Oversized donor heart transplantation—clinical experience with an underestimated problem

Abstract

Purpose

Heart transplantation is the definitive treatment for end-stage heart failure. With respect to donor-recipient size matching, the problems with undersized heart transplantation have been widely discussed, but there is a paucity of information on oversized transplants due to the presumed advantage of large hearts. We intend to share our center’s experience with oversized heart transplantation and its associated problems which would help to expand the knowledge on oversized cardiac allografts.

Methods

Patients who underwent isolated heart transplantation at our hospital between March 1, 2008, and March 1, 2020, were included. For adults, a donor-recipient predicted heart mass percentage difference exceeding 30% and for children, a donor-recipient weight ratio < 0.8 and > 2.0 was considered a mismatch. We collected data from the in-patient medical records and analyzed the in-hospital outcomes and survival post-transplant among various other parameters.

Results

Out of the 43 patients included in this study, 32 (74.4%) patients received a matched heart and 11 (25.6%) patients received oversized hearts. None of the patients received an undersized heart. The in-hospital mortality rate of oversized transplants was 18.2% whereas that of matched transplants was 9.4% (p = 0.432). The post-operative characteristics and 1-year survival were comparable between the groups. We encountered problems specific to oversizing in 5 of the 11 patients (45.4%) which are discussed.

Conclusion

With the liberalization of donor criteria to overcome organ shortage, oversized heart transplantation poses certain unique challenges, which when efficiently managed offers acceptable outcomes.

Introduction

Heart transplantation, though technically straightforward, relies on proper patient selection, the timing of transplant, and post-transplant care for optimal outcomes. An important part of pre-operative decision-making is donor-recipient size matching. Size matching has evolved over the years based on various parameters including age, sex, weight, height, body mass index (BMI), body surface area (BSA), and donor-recipient weight ratio (DRWR), to name a few. A more recent concept in size matching is predicted heart mass (PHM) which has been advocated as the ideal metric for donor-recipient size matching and also as a predictor of primary graft dysfunction (PGD) [1, 2]. The 2010 International Society of Heart and Lung Transplantation (ISHLT) guidelines recommend the use of hearts from donors whose body weight is within 30% of that of the recipient [3]. With the improvement in medical management of end-stage cardiac ailments, the number of potential recipients is constantly increasing on one hand, and donor organs are scarce worldwide on the other hand, which has forced transplant programs to accept marginal or suboptimal donors. The problems with undersized donor hearts have been extensively discussed in the literature but oversized transplantation has not received the attention it deserves due to the presumed luxury of transplanting a large heart to offset certain problems in the recipient such as pulmonary artery hypertension. This led us to study our series of heart transplant patients who received hearts from oversized donors and to understand their outcomes with specific attention to the problems encountered in their management.

Methodology

Study design

All patients who underwent isolated heart transplantation (n = 60) for heart failure of any etiology at our institute between March 1, 2008, and March 1, 2020 (a period of 12 years), were considered (Fig. 1). Among these, the donor data of 17 transplants could not be traced for calculating size mismatch, hence they were excluded. We studied 43 patients who satisfied our inclusion criteria. The pre-operative characteristics, intra-operative, and post-operative details of the recipients were collected from the in-patient records. The donor characteristics were collected from our hospital’s heart transplant registry. PHM and PHM percentage differences were calculated for all adult heart transplants using a validated online calculator (available at https://insights.unos.org/phm-calculator/) and DRWR was calculated for pediatric transplants because PHM is validated only for patients more than 18 years of age [1].

Fig. 1.

Study design (PHM, predicted heart mass; DRWR, donor-recipient weight ratio; MCS, mechanical circulatory support; PGD, primary graft dysfunction; VIS, vasoactive inotrope score)

Study groups

We grouped our patients into three categories based on the degree of size matching defined by PHM/ DRWR as follows:

• Ideal match—PHM percentage difference between −30 and + 30% for adults and a DRWR of 0.8 and 2.0 for children.

• Undersized—PHM percentage difference of less than −30% for adults and a DRWR of less than 0.8 for children.

• Oversized—PHM percentage difference of more than +30% for adults and a DRWR of more than 2.0 for children.

Study outcomes

The primary outcome was in-hospital survival to discharge. Secondary outcomes such as PGD, vasoactive inotrope score (VIS), need for mechanical circulatory support (MCS), duration of mechanical ventilation, need for renal replacement therapy (RRT), tracheostomy, duration of intensive care, degree of rejection at the time of discharge, and 1-year survival were also studied.

Statistical methods

Categorical data were expressed as percentages and continuous data as means with standard deviation (SD). Continuous outcomes were compared using the independent Student “t” test for means of normally distributed continuous variables and the Mann–Whitney U nonparametric test for skewed distributions. The chi-square analysis was used to compare categorical variables between the groups. Survival was calculated by the Kaplan–Meier method and survival comparisons were performed using the log-rank test. Analyses were performed using IBM Statistical Package for Social Sciences (SPSS) 20 Standard Edition (SPSS Inc., Chicago, IL, USA).

Ethical considerations

Our study conforms to ethical principles as per the Declaration of Helsinki. Our institutional academic ethics committee approved the study and waived the need for informed consent.

Results

Of the 43 patients included in this study, 32 (74.4%) received ideally matched hearts and 11 (25.6%) patients received oversized hearts. None of them received an undersized heart. A total of 35 (81.4%) adults and 8 (18.6%) children underwent heart transplantation for various indications such as ischemic cardiomyopathy (13 (30.2%)), dilated cardiomyopathy (DCM) (15 (34.9%)), restrictive cardiomyopathy (2 (4.6%)), complex univentricular congenital heart disease (4 (9.3%)), and arrhythmogenic right ventricular cardiomyopathy (1 (2.3%)) in adults and DCM (3 (7%)), complex univentricular congenital heart disease (3 (7%)), and restrictive cardiomyopathy (2 (4.6%)) in children. The demographic and baseline characteristics are discussed in Table 1.

Table 1.

Pre-operative baseline characteristics (EF, ejection fraction; PVR, pulmonary vascular resistance; WU, wood units; PHM, predicted heart mass; MCS, mechanical circulatory support; DRWR, donor-recipient weight ratio)

Variable	Matched transplants (n = 32)	Oversized transplants (n = 11)	p value
Recipient details (adults)
Number	28(87.5%)	7(63.6%)
Age (years)	40 ± 14	45 ± 22	0.568
Male	25(78.1%)	6(54.5%)	0.133
Weight (kg)	63.1 ± 7.6	56.2 ± 12.1	0.062
Pre-transplant EF (%)	21 ± 7	28 ± 13	0.196
PVR (WU)	2.33 ± 1.31	3.16 ± 1.81	0.209
PHM (gm)	157.5 ± 19	143.7 ± 24	0.115
Donor-recipient PHM % difference	10.4 ± 7.4	40.3 ± 22.5	0.000
Pre-op MCS	0	0
Recipient details (pediatric)
Number	4(12.5%)	4(36.4%)
Age (years)	13 ± 3	11 ± 4	0.573
Male	3(9.4%)	2(18.2%)	0.465
Weight (kg)	37.9 ± 18.5	26.6 ± 8.8	0.314
PVR (WU)	1.77 ± 0.46	3.67 ± 0.72	0.025
DRWR	1.47 ± 0.13	2.37 ± 0.64	0.034
Pre-op MCS	1(3.1%)	0	0.553
Donor details (for adult recipients)
Age	28 ± 7	24 ± 6	0.185
Male	22	6	0.673
Weight (kg)	70.1 ± 9.9	77.3 ± 10.2	0.127
EF (%)	54 ± 12	49 ± 11	0.404
PHM (gm)	167.8 ± 24	184.6 ± 21	0.102
Donor details (for pediatric recipients)
Age	26 ± 18	29 ± 10	0.827
Male	3	4	0.285
Weight (kg)	55 ± 23.4	59.5 ± 11	0.740
EF (%)	60 ± 5	58 ± 4	0.592

In the ideally matched group, the majority were adults (87.5%). Not surprisingly, 50% of the children received oversized hearts in our series whereas 20% of the adults received oversized hearts as the pediatric population tends to receive more oversized hearts for obvious reasons such as lesser body weight and a far less number of pediatric donors as compared to adult donors. In our series of oversized transplants, only 2 out of the 11 patients had a transplant for DCM and the remaining 9 patients had other diagnoses (non-DCM) as the bigger pericardial cavity of DCM can accommodate a large donor heart.

The operative characteristics (Table 2) including the ischemic time did not differ greatly between the groups. In the post-operative period (Table 3), mean VIS was comparable and the incidence of PGD (as defined by Kobashigawa et al. [4]) was also not significantly different between the matched and the oversized groups (p = 0.639). The in-hospital mortality of patients who suffered severe PGD was the same in both groups (33.3%). The requirement of MCS post-transplant was similar and the recovery rate being equal (66.6%) between the groups.

Table 2.

Operative characteristics

Variable	Matched transplants (n = 32)	Oversized transplants (n = 11)	p value
Redo-sternotomy	4 (12.5%)	2 (18.2%)	0.639
Cold ischemic time (min)	148 ± 71	127 ± 57	0.380
Technique of transplant			0.608
Bicaval   Bi-atrial	23 (71.9%) 9 (28.1%)	7 (63.6%) 4 (36.4%)
Delayed sternal closure	2 (6.2%)	1 (9.1%)	0.750

Table 3.

Post-operative characteristics

Variable	Matched transplants (n = 32)	Oversized transplants (n = 11)	p value
Vasoactive inotrope score (VIS)	12.8 ± 4.5	12.4 ± 5.6	0.837
Primary graft dysfunction*
None	27 (84.4%)	8 (72.7%)	0.392
Mild	0	0
Moderate	1 (3.1%)	1 (9.1%)	0.418
Severe	4 (12.5%)	2 (18.2%)	0.639
Need for mechanical circulatory support (MCS)	6 (18.75%)	3 (27.3%)	0.540
Re-exploration for bleeding	4 (12.5%)	0	0.218
Duration of mechanical ventilation (hours)	21.6 ± 22.4	21.5 ± 18.3	0.995
Tracheostomy	1 (3.1%)	2 (18.2%)	0.09
Renal replacement therapy	5 (15.6%)	4 (36.4%)	0.454
Duration of intensive care (days)	11 ± 6	19 ± 14	0.125
Duration of post-transplant hospital stay (days)	25 ± 11	28 ± 15	0.650
Severe rejection (Grade 3R) at 1 month	1 (3.1%)	0	0.553
In-hospital mortality	3 (9.4)	2 (18.18%)	0.432
Survival at 1 year	86.67%	85.71%	0.952

*As classified by Kobashigawa et al. [4]

The mean duration of mechanical ventilation, intensive care unit stay, and the need for hemodialysis were comparable. The need for tracheostomy was slightly higher in the oversized group but the indication was prolonged mechanical ventilation secondary to infection which was not attributable to the oversized hearts (due to airway compression). Additional procedures (such as re-exploration, pericardial drainage for effusion, and re-operation) were required in 18.8% of the matched transplants and 9.1% of the oversized transplants (p = 0.454).

The in-hospital mortality rate was comparable between the groups. The mortality data of both the groups between 30 days and 1 year are depicted in Table 4. Of the 38 patients who survived to discharge, the 1-year survival data was available for 22 (57.9%) patients as 7 transplants were performed in the preceding year and 9 patients were lost for follow-up. Among patients who survived hospital discharge, the 1-year survival in the matched group was estimated to be 86.67% (13/15) for matched transplants and 85.71% (6/7) for oversized transplants (p = 0.952). Though the mortality percentage seems high, in absolute terms, there were 3 deaths (of 32 patients) in the matched group and 2 deaths (of 11 patients) in the oversized group. Of the 5 deaths in our series, the pre-transplant functional class was New York Heart Association (NYHA) class 3 in 4 patients and class 4 in 1 patient. The cause of death in 4 of these 5 patients was moderate to severe PGD. One patient succumbed to disseminated intravascular coagulation (DIC) related to massive blood transfusion. The Kaplan–Meier survival curve comparing the survival of matched and oversized transplants is depicted in Fig. 2.

Table 4.

Mortality between 30 days and 1 year

Group	Number	Cause of death
Matched	2/32 (6.2%)	Unexplained sudden cardiac arrest at home
Oversized	1/11 (9.1%)	Intracranial hemorrhage secondary to warfarin (for SVC stent)

Fig. 2.

Kaplan–Meier survival curve depicting the survival of matched and oversized heart transplants in our series

Discussion

Size matching in heart transplantation has been a contentious domain since the time of its inception. There is plenty of published literature on problems with undersizing but the information on oversized transplants is scarce and it was probably neglected due to the assumption that “big is better” in terms of outcomes. This is the knowledge gap that we intended to bridge. The decision to accept a larger donor heart is challenging. At our center, all potential transplant recipients undergo a computed tomography (CT) of the chest as part of their pre-transplant workup. Using the CT scan, we do a volumetric analysis of the mediastinum which gives us an idea about the capacity of the pericardial cavity. At the donor end, we perform a transthoracic echocardiogram and measure the longitudinal length of the heart from the left atrial roof to the left ventricular apex, the transverse diameter across the atrio-ventricular valves, and the antero-posterior diameter to calculate the volume of the donor cardiac mass. By correlating the volume of the donor cardiac mass and the recipient pericardial cavity capacity, we decide on organ acceptability for a particular recipient. No donor was turned down solely because of size mismatch at our center. Poor ventricular function in an oversized donor heart is a definitive contraindication for transplantation.

Donor hearts tend to remodel themselves to suit the recipient over time [5, 6]. Fukushima et al. described a “shrink and grow” model wherein it was shown that oversized cardiac allografts in neonates tend to “shrink” during the initial few months after transplant and then “grow” with the child [7]. In pediatric heart transplants, it has been shown that oversizing does not adversely impact outcomes [8–10] and the same has been reiterated through our study as well. Pediatric oversizing has been associated with a higher inotropic requirement, higher rates of delayed primary sternal closure, need for MCS, and PGD [11] but the long-term outcomes are favorable [10]. Jayarajan et al. showed that a donor-recipient weight mismatch of up to 40% in adults may be safe in male-to-male, female-to-female, and male-to-female heart transplants [12]. Using an oversized donor has been shown to have positive survival outcomes in adults with a prior left ventricular assist device (LVAD) [13].

Donor-recipient PHM match is modestly associated with weight match and poorly associated with height match. It is well established that the recipients of undersized donors have increased mortality relative to size-matched donor-recipient pairs (PHM mismatch between −10 and + 10%). The 2019 ISHLT report on adult heart transplantation identified an increased 1-year and 5-year mortality risk for recipients of oversized hearts despite multivariable adjustment, although the factors that are responsible for this elevated risk remained unclear [14]. This report postulated that oversized donor hearts are possibly being accepted for sicker transplant candidates who invariably have higher post-transplant mortality. In children, the recent 2019 ISHLT report demonstrated that donor-recipient weight match was independently associated with 1-year survival, with undersized donors having a lower survival. Donor-recipient height match was independently associated with 5-year survival, with oversized donors having a lower survival [15]. However, in our series, we could not identify any statistically significant difference in the immediate and short-term outcomes between the matched and the oversized groups. In the oversized group, both the patients who died were adults. One was a 62-year old-gentleman with ischemic cardiomyopathy who died 20 days after transplant and the other was a 20-year-old gentleman with restrictive cardiomyopathy who died 31 days after transplant. The cause of death in both patients was severe PGD.

Though oversized transplantation has been vastly portrayed positively in literature, there are problems unique to this subset of mismatched hearts, which the transplant team has to be aware of, anticipate and recognize early as these are life-threatening problems which might not provide any margin for error. The clinical problems with oversized hearts (Table 5) can be categorized as follows:

Table 5.

Specific problems encountered with oversized heart transplantation in our series

Problems with oversizing	Incidence in the oversized group (n = 11)
Tricuspid regurgitation requiring annuloplasty	1(9.09%)
Superior vena cava obstruction	1(9.09%)
Delayed sternal closure	1(9.09%)
Big heart syndrome	2(18.18%)
Dry tamponade	0

Intra-operative concerns

• Vessel size discrepancy necessitating a change in anastomotic strategies. For caval anastomosis, a modified bicaval technique is effective in preventing anastomotic kink/narrowing without the hazard of developing tricuspid regurgitation (TR) [16]. In an extremely oversized donor heart, a LeCompte maneuver has been successfully attempted [17]. In our series, a patient with DRWR of 2.06 underwent heart transplantation with the bicaval technique and developed post-operative superior vena cava (SVC) obstruction. It was managed by balloon dilatation and stenting with complete resolution of symptoms concurring with published literature [18].

• While using the bi-atrial technique, the donor-recipient chamber size discrepancy results in deformation of the valve apparatus leading to valve incompetence, specifically TR with a reported post-transplant incidence as high as 84% [19]. The bicaval technique was thought to be better to reduce the occurrence of TR, but the tension in the bicaval anastomosis can distort the right atrial anatomy, thereby altering the geometry of the tricuspid annulus resulting in TR. A simple modified technique of inferior vena cava (IVC) anastomosis described by Marelli et al. has been demonstrated to reduce the incidence of TR [20]. In our series, one patient who had a bicaval technique of transplant developed severe tricuspid incompetence requiring ring annuloplasty.

• Difficulty in chest closure is encountered, especially in children with single ventricle physiology and patients with a previous sternotomy where the size of the pericardial cavity is not as capacious as in patients with DCM due to dense adhesions and fibrosis. To facilitate sternal closure in such situations, we routinely open both the pleurae widely and cut the pericardium down along the diaphragmatic reflection on the left side while making sure to protect the left phrenic nerve. In our experience, we were able to close the chest primarily in the operating room even in the most oversized heart transplanted in an adult for restrictive cardiomyopathy with a PHM % difference of 90.33 and the most oversized heart for a child with DCM and a DRWR of 3.33 with no hemodynamic compromise. Other techniques such as pericardiectomy (left/right/both), making relaxation incisions on the diaphragm [21], delayed primary sternal closure, and downsizing the atria have been described [22].

Post-operative concerns

• Big heart syndrome is an established problem [9, 21, 23] with large hearts due to supra-physiologic cardiac output in a patient who has been in a chronic low-output state which manifests as systemic hypertension and can lead to serious complications like intracranial hemorrhage and seizures. Effective blood pressure control is achieved with angiotensin-converting enzyme inhibitors, calcium channel blockers, or beta-blockers till the heart size decreases and remodels to adapt to the physiological demand. We encountered this problem in 2 of the 11 oversized transplant recipients and both were children with a DRWR of 3.33 and 2.05 respectively. Fortunately, both the patients did not have any problems related to hypertension, and effective blood pressure control was achieved pharmacologically.

• Dry tamponade—An oversized heart with post-operative myocardial edema secondary to transfer-time ischemia and subsequent reperfusion can snowball into a tamponade-like picture without an obvious pericardial collection. It can be effectively prevented by anticipating it and deciding to keep the chest open followed by delayed primary sternal closure with a very low morbidity risk [21]. In our series, 9 of the 11 oversized transplants were done for patients with non-DCM heart failure and 2 of those 9 were redo-sternotomies, of which only 1 patient needed a delayed sternal closure and all the patients had good outcomes. We did not encounter dry tamponade in our series.

Oversized donor hearts for moderate pulmonary artery hypertension

It is common practice to use oversized hearts for patients with borderline high pulmonary vascular resistance (PVR) to overcome the problem of right ventricular dysfunction post-transplant. In our series, 63.6% (7/11) of patients in the oversized group and 31.2% (10/32) in the matched group had PVR > 2.5 Wood units (WU). Shah et al. in their recent study showed no benefit in oversizing donor hearts in patients with PVR of 2.5–5 WU [24]. In our series as well, the in-hospital survival of patients with PVR of 2.5–5 was 85.7% (6/7) in the oversized group and 100% (10/10) in the matched group (p = 0.218) which supports this recent concept demonstrating no survival benefit in oversizing for moderate pulmonary hypertension.

Limitations

1. Being a retrospective study, it carries its limitations but conducting a prospective randomized controlled study in the setting of heart transplantation might not be feasible.

2. The small sample size from our single center is inadequate to arrive at concrete conclusions which could be the basis for a large multicenter study.

3. The immediate and mid-term results after oversized transplantation are favorable though the long-term results beyond the first decade need to be followed up.

4. Though the loss of follow-up is not justifiable, the number of patients lost to follow-up was similar between the groups.

5. We did not have any undersized heart transplantation in our series to compare its outcomes with that of oversized or ideally matched transplants.

Conclusion

Judicious utilization of donor hearts in the backdrop of a small donor pool is crucial to meet the spiraling demand of potential recipients. In our series, we could not identify any statistically significant difference in the in-hospital and short-term outcomes between oversized and matched transplants. Though there are established problems with undersized and oversized heart transplants, the efficient intra-operative and post-operative management of these patients decides their in-hospital survival and nature tends to remodel these mismatched hearts to meet the recipient’s physiological demand over a period of time. Oversized hearts pose unique challenges that are not uncommon, necessitating prior anticipation, and appropriate interventions to ensure successful outcomes.

Author contribution

All authors contributed to the study conception. The first draft of the manuscript was written by Srikanth Kasturi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

None.

Declarations

Ethics approval

The Narayana Health Academic Ethics Committee (NHAEC) approved the conduct of this study (letter no. NHH/AEC-CL-2020-509 dated 10.06.2020).

Informed consent

As this is a retrospective study, the need to obtain informed consent was waived off by the institutional ethics committee.

Statement of human and animal rights

There was no infringement of human or animal rights in this study.

Conflict of interest

The authors declare no competing interests.