Medrol

Context.-Graft vascular disease remains a significant source of morbidity and mortality in heart transplant patients. The influence of acute cellular rejection on the development of graft vascular disease is controversial.

Objective.-To determine the relationship between mean acute cellular rejection score and the presence of atherosclerosis or fibrointimal hyperplasia in cardiac allografts at autopsy.

Design.-This retrospective, autopsy-based study examined 27 heart transplant patients to evaluate for graft vascular disease. A rejection score for each patient was calculated as the average of all the rejection scores determined by endomyocardial biopsy. Gross and histologic examination of the heart was used to divide patients into 3 groups: no coronary artery disease, atherosclerosis, and fibrointimal hyperplasia. Mean rejection scores were calculated for each of these groups for all patients and patients who survived longer than 3 months. Mean rejection scores were compared by an analysis of variance and pairwise t tests.

Results.-Mean rejection scores demonstrated a trend of increasing value from no coronary disease (0.323) to atherosclerosis (0.569) to fibrointimal hyperplasia (0.835). Only fibrointimal hyperplasia had a significantly higher mean rejection score compared with patients with no coronary disease when examined in all patients (P = .01) and in patients who survived longer than 3 months (P = .049).

Conclusion.-This study showed that the development of coronary artery fibrointimal hyperplasia, but not atherosclerosis, was significantly related to mean acute rejection score.

(Arch Pathol Lab Med. 2005;129:1283-1287)

Heart transplantation is commonly used to extend the life of patients with end-stage cardiomyopathy, and more than 61000 of these procedures have been reported to the International Society for Heart and Lung Transplantation (ISHLT) through 2002.' The 1-year survival rate after transplantation is approximately 80%, and half of patients survive more than 9 years.1 With this length of survival, graft vascular disease (GVD) has become a significant factor that limits both allograft function and long-term survival.1-8

Graft vascular disease may take the form of typical atherosclerotic plaques or fibrointimal hyperplasia (FIH).9-14 Atherosclerotic plaques may be inherited from the donor heart and can continue to develop in the allograft recipient.12-14 Fibrointimal hyperplasia is a form of accelerated atherosclerosis that involves large epicardial vessels and their intramyocardial branches and takes the form of concentric fibrointimal hyperplasia that diffusely involves the vessel.9,11-13 The incidence of GVD is reported to be 5% to 25% at 1 year, 27% to 61% at 5 years, and 45% to 80% at 8 to 10 years.1,6,15-19 Various risk factors for GVD have been postulated, including donor age, recipient age, sex, obesity, hyperlipidemia, hypertension, pretransplantation diagnosis, ischemie time at transplantation, cytomegalovirus or hepatitis C virus infection, HLA antibodies, delayed hypersensitivity, complement activation, cell-mediated alloimmunity to donor vascular endothelium, vasculitis, interleukin 2 messenger RNA expression, and immunosuppressive protocol.6,10,18,20-35

Acute cellular rejection is characterized by an inflammatory infiltrate that may be associated with damage to the heart. The ISHLT grading system assigns grades of O to 4, depending on the nature of the infiltrate and the presence of myocardial and vascular damage.36 The role that acute cellular allograft rejection plays in GVD is debated. Studies have implicated recurrent major rejection episodes,15 increased numbers of rejection episodes within 3 months or 1 year of transplantation,37 a greater number of rejection episodes more than 1 year after transplantation,38 the intensity and frequency of rejection,9,17 early moderate rejection,23 composite or mean rejection,9,11,31,39 total number of rejection episodes,29,40 and recurrent mild rejection.41,42 Others have reported no relation between GVD and acute rejection.43,44

This article documents the presence of GVD as determined at autopsy with increasing time from transplantation. We determined whether the occurrence of no coronary artery disease, typical atheromatous plaques, and FIH was significantly related to mean acute rejection score.

MATERIALS AND METHODS

From 1985 to August 2001, 325 orthotopic heart transplantations were performed at the Duke University Medical Center. Ninety-seven of these patients subsequently died. The study was limited to first-time heart transplant recipients; additional heart transplantations and heart-lung transplantations were excluded. Only patients with at least 1 antemortem endomyocardial biopsy specimen to evaluate for rejection were included in the study.

The immunosuppression therapy received by most of the patients consisted of induction with rabbit antithymocyte globulin and maintenance with cyclosporine, azathioprine, and prednisone. One patient did not receive any induction therapy due to hepatitis C infection. Three patients who underwent transplantation in 2000 or later received daclizumab instead of rabbit antithymocyte globulin for induction. One patient started maintenance immunosuppression therapy with cyclosporine, mycophenolate mofetil, and prednisone.

The standard protocol for treating acute cellular allograft rejection was as follows. No change in therapy was instituted for ISHLT grade rejection of IA or IB. If treated, oral prednisone was used for recurrent grade 2 rejection. Grade 3A or 3B rejection was treated with intravenous methylprednisolone sodium succinate (Solu-Medrol) for 3 days followed by an oral prednisone taper. Grade 4 rejection or rejection associated with hemodynamic compromise resulted in hospitalization of the patient and treatment with additional immunosuppression medications, such as muromonab-CD3 or cyclophosphamide. Any patient treated for rejection typically underwent an additional biopsy in 2 weeks to evaluate response to therapy.

At autopsy, the coronary arteries were serially sectioned, and the most severe lesions within the vessels were noted. A stenosis that narrowed the cross-sectional area of the lumen of a coronary artery more than 50% based on a gross estimation was considered significant. Representative sections of these lesions were submitted for histologie evaluation. Based on the histologie appearance, the coronary artery disease was readily divided into 2 types: the typical eccentric atherosclerotic plaques seen in the general population (hereafter referred to as atherosclerosis) and the concentric FIH of accelerated allograft vasculopathy that is characteristic of transplanted hearts. The criteria that can be used in making a diagnosis of atherosclerosis versus FIH have been described elsewhere.10 Although these 2 diseases are not mutually exclusive,45 a patient was assigned to 1 category based on the predominant disease present. The patients were thus divided into 3 groups: no coronary disease, atherosclerosis, and FIH.

A rejection score was calculated for each patient as the average of all of the acute rejection episodes as measured on endomyocardial biopsy. The ISHLT grade of rejection was used with the A and B designation dropped for this analysis (ie, IA - IB = 1; 3A = 3B = 3). A biopsy specimen without acute rejection was assigned a score of O. The relationship of rejection score to coronary disease was evaluated by calculating a mean rejection score for each of the 3 subpopulations of interest. This mean rejection score was the average of the rejection scores of all the patients in a group. Mean rejection scores were calculated for all patients and for those who survived more than 3 months after transplantation. A 3-month cutoff was chosen because severe FIH has been documented to occur this soon after transplantation.10 A 3-month cutoff also excluded patients with rejection scores of O based on few biopsy specimens. An analysis of variance was used to determine whether any significant differences existed in the mean rejection scores among the 3 groups. Two-way comparisons among the groups were then made by a Bonferroni t test. To achieve approximately normally distributed residuals, we used the square root of the rejection score as the dependent variable; no coronary disease, atherosclerosis, and FIH were treated as dummy variables. P ≤ .05 was considered statistically significant.

RESULTS

The patient characteristics are given in Table 1. The demographics of all patients and those who survived longer than 3 months after transplantation were similar except that the minimum and average survival after transplantation were longer for the latter group, as expected. Two pediatrie patients, aged 13 and 15 years, survived 3.2 and 1.9 years after transplantation, respectively. Both had FIH of their coronary arteries at postmortem examination. The indications for transplantation are given in Table 2; the relationship of this and other clinical variables with respect to the development of GVD are given in Table 2.

The 27 patients in the study underwent a total of 533 endomyocardial biopsies (Table 1). The total number of biopsies decreased slightly to 513 when only patients surviving longer than 3 months after transplantation were considered. The minimum number of biopsies per patient, however, increased significantly from 1 to 10 when all patients were compared with the subgroup with longer survival.

The rejection scores of the patients versus survival time after transplantation are shown in Figure 1. There was no significant relationship between rejection score and survival time (P = .25 by linear regression analysis). Patients without coronary disease were seen immediately and up to 3.1 years after transplantation. Beyond 3.1 years, all patients had either atherosclerosis or FIH. In some patients, atherosclerosis was seen soon after transplantation. The rejection scores of patients with atherosclerosis exhibited a scatter that overlapped substantially with no coronary disease and FIH. The patients with FIH in general had higher rejection scores than those with no coronary disease. The first patient with FIH did not have the condition diagnosed until 1.9 years after transplantation.

Five patients with survival times of fewer than 2 months after transplantation had rejection scores of O (Figure 1). Three of these patients had no coronary artery disease and 2 had atherosclerosis. All of these patients had fewer than 6 biopsy specimens. Two additional patients with survival times of fewer than 3 months had atherosclerosis. All remaining patients survived longer than 3 months.

The mean ± 1 SD rejection scores for patients with no coronary disease, atherosclerosis, and FIH are shown in Figure 2. The mean rejection scores in all patients demonstrated an increasing trend from no coronary disease (0.323) to atherosclerosis (0.569) to FIH (0.835). Analysis of variance revealed that not all mean rejection scores for the 3 groups were equal (P = .05). The 3 two-way comparisons of the groups yielded one significant difference in mean scores, that between patients with FIH and those with no coronary disease (P = .01). A similar trend was present for patients who survived longer than 3 months; the mean rejection scores increased from no coronary disease (0.518) to atherosclerosis (0.595) to FIH (0.835). Analysis of variance results for differences in mean rejection scores for patients who survived longer than 3 months were not significant (P = .11). However, 1 of the 3 two-way comparisons revealed a significant difference, that between mean rejection scores of the FIH patients and those with no coronary disease (P = .049).

COMMENT

Although most reports in the literature have also found some type of association between GVD and acute rejection, the nature of the reported relationships was variable.* Hauptman et al27 summarized reasons for the lack of consistency among these clinical studies, which include retrospective designs, small study sizes, different immunosuppression regimens, lack of control for infections, varying endomyocardial biopsy schedules, different treatment philosophies for acute rejection, and nonsensitive methods for diagnosing GVD. The use of coronary angiography for the diagnosis of GVD has been a particular problem, since this modality may underestimate the incidence of FIH due to the diffuse nature of this disease process.13,46 Intravascular ultrasound, which provides a more accurate assessment of GVD,47-49 has been used in a few studies.14,26,31,35,42,50

Atherosclerosis was not significantly related to mean acute rejection score. Most reported studies in the literature have focused on FIH, but Schutz et al9 noted that 3 of 16 patients with GVD had atherosclerosis. The mean rejection scores in this study were higher in a cohort of patients with GVD that included both atherosclerosis and FIH.

Fibrointimal hyperplasia did not appear in any of the patients until 1.9 years after transplantation. Only patients who survived more than 2 years had FIH that narrowed a coronary more than 75%. These results are consistent with the well-established observation that FIH needs some time, 3 months or more,10 to become established after transplantation and then subsequently increases in severity. The development of GVD seemed inevitable in patients who survived much longer than 3 years after transplantation.

Several clinical variables seemed to affect the development of GVD. Atherosclerosis was more common in patients taking cholesterol-lowering drugs (71.4%) than in those not taking such medications (23.1%). It is possible that the hypercholesterolemia that necessitated such drugs contributed to atherosclerosis. Diabetes mellitus did not seem to predispose to allograft atherosclerosis. The patients who underwent transplantation for ischemic cardiomyopathy were less likely to develop atherosclerosis and more likely to develop FIH than patients who underwent transplantation for idiopathic cardiomyopathy; the reasons for these trends are not obvious.

The causes of death of the 6 patients with FIH were GVD (3 [50%]), acute rejection (1 [16.7%]), complications of noncardiac surgery (1 [16.7%]), and cerebral hemorrhage and infarction (1 [16.7%]).8 The causes of death of the 13 patients with atherosclerosis were complications of transplantation (2 [15.4%]), infection (2 [15.4%]), malignancy (2 [15.4%]), arrhythmia (2 [15.4%]), acute rejection (1 [7.7%]), complications of noncardiac surgery (1 [7.7%]), cirrhosis (1 [7.7%]), and unclear (2 [15.4%]).8 We suggest that patients who developed FIH were at an increased risk of death as a direct result of their GVD. It is worth noting that none of the patients with atherosclerosis died as a result of their GVD. Since patients with FIH had the highest mean rejection scores, another potential risk would be the increased levels of immunosuppression used in their treatment. Complications of noncardiac surgery may result from immunosuppression-related delayed wound healing and infection.8

Several limitations of our study need to be stated. Since our study was retrospective and autopsy based, a potential for selection bias existed. We examined the coronary arteries only at one point, the end point of patient death. The severity of atherosclerosis was determined by the most severe disease found at one point within a coronary artery; we did not attempt to assess the severity of GVD along the length of the coronary arteries. Certainly, following up a cohort of patients prospectively through time, preferably with intravascular ultrasound, and then examining their coronary arteries at necropsy would be a more robust approach. Finally, we do not control for other clinical factors, such as diabetes, hyperlipidemia, or irnmunosuppressive drug regimens that have been shown to influence the development of GVD. We would agree with the conclusion of Mehra et al31 that the development of GVD is influenced by an interplay of acute rejection, immunosuppression, and other clinical factors such as donor age.

* References 9, 11, 15, 17, 23, 29, 31, 36-42.

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Russell T. Alexander, MD; Sarah Lathrop, DVM, PhD; Robin Vollmer, MD; Laura Blue, NP; Stuart D. Russell, MD; Charles Steenbergen, MD, PhD

Accepted for publication June 15, 2005.

From the Departments of Pathology (Drs Alexander and Steenbergen) and Cardiology (Ms Blue and Dr Russell), Duke University Medical Center, Durham, NC; the Office of the Medical Investigator, University of New Mexico, Albuquerque (Dr Lathrop); and the Department of Pathology, Veterans Affairs Medical Center, Durham, NC (Dr Vollmer). Dr Alexander is now with the Milwaukee County Medical Examiner's Office, Milwaukee, Wis. Dr Russell is now with the Department of Medicine-Cardiovascular, Johns Hopkins University, Baltimore, Md.

The authors have no relevant financial interest in the products or companies described in this article.

Presented in abstract form at the College of American Pathologists national meeting, San Diego, Calif, September 12, 2003. The abstract was published in the ARCHIVES (Alexander RT, Steenbergen C. Coronary artery fibrointimal hyperplasia is related to mean acute rejection score in the cardiac allograft; coronary artery atherosclerosis and systemic malignancy are not. Arch Pathol Lab Med. 2004;128:142-143).

Reprints: Russell T. Alexander, MD, Milwaukee County Medical Examiner's Office, 933 W Highland Ave, Milwaukee, Wl 53233-1458 (e-mail: rusty4i@yahoo.com).

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