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Sizing heart transplant donors in adults with congenital heart disease
Clark et al
Congenital
Sizing heart transplant donors in adults with congenital heart disease Daniel E. Clark, MD, MPH,a Ryan D. Byrne, MD,b Jeremy A. Mazurek, MD,c Alexander R. Opotowsky, MD, MPH, MMSc,d Kelly H. Schlendorf, MD, MHS,a Meng Xu, MS,e Sandip Zalawadiya, MBBS,a and Jonathan N. Menachem, MDa ABSTRACT
Sizing Donor Hearts for ACHD Transplants: 825 Patients from the UNOS Registry
Objective: Optimal donor sizing for heart transplantation (HT) in adults with congenital heart disease (CHD) remains unclear, given the propensity for pulmonary hypertension related to shunting, staged repairs, and periods of pulmonary overcirculation. We studied HT outcomes related to donor size matching in the adult CHD population. Methods: We conducted a retrospective cohort analysis of patients with CHD undergoing HT in the United States from January 1, 2000, to December 31, 2015. Patients were selected from the United Network for Organ Sharing database; 827 patients met inclusion criteria and were analyzed. Results: At a median follow-up of 1462 days, 548 (66.3%) subjects were alive and 279 (33.7%) were deceased. All-cause mortality did not differ based on donor sizing (by predicted heart mass ratio: hazard ratio, 1.03; confidence interval, 0.86-1.23; P ¼ .74). Pulmonary hypertension was not significantly associated with survival (by predicted heart mass ratio, c2 ¼ 2.01, P ¼ .73).
Undersized Donor (48)
Size Matched Donor (580)
No mortality difference based on 5 sizing metrics
Oversized Donor (197)
Mortality 33.7% at median of 4 years follow-up
UNOS analysis of donor sizing for CHD patients undergoing HT.
CENTRAL MESSAGE
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This study evaluated the impact of HT donor–recipient sizing on outcomes in adults with Conclusions: Our data demonstrate that donor oversizing, to the extent used in congenital heart disease and current practice, does not affect survival after HT in adults with CHD. Our findings from the United Network for Organ Sharing database demonstrate that donor found no correlation between oversizing in these patients is not associated with improved mortality. (J Thorac donor oversizing and improved Cardiovasc Surg 2020;-:1-7) post-HT survival. PERSPECTIVE There is a paucity of data and guideline recommendations for adults with CHD undergoing HT. Some centers extrapolated findings from nonCHD studies showing worse outcomes for undersized donors and have advocated for empirically oversizing donors. This paper studied donor– recipient sizing outcomes in adults with CHD and shows no correlation between donor oversizing and improved post-HT survival. See Commentary on page XXX.
Heart transplantation (HT) for adults with congenital heart disease (CHD) and refractory heart failure is complex and challenging. In the absence of adequately powered clinical trials, these complex decisions tend to rely on expert
opinion1 and small, single-center case series.2-4 Numerous factors impact HT outcomes, including institution-specific factors (center size and CHD expertise)5 and patientspecific factors (the anatomic congenital lesion, bleeding,
From aCardiovascular Medicine, bInternal Medicine-Pediatrics, and eDepartment of Biostatistics, Vanderbilt University Medical Center, Nashville, Tenn; cCardiovascular Medicine, University of Pennsylvania, Philadelphia, Pa; and dPediatrics, University of Cincinnati, Cincinnati, Ohio. Received for publication Oct 10, 2019; revisions received Jan 15, 2020; accepted for publication Jan 20, 2020.
Address for reprints: Daniel E. Clark, MD, MPH, 1215 21st Ave South, Nashville, TN 37232-8802 (E-mail: [email protected]). 0022-5223/$36.00 Copyright Ó 2020 by The American Association for Thoracic Surgery https://doi.org/10.1016/j.jtcvs.2020.01.099
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Abbreviations and Acronyms ACHD ¼ adult congenital heart disease BMI ¼ body mass index CHD ¼ congenital heart disease HT ¼ heart transplantation IQR ¼ interquartile range LV ¼ left ventricle MI ¼ multiple imputation mPAP ¼ mean pulmonary artery pressure PH ¼ pulmonary hypertension PHM ¼ predicted total heart mass UNOS ¼ United Network for Organ Sharing VAD ¼ ventricular assist device
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previous sternotomies, need for dual organ transplantation, and pulmonary hypertension [PH]).6,7 The impact donor and recipient size have on post-HT outcomes in adults with CHD, however, has not been systematically studied. The International Society for Heart and Lung Transplantation guidelines recommend using a donor whose body weight is no more than 30% less than the recipient body weight (<20% if a female donor).8 Although some transplant centers argue that height or weight are the best metrics for size matching,9 a more recent report described predicted heart mass as the optimal metric by which to make allograft acceptance decisions.10 These recommendations are for any HT; there is no specific guidance for adults with CHD. Data from the non-CHD population have consistently shown worse HT outcomes for undersized donors. Patients without CHD who received a graft from an undersized donor are at greater risk of mortality and graft failure,11 particularly those with pre-existing PH.12 Undersizing of donor organs >15% of the recipient’s predicted total heart mass (PHM) is associated with a markedly increased risk of mortality,13 and one center found undersizing as determined by PHM percent difference to be associated with increased rates of primary graft dysfunction.14 Some centers have extrapolated these findings to patients with CHD undergoing HT and developed a practice of empirically oversizing donors.15,16 These centers argue that empiric oversizing of donors may improve right ventricular–pulmonary arterial coupling and prevent graft failure in the face of underappreciated pulmonary vascular disease.8,15-17 These centers emphasize that 2
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hemodynamic assessment of PH in adults with CHD, specifically those with single-ventricle Fontan circulation, remains challenging, as these patients may have multiple shunts, nonpulsatile blood flow, and asymmetric pulmonary blood flow. There are potential negative implications of this practice, however, since waiting for an oversized donor organ may increase waitlist time and waitlist mortality.18 We hypothesized that no differential survival would exist among adults with CHD receiving oversized donor hearts compared with those receiving sizematched donor hearts. Due to the paucity of data related to donor–recipient size matching for adults with CHD undergoing HT, we evaluated the association of 5 metrics of donor/recipient size with post-HT mortality: height, weight, body mass index (BMI), left ventricular (LV) mass, and PHM donor:recipient ratio. METHODS Data Source/Study Design This study was approved by the institutional review board at Vanderbilt University Medical Center. Retrospective analyses of deidentified data from the United Network for Organ Sharing (UNOS) were performed. We assessed adults with CHD (age 18 years) who underwent their first HT between January 1, 2000, and December 31, 2015; follow-up was available through June 2017. Those with a previous history of any other solid-organ transplantation or those undergoing retransplantation were excluded from the data analyses. The relationship of donor to recipient size was assessed using continuous variables using the donor–recipient ratios of height, weight, BMI, LV mass, and PHM ratio, as these variables have been studied in the non-CHD population.10-14,19,20
Statistical Analysis Categorical variables were compared using the c2 test and presented as frequency and percentage, whereas continuous variables compared using the Wilcoxon rank sum and were presented as median and interquartile range (IQR). Missingness in our dataset is assumed to be missing at random. Multiple imputation (MI) was performed using predictive mean matching method and with weighted probability sampling of available data using the aregImpute function in Hmisc R package (R Project for Statistical Computing, Vienna, Austria). MI was repeated for 10 times to account for variability introduced by imputation and coefficient estimates were averaged for 10 imputations. The variance–covariance matrix for parameter estimates was also adjusted for MI. Cox proportional hazard modeling was performed to assess the effect of the variables of interest, controlled for covariates, with the primary outcome of all-cause post-transplantation mortality (survival analysis). The variables of interest were log transformed before fitting the model. Covariates were sex mismatch, age (recipient and donor), total bilirubin (recipient), renal dysfunction (recipient), inotropic support (recipient), intra-aortic balloon pump/ventricular assist device (VAD) support (recipient), ischemic time, pulmonary vascular resistance, mean pulmonary artery pressure (mPAP), transpulmonary gradient, and diastolic pulmonary pressure gradient. The 4 pulmonary covariates (pulmonary vascular resistance, mPAP, transpulmonary gradient, and diastolic pulmonary pressure gradient) were analyzed using a ‘‘chunk test,’’ which is used to test the joint importance of a group of variables. Its degrees of freedom are the sum of all the degrees of freedom for the individual predictors, which
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equals the number of predictors being jointly tested when linearity is assumed for all. Restricted cubic splines with 3 knots were used for all continuous variables to evaluate the effect of the log ratios on the outcomes of interest. All nonlinear terms were removed if the combined test for all nonlinear effects had P >.1. Since the combined test for all nonlinear effects had a P >.1 for all the models, the nonlinear terms were removed. Transplants after December 31, 2015, were censored, given that follow-up data are only provided through June 2017. All hemodynamic PH variables were assigned as missing and were imputed during MI procedure if the individual variables used for calculation fell into a range deemed physiologically implausible. These ranges were: mPAP <10 or >80 mm Hg (n ¼ 15); thermodilution cardiac output<2 or >12 L per minute (n ¼ 12); diastolic pulmonary artery pressure <3 or >40 (n ¼ 15); and/or pulmonary capillary wedge pressure <5 or >50 (n ¼ 15), as has been previously described.21,22 LV mass (grams) was calculated as: a * (Height)^0.54 (m) * (weight)^0.61 (kg), where a ¼ 6.82 and 8.25, for women and men, respectively).14 PHM (LV þ right ventricular mass) was calculated consistent with prior publications.10,13,14 PHM ratio was defined as PHM donor/PHM recipient.10
RESULTS There were 827 adults with CHD who met inclusion criteria and were included in the analysis. At last available follow-up (median 1462 days), 548 (66.3%) HT recipients were still alive, whereas 279 (33.7%) had died (Figure 1). In total, 15.2% of HT patients received an allograft from an opposite-sex donor. Nearly one half (49.1%) of recipients were on inotropes at time of HT, and 9.5% had durable mechanical support with a VAD (Table 1). Donor Sizing Donor sizing was evaluated by height, weight, BMI, LV mass, and PHM ratios and studied as continuous variables. Sizing Donor Hearts for ACHD Transplants: 825 Patients from the UNOS Registry
Undersized Donor (48)
No mortality difference based on 5 sizing metrics
Size Matched Donor (580)
Oversized Donor (197)
Mortality 33.7% at median of 4 years follow-up
FIGURE 1. Sizing donor hearts for adult congenital heart disease transplants. In total, 825 UNOS Registry patients were studied: 48 undersized, 580 size matched, and 197 oversized. There was an overall mortality of 33.7% at a median of 4 years follow-up with no mortality difference based on donor size matching. ACHD, Adult congenital heart disease; UNOS, United Network for Organ Sharing.
The mean PHM of adult congenital heart disease (ACHD) recipients was 162.4 g, which is lower than the published mean PHM in the non-ACHD population of 180.74 g.10 Using this array of variables analyzed in previous studies to define oversized donors, there was a wide range of donor oversizing prevalence (based on donor size >120% recipient size): height (3/826, 0.4%), weight (227/826, 27.5%), BMI (184/825, 22.3%), LV mass (202/825, 24.5%), and PHM (197/825, 23.9%) as seen in Figure 2. Effects on Survival Regardless of which of the 5 donor sizing metrics was used, Cox proportional hazard models showed that sex mismatch, preoperative renal dysfunction, and longer ischemic times were statistically significantly associated with reduced survival (Table 2, displaying PHM ratio). When controlled for the 12 prespecified covariates, survival analysis suggested no substantial relationship between donor sizing and all-cause post-HT mortality when using any of the variables studied (Table 3). Thus, PHM will herein be used as the representative sizing metric, in accordance with the recent findings among the non-ACHD HT population.10 Figure 3 shows a histogram of the distribution of PHM and a lack of a statistically significant association between donor sizing and mortality. Figure 1 shows the 3 groups of donor size matching using PHM as the representative sizing metric: 48 undersized, 580 size matched, and 197 oversized patients with ACHD. There was an overall mortality of 33.7% at a median of 4 years follow-up with no mortality difference based on donor size matching. In addition, analyzed both individually (Table 2) and collectively (Table E1), PH variables were not significantly associated with survival. We performed further univariate analysis of sex mismatch, given the association of sex mismatch with worse post-HT survival. We found patients without sex mismatch had a greater survival compared with patients with sex mismatch at 4-year follow-up (73.5%, IQR 70.2%-77.0% vs 62.8%, IQR 54.6%-72.1%). Patients with a male donor had a greater survival compared with patients with a female donor at 4-year follow-up (73.3%, IQR 69.5%-77.5% vs 69.4%, IQR 64.3%-74.8%). DISCUSSION This study evaluated the impact donor–recipient sizing has on outcomes in adults with CHD undergoing HT. Despite publications encouraging empiric donor oversizing for CHD patients,15,16 oversizing occurs in the minority of patients, and its prevalence varies based on which of the 5 sizing metrics is analyzed. However, to the extent donor oversizing is used in current practice, there was no relationship between oversizing donor–recipient size and post-HT mortality. Five distinct donor sizing metrics, all controlled
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TABLE 1. Demographic and baseline characteristics of UNOS patients with CHD undergoing HT N
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Demographics Age, y Donor Recipient Last follow-up, d Donor sex Male Female Recipient sex Male Female Height, cm Donor Recipient Weight, kg Donor Recipient BMI, kg/m2 Donor Recipient Preoperative clinical features LV mass, g Donor Recipient PHM, g Donor Recipient Height ratio Weight ratio BMI ratio LV mass ratio PHM ratio Sex mismatch Total bilirubin, mg/dL Renal dysfunction Inotropes VAD Ischemic time, h PH variables PVR, Wood units mPAP, mm Hg TPG, mm Hg dPG, mm Hg Pulmonary capillary wedge pressure, mm Hg Cardiac output (thermodilution; L/min) Outcomes Recipient status (last available time)
Median [lower quartile, upper quartile*], n (%)
827
827 827 520 307 827 499 328
25.0 [19.0, 36.0] 34.0 [24.0, 45.0] 1462 [460, 2934]
Alive Deceased Postoperative dialysis
N
Median [lower quartile, upper quartile*], n (%)
548 279 811
66.3% 33.7% 169 (20.8%)
N indicates the number of non-missing values. BMI, Body mass index; LV, left ventricle; PHM, predicted heart mass; VAD, ventricular assist device; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; mPAP, mean pulmonary artery pressure; TPG, transpulmonary gradient; dPG, diastolic pulmonary gradient. *Lower and upper quartile ranges presented for continuous variables.
62.9% 37.1% 60.3% 39.7%
827 826
170.2 [165.0, 178.0] 170.0 [161.1, 177.8]
827 826
72.6 [62.0, 82.5] 68.0 [58.0, 81.1]
827 825
24.3 [21.8, 27.9] 23.6 [20.8, 27.7]
827 825
144.3 [118.6, 162.5] 137.2 [110.8, 160.0]
827 825 826 826 825 825 825 827 792 808 827 716 802
173.5 [143.5, 193.5] 162.5 [132.4, 187.2] 1.01 [1.0, 1.1] 1.04 [0.9, 1.2] 1.04 [0.9, 1.2] 1.04 [0.9, 1.2] 1.05 [0.9, 1.2] 126 (15.2%) 0.9 [0.5, 1.5] 98 (12.1%) 406 (49.1%) 68 (9.5%) 3.5 [2.7, 4.2]
483 647 579 542 629
1.8 [1.1, 2.8] 24.0 [18.0, 33.0] 7.0 [4.0, 11.0] 1.0 [-2.0, 4.0] 16.0 [11.0, 22.0]
569
4.2 [3.2, 5.3]
827 (Continued)
4
TABLE 1. Continued
for 12 potential confounders, were studied, arguing for the robustness of this finding. Although some centers support empiric donor oversizing for CHD HT recipients to counteract underappreciated pulmonary vascular disease, our data did not reveal an association between PH and post-HT survival. The generalizability of this finding may be limited, given (1) selection bias may have precluded those with significant PH from being listed for HT; (2) the limited prevalence of PH in our cohort (Table 1); and (3) potential inaccuracies of preoperative hemodynamic assessments of PH. We next analyzed the impact of sex mismatch on outcomes, as previous studies in the non-CHD population have demonstrated that sex mismatch was significantly associated with death.23,24 Female-to-male pairings were associated with the worst survival, similar to the nonCHD population.23,24 When donor size was controlled for sex mismatch, no differential outcomes were noted in our study. Further investigation of sex mismatch in this subset of HT patients should be explored to better understand differences from the non-CHD population. n addition, we found recipient age was not significantly associated with death in the adults with CHD population. Although similar studies in the non-CHD population have found advanced age to be associated with death after transplantation,25 most adults with CHD are young (median 34 years, IQR ¼ 24-45 years old in our study). Finally, as a marker of illness severity, we analyzed pretransplant use of inotropes and mechanical support (VADs) and found that neither was associated with death. We believe this to be an important distinction, as it demonstrates both the urgency for HT (49.1% of patients were on inotropes and 9.5% had VADs at the time of HT) among these patients and shows no worse survival among this subgroup of patients. An empiric strategy of preferentially accepting oversized donors for patients with CHD is not supported by the current analysis. In addition, such a strategy of empirically oversizing donors may be harmful by lengthening wait times for transplantation, which has a known
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Height ratio
Weight ratio
300 215
112
200
Frequency
141
150
112
100
70
50
51
50
35 20 11 9 6 4 2 1 0 0 0 0 1 0 1
14
11
0
86 67
29 1
104
100
3
0
0 0.8
0.9
1.0
1.1
1.0
1.2
BMI ratio
100
Frequency
Frequency
80
66 45
50
27 17
26 7
2.5
94 90 82 79
100
116
69
2.0
LV mass ratio
142 147 134
150
1.5
64
64
60
46 36 33 32 22 22 12 88
50 36
40
19
20 9 8 5 2 1 3 0 0 0 0 0 1
12
6
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Frequency
150
244
250
152 150
4433121 1 0
0
0 0.5
1.0
2.0
1.5
2.5
0.5
1.0
1.5
2.0
PHM ratio 96
100
91
93 87
80 Frequency
61
60
55
54
42 37
43
40
27 24 26
26
10 10 3643311
15
20
25
0 0.6
0.8
1.0
1.2
1.4
1.6
1.8
FIGURE 2. Donor sizing by different metrics. BMI, Body mass index; LV, left ventricle; PHM, predicted heart mass.
correlation with increased mortality.21 Further investigation comparing HT waitlist outcomes for patients with CHD versus patients without CHD should be performed and include granular detail of factors prompting declining of organs, including donor:recipient size. The lack of a signal toward reduced survival among undersized donors is likely related to underpowered analysis considering the low numbers of undersized donors in this cohort (<6% were undersized by >15% by PHM), as seen by the wide confidence intervals in Figure 3, and is similar to published reports.14
HT providers face complex selection decisions and must weigh the benefits of waiting for an optimal donor with the risks of cumulative symptom burden and mortality for the adult with CHD waiting for HT. While examples may exist of oversizing providing benefit, our overall findings from the UNOS database show that donor oversizing for adults with CHD undergoing HT does not provide protective benefit against postoperative death. There are important limitations to this retrospective cohort obtained from the UNOS data set, including missing
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TABLE 2. Cox proportional hazard model for outcomes by PHM ratio
2.0
Survival Hazard ratio (95% CI)
Recipient age, y
0.93 (0.75-1.14)
Donor age, y
1.10 (0.91-1.32)
Sex mismatch
1.50 (1.05-2.14)
TBili, mg/dL
1.06 (0.99-1.14)
VAD
0.93 (0.56-1.55)
Preoperative renal dysfunction (dialysis or postoperative eGFR <45 mL/min/BSA)
1.68 (1.18-2.39)
Inotropes
1.07 (0.83-1.37)
Ischemic time, min
1.27 (1.09-1.48)
PVR, Wood units
1.03 (0.82-1.28)
TPG, mm Hg
0.92 (0.65-1.31)
dPG, mm Hg
1.07 (0.91-1.25)
mPAP, mm Hg
0.93 (0.72-1.19)
15 1.0 10 0.5
5
0
0.0
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Sex mismatch, preoperative renal dysfunction, and longer ischemic times were statistically significantly associated with reduced survival. CI, Confidence interval; PHM, predicted heart mass; TBili, total bilirubin; VAD, ventricular assist device; eGFR, estimated glomerular filtration rate; BSA, body surface area; PVR, pulmonary vascular resistance; TPG, transpulmonary gradient; dPG, diastolic pulmonary gradient; mPAP, mean pulmonary artery pressure.
data, reporting inaccuracies, and incomplete follow-up. As previously mentioned, the data obtained from UNOS as it pertains to HT are subject to selection bias, as adults with CHD who have unfavorable hemodynamics or comorbidities may not have been listed for transplantation. In addition, the precise selection of a CHD subgroup, such as those with single-ventricle physiology, was not possible and limits our understanding of whether donor sizing matters within a particular anatomic CHD diagnosis. Of note, proactive clinical decisions to oversize donors for patients at greatest risk may confound our analysis. Although we adjusted for key measured covariates, residual confounding may exist.
TABLE 3. Cox proportional hazard model for outcomes by all sizing metrics Survival Hazard ratio (95% CI) Height ratio*
1.05 (0.87-1.27)
Weight ratio
0.97 (0.84-1.12)
BMI ratio
0.95 (0.82-1.10)
LV mass ratio
1.02 (0.85-1.25)
PHM ratio
1.03 (0.86-1.23)
Survival analysis suggested no substantial relationship between donor sizing and allcause post-HT mortality using any of the variables studied. CI, Confidence interval; BMI, body mass index; LV, left ventricle; PHM, predicted heart mass. * *All hazard ratios are per 30% increase except for height ratio, which is present per 10% increase.
6
1.5 Hazard Ratio
1.03 (0.86-1.23)
%
PHM ratio
20
0.67
0.82
1 1.22 PHM Ratio
1.49
1.82
FIGURE 3. PHM ratios’ association with relative hazard of mortality, 95% confidence intervals. PHM ratios’ association with relative hazard of mortality (y-axis on the left). Histogram with % of all recipients based on PHM ratios (y-axis on the right). PHM, Predicted heart mass.
CONCLUSIONS This study evaluated the impact of HT donor–recipient sizing on outcomes in adults with CHD. In this series, sex mismatch, preoperative renal dysfunction, and longer ischemic times were associated with reduced survival. There was no correlation between donor oversizing and improved post-HT survival. Conflict of Interest Statement Authors have nothing to disclose with regard to commercial support. The authors thank the Pete Huttlinger Fund for Congenital Cardiac Research for its continued support and dedication to improving outcomes for patients with adult congenital heart disease. We also thank the following individuals for their contributions to this work: Dr Danielle Burnstein, Dr Matthew Danter, Dr Michael Diamant, Rachel Fowler, RN, Dr Benjamin Frischhertz, Dr Frank Harrell, Dr Joann Lindenfeld, Dr Brett Mettler, Dr Tadarro L. Richardson, Emily Sandhaus, RN, Dr Jeffrey Schmeckpeper, Dr Ashish Shah, and Dr Angela Weingarten.
References 1. Ross HJ, Law Y, Book WM, Broberg CS, Burchil 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. 2. Menachem JN, Golbus JR, Molina M, Mazurek JA, Hornsby N, Atluri P, et al. Successful cardiac transplantation outcomes in patients with adult congenital heart disease. Heart. 2017;103:1449-54. 3. 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. 4. Reardon LC, DePasquale EC, Tarabay J, Cruz D, Laks H, Biniwale RM, et al. Heart and heart-liver transplantation in adults with failing Fontan physiology. Clin Transplant. 2018;32:e13329. 5. Menachem JN, Lindenfeld J, Schlendorf K, Shah AS, Bichell DP, Book W, et al. Center volume and post-transplant survival among adults with congenital heart disease. J Heart Lung Transplant. 2018;37:1351-60.
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6. Bruto VC, Harrison DA, Fedak PW, Rockert W, Siu SC. Determinants of healthrelated quality of life in adults with congenital heart disease. Congenit Heart Dis. 2007;2:301-13. 7. Engelfriet PM, Duffels MG, M€oller T, Boersma E, Tijssen JG, Thaulow E, et al. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro heart survey on adult congenital heart disease. Heart. 2007;93:682-7. 8. Mehra MR, Kobashigawa J, Starling R, Russell S, Uber PA, Parameshwar J, et al. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006. J Heart Lung Transplant. 2006;25:1024-42. 9. Kobashigawa J, Khush K, Colvin M, Acker M, Van Bakel A, Eisen H, et al. Report from the American Society of Transplantation conference on donor heart selection in adult cardiac transplantation in the United States. Am J Transplant. 2017;17:2559-66. 10. Kransdorf EP, Kittleson MM, Benck LR, Patel JK, Chung JS, Esmailian F, et al. Predicted heart mass is the optimal metric for size match in heart transplantation. J Heart Lung Transplant. 2019;38:156-65. 11. Chen JM, Sinha P, Rajasinghe HA, Suratwala SJ, McCue JD, McCarty MJ, et al. Do donor characteristics really matter? Short- and long-term impact of donor characteristics on recipient survival, 1995-1999. J Heart Lung Transplant. 2002;21:608-10. 12. Russo MJ, Iribarne A, Hong KN, Ramlawi B, Chen JM, Takayama H, et al. Factors associated with primary graft failure after heart transplantation. Transplantation. 2010;90:444-50. 13. Reed RM, Netzer G, Hunsicker L, Mitchell BD, Rajagopal K, Scharf S, et al. Cardiac size and sex-matching in heart transplantation: size matters in matters of sex and the heart. JACC Heart Fail. 2014;2:73-83. 14. Gong TA, Joseph SM, Lima B, Gonzalez-Stawinski GV, Jamil AK, Felius J, et al. Donor predicted heart mass as predictor of primary graft dysfunction. J Heart Lung Transplant. 2018;37:826-35. 15. 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. 16. Kenny LA, DeRita F, Nassar M, Dark J, Coats L, Hasan A. Transplantation in the single ventricle population. Ann Cardiothorac Surg. 2018;7: 152-9.
17. Michielon G, Carotti A, Pongiglione G, Cogo P, Parisi F. Orthotopic heart transplantation in patients with univentricular physiology. Curr Cardiol Rev. 2011;7: 85-91. 18. 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 U.S. J Am Coll Cardiol. 2016;68:908-17. 19. Patel ND, Weiss ES, Nwakanma LU, Russell SD, Baumgartner WA, Shah AS, et al. Impact of donor-to-recipient weight ratio on survival after heart transplantation: analysis of the United Network for Organ Sharing Database. Circulation. 2008;118:S83-8. 20. Jayarajan SN, Taghavi S, Komaroff E, Mangi AA. Impact of low donor to recipient weight ratios on cardiac transplantation. J Thorac Cardiovasc Surg. 2013; 146:1538-43. 21. 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 United States. J Heart Lung Transplant. 2016;35:619-24. 22. Vakil K, Duval S, Sharma A, Adabag S, Abidi KS, Taimeh Z, et al. Impact of pretransplant pulmonary hypertension on survival after heart transplantation: a UNOS registry analysis. Int J Cardiol. 2014;176:595-9. 23. Khush KK, Kubo JT, Desai M. Influence of donor and recipient sex mismatch on heart transplant outcomes: analysis of the International Society for Heart and Lung Transplantation Registry. J Heart Lung Transplant. 2012;31:459-66. 24. Weiss ES, Allen JG, Patel ND, Russell SD, Baumgartner WA, Shah AS, et al. The impact of donor-recipient sex matching on survival after orthotopic heart transplantation: analysis of 18 000 transplants in the modern era. Circ Heart Fail. 2009;2:401-8. 25. Bourge RC, Naftel DC, Costanzo-Nordin MR, Kirklin JK, Young JB, Kubo SH, et al. Pretransplantation risk factors for death after heart transplantation: a multiinstitutional study. The transplant cardiologists research database group. J Heart Lung Transplant. 1993;12:549-62.
Key Words: donor sizing, heart transplantation, adult congenital heart disease, predicted heart mass
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TABLE E1. Association test for pulmonary hypertension variables Survival c2
P value
Height ratio
1.99
.74
Weight ratio
1.87
.76
BMI ratio
1.85
.76
LV mass ratio
1.98
.74
PHM ratio
2.01
.73
PHM % difference
2.02
.73
BMI, Body mass index; LV, left ventricle; PHM, predicted heart mass.
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Sizing heart transplant donors in adults with congenital heart disease Daniel E. Clark, MD, MPH, Ryan D. Byrne, MD, Jeremy A. Mazurek, MD, Alexander R. Opotowsky, MD, MPH, MMSc, Kelly H. Schlendorf, MD, MHS, Meng Xu, MS, Sandip Zalawadiya, MBBS, and Jonathan N. Menachem, MD, Nashville, Tenn; Philadelphia, Pa; and Cincinnati, Ohio This study evaluated the impact of HT donor–recipient sizing on outcomes in adults with congenital heart disease and found no correlation between donor oversizing and improved post-HT survival.
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Sizing heart transplant donors in adults with congenital heart disease Daniel E. Clark, MD, MPH,a Ryan D. Byrne, MD,b Jeremy A. Mazurek, MD,c Alexander R. Opotowsky, MD, MPH, MMSc,d Kelly H. Schlendorf, MD, MHS,a Meng Xu, MS,e Sandip Zalawadiya, MBBS,a and Jonathan N. Menachem, MDa ABSTRACT
Sizing Donor Hearts for ACHD Transplants: 825 Patients from the UNOS Registry
Objective: Optimal donor sizing for heart transplantation (HT) in adults with congenital heart disease (CHD) remains unclear, given the propensity for pulmonary hypertension related to shunting, staged repairs, and periods of pulmonary overcirculation. We studied HT outcomes related to donor size matching in the adult CHD population. Methods: We conducted a retrospective cohort analysis of patients with CHD undergoing HT in the United States from January 1, 2000, to December 31, 2015. Patients were selected from the United Network for Organ Sharing database; 827 patients met inclusion criteria and were analyzed. Results: At a median follow-up of 1462 days, 548 (66.3%) subjects were alive and 279 (33.7%) were deceased. All-cause mortality did not differ based on donor sizing (by predicted heart mass ratio: hazard ratio, 1.03; confidence interval, 0.86-1.23; P ¼ .74). Pulmonary hypertension was not significantly associated with survival (by predicted heart mass ratio, c2 ¼ 2.01, P ¼ .73).
Undersized Donor (48)
Size Matched Donor (580)
No mortality difference based on 5 sizing metrics
Oversized Donor (197)
Mortality 33.7% at median of 4 years follow-up
UNOS analysis of donor sizing for CHD patients undergoing HT.
CENTRAL MESSAGE
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This study evaluated the impact of HT donor–recipient sizing on outcomes in adults with Conclusions: Our data demonstrate that donor oversizing, to the extent used in congenital heart disease and current practice, does not affect survival after HT in adults with CHD. Our findings from the United Network for Organ Sharing database demonstrate that donor found no correlation between oversizing in these patients is not associated with improved mortality. (J Thorac donor oversizing and improved Cardiovasc Surg 2020;-:1-7) post-HT survival. PERSPECTIVE There is a paucity of data and guideline recommendations for adults with CHD undergoing HT. Some centers extrapolated findings from nonCHD studies showing worse outcomes for undersized donors and have advocated for empirically oversizing donors. This paper studied donor– recipient sizing outcomes in adults with CHD and shows no correlation between donor oversizing and improved post-HT survival. See Commentary on page XXX.
Heart transplantation (HT) for adults with congenital heart disease (CHD) and refractory heart failure is complex and challenging. In the absence of adequately powered clinical trials, these complex decisions tend to rely on expert
opinion1 and small, single-center case series.2-4 Numerous factors impact HT outcomes, including institution-specific factors (center size and CHD expertise)5 and patientspecific factors (the anatomic congenital lesion, bleeding,
From aCardiovascular Medicine, bInternal Medicine-Pediatrics, and eDepartment of Biostatistics, Vanderbilt University Medical Center, Nashville, Tenn; cCardiovascular Medicine, University of Pennsylvania, Philadelphia, Pa; and dPediatrics, University of Cincinnati, Cincinnati, Ohio. Received for publication Oct 10, 2019; revisions received Jan 15, 2020; accepted for publication Jan 20, 2020.
Address for reprints: Daniel E. Clark, MD, MPH, 1215 21st Ave South, Nashville, TN 37232-8802 (E-mail: [email protected]). 0022-5223/$36.00 Copyright Ó 2020 by The American Association for Thoracic Surgery https://doi.org/10.1016/j.jtcvs.2020.01.099
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Abbreviations and Acronyms ACHD ¼ adult congenital heart disease BMI ¼ body mass index CHD ¼ congenital heart disease HT ¼ heart transplantation IQR ¼ interquartile range LV ¼ left ventricle MI ¼ multiple imputation mPAP ¼ mean pulmonary artery pressure PH ¼ pulmonary hypertension PHM ¼ predicted total heart mass UNOS ¼ United Network for Organ Sharing VAD ¼ ventricular assist device
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previous sternotomies, need for dual organ transplantation, and pulmonary hypertension [PH]).6,7 The impact donor and recipient size have on post-HT outcomes in adults with CHD, however, has not been systematically studied. The International Society for Heart and Lung Transplantation guidelines recommend using a donor whose body weight is no more than 30% less than the recipient body weight (<20% if a female donor).8 Although some transplant centers argue that height or weight are the best metrics for size matching,9 a more recent report described predicted heart mass as the optimal metric by which to make allograft acceptance decisions.10 These recommendations are for any HT; there is no specific guidance for adults with CHD. Data from the non-CHD population have consistently shown worse HT outcomes for undersized donors. Patients without CHD who received a graft from an undersized donor are at greater risk of mortality and graft failure,11 particularly those with pre-existing PH.12 Undersizing of donor organs >15% of the recipient’s predicted total heart mass (PHM) is associated with a markedly increased risk of mortality,13 and one center found undersizing as determined by PHM percent difference to be associated with increased rates of primary graft dysfunction.14 Some centers have extrapolated these findings to patients with CHD undergoing HT and developed a practice of empirically oversizing donors.15,16 These centers argue that empiric oversizing of donors may improve right ventricular–pulmonary arterial coupling and prevent graft failure in the face of underappreciated pulmonary vascular disease.8,15-17 These centers emphasize that 2
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hemodynamic assessment of PH in adults with CHD, specifically those with single-ventricle Fontan circulation, remains challenging, as these patients may have multiple shunts, nonpulsatile blood flow, and asymmetric pulmonary blood flow. There are potential negative implications of this practice, however, since waiting for an oversized donor organ may increase waitlist time and waitlist mortality.18 We hypothesized that no differential survival would exist among adults with CHD receiving oversized donor hearts compared with those receiving sizematched donor hearts. Due to the paucity of data related to donor–recipient size matching for adults with CHD undergoing HT, we evaluated the association of 5 metrics of donor/recipient size with post-HT mortality: height, weight, body mass index (BMI), left ventricular (LV) mass, and PHM donor:recipient ratio. METHODS Data Source/Study Design This study was approved by the institutional review board at Vanderbilt University Medical Center. Retrospective analyses of deidentified data from the United Network for Organ Sharing (UNOS) were performed. We assessed adults with CHD (age 18 years) who underwent their first HT between January 1, 2000, and December 31, 2015; follow-up was available through June 2017. Those with a previous history of any other solid-organ transplantation or those undergoing retransplantation were excluded from the data analyses. The relationship of donor to recipient size was assessed using continuous variables using the donor–recipient ratios of height, weight, BMI, LV mass, and PHM ratio, as these variables have been studied in the non-CHD population.10-14,19,20
Statistical Analysis Categorical variables were compared using the c2 test and presented as frequency and percentage, whereas continuous variables compared using the Wilcoxon rank sum and were presented as median and interquartile range (IQR). Missingness in our dataset is assumed to be missing at random. Multiple imputation (MI) was performed using predictive mean matching method and with weighted probability sampling of available data using the aregImpute function in Hmisc R package (R Project for Statistical Computing, Vienna, Austria). MI was repeated for 10 times to account for variability introduced by imputation and coefficient estimates were averaged for 10 imputations. The variance–covariance matrix for parameter estimates was also adjusted for MI. Cox proportional hazard modeling was performed to assess the effect of the variables of interest, controlled for covariates, with the primary outcome of all-cause post-transplantation mortality (survival analysis). The variables of interest were log transformed before fitting the model. Covariates were sex mismatch, age (recipient and donor), total bilirubin (recipient), renal dysfunction (recipient), inotropic support (recipient), intra-aortic balloon pump/ventricular assist device (VAD) support (recipient), ischemic time, pulmonary vascular resistance, mean pulmonary artery pressure (mPAP), transpulmonary gradient, and diastolic pulmonary pressure gradient. The 4 pulmonary covariates (pulmonary vascular resistance, mPAP, transpulmonary gradient, and diastolic pulmonary pressure gradient) were analyzed using a ‘‘chunk test,’’ which is used to test the joint importance of a group of variables. Its degrees of freedom are the sum of all the degrees of freedom for the individual predictors, which
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equals the number of predictors being jointly tested when linearity is assumed for all. Restricted cubic splines with 3 knots were used for all continuous variables to evaluate the effect of the log ratios on the outcomes of interest. All nonlinear terms were removed if the combined test for all nonlinear effects had P >.1. Since the combined test for all nonlinear effects had a P >.1 for all the models, the nonlinear terms were removed. Transplants after December 31, 2015, were censored, given that follow-up data are only provided through June 2017. All hemodynamic PH variables were assigned as missing and were imputed during MI procedure if the individual variables used for calculation fell into a range deemed physiologically implausible. These ranges were: mPAP <10 or >80 mm Hg (n ¼ 15); thermodilution cardiac output<2 or >12 L per minute (n ¼ 12); diastolic pulmonary artery pressure <3 or >40 (n ¼ 15); and/or pulmonary capillary wedge pressure <5 or >50 (n ¼ 15), as has been previously described.21,22 LV mass (grams) was calculated as: a * (Height)^0.54 (m) * (weight)^0.61 (kg), where a ¼ 6.82 and 8.25, for women and men, respectively).14 PHM (LV þ right ventricular mass) was calculated consistent with prior publications.10,13,14 PHM ratio was defined as PHM donor/PHM recipient.10
RESULTS There were 827 adults with CHD who met inclusion criteria and were included in the analysis. At last available follow-up (median 1462 days), 548 (66.3%) HT recipients were still alive, whereas 279 (33.7%) had died (Figure 1). In total, 15.2% of HT patients received an allograft from an opposite-sex donor. Nearly one half (49.1%) of recipients were on inotropes at time of HT, and 9.5% had durable mechanical support with a VAD (Table 1). Donor Sizing Donor sizing was evaluated by height, weight, BMI, LV mass, and PHM ratios and studied as continuous variables. Sizing Donor Hearts for ACHD Transplants: 825 Patients from the UNOS Registry
Undersized Donor (48)
No mortality difference based on 5 sizing metrics
Size Matched Donor (580)
Oversized Donor (197)
Mortality 33.7% at median of 4 years follow-up
FIGURE 1. Sizing donor hearts for adult congenital heart disease transplants. In total, 825 UNOS Registry patients were studied: 48 undersized, 580 size matched, and 197 oversized. There was an overall mortality of 33.7% at a median of 4 years follow-up with no mortality difference based on donor size matching. ACHD, Adult congenital heart disease; UNOS, United Network for Organ Sharing.
The mean PHM of adult congenital heart disease (ACHD) recipients was 162.4 g, which is lower than the published mean PHM in the non-ACHD population of 180.74 g.10 Using this array of variables analyzed in previous studies to define oversized donors, there was a wide range of donor oversizing prevalence (based on donor size >120% recipient size): height (3/826, 0.4%), weight (227/826, 27.5%), BMI (184/825, 22.3%), LV mass (202/825, 24.5%), and PHM (197/825, 23.9%) as seen in Figure 2. Effects on Survival Regardless of which of the 5 donor sizing metrics was used, Cox proportional hazard models showed that sex mismatch, preoperative renal dysfunction, and longer ischemic times were statistically significantly associated with reduced survival (Table 2, displaying PHM ratio). When controlled for the 12 prespecified covariates, survival analysis suggested no substantial relationship between donor sizing and all-cause post-HT mortality when using any of the variables studied (Table 3). Thus, PHM will herein be used as the representative sizing metric, in accordance with the recent findings among the non-ACHD HT population.10 Figure 3 shows a histogram of the distribution of PHM and a lack of a statistically significant association between donor sizing and mortality. Figure 1 shows the 3 groups of donor size matching using PHM as the representative sizing metric: 48 undersized, 580 size matched, and 197 oversized patients with ACHD. There was an overall mortality of 33.7% at a median of 4 years follow-up with no mortality difference based on donor size matching. In addition, analyzed both individually (Table 2) and collectively (Table E1), PH variables were not significantly associated with survival. We performed further univariate analysis of sex mismatch, given the association of sex mismatch with worse post-HT survival. We found patients without sex mismatch had a greater survival compared with patients with sex mismatch at 4-year follow-up (73.5%, IQR 70.2%-77.0% vs 62.8%, IQR 54.6%-72.1%). Patients with a male donor had a greater survival compared with patients with a female donor at 4-year follow-up (73.3%, IQR 69.5%-77.5% vs 69.4%, IQR 64.3%-74.8%). DISCUSSION This study evaluated the impact donor–recipient sizing has on outcomes in adults with CHD undergoing HT. Despite publications encouraging empiric donor oversizing for CHD patients,15,16 oversizing occurs in the minority of patients, and its prevalence varies based on which of the 5 sizing metrics is analyzed. However, to the extent donor oversizing is used in current practice, there was no relationship between oversizing donor–recipient size and post-HT mortality. Five distinct donor sizing metrics, all controlled
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TABLE 1. Demographic and baseline characteristics of UNOS patients with CHD undergoing HT N
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Demographics Age, y Donor Recipient Last follow-up, d Donor sex Male Female Recipient sex Male Female Height, cm Donor Recipient Weight, kg Donor Recipient BMI, kg/m2 Donor Recipient Preoperative clinical features LV mass, g Donor Recipient PHM, g Donor Recipient Height ratio Weight ratio BMI ratio LV mass ratio PHM ratio Sex mismatch Total bilirubin, mg/dL Renal dysfunction Inotropes VAD Ischemic time, h PH variables PVR, Wood units mPAP, mm Hg TPG, mm Hg dPG, mm Hg Pulmonary capillary wedge pressure, mm Hg Cardiac output (thermodilution; L/min) Outcomes Recipient status (last available time)
Median [lower quartile, upper quartile*], n (%)
827
827 827 520 307 827 499 328
25.0 [19.0, 36.0] 34.0 [24.0, 45.0] 1462 [460, 2934]
Alive Deceased Postoperative dialysis
N
Median [lower quartile, upper quartile*], n (%)
548 279 811
66.3% 33.7% 169 (20.8%)
N indicates the number of non-missing values. BMI, Body mass index; LV, left ventricle; PHM, predicted heart mass; VAD, ventricular assist device; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; mPAP, mean pulmonary artery pressure; TPG, transpulmonary gradient; dPG, diastolic pulmonary gradient. *Lower and upper quartile ranges presented for continuous variables.
62.9% 37.1% 60.3% 39.7%
827 826
170.2 [165.0, 178.0] 170.0 [161.1, 177.8]
827 826
72.6 [62.0, 82.5] 68.0 [58.0, 81.1]
827 825
24.3 [21.8, 27.9] 23.6 [20.8, 27.7]
827 825
144.3 [118.6, 162.5] 137.2 [110.8, 160.0]
827 825 826 826 825 825 825 827 792 808 827 716 802
173.5 [143.5, 193.5] 162.5 [132.4, 187.2] 1.01 [1.0, 1.1] 1.04 [0.9, 1.2] 1.04 [0.9, 1.2] 1.04 [0.9, 1.2] 1.05 [0.9, 1.2] 126 (15.2%) 0.9 [0.5, 1.5] 98 (12.1%) 406 (49.1%) 68 (9.5%) 3.5 [2.7, 4.2]
483 647 579 542 629
1.8 [1.1, 2.8] 24.0 [18.0, 33.0] 7.0 [4.0, 11.0] 1.0 [-2.0, 4.0] 16.0 [11.0, 22.0]
569
4.2 [3.2, 5.3]
827 (Continued)
4
TABLE 1. Continued
for 12 potential confounders, were studied, arguing for the robustness of this finding. Although some centers support empiric donor oversizing for CHD HT recipients to counteract underappreciated pulmonary vascular disease, our data did not reveal an association between PH and post-HT survival. The generalizability of this finding may be limited, given (1) selection bias may have precluded those with significant PH from being listed for HT; (2) the limited prevalence of PH in our cohort (Table 1); and (3) potential inaccuracies of preoperative hemodynamic assessments of PH. We next analyzed the impact of sex mismatch on outcomes, as previous studies in the non-CHD population have demonstrated that sex mismatch was significantly associated with death.23,24 Female-to-male pairings were associated with the worst survival, similar to the nonCHD population.23,24 When donor size was controlled for sex mismatch, no differential outcomes were noted in our study. Further investigation of sex mismatch in this subset of HT patients should be explored to better understand differences from the non-CHD population. n addition, we found recipient age was not significantly associated with death in the adults with CHD population. Although similar studies in the non-CHD population have found advanced age to be associated with death after transplantation,25 most adults with CHD are young (median 34 years, IQR ¼ 24-45 years old in our study). Finally, as a marker of illness severity, we analyzed pretransplant use of inotropes and mechanical support (VADs) and found that neither was associated with death. We believe this to be an important distinction, as it demonstrates both the urgency for HT (49.1% of patients were on inotropes and 9.5% had VADs at the time of HT) among these patients and shows no worse survival among this subgroup of patients. An empiric strategy of preferentially accepting oversized donors for patients with CHD is not supported by the current analysis. In addition, such a strategy of empirically oversizing donors may be harmful by lengthening wait times for transplantation, which has a known
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Height ratio
Weight ratio
300 215
112
200
Frequency
141
150
112
100
70
50
51
50
35 20 11 9 6 4 2 1 0 0 0 0 1 0 1
14
11
0
86 67
29 1
104
100
3
0
0 0.8
0.9
1.0
1.1
1.0
1.2
BMI ratio
100
Frequency
Frequency
80
66 45
50
27 17
26 7
2.5
94 90 82 79
100
116
69
2.0
LV mass ratio
142 147 134
150
1.5
64
64
60
46 36 33 32 22 22 12 88
50 36
40
19
20 9 8 5 2 1 3 0 0 0 0 0 1
12
6
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Frequency
150
244
250
152 150
4433121 1 0
0
0 0.5
1.0
2.0
1.5
2.5
0.5
1.0
1.5
2.0
PHM ratio 96
100
91
93 87
80 Frequency
61
60
55
54
42 37
43
40
27 24 26
26
10 10 3643311
15
20
25
0 0.6
0.8
1.0
1.2
1.4
1.6
1.8
FIGURE 2. Donor sizing by different metrics. BMI, Body mass index; LV, left ventricle; PHM, predicted heart mass.
correlation with increased mortality.21 Further investigation comparing HT waitlist outcomes for patients with CHD versus patients without CHD should be performed and include granular detail of factors prompting declining of organs, including donor:recipient size. The lack of a signal toward reduced survival among undersized donors is likely related to underpowered analysis considering the low numbers of undersized donors in this cohort (<6% were undersized by >15% by PHM), as seen by the wide confidence intervals in Figure 3, and is similar to published reports.14
HT providers face complex selection decisions and must weigh the benefits of waiting for an optimal donor with the risks of cumulative symptom burden and mortality for the adult with CHD waiting for HT. While examples may exist of oversizing providing benefit, our overall findings from the UNOS database show that donor oversizing for adults with CHD undergoing HT does not provide protective benefit against postoperative death. There are important limitations to this retrospective cohort obtained from the UNOS data set, including missing
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TABLE 2. Cox proportional hazard model for outcomes by PHM ratio
2.0
Survival Hazard ratio (95% CI)
Recipient age, y
0.93 (0.75-1.14)
Donor age, y
1.10 (0.91-1.32)
Sex mismatch
1.50 (1.05-2.14)
TBili, mg/dL
1.06 (0.99-1.14)
VAD
0.93 (0.56-1.55)
Preoperative renal dysfunction (dialysis or postoperative eGFR <45 mL/min/BSA)
1.68 (1.18-2.39)
Inotropes
1.07 (0.83-1.37)
Ischemic time, min
1.27 (1.09-1.48)
PVR, Wood units
1.03 (0.82-1.28)
TPG, mm Hg
0.92 (0.65-1.31)
dPG, mm Hg
1.07 (0.91-1.25)
mPAP, mm Hg
0.93 (0.72-1.19)
15 1.0 10 0.5
5
0
0.0
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Sex mismatch, preoperative renal dysfunction, and longer ischemic times were statistically significantly associated with reduced survival. CI, Confidence interval; PHM, predicted heart mass; TBili, total bilirubin; VAD, ventricular assist device; eGFR, estimated glomerular filtration rate; BSA, body surface area; PVR, pulmonary vascular resistance; TPG, transpulmonary gradient; dPG, diastolic pulmonary gradient; mPAP, mean pulmonary artery pressure.
data, reporting inaccuracies, and incomplete follow-up. As previously mentioned, the data obtained from UNOS as it pertains to HT are subject to selection bias, as adults with CHD who have unfavorable hemodynamics or comorbidities may not have been listed for transplantation. In addition, the precise selection of a CHD subgroup, such as those with single-ventricle physiology, was not possible and limits our understanding of whether donor sizing matters within a particular anatomic CHD diagnosis. Of note, proactive clinical decisions to oversize donors for patients at greatest risk may confound our analysis. Although we adjusted for key measured covariates, residual confounding may exist.
TABLE 3. Cox proportional hazard model for outcomes by all sizing metrics Survival Hazard ratio (95% CI) Height ratio*
1.05 (0.87-1.27)
Weight ratio
0.97 (0.84-1.12)
BMI ratio
0.95 (0.82-1.10)
LV mass ratio
1.02 (0.85-1.25)
PHM ratio
1.03 (0.86-1.23)
Survival analysis suggested no substantial relationship between donor sizing and allcause post-HT mortality using any of the variables studied. CI, Confidence interval; BMI, body mass index; LV, left ventricle; PHM, predicted heart mass. * *All hazard ratios are per 30% increase except for height ratio, which is present per 10% increase.
6
1.5 Hazard Ratio
1.03 (0.86-1.23)
%
PHM ratio
20
0.67
0.82
1 1.22 PHM Ratio
1.49
1.82
FIGURE 3. PHM ratios’ association with relative hazard of mortality, 95% confidence intervals. PHM ratios’ association with relative hazard of mortality (y-axis on the left). Histogram with % of all recipients based on PHM ratios (y-axis on the right). PHM, Predicted heart mass.
CONCLUSIONS This study evaluated the impact of HT donor–recipient sizing on outcomes in adults with CHD. In this series, sex mismatch, preoperative renal dysfunction, and longer ischemic times were associated with reduced survival. There was no correlation between donor oversizing and improved post-HT survival. Conflict of Interest Statement Authors have nothing to disclose with regard to commercial support. The authors thank the Pete Huttlinger Fund for Congenital Cardiac Research for its continued support and dedication to improving outcomes for patients with adult congenital heart disease. We also thank the following individuals for their contributions to this work: Dr Danielle Burnstein, Dr Matthew Danter, Dr Michael Diamant, Rachel Fowler, RN, Dr Benjamin Frischhertz, Dr Frank Harrell, Dr Joann Lindenfeld, Dr Brett Mettler, Dr Tadarro L. Richardson, Emily Sandhaus, RN, Dr Jeffrey Schmeckpeper, Dr Ashish Shah, and Dr Angela Weingarten.
References 1. Ross HJ, Law Y, Book WM, Broberg CS, Burchil 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. 2. Menachem JN, Golbus JR, Molina M, Mazurek JA, Hornsby N, Atluri P, et al. Successful cardiac transplantation outcomes in patients with adult congenital heart disease. Heart. 2017;103:1449-54. 3. 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. 4. Reardon LC, DePasquale EC, Tarabay J, Cruz D, Laks H, Biniwale RM, et al. Heart and heart-liver transplantation in adults with failing Fontan physiology. Clin Transplant. 2018;32:e13329. 5. Menachem JN, Lindenfeld J, Schlendorf K, Shah AS, Bichell DP, Book W, et al. Center volume and post-transplant survival among adults with congenital heart disease. J Heart Lung Transplant. 2018;37:1351-60.
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6. Bruto VC, Harrison DA, Fedak PW, Rockert W, Siu SC. Determinants of healthrelated quality of life in adults with congenital heart disease. Congenit Heart Dis. 2007;2:301-13. 7. Engelfriet PM, Duffels MG, M€oller T, Boersma E, Tijssen JG, Thaulow E, et al. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro heart survey on adult congenital heart disease. Heart. 2007;93:682-7. 8. Mehra MR, Kobashigawa J, Starling R, Russell S, Uber PA, Parameshwar J, et al. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006. J Heart Lung Transplant. 2006;25:1024-42. 9. Kobashigawa J, Khush K, Colvin M, Acker M, Van Bakel A, Eisen H, et al. Report from the American Society of Transplantation conference on donor heart selection in adult cardiac transplantation in the United States. Am J Transplant. 2017;17:2559-66. 10. Kransdorf EP, Kittleson MM, Benck LR, Patel JK, Chung JS, Esmailian F, et al. Predicted heart mass is the optimal metric for size match in heart transplantation. J Heart Lung Transplant. 2019;38:156-65. 11. Chen JM, Sinha P, Rajasinghe HA, Suratwala SJ, McCue JD, McCarty MJ, et al. Do donor characteristics really matter? Short- and long-term impact of donor characteristics on recipient survival, 1995-1999. J Heart Lung Transplant. 2002;21:608-10. 12. Russo MJ, Iribarne A, Hong KN, Ramlawi B, Chen JM, Takayama H, et al. Factors associated with primary graft failure after heart transplantation. Transplantation. 2010;90:444-50. 13. Reed RM, Netzer G, Hunsicker L, Mitchell BD, Rajagopal K, Scharf S, et al. Cardiac size and sex-matching in heart transplantation: size matters in matters of sex and the heart. JACC Heart Fail. 2014;2:73-83. 14. Gong TA, Joseph SM, Lima B, Gonzalez-Stawinski GV, Jamil AK, Felius J, et al. Donor predicted heart mass as predictor of primary graft dysfunction. J Heart Lung Transplant. 2018;37:826-35. 15. 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. 16. Kenny LA, DeRita F, Nassar M, Dark J, Coats L, Hasan A. Transplantation in the single ventricle population. Ann Cardiothorac Surg. 2018;7: 152-9.
17. Michielon G, Carotti A, Pongiglione G, Cogo P, Parisi F. Orthotopic heart transplantation in patients with univentricular physiology. Curr Cardiol Rev. 2011;7: 85-91. 18. 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 U.S. J Am Coll Cardiol. 2016;68:908-17. 19. Patel ND, Weiss ES, Nwakanma LU, Russell SD, Baumgartner WA, Shah AS, et al. Impact of donor-to-recipient weight ratio on survival after heart transplantation: analysis of the United Network for Organ Sharing Database. Circulation. 2008;118:S83-8. 20. Jayarajan SN, Taghavi S, Komaroff E, Mangi AA. Impact of low donor to recipient weight ratios on cardiac transplantation. J Thorac Cardiovasc Surg. 2013; 146:1538-43. 21. 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 United States. J Heart Lung Transplant. 2016;35:619-24. 22. Vakil K, Duval S, Sharma A, Adabag S, Abidi KS, Taimeh Z, et al. Impact of pretransplant pulmonary hypertension on survival after heart transplantation: a UNOS registry analysis. Int J Cardiol. 2014;176:595-9. 23. Khush KK, Kubo JT, Desai M. Influence of donor and recipient sex mismatch on heart transplant outcomes: analysis of the International Society for Heart and Lung Transplantation Registry. J Heart Lung Transplant. 2012;31:459-66. 24. Weiss ES, Allen JG, Patel ND, Russell SD, Baumgartner WA, Shah AS, et al. The impact of donor-recipient sex matching on survival after orthotopic heart transplantation: analysis of 18 000 transplants in the modern era. Circ Heart Fail. 2009;2:401-8. 25. Bourge RC, Naftel DC, Costanzo-Nordin MR, Kirklin JK, Young JB, Kubo SH, et al. Pretransplantation risk factors for death after heart transplantation: a multiinstitutional study. The transplant cardiologists research database group. J Heart Lung Transplant. 1993;12:549-62.
Key Words: donor sizing, heart transplantation, adult congenital heart disease, predicted heart mass
The Journal of Thoracic and Cardiovascular Surgery c Volume -, Number -
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TABLE E1. Association test for pulmonary hypertension variables Survival c2
P value
Height ratio
1.99
.74
Weight ratio
1.87
.76
BMI ratio
1.85
.76
LV mass ratio
1.98
.74
PHM ratio
2.01
.73
PHM % difference
2.02
.73
BMI, Body mass index; LV, left ventricle; PHM, predicted heart mass.
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The Journal of Thoracic and Cardiovascular Surgery c - 2020
Clark et al
Sizing heart transplant donors in adults with congenital heart disease Daniel E. Clark, MD, MPH, Ryan D. Byrne, MD, Jeremy A. Mazurek, MD, Alexander R. Opotowsky, MD, MPH, MMSc, Kelly H. Schlendorf, MD, MHS, Meng Xu, MS, Sandip Zalawadiya, MBBS, and Jonathan N. Menachem, MD, Nashville, Tenn; Philadelphia, Pa; and Cincinnati, Ohio This study evaluated the impact of HT donor–recipient sizing on outcomes in adults with congenital heart disease and found no correlation between donor oversizing and improved post-HT survival.
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The Journal of Thoracic and Cardiovascular Surgery c Volume -, Number -