Patel ND, Weiss ES, Allen JG, Russell SD, Shah AS, Vricella LA, et al. Heart transplantation for adults with congenital heart disease: analysis of the United Network for organ sharing database. Ann Thorac Surg. 2009;88:814–21.
Karamlou T, Hirsch J, Welke K, Ohye RG, Bove EL, Devaney EJ, et al. A United Network for Organ Sharing analysis of heart transplantation in adults with congenital heart disease: outcomes and factors associated with mortality and retransplantation. J Thorac Cardiovasc Surg. 2010;140:161–8.
Davies RR, Russo MJ, Yang J, Quaegebeur JM, Mosca RS, Chen JM. Listing and transplanting adults with congenital heart disease. Circulation. 2011;123:759–67.
Lamour JM, Kanter KR, Naftel DC, Chrisant MR, Morrow WR, Clemson BS, et al. The effect of age, diagnosis, and previous surgery in children and adults undergoing heart transplantation for congenital heart disease. J Am Coll Cardiol. 2009;54:160–5.
Burchill LJ, Edwards LB, Dipchand AI, Stehlik J, Ross HJ. Impact of adult congenital heart disease on survival and mortality after heart transplantation. J Heart Lung Transplant. 2014;33:1157–63.
Ross HJ, Law Y, Book WM, Broberg CS, Burchill L, Cecchin F, et al. Transplantation and mechanical circulatory support in congenital heart disease: a scientific statement from the American Heart Association. Circulation. 2016;133:802–20.
Everitt MD, Donaldson AE, Stehlik J, Kaza AK, Budge D, Alharethi R, et al. Would access to device therapies improve transplant outcomes for adults with congenital heart disease? Analysis of the United Network for Organ Sharing (UNOS). J Heart Lung Transplant. 2011;30:395–401.
Alshawabkeh LI, Hu N, Carter KD, Opotowsky AR, Light-McGroary K, Cavanaugh JE, et al. Wait-list outcomes for adults with congenital heart disease listed for heart transplantation in the US. J Am Coll Cardiol. 2016;68:908–17.
Cohen S, Houyel L, Guillemain R, Varnous S, Jannot AS, Ladouceur M, et al. Temporal trends and changing profile of adults with congenital heart disease undergoing heart transplantation. Eur Heart J. 2016;37:783–9.
Karamlou T, Diggs BS, Welke K, Tibayan F, Gelow J, Guyton SW, et al. Impact of single-ventricle physiology on death after heart transplantation in adults with congenital heart disease. Ann Thorac Surg. 2012;94:1281–7.
Lewis M, Ginns J, Schulze C, Lippel M, Chai P, Bacha E, et al. Outcomes of adult patients with congenital heart disease after heart transplantation: impact of disease type, previous thoracic surgeries, and Bystander organ dysfunction. J Card Fail. 2016;22:578–82.
Goldberg SW, Fisher SA, Wehman B, Mehra MR. Adults with congenital heart disease and heart transplantation: optimizing outcomes. J Heart Lung Transplant. 2014;33:873–7.
Mehra MR, Canter CE, Hannan MM, Semigran MJ, Uber PA, Baran DA, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update. J Heart Lung Transplant. 2016;35:1–23.
Davies RR, Sorabella RA, Quaegebeur JM. Outcomes after transplantation for failed Fontan: a single institutional experience. J Thorac Cardiovasc Surg. 2012;143:1183–92.
Simpson E, Cibulka N, Lee CK, Huddleston CH, Canter CE. Failed Fontan heart transplantation candidates with preserved ventricular function: 2 distinct patient populations. J Heart Lung Transplant. 2012;31:545–7.
Miller J, Simson KE, Epstein DJ, Lancaster TS, Henn MC, Schuessler RB, et al. Improved survival after heart transplant for failed Fontan patients with preserved ventricular function. J Heart Lung Transplant. 2016;35:877–83.
Krishnamurthy Y, Cooper LB, Lu D, Schroder JN, Daneshmand MA, Rogers JG, et al. Trends and outcomes of patients with adult congenital heart disease and pulmonary hypertension listed for orthotopic heart transplantation in the US. J Heart Lung Transplant. 2016;35:619–24.
Kavarana MN, Savage A, O’Connell R, Rubinstein CS, Flynn-Reeves J, Joshi K, et al. Composite risk factors predict survival after transplantation for congenital heart disease. J Thorac Cardiovasc Surg. 2013;146:888–93.
Doumouras BS, Alba AC, Foroutan F, Burchill LJ, Dipchand AI, Ross HJ. Outcomes in adult congenital heart disease patients undergoing heart transplantation: a systematic review and meta-analysis. J Heart Lung Transplant. 2016;35:1337–47.
González-López MT, Pérez-Caballero-Martínez R, Amoros-Rivera C, Zamorano-Serrano J, Pita-Fernández AM, Gil-Jaurena JM. Orthotopic heart transplantation in an adult patient with heterotaxy syndrome: surgical implications. J Card Surg. 2015;30:910–2.
Matsuda H, Fukushima N, Ichikawa H, Sawa Y. Orthotropic heart transplantation for adult congenital heart disease: a case with heterotaxy and dextrocardia. Gen Thorac Cardiovasc Surg. 2017;65:47–51.
Marcelletti CF, Hanley FL, Mavroudis C, McElhinney DB, Abella RF, Marianeschi SM, et al. Revision of previous Fontan connection to total extracardiac cavopulmonary anastomosis: a multicenter experience. J Thorac Cardiovasc Surg. 2000;119:340–6.
Khambadkone S. The Fontan pathway: what’s down the road? Ann Pediatr Cardiol. 2008;1:83–92.
Rychik J. Protein-losing enteropathy after Fontan operation. Congenit Heart Dis. 2007;2:288–300.
Michielon G, van Melle JP, Wolff D, Di Carlo D, Jacobs JP, Mattila IP, et al. Favourable mid-term outcome after heart transplantation for late Fontan failure. Eur J Cardiothorac Surg. 2015;47:665–71.
Pundi K, Pundi KN, Kamath PS, Cetta F, Li Z, Poterucha JT, et al. Liver disease in patients after the Fontan operation. Am J Cardiol. 2016;117:456–60.
Greenway SC, Crossland DS, Hudson M, Martin SR, Myers RP, Prieur T, et al. Fontan-associated liver disease: implication for heart transplantation. J Heart Lung Transplant. 2016;35:26–33.
Backer CL, Russell HM, Pahl E, Mongé MC, Gambetta K, Kindel SJ, et al. Heart transplantation for the failing Fontan. Ann Thorac Surg. 2013;96:1413–9.
Gamba A, Merlo M, Fiocchi R, Terzi A, Mammana C, Sebastiani R, et al. Heart transplantation in patients with previous Fontan operations. J Thorac Cardiovasc Surg. 2004;127:555–62.
Jayakumar KA, Addonizio LJ, Kichuk-Chrisant MR, Galantowicz ME, Lamour JM, Quaegebeur JM, et al. Cardiac transplantation after the Fontan or Glenn procedure. J Am Coll Cardiol. 2004;44:2065–72.
Griffiths ER, Kaza AK, Wyler von Ballmoos MC, Loyola H, Valente AM, Blume ED, et al. Evaluating failing Fontan for heart transplantation: predictors of death. Ann Thorac Surg. 2009;88:558–63.
Pundi KN, Pundi K, Driscoll DJ, Dearani JA, Li Z, Dahl SH, et al. Heart transplantation after Fontan: results from a surgical Fontan cohort. Pediatr Transplant. 2016;20:1087–92.
Matsuda H, Covino E, Hirose H, Nakano S, Kishimoto H, Miyamoto Y, et al. Acute liver dysfunction after modified Fontan operation for complex cardiac lesions. Analysis of the contributing factors and its relation to the early prognosis. J Thorac Cardiovasc Surg. 1988;96:219–26.
Deo SV, Al-Kindi SG, Altarabsheh SE, Hang D, Kumar S, Ginwalla MB, et al. Model for end-stage liver disease excluding international normalized ratio (MELD-XI) score predicts heart transplant outcomes: evidence from the registry of the United Network for Organ Sharing. Heart Lung Transplant. 2016;35:222–7.
Murtuza B, Hermuzi A, Crossland DS, Parry G, Lord S, Hudson M, et al. Impact of mode of failure and end-organ dysfunction on the survival of adult Fontan patients undergoing cardiac transplantation. Eur J Cardiothorac Surg. 2017;51:135–41.
Elder RW, McCabe NM, Hebson C, Veledar E, Romero R, Ford RM, 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.
Davies RR, Russo MJ, Hong KN, O’Byrne ML, Cork DP, Moskowitz AJ, et al. The use of mechanical circulatory support as a bridge to transplantation in pediatric patients: an analysis of the United Network for Organ Sharing database. J Thoracic Cardiovasc Surg. 2008;135:421–7.
De Rita F, Hasan A, Haynes S, Crossland D, Kirk R, Ferguson L, et al. Mechanical cardiac support in children with congenital heart disease with intention to bridge to heart transplantation. Eur J Cardiothorac Surg. 2014;46:656–62.
Shah NR, Lam WW, Rodriguez FH, Ermis PR, Simpson L, Frazier OH, et al. Clinical outcomes after ventricular assist device implantation in adults with congenital heart disease. J Heart Lung Transplant. 2013;32:615–20.
Maxwell BG, Wong JK, Sheikh AY, Lee PH, Lobato RL. Heart transplantation with or without prior mechanical circulatory support in adults with congenital heart disease. Eur J Cardiothorac Surg. 2014;45:842–6.
Joyce DL, Crow SS, John R, St Louis JD, Braunlin EA, Pyles LA, et al. Mechanical circulatory support in patients with heart failure secondary to transposition of the great arteries. J Heart Lung Transplant. 2010;29:1302–5.
Maly J, Netuka I, Besik J, Dorazilova Z, Pirk J, Szarszoi O. Bridge to transplantation with long-term mechanical assist device in adults after the Mustard procedure. J Heart Lung Transplant. 2015;34:1177–81.
Morales DLS, Adachi I, Heinle JS, Fraser CD Jr. A new era: use of an intracorporeal systemic ventricular assist device to support a patient with a failing Fontan circulation. J Thorac Cardiovasc Surg. 2011;142:e138–40.
Prêtre R, Häussler A, Bettex D, Genoni M. Right-sided univentricular cardiac assistance in a failing Fontan circulation. Ann Thorac Surg. 2008;86:1018–20.
Derk G, Laks H, Biniwale R, Patel S, De LaCruz K, Mazor E, et al. Novel techniques of mechanical circulatory support for the right heart and Fontan circulation. Int J Cardiol. 2014;176:828–33.
Riemer RK, Amir G, Reichenbach SH, Reinhartz O. Mechanical support of total cavopulmonary connection with axial flow pump. J Thorac Cardiovasc Surg. 2005;130:351–4.
Horne D, Conway J, Rebeyka IM, Bouchholz. Mechanical circulatory support in univentricular hearts: current management. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2015;18:17–24.
Gondolfo F, Brancaccio G, Donatiello S, Filippelli S, Perri G, Iannace E, et al. Mechanically assisted to total cavopulmonary connection with an axial flow pump: computational and in Vivo study. Artif Organs. 2016;40:43–9.
Haggerty CM, Fynn-Thompson F, McElinney DB, Valente AM, Saikrishnan, Del Nido PJ, et al. Experimental and numeric investigation of Impella pumps as cavopulmonary assistance for failing Fontan. J Thorac Cardiovasc Surg. 2012;144:563–9.
Shimizu S, Kawada T, Une D, Fukumitsu M, Turner MJ, Kamiya A, et al. Partial cavopulmonary assist from the inferior vena cava to the pulmonary artery improves hemodynamics in failing Fontan circulation: a theoretical analysis. J Physiol Sci. 2016;66:249–55.
Adachi I, Burki S, Zafar F, Morales DL. Pediatric ventricular assist devices. J Thorac Dis. 2015;7:2194–202.
Gelow JM, Song HK, Weiss JB, Mudd JO, Broberg CS. Organ allocation in adults with congenital heart disease listed for heart transplant: impact of ventricular assist devices. J Heart Lung Transplant. 2013;32:1059–64.
Meyer DM, Rogers JG, Edwaards LB, Callahan ER, Webber SA, Johnson MR, et al. The furure direction of the adult heart allocation system in the US. Am J Transplant. 2015;15:45–54.
Rogers JG. Changes in US heart allocation: a community energized to improve policy. J Thorac Cardiovasc Surg 2016;1484–1486.
Matsuda H, Fukushima N, Sawa Y, Nishimura M, Matsumiya G, Shirakura R. First brain dead donor heart transplantation under new legislation in Japan. Jpn J Thorac Cardiovasc Surg. 1999;47:499–505.
Nakatani T, Fukushima N, Ono M, Saiki Y, Matsuda H, Nunoda S, et al. The Registry Report of Heart Transplantation in Japan (1999–2014). Cir J. 2016;80:44–50.
Tanoue Y, Jinzai Y, Tominaga R. Jarvik 2000 axial-flow ventricular assist device placement to a systemic morphologic right ventricle in congenitally corrected transposition of the great arteries. J Artif Organs. 2016;19:97–9.
Ohuchi H, Kagisaki K, Miyazaki A, Kitano M, Yazaki S, Sakaguchi H, 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.
Nakano T, Kado H, Tatewaki H, Hinokiyama K, Oda S, Ushinohama H, et al. Results of extracardiac conduit total cavopulmonary connection in 500 patients. Eur J Cardiothorac Surg. 2015;48:825–32.
Hoashi T, Ichikawa H, Fukushima N, Ueno T, Kogaki S, Sawa Y. Long-term clinical outcome of atrial isomerism after univentricular repair. J Cardiac Surg. 2009;24:19–23.
Sakamoto T, Nagashima M, Hiramatsu T, Matsumura G, Park IS, Yamazaki K. Fontan circulation over 30 years. What should we learn from those patients? Asian Cardiovasc Thorac Ann. 2016;24:765–71.
Ozawa H, Ueno T, Iwai S, Kawata H, Nishigaki K, Kishimoto H, et al. Contractility-afterload mismatch in patients with protein-losing enteropathy after the Fontan operation. Pediatr Cadiol. 2014;35:1225–31.
Gurvitz M, Burns KM, Brindis R, Broberg CS, Daniels CJ, Fuller SM, et al. Emerging research directions in adult congenital heart disease. A report from an NHLBI/ACHA Working Group. J Am Coll Cardiol. 2016;67:1956–64.
d’Udekem Y, Iyengar AJ, Galati JC, Forsdick V, Weintraub RG, Wheaton GR, 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.
Schilling C, Dalziel K, Nunn R, Du Plessis K, Shi WY, Celermajer D, et al. The Fontan epidemic: population projections from the Australia and New Zealand Fontan Registry. Int J Cardiol. 2016;219:14–9.
Jaquiss H, Aziz H. Is four stage management the future of univentricular hearts? Destination therapy in the young. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2016;19:50–4.
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The authors have declared that no conflict of interests exists.
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Matsuda, H., Ichikawa, H., Ueno, T. et al. Heart transplantation for adults with congenital heart disease: current status and future prospects. Gen Thorac Cardiovasc Surg 65, 309–320 (2017). https://doi.org/10.1007/s11748-017-0777-x
- Adult congenital heart disease
- Heart transplantation
- Failed Fontan
- Ventricular assist device
- Organ allocation system