CLINICAL STUDIES: HEART TRANSPLANT
The medium-term findings in coronary arteries by intravascular ultrasound in infants and children after heart transplantation
Micheal A. Kuhn, MD, FACC*   ,
Kenneth R. Jutzy, MD, FACC*,
Douglas D. Deming, MD,
Constance E. Cephus, NP* ,
Richard E. Chinnock, MD,
Joyce Johnston, RN,
Leonard L. Bailey, MD, FACC and
Ranae L. Larsen, MD, FACC*
* Cardiology, Loma Linda University, Children’s Hospital and Medical Center, Loma Linda, California, USA
Cardiothoracic Surgery, Loma Linda University, Children’s Hospital and Medical Center, Loma Linda, California, USA
Pediatric Heart Transplant Team, Loma Linda University, Children’s Hospital and Medical Center, Loma Linda, California, USA
Manuscript received December 15, 1998;
revised manuscript received January 17, 2000,
accepted March 1, 2000.
Reprint requests and correspondence: Dr. Micheal A. Kuhn, Department of Pediatric Cardiology, Loma Linda International Heart Institute, 11234 Anderson Street, Room Mc-4433, Loma Linda, California 92354
mkuhn{at}ahs.llumc.edu
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Abstract
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OBJECTIVES
The study purposes were to determine 1) whether intravascular ultrasound (IVUS) was more sensitive than angiography for the detection of post-transplant coronary artery disease (PTCAD) in pediatric patients; and 2) whether those transplanted as neonates reacted differently than older patients.
BACKGROUND
Experience with IVUS for the diagnosis of PTCAD in children is limited.
METHODS
Patients were divided into two groups: those transplanted as neonates (early group) and those transplanted in infancy or childhood (late group). Morphometric analysis was performed, including maximal intimal thickness (MIT) and intimal index (II). Stanford classification was used to grade lesion severity. Acute rejection and cytomegalovirus (CMV) status were correlated with MIT and II.
RESULTS
Thirty children were studied (early group, n = 13; late group, n = 17). All segments studied were angiographically normal. Mean MIT and mean II were significantly greater in the late group (0.26 ± 0.14 vs. 0.13 ± 0.04 mm, p < 0.001 and 0.11 ± 0.07 vs. 0.07 ± 0.03 mm, p = 0.04, respectively). There was a significant correlation between MIT and II in those who had acute rejection in the late group. Patients in the late group who were CMV-positive had a significantly higher MIT compared with those in the late group with negative serology (p = 0.04).
CONCLUSIONS
Intravascular ultrasound was more sensitive than angiography in detecting PTCAD after pediatric heart transplantation. There is a possible role for acute rejection and CMV in the development of PTCAD.
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Abbreviations and Acronyms
| | CMV | = cytomegalovirus | | II | = intimal index | | IRB | = Institutional Review Board | | IVUS | = intravascular ultrasound | | MIT | = maximal intimal thickness | | PTCAD | = post-transplant coronary artery disease |
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Chronic graft vasculopathy or post-transplant coronary artery disease (PTCAD) is a long-term complication after heart transplantation. The pathogenesis of chronic graft vasculopathy results in diffuse, heterogeneous and concentric intimal hyperplasia that affects the large- and medium-sized epicardial coronary arteries. Intravascular ultrasound (IVUS) has been used extensively in adults for the diagnosis of PTCAD. Intravascular ultrasound is more sensitive than angiography for detecting PTCAD in this group (1,2). The degree of intimal thickening seen with IVUS is progressive and predicts the development of angiographic or clinically significant PTCAD in these patients (3,4). However, experience with IVUS in children who have received a new heart is limited (5). This study describes the initial experience with IVUS in our infant and pediatric heart transplant study group. We hypothesized that 1) IVUS was more sensitive than angiography for detecting PTCAD in pediatric heart transplantation recipients; and 2) patients transplanted at <1 year of age had less intimal changes than did patients transplanted at >1 year of age.
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Methods
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Patient group.
Intravascular ultrasound was performed in conjunction with annual transplant catheterization under a protocol approved by the hospital’s Institutional Review Board (IRB). As part of the criteria from the IRB, only children  7 years old were studied. The children were divided into two groups based on whether they were transplanted as neonates (early transplant group) or in infancy or childhood (late transplant group).
IVUS procedure.
Each child underwent a routine outpatient annual evaluation consisting of right and left heart catheterization, endomyocardial biopsy and coronary and ventricular angiography. Heparin, 10 U/kg, was given intravenously after access was established. At the end of the annual study, a 7F sheath (Cook, Bloomington, Indiana) was placed in the femoral artery. Intravascular ultrasound was performed through a 7F FL-3 guide catheter (SCIMED, Las Vegas, Nevada) for the left coronary artery. In some instances, IVUS was performed in the right coronary artery using a 7F modified hockey stick guide catheter (SCIMED). An 0.014 in. traverse wire (ACS, Menlo Park, California) was maneuvered into the distal vessel. Nitroglycerin, 1.0 µg/kg, was given intracoronarily before advancement of the coronary guide wire. A Micro View 30-MHz, 2.9F coronary imaging catheter (SCIMED) was used to perform IVUS. The catheter was connected to a Hewlett Packard M2400A ultrasound machine (Hewlett Packard, Andover, Massachusetts). The ultrasound catheter was mounted on an automatic pullback device, and the procedure was recorded on standard VHS tape.
Morphometric analysis.
Morphometric analysis of the ultrasound images was performed on each studied vessel by a cardiologist experienced in IVUS. Outer and lumen diameter, maximal intimal thickness (MIT) total area and lumen area were obtained by planimetry. Intimal index (II) was calculated as (total area – lumen area)/total area. Ten segments were analyzed in equally divided sections over time and were averaged together for each vessel. If IVUS was performed on more than one coronary artery, the overall results from each vessel were averaged. The results of the morphometric analysis were compared between the two groups. The Stanford classification (1) was used to grade lesion severity: class 0 = no intimal thickening; class 1 (minimal) = intimal layer <0.3 mm and <180° circumference; class 2 (mild) = intimal layer <0.3 mm and >180° circumference; class 3 (moderate) = intimal layer >0.3 mm and <0.5 mm or intimal layer >0.5 mm and <180° circumference; and class 4 (severe) = intimal layer >0.5 mm and >180° circumference or >1.0 mm intimal layer in any one area. The total number of biopsy-proven rejection episodes (International Society for Heart and Lung Transplantation grade 3A), the cytomegalovirus (CMV) status (based on serum CMV immunoglobulin G at the time of catheterization) and the presence of polymerase chain reaction to viruses (6) were compared with the MIT and II for each group.
Statistics.
The groups were compared using chi-square analysis, the Student t test, Pearson’s correlation and multivariate analysis (SPSS 8.0, SPSS, Inc., Chicago, Illinois). A p value  0.05 was considered significant. All results are given as the mean value ± SD.
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Results
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A total of 321 children underwent heart transplantation from 1986 to June 1997, with 216 managed at Loma Linda University, Children’s Hospital and Medical Center. Between July 1996 and June 1997, 30 children who fulfilled the IRB criteria were serially enrolled (early transplant group, n = 13; late transplant group, n = 17). The patient demographic data are shown in Table 1. There was a significant difference in the age of the transplanted heart (p < 0.001), weight (p = 0.002) and body surface area (p < 0.001) between the two groups. There was no significant difference in gender between the two groups. During the study period, 101 children were or would have been at least seven years old. There were 71 children 7 years old who did not have IVUS performed. The reasons for patient exclusion (death before study, study decline, poor access, unavailability) are shown in Table 2.
Cardiac catheterization.
A total of 390 segments were evaluated in 39 vessels. The left anterior descending artery was evaluated in 25 patients, the circumflex artery in 4 patients and the right coronary artery in 10 patients. Two coronary arteries were evaluated in nine patients. There was no angiographic evidence of PTCAD in any of the coronary arteries studied. The coronary artery anatomy was well visualized with IVUS in all patients. Some degree of intimal thickness was evident by IVUS in all patients studied. The intimal changes were heterogeneous, occurring throughout the course of the vessel, and were more pronounced at vessel branch points. When two vessels were studied, the process occurred with equal severity in each vessel.
There were no major complications associated with the procedure. Two patients had coronary vasospasm with ST segment changes and elevated CK MB fractions. Both were treated with additional intracoronary nitroglycerin and had no sequelae. There was no segmental wall motion abnormality noted on the echocardiogram in either patient immediately after the procedure. Follow-up angiography in both patients showed normal coronary arteries. Both patients had at least moderate intimal thickening noted on ultrasound.
Morphometric analysis.
The data from morphometric analysis are shown in Table 3. In the late transplant group, the mean outer diameter, mean lumen diameter and mean MIT were significantly greater (p < 0.001) than those measurements in the early transplant group. In the late transplant group, the mean total and mean lumen areas, measured in cm2, were significantly greater (p < 0.001) than those areas in the early transplant group. The mean II was significantly greater in the late transplant group (p = 0.04).
The distribution of the Stanford classification is shown in Table 4. Three patients in the late transplant group had class 3 and one patient had class 4 intimal thickening. No patient in the early transplant group had class 3 or 4 intimal thickening. Although there were differences in lesion severity between the two groups, they were not statistically significant.
Comparison with biopsy-proven rejection.
There was a significant correlation (p = 0.019) between MIT and the number of biopsy-proven acute rejections in the late transplant group (Fig. 1), but not in the early transplant group. There was a significant correlation (p = 0.021) between II and the number of biopsy-proven acute rejections in the late transplant group (Fig. 2), but not in the early transplant group.
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Figure 1 A comparison of MIT with the total number of biopsy-proven rejections for each patient is shown by the scatter graph. Open circles = early transplant group (r = 0.211, p = 0.488); shaded squares = late transplant group (r = 0.561, p = 0.019).
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Figure 2 A comparison of II with the total number of biopsy-proven rejections for each patient is shown by the scatter graph. Open circles = early transplant group (r = 0.470, p = 0.105); shaded squares = late transplant group (r = 0.554, p = 0.021).
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Comparison with CMV status and polymerase chain reaction to viruses.
When MIT was compared with CMV status in the late transplant group (Fig. 3), MIT was significantly greater in those patients who tested positive for CMV (p = 0.04). When MIT was compared with CMV status in the early transplant group, there was no significant difference. When II was compared with CMV status (Fig. 4), there was no significant difference in either group. There was no significant difference between polymerase chain reaction to viruses and MIT or between polymerase chain reaction to viruses and II in either group.
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Figure 3 A comparison of MIT with CMV status of each patient is shown. The patient groups are shown on the x axis. Patients who tested positive for CMV are represented by the shaded columns. Patients who tested negative for CMV are represented by the open columns.
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Figure 4 A comparison of II with CMV status of each patient is shown. The patient groups are shown on the x axis. Patients who tested positive for CMV are represented by the shaded columns. Patients who tested negative for CMV are represented by the open columns.
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Discussion
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Comparison with angiography.
Post-transplant coronary artery disease is a major contributor to the long-term morbidity and mortality in heart transplant recipients. The reported incidence in adult recipients is 50% by five years (7,8). In children, the reported incidence is 15% by five years (9). Because PTCAD is a heterogeneous and diffuse process, detection by angiography is only possible late in the course, when focal lesions or distal vessel pruning is prevalent (10). Historically, our patients have also presented with late angiographic findings. Intravascular ultrasound is a more sensitive tool for detecting the intimal changes associated with PTCAD (1,2,10). Our study showed similar findings to those of previous studies in adults. Intravascular ultrasound was more sensitive than angiography for detecting intimal thickening. Every patient in our group had at least minimal intimal changes detected by IVUS, and no patient had angiographic evidence of PTCAD.
Complications.
In adult transplant recipients and in normal children, the only reported complication of IVUS has been coronary vasospasm, with an incidence of 0% to 12% (4,11–14). The incidence of complications in our study group was low and restricted to coronary vasospasm. There were no major complications and no adverse sequelae from the vasospasm.
Study limitations.
Because the study was limited to patients 7 years old, the early transplant group had significantly older transplanted organs (longer time since transplantation). It is possible that the patients with the most severe PTCAD were excluded by seven years after heart transplantation. This potential selection bias could have influenced comparison between the two groups.
Another limitation of this study relates to the differences in patient age, weight and body surface area between the two groups. Because of limited use of intracoronary ultrasound in pediatric patients, it is not known how intimal thickness and II vary with patient size and age. In our analysis of this data, we have assumed that a normal II does not vary with patient size or age (intimal thickness increases proportional to artery size). If this assumption is not true and II normally increases with size and age, we might be overestimating differences in II between the groups. In contrast, small changes in II would cause relatively greater changes in II in small arteries, which might lead to underestimating group differences.
Comparison between the early and late groups.
The late transplant group had a higher degree of intimal thickening, as shown by the greater MIT, II and Stanford classification. Maximal intimal thickness and II correlated with the number of biopsy-proven rejections, suggesting that episodes of acute rejection may play a role in the etiology of PTCAD. These findings support a recent correlation between acute rejection in the late transplant group and the development of PTCAD (15). In the late transplant group, the increased MIT in patients who were CMV-positive suggests that the presence of CMV might be associated with the development of PTCAD. These findings are similar to those found in adult transplant recipients (16,17).
The early transplant group had very little intimal thickening, even at a mean of eight years after transplantation. Neither the number of biopsy-proven rejections nor CMV status correlated in this patient group. This lack of correlation could be partly due to selection bias limiting the significance of comparing the two groups. However, these patients could have accepted their organ more readily, irrespective of the number of rejections or CMV status. One of the reasons for performing infant transplantation is that the neonatal immune system is not fully developed at the time of transplantation (18). It is possible that in this subgroup of patients, the organ was more readily accepted, which helped limit the development of PTCAD. Even with selection bias, it is impressive that this group only developed mild intimal thickening after a mean of eight years after transplantation. One could speculate that in this group, the long-term risk of developing PTCAD is low. Serial studies of both groups would be useful in evaluating the long-term risk of PTCAD. With the impending introduction of smaller and higher frequency IVUS catheters, these studies could be safely expanded to a younger age.
Conclusions.
Intravascular ultrasound was more sensitive than angiography for detecting intimal thickening, with a low incidence of complications comparable to that in the adult transplantation population. There is a possible role for acute rejection and CMV in the development of PTCAD. Patients who were transplanted as neonates had less intimal changes, which we speculate may be partly due to better immunologic acceptance of the transplanted organ at that age.
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Footnotes
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This research was supported by a grant from the Department of Pediatrics, Loma Linda University.
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References
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Abstract
Methods