ORIGINAL ARTICLE

Reverse Ventricular Remodeling and Improved VentricularCompliance After Heart Transplantation in Infants and YoungChildren

Kanwal M. Farooqi • Leo Lopez • Robert H. Pass •

Daphne T. Hsu • Jacqueline M. Lamour

Received: 28 November 2013 / Accepted: 24 January 2014

� Springer Science+Business Media New York 2014

Abstract After heart transplantation (HT) in infants and

young children, environmental and intrinsic factors may

lead to changes in the geometry and compliance of the

donor heart. Serial demographic, clinical, hemodynamic,

and echocardiographic data were obtained from HT

recipients younger than 4 years of age. Echocardiographic

chamber measurement z-scores were compared using

recipient body surface area from the time of HT to 1 week,

3 months, and last follow-up visit. Left ventricular end-

diastolic volume (LVEDV) z-scores were correlated with

pulmonary capillary wedge pressure (PCWP) at each time

point. Heart transplantation was performed for 13 children

between March 2009 and December 2012, 9 of whom

(69 %) were boys. The median age at HT was 8 months

(range, 4–43 months), and the mean follow-up period was

13 ± 7 months. Left ventricular end-diastolic dimension z-

scores decreased significantly (p = 0.03) between HT and

1 week, then increased from 1 week to 3 and 12 months.

(-1.32 ± 1.7, -0.71 ± 1.8, 0.41 ± 2.1, 0.79 ± 2.3,

respectively). A positive relationship (R2 = 0.48) between

the LVEDV z-score and PCPW was present at the last

follow-up visit. For infants and young children, the allo-

graft demonstrates appropriate growth by 1 year after HT.

Left ventricular compliance improves over time.

Keywords Pediatric heart transplantation � Cardiac

transplant growth � Cardiac transplant ventricular

compliance

Introduction

Pediatric heart transplantation is the only option for the

long-term survival of children with end-stage heart failure.

In children, donor–recipient size mismatch, normal somatic

growth, and the effect of immunosuppressive agents such

as steroids may be factors that affect the growth of the

allograft.

Early studies of pediatric heart transplant recipients

from infants to adolescents demonstrated that left ventric-

ular (LV) volumes increase in proportion to the recipient’s

body size. In some cases, the mass-to-volume ratio has

been elevated, with and without the presence of LV

hypertrophy [2, 19, 20]. The majority of patients in these

early studies were treated with triple immunosuppression

consisting of cyclosporine, azathioprine, and prednisone.

More recent studies have shown that donor–recipient

mismatch may contribute to the finding of LV hypertrophy

in the immediate posttransplantation period but does not

affect longer-term growth of the transplanted heart [6, 9].

In a study of pediatric transplant recipients ranging in age

from 0 to 17 years who had been treated with triple-drug

immunosuppression consisting of cyclosporine, myoco-

phenolate mofetil (MMF), steroids, the findings showed

that right and left ventricular end-diastolic diameters, vol-

umes, and myocardial mass were increased during early

follow-up assessment and subsequently decreased during

the first year after transplantation. These dimensions

returned to within the normal range and then increased

appropriately in later follow-up assessments [5].

K. M. Farooqi (&)

Division of Pediatric Cardiology, Department of Pediatrics,

The Mount Sinai Medical Center, New York, NY, USA

e-mail: kanwal.farooqi@mssm.edu

L. Lopez � R. H. Pass � D. T. Hsu � J. M. Lamour

Division of Pediatric Cardiology, Department of Pediatrics,

The Children’s Hospital at Montefiore/Albert Einstein College

of Medicine, 3415 Bainbridge Avenue, Rosenthal 1,

Bronx, NY 10467, USA

e-mail: jlamour@montefiore.org

123

Pediatr Cardiol

DOI 10.1007/s00246-014-0876-8

We sought to demonstrate the changes in LV dimen-

sions that occurred in a contemporary cohort of infants and

young children treated with a steroid-sparing regimen. The

younger pediatric population was specifically chosen

because the steep growth trajectory in infants and young

children may demonstrate more rapid changes in dimen-

sions and adaptive growth than the growth trajectory of

older children and adolescents. We also studied the change

in compliance of the transplanted heart as it adapts to the

recipient physiology.

Methods

Patients

A retrospective review of all the patients who underwent

transplantation at the Children’s Hospital at Montefiore

between March 2009 and December 2012 was undertaken

to identify recipients younger than 4 years at the time of

transplantation. The age, sex, height, weight, and body

surface area (BSA) of both the donor and the recipient were

collected. The indication for transplantation, the donor–

recipient BSA ratio, and the ischemic time for the trans-

plantation also were retrieved. The posttransplantation

course including immunosuppression treatment, rejection

history, and catheterization hemodynamics was recorded.

Immunosuppression Regimen

All but one patient received induction with methylpredniso-

lone and antithymocyte globulin (ATG) and were treated using

a steroid-sparing maintenance immunosuppression protocol.

Methylprednisolone was administered intraoperatively with

the release of cross-clamp at a dose of 20 mg/kg and then

continued on postoperative day (POD) 1 at a dose of 2 mg/kg,

which was weaned to 0.25 mg/kg by POD 5. During PODs 1 to

5, ATG was administered at a dose of 1.5 mg/kg. Tacrolimus

and MMF were instituted on PODs 2 to 3. Tacrolimus was

administered twice daily at a total dose of 0.05–0.1 mg/kg/day

to achieve levels of 8–12 ng/ml. Twice daily administration of

MMF was initiated at a total dose of 1,200 mg/m2/day. Cor-

ticosteroids were discontinued 6 ± 2 days after transplanta-

tion for 12 of the 13 patients in this study. One patient did not

undergo induction with ATG and received prednisone for the

first 3 months after transplantation.

Echocardiographic Measurements

The echocardiographic dimensions of the donor were col-

lected from the data provided at the time of the donor heart

acceptance. The LV dimensions of the recipient that were

recorded included left ventricular end-diastolic dimension

(LVEDD), left ventricular end-diastolic volume (LVEDV),

and LV mass (LVM). These measurements were adjusted

for BSA using a database of echo measurements from

normal children, and z-scores were calculated for each

measurement [18].

The LVEDD was measured in the parasternal short-axis

view at end diastole between the papillary muscles. The

LVEDV calculation used the LV cross-sectional area

(LVEDA) measured in the parasternal short-axis view at end

diastole and the LV length (LVEDL) measured from the

apical four-chamber view at end diastole from the midpoint

of the mitral valve annulus to the apical endocardium. The

LVEDV was calculated using the area length method as

follows: LVEDV = 5/6 9 (LVEDA 9 LVEDL). The

LVM was calculated by subtracting the endocardial LVEDV

from the epicardial LVEDV and multiplying the difference

by the myocardial specific density (1.05 g/ml). The LVM/V

ratio was calculated by dividing the LVM by the LVEDV.

The LV dimensions were collected at three time points: from

transplantation to 1 week, 3 months, and last follow-up visit.

Cardiac Catheterization

Cardiac catheterization with endomyocardial biopsy was

performed routinely for all patients after transplantation to

obtain right-sided hemodynamics and to assess for cellular

rejection. The catheterizations were performed initially

2 weeks after transplantation and then monthly afterward.

Venous access was obtained either from a femoral vein or

via an internal jugular approach. The pulmonary capillary

wedge pressure (PCWP) was used as a surrogate for LV end-

diastolic pressures. The cardiac catheterization performed in

closest proximity to the designated time point at which LV

dimensions were measured was used for correlation analysis.

The time between the echocardiograms and the cardiac

catheterizations were 6 ± 4 days at 1 week, 11 ± 9 days at

3 months, and 28 ± 21 days at the last follow-up visit.

Statistical Analysis

The z-scores were compared between donor and recipient

at 1 week, 3 months, and last follow-up visit by one-way

analysis of variance (ANOVA), with a p value lower than

0.05 considered significant. The PCWP and LV measure-

ments were correlated using regression analysis.

Results

Patient Characteristics

Heart transplantation was performed for 13 children

younger than 4 years between March 2009 and December

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2012. Nine of these patients (69 %) were boys. The median

age at transplantation was 8 months, and the mean follow-

up period was 13 ± 7 months. The mean recipient BSA

was 0.38 ± 0.09 kg/m2, and the mean donor–recipient

BSA ratio was 1.15 ± 0.25.

The patient characteristics including primary diagnoses are

detailed in Table 1. At the time of the first biopsy, 10 patients

were inpatients, and all patients were receiving furosemide.

Two of the inpatients were receiving inotropic support. None

of the patients in this study group were hypertensive during the

entire follow-up period. There was no significant cellular

rejection (greater than 1 R) noted on the endomyocardial

biopsies performed during the entire follow-up period. Of the

13 biopsies, 4 at the initial time point showed evidence of

myocardial edema or inflammation.

Linear Growth

The patients showed appropriate linear growth over time.

The change in BSA over time is plotted in Fig. 1.

Changes in LV Dimensions

The changes in LV dimensions over time are shown in

Table 2 and Fig. 2. The mean LVM, LVEDD, and LVEDV

were within the normal range at all time points. The

LVEDD z-scores increased significantly (p = 0.03) from

the time of transplantation to the last follow-up visit. No

significant change in the LVEDV (p = 0.11) or LVM

(p = 0.23) z-score occurred during the follow-up period

(Fig. 2).

Figure 3 compares the mean LVM/V ratio z-scores over

time. The mean LVM/V ratio z- score was elevated com-

pared with normal 1 week after transplantation, with a z-

score of 2.77. The LVM/V ratio decreased by the 3-month

time point (z-score, 1.37) and continued to normalize over

time, reaching a normal value at the last evaluation (z-

score, -0.06).

Relationship of LVEDV and PCWP

The relationship between LVEDV and the PCPW was

determined at each time point, as shown in Fig. 4. No

correlation between LVEDV and PCWP was found 1 week

after transplantation. At the last follow-up visit, LVEDV

and PCWP showed a significant correlation (R2 = 0.48).

Table 1 Characteristics of the 13 study patients

Median age at transplantation (months) 8

Range (months) 4–43

Male/female (n) 9/4

Indication for transplantation (n)

Cardiomyopathy 12

Congenital heart disease 1

Donor BSA (kg/m2) 0.43 ± 0.14

Recipient BSA (kg/m2) 0.38 ± 0.09

Donor–recipient BSA ratio 1.15 ± 0.26

Ischemic time (min) 209.7 ± 62.1

Follow-up (days) 395 ± 228

Values are expressed as mean ± standard deviation unless otherwise

noted

BSA body surface area

Fig. 1 Change in body surface

area (BSA) over time

Table 2 Left ventricular (LV) dimension z-scores

LV

dimension

Donor 1 Week 3 Months Last follow-

up

LVEDD –1.32 ± 1.7 –0.71 ± 1.8 0.41 ± 2.1 0.79 ± 2.3

LVEDV –1.1 ± 1.2 –0.48 ± 2.1 0.29 ± 2.1 0.78 ± 2.6

LVM 0.11 ± 0.9 0.75 ± 1.5 1.03 ± 1.0 1.37 ± 1.2

LVM/V 2.77 ± 3.6 1.37 ± 2.5 –0.06 ± 2.5

LVEDD LV end-diastolic dimension, LVEDV, LV end-diastolic vol-

ume, LVM, LV mass, LVM/V

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Discussion

In characterizing the changes that occur in a transplanted

heart as it adjusts to the donor circulation, we sought to

determine how LV dimensions evolve over time. The

relationship between the LVEDV and the PCWP also was

analyzed using data from echocardiograms and cardiac

catheterization to understand better the change in compli-

ance of the donor heart.

The LV dimensions were normal within 1 week after

transplantation in this group of infants and young children

undergoing transplantation. The LVEDD z-score increased

significantly during the first year after transplantation but

remained within the normal range. This growth was inde-

pendent of factors such as donor–recipient BSA ratio, age

at transplantation, sex of the recipient, and ischemic time.

These findings confirm results reported in other studies

of pediatric patients that included adolescents and also used

various methods for normalization of the echocardio-

graphic variables [2, 6]. Our results differ from those

reported by Delmo Walter et al. [5], who found that right

ventricular (RV) and LV dimensions were higher at the

initial time point (30 days after transplantation) than

measurements obtained 1 year after transplantation.

Prior studies have described LV hypertrophy in the early

posttransplantation period. However in our contemporary

cohort of very young patients receiving a steroid-sparing

immunosuppressive protocol, the LVM was normal 1 week

after transplantation. The LV mass in our cohort increased

over time but remained within a normal range during the

follow-up period. Zales et al. [20] reported similar findings,

with LVM and the LVM/V ratio remaining within normal

limits in older patients.

Fig. 2 Change in left ventricular (LV) dimensions after transplanta-

tion. All values are expressed as z-scores. LVEDD, LV end-diastolic

diameter; LVEDV, LV end-diastolic volume; LVM, LV mass

Fig. 3 Changes in left ventricular (LV) mass–volume ratio z-scores

over time

Fig. 4 Regression analysis of

the correlation between left

ventricular end-diastolic volume

(LVEDV) and pulmonary

capillary wedge pressure

(PCWP) (mmHg). The R2 value

was 0.0099 at the initial follow-

up time, 0.3676 at the 3-month

follow-up time, and 0.4768 at

the last follow-up time

Pediatr Cardiol

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In studies noting LV hypertrophy during the initial

postoperative period, regression and resolution occurred

1 year after transplantation [9, 17]. The initial increased

LVM was related to a higher donor–recipient size mis-

match, with donor–recipient weight ratios greater than 1.2

associated with increased LVMI [9]. The mean decrease in

LVMI after the immediate posttransplantation period was

found to be related to a donor–recipient weight ratio greater

than 1.5 [17]. Steroid administration and cyclosporine-

induced hypertension are hypothesized in some studies to

be the mechanisms behind LVH in the adult population,

although other studies have not found this association to be

significant [10, 13, 14].

Cyclosporine was not part of our immunosuppression

regimen, and our patients were not hypertensive during the

duration of the follow-up period for this study, perhaps

explaining our findings. There are reports of tacrolimus

possibly resulting in a hypertrophic obstructive cardiomy-

opathy in pediatric patients after liver and small bowel

transplantations. This finding has not been described after

cardiac transplantation [1, 3].

At the earliest time point after transplantation, the LVM/

V ratio was found to be abnormally high. This ratio nor-

malized over time. Postoperative myocardial inflammation

partially secondary to cardiopulmonary bypass as well as

reperfusion injury results in fluid retention in the myocar-

dium, which may partially explain this observation. Myo-

cardial edema or inflammation was in fact noted in

multiple biopsies at the initial time point. Findings have

shown LV mass to increase concurrently with a decrease in

LV compliance after ischemia and reperfusion on the car-

diopulmonary bypass in canine models [11, 12]. As

expected, this myocardial edema appears to resolve over

time.

The compliance of a transplanted heart in infants or

young children has not been investigated previously. Over

time, the pressure–volume relationship in our cohort tran-

sitioned toward improved compliance. In the early post-

operative period, small increases in LVEDD and LVEDV

correlated with large changes in the PCWP, suggesting

poor compliance of the LV.

Myocardial edema has been shown to alter the pressure–

volume relationship of the LV in a manner that decreases

the ability of the LV to distend [4]. In animal models, an

increased myocardial water content and an increased LV

mass have been associated with decreased LV compliance

[4, 15, 16]. In our cohort, there appeared to be improve-

ment in the stiffness of the ventricle over time, with

increases in the LVEDD and LVEDV resulting in less

significant increases in the PCWP.

Taking into consideration the immediate postoperative

period and the multiple possible sources contributing to

myocardial edema of the transplanted heart, these findings

are not surprising. Ischemic time, fluid administration in

the operating room, inflammation of the myocardium after

having undergone bypass, and hypotonic cardioplegia

perfusing the coronary arteries all may contribute to the

poor compliance of the heart [8]. As the myocardium

recovers and diuresis occurs, this edema improves. This

appeared to be a gradual process that continued to improve

during the follow-up period of 14 ± 6 months. Although

impaired compliance has been related to transplant rejec-

tion, the trend toward normal and the failure to demonstrate

significant rejection on endomyocardial biopsy makes this

an unlikely mechanism for the change in the pressure–

volume relationship [7].

Because this was a retrospective study, a lag occurred

between some of the echocardiograms and the cardiac

catheterizations performed. As the patients were farther

from the time of the transplantation, the catheterizations

and echocardiograms became less frequent. This rendered

it challenging to obtain data from the two studies that were

temporally better related. Ideally, the hemodynamic data

and the chamber dimensions would be measured within a

short period to avoid changes in loading conditions

affecting our results. In addition, our small sample size

limited our data.

In conclusion, we report normal growth of the trans-

planted heart in our cohort of infants and young children.

There was a trend toward improved compliance of the

transplanted heart over time. Further follow-up evaluation

is needed for a better understanding of whether this trend

continues over time, taking into consideration the possi-

bility of long-term rejection influencing compliance of the

transplanted heart.

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