Ann Thorac Surg 1995;60:1659-1663
© 1995 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Growth of Oversized Grafts in Neonatal Heart Transplantation
Norihide Fukushima, MD,
Steven R. Gundry, MD,
Anees J. Razzouk, MD,
Leonard L. Bailey, MD
Division of Cardiothoracic Surgery, Department of Surgery, Loma Linda University Medical Center, Loma Linda, California
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Abstract
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Background. Because of the severe shortage of neonatal organ donors, oversized cardiac allografts are frequently transplanted. This study examined body and graft growth of neonates who receive an oversized heart.
Methods. We studied 51 neonates, who received transplants between November 1986 and August 1992, for changes in body weight, left ventricular mass, and end-diastolic volume measured at 1 week, 1, 3, and 6 months, and yearly after cardiac transplantation. Patients were divided into two groups according to donor/recipient weight ratios: the normal group, where the donor/recipient weight ratio was 1.5 or less (1.06 ± 0.05; n = 24), and the oversized group, where the donor/recipient weight ratio was more than 1.5 (2.22 ± 0.10; n = 27).
Results. After cardiac transplantation, body weight increased continuously in both groups with no difference between groups. In the oversized group, left ventricular end-diastolic volume at 1 week and left ventricular mass at 1 week and 1 month were significantly higher than those in the normal group (p < 0.01). In the normal group, end-diastolic volume and left ventricular mass increased continuously. In the oversized group, however, left ventricular mass significantly decreased until 3 months after cardiac transplantation and then increased continuously, whereas end-diastolic volume increased continuously throughout the posttransplantation period.
Conclusions. These data suggest that oversized cardiac allografts shrink at first and then grow as the recipient grows. There appears to be a size adaptation of the large cardiac allograft to accommodate to the reduced requirements of the neonate.
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Introduction
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See also page 1663.
Orthotopic heart transplantation (HTx) in neonates and infants has been demonstrated to be extremely effective therapy for patients with otherwise incurable congenital heart disease [1, 2]. Unfortunately, the current supply of donor hearts for neonates and infants is severely limited. Thus, oversized cardiac allografts are frequently transplanted, especially in neonatal HTx. The growth of almost evenly size-matched allografts has been reported [3–7]. To evaluate body and graft growth in neonates who received an oversized heart, we performed a retrospective analysis of our 51 neonate recipients who underwent HTx between November 1986 and August 1992 at Loma Linda University Medical Center.
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Material and Methods
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From November 1986 to August 1992, 58 neonate patients underwent 59 HTxs. Seven of these patients died within 3 months after HTx. Fifty-one neonates were followed up for more than 6 months after HTx. According to recipient/donor weight ratios, the patients were divided into two groups: group N (normal), with a recipient/donor weight ratio of 1.5 or less (1.06 ± 0.05; n = 24), and group O (oversized), with a recipient/donor weight ratio greater than 1.5 (2.22 ± 0.10; n = 28).
In group N, the mean age of recipients and donors at transplantation was 16.7 ± 1.4 days (mean ± standard deviation) (range, 4 to 30 days) and 52.1 ± 16.8 days, respectively. The underlying disease requiring HTx was hypoplastic left heart syndrome in 18 patients and other congenital heart diseases in 6 patients. The mean graft ischemic time was 260 ± 25.4 minutes. The mean duration of follow-up was 37.3 ± 3.6 months, ranging from 9 to 63 months (Table 1
).
In group O, the mean age of recipients at transplantation was 18.4 ± 1.4 days (range, 4 to 30 days). The mean age of donors was 201.5 ± 33.7 days. These donors were significantly older than those in group N (p < 0.01). The underlying disease requiring HTx was hypoplastic left heart syndrome in 20 patients and other congenital heart diseases in 7 patients. The mean graft ischemic time was 322 ± 17.6 minutes, which was significantly longer than that in group N (p < 0.05). The mean duration of follow-up was 30.9 ± 3.1 months, ranging from 9 to 56 months (see Table 1
).
Immunosuppression was achieved with a double-drug regimen of cyclosporine and azathioprine as previously described [1]. Body weight, height, and body surface area were measured at 1 week, 1, 3, and 6 months, and yearly after HTx.
Routine echocardiographic studies were performed as part of the posttransplantation evaluation, biweekly early after HTx and monthly late after HTx. Two-dimensional guided M-mode tracings were digitized and quantified with a computer-assisted format as previously described [8]. Left ventricular volume (LVV) was estimated from the cube method and from the prolate ellipse method. Left ventricular mass (LVM) was calculated according to the American Society for Echocardiography convention. Percent LVM was also calculated as a percent of predicted normal mass for body surface area. Left ventricular posterior wall and interventricular septal thickness at end-systole were measured from the M-mode recording of the left ventricle. In the present study, LVV, LVM, percent LVM, left ventricular posterior wall, and interventricular septal thickness at 1 week, 1, 3, and 6 months, and yearly after HTx were compared between the two groups. Statistic analysis was performed using Student's paired or unpaired t test (using the STAX computer program; Nakayama Shoten, Tokyo, Japan). A value of p less than 0.05 was considered significant. The data are routinely presented as the mean ± the standard deviation.
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Results
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Body Weight, Height, and Body Surface Area
After HTx, body weight, height, and body surface area increased continuously in both groups without differences between the two groups (Figs 1–3).
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Fig 1. . Body weight of recipients after heart transplantation in both groups. (Group N = normal-sized donor heart group; Group O = oversized donor heart group.)
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Fig 2. . Height of recipients after heart transplantation in both groups. (Group N = normal-sized donor heart group; Group O = oversized donor heart group.)
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Fig 3. . Body surface area of recipients after heart transplantation in both groups. (Group N = normal-sized donor heart group; Group O = oversized donor heart group.)
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Left Ventricular Volume
The LVV at 1 week in group O (7.7 ± 0.6 mL) was significantly larger than that in group N (5.9 ± 0.5 mL; p < 0.01) (Fig 4). In group N, there were significant increases in LVV continuously from 1 week to 3 years after HTx. In group O, there was no significant difference in LVV between 1 week and 1 or 3 months after HTx, but LVV increased significantly after 3 months.
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Fig 4. . Left ventricular volume of heart grafts after heart transplantation in both groups. (Group N = normal-sized donor heart group; Group O = oversized donor heart group.)
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Left Ventricular Mass
The LVM at 1 week and 1 month in group O (25.7 ± 1.2 and 26.6 ± 1.7 g, respectively) were significantly greater than those in group N (15.3 ± 1.1 and 18.0 ± 1.2 g, respectively; both p < 0.01) (Fig 5). In group N, LVM increased continuously after HTx. In group O, however, LVM significantly decreased from 1 month to 3 months after HTx (26.6 ± 1.7 versus 21.1 ± 1.1 g; p < 0.01) and then increased continuously.
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Fig 5. . Left ventricular mass of heart grafts after heart transplantation in both groups. (Group N = normal-sized donor heart group; Group O = oversized donor heart group.)
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Percent LVM at 1 week and 1 month in group O were 144.2% ± 5.9% and 147.3% ± 7.4%, respectively (Fig 6). Percent LVM in group O significantly decreased up to 3 months (96.5% ± 4.9%; p < 0.01) and became stable around 100% of predicted normal mass for body surface area. Percent LVM at 1 week and 1 month in group N (84.3% ± 4.7% and 85.3% ± 7.8%, respectively) were smaller than the 100% of predicted normal mass but became normal 3 months after HTx.
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Fig 6. . Percentage left ventricular mass of heart grafts after heart transplantation in both groups. (Group N = normal-sized donor heart group; Group O = oversized donor heart group.)
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Left Ventricular Wall Thickness
Posterior wall thickness in group O was thicker than that in group N at 1 week and 1 month after HTx (9.2 ± 1.3 versus 6.9 ± 1.6 mm at 1 week; 9.4 ± 2.0 versus 7.2 ± 1.3 mm at 1 month; both p < 0.01) (Fig 7). In group N, posterior wall thickness increased continuously after HTx. In group O, however, posterior wall thickness significantly decreased from 1 month to 3 months after HTx (9.4 ± 2.0 versus 8.6 ± 1.1; p < 0.05) and then increased continuously.
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Fig 7. . Left ventricular posterior wall thickness of heart grafts after heart transplantation in both groups. (Group N = normal-sized donor heart group; Group O = oversized donor heart group.)
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Interventricular septal wall thickness in group O was greater than that in group N at 1 week and 1 month after HTx (9.4 ± 1.5 versus 7.8 ± 1.6 mm at 1 week, 9.5 ± 1.2 versus 7.4 ± 1.4 mm at 1 month; both p < 0.01) (Fig 8). In group N, there was no significant change in interventricular septal wall thickness throughout the period after HTx. In group O, however, interventricular septal wall thickness significantly decreased from 1 month to 3 months after HTx (9.5 ± 1.2 versus 8.5 ± 2.0 mm; p < 0.05) and then did not change significantly.
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Fig 8. . Interventricular septal wall thickness of heart grafts after heart transplantation in both groups. (Group N = normal-sized donor heart group; Group O = oversized donor heart group.)
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Right Ventricular Volume
The right ventricular volume at 1 week in group O (9.5 ± 2.9 mL) was significantly larger than that in group N (7.6 ± 2.0 mL; p < 0.05) (Fig 9). In group N, there was a significant increase in right ventricular volume from 1 week to 1 month after HTx, but there was no significant change in right ventricular volume after then. In group O, there was no significant change in right ventricular volume throughout the period after HTx.
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Fig 9. . Right ventricular volume of heart grafts after heart transplantation in both groups. (Group N = normal-sized donor heart group; Group O = oversized donor heart group.)
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Comment
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Improved immunosuppressive regimens, starting with the introduction of cyclosporine in 1979, have allowed the proliferation of HTx in pediatric age groups [1, 2, 9, 10]. However, the current supply of donor hearts for neonates and infants is severely limited. By necessity, oversized cardiac allografts are frequently transplanted, especially in the neonate. We have previously reported that large size mismatches appear to be well tolerated in infant and pediatric HTx [11]. As the growth of almost evenly size-matched allografts has been reported [3–7], we chose to investigate body and graft growth in neonates who received an oversized heart.
As described by Zak [12, 13], cardiac growth is considered to be controlled by two sets of factors. Intrinsic factors include cardiac morphogenesis and the ability of myocytes to undergo hyperplasia and be affected by humoral growth substances. Extrinsic factors are those that are related to contractile function: the cardiac response to altered hemodynamics. In normal children, extrinsic factors are thought to be responsible for most of cardiac growth after the neonatal period. Rakusan [14] has shown that the human heart has the greatest increase in weight during the first postnatal year. The weight of the heart doubles by 6 months and triples by 1 year of age. Afterward, growth of the heart becomes more gradual and is proportional to increases in body weight of the individual but not to age.
A number of centers have reported on the growth of almost evenly size-matched cardiac allografts [3–9]. Echocardiographic data and the cardiac silhouette on radiography of infants who receive transplants in the first months of life show that the heart enlarges concomitantly with body weight and the thorax [5, 6]. The hemodynamic, macrodimensional, and histologic aspects of cardiac growth in pediatric cardiac transplant patients were addressed by Bernstein and associates [3], who concluded that normal cardiac chamber dimensional growth occurs at more than 3 years' follow-up after pediatric HTx.
In 3 of the 13 patients in the Bernstein and associates study [3] who were in the smaller body surface area range, left ventricular end-diastolic dimension diminished by a stratification class, and these individuals thus did not demonstrate normal chamber growth. These children may have received a large donor heart and therefore had little demand for increased left ventricular end-diastolic dimension with body growth. In the present study, LVV in the even-sized donor heart group (group N) increased continuously and concomitantly with body weight, whereas LVV in the oversized donor heart group (group O) did not markedly increase until 6 months after HTx. Patients who received a large donor heart and remained in the same stratification class of left ventricular end-diastolic dimension or LVV may have done so not because of cardiac growth but as a result of ``growing into'' the donor heart size. The requirements for increased cardiac output with body growth may not have been a stimulus for uniform growth in a heart that was already large.
In the present study, LVM increased continuously after HTx in the even-sized donor heart group (group N), as Cutilletta and associates [6] reported. In the oversized donor heart group (group O), however, percent LVM was 144% and 147% at 1 week and 1 month after HTx, decreased from 1 month to 3 months after HTx, and then normalized. Similar differences were also observed in posterior wall thickness and interventricular septal wall thickness between the two groups. These data suggest that the oversized donor heart decreases in size until the recipient body grows into the donor heart and only then increases in size.
Regressions of ventricular hypertrophy have been observed after removal of pressure or volume overloads [15–18]. Clinical examples of this phenomenon include the observed decrease in right ventricular mass [15] after open valvotomy of pulmonary infundibular stenosis, and in the treatment of hypertension that decreases left ventricular mass [16]. Closure of ventricular septal defects or a ductus arteriosus has also been shown to decrease left ventricular mass and volume [17, 18]. However, these regressions do not always result in normalization of ventricular mass. Jarmakani and colleagues [18] showed that LVV and LVM remained larger than normal in asymptomatic children 1 year after closure of a ventricular septal defect. In the present study, however, LVM of the oversized donor hearts normalized by 3 months after HTx. Of course, regression of LVM of normal hearts may be different from that of hypertrophied hearts. Studies in animals, as well as humans, have shown that with decreased body weight from fasting and starvation, the heart weight is the same as that of normal younger animals of similar body weight [14]. Thus, body weight as the probable determinant of the functional load placed on the heart appears to be the most important influence on normal cardiac weight and cardiac growth throughout early life.
The present study can not answer how the oversized donor heart decreases in size, because we do not perform endomyocardial biopsies routinely after HTx in neonates. There are two mechanisms of organ growth: hyperplasia (increase in cell number) and hypertrophy (increase in cell size). The main mechanism of liver growth is considered to be hyperplasia. Therefore, hepatocytes do not change in size so much but increase in number. If demands on the liver increase, hyperplasia of hepatocytes results in an increase in liver size, but the liver does not shrink rapidly even if demands decrease. In liver transplantation, a smaller liver rapidly grows into the recipient's body [19, 20]. The oversized donor liver does not shrink after transplantation but does stop growing until the recipient's body grows into the size of the liver graft. At this point, the liver graft starts growing [21]. On the other hand, the main mechanism of cardiac growth after the prenatal period is considered to be the hypertrophy of myocytes [12, 13]. Myocytes can change in size but do not change in number physiologically after the prenatal period. If the load on the heart is decreased, the heart may decrease in size without a corresponding decrease in cell number. These findings suggest that regression of an oversized donor heart results from decreases in myocyte size caused by decreases in volume load.
In conclusion, these data suggest that oversized cardiac allografts shrink at first and then grow as the recipient grows. There appears to be a size adaptation of the large cardiac allograft to accommodate to the reduced requirements of the neonate.
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Footnotes
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Presented at the Thirtieth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 31–Feb 2, 1994.
Address reprint requests to Dr Gundry, Division of Cardiothoracic Surgery, Loma Linda University Medical Center, 11234 Anderson St, Loma Linda, CA 92354.
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Abstract
Introduction
