DOI: 10.1148/radiol.2251010698
(Radiology 2002;225:97-103.)
© RSNA, 2002
Acute Cardiac Transplant Rejection: Detection and Grading with MR Imaging with a Blood Pool Contrast Agent—Experimental Study in the Rat1
Lars Johansson, MD,
Cecilia Johnsson, PhD,
Eva Penno, MD,
Atle Björnerud, MSc and
Håkan Ahlström, MD, PhD
1 From the Departments of Diagnostic Radiology (L.J., E.P., H.A.) and Transplantation Surgery (C.J.), Uppsala University Hospital, Magnetkameran Ing 24, 751 85 Uppsala, Sweden; and Nycomed Amersham Imaging, Oslo, Norway (L.J., A.B.). Received March 29, 2001; revision requested May 21; final revision received March 5, 2002; accepted March 22. Supported in part by a grant from Nycomed Amersham and by the Swedish Medical Research Council project K2001-04X-06676-19A. Address correspondence to L.J. (e-mail: lars.johansson@radiol.uu.se).
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ABSTRACT
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PURPOSE: To investigate the possibility of detecting cardiac transplant rejection and determining its degree of severity with magnetic resonance (MR) imaging with a blood pool contrast agent.
MATERIALS AND METHODS: Rat allogeneic (PVG to Wistar/Kyoto, n = 9) and syngeneic (Wistar/Kyoto to Wistar/Kyoto, n = 6) heterotopic heart transplantations were performed. On the 2nd and 6th postoperative days, an ultrasmall superparamagnetic iron oxide, or USPIO, contrast agent was injected intravenously at a dose of 2 mg of iron per kilogram of body weight. The injection was followed by three-dimensional T1-weighted MR imaging of the heart grafts with an imaging time of approximately 2 minutes for each image for 44 minutes. The signal intensity (SI) was measured in the myocardium over time, and the relative enhancement was calculated. After the 6th day, the rats were sacrificed, and the morphology of the transplanted hearts was assessed histologically. The CIs for the difference of the means on day 2 and day 6 were calculated by using a bootstrap technique, and the correlation between the relative SI change and the histologically determined degree of rejection were calculated with the Spearman rank order correlation coefficient.
RESULTS: On day 6, a statistically significant difference between the groups was found at 4 minutes after injection of the contrast agent and increased with increasing time after injection. The mean percentage change in SI at the last time point for the allogeneic group on day 2 was -8.7% (SD, 8.5) and for the syngeneic group was -6.6% (SD, 6.0). On day 6, the allogeneic group had a relative SI change of 17.7% (SD, 8.7), whereas the syngeneic group had a change of -7.4% (SD, 2.6). There was a significant difference between only the two groups on day 6 (P < .001). Furthermore, in the allogeneic group the histologically determined degree of rejection correlated positively with the relative SI enhancement (r = 0.89, P < .005).
CONCLUSION: Acutely rejecting heart transplants can be distinguished from nonrejecting ones in an animal model with MR imaging and a blood pool contrast agent. In addition, the relative SI enhancement reflects the histologically determined degree of rejection.
© RSNA, 2002
Index terms: Heart, MR, 51.121412, 51.12143, 51.12144, 51.12146 • Heart, transplantation, 51.459 • Iron • Magnetic resonance (MR), contrast enhancement, 51.121412, 51.12143
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INTRODUCTION
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Despite the recent introduction of new immunosuppressive drugs, acute rejection is still a major problem in the field of organ transplantation. The incidence of biopsy-proven rejection within the first 6 months after transplantation ranges between 15% and 55%, depending on the immunosuppressive therapy used and the type of organ transplanted (1,2). In kidney transplantation histologic analysis of graft biopsies is used to diagnose rejection and to determine its severity, whereas after heart transplantation endomyocardial biopsies are still the main technique for rejection surveillance. However, the biopsy technique is not only inconvenient for the patient but is also associated with a certain risk of complications (3). Thus, there is a need for noninvasive methods for monitoring rejection. For that purpose, several methods with magnetic resonance (MR) imaging have been proposed. Characterization of relaxation times in vivo (4,5) and findings at MR spectroscopy have been studied (6,7). Perfusion of organ transplants by using both arterial spin labeling (8) and first-pass imaging of low-molecular-weight gadolinium chelates (9,10) have been proposed. The use of ultrasmall superparamagnetic iron oxides, or USPIOs, has been suggested as a tool for minimally invasive assessment of transplant rejection, with both T2-weighted perfusion (11) and delayed MR imaging, to take advantage of the increased T2* effects that occur when the particles are taken up by macrophages (12,13), which are associated with transplant rejection.
It has been shown that blood pool contrast agents (eg, ultrasmall superparamagnetic iron oxide) can be used to demonstrate increased permeability in tumor vessels (14). We therefore hypothesized that such a contrast agent, which normally remains within the vascular space, might leak into the interstitial space in areas of inflammation associated with rejection, where the vessels should display increased permeability. This would lead to increased signal intensity (SI) relative to normal tissue with a contrast agent that causes shortened T1. The purpose of this study was therefore to investigate the possibility of detecting cardiac transplant rejection and determining its degree of severity with MR imaging with a blood pool contrast agent.
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MATERIALS AND METHODS
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Animals
Nine male PVG (RT1c; M&B, Skensved, Denmark)) and 21 male Wistar/Kyoto (RT1lv; M&B) rats weighing 175–250 g were used to perform syngeneic (Wistar/Kyoto to Wistar/Kyoto) and allogeneic (PVG to Wistar/Kyoto) heart transplants. The animals were obtained and then allowed to settle for at least 1 week before surgery. Anesthesia was induced with a mixture of chloral hydrate (180 mg/kg), pentobarbital sodium (40 mg/kg), and magnesium sulfate (90 mg/kg) administered intraperitoneally. The regional ethical committee approved the experiments, and the handling of the animals conformed to the guidelines for the care and use of laboratory animals (15).
Heterotopic Heart Transplantation
Heterotopic heart transplantations were performed with anastomosis of the aorta of the donor heart to the right common carotid artery of the recipient and of the pulmonary artery to the right jugular vein by using a nonsuture technique (16). In brief, the carotid artery and the jugular vein were dissected free, cross clamped caudally, and cut cranially. Short plastic tubes were placed around the vessels, which were then turned inside out over the tubes and fixed with ligatures. The donor heart was anastomosed by pulling the vessels of the graft over the tubes and fastening them with ligatures. When the transplantation was completed, a single dose of cefuroxime (Zinacef; Glaxo, Greenford, UK), 20 mg for each rat, was administered intramuscularly. Graft function was monitored by means of daily palpation.
Experimental Groups
Two repeated MR imaging investigations were performed in the same animal on days 2 and 6 after transplantation. Syngeneic transplantation was performed with a heart transplant from one rat to another within the same species, whereas allogeneic transplantation was performed with a heart transplant between rats from different species. Rats with allogeneic (PVG to Wistar/Kyoto, n = 6) and those with syngeneic (Wistar/Kyoto to Wistar/Kyoto, n = 6) transplants were studied. In addition, three more rats with allogeneic transplants (PVG to Wistar/Kyoto) were included in the study. The conditions of these rats were analyzed on day 5 (n = 2) and day 7 (n = 1) and did not contribute to the statistical comparison between the two groups. They were added to increase the number of samples in the allogeneic group to test the correlation between SI change and histologically evaluated rejection grade.
MR Imaging
A 1.5-T clinical MR imager (Gyroscan ACS-NT; Philips Medical Systems, Best, the Netherlands) with a 22-mm surface coil was used for the acquisition, with the rat in a supine position. The acquisition sequence was three-dimensional spoiled gradient echo (20/3.1 [repetition time msec/echo time msec]; flip angle of 35°; field of view of 70 mm with a 256 x 256 matrix, which yielded an in-plane resolution of 0.27 mm). The three-dimensional volume consisted of 20 partitions with a section thickness of 0.5 mm. The large field of view in comparison with the coil size was used to avoid any phase wraps. The acquisition was performed in a transverse plane, yielding a long-axis or semi–long-axis view of the heart, since the heart was positioned this way at surgery. Twenty-one phases were acquired: The first phase (time point) started at 1 minute after injection and the last phase started at 43 minutes after injection, giving an imaging time (temporal resolution) of 2 minutes 10 seconds. The time point for each image was defined as the middle of acquisition of the image since linear k-space filling was used.
Contrast Agent
NC100150 Injection (Clariscan; Nycomed Imaging, Oslo, Norway), an ultrasmall superparamagnetic iron oxide contrast agent (17) with a particle size of 15 nm, was injected manually into the femoral vein at a dose of 2 mg of iron per kilogram of body weight in less than 5 seconds. The total volume injected was approximately 170 µL, depending on the body weight. NC100150 Injection is characterized by a long vascular half-life and no extravascular leakage in normal vessels (18). Results from preclinical and clinical trials have shown that it also has good T1-shortening properties at low to moderate doses (18,19), while the T2-T2* effects dominate at higher doses (19,20). The dose was chosen to maximize the T1 effect while maintaining the T2* effect at a level at which it can be neglected for the chosen acquisition parameters. NC100150 Injection has been through phase II clinical trials for MR angiography, and no serious adverse events have been reported (21).
Histopathologic Analysis
Immediately after the second MR investigation, the rat was sacrificed and the heart transplant was excised and fixed in 4% formalin. Subsequently, the graft was embedded in paraffin, cut into 4-µm-thick slices, in the same direction as the heart was imaged, and stained with Mayer hematoxylin and eosin. The left ventricle was evaluated blindly (C.J.) on the slides with respect to general morphology, edema, number of infiltrating mononuclear cells, and myocyte necrosis. The sections were scored arbitrarily according to an ascending five-step scale: 1, grafts with mild interstitial edema and no or few infiltrating cells (mild rejection); 2, grafts with mild edema and scattered infiltrating cells (mild to moderate rejection); 3, grafts with moderate edema and a moderate number of infiltrating cells (moderate rejection); 4, grafts with moderate to severe edema and areas with massive cellular infiltration (moderate to severe rejection); and 5, grafts with pronounced interstitial edema and homogeneous massive infiltration (severe rejection).
Imaging and Statistical Analyses
The SI on MR images was measured in the myocardium and in the blood (L.J.) by using a region of interest that contained an average of 35 pixels (range, +12 to -15 pixels). The myocardium measurements were performed with a region of interest that was positioned in the middle of the septum and that covered at least 50% of the septum. The blood SI was measured inside the left ventricle. An example of the positions of the regions of interest is shown in Figure 1. The relative change in SI (percentage) was calculated at each time point, with the first time point after injection as a reference in each animal. This means that the findings of no permeability to the contrast agent NC100150 Injection would show a decrease in SI because of clearance from the blood pool whereas a high permeability would lead to an increase in SI.
The confidence levels for the differences of the means were calculated with bootstrap techniques (22) at every time point. These techniques were used instead of nonparametric tests to avoid reliance on asymptotic approximations, which are a potential problem with a limited number of samples.
In short: Let the statistic of interest be denoted as
that is, the difference of the means between the allogeneic and syngeneic groups. If 
is significantly greater than 0, the results support the hypothesis that rejecting heart transplants can be distinguished from nonrejecting ones in an animal model of acute rejection with MR imaging and a blood pool contrast agent.
Let i = 1, 2, ..., k denote the k bootstrap samples from the allogeneic group and let j = 1, 2, ..., k denote the k bootstrap samples from the syngeneic group. For each of the bootstrap samples, we then calculate the statistic
. The percentile method yields the CIs
where
is the pth quantile of the bootstrap distribution
.
In the calculations, we use 10,000 bootstrap replications (k = 10,000) and the 95% confidence level (ie, we pick out the values of the bootstrap statistic at the 2.5 and 97.5 percentiles). The distributions have been estimated with a kernel density estimator with an Epanechnikov kernel (22).
In all animals, six with syngeneic and nine with allogeneic transplants, the correlation between the histologically classified morphologic changes and the mean of the relative SI changes at the last 10 measurement points was tested with the Spearman rank order correlation coefficient. The last 10 points were chosen since we wanted to average data points to increase the signal-to-noise ratio of the measurements and at the same time have enough separation from the baseline to be able to perform the correlation. This correlation was also tested in the allogeneic group alone. Bootstrap techniques were used to test the null hypothesis that the mean relative change in SI at the last 10 time points and the histologically assessed rejection grade are not correlated.
We calculated two CIs (by using the 95% confidence level). Let 
obs be the observed value of the statistic (in our case Spearman rank correlation coefficient), that is, the value of the statistic calculated from the original data set. Let i = 1, 2, ..., k denote the k bootstrap samples, and let
be the values of the statistic computed with each of these samples. The standard error (se) is estimated as
where
The percentile method yields the CIs
where
is the pth quantile of the bootstrap distribution
.
The distributions have been estimated with a kernel density estimator with an Epanechnikov kernel.
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RESULTS
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MR SI Changes
On day 2 after transplantation, the mean relative SI change in the myocardium did not differ significantly between the allogeneic and syngeneic groups except at three time points (12, 21, and 28 minutes) (Fig 2). On day 6, the two groups showed a significant difference in mean SI relative change as early as 4 minutes after acquisition of the reference image. There was a clear increase in the confidence level for the difference in mean relative SI change between the two groups, with an increase in time after injection on day 6.
The mean change in blood SI did not differ significantly between the syngeneic and allogeneic groups at any time point or between the measurements performed on days 2 and 6; this finding indicates that the intravascular half-life of the contrast agent was the same in all situations. As seen in Figure 3, the syngeneic transplants showed a decrease in SI over time, whereas the allogeneic transplants showed increased SI over time.
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Figure 3. Box and whisker plot shows the SI change over time after administration of the contrast agent in the syngeneic (x, n = 6) and allogeneic ( , n = 6) groups on day 6 after transplantation. The error bars represent the SD at each time point in the two groups. The time points represent the middle of each image acquisition.
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Histopathologic Analysis
All the cardiac grafts in the syngeneic group displayed a homogeneous morphology, scored as grade 1, with mild interstitial edema and with cellular infiltration restricted to the peripheral region of the transplant. In the allogeneic group there was a wider variation, with scores ranging from 3 to 5 (Fig 4). A positive correlation was found between the mean relative change in SI at the last 10 time points and the histologically assessed rejection grade in analysis of the allogeneic group alone (r = 0.89, P < .005) and in analysis of both the syngeneic and allogeneic groups (r = 0.94, P < .001), with the bootstrap Spearman rank correlation coefficient.
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Figure 4a. Photomicrographs of sections of rat cardiac grafts on day 6 after transplantation. The morphologic changes were scored according to a five-step scale, where 1 represents grafts with mild interstitial edema and no or few infiltrating cells and 5 represents grafts with pronounced interstitial edema and massive infiltration. The sections are from (a) a syngeneic graft, grade 1; (b) an allogeneic graft with mild rejection, grade 3; and (c) an allogeneic graft with severe rejection, grade 5. (Mayer hematoxylin-eosin stain; original magnification, x100.)
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Figure 4b. Photomicrographs of sections of rat cardiac grafts on day 6 after transplantation. The morphologic changes were scored according to a five-step scale, where 1 represents grafts with mild interstitial edema and no or few infiltrating cells and 5 represents grafts with pronounced interstitial edema and massive infiltration. The sections are from (a) a syngeneic graft, grade 1; (b) an allogeneic graft with mild rejection, grade 3; and (c) an allogeneic graft with severe rejection, grade 5. (Mayer hematoxylin-eosin stain; original magnification, x100.)
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Figure 4c. Photomicrographs of sections of rat cardiac grafts on day 6 after transplantation. The morphologic changes were scored according to a five-step scale, where 1 represents grafts with mild interstitial edema and no or few infiltrating cells and 5 represents grafts with pronounced interstitial edema and massive infiltration. The sections are from (a) a syngeneic graft, grade 1; (b) an allogeneic graft with mild rejection, grade 3; and (c) an allogeneic graft with severe rejection, grade 5. (Mayer hematoxylin-eosin stain; original magnification, x100.)
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A set of images from allogeneic and syngeneic transplants acquired at different time points on day 6 is shown in Figure 5.
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Figure 5a. In a and b, LV = left ventricle, RV = right ventricle. (a) Three MR images of an allogeneic transplant, acquired at 1, 15, and 30 minutes after injection. The increase in SI in the myocardium from 1 to 30 minutes after injection is approximately 20% in this case. The increased SI adjacent to the left ventricle is probably a result of leakage of contrast agent into pericardial fluid. (b) Three MR images of a syngeneic transplant, acquired at 1, 15, and 30 minutes after injection. The decrease in SI from 1 to 30 minutes after injection is approximately 5%, which may make appreciation of the decrease hard on these images.
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Figure 5b. In a and b, LV = left ventricle, RV = right ventricle. (a) Three MR images of an allogeneic transplant, acquired at 1, 15, and 30 minutes after injection. The increase in SI in the myocardium from 1 to 30 minutes after injection is approximately 20% in this case. The increased SI adjacent to the left ventricle is probably a result of leakage of contrast agent into pericardial fluid. (b) Three MR images of a syngeneic transplant, acquired at 1, 15, and 30 minutes after injection. The decrease in SI from 1 to 30 minutes after injection is approximately 5%, which may make appreciation of the decrease hard on these images.
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DISCUSSION
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The results presented herein support the hypothesis that rejecting heart transplants can be distinguished from nonrejecting ones in an animal model of acute rejection using MR imaging and a blood pool contrast agent. Furthermore, the relative SI change reflects the degree of rejection. This result correlated with the findings in the histologic slides, where all grafts in the allogeneic group were classified as rejecting (ie, containing considerable amounts of infiltrating cells), whereas all grafts in the syngeneic group were classified as nonrejecting (ie, containing no or few infiltrating cells), except in the periphery (Fig 4).
As illustrated in Figure 3, there was a larger variability in relative SI change in the allogeneic than in the syngeneic group. This variability can be explained by the individual differences in rejection grade in the allogeneic group, whereas the nonrejecting syngeneic group showed less individual morphologic variation. The positive correlation between the relative SI change and the histologic rejection grade also confirms this explanation.
Several approaches for identifying rejection with MR imaging have been described in the literature. The initial methods used, such as relaxation time measurements (4,5) and spectroscopy (6,7), have not become clinically routine, since these techniques are cumbersome to perform and few imagers that offer these capabilities are available. Differences with the use of arterial spin labeling (8) showed good statistical significance in comparisons with rejecting and nonrejecting groups. That study, however, was performed at 4.7 T, and it is not clear whether this method would offer a sufficient signal-to-noise ratio at clinical field strengths. Although significant differences have been found on the group level with regard to perfusion with low-molecular-weight gadolinium chelates, this method suffers from overlap between rejecting and nonrejecting organs in the individual case (9,10). This is probably due to the fact that leakage of low-molecular-weight gadolinium chelates through the vessel wall will also take place in the nonrejecting organs. Studies with ultrasmall superparamagnetic iron oxides (11–13) have been carried out at 4.7 T, and the results have not been validated at clinical field strengths; furthermore, some of these methods (12,13) require imaging at several hours after administration of the contrast agent, which may limit their clinical usefulness.
In comparison with previously described techniques, the method used in the current study seems feasible at clinical field strengths, with high statistical significance without a need for delayed imaging. A possible advantage over other methods used for detecting rejection, such as nuclear medicine with uptake of technetium 99m–labeled particles, may be that this investigation offers high-spatial-resolution images and can also be combined with assessment of the vessels by virtue of the intravascular characteristics of NC100150 Injection.
In this article, we describe the use of relative SI changes to detect and quantify the degree of rejection. We hypothesized that discrimination between the different groups is based on the differences in permeability of the microvasculature between rejecting and nonrejecting organs. As shown in Figure 3, the relative SI in the nonrejecting group decreases over time, a fact that might be explained by low permeability and the intravascular half-life of the contrast agent. In the rejecting group the SI increases over time, and we propose that this is a result of a high permeability of these vessels, similar to that in an inflammatory reaction. This dynamic difference in SI between the groups can also be quantified with a two-compartment kinetic model where the blood half-life and blood volume are taken into account (23,24). This approach has been described previously in a tumor model (14) and could also have been used in the present model. The statistical significance would probably increase between the groups with this approach since it involves not a comparison of time point by time point but a comparison of the entire curve. In the present experiment, however, we did not assess the blood volume or the T1, and we were therefore unable to quantify the permeability. Our aim was purely to look at the SI changes to determine whether they were reproducible and differed significantly between the groups.
The injection scheme used in the current study allowed the contrast agent to reach steady state in the blood pool before the acquisition began. The comparison was then performed with the first image after injection as the reference. This approach was used since it was assumed that the size of the contrast agent particles would lead to a permeability-limited distribution rather than a flow-limited distribution in contrast with low-molecular-weight gadolinium chelates, where a first-pass approach is needed. This assumption is also supported by findings in studies with this contrast agent in preclinical tumor models (25). Assessment of the difference from before to after injection could facilitate extraction of blood volume if baseline T1 were measured; however, this was not done in this study. By waiting 1 minute after injection before imaging, we also decreased possible effects of differences in flow between rejecting and nonrejecting transplants that otherwise could contaminate the permeability assessment.
The statistically significant differences between the syngeneic and allogeneic transplants at 12, 21, and 28 minutes after injection on day 2 is probably explained by the small sample size, which makes the analysis more sensitive to outliers. This is also confirmed by the negative difference in these two cases, for which we can find no other explanation.
Practical application: To our knowledge, there have been no previous studies in which MR imaging at clinical field strengths has depicted transplant rejection and demonstrated its extent within minutes after injection of a blood pool agent. Furthermore, in contrast to results with low-molecular-weight gadolinium chelates, we found no overlap between individual cases in the rejecting and nonrejecting groups. This technique may therefore be of importance in the clinical assessment of patients after transplantation. A possible limitation in the study is that we used acute rejection instead of chronic rejection. It is possible that a smaller difference between groups would have been noticed if chronic rejection was studied, since the vasculature may be more permeable in acute rejection than in chronic rejection.
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ACKNOWLEDGMENTS
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The technical assistance of Silvia Harfman and the statistical analysis by Matz Dahlberg are gratefully acknowledged.
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FOOTNOTES
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Abbreviation: SI = signal intensity
Author contributions: Guarantors of integrity of entire study, L.J., H.A.; study concepts, L.J., C.J., H.A.; study design, L.J., C.J., A.B., E.P.; literature research, L.J., A.B., C.J.; experimental studies, L.J., E.P., C.J.; data acquisition, L.J., E.P., C.J.; data analysis/interpretation, L.J., C.J., A.B.; statistical analysis, L.J.; manuscript preparation, L.J., C.J., E.P.; manuscript definition of intellectual content, L.J., A.B., H.A., C.J.; manuscript editing, L.J., A.B., H.A., E.P.; manuscript revision/review and final version approval, all authors.
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ABSTRACT
INTRODUCTION
) after surgery as a function of time after injection of the contrast agent. Error bars indicate bootstrap 95% CIs. On day 2 after transplantation, the confidence level did not change over time after injection, but on day 6 it increased with time. The time points represent the middle of each image acquisition.