Risk Factors for Survival After Heart Transplantation in Children and Young Adults: A 22-Year Study of 179 Transplants

Abstract

Background:

This article reviews all patients who underwent heart transplantation (HTx) within a single institution (172 patients underwent 179 HTx [167 first-time HTxs, 10 second HTxs, 2 third HTxs]) to describe diagnostic characteristics, management protocols, and risk factors for mortality.

Methods:

Descriptive analysis was performed for the entire cohort using mean, standard deviation, median, interquartile range, and overall range, as appropriate. Univariable and multivariable Cox proportional hazards models were performed to identify prognostic factors for outcomes over time. The primary outcome of interest was mortality, which was modeled by Kaplan-Meier analysis.

Results:

Median age at HTx was 263 days (range, 5 days to 24 years; mean = 4.63 ± 5.95 years; 18 neonates, 79 infants). Median weight at HTx was 7.5 kg (range, 2.2-113 kg; mean = 19.36 ± 23.54). Diagnostic categories were cardiomyopathy (n = 62), primary transplantation for hypoplastic left heart syndrome (HLHS) or HLHS-related malformation (n = 33), transplantation after cardiac surgery for HLHS or HLHS-related malformation (n = 17), non-HLHS congenital heart disease (n = 55), and retransplant (n = 12). Operative mortality was 10.1% (18 patients). Cumulative total follow-up is 1,355 years. Late mortality was 18.4% (33 patients). Overall Kaplan-Meier five-year survival was 76.2%. One hundred twenty-one patients are alive with a mean follow-up of 7.61 ± 6.46 years. No survival differences were seen among the five diagnostic subgroups (P = .064) or between immunosensitized patients (n = 31) and nonimmunosensitized patients (n = 141; P = .422).

Conclusions:

Excellent results are expected for children undergoing HTx with comparable results among diagnostic groups. Pretransplant mechanical circulatory support and posttransplant mechanical circulatory support are risk factors for decreased survival. Survival after transplantation for HLHS or HLHS-related malformation is better with primary HTx in comparison to HTx after prior cardiac surgery.

Keywords

transplantation heart hypoplastic left heart syndrome cardiomyopathy ECMO (extracorporeal membrane oxygenation)circulatory assist devices (LVAD RVAD BVAD TAH)

Introduction

The care of pediatric and congenital cardiac patients undergoing heart transplantation (HTx) continues to evolve. At Johns Hopkins All Children’s Hospital (JHACH), we performed our first heart transplant on June 19, 1995. We have previously published analyses of selected subsets of the 172 patients in the current report (who underwent 179 HTx at JHACH through June 2017).^1

–5 As our team gained experience with HTx, our strategies of immunosuppression evolved, and we began offering HTx to patients with diagnoses and factors thought to be associated with higher risk, including patients with elevated panel reactive antibody (PRA)¹, patients with hypoplastic left heart syndrome (HLHS) who have failed previous surgical intervention², and patients bridged to HTx with mechanical circulatory support devices including extracorporeal membrane oxygenation (ECMO) and ventricular assist device (VAD). In 2004, we published our initial experience with HTx in immunosensitized patients with elevated PRA (defined as PRA >10%) and reported that although HTx can offer children with end-stage heart failure and elevated PRA their only chance of survival, overall survival after HTx seems to be worse for those patients with an elevated PRA compared with those without elevated PRA.¹ In 2006, we published our initial experience with HTx as treatment for failing staged palliation in patients with HLHS and reported that although HTx could offer children with failing staged palliation of HLHS their only chance of survival, HTx carries a higher risk in this subgroup, especially in the setting of elevated PRA.² In 2011, we published a review of all patients who underwent HTx at our program during its first 14 years (1995-2009), a cohort at that time of 116 patients who underwent 119 HTx as treatment for pediatric and congenital heart disease. This previous analysis of 119 transplants identified the following risk factors for inferior survival: (1) pretransplant mechanical circulatory support, (2) posttransplant mechanical circulatory support, (3) cardiopulmonary bypass time, (4) donor heart ischemic time, and (5) heterotaxy. Of note, in this 2011 publication, elevated PRA no longer appeared to be a significant risk factor, and retransplantation was not a risk factor. Once again, survival after transplantation after prior cardiac surgery for HLHS or HLHS-related malformation appeared to be worse than survival after primary transplantation for HLHS or HLHS-related malformation.

In our previous publications, no formal adjustment for multiple comparisons was made. Given the small number of patients and deaths, multivariable analyses were not considered stable and were not performed. Our current article includes multivariable analyses and reviews our first 179 consecutive HTxs over a 22-year period from June 1995 to June 2017, a cohort of 172 patients who underwent HTx as treatment for pediatric and congenital cardiac disease. The purpose of this article is to describe the diagnostic characteristics and management protocols of all patients who underwent HTx at our institution and to assess risk factors for mortality in this updated cohort.

Methods

Diagnostic Classification

Transplants were classified into five diagnostic categories: cardiomyopathy, primary HTx for HLHS or HLHS-related malformation, HTx after prior cardiac surgery for HLHS or HLHS-related malformation, non-HLHS congenital heart disease, and retransplant.

Operative Technique

Operative technique involved bicaval cannulation and anastomoses with continuous cardiopulmonary bypass and either short periods of circulatory arrest or continuous antegrade cerebral perfusion for aortic arch reconstruction in HLHS. The bicaval implantation technique was used with a superior vena caval reconstruction with a spatulated sliding cavoplasty or a patch cavoplasty to prevent narrowing.

Protocol for Immunosuppression and Surveillance

Before 2005, PRA was determined using cytotoxic PRA assay and dithiothreitol-treated assay to factor out immunoglobulin M and enhance the detection and measurement of immunoglobulin G (IgG). We now assess PRA by flow cytometry using the Luminex single antigen bead method. Our current protocols for immunosuppression were instituted in 2006; prior to 2006, somewhat different protocols were utilized, as described below.

For patients without high PRA, our protocol for immunosuppression before 2006 was as follows: induction immunosuppressive therapy included pulse steroids for four days, gamma globulin, and polyclonal rabbit antithymocyte globulin. Initial immunosuppression was a double dose regimen: a calcineurin inhibitor (cyclosporin A or tacrolimus [Prograf], usually cyclosporin A) and an antiproliferative agent (either azathioprine [Imuran] or mycophenolate mofetil [MMF] to target levels of 2 to 4).

For patients with high PRA, our protocol for immunosuppression before 2006 was as follows: preoperative intravenous IgG was given weekly or preoperative cyclophosphamide (Cytoxan) or MMF was given daily from the time of listing until the time of transplantation. Preoperative and postoperative (up to five days) exchange transfusions (infants) or plasmapheresis (children) was used. Also, cyclophosphamide (Cytoxan; 1 mg/kg/d) was the initial antiproliferative agent with conversion to MMF when oral intake was established.

For patients without high PRA, our current protocol for immunosuppression includes the following regimens for induction and maintenance: for induction, a standard Solu-Medrol pulse is administered at a dose of 10 mg/kg per dose every 12 hours for eight doses. Also, Thymoglobulin is administered at a dose of 0.5 to 1 mg/kg for five days, except for patients with suspected infection or delayed sternal closure who receive two doses of Basiliximab instead. For maintenance, tacrolimus and MMF (MMF-CellCept; Roche Laboratories, Nutley, New Jersey) are used. (Cyclosporin is used for maintenance in patients who do not tolerate tacrolimus, and sirolimus or everolimus is used for maintenance in patients who do not tolerate MMF.) Also, oral prednisolone or prednisone is given at a dose of 1 mg/kg per dose twice daily for two weeks with weaning during the first two to three months.

For patients with high PRA, our current protocol for immunosuppression includes the following regimens for preinduction, induction, and maintenance: Preinduction is performed while patients are on the waiting list, from the time of listing until the time of transplantation, and includes two components (1) potential recipients are given monthly intravenous IgG and (2) potential recipients undergo plasmapheresis every 48 hours up to five rounds. Perioperative and postoperative (up to five rounds) exchange transfusions (infants) or plasmapheresis (children) is also used. Then, patients with high PRA receive the same induction and maintenance as those without high PRA. We reserve the administration of rituximab for patients with high PRA who also have high titers or high mean fluorescent intensity (MFI) of individual anti-human leukocyte antigen (HLA) preformed antibodies before transplant, or patients who have rapidly rising donor-specific antibody titers after transplant, or patients with positive retrospective crossmatch. This protocol for patients with high PRA has been shown to lead to a significant decrease in PRA after desensitization.⁵

Rejection surveillance was conducted by echocardiography, with the timing of right ventricular endomyocardial biopsies guided by echocardiographic findings, as previously described,^6

–10 and protocol-timed biopsies. Echocardiographic surveillance of systolic and diastolic function predicts biopsy abnormalities and decreases the number of cardiac catheterizations. Biopsy was performed when the echocardiogram is suggestive of rejection. We also used protocol-timed biopsies at two weeks, three months (after discontinuing steroids), six months, and one year.

Posttransplant retrospective crossmatching was performed for all patients. No prospective crossmatching was performed in our program before 2005. However, since January 2005, we do perform prospective virtual crossmatch on all highly sensitized patients prior to accepting an organ. If possible, we also perform an actual preliminary crossmatch on patients who have high PRA and have a local donor. We will not perform HTx if there is a positive virtual crossmatch unless the avoidable anti-HLA antibodies are low (<1,500 MFI). We have performed HTx in four patients with high PRA who had a negative virtual crossmatch but were found to have a positive retrospective crossmatch.

Statistics and Database

Descriptive analysis was performed for the entire cohort using mean, standard deviation, median, interquartile range, and overall range, as appropriate. Univariable and multivariable Cox proportional hazards models were performed to identify prognostic factors for outcomes over time; overall mortality was the outcome used for the univariable and multivariable analyses. Multivariable models included only significant predictors from univariable models.

The primary outcome was mortality. Operative mortality is defined as (1) all deaths, regardless of cause, occurring during the hospitalization in which the HTx was performed, even if after 30 days (including patients transferred to other acute care facilities) and (2) all deaths, regardless of cause, occurring after discharge from the hospital, but before the end of the 30th postoperative day.^11,12 Deaths that did not meet the definition of operative mortality were described as “late mortality.” The incidence of operative mortality was calculated overall and within subgroups. In Tables 1 to 4, mortality at one and five years is a proportion of those who were eligible for the calculation after having ample elapsed time since the date of HTx. In the figures, the Kaplan-Meier method was used to estimate posttransplant survival probabilities as a function of time since HTx. The unit of analysis for the Cox proportional hazards models was a patient. Other analyses were either based on patients (n = 172) or HTxs (n = 179), as specified in the results. A P value <.05 was considered to be significant. Institutional review board approval and waiver of the need for consent have been obtained (JHACH IRB ID: IRB00106013).

Table 1.

Descriptive Characteristics—Proportional Measures.

	n	Eligible	%
Male	91	179	50.8
Race
White	110	179	61.5
Black	29	179	16.2
Hispanic	34	179	19
Other	6	179	3.4
Age categories
Neonate	18	179	10.1
Infant	79	179	44.1
Child	80	179	44.7
Adult	2	179	1.1
High PRA	35	179	19.6
Pretransplant mechanical support	18	179	10.1
Posttransplant mechanical support	12	179	6.7
Redo sternotomy	73	179	40.8
Heterotaxy	9	179	5
Prior HTx	12	179	6.7
Overall mortality	51	179	28.5
Operative mortality	18	179	10.1
Late mortality	33	179	18.4
Mortality at 1 year	25	173	14.5
Mortality at 5 years	39	138	28.3

Abbreviations: HTx, heart transplantation; PRA, panel reactive antibody.

Table 2.

Descriptive Characteristics—Continuous Measures.

	Mean (SD)	Median	Interquartile Range	Range
Age at transplant (years)	4.63 (5.95)	0.72	0.15-9.00	0-24
Weight (kilograms)	19.36 (23.54)	7.5	4.30-26.00	2.2-113.0
Days on waiting list	44.06 (50.99)	27	11.00-59.00	1-341
Number of prior cardiac operations	1.28 (1.67)	1	0.00-2.00	0-9.0
Cardiopulmonary bypass time (minutes)	162.17 (51.10)	149	124.00-188.00	80-426
Donor heart ischemic time (minutes)	238.18 (69.90)	245	192.00-290.00	77-426
Length of follow-up in years	7.61 (6.46)	6.86	1.77-11.50	0.01-21.95
Cumulative years total follow-up = 1,355

Abbreviation: SD, standard deviation.

Table 3.

Patient Factors and Survival.

	No. of HTxs	Operative Mortality		Late Mortality		1-Year Survival		5-Year Survival
	No. of HTxs	n	%	n	%	n	%	n	%
All transplants	179	18	10.1	33	18.4	148/173	85.5	99/138	71.7
Neonate	18	2	11.1	1	5.6	16/18	88.9	13/15	86.7
Infant	79	9	11.4	16	20.3	61/77	79.2	40/57	70.2
Child	80	7	8.8	16	20.0	69/76	90.8	45/59	76.3
Adult	2	0	0	0	0	2/2	100	1/1	100
High PRA	35	3	8.6	6	17.1	29/33	87.9	14/21	66.7
Pretransplant mechanical support	18	6	33.3	3	16.7	12/18	66.7	8/17	47.1
Posttransplant mechanical support	12	6	50.0	0	0.0	6/12	50.0	3/7	42.9
Redo sternotomy	73	10	13.7	19	26.0	53/68	77.9	32/51	62.7
Heterotaxy	9	2	22.2	2	22.2	5/9	55.6	2/5	40.0
Prior HTx	12	1	8.3	4	33.3	11/12	91.7	4/8	50.0
Intentional ABO incompatible HTx	4	0	0.0	1	25.0	2/3	66.7	None eligible

Abbreviations: HTx, heart transplantation; PRA, panel reactive antibody.

Table 4.

Mortality and Survival Across Diagnostic Subgroups.

	No. of HTxs	Operative Mortality		Late Mortality		1-Year Survival		5-Year Survival
	No. of HTxs	n	%	n	%	n	%	n	%
Cardiomyopathy	62	3	4.8	10	16.1	56/61	91.8	33/40	82.5
HLHS or HLHS-related malformation after primary transplant	33	3	9.1	5	15.1	28/33	84.8	24/29	82.8
HLHS or HLHS-related malformation after prior cardiac surgery	17	4	23.5	4	23.5	10/15	66.7	5/10	50.0
Complex congenital heart disease	55	7	12.7	10	18.2	43/52	82.7	33/45	73.3
Retransplant	12	1	8.3	4	33.3	11/12	91.7	4/8	50.0

Abbreviations: HLHS, hypoplastic left heart syndrome; HTx, heart transplantation.

Results

Patient Characteristics

One hundred seventy-nine consecutive HTxs have been performed in 172 patients. All were orthotopic. The recipients included 18 neonates (0 to 30 days), 79 infants excluding neonates (31 days to 1 year), 80 children (>1 year to <18 years), and two adults with congenital heart disease (18 years and above). All patients in this series were younger than 17 years of age at the time of HTx except for two patients: one patient was 19.5 years at the time of HTx with the diagnosis of pulmonary atresia and intact ventricular septum (who underwent prior biventricular repair and developed late severe biventricular dysfunction) and one patient was 23.8 years old at the time of her third HTx after failed staged palliation for double inlet left ventricle.

Median age at HTx was 263 days (range, 5 days to 24 years; mean = 4.63 +/- 5.95 years). Median weight at HTx was 7.5 kg (range, 2.2 to 113 kg; mean = 19.36 +/- 23.54). Tables 1 and 2 document the descriptive characteristics and basic survival data for all 179 HTx.

The 12 retransplants included 7 retransplants after prior HTx at JHACH and five patients who underwent their initial HTx elsewhere. Ten of these retransplants are second-time HTxs and two are third-time HTxs.

Operative mortality was 10.1% (18 patients). Late mortality was 18.4% (33 patients). One hundred twenty-one patients are alive. Mean follow-up was 7.61 ± 6.46 years. Median follow-up was 6.86 years (range, 2 days to 21.95 years). Cumulative follow-up time was 1,355 years. Overall Kaplan-Meier five-year survival was 76.23%.

Risk Factor Analysis

Table 3 documents patient factors and survival associated with these factors. Several HTxs were in one or more potentially high-risk subgroups: (1) high PRA (defined as PRA >10%; n = 35), (2) patients with HLHS who have failed previous surgical intervention (n = 17), (3) pretransplant mechanical circulatory support (n = 18), (4) posttransplant mechanical circulatory support (n = 12), (5) retransplantation (n = 12), and (6) intentional ABO-incompatible HTx (n = 4). One patient died after intentional ABO-incompatible HTx on postoperative day 325 after aspiration at home.

Of the 18 HTxs associated with pretransplant mechanical circulatory support, 10 (55.6%) were managed exclusively with pretransplant ECMO, 5 (27.8%) exclusively with pretransplant VAD, 2 (11.1%) with both pretransplant ECMO and pretransplant VAD (2 patients with ECMO were transitioned to the Berlin Heart [EXCOR]), and 1 (5.6%) exclusively with pretransplant intra-aortic balloon pump. Of the seven patients supported pretransplant with VAD, four were supported with Berlin Heart and three were supported with Abiomed. Of the 12 transplants associated with posttransplant mechanical circulatory support, 10 (83.3%) of 12 were placed on ECMO, while 2 (16.7%) of 12 were placed on VAD.

Several HTxs belonged to more than one high-risk group. For example, many of the patients undergoing HTx after prior cardiac surgery for HLHS or HLHS-related malformation also had high PRA.

Table 4 stratifies the 179 HTxs into five diagnostic subgroups and reports operative mortality, late mortality, and one- and five-year survival. In the second half of the 1990s, our program used both primary HTx and staged palliation as treatment for HLHS.¹³ Currently, the overwhelming majority of our patients with HLHS and HLHS-related malformations are treated with staged palliation via the ‘Norwood’ approach; we now only use primary HTx for HLHS very selectively for specific indications. We now selectively offer HTx for HLHS in the setting of significant ventricular dysfunction, severe atrioventricular or ventriculoarterial valvar regurgitation, severe ventricle to coronary artery fistulas with ventricular-dependent coronary circulation,¹⁴ strong family preference, and for patients experiencing failure at any point in the process of staged palliation. Between 1995 and 2002, inclusive, 21 patients underwent primary HTx as treatment for HLHS or HLHS-related malformation; between 2003 and 2009, inclusive, only 8 patients underwent primary HTx as treatment for HLHS or HLHS-related malformation; and, between 2010 and 2017, inclusive, only 4 patients underwent primary HTx as treatment for HLHS or HLHS-related malformation. Meanwhile, between 1995 and 2002, inclusive, 105 patients underwent the Norwood procedure; between 2003 and 2009, inclusive, 136 patients underwent the Norwood procedure; and between 2010 and 2017, inclusive, 80 patients underwent the Norwood procedure.

Univariable analysis revealed the following risk factors for mortality: pretransplant mechanical support (P = .017), posttransplant mechanical support (P = .008), redo sternotomy (P = .004), prior HTx (P = .047), number of prior cardiac operations (P = .000), and donor heart ischemic time (P = .029; Table 5). Multivariable analyses revealed that only posttransplant mechanical support (P = .003) was a risk factor for mortality (Table 6). As a sensitivity analysis, the multivariable analysis was repeated with the exclusion of posttransplant mechanical support, because posttransplant mechanical support may be treated as an outcome variable in some analyses; in this sensitivity analysis, only pretransplant mechanical support (P = .035) was a risk factor for mortality (Table 7).

Table 5.

Univariable Cox Proportional Hazards Models.

	Hazard Ratio (95% CI)	P Value
Age at transplant	1.02 (0.98-1.07)	.361
Weight	1.00 (0.99-1.02)	.501
Gender (male)	1.38 (0.78-2.45)	.266
Race (white)	1.57 (0.81-3.04)	.186
High PRA	1.35 (0.65-2.80)	.424
Pretransplant mechanical support	2.42 (1.17-5.01)	.017
Posttransplant mechanical support	3.22 (1.36-7.60)	.008
Redo sternotomy	2.31 (1.31-4.06)	.004
Prior HTx	3.32 (1.02-10.81)	.047
Heterotaxy	2.33 (0.84-6.51)	.106
Days on waiting list	1.00 (0.99-1.01)	.652
Number of prior cardiac operations	1.34 (1.16-1.56)	.000
Cardiopulmonary bypass time	1.00 (0.99-1.01)	.091
Donor heart ischemic time	1.01 (1.00-1.01)	.029
ABO incompatibility	1.67 (0.23-12.33)	.616

Abbreviations: CI, confidence interval; HTx, heart transplantation; PRA, panel reactive antibody.

Table 6.

Multivariable Cox Proportional Hazards Models.

	Hazard Ratio (95% CI)	P Value
Pretransplant mechanical support	1.88 (0.88-4.01)	.103
Posttransplant mechanical support	3.96 (1.58-9.92)	.003
Redo sternotomy	1.57 (0.75-3.28)	.229
Prior HTx	2.62 (0.77-8.93)	.122
Number of prior cardiac operations	1.20 (0.98-1.47)	.081
Donor heart ischemic time	1.00 (1.00-1.01)	.074

Abbreviations: CI, confidence interval; HTx, heart transplantation.

Table 7.

Multivariable Cox Proportional Hazards Models Excluding Posttransplant Mechanical Support.

	Hazard Ratio (95% CI)	P Value
Pretransplant mechanical support	2.23 (1.06-4.72)	.035
Redo sternotomy	1.38 (0.66-2.87)	.387
Prior HTx	2.51 (0.74-8.55)	.141
Number of prior cardiac operations	1.19 (0.96-1.46)	.109
Donor heart ischemic time	1.00 (1.00-1.01)	.065

Abbreviations: CI, confidence interval; HTx, heart transplantation.

Kaplan-Meier Survival Analyses

Figure 1 shows overall survival of all 172 patients with a Kaplan-Meier analysis of patient survival from the time of our first HTx at JHACH. Overall Kaplan-Meier five-year survival was 76.23%.

Figure 2 documents the Kaplan-Meier analysis of patient survival stratified by diagnostic category: cardiomyopathy (n = 62), primary transplantation for HLHS or HLHS-related malformation (n = 33), transplantation after prior cardiac surgery for HLHS or HLHS-related malformation (n = 17), non-HLHS congenital heart disease (n = 55), and retransplant (n = 12). This figure demonstrates that survival is not statistically different in these five diagnostic groups (log-rank P = .064). These analyses were performed at the transplant level for 179 transplants.

Figure 3 documents the Kaplan-Meier analysis of patient survival by diagnostic category only for patients with the diagnosis of HLHS or HLHS-related malformation (n = 50) and compares primary HTx (n = 33) with HTx after prior cardiac surgery (n = 17). This figure documents that survival after HTx after prior cardiac surgery for HLHS or HLHS-related malformation appears to be worse than survival after primary transplantation for HLHS or HLHS-related malformation (log-rank P = .043).

Figure 4 documents the Kaplan-Meier analysis of patient survival for all patients comparing patients with high PRA (n = 31) with patients without high PRA (n = 141) and demonstrates no significant increase in risk for patients with high PRA (log-rank P = .422). (Patients who underwent retransplantation are only shown in this figure for their initial transplant.) We previously reported a subset of eight patients with PRA >50%, including four patients with PRA >90%⁵; seven of these eight patients are alive and doing well. The only death was a patient with PRA of 99% who developed rejection due to medication noncompliance. This patient underwent HTx at age 14 and had no rejection for the first four years (when her mother administered her medications). But, when she turned 18 years old, her mother gave her control of her medications, and that is when she developed rejection. Additional causes of death in the high PRA group include one patient with coronary vasculopathy, one patient with cellular rejection, and one infant with a history of seizure who died during sleep—we believe from seizure.

Figure 5 documents the Kaplan-Meier analysis of patient survival for all patients comparing survival in patients undergoing primary HTx (n = 167) with those undergoing retransplantation (n = 12) and documenting no statistically significant increase in risk for those undergoing retransplantation (log-rank P = .248). This statistical finding may be due to the wide confidence intervals associated with the small sample size for the retransplant group. (This analysis is performed at the transplant level for 179 transplants.)

Comment

Excellent results are expected for children undergoing HTx regardless of diagnostic classification. Pretransplant mechanical circulatory support and posttransplant mechanical circulatory support are risk factors for inferior survival. Survival after transplantation after prior cardiac surgery for HLHS or HLHS-related malformation is worse than survival after primary transplantation for HLHS or HLHS-related malformation.

In 2004, we published that HTx can offer children with end-stage heart failure and elevated PRA their only chance of survival; however, these patients remain at high risk despite aggressive immunosuppression.¹ In this report from 2004, 30-day mortality for patients with high PRA was 25% and for those without high PRA was 7.9% (P = .178). Overall mortality for patients with high PRA was 50% and for those without high PRA was 15.4% (P = .043).

In 2006, we modified our protocol for immunosuppression in patients with elevated PRA. We initially used pulsed Cytoxan, but have since switched to rituximab for the subgroup with high individual titers and rising donor-specific antibody titers after transplant. In our report from 2004, 30-day mortality for transplantation with high PRA was 25% and overall mortality for transplantation with high PRA was 50%. After modification of our protocols, 30-day mortality for transplantation with high PRA is now 8.6% and overall five-year mortality for transplantation with high PRA is 33.3%. This current study confirms that elevated PRA may no longer be a significant risk factor for survival with modern immunosuppressive protocols.

In 2006, we published that HTx can offer children with failing staged palliation of HLHS their only chance of survival; however, transplantation carries a high risk in this subgroup, especially in the setting of elevated PRA.² In this 2006 analysis of the 31 patients with HLHS, 23 underwent primary transplantation and 8 underwent transplantation after prior cardiac surgery. Thirty-day survival (P = .156) and overall survival (P = .053) were better in those having primary HTx, although these differences were not statistically significant when a probability value of less than .05 is considered to be significant. Our current analysis again reveals that survival after HTx after prior cardiac surgery for HLHS or HLHS-related malformation is worse than survival after primary HTx for HLHS or HLHS-related malformation (P = .043). These findings are consistent with those reported by Voeller and colleagues in a 24-year single-center review of 307 patients undergoing pediatric HTx, which concluded that “Transplantation for heart failure related to failed SV palliation has become the most common indication for patients with CHD. The high-risk nature of these transplants will have significant implications for heart transplant programs as more infants with SV anomalies survive palliative procedures performed during infancy (pp. 807)”.¹⁵

It is notable that our current analysis reveals that survival after HTx after prior cardiac surgery for HLHS or HLHS-related malformation is worse than survival after primary HTx for HLHS or HLHS-related malformation. It is also notable that early survival after primary HTx for HLHS or HLHS-related malformation is 90.9% (30/33) and one-year and five-year survival are 84.8% (38/33) and 82.8% (24/29). These rates of survival are better than current rates of survival associated with staged palliation for HLHS or HLHS-related malformation. In the Society of Thoracic Surgeons Congenital Heart Surgery Database (2013-2016), operative mortality for Norwood operation is 15.8%, so early survival is 84.2%.¹⁶ Meanwhile, data from the Single Ventricle Reconstruction trial of the Pediatric Heart Network reveal that at six years after Norwood Operation, transplant-free survival is only 59% to 64%.¹⁷ Nevertheless, suitable donor hearts are certainly not available for the nearly 700 patients who undergo Norwood operation every year.¹⁶ These facts support the selective use of HTx for patients felt to be at high risk for Norwood operation. Although our 5-year survival after primary HTx for HLHS or HLHS-related malformation is >80%, which is better than almost any long-term HLHS Norwood series, we would not recommend HTx as primary therapy for all patients with HLHS because of the lack of adequate donor organs to meet this need and the uncertain long-term fate of HTx recipients.

Conclusion

Excellent results are expected for children undergoing HTx regardless of diagnostic classification. In this consecutive series of 179 pediatric and/or congenital HTxs, pretransplant and posttransplant mechanical circulatory support are risk factors for inferior survival. Of note, elevated PRA is not a risk factor for survival with current immunosuppressive protocols. Survival after transplantation for HLHS or HLHS-related malformation is better with primary HTx in comparison to HTx after prior cardiac surgery.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Abbreviations and Acronyms

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