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Original research article
Successful cardiac transplantation outcomes in patients with adult congenital heart disease
  1. Jonathan N Menachem1,
  2. Jessica R Golbus2,
  3. Maria Molina3,
  4. Jeremy A Mazurek1,
  5. Nicole Hornsby1,
  6. Pavan Atluri3,
  7. Stephanie Fuller4,
  8. Edo Y Birati1,
  9. Yuli Y Kim1,
  10. Lee R Goldberg1,
  11. Joyce W Wald1
  1. 1 Division of Cardiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  2. 2 Division of Cardiology, University of Michigan, Ann Arbor, Michigan, USA
  3. 3 Department of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  4. 4 Division of Cardiothoracic Surgery, Department of Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Jonathan N Menachem, Hospital of the University of Pennsylvania, Perelman Center for Advanced Medicine, South Pavilion, 11th Floor, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA; jonathan.menachem{at}uphs.upenn.edu

Abstract

Objectives The purpose of our study is (1) to characterise patients with congenital heart disease undergoing heart transplantation by adult cardiac surgeons in a large academic medical centre and (2) to describe successful outcomes associated with our multidisciplinary approach to the evaluation and treatment of adults with congenital heart disease (ACHD) undergoing orthotopic heart transplantation (OHT).

Background Heart failure is the leading cause of death in patients with ACHD leading to increasing referrals for OHT.

Methods The Penn Congenital Transplant Database comprises a cohort of patients with ACHD who underwent OHT between March 2010 and April 2016. We performed a retrospective cohort study of the 20 consecutive patients. Original cardiac diagnoses include single ventricle palliated with Fontan (n=8), dextro-transposition of the great arteries after atrial switch (n=4), tetralogy of Fallot (n=4), pulmonary atresia (n=1), Ebstein anomaly (n=1), unrepaired ventricular septal defect (n=1) and Noonan syndrome with coarctation of the aorta (n=1).

Results Eight patients required pretransplant inotropes and two required pretransplant mechanical support. Nine patients underwent heart–liver transplant and three underwent heart–lung transplant. Three patients required postoperative mechanical circulatory support. Patients were followed for an average of 38 months as of April 2016, with 100% survival at 30 days and 1 year and 94% overall survival (19/20 patients).

Conclusions ACHD–OHT patients require highly specialised, complex and multidisciplinary healthcare. The success of our programme is attributed to using team-based, patient-centred care including our multidisciplinary staff and specialists across programmes and departments.

  • Heart transplantation
  • Congenital heart disease

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Introduction

Eighty-five per cent of children with congenital heart disease (CHD) reach adulthood with morbidity and mortality attributed most commonly to heart failure. In fact, heart failure is the leading cause of death in adults with congenital heart disease (ACHD) leading to increasing referrals for orthotopic heart transplantation (OHT).1–3

The challenge of transplantation in the ACHD population includes the fact that ACHD is a multi systemic disease, and renal, pulmonary, and hepatic dysfunction, as well as the effects of chronic cyanosis in a subset of patients, can lead to many immediate postoperative complications, as well as a long-term concerns.4 Furthermore, ‘heart transplant specialists (HTx) face the challenge of determining eligibility for advanced Heart Failure (HF) treatments among an increasingly complex population of CHD patients in whom guidelines for HTx and mechanical circulatory support are scant’.5

There remain little data to support best practices prior to transplant as well as its optimal timing. Thus, patients with ACHD undergo transplantation less frequently than those without. So, the ‘close interaction of ACHD programmes with adult heart failure programmes will be necessary in upcoming years to ensure a structured approach to end-stage heart failure in ACHD, and ideally, an early approach to consideration for listing for transplantation when appropriate.’6

The purpose of our study is (1) to characterise patients with CHD undergoing heart transplantation by adult cardiac surgeons in a large academic medical centre and (2) to describe successful outcomes associated with our multidisciplinary approach to the evaluation and treatment of ACHD undergoing OHT.

Methods

The Penn Congenital Transplant Database comprises a cohort of patients with ACHD who underwent OHT between March 2010 and April 2016. The database includes demographics, preoperative and postoperative haemodynamics, surgical data as well as donor information. We performed a retrospective cohort study of the 20 consecutive patients contained within this database.

Patient population

Demographic data were collected with respect to patient’s age, gender, ethnicity, weight, and medications. Preoperative data included congenital diagnosis and current anatomy, medical comorbidities, laboratory data, invasive haemodynamics, need for inotropes or mechanical circulatory support and listing status. Operative data included location of hospital, surgeon, number of prior surgeries, donor ischaemic time, cardiopulmonary bypass time and total operative time.

Care environment

Patients were evaluated by a multidisciplinary team of adult and paediatric subspecialists. All operations were performed by an adult transplant surgeon with congenital surgical consultation within an adult hospital. Adult cardiac anaesthesia teams were used with each case. Perioperatively, patients were comanaged by HTx, ACHD, cardiac surgery teams, cardiac surgical intensivists (cardiac anaesthesia), and, when indicated, hepatology, infectious disease, pulmonary and renal teams at an adult hospital.

Institutional review board

Institutional review board approval was obtained and individual patient consent was obtained.

Results

Characteristics of patients

Patients were transplanted at a median age of 40 years (range, 23–57 years) (table 1). Thirty-five per cent of subjects were male (n=7), 75% Caucasian (n=15) and 15% African-American (n=3). Original cardiac diagnoses include single ventricle palliated with Fontan (n=8), dextro-transposition of the great arteries after atrial switch (n=4), tetralogy of Fallot (n=4), pulmonary atresia (n=1), Ebstein anomaly (n=1), unrepaired ventricular septal defect (n=1) and Noonan syndrome with coarctation of the aorta and pulmonary hypertension (n=1). One patient had diabetes mellitus, one had hypertension, two had been on dialysis and six had a previous history of tobacco use. None of the patients had hyperlipidaemia. All nine patients who underwent heart–liver transplantation had cirrhosis or fibrosis and three of the eight patients who underwent Fontan had protein-losing enteropathy (PLE). Eight patients were listed for transplant United Network for Organ Sharing (UNOS) status 1A or 1Ae and 13 patients were not allosensitised (calculated panel reactive antibody=0%) (table 2). Eleven patients were listed either UNOS status 1A or 1B by exception as they were not otherwise eligible based on the current UNOS criteria.

Table 1

Demographics

Table 2

Preoperative characteristics

Transplant outcomes

Three patients who underwent heart–lung transplant had never undergone prior open-heart surgical procedures (table 2). Fifteen patients had at least two previous cardiac surgeries. Eight patients required pretransplant inotropes and two required pretransplant mechanical support. Nine patients underwent heart–liver transplant and three underwent heart–lung transplant. Median ischaemic time was 211 min and median bypass time was 221 min. Three patients, two of which underwent heart–lung transplants, required postoperative mechanical circulatory support. Patients were followed for an average of 38 months as of April 2016, with 100% survival at 30 days and 1 year and 94% overall survival (19/20 patients). One death due to infection occurred at 23 months post-transplant in a patient with a previous atrial switch operation.

Discussion

Heart transplantation has been an underused therapy in failing patients with ACHD due to early postoperative risk leading to poor patient outcomes. However, if this early risk can be mitigated, these patients have been shown to have a median life expectancy, conditioned on survival to year 1, of 18 years.5 As such, despite the early risks previously reported, our series demonstrates that with strong collaboration, evaluation and meticulous planning early failures can be mitigated (figure 1).

Figure 1

The ACHD to transplantation process.  *Consultants:  hepatology, infectious disease, nephrology, pulmonology, immunology laboratory and toxicology. Transplant staff: social work, financial coordinators and nutrition. ACHD, adult congenital heart disease; CHD, congenital heart disease; CT, cardiothoracic; HF, heart failure; HTx, heart failure/transplant; NP, nurse practitioner; OHT, orthotopic heart transplantation.

Prelisting

Within the ACHD and HTx community, there is the belief that we often ‘miss the window’ to transplant patients as the onset of symptoms is often closely coupled with end-organ dysfunction, significantly increasing the risk of transplantation. Recognising cardiac decompensation, however, is challenging as patients with ACHD differ pathophysiologically from those with normal cardiac anatomy. Typical prognostic indicators such as exercise intolerance, progressive cyanosis and peak VO2 have not been validated in order to signal appropriate timing.6 As we have yet to identify predictors of impending mortality, our institution has moved towards a proactive multidisciplinary approach to the evaluation of patients with ACHD in this ‘grey zone’—those who are momentarily too healthy for transplant but in whom we anticipate a future need for transplantation or mechanical circulatory support.

Our ACHD team, comprised both paediatric and adult medical and surgical specialists, holds bimonthly meetings to discuss medical and surgical management of complicated patients with ACHD. We have HTx specialists who jointly manage these patients and participate in the meetings as well. We have found that this provides a unique perspective and earlier HTx consideration, in line with current recommendations from the American Heart Association.5 Anecdotally, we believe this early involvement has led to improvements in prediction strategies and appropriate patient selection.

Listing

Transplant listing for our patients without CHD starts with a formal presentation by the HTx team to a committee of medical and surgical transplant physicians, social workers and nurses similar to many institutions. Our patients with ACHD are presented to the committee jointly by the HTx and ACHD teams. We believe our multidisciplinary approach to transplant listing has unique advantages in this population. First, it enhances our understanding of these patients’ unique pathophysiology and the associated medical risks such as PLE, complex collateral circulation and early hepatic congestion. Second, it allows for a preliminary discussion of the surgical considerations given these patients’ unique anatomy.

There is a perception of increased post-transplant morbidity and mortality in patients with ACHD which often delays or discourages listing of patients.7 Our prelisting collaboration has enhanced both our medical and surgical understanding of ACHD, allowing us to be confident in successful outcomes for the patients who have been listed. Since 2010, we have formally evaluated 41 patients with CHD for transplantation (table 3). Twenty-six patients have been listed with 20 proceedings to transplantation. Of the 15 who were turned down, the largest proportion was patients with single ventricle physiology. As with patients without CHD, the main reasons for ineligibility were surgical risk, additional medical comorbidities, and social non-compliance or lack of social support. The surgical risks were most commonly due to a high burden of collateral circulation. Medical comorbidities were mainly due to multisystem organ dysfunction. Not captured in the 41 patients evaluated are those patients who were followed by ACHD who were never formally presented to the joint team due to medical issues or patient preference not to be considered for transplant. A description of the 20 consecutive patients transplanted is shown in table 4.

Table 3

Patient evaluations

Table 4

Patient diagnosis and transplant type

Methods for listing

Since 1996, the number of patients who are listed status 2 has not changed for patients with CHD, but that percentage has fallen from 66% to 40% in patients without CHD. In the era from 2006 to 2010, there was a significantly higher percentage of patients without CHD upgraded to status 1 than patients with CHD (55% vs 43%).8 While multifactorial, this shift has been driven by multiple changes in the organ allocation policy, including a provision stating that patients with a ventricular assist device (VAD) are listed as status 1B. In addition, patients with VAD receive UNOS status 1A for 30 days to be used at their physician’s discretion or additional status 1A time for any VAD complication. This places patients with ACHD at a disadvantage as use of VAD support is rare in these patients. Additionally, typical metrics such as inotrope dependence or use of mechanical circulatory support do not apply to these patients. A study by Everitt et al 9 based on evaluation of the UNOS database from 2005 to 2009, showed that 36% of patients with ACHD were listed 1A/B compared with 55% of patients without ACHD.9 Fourteen per cent of exemptions requested between July 2009 and 2011 were for patients with ACHD.10

Eight-five per cent (n=17) of our patients were listed 1A/B. Five of the 1A patients were listed by exception and six of the nine 1B patients were listed by exception. While our patients with CHD often do not meet standard criteria for status 1A or 1B listing, we have successfully petitioned UNOS for exception listing in critical circumstances, citing our large body of anecdotal evidence. In our experience, more than 50% of listed patients with ACHD have required an exception in order to undergo transplantation.

Surgical planning

It is standard for both transplant and CHD surgeons to attend and participate in our listing meetings. Pretransplant anatomic considerations include the presence of anomalous pulmonary venous or systemic venous return, abnormal atrial situs or connexions and alterations of pulmonary arteries or aortas that often require reconstruction.11 Prior discussions associated with organ procurement and perioperative implantation unique to the CHD population are essential to minimising complications and reducing ischaemic time. As these patients have undergone multiple procedures and modifications, increased length of donor vessels may be necessary to correct abnormalities of the atria, great vessels, or systemic or pulmonary venous return.7

There are a variety of opinions regarding which specific surgeons should implant the donor heart in the complex congenital adult patient. In regard to patients with ACHD, it has been shown that in-hospital mortality is lower when the congenital operations are performed by specialised paediatric heart surgeons with outcomes correlated with the annual percentage of paediatric heart operations performed.12 Recently, data from Mori et al 11 detailed successful transplantation in an ACHD population undergoing surgery by an adult congenital cardiac surgeon. In contrast, Goldberg et al 6 have suggested that survival is improved if the transplant is performed at a high-volume centre that performs paediatric transplant with access to paediatric heart transplant teams. Our transplants were performed at a high-volume adult transplant centre by adult transplant surgeons with consultation and surgical assistance of our CHD surgeons. The patients recovered in the adult cardiothoracic intensive care unit and adult surgical/medical wards. We feel this is the best method of treatment for these patients. However, we agree with Mori et al that meticulous care and cooperation are essential to success and believe that there are significant benefits postoperatively if the surgery is completed at an adult hospital.

Preoperative management

It would be incorrect to assume that patients with ACHD awaiting transplant are like our patients without CHD. Prior to transplant, these patients similarly require close haemodynamic monitoring and laboratory evaluation, which we have found is best managed jointly by the HTx and ACHD teams. Most heart failure specialists lack a full appreciation of the complex congenital physiology and pretransplant haemodynamics. In non-CHD transplants, accurately evaluating, interpreting and treating elevated pulmonary vascular resistance (PVR) is challenging. In patients with ACHD, this is further complicated by anatomic alterations. Accuracy of calculations is often impossible due to anomalies of the pulmonary vasculature or dual supplies of pulmonary blood flow. Furthermore, sluggish blood flow to the two pulmonary arteries or loss of hepatic blood flow places patients at risk for microemboli or arteriovenous malformations that may alter the distribution between the right and left lungs, making the PVR variable between the lungs.13

PVR is often measured or interpreted incorrectly in the ACHD population which has the potential for either missed transplant opportunities or postoperative right heart failure.1 While paediatric transplanted hearts may be able to handle elevated PVR, in the adult this has not been replicated.14 One study found a preoperative PVR greater than 4 Wood units was associated with a perioperative mortality of 21%, but with no significant difference in long-term survival based on pretransplantation PVR.15 The average PVR for our patients with ACHD awaiting transplantation was 1.6 Wood units with two patients on pulmonary vasodilators. This excludes the three patients who underwent heart–lung transplantation. None of the patients developed right heart failure necessitating mechanical support. Two of three patients who required postoperative mechanical support were heart–lung transplants. These outcomes support our belief that with collaborative evaluation of PVR, the risk of right heart failure can be mitigated.

Donor selection/ischaemic time

Irving et al 7 have described their practice of using oversized donors in the setting of elevated PVR. This is especially useful in the setting of technically complicated evaluation of PVR. On average, the body surface areaof our donors was 13% above our recipients and the donors were on average 9 years younger. Of the 20 transplants, seven were male donors to female recipients and three were female donors to male recipient transplants.

Additional studies have demonstrated worse outcomes with longer ischaemic times. Lamour found that there was an increase in 1 year mortality from 15% to 40% in a 40-year-old ACHD recipient of a heart from a 50-year-old simply by increasing the ischaemic time from 3 hours to >5 hours.13 Again, the preoperative surgical planning including our harvest team has kept our median ischaemic time to 211 min.

Bystander organ dysfunction

As in non-CHD transplants, thorough evaluation of end-organ dysfunction is essential. With the input of our hepatology team, we plan on a heart and liver transplant for all patients with Fontan physiology who have evidence of liver dysfunction and fibrosis/cirrhosis. While the decision is finalised after visual inspection and pathologic diagnosis of cirrhosis at the time of OHT, all of the patients with Fontan physiology have required combined heart and liver transplantation.

It has been previously documented that post-transplant outcomes in patients who underwent Fontan are worse than their non-Fontan counterparts. One study by Lamour et al 13 reports a 71% 1-year survival of patients who underwent Fontan and 83% in patients who did not undergo Fontan. Five-year survival was 60% in patients who underwent Fontan and 74% in patients who did not undergo Fontan. While 5-year data are not yet available, our 1-year survival was 100%. In addition to PVR, bleeding risk is also a concern in patients with Fontan physiology. It has been postulated that the addition of liver transplant reduces the risk of postoperative hepatic dysfunction and reduces bleeding risk as Fontan-associated liver disease often causes thrombocytopenia, mild elevation in the international normalised ratio and clotting factor abnormalities.16 Furthermore, there is growing evidence that cardiac cellular and antibody-mediated rejection is less frequent after heart–liver transplantation possibly allowing for reduced immunosuppression when necessary.17

Perioperative management

Beyond the complicated nature of the haemodynamic management and surgical preparation, the immediate perioperative period is perhaps the most tenuous and potentially morbid. The benefits of transplant at large centres are often underappreciated. These include the care patients receive from cardiac intensivists (cardiac anaesthesia) as well as from cardiac nurses who have been exposed to hundreds of cardiac surgeries, specifically cardiac transplants. Since 2010, our institution has completed >300 cardiac transplants. The experience our team has with perioperative complications is challenging to quantify though has undeniably led to positive outcomes when it comes to patients with ACHD undergoing transplant.

Postoperative management

In the postoperative setting, the ACHD team is available for consultative input but does not typically follow these patients. The management falls most heavily on HTx physicians and nurse practitioners. At our institution, this team is responsible for managing approximately 850 active patients from the time of transplant evaluation to the early perioperative phase through the remainder of their lifespan post-transplant. The coordination of consultative teams, immunosuppressive management as well as treatment of comorbidities is led by the HTx group as this is the group with the greatest experience in this area.

Limitations

This study is limited by its observational, retrospective single-centre nature. It is further limited by the small number of patients who underwent cardiac transplantation.

Conclusions

Adult congenital heart transplant patients are a challenging population which requires highly specialised, complex and multidisciplinary healthcare across the transition from acute inpatient illness to recovery and outpatient care. Our programme is a university-based, large-volume centre with over 25 years of heart transplant experience including cardiologists, surgeons, nurses, pharmacists and social workers, as well as an extended team within the transplant institute including hepatology, infectious disease, nephrology, pulmonology, immunology lab, toxicology and many others who all contribute to our outcomes. The success of our programme is attributed to using team-based, patient-centred care including our multidisciplinary staff and specialists across programmes and departments.

Key messages

What is already known on this subject?

There are limited current data regarding timing and transplanting patients with complex ACHD. To our knowledge, this is the largest recent single-centre study published describing transplantation in congenital heart patients.

What might this study add?

This study adds to an area within the literature in which there is a paucity of data regarding transplantation in failing adult congenital patients. We describe successful transplantation outcomes in 20 consecutive complex congenital patients.

How might this impact on clinical practice?

Beginning at our 2016 American College of Cardiology presentation we began seeing the far reaching impact this would have on the lives of failing congenital patients. New evaluations and collaborations with transplant centres across the country began. It is our belief that this paper will help foster continued discussion within the community and lead to successful outcomes in a very challenging and high-risk patient population.

References

Footnotes

  • Competing interests None declared.

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

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