(Circulation. 2000;102:890.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Changes in Surface Expression of Platelet Membrane Glycoproteins and Progression of Heart Transplant Vasculopathy
From Innere Medizin, Kardiologie, Charité-Campus Virchow and Deutsches Herzzentrum Berlin, Humboldt Universität zu Berlin (S.F.-M., W.B., M.S., E.F.); Zentrum für Labormedizin, Mikrobiologie and Transfusionsmedizin, Klinikum Karlsruhe (A.R.); 1. Medizinische Klinik, Klinikum rechts der Isar and Deutsches Herzzentrum, Technische Universität München (T.D., G.P.-M., M.G.); and Klinik für Herz-/Thorax- und Gefäßchirurgie, Deutsches Herzzentrum Berlin, Germany (R.H.).
Correspondence to Meinrad Gawaz, MD, 1. Medizinische Klinik Klinikum rechts der Isar and Deutsches Herzzentrum, Technische Universität München, Lazarettstraße 36, 80636 München, FRG. E-mail gawaz{at}dhm.mhn.de or to Wolfgang Bocksch, MD, Deutsches Herzzentrum, Augustenburgerplatz 1, 13353 Berlin, Germany.
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Abstract |
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Background—Transplant vasculopathy is the main limiting factor of the long-term success of heart transplantation. We sought to establish the role of platelets in the development and progression of transplant vasculopathy.
Methods and Results—Platelet analysis and intracoronary ultrasound examination were performed in 78 heart transplant recipients. Quantitative intracoronary ultrasound was used to define the severity of disease at baseline (48.8±4.5 months after transplantation) and at 1-year follow-up. Platelet activation was assessed with the use of immunological surface markers of activation (ligand-induced binding site 1 [LIBS-1], P-selectin, GPIIb-IIIa) and flow cytometry. We found that LIBS-1 immunoreactivity was significantly increased in patients with diffuse disease when compared with focal transplant disease (median [quartile], 27[14, 64] versus 18[7.9, 47], P=0.04). In a logistic regression model, we found that LIBS-1 was an independent predictor for the presence and progression of diffuse transplant vasculopathy (P=0.04). Patients with enhanced LIBS-1 levels (>75% quartile) had a 3.3-fold increased relative risk (95% CI 1.8 and 18.9, P=0.002) for the presence of diffuse transplant vasculopathy. When a cutoff value of 16.5 for the level of LIBS-1 was used, patients had a 4.8-fold increased relative risk (95% CI 1.9 and 12.5, P<0.01) for the progression of transplant vasculopathy.
Conclusions—Enhanced platelet activation is strongly associated with the development and progression of transplant vasculopathy. Understanding the underlying pathophysiological mechanisms might contribute to the development of treatment strategies to prevent transplant vasculopathy.
Key Words: vasculature • platelets • glycoproteins • transplantation
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Introduction |
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Transplant vasculopathy is the leading cause of late mortality and limits the long-term success of heart transplantation.1 2 3 Transplant vasculopathy is a diffuse and progressive thickening of the arterial intima that develops in the major and minor coronary arteries of transplanted heart allografts.2 The result is sudden and/or chronic progressive ischemic damage to the transplanted heart with subsequent functional organ failure.4 Similar phenomena exist between ordinary atherosclerosis and transplant vasculopathy, which includes the presence of a concentration of subendothelial inflammatory cells (monocytes/macrophages, T-lymphocytes), intimal smooth muscle cell proliferation, and extracellular matrix reorganization.5 Transplant vasculopathy is diffuse and frequently involves long segments of the affected arteries. It is characterized by concentric intimal thickening,6 whereas ordinary atherosclerosis usually involves one part of the artery more heavily than other parts, the latter producing prominent eccentric lesions.7
In the past, numerous pathomechanisms have been thought to be involved in the development of transplant vasculopathy, which includes immune-mediated vascular injury, inflammation of the vascular endothelium, ischemia-reperfusion injury, cytomegalovirus infection, or metabolic risk factors.2 Although the role of platelets in the development of atherosclerosis has been well recognized, the pathophysiological alterations of platelets in the context of transplant vasculopathy have been poorly studied. Platelets contain a variety of proinflammatory and proliferative compounds that are released in the microenvironment of thrombus formation.8 Contact of platelets with the endothelium induces alterations in the adhesive and chemotactic properties of the endothelial cells that support monocyte adhesion and transmigration and thereby the early inflammatory mechanisms in the process of atherosclerotic changes within the vessel wall.9 10 11 12
The purpose of this study was to evaluate the changes of platelet membrane glycoproteins as immunological activation markers of circulating platelets in patients with transplant vasculopathy.
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Methods |
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Patients and Study Design
A total of 78 consecutive patients, who underwent routine clinical follow-up after allograft heart transplantation, were entered into the study. The indications for heart transplantation were terminal congestive heart failure caused by idiopathic cardiomyopathy (n=57), primary pulmonary hypertension (n=3), ischemic heart disease (n=17), and congenital valve disease (n=1). Patients were treated with standard triple-drug immunosuppressive therapy that consisted of cyclosporine, corticosteroids, and azathioprine. Prospectively, we hypothesized that changes in platelet membrane glycoproteins, which occur in patients with transplant vasculopathy, are associated with the severity and progression of the disease. All patients (n=78) were evaluated by heart catheterization, coronary angiography, and quantitative intracoronary ultrasound at the commencement of the study, and 71% of the patients (n=55) were reevaluated after 1 year. The time from transplant to initial enrollment of all patients was 48.8±4.5 months (mean±SEM; range 12.3 to 56.3 months) (Table 1
).
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According to quantitative intracoronary ultrasound (ICUS), described below,13 we divided the study patients in 2 groups: group 1, diffuse, circumferential plaque formation, and group 2, focal or polyfocal plaque formation located at isolated sites with noncircumferential changes.
Blood samples were taken from the femoral artery before cardiac catheterization. With the use of a multiple-syringe sampling technique, the first 2 mL of blood was discarded. Thereafter, 2.5 mL of blood collected in EDTA was used for the determination of blood count, PlA polymorphism, and cyclosporine plasma levels. For flow cytometric analysis, 0.5 mL of blood was collected into a polypropylene syringe that contained 1.0 mL of a fixative that contained methacrolein (CyfixII).14 The study protocol was approved by the Institutional Ethics Committee, and all patients provided informed written consent.
Heart Catheterization and ICUS
After intracoronary administration of 0.2 mg
nitroglycerin, an intravascular ultrasound catheter
(Five-64, F/X Endosonics) was pushed into the left coronary
artery, and catheter pullback was performed manually. For longitudinal
orientation, septal or diagonal branches were used as anatomic
landmarks. Qualitative and quantitative plaque analysis was
done at the site of minimum lumen diameter for the left main
coronary artery and for every left anterior descending (LAD)
segment. Evaluation of plaque morphology was carried out following
published guidelines on ICUS imaging.15
Because the conventional Stanford classification6
considers only the cross-sectional changes, we used the following
classification,13 which also takes into account the
longitudinal distribution of the plaque. Axial plaque distribution was
classified as (1) "circumferential" if intimal thickening or plaque
burden involved the total cross section of the vessel (Figure 1, top), and (2) as
"noncircumferential" if 
10% of the cross section was free of
plaque burden or intimal thickening (Figure 1, bottom).
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] with continuous plaque formation in entire LAD in
longitudinal reconstruction) and (top) with focal plaque formation of
LAD (noncircumferential, homogeneous plaque formation
without calcification [
Longitudinal plaque distribution was classified as focal if only 1
(focal) or more (polyfocal) discrete coronary lesions separated
by nondiseased were found throughout the ICUS pullback (Figure 1
, bottom) and as diffuse if continuous plaque formation that
involved at least 1 complete coronary segment occurred (Figure 1, top). According to the guidelines of intravascular
ultrasound,15 average plaque thickness, maximum plaque
thickness (MPT), average plaque area, maximum plaque area, average
intimal index, and maximum intimal index were calculated. Differences
in plaque thickness within 1 year
(
MPT=MPT2-MPT1) were
calculated from MPT determined at time of the commencement of the study
(MPT1) and at 1-year follow-up
(MPT2). Disease progression was defined as an
increase of >0.3 mm of MPT after 1 year at a precise anatomic
site (Figure 2).16
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) has increased from 1.1.
to 1.7 mm.
Platelet Flow Cytometry and Analysis of PlA
(GPIIIa) Polymorphism
Evaluation of surface expression of platelet membrane
glycoproteins was performed with the use of specific
monoclonal antibodies and 2-color whole-blood flow cytometry, as
described in detail elsewhere.9 17 18 Specific monoclonal
antibody binding was expressed as relative mean particle
immunofluorescence (fluorescin) (CD41,
ligand-induced binding site 1 [LIBS-1], generously provided by Dr
Mark Ginsberg, Scripps Clinic, La Jolla, Calif)9 19 or
percentage of positive platelets (CD62P) of total platelet
population and was used as a quantitative measurement of
glycoprotein surface expression. Five thousand events were
analyzed. MAb anti–CD-42 (clone SZ 2), anti-CD62P (clone CLB
Thromb/6), and anti-CD41 (clone P2) were purchased from Immunotech. PlA
genotypes were determined by allele-specific restriction
enzyme analysis as described by Gawaz et
al.18
Statistical Analysis
Results of flow cytometric parameters are reported
as medians (interquartile range) unless otherwise indicated.
Differences between the 2 study groups were evaluated by means of
appropriate unpaired nonparametric tests (Mann-Whitney
U test). A multiple logistic regression analysis
that implemented an automatic stepwise selection algorithm for risk
factor inclusion was performed to assess independent risk factors for
transplant vasculopathy and the progression of the disease. A receiver
operating characteristic (ROC) curve for predicting progression of
transplant vasculopathy was determined with an automatic algorithm
(SPSS, Windows, version 9.0).
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Results |
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Patient Characteristics
Between November 1996 and February 1999, we consecutively investigated 78 adult heart transplant recipients who underwent cardiac catheterization and intravascular ultrasound as a routine follow-up examination after transplantation (Tables 1
and 2). There was no statistically
significant difference between the 2 groups for minimum lumen diameter
(in millimeters) and diffuse versus focal disease (left main
coronary artery: 4.7±1.2 versus 4.3±1.3; proximal LAD:
3.2±0.9 versus 3.4±1.5; mid-LAD: 3±0.8 versus 3.2±1; distal LAD:
2.7±1 versus 2.8±1.1). According to published ICUS
criteria,13 16 initially 43 patients had diffuse and 35
patients had focal transplant disease. At 1-year follow-up, paired
intravascular ultrasound data were available for 55 (71%) of the 78
enrolled patients. The causes for dropout were death (n=1), acute
myocardial infarction (n=1), refusal by the patient (n=12), and failure
to attend the regular time interval of exactly 1 year ±1 month after
the first examination (n=8). Eight patients during the observation
period of 1 year had a cardiac event, which included death (n=1),
myocardial infarction (n=1), and coronary balloon angioplasty
for progression of the disease (n=7).
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Platelet Membrane Glycoproteins and Transplant
Vasculopathy
At the time of enrollment, activated fibrinogen receptor
on circulating platelets, as assessed by LIBS-1 immunoreactivity,
was significantly increased in patients with diffuse disease when
compared with those with focal transplant disease (P=0.04)
(Table 3 and Figure 3). Similarly, in the group of patients
with diffuse transplant vasculopathy, degranulation of 
-granula
(P-selectin surface expression) was significantly enhanced
(P=0.04) (Table 3 and Figure 3). No
differences in surface density of GPIIb-IIIa (CD41) and GPIb (CD42) or
platelet count were found between the 2 groups (Table 3).
Furthermore, distribution of the platelet polymorphic
allele PlA2 (GPIIIa) was not significantly different in both groups
(Table 3).
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LIBS-1 as Predictor of Diffuse Transplant Vasculopathy and
Progression of Disease
Baseline patient and platelet variables were included in a
logistic regression model to determine whether LIBS-1 is an independent
variable that predicts the presence of diffuse transplant
vasculopathy. As shown in Table 4,
platelet surface expression of LIBS-1 was independently associated
with diffuse transplant vasculopathy. For patients with enhanced LIBS-1
immunoreactivity (>75% quartile), there was a 3.3-fold increased
relative risk (95% CI 1.8 and 18.9, P=0.002) of diffuse
transplant vasculopathy when compared with patients with LIBS-1 values
in the range 
75% quartile.
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In 55 of the 78 enrolled patients, we were able to calculate changes in
MPT from follow-up paired intravascular ultrasound data at 1 year
(Table 2). We found that LIBS-1 immunoreactivity correlated with
plaque progression (increase of 0.3 mm in MPT after 1 year)
(r=0.681, P=0.002) (Figure 4). LIBS-1 immunoreactivity was
significantly increased in patients with disease progression when
compared with those with no disease progression (median [quartile],
10.1[5.0,15.7] versus 26.5 [15.5,47.5], P<0.01) (Figure 5). To test whether LIBS-1 is associated
with plaque progression independent of baseline patient and
platelet variables, we performed a linear regression
analysis that included the parameters given in
Table 5. Among the variables tested,
only LIBS-1 immunoreactivity was associated independently with the
progression of transplant vasculopathy. To predict progression for an
individual heart transplant recipient by using the levels of LIBS-1
immunoreactivity, we calculated the ROC curve. The area under the ROC
curve for the prediction of progression of transplant vasculopathy by
LIBS-1 immunoreactivity was 0.811. The optimum cutoff value was 16.5
(Figure 5), with a sensitivity of 75.8%±5.76 (95% CI 64.5 and
87.1), specificity of 80%±5.39 (95% CI 69.4 and 90.6), positive
predictive value of 86%±4.68 (95% CI 76.8 and 95.17), and negative
predictive value of 66.7%±6.35 (95% CI 54.2 and 79.2). The
prevalence of progression in this population was 60%. Thus, patients
with LIBS-1 level >16.5 have a 4.8-fold relative risk (95% CI 1.2 and
12.5) of progression of transplant vasculopathy.
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Discussion |
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The major findings of this prospective study are as follows: (1) diffuse transplant vasculopathy, as assessed by intracoronary ultrasound, is associated with enhanced fibrinogen receptor activation (LIBS-1 expression) and degranulation of
-granula (P-selectin
surface expression) of the circulating platelets; (2) progression
of MPT within 1 year correlates with the activation of the platelet
fibrinogen receptor; and (3) LIBS-1 surface expression on
circulating platelets is a predictor of the progression of
transplant vasculopathy independent of demographic variables and
conventional cardiovascular risk factors. These
findings imply that enhanced activation of circulating platelets in
patients with heart transplants might contribute to the development and
progression of transplant vasculopathy. If the activation of
platelets induces atherogenesis, effective antiplatelet
strategies may be beneficial for the long-term success of heart
transplantation. However, platelet activation could serve as a
passive indicator of transplant vasculopathy.
Transplant Vasculopathy, Atherosclerosis, and
Platelets
In this study, we found that diffuse transplant vasculopathy, as
assessed by the ICUS technique, is associated with increased surface
expression of platelet membrane glycoproteins, which
indicates activation of circulating platelets. This observation is
concordant with previous studies20 that demonstrated an
enhanced ADP-induced platelet aggregation in patients after
orthotopic heart transplantation.
In the early days of transplantation, the formation of platelet microthrombi and injury of the endothelium, followed by intimal smooth muscle cell proliferation, were suspected to be the cause of accelerated coronary graft disease.21 In our study, we found a significant association between the activated state (LIBS-1 immunoreactivity) of the platelet fibrinogen receptor GPIIb-IIIa, which plays a fundamental role in arterial thrombotic events, and platelet adhesion to the endothelium.22 23 24
In multivariate logistic regression analysis, we revealed that the association of LIBS-1 immunoreactivity with diffuse transplant vasculopathy is independent of other cardiovascular and transplant vasculopathy risk factors, which include hypercholesterolemia, plasma fibrinogen, diabetes, or smoking.
We also found that platelet degranulation (surface expression of P-selectin) is enhanced in patients with diffuse transplant vasculopathy, which implies that systemic release of proinflammatory (eg, platelet factor 4) and proliferative (eg, platelet-derived growth factor) compounds from activated platelets occurred. Thus, an enhanced release of platelet-derived mediators, either locally or systemically, might contribute to the acceleration and progression of transplant vasculopathy.
Pathophysiological Considerations
Intravascular examination of 78 heart transplant recipients
revealed 43 patients with diffuse concentric lesions and 35 with focal
eccentric lesions. Kapadia et al16 and Tuzcu et
al,13 who performed serial intravascular ultrasound
imaging with early baseline examination, detected focal eccentric
lesions within a few weeks of transplantation, whereas the diffuse
concentric lesions were only seen in the long-term follow-up. The
authors believe that the diffuse changes probably represent the
"real" transplant vasculopathy and regard the focal changes as
donor-transmitted conventional atherosclerosis. Thus,
the strong association between platelet LIBS-1 immunoreactivity and
diffuse vasculopathy suggests that activation of platelets plays a
fundamental part in the pathophysiology of transplant vasculopathy.
Platelets have an important role in the onset of thrombosis,
particularly in acute coronary syndromes.25 26
Less clear is whether platelets contribute to the origin and
progression of atherosclerosis over an extended period
of time.26 Functional alterations of
endothelial cells are an essential feature of the
initial lesion that leads to monocyte/macrophage and lymphocyte
accumulation that marks the beginning of
atherosclerosis.26 In this context,
platelets may become involved in the process as early as the
endothelial cells start losing their unique and
essential ability to inhibit thrombogenic processes. The platelet
fibrinogen receptor GPIIb-IIIa has been shown to mediate
platelet/endothelium adhesion,23 24
which indicates that vascular lesions are not necessarily required for
platelet attachment to the vessel wall. Thus, enhanced intermediate
platelet deposition in coronary arteries of the
transplanted heart may contribute to the localized release of various
growth factors and cytokines, which cause the migration of
monocytes and lymphocytes and the proliferation of smooth muscle cells
and are early mechanisms that determine the progression of
atherosclerosis.10 11 25 26 Experimental
data show that activated platelets are able to induce
secretion of the monocyte chemoattractant protein-1, a central factor
for the chemotaxis of monocytes to the vessel wall.10 11
Moreover, platelets induce enhanced surface expression of adhesion
receptors such as intracellular adhesion molecule-1 on
endothelium that mediate adhesion and transmigration of
leukocytes.26
Study Limitations
Although we show in this study that platelet activation and
transplant vasculopathy are strongly associated, we do not provide
evidence that platelets are directly and actively involved in the
pathophysiology of transplant vasculopathy. However, our findings show
that LIBS-1 expression is a good predictor for the progression of
transplant vasculopathy, which suggests a direct role of platelet
activation in the disease. At present, we cannot provide conclusive
data that address the cause of enhanced activation of circulating
platelets in patients with transplant vasculopathy. Future serial
ultrasound examination, combined with flow cytometric platelet
evaluation, performed within weeks of transplantation, might contribute
to the elucidation of this issue. Because cyclosporine has
been shown to induce hyperresponsive platelets,27 28 29
one might speculate that the long-term administration of
cyclosporine contributes to enhanced systemic platelet
activation. Moreover, cyclosporine has been described as
damaging endothelial cells and reducing the generation
of prostacyclin, a major antiplatelet and vasodilator
compound,30 in heart transplant recipients. In our study,
we did not find a correlation between the observed LIBS-1 expression
and the plasma cyclosporine level; thus,
cyclosporine is unlikely to be the cause for the observed
platelet activation in the patient group with the diffuse changes
but might act synergistically with other hitherto unknown factors to
stimulate platelet activation.
We used MPT measured at specific anatomic sites to monitor the progression of lesions because this is the most commonly reported parameter in the literature.16 Progression of plaque thickness measured at 1 site only does not represent the progression of the total plaque burden. For this purpose, serial ECG-gated plaque volume calculations of the target vessel are necessary.30
Therapeutic Implications
Although platelets are a good candidate for pharmacological
intervention of platelet-mediated atherosclerosis,
conventional antiplatelet strategies with a monotherapy of aspirin
have been found to be ineffective in preventing experimental and
clinical transplant vasculopathy.31 Only limited data with
other antiplatelet drugs, such as thienopyridines, are available to
date.32 Because platelets can be activated by
multiple pathways, administration of a single antiplatelet drug
does not substantially reduce platelet activation and
degranulation, particularly when a variety of strong agonists might
contribute to platelet activation in vivo. Thus, it is of interest
whether a combination of antiplatelet drugs that target various
platelet activation pathways (aspirin, clopidogrel, fibrinogen
receptor antagonists) might be more effective in limiting
platelet activation in heart transplant recipients. In this
context, Candinas and coworkers33 demonstrated that a
specific and selective platelet GPIIb-IIIa antagonist
was effective in prolonging cardiac xenograft survival in a
small-animal model. Further clinical studies are needed to show whether
effective antiplatelet strategies are beneficial and safe for the
long-term clinical course of patients after heart transplantation.
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Acknowledgments |
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The study was supported in part by a grant from the Deutsche Forschungsgemeinschaft (Ga 381/4-1) and Wilhelm Sander-Stiftung. The authors appreciate the excellent technical assistance of Kirsten Langenbrink and Antje Wallmuth. We thank Dipl Ing Axel Mohnhaupt, Institute of Medical Biometry of the Humboldt Universität Berlin, for his statistical advice. The authors are grateful to Dr Mark Ginsberg for generously supplying us with LIBS-1 monoclonal antibody (supported by grant HL-48728) and for helpful discussions. We would also like to thank Tonie Derwent for help in the preparation of the manuscript.
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Footnotes |
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The first 2 authors contributed equally to this work.
Received September 13, 1999; revision received March 17, 2000; accepted March 22, 2000.
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