(Circulation. 1996;93:1133-1140.)
© 1996 American Heart Association, Inc.
Articles |
Heart Transplantation–Associated Perioperative Ischemic Myocardial Injury
Morphological Features and Clinical Significance
From the Departments of Pathology (G.L.W., F.J.S.), Medicine (Cardiovascular Division) (E.L., A.I.K.), and Surgery (Division of Cardiac Surgery) (G.S.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, Mass, and the Department of Pathology (B.F.), Mt Sinai College of Medicine, New York, NY.
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Abstract |
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Background The frequency and clinical significance of perioperative ischemic myocardial injury (PIMI) after heart transplantation and the diagnostic features distinguishing PIMI from rejection are not well defined.
Methods and Results We evaluated PIMI in the first four weekly endomyocardial biopsies and/or autopsy myocardium from 140 consecutive orthotopic heart transplantation recipients (1984 to 1991) by grading the severity of coagulative myocyte necrosis (CMN) as absent, 0; mild-focal, 1; moderate-multifocal, 2; or severe-confluent, 3, and determining the evolution of morphological features of its healing. CMN (often with contraction bands) was noted in 124 patients (89%); 24 patients (17%) had grade 3 CMN, of which 4 died within 30 days of transplantation. Nevertheless, at 1 year after surgery, survival was similar in patients with and without severe injury. Increased cold ischemic time but neither donor age nor intensity of inotropic support correlated with more severe early ischemic injury. PIMI inflammation was characterized by a predominantly polymorphonuclear/histiocytic infiltrate that contained lymphocytes and plasma cells, expanding the interstitium but not encroaching upon and separable from adjacent viable myocytes. Histological features of PIMI developed and resolved more slowly than those of typical myocardial infarct necrosis in nonimmunosuppressed patients; at 4 weeks, CMN persisted in 20% of patients and residual healing in nearly half. Diagnostic rejection was observed concurrently with PIMI in 54 of 533 biopsies (10%).
Conclusions Diagnosed by conventional histological criteria, PIMI is prevalent early after heart transplantation and has a protracted healing phase that can mimic or coexist with rejection. Extensive PIMI has deleterious impact on short-term survival, but the long-term impact of PIMI remains to be established.
Key Words: pathology • rejection • transplantation • biopsy
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Introduction |
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Perioperative ischemic myocyte injury (PIMI) has been described in endomyocardial biopsies and autopsy heart specimens examined in the first several weeks after orthotopic heart transplantation.1 2 3 4 It is reasonable to expect that severe PIMI would impact markedly on short-term function and survival after heart transplantation and to hypothesize that lesser degrees of PIMI could contribute to late deterioration of function through myocardial fibrosis and possibly stimulate the development of graft arteriosclerosis. PIMI most likely arises predominantly during the obligatory ischemic time that accompanies procurement and implantation of a donor heart.
The histological features that characterize PIMI and those that specifically distinguish ischemic injury and its repair from other pathological processes, such as acute allograft rejection,5 have yet to be systematically described. Furthermore, the incidence, rate of evolution, and clinical significance of PIMI on immediate or long-term survival after orthotopic heart transplantation have not previously been studied in a large cohort of heart transplant recipients. Increasing awareness of and appreciation for PIMI as a distinct clinicopathological entity distinct from myocyte rejection should decrease augmentation of early postoperative immunosuppression, with its resultant short- and long-term sequelae such as infection, diabetes, renal impairment, osteoporosis, cataracts, and posttransplant lymphoproliferative disorders.
Accordingly, the objectives of this study were (1) to develop a comprehensive and systematic pathological description of PIMI; (2) to compare the effects of donor and procurement-related variables on the incidence and severity of PIMI; and (3) to determine the relationship between PIMI and patient prognosis after cardiac transplantation.
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Methods |
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This study was based on a retrospective review of endomyocardial biopsies and clinical data obtained from 140 consecutive patients who underwent orthotopic heart transplantation at Brigham and Women's Hospital between 1984 and 1991.
Clinical Data
All data were retrieved from patient files and
donor information
sheets obtained at the time of organ procurement. Donor data included
age, sex, administration of inotropic or vasopressor agents before
organ harvesting, and total ischemic time. For the purpose of
one facet of this analysis, we arbitrarily divided our
population to four classes with regard to ischemic time: <100
minutes, 100 to 149 minutes, 150 199 minutes, and 
200 minutes.
Recipient data included age, sex, and the primary disease process that
necessitated cardiac transplantation. Recipient outcome
parameters included number of rejection episodes within the
first year after transplantation, actuarial survival after
transplantation, and, as appropriate, cause of death and other autopsy
findings.
Hearts were procured according to a standard protocol that included administration of 1 L of cold potassium crystalloid cardioplegia (K=30 mEq/L) over 5 to 8 minutes via the aortic root. Hearts were then triple-bagged in iced saline and transported. In rare instances, additional cold crystalloid cardioplegia or terminal warm blood cardioplegia was administered during implantation, according to expected prolonged ischemic time or surgeon preference.
Maintenance immunosuppression consisted of cyclosporine, azathioprine, and prednisone; no patient received lymphocytolytic induction therapy with OKT3 or polyclonal antithymocyte globulin.
Endomyocardial Biopsies
Endomyocardial biopsy samples
(usually three
or four pieces from each procedure) were obtained from the right
ventricle of the transplanted heart using conventional
endomyocardial biopsy technique.6
Surveillance endomyocardial biopsies (EMBs) during
the first posttransplant year were performed routinely according to the
following schedule: weekly for the first 4 weeks, biweekly for 4 weeks,
monthly for 6 months, then every other month to 1 year. Additional
unscheduled biopsies may have been performed due to an adverse change
in the recipient's clinical condition or new findings on objective
testing. The tissues were fixed in buffered formalin, paraffin
embedded, serially sectioned at 3 to 4 µm, and stained with
hematoxylin and eosin by routine techniques. At least three separate
slides (levels) were examined for each biopsy. A Masson's trichrome
stain was performed on one level of most biopsies. All biopsies
performed during the first 4 weeks after transplantation were examined
for each patient. Four patients who died before the first biopsy were
included on the basis of heart examination at autopsy. Six additional
patients who died during the review period were classified on the basis
of their previous biopsies, and comparisons of
endomyocardial biopsy findings with those of the
heart at autopsy were made when available. In total, 533
endomyocardial biopsies were examined (136 at 1
week, 135 at 2 weeks, 132 at 3 weeks, and 130 at 4 weeks). Care was
taken to identify prior biopsy sites to exclude these from the
estimation of myocyte damage. The following features were noted and
recorded for each biopsy.
Myocyte necrosis. Diagnosis of PIMI required the presence of its most definitive manifestation, coagulative myocyte necrosis (CMN), with or without contraction bands in the necrotic cells. Contraction bands in viable cells were considered to be artifact. The extent of myocyte injury was graded semiquantitatively: grade 0, no evidence of CMN; grade 1, mild (focal) CMN; grade 2, moderate (multifocal) CMN; grade 3, severe (confluent) CMN, and its location and distribution were recorded. The CMN grade used in the data represents the most extensive injury noted in the four biopsies on a particular patient.
Myocyte vacuolization. Vacuolization (myocytolysis) of subendocardial or peri-infarct myocytes was considered to be a marker of sublethal ischemic injury.7
Inflammation. Inflammation was classified by cell type (ie, polymorphonuclear leukocytes, macrophages [including macrophage giant cells], lymphocytes, plasma cells, and eosinophils) and location (ie, endocardial, perivascular, interstitial).
Vascular changes. Intramyocardial blood vessels were examined for endothelial swelling, endothelial cell-leukocyte adhesion, thrombosis, and frank vasculitis.
Rejection. Acute cellular rejection was graded according to the International Society for Heart and Lung Transplantation (ISHLT) criteria8 regardless of the presence or absence of CMN within the same biopsy.
Autopsy Analysis
Autopsy material was reviewed from all
patients who died during
the study. Multiple transmural sections from the left
ventricular anterior, lateral, and posterior free walls,
septum, and right ventricle were examined in the same manner as the
endomyocardial biopsies for presence or absence of
ischemic injury. The cause of death was recorded.
Statistical Analysis
Pathological and clinical data were
analyzed using the
SAS statistical analysis package (SAS/PC version 6.04).
Contingency tables were analyzed using Pearson and
Mantel-Haenzel 
2 (PROC FREQ). Continuous
variables between the classes were compared by ANOVA, Tukey's
method was used for pairwise comparisons (PROC GLM), and the
distribution of discrete variables was compared by the
Kolmogorov-Smirnov test (PROC NPAR1WAY). Survival data were
analyzed using the product-limit method (PROC
LIFETEST). A value of P<.05 was considered statistically
significant.
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Results |
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Patient Characteristics
The age of the recipient population was 45±12 years (mean±SD; range, 14 to 62 years). There were 106 male subjects and 34 female subjects. Indications for transplantation were ischemic heart disease in 53, idiopathic dilated cardiomyopathy in 71, valvular heart disease in 8, and "other" in 8 patients.
The mean age of the donor population was 27±6 years (range, 11 to 55 years). There were 108 male subjects and 32 female subjects. Eighty-four (60%) were maintained on ß-adrenergic agents before cardiac procurement. The mean ischemic time was 157±48 minutes (range, 59 to 310 minutes).
Histological Characteristics of PIMI
PIMI was characterized
by the following morphological features:
CMN with or without contraction bands (in necrotic tissue) observed
within 4 weeks of transplantation, usually followed by a
heterogeneous interstitial, perivascular,
and/or endocardial inflammatory infiltrate that was primarily composed
of polymorphonuclear leukocytes and histiocytes
(macrophages). The inflammatory response also included plasma
cells and occasional lymphocytes, and myocyte injury was often
accompanied by fat necrosis, vacuolization of adjacent viable myocytes,
and/or ischemic microvascular injury (Figs 1
and
2 and Table 1).
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Myocyte
hypereosinophilia, loss of nuclei, smudging, and loss of
cytoplasmic detail and scattered polymorphonuclear leukocytes were
the most characteristic features of early CMN (see Fig 1
, A and
B).
However, in the very early biopsies (approximately 1 week after
surgery), necrotic cells were frequently difficult to distinguish in
sections stained with hematoxylin and eosin; they were more prominent
on the Masson's trichrome stain. The highest concentration of necrotic
myocytes was often immediately beneath the endocardial surface; indeed,
an intervening zone of viable myocardium (presumably
usually perfused directly from blood in the ventricular
cavity) that characterizes typical myocardial infarction (occurring in
a blood-filled heart) was frequently absent. Necrotic cells were
either isolated or, more frequently, clustered into small groups.
Severe CMN was denoted by large areas of confluent myocardial
necrosis.
Later biopsies revealed an extensive macrophage infiltrate
clearing necrotic myocytes; lymphocytes were a lesser but regular
component of this inflammation (Fig 1, C and D). The
inflammatory
response was predominantly in the interstitium or in perivascular
spaces, not encroaching on and usually with a clear separation from
adjacent myocytes. Polymorphonuclear leukocytes and obvious
cellular debris were frequently present in the inflammatory foci,
but eosinophils, often considered characteristic of
rejection-associated inflammatory infiltrates in
cyclosporine-treated patients,1 were
not frequently noted.
Healing fat necrosis, characterized by empty
spaces that resembled
adipocytes without nuclei, with a surrounding mononuclear inflammatory
infiltrate containing macrophage giant cells, was observed in
many biopsies (Fig 2A). There was no correlation between the
severity
of CMN and the observation of fat necrosis. Myocyte vacuolization was
often prominent adjacent to necrotic myocardium (Fig 2B).
Small blood vessels with endothelial cell swelling,
adherent intraluminal polymorphonuclear or mononuclear leukocytes,
and mural or perivascular inflammation were occasionally seen.
Microvascular thrombosis was not observed. There was no correlation
between the severity of CMN and microvascular changes, but the
population exhibiting these changes was very small. All of the biopsies
with microvascular injury had obvious CMN.
Prevalence and Progression of PIMI
PIMI was frequently
observed on endomyocardial
biopsies taken within 4 weeks after surgery. Overall, 124 of 140 (89%)
recipients had some degree of CMN diagnosed either on
endomyocardial biopsies performed 1 to 4 weeks
after transplantation or on autopsy material when patients died before
the first biopsy (Fig 3). CMN was most frequently seen
initially in the first 2 weeks after transplantation (76% of first
biopsies and 72% of second biopsies), and the associated inflammation
occurred in a protracted fashion, with maximal prevalence at 2 to 3
weeks after transplantation (76% and 77% at weeks 2 and 3,
respectively; Fig 4). The amount and progression of PIMI
were remarkably consistent on successive biopsies from an
individual patient. The posttransplant interval to the initial
histological diagnosis of CMN was significantly shorter
than the posttransplant interval to the initial onset of inflammation
(P<.0001, Kolmogorov-Smirnov test).
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Protracted Healing Phase of PIMI and Concurrent
Rejection
The healing phase of PIMI was frequently quite protracted.
Persistent CMN was noted at 4 weeks in 26 of 130 biopsies (20%).
Nearly half (49%) of the biopsies examined 4 weeks after
transplantation had residual inflammation with a morphology appropriate
for PIMI and not diagnostic of rejection (Fig 1E). The
duration of inflammation tended to be longer in patients with more
severe CMN.
Nevertheless, the presence of acute or healing PIMI within a biopsy did not preclude the presence of acute cellular rejection within the same biopsy. Acute cellular rejection was noted in 77 of 533 (14%) of the biopsies examined. In only 23 (4%) was rejection isolated; in 54 (10%), rejection and PIMI coexisted.
Clinicopathological Correlations
Increased CMN grade was
associated with longer total
ischemic time. This correlation was statistically significant
(P=.05 Pearson 2 test,
P=.002 Mantel-Haenszel 2; Table
2). No patient with ischemic time less than 108
minutes had CMN grade 3, and no patient with ischemic time
greater than 194 minutes had CMN grade 0. Comparison of mean
ischemic time between patients with different CMN grade also
shows significant difference (P=.02 by ANOVA), but pairwise
only CMN grades 0 and 3 differ at the .05 level. The ischemic
times (mean±SD) corresponding to each CMN grade were 133±39,
156±44,
156±55, and 179±35 for grades 0, 1, 2, and 3, respectively.
Higher
CMN grade was not associated with increased pressor dosage, advanced
age, or sex of the donor. Finally, no correlation was observed between
the presence or severity of CMN and the number of treated rejection
episodes (EMBs with ISHLT grade 3A) occurring during the first
posttransplant year.
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Moreover, no difference in 1-year actuarial
survival was observed in
patients with CMN grade 3 versus patients with grade 0, 1, or 2
combined (P=.41, Fig 5). Since the survival
curves have essentially the same slope after the first month, the
slight survival difference is due to early mortality. Ten patients died
early (within 30 days of transplant); of these, 9 had some CMN, with
44% (4 patients) being grade 3 (P=NS). Indeed, recipients
with grade 3 CMN suffered early postoperative death from otherwise
unexplainable graft failure more frequently than patients with <grade
3 CMN (4 of 24 versus 2 of 116, P<.05).
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Discussion |
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The present study documented a high frequency of perioperative ischemic myocyte injury diagnosed by conventional histological criteria on endomyocardial biopsies obtained during the early posttransplant period of our heart transplant patients. The specific morphological characteristics of PIMI included CMN and a cellular infiltrate comprised predominantly of polymorphonuclear leukocytes and macrophages, with some lymphocytes and plasma cells. These features are distinct from those of other entities that occur during this period, including cellular allograft rejection. Prolonged total ischemic time of the allograft was associated with more severe grades of CMN. Finally, severe (grade 3) CMN was associated with an increased rate of early postoperative death, but actuarial 1-year recipient survival was not significantly decreased.
Recognition of PIMI and Differentiation From
Rejection
In the vast majority of cases, PIMI can be distinguished
from
acute cellular rejection using conventional
histological criteria (Table 3). The
morphology of myocyte necrosis observed in PIMI was largely typical for
that of non–transplant-associated ischemic coagulation
necrosis, with cellular hypereosinophilia, stretching, thinning, and
loss of nuclei. However, in contrast to typical myocardial infarction,
myocyte necrosis often extended to the endocardial surface, suggesting
that the injury occurred while the heart was not filled with
oxygenated blood. Moreover, the inflammation due to healing
PIMI is generally more diffuse and rich in neutrophils and
macrophages but has less lymphocytes than that of acute
cellular rejection. In addition, in early PIMI, the extent of myocyte
injury usually seems out of proportion to the associated inflammation.
Nevertheless, the most important histological features
that distinguish PIMI from acute rejection are CMN and a sharp border
between polymorphous inflammation and nearby viable myocytes in
PIMI. In contrast, cellular rejection is characterized by a
predominantly lymphocytic infiltrate closely apposed to individual
myocytes, some of which are frayed, scalloped, and/or vacuolated.
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Recognition of PIMI on endomyocardial biopsy will contribute to reducing the long-term clinical sequelae of excessive immunosuppression. On the basis of the data in this study, it is apparent how pathologists could overdiagnose PIMI as acute rejection, particularly during its cellular healing phase. From the pathologist's perspective, this is the "safe" approach, since underdiagnosing a rejection episode may have serious consequences, yet the short-term risks of augmented immunosuppressive therapy are relatively small. There is little support in the literature for doing otherwise. Moreover, diminution of the infiltrate after augmented immunosuppression does not constitute evidence that an infiltrate represented rejection, since inflammation due to healing ischemic injury is expected to progressively resolve and such inflammation is likely to be suppressed by steroids.
Several factors
could affect the reliability of diagnosing PIMI after
heart transplantation. First, PIMI and cellular rejection are most
difficult to distinguish in later (3 weeks)
endomyocardial biopsies because CMN frequently is
resolved and the healing response of PIMI is protracted due to the
anti-inflammatory effects of maintenance
immunosuppression.9 Indeed, although not part of this
study, we have observed inflammation considered to be healing
ischemic damage more than 6 weeks after surgery in some
patients. Moreover, concurrent rejection and PIMI were diagnosed in
10% of the biopsies taken during this period. Second, lymphocytolytic
induction therapy may influence the appearance of PIMI in the early
posttransplant period. In some studies, induction with OKT3 has been
shown to delay the onset of the first rejection episode,10
and it also may diminish inflammatory infiltrates involved in repair.
Interestingly, such therapy was used in a center at which vascular
rejection was widely reported11 12 ; the vascular
rejection
grading schema used in these studies acknowledges the difficulty in
distinguishing PIMI from vascular rejection and attributes
endothelial swelling and ischemic myocyte
changes seen in early biopsies to PIMI. Moreover, the healing response
to PIMI is likely to be depressed and potentially more prolonged in
patients receiving induction therapy. The results of this study would
suggest, however, that biopsies taken even 4 weeks after
transplantation can have characteristics of healing ischemic
injury and that the associated inflammation may mimic cellular and/or
vascular rejection.
Causes of PIMI
Distant procurement of hearts has been
associated with decreased
long-term recipient survival,13 and a recent study
demonstrated the negative influence of increasing cold ischemic
time on graft survival after cardiac transplantation.14
Hearts preserved for more than 4 hours had a significantly lower
survival rate than those preserved for less than 4 hours; a trend
toward decreased survival time with longer cold ischemia was
observed at times less than 4 hours. Three intervals probably are
important: (1) the brief ischemic period from donor aortic
cross-clamping for cold cardioplegic infusion to immersion of the
heart in iced saline, (2) the cold ischemic period that
comprises the time of transportation while the heart is immersed in
iced saline, and (3) the ischemic period in the operating room
during donor heart implantation to the initiation of warm,
oxygenated blood reperfusion in the recipient. Efforts to
limit the occurrence of PIMI have concentrated on donor selection,
preservation media, and reperfusion techniques.15 16
While procurement-related ischemic injury is considered most important in this setting,17 other mechanisms of myocyte injury are possible. Donor-associated injury could be secondary to CNS trauma and brain death with resultant endogenous catecholamine-induced myocardial necrosis and/or the exogenous administration of catecholamines.18 19 The dominant morphological pattern of catecholamine-induced injury is focal myocyte necrosis with contraction bands and histiocytic inflammation.20 Furthermore, the specific type of CNS trauma and the duration from declaration of brain death to organ procurement may affect the expression of these lesions in the donor heart.21 22 The possibility of postoperative ischemic injury is also recognized.
Other Clinical Implications
Although PIMI probably has a
multifactorial pathogenesis during
transplantation, the strongest measurable determinant of allograft
ischemic injury was total ischemic time. Prolonged
ischemic times have been associated with decreased survival
after transplantation, graft dysfunction, and increased incidence of
rejection and infection.14 23 24 This
study suggests that
the previously reported decreased 1-year actuarial survival associated
with increasing ischemic time14 may be due to the
effects of ischemic myocyte injury.
Ischemic injury could lead to late allograft dysfunction either by fibrosis or by promoting graft arteriosclerosis. The long-term sequelae of the perioperative ischemic myocyte injury and resultant myocardial scarring remain to be studied. Both abnormal left ventricular diastolic filling patterns at 1 year after transplantation and fibrosis in early posttransplant biopsies have been correlated with ischemic time.25 26 Moreover, ischemic damage could contribute to the development of graft arteriosclerosis through endothelial injury,27 increased susceptibility to cytomegalovirus infection, and/or the promotion of rejection through release of donor alloantigens.28 Ischemic allograft injury caused by distant heart procurement and prolonged ischemic time has been shown to correlate with endothelial cell injury in ultrastructural studies.29 In the present study, ischemic microvascular injury was one of the features of the overall perioperative ischemic insult. Nevertheless, a previous experimental study showed no correlation of graft coronary disease with the severity of PIMI.30
Conclusions
The recognition of PIMI on endomyocardial
biopsy by pathologists is important after orthotopic cardiac
transplantation. The accurate diagnosis of PIMI and distinction of this
entity from cellular and/or vascular allograft rejection will decrease
unnecessary augmentation of immunosuppression and its associated short-
and long-term sequelae. Modifications of preservation techniques
aimed at reduction of PIMI incurred during transplantation may decrease
early mortality and perhaps decrease late graft dysfunction through
scarring and/or vascular lesions. Finally, widespread recognition and
consistent grading of PIMI will aid in the evaluation of
multi-institutional studies designed to evaluate potentially new
immunosuppressive therapies. Further studies are needed to determine
whether the high frequency of perioperative
ischemic injury reported in this study exists at other
institutions but is diagnosed as rejection, or whether it reflects a
large institutional/regional variation in the incidence of this
phenomenon.
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Acknowledgments |
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Dr Loh is the recipient of a Physician Scientist Award, K11-HL-02514, from the National Institutes of Health. Dr Schoen is supported in part by grant HL-43364 from the National Institutes of Health (Peter Libby, PI). We thank the members of the Brigham and Women's Hospital Cardiac Transplant Service for their efforts in the clinical management of the patients reported in this study. We appreciate the helpful comments of Dr Richard Mitchell on the study and manuscript. We also acknowledge the efforts of Claudia Davis in typing the manuscript. Dr Fyfe is presently with the Department of Pathology, Medical College of Pennsylvania and Hahnemann University, Philadelphia, Pa; Dr Loh is presently with the Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia.
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Note Added in Proof |
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Since the submission of this article, a study by Day et al has examined the role of peritransplant ischemic injury in the pathogenesis of cardiac allograft vasculopathy (Day JD, Rayburn BK, Gaudin PB, Baldwin WM, Lowenstein CJ, Kasper EK, Baughman KL, Baumgartner WA, Hutchins GM, Hruban RH. Cardiac allograft vasculopathy: the central pathogenetic role of ischemia-induced endothelial cell injury. J Heart Lung Transplant. 1995;14:S142-S149.). This study proposes that early ischemic injury to vascular endothelial cells initiates a process that ultimately leads to the development of allograft vasculopathy. These authors not only confirm the presence of ischemic myocardial injury in early posttransplant biopsies but also suggest its diagnostic significance in identifying patients at risk for developing allograft vasculopathy.
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Footnotes |
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Reprint requests to Frederick J. Schoen, MD, PhD, Department of Pathology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail fjschoen@bics.bwh.harvard.edu.
Received July 17, 1995; revision received October 16, 1995; accepted October 18, 1995.
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